Unit dose, aerosol, kit and method for treating a cardiac condition by pulmonary administration

文档序号：1408798 发布日期：2020-03-06 浏览：28次中文

阅读说明：本技术 通过肺部施用治疗心脏病况的单位剂量、气雾剂、试剂盒和方法 (Unit dose, aerosol, kit and method for treating a cardiac condition by pulmonary administration ) 是由卡洛斯·舒乐兰加查里·纳拉辛汉路易斯·贝拉尔迪内利普拉尚蒂·马德哈瓦佩迪于 2018-05-10 设计创作，主要内容包括：治疗心脏病况的方法包括通过吸入向有需要的患者施用有效量的至少一种抗心律失常药剂。还考虑了雾化药物产品和试剂盒。(A method of treating a cardiac condition comprises administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation. Aerosolized pharmaceutical products and kits are also contemplated.)

1. A method of treating atrial arrhythmia comprising: administering an effective amount of at least one antiarrhythmic agent selected from the group consisting of class I, class II, class III, and class IV antiarrhythmic agents to the pulmonary vein of a subject in need thereof by inhalation through the pulmonary airway, wherein the effective amount of the at least one antiarrhythmic agent is in a total amount of 0.1mg to 200mg and has:

i) t from about 0.1 to about 30 minutes_max；

ii) C from about 10ng/mL to about 5000ng/mL_max；

iii) AUC of about 100hr ng/mL to about 10000hr ng/mL_Last；

iv) a profile t of about 0.1 to about 15 minutes_1/2；

v) elimination of t from about 1 hour to about 25 hours_1/2；

vi) a maximum Δ QRS of about 0.01 milliseconds to about 100 milliseconds;

or any combination thereof.

2. The method of claim 1, wherein the at least one anti-arrhythmic agent is administered via multiple inhalations.

3. The method of claim 2, wherein the at least one anti-arrhythmic agent is administered in up to 6 inhalations.

4. The method of any one of claims 1 to 3, wherein the subject's sinus rhythm returns to normal within 30 minutes of the administering.

5. The method of any one of claims 1 to 4, wherein the level of the at least one anti-arrhythmic agent peaks in the coronary sinus of the heart at a time between 30 seconds and 20 minutes from administration.

6. The method of any one of claims 1 to 5, wherein the concentration of the at least one anti-arrhythmic agent in the coronary sinus of the heart is in the range of 0.1mg/L to 60mg/L at 2.5 minutes after the administering.

7. The method of any one of claims 1 to 6, wherein the concentration of the at least one antiarrhythmic agent in the coronary sinus of the heart is less than 0.1mg/L at 30 minutes after the administering.

8. The method of any one of claims 1-7, wherein 5% to 60% of a nominal dose of the administered at least one anti-arrhythmic agent reaches the coronary sinus.

9. The method of any one of claims 1 to 8, wherein the effective amount of T of the at least one anti-arrhythmic agent_maxFrom about 0.1 minutes to about 30 minutes.

10. The method of any one of claims 1 to 8, wherein the effective amount of T of the at least one anti-arrhythmic agent_maxFrom about 0.1 minutes to about 3 minutes.

11. The method of any one of claims 1 to 8, wherein the effective amount of T of the at least one anti-arrhythmic agent_maxFrom about 0.2 minutes to about 5 minutes.

12. The method of any one of claims 1 to 11, wherein the effective amount of C of the at least one antiarrhythmic agent_maxFrom about 50ng/mL to about 500 ng/mL.

13. The method of any one of claims 1 to 11, wherein the effective amount of C of the at least one antiarrhythmic agent_maxFrom about 100ng/mL to about 250 ng/mL.

14. The method of any one of claims 1 to 13, wherein the effective amount of the at least oneAUC of antiarrhythmic agents_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

15. The method of any one of claims 1 to 13, wherein the effective amount of the at least one anti-arrhythmic agent's AUC_LastFrom about 500hr ng/mL to about 800hr ng/mL.

16. The method of any one of claims 1 to 13, wherein the effective amount of the at least one anti-arrhythmic agent's AUC_LastFrom about 400hr ng/mL to about 600hr ng/mL.

17. The method of any one of claims 1 to 16, wherein the effective amount of the distribution t of the at least one anti-arrhythmic agent_1/2From about 3 minutes to about 5 minutes.

18. The method of any one of claims 1 to 17, wherein the effective amount of abrogation t of the at least one anti-arrhythmic agent_1/2From about 8.5 hours to about 10.5 hours.

19. The method of any one of claims 1-18, wherein the effective amount of the at least one anti-arrhythmic agent has a maximum Δ QRS of about 1 millisecond to about 10 milliseconds.

20. The method of any one of claims 1-18, wherein the effective amount of the at least one anti-arrhythmic agent has a maximum Δ QRS of about 5 milliseconds to about 20 milliseconds.

21. The method of any one of claims 1-20, wherein the maximum Δ QRS and C produced by the effective amount of the at least one antiarrhythmic agent delivered intravenously_maxCompared to the ratio of the maximum Δ QRS to C of the effective amount of the at least one antiarrhythmic agent delivered by inhalation through the lung airways_maxThe ratio of (A) to (B) is higher.

22. The method of claim 21, wherein the maximum Δ QRS and C produced by inhalation of the effective amount of the at least one anti-arrhythmic agent delivered through the lung airways_maxRatio of maximum Δ QRS to C produced by an effective amount of the at least one antiarrhythmic agent delivered intravenously_maxThe ratio of (A) to (B) is at least 2 times higher.

23. The method of any one of claims 1-22, wherein the atrial arrhythmia comprises tachycardia.

24. The method of claim 23, wherein the tachycardia comprises supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, or isolated atrial fibrillation.

25. The method of any one of claims 1 to 24, comprising administering a liquid, a dry powder, extruded droplets, or aerosolized droplets comprising the at least one anti-arrhythmic agent, wherein the mass median aerodynamic diameter of the powder or aerosolized droplets is less than 10 μ ι η.

26. The method of any one of claims 1-25, wherein the antiarrhythmic agent is a class I antiarrhythmic.

27. The method of claim 26, wherein the class I antiarrhythmic agent is a class Ia, Ib, or Ic antiarrhythmic agent.

28. The method of claim 27, wherein the class Ic antiarrhythmic drug is flecainide.

29. The method of any one of claims 1-25, wherein the antiarrhythmic agent is a class II antiarrhythmic.

30. The method of claim 29, wherein the class II antiarrhythmic is esmolol hydrochloride.

31. The method of claim 30, wherein the dose of esmolol hydrochloride is between 0.5mg/kg body weight and 0.75mg/kg body weight.

32. The method of any one of claims 1-25, wherein the antiarrhythmic agent is a class IV antiarrhythmic.

33. The method of claim 32, wherein the class IV antiarrhythmic is diltiazem.

34. A method according to claim 33 wherein the dose of diltiazem is 0.25mg/kg body weight.

35. The method of any one of claims 1-34, wherein the at least one anti-arrhythmic agent is aerosolized in a nebulizer.

36. The method of claim 35, wherein the nebulizer is a breath activated or breath actuated nebulizer.

37. The method of claim 35 or 36, wherein the nebulizer is configured to administer a liquid drug formulation of the at least one anti-arrhythmic agent.

38. The method of any one of claims 35 to 37, wherein the aerosolization occurs at room temperature.

39. The method of claim 38, wherein the at least one anti-arrhythmic agent is self-administered by the subject.

40. The method of any one of claims 1 to 39, wherein the effective amount of T of the at least one anti-arrhythmic agent_max、C_max、AUC_LastDistribution t_1/2And eliminate t_1/2Or maximum Δ QRS, was measured in a human PK/PD study.

41. A method of treating a cardiac condition comprising administering to a patient in need thereof a pharmaceutically effective amount of an antiarrhythmic agent by inhalation, wherein the pharmaceutically effective amount of the antiarrhythmic agent's T after inhalation_maxFrom about 0.1 minute to about 30 minutes; c of said pharmaceutically effective amount of said antiarrhythmic agent after inhalation_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of said pharmaceutically effective amount of said antiarrhythmic agent after inhalation_LastFrom about 100hr ng/mL to about 10000hr ng/mL.

42. The method of claim 41, wherein said T_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or the AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

43. The method of claim 42, wherein said T is_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL.

44. The method of claim 42, wherein said T is_maxIs from about 0.1 minute to about 5 minutes, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

45. The method of claim 42, wherein C is_maxIs about 50ng/mL to about 500ng/mL, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

46. The method of any one of claims 41-45, wherein the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent.

47. The method of claim 46, wherein the antiarrhythmic agent comprises a class Ic antiarrhythmic agent.

48. The method of claim 47, wherein the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof.

49. The method of any one of claims 41-45, wherein the method comprises administering to the patient in need thereof 20mg to 100mg of flecainide, or a pharmaceutically acceptable salt thereof, by inhalation.

50. The method of any one of claims 41-45, wherein the method comprises administering to the patient in need thereof 0.25mg/kg body weight to 1.5mg/kg body weight of flecainide, or a pharmaceutically acceptable salt thereof, by inhalation.

51. The method of any one of claims 41-50, wherein the anti-arrhythmic agent is delivered via two or more inhalations.

52. The method of claim 51, wherein the time between the two or more inhalations is about 0.1 to 10 minutes.

53. An aerosolized pharmaceutical product comprising a pharmaceutically effective amount of an antiarrhythmic agent, wherein said pharmaceutically effective amount of the T of said antiarrhythmic agent upon inhalation_maxFrom about 0.1 minute to about 30 minutes; c of said pharmaceutically effective amount of said antiarrhythmic agent after inhalation_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of said pharmaceutically effective amount of said antiarrhythmic agent after inhalation_LastFrom about 100hr ng/mL to about 10000hr ng/mL.

54. Such asThe aerosolized pharmaceutical product of claim 53, wherein the T is_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or the AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

55. The aerosolized pharmaceutical product of claim 54, wherein the T is_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL.

56. The aerosolized pharmaceutical product of claim 54, wherein the T is_maxIs from about 0.1 minute to about 5 minutes, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

57. The aerosolized pharmaceutical product of claim 54, wherein the C is_maxIs about 50ng/mL to about 500ng/mL, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

58. The aerosolized pharmaceutical product of any one of claims 53-57, wherein the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic drug.

59. The aerosolized pharmaceutical product of claim 58, wherein the antiarrhythmic agent comprises a class Ic antiarrhythmic drug.

60. The aerosolized pharmaceutical product of claim 59, wherein the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof.

61. The aerosolized pharmaceutical product of any one of claims 53-60, comprising 20mg to 100mg of flecainide, or a pharmaceutically acceptable salt thereof.

62. A method of making a formulation for treating a cardiac condition, the formulation comprising a pharmaceutically effective amount of an antagonistAn arrhythmia medicament, wherein the formulation, upon aerosolization and inhalation by a patient in need thereof, the pharmaceutically effective amount of the T of the antiarrhythmic medicament_maxFrom about 0.1 minute to about 30 minutes; said pharmaceutically effective amount of C of said antiarrhythmic agent after nebulization and inhalation by a patient in need thereof_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of said pharmaceutically effective amount of said antiarrhythmic agent following aerosolization and inhalation of said formulation by a patient in need thereof_LastFrom about 100hr ng/mL to about 10000hr ng/mL.

63. The method of claim 62, wherein said T_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or the AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

64. The method of claim 63, wherein T is_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL.

65. The method of claim 63, wherein T is_maxIs from about 0.1 minute to about 5 minutes, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

66. The method of claim 63, wherein C is_maxIs about 50ng/mL to about 500ng/mL, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

67. The method of any one of claims 62-66, wherein the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent.

68. The method of claim 67, wherein the antiarrhythmic agent comprises a class Ic antiarrhythmic agent.

69. The method of claim 68, wherein the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof.

70. The method of any one of claims 62-69, wherein the anti-arrhythmic agent is delivered via two or more inhalations.

71. The method of claim 70, wherein the time between the two or more inhalations is about 0.1 to 10 minutes.

72. An aerosolized pharmaceutical product comprising a pharmaceutically effective amount of an antiarrhythmic agent for treating a cardiac condition, wherein the pharmaceutically effective amount of the antiarrhythmic agent's T after inhalation_maxFrom about 0.1 minute to about 30 minutes; c of said pharmaceutically effective amount of said antiarrhythmic agent after inhalation_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of said pharmaceutically effective amount of said antiarrhythmic agent after inhalation_LastFrom about 100hr ng/mL to about 10000hr ng/mL.

73. The aerosolized pharmaceutical product of claim 72, wherein the T is_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or the AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

74. The aerosolized pharmaceutical product of claim 73, wherein the T is_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL.

75. The aerosolized pharmaceutical product of claim 73, wherein the T is_maxIs from about 0.1 minute to about 5 minutes, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

76. The aerosolized pharmaceutical product of claim 73, whereinC is_maxIs about 50ng/mL to about 500ng/mL, and said AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL.

77. The aerosolized pharmaceutical product of any one of claims 72-76, wherein the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic drug.

78. The aerosolized pharmaceutical product of claim 77, wherein the antiarrhythmic agent comprises a class Ic antiarrhythmic.

79. The aerosolized pharmaceutical product of claim 78, wherein the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof.

80. The aerosolized pharmaceutical product of any one of claims 72 to 79, comprising 20mg to 100mg of flecainide, or a pharmaceutically acceptable salt thereof.

1. Field of the invention

The present invention relates to compositions, unit doses, aerosols and kits for treating certain cardiac conditions by pulmonary administration, and methods thereof.

2. Background of the invention

Arrhythmia (also known as dysrhythmia) is a term for any of a large diverse group of conditions in which the heart has abnormal electrical activity. The heart may beat too fast or too slow and may be regular or irregular.

Atrial arrhythmia treatment is a highly unmet field of clinical need. Many drugs in use today have been marketed since the 80 s and early 90 s of the 20 th century, but most are unsatisfactory due to lack of efficacy or the presence of frequently cardiac-related side-effect profiles that require close monitoring of patients.

The therapies required for rapid and safe cardioversion (to resolve arrhythmias) are:

(a) little or no risk of ventricular rate acceleration prior to cardioversion;

(b) slowing Atrioventricular (AV) conduction such that ventricular rate control and cardioversion are present simultaneously;

(c) the QRS interval is hardly or not extended at all beyond the upper limit of the normal value (about 120 ms) and the risk of torsade de pointes ventricular tachycardia should be low; and is

(d) Little or no negative muscle effects; when the patient recovers sinus rhythm, it has only a slight negative chronotropic effect without the risk of severe bradycardia.

None of the currently approved pharmaceutical products show these features. The high oral and Intravenous (IV) doses required to compensate for absorption, metabolism and dilution can lead to prolonged high blood levels in the blood, which can lead to dangerous adverse cardiac events such as proarrhythmia, QT interval prolongation and torsades de pointes. FELDMAN et al, "Analysis of coronary Response to valves of Intra coronary Nitroglycerine," Circulation,66: 321-; and BARBARBO et al, "Adrenergic Receptors in human Atherostatic Coronary enterprises," Circulation,111: 288-. Comorbid conditions also limit the use of ideal drugs in some patients, such as the case with intravenous adenosine. GAGLIONE et al, "Is the same angular vacuum organization after Intra Beta-advanced Block in substrates with a angular area approach," J Am Coll Cold Cardiol,10:299-310 (1987). Verapamil and diltiazem injection are second-line treatments and require close monitoring of the patient. NOGUCHI et al, "effective intracellular pro pranol on Coronary Blood Flow and Regional myographic function in Dogs," Eur J Pharmacol, 144(2):201-10 (1987); and ZALEWSKI et al, "molecular Protection reducing conductive Coronary array occupancy in Man: Benedical Effects of Regional Beta-acquired Block," Circulation,73:734-73 (1986).

Paroxysmal Atrial Fibrillation (PAF) is a subset of the total population of Atrial Fibrillation (AF), estimated to be 25-30% of the total population of AF. In the united states, approximately 250 thousands of patients are affected by AF. The population of PAF patients worldwide is estimated to be 90 to 150 thousands.

Paroxysmal supraventricular tachycardia (PSVT) is an arrhythmia affecting about 500,000 to 600,000 patients in the united states.

Ablation, such as RF ablation, is often used to treat cardiac arrhythmias. Ablation is expensive, however, and typically costs between $ 25,000 and $ 36,000 per procedure. In addition to being expensive, ablation may not be able to completely correct the arrhythmia. Multiple ablation procedures are often required to achieve satisfactory treatment results.

Oral medications, such as pills, often require large doses and long periods of time to be effective. Oral doses of cardiac drugs generally tend to be well above 1 mg. Since these patients typically take multiple drugs, high doses increase the likelihood of side effects and drug interactions. The onset of action of an oral cardiovascular drug is typically about 60 minutes. Oral antiarrhythmic drugs are mainly developed for prophylaxis, while treatment is by intravenous administration.

Intravenous injection typically requires a hospital environment to administer the drug, typically involving travel to an Emergency Room (ER). These costs result in the therapy being more expensive than a therapy in which the patient can self-administer their drug. To compensate for dilution and metabolism, intravenous injection requires higher doses than are actually required by the heart. IV injected drugs pass through the right side of the heart, then through the lungs, and then to the left side of the heart. See fig. 1. The drug remains in the bloodstream in high concentrations, exposing all organs and tissues to high concentrations of the drug until the drug is excreted through the kidneys or other metabolic pathways (e.g., the liver). As a result, IV drugs may cause undesirable side effects. Drugs administered by the IV route will be significantly diluted in venous blood volume and lungs before reaching the cardiac cycle.

Injecting drugs directly into the heart is often the last life saving measure to be taken by cardiologists in an emergency. The dose of drug injected directly into the heart in this manner is typically less than its IV dose and/or oral dose.

In some cases, an unscheduled procedure is required to save the patient's life. Of course, unplanned surgery is expensive and risky to the patient.

Cardiac arrhythmias are associated with chest tightness, palpitations, fatigue, shortness of breath, and occasional chest pain.

In view of the above, cardiac arrhythmias often result in emergency room visits where intravenous medications are administered, sometimes requiring long hospital stays, and in some cases resulting in unplanned invasive surgery. Pipeline instruments, Antiarrhythmics, Datamonitor (06/2006); and TWISS et al, "Efficacy of Calciful channel blocks as Maintenance Therapy for Asthma," British J of clinical pharmacy (11 months 2001).

However, a need still exists for improved compositions and methods for treating cardiac conditions. Accordingly, a need still exists for methods of making these compositions.

Disclosure of Invention

Accordingly, the present invention provides compositions, unit doses, aerosols, kits and methods for treating certain cardiac conditions. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the invention. The invention may be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof.

A first embodiment of the invention is directed to a method of treating atrial arrhythmia. The method includes administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent such that the at least one anti-arrhythmic agent enters the heart first through the pulmonary veins to the left atrium.

In another aspect, the invention relates to a method of treating atrial arrhythmias, such as tachycardia. The method comprises administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation), wherein the amount of the at least one anti-arrhythmic agent peaks in the coronary circulation of the heart within a time range of 10 seconds to 30 minutes from administration (e.g., beginning or ending administration). In some cases, the coronary circulation may be a coronary artery or a coronary vein, including the coronary sinus.

In another aspect, the invention relates to a method of self-diagnosing and treating atrial arrhythmias. The method includes self-diagnosing atrial arrhythmia by detecting at least one of tachypnea, palpitations, and a higher than normal heart rate. The method further comprises self-administering an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation) within two hours, one hour, thirty minutes, or fifteen minutes of self-diagnosis.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation), wherein an electrophysiological effect is observed by electrocardiography within a time range from 10 seconds to 30 minutes from administration.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation), wherein a heart score of a monitor executing an arrhythmia detection algorithm shows a transition from an arrhythmic state to a normal sinus rhythm in the patient within a time frame of 10 seconds to 30 minutes from administration.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation), wherein the patient's quality of life profile-36 score is increased over a time period ranging from 10 seconds to 30 minutes from administration.

In another aspect, the present invention is directed to a unit dose comprising a unit dose vessel and a composition within the unit dose vessel. The composition comprises at least one antiarrhythmic agent in an amount less than or equal to the amount of the same at least one antiarrhythmic agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation, and a pharmaceutically acceptable excipient.

In another aspect, the invention relates to an aerosol comprising particles having a mass median aerodynamic diameter of less than 10 μm. The particles comprise at least one antiarrhythmic agent in an amount less than or equal to the amount of the same at least one antiarrhythmic agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation, and a pharmaceutically acceptable excipient.

Another aspect of the invention relates to a kit. The kit includes a container containing at least one antiarrhythmic agent and an aerosolization device.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent such that the at least one anti-arrhythmic agent enters the heart first through the pulmonary veins to the left atrium. In some cases, the amount of the at least one antiarrhythmic agent peaks in the coronary circulation of the heart within a time range from 10 seconds to 30 minutes from administration. In some cases, the amount of the at least one anti-arrhythmic agent in the coronary circulation of the heart peaks in a time range from 2 minutes to 8 minutes from administration. In some cases, the amount of the at least one anti-arrhythmic agent in the coronary circulation of the heart ranges from 0.1mg/L to 60mg/L at 2.5 minutes after administration. In some cases, the amount of the at least one anti-arrhythmic agent in the coronary circulation of the heart is less than 0.1mg/L at 30 minutes after administration. In some cases, an effective amount is an effective amount that is passed through the heart only once. In some cases, 10% to 60% of the nominal dose of the at least one antiarrhythmic agent administered reaches the coronary circulation. In some cases, the amount of the administered antiarrhythmic agent that enters the patient is 0.1mg to 200 mg. In some cases, the nominal amount of the at least one anti-arrhythmic agent administered by inhalation (e.g., oral inhalation) is less than or equal to the amount of the same anti-arrhythmic agent administered intravenously in the arm to achieve the same amount in the coronary circulation. In some cases, administration comprises 1 to 6 inhalations.

In some cases, the at least one antiarrhythmic agent comprises at least one selected from the group consisting of class Ia, class Ib, class Ic, class II, class III, class IV, and class V antiarrhythmic agents. In some cases, the at least one antiarrhythmic agent includes at least one class Ia antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent includes at least one class Ia antiarrhythmic agent selected from quinidine, procainamide, and propiram. In some cases, the at least one antiarrhythmic agent comprises at least one class Ib antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class Ib antiarrhythmic agent selected from lidocaine, tocainide, phenytoin, moxidezine, and mexiletine. In some cases, the at least one antiarrhythmic agent comprises at least one class Ic antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class Ic antiarrhythmic agent selected from the group consisting of flecainide, propafenone, and moraxezine. In some cases, the at least one antiarrhythmic agent includes at least one class II antiarrhythmic drug. In some cases, the at least one antiarrhythmic agent comprises at least one class II antiarrhythmic agent selected from propranolol, acebutolol, sotalol, esmolol, timolol, metoprolol, and atenolol. In some cases, the at least one antiarrhythmic agent includes at least one class III antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class III antiarrhythmic selected from amiodarone, sotalol, bromobenzylamine, ibutilide, methanesulfonamide, venocaran, and dofetilide. In some cases, the at least one antiarrhythmic agent includes at least one class IV antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class IV antiarrhythmic agent selected from the group consisting of bepridil, nitrendipine, amlodipine, isradipine, nifedipine, nicardipine, verapamil, and diltiazem. In some cases, the at least one antiarrhythmic agent includes at least one class V antiarrhythmic drug. In some cases, the at least one antiarrhythmic agent comprises at least one class V antiarrhythmic selected from digoxin and adenosine.

In some cases, the atrial arrhythmia includes tachycardia. In some cases, the atrial arrhythmia includes supraventricular tachycardia. In some cases, the atrial arrhythmia includes paroxysmal supraventricular tachycardia. In some cases, the atrial arrhythmia includes atrial fibrillation. In some cases, the atrial arrhythmia includes paroxysmal atrial fibrillation. In some cases, atrial arrhythmias include acute episodes of persistent and permanent atrial fibrillation. In some cases, the atrial arrhythmia includes atrial flutter. In some cases, the atrial arrhythmia includes paroxysmal atrial flutter. In some cases, the atrial arrhythmia includes isolated atrial fibrillation. In some cases, administering comprises administering a liquid comprising at least one anti-arrhythmic agent. In some cases, administering comprises administering a powder comprising at least one anti-arrhythmic agent. In some cases, administering comprises administering a condensation aerosol comprising at least one anti-arrhythmic agent. In some cases, administering comprises administering a composition comprising at least one anti-arrhythmic agent, wherein the composition is not a condensation aerosol.

In some cases, pulmonary administration includes nebulizing a solution comprising at least one anti-arrhythmic agent. In some cases, atomizing comprises atomizing with a vibrating mesh atomizer. In some cases, atomizing comprises atomizing with a jet atomizer. In some cases, nebulization comprises nebulization with a breath-activated nebulizer. In some cases, atomizing comprises forming droplets having a mass median aerodynamic diameter of less than 10 μm. In some cases, pulmonary administration includes administering a dry powder comprising at least one anti-arrhythmic agent. In some cases, the dry powder comprises particles having a mass median aerodynamic diameter of less than 10 μm. In some cases, the dry powder is administered by an active dry powder inhaler. In some cases, the dry powder is administered by a passive dry powder inhaler. In some cases, pulmonary administration includes administering at least one anti-arrhythmic agent by a metered dose inhaler. In some cases, the metered dose inhaler forms particles having a mass median aerodynamic diameter of less than 10 μm. In some cases, the metered dose inhaler comprises at least one antiarrhythmic agent formulated in a carrier selected from hydrofluoroalkanes and chlorofluorocarbons. In some cases, the treatment includes an emergency treatment after detecting the atrial arrhythmia. In some cases, the patient has a normal sinus rhythm within 10 minutes of the initial administration.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g. oral inhalation), wherein the amount of the at least one anti-arrhythmic agent peaks in the coronary circulation of the heart within a time range of 10 seconds to 30 minutes from administration. In some cases, the amount of the at least one anti-arrhythmic agent in the coronary circulation of the heart peaks in a time range from 2 minutes to 8 minutes from administration. In some cases, the amount of the at least one anti-arrhythmic agent in the coronary circulation of the heart at 2.5 minutes after administration is in the range of 0.1mg/L to 60 mg/L. In some cases, the amount of the at least one anti-arrhythmic agent in the coronary circulation of the heart is less than 0.1mg/L at 30 minutes after administration. In some cases, an effective amount is an effective amount that is passed through the heart only once. In some cases, 10% to 60% of the nominal dose of the at least one antiarrhythmic agent administered reaches the coronary circulation. In some cases, the amount of the administered antiarrhythmic agent that enters the patient is 0.1mg to 200 mg. In some cases, the nominal amount of the at least one anti-arrhythmic agent administered by inhalation (e.g., oral inhalation) is less than or equal to the amount of the same anti-arrhythmic agent administered intravenously in the arm to achieve the same amount in the coronary circulation. In some cases, administration comprises 1 to 6 inhalations.

In some cases, administering comprises administering a liquid comprising at least one anti-arrhythmic agent. In some cases, administering comprises administering a powder comprising at least one anti-arrhythmic agent. In some cases, administering comprises administering a condensation aerosol comprising at least one anti-arrhythmic agent. In some cases, administering comprises administering a composition comprising at least one anti-arrhythmic agent, wherein the composition is not a condensation aerosol. In some cases, pulmonary administration includes nebulizing a solution comprising at least one anti-arrhythmic agent. In some cases, atomizing comprises atomizing with a vibrating mesh atomizer. In some cases, atomizing comprises atomizing with a jet atomizer. In some cases, atomizing comprises forming droplets having a mass median aerodynamic diameter of less than 10 μm. In some cases, pulmonary administration includes administering a dry powder comprising at least one anti-arrhythmic agent. In some cases, the dry powder comprises particles having a mass median aerodynamic diameter of less than 10 μm. In some cases, the dry powder is administered by an active dry powder inhaler. In some cases, the dry powder is administered by a passive dry powder inhaler. In some cases, pulmonary administration includes administering at least one anti-arrhythmic agent by a metered dose inhaler. In some cases, the metered dose inhaler forms particles having a mass median aerodynamic diameter of less than 10 μm. In some cases, the metered dose inhaler comprises at least one antiarrhythmic agent formulated in a carrier selected from hydrofluoroalkanes and chlorofluorocarbons.

In some cases, the treatment includes an emergency treatment after detecting the atrial arrhythmia. In some cases, the patient has a normal sinus rhythm within 30 minutes of the initial administration. In some cases, the patient has a normal sinus rhythm within 10 minutes of the initial administration.

In another aspect, the invention relates to a method of self-diagnosing and treating atrial arrhythmias, comprising: self-diagnosing atrial arrhythmia by detecting at least one of shortness of breath, palpitations, and a higher than normal heart rate; and self-administering an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation) within two hours after self-diagnosis. In some cases, self-administration occurs within one hour after self-diagnosis. In some cases, self-administration occurs within 30 minutes after self-diagnosis. In some cases, self-administration occurs within 15 minutes after self-diagnosis. In some cases, self-administration continues until the patient no longer detects at least one of shortness of breath, palpitations, and a higher than normal heart rate.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g. oral inhalation), wherein the electrophysiological effect is observed by electrocardiography within a time range of 10 seconds to 30 minutes from administration. In some cases, the electrophysiological effects include a transition from an arrhythmia to a normal sinus rhythm. In some cases, the electrophysiological effect includes a transition from the absence of P-waves to the presence of P-waves.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation), wherein a cardiac score of a monitor executing an arrhythmia detection algorithm displays a transition from an arrhythmic state to a normal sinus rhythm in the patient within a time frame of 10 seconds to 30 minutes from administration. In some cases, the monitor includes a Holter monitor, a telemeter, and a mobile ECG machine.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation (e.g., oral inhalation), wherein the patient's quality of life profile-36 score is increased over a time period ranging from 10 seconds to 30 minutes from administration.

In another aspect, the invention relates to a unit dose comprising: a unit dose vessel; a composition in a unit dose vessel, the composition comprising: at least one anti-arrhythmic agent in an amount less than or equal to the amount of the same at least one anti-arrhythmic agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation; and a pharmaceutically acceptable excipient. In some cases, the composition comprises a solution. In some cases, the composition comprises a solution having a tonicity in the range of isotonic to physiological isotonic. In some cases, the composition comprises an aqueous solution. In some cases, the composition comprises a non-aqueous solution. In some cases, the composition further comprises a pH buffer. In some cases, the composition further comprises a pH buffer selected from citrate, phosphate, phthalate, and lactate. In some cases, the composition consists essentially of at least one anti-arrhythmic agent and water. In some cases, the composition consists essentially of at least one antiarrhythmic agent, water, and a pH buffer. In some cases, the pH of the composition is 3.5 to 8.0.

In some cases, the pharmaceutically acceptable excipient comprises a hydrofluoroalkane. In some cases, the pharmaceutically acceptable excipient comprises a chlorofluoroalkane. In some cases, the composition is substantially free of preservatives. In some cases, the at least one antiarrhythmic agent comprises at least one selected from the group consisting of class Ia, class Ib, class Ic, class II, class III, class IV, and class V antiarrhythmic agents. In some cases, the at least one antiarrhythmic agent includes at least one class Ia antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent includes at least one class Ia antiarrhythmic agent selected from the group consisting of quinidine, procainamide, and propiram, and pharmaceutically acceptable salts thereof. In some cases, the at least one antiarrhythmic agent comprises at least one class Ib antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class Ib antiarrhythmic agent selected from lidocaine, tocainide, phenytoin, moraxezine, and mexiletine, and pharmaceutically acceptable salts thereof. In some cases, the at least one antiarrhythmic agent comprises at least one class Ic antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class Ic antiarrhythmic agent selected from the group consisting of flecainide, propafenone, and moraxezine, and pharmaceutically acceptable salts thereof. In some cases, the at least one antiarrhythmic agent includes at least one class II antiarrhythmic drug. In some cases, the at least one anti-arrhythmic agent comprises at least one class II anti-arrhythmic agent selected from propranolol, acebutolol, sotalol, esmolol, timolol, metoprolol, and atenolol, and pharmaceutically acceptable salts thereof. In some cases, the at least one antiarrhythmic agent includes at least one class III antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class III antiarrhythmic selected from amiodarone, sotalol, bromobenzylamine, ibutilide, methanesulfonamide, vinnackal, and dofetilide, and pharmaceutically acceptable salts thereof. In some cases, the at least one antiarrhythmic agent includes at least one class IV antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class IV antiarrhythmic agent selected from the group consisting of bepridil, nimodipine, nisoldipine, nitrendipine, amlodipine, isradipine, nifedipine, nicardipine, verapamil, and diltiazem, and pharmaceutically acceptable salts thereof. In some cases, the at least one antiarrhythmic agent includes at least one class V antiarrhythmic drug. In some cases, the at least one antiarrhythmic agent comprises at least one class V antiarrhythmic selected from digoxin and adenosine, and pharmaceutically acceptable salts thereof. In some cases, the vessel contains 0.1mg to 200mg of the at least one antiarrhythmic agent. In some cases, the unit dose is substantially tasteless.

In another aspect, the present invention relates to an aerosol comprising particles having a mass median aerodynamic diameter of less than 10 μm, wherein the particles comprise: at least one anti-arrhythmic agent in an amount less than or equal to the amount of the same at least one anti-arrhythmic agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation; and a pharmaceutically acceptable excipient.

In some cases, the particles comprise an atomized solution. In some cases, the particles comprise an atomized aqueous solution. In some cases, the particles further comprise a pH buffer. In some cases, the particles further comprise a pH buffer selected from citrate, phosphate, phthalate, and lactate. In some cases, the particles consist essentially of at least one anti-arrhythmic agent and water. In some cases, the particles consist essentially of at least one antiarrhythmic agent, water, and a pH buffer. In some cases, the pH of the particles is 3.5 to 8.0. In some cases, the particles are substantially free of preservatives.

In some cases, the at least one antiarrhythmic agent comprises at least one selected from the group consisting of class Ia, class Ib, class Ic, class II, class III, class IV, and class V antiarrhythmic agents. In some cases, the at least one antiarrhythmic agent includes at least one class Ia antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent includes at least one class Ia antiarrhythmic agent selected from quinidine, procainamide, and propiram. In some cases, the at least one antiarrhythmic agent comprises at least one class Ib antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class Ib antiarrhythmic agent selected from lidocaine, tocainide, phenytoin, moxidezine, and mexiletine. In some cases, the at least one antiarrhythmic agent comprises at least one class Ic antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class Ic antiarrhythmic agent selected from the group consisting of flecainide, propafenone, and moraxezine. In some cases, the at least one antiarrhythmic agent includes at least one class II antiarrhythmic drug. In some cases, the at least one antiarrhythmic agent comprises at least one class II antiarrhythmic agent selected from propranolol, acebutolol, sotalol, esmolol, timolol, metoprolol, and atenolol. In some cases, the at least one antiarrhythmic agent includes at least one class III antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class III antiarrhythmic selected from amiodarone, sotalol, bromobenzylamine, ibutilide, methanesulfonamide, venocaran, and dofetilide. In some cases, the at least one antiarrhythmic agent includes at least one class IV antiarrhythmic agent. In some cases, the at least one antiarrhythmic agent comprises at least one class IV antiarrhythmic agent selected from the group consisting of bepridil, nimodipine, nisoldipine, nitrendipine, amlodipine, isradipine, nifedipine, nicardipine, verapamil, and diltiazem. In some cases, the at least one antiarrhythmic agent includes at least one class V antiarrhythmic drug. In some cases, the at least one antiarrhythmic agent comprises at least one class V antiarrhythmic selected from digoxin and adenosine. In some cases, the aerosol is substantially tasteless.

In another aspect, the invention relates to a kit comprising: a container containing at least one anti-arrhythmic agent; and an air atomization device. In some cases, the aerosolization device comprises an atomizer. In some cases, the aerosolization device comprises a vibrating mesh nebulizer. In some cases, the aerosolization device comprises a jet nebulizer. In some cases, the aerosolization device comprises a dry powder inhaler. In some cases, the aerosolization device comprises an active dry powder inhaler. In some cases, the aerosolization device comprises a passive dry powder inhaler. In some cases, the aerosolization device comprises a metered dose inhaler. In some cases, the amount of the at least one anti-arrhythmic agent is sufficient to produce an electrophysiological effect in as few as one pass through the heart. In some cases, the effective amount of the at least one anti-arrhythmic agent is sub-therapeutic when diluted by total blood volume.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering an effective amount of at least one antiarrhythmic agent selected from the group consisting of class I, class II, class III, and class IV antiarrhythmic agents through the pulmonary airways and by using an aerosolization device to one or more pulmonary veins of a patient in need thereof, wherein the effective amount of the at least one antiarrhythmic agent is in a total amount of 0.1mg to 200mg, administered over multiple inhalations, wherein the level of the at least one antiarrhythmic agent peaks in the coronary circulation of the heart within a time range of 30 seconds to 20 minutes from pulmonary administration, and the patient's sinus rhythm returns to normal within 30 minutes of initial administration.

In some cases, the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart ranges between 0.1mg/L and 60 mg/L2.5 minutes after pulmonary administration, and the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart is less than 0.1 mg/L30 minutes after pulmonary administration, or wherein 10% to 60% of the nominal dose of the at least one anti-arrhythmic agent administered reaches the coronary circulation. In some cases, the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart is 0.1mg/L to 20 mg/L2.5 minutes after pulmonary administration, and the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart is less than 0.1 mg/L30 minutes after pulmonary administration, or wherein 5% to 60% of the nominal dose of the at least one anti-arrhythmic agent administered reaches the coronary circulation. In some cases, the method comprises pulmonary administration of at least one antiarrhythmic drug in up to 6 inhalations. In some cases, the atrial arrhythmia includes tachycardia. In some cases, the tachycardia includes supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, or isolated atrial fibrillation. In some cases, the method comprises administering a liquid, dry powder, or aerosolized droplets comprising at least one anti-arrhythmic agent, wherein the mass median aerodynamic diameter of the powder or aerosolized droplets is less than 10 μm.

In some cases, the antiarrhythmic agent is a class I antiarrhythmic agent. In some cases, the class I antiarrhythmic agent is a class Ia, Ib, or Ic antiarrhythmic agent. In some cases, the antiarrhythmic agent is a class II antiarrhythmic. In some cases, the class II antiarrhythmic agent is esmolol hydrochloride. In some cases, the dose of esmolol hydrochloride is from 0.5 to 0.75mg/kg body weight. In some cases, the antiarrhythmic agent is a class IV antiarrhythmic. In some cases, the class IV antiarrhythmic agent is diltiazem. In some cases, the dose of diltiazem is 0.25mg/kg body weight. In some cases, the level of the at least one anti-arrhythmic agent peaks in the coronary circulation of the heart at a time between 1 minute and 10 minutes. In some cases, the aerosolization device is a nebulizer configured to administer the at least one anti-arrhythmic agent in the form of a liquid pharmaceutical formulation, wherein aerosolization occurs at room temperature. In some cases, the at least one anti-arrhythmic agent is self-administered by the patient.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering an effective amount of at least one antiarrhythmic agent selected from the group consisting of class I, class II, class III, and class IV antiarrhythmic agents through the pulmonary airways and by using an aerosolization device to one or more pulmonary veins of a patient in need thereof, wherein the patient self-administers and self-titrates an effective inhaled dose of the at least one antiarrhythmic agent to convert the atrial arrhythmia to a normal sinus rhythm, wherein a level of the at least one antiarrhythmic agent peaks in the coronary circulation of the heart at a time between 30 seconds and 20 minutes of pulmonary administration, and wherein the patient's sinus rhythm returns to normal within 30 minutes of initial administration.

In some cases, the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart ranges between 0.1mg/L and 20 mg/L2.5 minutes after pulmonary administration, and the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart is less than 0.1 mg/L30 minutes after pulmonary administration, or wherein 5% to 60% of the nominal dose of the at least one anti-arrhythmic agent administered reaches the coronary circulation. In some cases, the method comprises pulmonary administration of at least one antiarrhythmic drug in up to 6 inhalations.

In some cases, the atrial arrhythmia includes tachycardia. In some cases, the tachycardia includes supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, or isolated atrial fibrillation. In some cases, the method comprises administering a liquid, a dry powder, or aerosolized droplets comprising at least one anti-arrhythmic agent, wherein the dry powder or aerosolized droplets have a mass median aerodynamic diameter of less than 10 μm.

In some cases, the antiarrhythmic agent is a class I antiarrhythmic agent. In some cases, the class I antiarrhythmic agent is a class Ia, Ib, or Ic antiarrhythmic agent. In some cases, the antiarrhythmic agent is a class II antiarrhythmic. In some cases, the class II antiarrhythmic agent is esmolol hydrochloride. In some cases, an effective inhaled dose of esmolol hydrochloride is 0.5 to 0.75mg/kg body weight. In some cases, the antiarrhythmic agent is a class IV antiarrhythmic. In some cases, the class IV antiarrhythmic agent is diltiazem. In some cases, an effective inhaled dose of diltiazem is 0.25mg/kg body weight. In some cases, the level of the at least one anti-arrhythmic agent peaks in the coronary circulation of the heart at a time between 1 minute and 10 minutes. In some cases, the aerosolization device is a nebulizer configured to administer the at least one anti-arrhythmic agent in the form of a liquid pharmaceutical formulation, wherein aerosolization occurs at room temperature.

In another aspect, the invention relates to a method of treating atrial arrhythmia comprising: administering an effective amount of at least one antiarrhythmic agent selected from the group consisting of class I, class II, class III, and class IV antiarrhythmic agents to one or more pulmonary veins of a subject in need thereof by inhalation (e.g., oral inhalation), wherein the effective amount of the at least one antiarrhythmic agent is in a total amount of 0.1mg to 200mg and has: i) t from about 0.1 minute to about 30 minutes_max(ii) a ii) C from about 10ng/mL to about 5000ng/mL_max(ii) a iii) AUC of about 100hr ng/mL to about 10000hr ng/mL_Last(ii) a IV) a profile t of about 0.1 minute to about 15 minutes_1/2(ii) a v) elimination of t from about 1 hour to about 25 hours_1/2(ii) a vi) a Δ QRS of about 0.01 milliseconds to about 100 milliseconds; or any combination thereof.

In some cases, the at least one antiarrhythmic agent is administered via multiple inhalations. In some cases, the at least one anti-arrhythmic agent is administered in up to 6 inhalations. In some cases, the subject's sinus rhythm returns to normal within 30 minutes of the initial administration. In some cases, the level of the at least one anti-arrhythmic agent peaks in the coronary circulation of the heart at a time between 30 seconds and 20 minutes from administration. In some cases, the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart is in the range of 0.1mg/L to 60mg/L at 2.5 minutes after administration. In some cases, the concentration of the at least one anti-arrhythmic agent in the coronary circulation of the heart is less than 0.1mg/L at 30 minutes after administration. In some cases, the nominal of the at least one antiarrhythmic agent administered is5% to 60% of the dose reaches the coronary circulation. In some cases, an effective amount of T of at least one antiarrhythmic agent_maxFrom about 0.1 minutes to about 30 minutes. In some cases, an effective amount of T of at least one antiarrhythmic agent_maxFrom about 1 minute to about 5 minutes. In some cases, an effective amount of T of at least one antiarrhythmic agent_maxFrom about 0.1 minutes to about 3 minutes. In some cases, an effective amount of T of at least one antiarrhythmic agent_maxFrom about 0.2 minutes to about 5 minutes. In some cases, an effective amount of C of at least one antiarrhythmic agent_maxFrom about 50ng/mL to about 500 ng/mL. In some cases, an effective amount of C of at least one antiarrhythmic agent_maxFrom about 100ng/mL to about 250 ng/mL. In some cases, the AUC of the effective amount of the at least one antiarrhythmic agent_LastFrom about 100hr ng/mL to about 10000hr ng/mL. In some cases, the AUC of the effective amount of the at least one antiarrhythmic agent_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, the AUC of the effective amount of the at least one antiarrhythmic agent_LastFrom about 500hr ng/mL to about 800hr ng/mL. In some cases, the AUC of the effective amount of the at least one antiarrhythmic agent_LastFrom about 400hr ng/mL to about 600hr ng/mL. In some cases, the distribution t of the effective amount of the at least one antiarrhythmic agent_1/2From about 0.1 minutes to about 15 minutes. In some cases, the distribution t of the effective amount of the at least one antiarrhythmic agent_1/2From about 3 minutes to about 4 minutes. In some cases, the distribution t of the effective amount of the at least one antiarrhythmic agent_1/2From about 3 minutes to about 5 minutes. In some cases, the elimination of the effective amount of at least one antiarrhythmic agent is t_1/2From about 1 hour to about 25 hours. In some cases, the elimination of the effective amount of at least one antiarrhythmic agent is t_1/2From about 8.5 hours to about 10.5 hours. In some cases, the effective amount of the at least one antiarrhythmic agent has a Δ QRS of about 0.01 milliseconds to about 100 milliseconds. In some cases, the effective amount of the at least one anti-arrhythmic agent has a Δ QRS of about 1 millisecond to about 10 milliseconds. In thatIn some cases, the effective amount of the at least one antiarrhythmic agent has a Δ QRS of about 5 milliseconds to about 20 milliseconds. In some cases, the maximum Δ QRS and C produced in combination with an effective amount of at least one antiarrhythmic agent delivered intravenously_maxCompared to the ratio of maximum Δ QRS to C of an effective amount of at least one antiarrhythmic agent delivered by inhalation through the lung airways_maxThe ratio of (A) to (B) is higher. In some cases, the maximum Δ QRS and C produced by inhalation of an effective amount of at least one antiarrhythmic agent delivered through the lung airways_maxThe ratio of maximum Δ QRS to C of an effective amount of at least one anti-arrhythmic agent delivered intravenously_maxThe ratio of (A) to (B) is at least 2 times higher. In some cases, the atrial arrhythmia includes tachycardia. In some cases, the tachycardia includes supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, or isolated atrial fibrillation. In some cases, the method comprises administering a liquid, dry powder, extruded droplets, or aerosolized droplets comprising at least one anti-arrhythmic agent, wherein the mass median aerodynamic diameter of the powder or aerosolized droplets is less than 10 μm. In some cases, the antiarrhythmic agent is a class I antiarrhythmic agent. In some cases, the class I antiarrhythmic agent is a class Ia, Ib, or Ic antiarrhythmic agent. In some cases, the class Ic antiarrhythmic drug is flecainide. In some cases, the antiarrhythmic agent is a class II antiarrhythmic. In some cases, the class II antiarrhythmic agent is esmolol hydrochloride. In some cases, the dose of esmolol hydrochloride is from 0.5 to 0.75mg/kg body weight. In some cases, the antiarrhythmic agent is a class IV antiarrhythmic. In some cases, the class IV antiarrhythmic agent is diltiazem. In some cases, the dose of diltiazem is 0.25mg/kg body weight. In some cases, the at least one anti-arrhythmic agent is aerosolized in a nebulizer. In some cases, the nebulizer is a breath activated nebulizer. In some cases, the nebulizer is a breath actuated nebulizer. In some cases, the nebulizer is configured forAdministering a liquid pharmaceutical formulation of at least one antiarrhythmic agent. In some cases, aerosolization occurs at room temperature. In some cases, the at least one anti-arrhythmic agent is self-administered by the subject. In some cases, the T of an effective amount of at least one antiarrhythmic agent is measured in a human PK/PD study_max、C_max、AUC_LastDistribution t_1/2And eliminate t_1/2Or maximum Δ QRS. In some cases, the human PK/PD study is a single dose PK/PD study. In some cases, the human PK/PD study is a multi-dose (e.g., dose escalation) PK/PD study.

In another aspect, disclosed herein is a method of treating a cardiac condition comprising administering to a patient in need thereof a pharmaceutically effective amount of an antiarrhythmic agent by inhalation, wherein the pharmaceutically effective amount of the antiarrhythmic agent's T after inhalation_maxFrom about 0.1 minute to about 30 minutes; pharmaceutically effective amount of antiarrhythmic agent C after inhalation_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of a pharmaceutically effective amount of an antiarrhythmic agent after inhalation_LastFrom about 100hr ng/mL to about 10000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, C_maxIs about 50ng/mL to about 500ng/mL, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises a class Ic antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof. In some cases, the method comprises administering to a patient in need thereof 20mg to 100mg of flecainide, or a pharmaceutically acceptable salt thereof, by inhalation. In some cases, the method comprises treating the mammal with a composition comprisingInhalation administering to a patient in need thereof 0.25mg/kg body weight to 1.5mg/kg body weight of flecainide or a pharmaceutically acceptable salt thereof. In some cases, the anti-arrhythmic agent is delivered via two or more inhalations. In some cases, the time between two or more inhalations is about 0.1 to 10 minutes.

In another aspect, disclosed herein is a nebulized pharmaceutical product comprising a pharmaceutically effective amount of an antiarrhythmic agent, wherein the pharmaceutically effective amount of the antiarrhythmic agent's T after inhalation_maxFrom about 0.1 minute to about 30 minutes; pharmaceutically effective amount of antiarrhythmic agent C after inhalation_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of a pharmaceutically effective amount of an antiarrhythmic agent after inhalation_LastFrom about 100hr ng/mL to about 10000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, C_maxIs about 50ng/mL to about 500ng/mL, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises a class Ic antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof. In some cases, the aerosolized pharmaceutical product comprises 20mg to 100mg of flecainide, or a pharmaceutically acceptable salt thereof.

In another aspect, disclosed herein is a method of preparing a formulation for treating a cardiac condition, the formulation comprising a pharmaceutically effective amount of an antiarrhythmic agent, wherein the formulation, upon aerosolization and inhalation by a patient in need thereof, comprises a pharmaceutically effective amount of a T of the antiarrhythmic agent_maxFrom about 0.1 minute to about 30 minutes; the formulation is administered by nebulization and inhalation to a patient in need thereof, with a pharmaceutically effective amount of an anti-cardioprotective agentArrhythmia agent C_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of a pharmaceutically effective amount of the antiarrhythmic agent following aerosolization and inhalation by a patient in need thereof_LastFrom about 100hr ng/mL to about 10000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, C_maxIs about 50ng/mL to about 500ng/mL, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises a class Ic antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof. In some cases, the antiarrhythmic agent is delivered via two or more inhalations. In some cases, the time between two or more inhalations is about 0.1 to 10 minutes.

In another aspect, disclosed herein is a nebulized pharmaceutical product comprising a pharmaceutically effective amount of an anti-arrhythmic agent for treating a cardiac condition, wherein the T of the pharmaceutically effective amount of the anti-arrhythmic agent upon inhalation_maxFrom about 0.1 minute to about 30 minutes; pharmaceutically effective amount of antiarrhythmic agent C after inhalation_maxFrom about 10ng/mL to about 5000 ng/mL; or AUC of a pharmaceutically effective amount of an antiarrhythmic agent after inhalation_LastFrom about 100hr ng/mL to about 10000hr ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, C_maxIs about 50ng/mL to about 500ng/mL, or AUC_LastFrom about 200hr ng/mL to about 2000hr ng. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and C_maxFrom about 50ng/mL to about 500 ng/mL. In some cases, T_maxFrom about 0.1 minute to about 5 minutes, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, C_maxIs about 50ng/mL to about 500ng/mL, and AUC_LastFrom about 200hr ng/mL to about 2000hr ng/mL. In some cases, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises a class Ic antiarrhythmic agent. In some cases, the antiarrhythmic agent comprises flecainide or a pharmaceutically acceptable salt thereof. In some cases, the aerosolized pharmaceutical product comprises 20mg to 100mg of flecainide, or a pharmaceutically acceptable salt thereof.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The invention is further described in the following description of the invention with reference to the noted plurality of non-limiting drawings, in which:

figure 1 shows how a prior art intravenous drug passes through the heart and lungs and then to the coronary arteries to reach the coronary circulation.

Figure 2A shows how the inhaled medicament of the present invention passes directly through the lungs to the left atrium, left ventricle and then into the coronary arteries.

Figure 2B shows how the inhaled medicament of the present invention passes through the pulmonary veins to the left atrium.

Figure 3 shows that molecules with high Log-P values and molecules with high lipid solubility are likely to exhibit faster absorption through the lung.

Figure 4 shows a six-compartment PK-PD model for comparing intravenous and pulmonary delivery.

Figure 5 shows the results of a simulation comparing intravenous and pulmonary delivery of verapamil.

Figure 6 shows the results of a simulation comparing intravenous and pulmonary delivery of lidocaine.

Figure 7 shows a representative study profile: the effect of flecainide (FLE, n ═ 2), diltiazem (DIL, n ═ 2), and dofetilide (DOF, n ═ 2) on induced atrial fibrillation. NSR: normal sinus rhythm.

Figure 8 shows a representative study profile: dose response of Intratracheal (IT) esmolol hydrochloride (ESM, n < 2) or adenosine (ADN, n < 2) to induced supraventricular tachycardia (SVT). NSR: normal sinus rhythm. IV: intravenous administration of drugs

Fig. 9 shows an ECG trace showing dogs in atrial fibrillation (Afib) prior to vehicle or test article administration.

Fig. 10 shows an ECG trace showing dogs continuing in Afib after pulmonary administration of vehicle (water, 3 ml).

Fig. 11 shows an ECG trace showing that Afib reverts to normal sinus rhythm when 4mg/kg body weight of flecainide acetate is administered to dogs by intratracheal instillation.

Fig. 12 shows an ECG trace showing that once administered 2mg/kg body weight of flecainide acetate, Afib is immediately repeated.

FIG. 13 shows an ECG trace showing Afib turnover following administration of diltiazem hydrochloride at 0.25mg/kg body weight.

Figure 14 shows results from a supraventricular tachycardia model in which the P-R interval and mean arterial blood pressure (MAP) were varied over time following pulmonary administration of 0.25mg/kg of pulmonary diltiazem.

Figure 15 shows results from a supraventricular tachycardia model in which the P-R interval and mean arterial blood pressure (MAP) were varied over time following intravenous administration of 0.25mg/kg of pulmonary diltiazem.

FIG. 16 shows results from a supraventricular tachycardia model showing the effect of transpulmonary (IT) administration of esmolol hydrochloride at 0.5mg/kg body weight on P-R interval over time.

FIG. 17 shows results from a supraventricular tachycardia model showing the atrioventricular conduction block (AV block) phase induced by pulmonary administration of 0.5mg/kg esmolol.

FIG. 18 shows results from a supraventricular tachycardia model showing the AV block phase induced by 0.5mg/kg esmolol administered pulmonary.

FIG. 19 shows results from a supraventricular tachycardia model showing the effect of transpulmonary (IT) administration of esmolol hydrochloride at 0.5mg/kg body weight on P-R interval over time.

FIG. 20 shows results from a supraventricular tachycardia model showing the AV block phase induced by 0.75mg/kg esmolol administered pulmonary.

Figure 21 shows the design of a phase 1 clinical study.

Figure 22 shows the time course of change in heart rate (Δ HR) from baseline (pre-dose) following oral inhalation of 20mg of the eltld (estimated total lung dose) flecainide acetate solution and placebo in subjects in group 1. Values are mean ± Standard Error of Mean (SEM).

Figure 23 shows the heart rate change (Δ HR) after inhalation of 40mg of eltld in flecainide acetate and placebo solution by the subjects of group 2 relative to the pre-dose values. Values are mean ± SEM.

Figure 24 shows heart rate (bpm) for subjects in group 5 after oral Inhalation (IH) and IV administration of flecainide acetate solution (30 mg/kg). Values are mean ± Standard Deviation (SD).

Figure 25A shows the change in systolic blood pressure (systolic BP) from subjects in group 1 after inhalation of 20mg of the eltld in flecainide acetate and placebo solution.

Figure 25B shows the change in diastolic pressure in subjects from group 1 after inhalation of 20mg of the eltld in flecainide acetate and placebo solution.

Figure 26A shows the change in systolic blood pressure for subjects from group 2 after inhalation of 40mg of the eltld in flecainide acetate and placebo solution.

Figure 26B shows the change in diastolic pressure in subjects from group 2 after inhalation of 40mg of the eltld in flecainide acetate and placebo solution.

Figure 27A shows the change in systolic blood pressure in subjects from group 5 after single dose administration of Inhaled (IH) flecainide (30mg eTLD) and IV flecainide (2 mg/kg). Values are mean ± SD.

Figure 27B shows the change in diastolic pressure in subjects from group 5 after single dose administration of Inhaled (IH) flecainide (30mg eTLD) and IV flecainide (2 mg/kg). Values are mean ± SD.

FIG. 28 shows the mean intravenous plasma concentration versus time after inhalation of 20mg eTLD, 30mg eTLD and 40mg eTLD in Flucarney acetate.

FIG. 29A shows the mean intravenous plasma concentration-time curve after IV administration of a flecainide acetate solution (2 mg/kg). Data points represent mean ± SD.

FIG. 29B shows the mean intravenous plasma concentration-time profiles after administration of flecainide acetate solution by inhalation (IH; 30mg eTLD) or IV (2 mg/kg). Data points represent mean ± SD.

FIG. 30 shows the time course of the change in duration of the P-R interval (Δ PR) after oral inhalation of 20mg of eTLD in flecainide acetate and acetate buffer (placebo) relative to baseline (pre-dose). Values are mean ± SEM; n-6 (flecainide) and n-2 (placebo).

Fig. 31 shows the time course of the change in duration of QRS interval (Δ QRS) after oral inhalation of 20mg of the eltld in flecainide acetate solution and placebo, relative to baseline (before dosing). Values are mean ± SEM; n-6 (flecainide) and n-2 (placebo).

Fig. 32 shows the time course of QRS interval duration change (Δ QRS) relative to baseline (before dosing) after oral inhalation of 40mg of the eltld in flecainide acetate solution and placebo. Values are mean ± SEM; n-10 (flecainide) and n-4 (placebo).

Fig. 33A shows a digitized Electrocardiogram (ECG) trace selected from the V5 lead depicting complexes of P-waves, QRS-waves and T-waves recorded at different times before (before) and after (after) completion of inhalation of 40mgeTLD of flecainide. The values of QRS interval duration (QRSd, ms) in milliseconds and R wave amplitude (QRSa, μ V) in microvolts are shown in the figures.

Fig. 33B shows a bar graph summarizing the time course of changes in QRS interval duration measured from an ECG at various times and obtained from the same subject in fig. 13A. P < 0.05.

Fig. 33C shows a bar graph summarizing the time course of R-wave amplitude changes measured from the ECG at various times and obtained from the same subject in fig. 13A. P < 0.05.

Fig. 34 shows the results obtained in a) by IV administration of flecainide acetate solution (2 mg/kg; infusion for 10 minutes, intra-ventricular conduction delay lasting 5-10 minutes) and B) oral inhalation of 30mg of the tld in flecainide acetate solution (4 minutes of inhalation), QRS interval duration change (Δ QRS) relative to baseline (pre-dose) in subjects in cohort 5 (IV-inhalation cross).

FIG. 35 shows the time course of the change in QTcF interval duration (. DELTA.QTcF) after oral inhalation of 20mg of eTLD in flecainide acetate and placebo relative to baseline (pre-dose). Values are mean ± SEM; n-6 (flecainide) and n-2 (placebo).

Figure 36 shows ECG traces recorded from subjects administered flecainide (2mg/kg) by IV. The small arrows on the electrogram represent the T-waves.

Figure 37 shows the venous plasma concentration of IV or orally administered flecainide at Atrial Fibrillation (AF) cardioversion in patients with new AF (left panel), venous plasma concentration of healthy volunteers after oral inhalation of 40mg of the eTLD flecainide acetate solution (middle panel), and venous plasma concentration of dogs after Intratracheal (IT) instillation of 0.75mg/kg of flecainide at the time of AF reversion to NSR (right panel). LV ═ left ventricle; mean values of plasma concentrations extrapolated from animal studies in dogs ± SD (x 1.96-fold) in cardioversion.

Figure 38 shows the relative delta QRS interval prolongation (milliseconds) associated with flecainide or vernakalant administration at the time of AF cardioversion in patients with new AF and following oral inhalation of 30mgeTLD of flecainide acetate solution in healthy volunteers.

FIGS. 39-67 refer to data obtained from swine. FIG. 39 shows venous and Left Ventricular (LV) plasma levels of flecainide at various time points after 2 min intravenous administration of 2.0mg/kg of flecainide.

Figure 40 shows intravenous and LV plasma levels of flecainide at various time points after an intratracheal instillation of 0.75 mg/kg.

Figure 41 shows venous and LV plasma levels of flecainide at different time points after an intratracheal instillation of 1.5 mg/kg.

Figure 42 shows the effect of intravenous administration of flecainide (2.0mg/kg) on heart rate (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

FIG. 43 shows the effect of intravenous administration of flecainide (2.0mg/kg) on mean arterial blood pressure (MAP; major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

Figure 44 shows the effect of intravenous administration of flecainide (2.0mg/kg) on P-R interval duration (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

Figure 45 shows the effect of intravenous administration of flecainide (2.0mg/kg) on QRS interval duration (primary vertical axis) and LV plasma levels (secondary vertical axis) at different time points.

Figure 46 shows the effect of intravenous administration of flecainide (2.0mg/kg) on QTc interval duration (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

FIG. 47 shows the effect of intravenous administration of flecainide (2.0mg/kg) on JTc interval duration (major longitudinal axis) and LV plasma levels (minor longitudinal axis) at different time points.

Figure 48 shows the effect of intratracheal instillation of a lower dose of flecainide (0.75mg/kg) on heart rate (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

Figure 49 shows the effect of intratracheal instillation of a lower dose of flecainide (0.75mg/kg) on MAP (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

FIG. 50 shows the effect of intratracheal instillation of a lower dose of flecainide (0.75mg/kg) on P-R interval (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

Fig. 51 shows the effect of intratracheal instillation of a lower dose of flecainide (0.75mg/kg) on QRS interval duration (primary vertical axis) and LV plasma levels (secondary vertical axis) at different time points.

Figure 52 shows the effect of intratracheal instillation of a lower dose of flecainide (0.75mg/kg) on QTc interval (major longitudinal axis) and LV plasma levels (minor longitudinal axis) at different time points.

FIG. 53 shows the effect of intratracheal instillation of a lower dose of flecainide (0.75mg/kg) on JTc interval (major longitudinal axis) and LV plasma levels (minor longitudinal axis) at different time points.

Figure 54 shows the effect of intratracheal instillation of a higher dose of flecainide (1.5mg/kg) on heart rate (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

Figure 55 shows the effect of intratracheal instillation of a higher dose of flecainide (1.5mg/kg) on MAP (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

FIG. 56 shows the effect of intratracheal instillation of a higher dose of flecainide (1.5mg/kg) on P-R interval (major vertical axis) and LV plasma levels (minor vertical axis) at different time points.

Fig. 57 shows the effect of intratracheal instillation of a higher dose of flecainide (1.5mg/kg) on QRS interval duration (primary vertical axis) and LV plasma levels (secondary vertical axis) at different time points.

Figure 58 shows the effect of intratracheal instillation of a higher dose of flecainide (1.5mg/kg) on QTc interval (major longitudinal axis) and LV plasma levels (minor longitudinal axis) at different time points.

FIG. 59 shows the effect of intratracheal instillation of a higher dose of flecainide (1.5mg/kg) on JTc interval (major longitudinal axis) and LV plasma levels (minor longitudinal axis) at different time points.

Figure 60 shows a protocol and representative examples for testing IT for repeated induced Atrial Fibrillation (AF) by flecainide.

Figure 61 shows a summary of data from experiments evaluating the effect of intratracheal instillation of flecainide (1.5mg/kg) on AF duration (n-3).

Figure 62A shows the effect of slow or rapid infusion of IV administered flecainide on venous plasma levels of flecainide.

Fig. 62B shows the effect of slow or rapid infusion of IV administered flecainide on QRS interval duration.

Fig. 62C shows the correlation between venous plasma levels and QRS broadening for slow or fast infusion of IV administered flecainide.

Figure 63 shows catheter placement in anesthetized yorkshire pigs.

Figure 64 shows AF duration correlated with IT flecainide dose.

Figure 65 shows a representative electrogram, demonstrating AF turnover at 5 minutes after IT flecainide (1.5mg/kg) (lower panel), compared to no turnover at 10 minutes without drug (upper panel).

FIG. 66A shows that the plasma concentration of flecainide reached the level required to convert AF to NSR within 10 minutes after IT flecainide (0.75mg/kg and 1.5 mg/kg).

FIG. 66B shows the plasma concentration of flecainide after IT instillation of flecainide (0.75mg/kg and 1.5mg/kg) at the time of AF switch to NSR.

FIG. 67 shows that IT flecainide (0.75mg/kg and 1.5mg/kg) reduced the dominant frequency of AF.

FIGS. 68A-71 refer to data obtained in dogs. Fig. 68A shows a representative ECG, which demonstrates AF prior to dosing.

Fig. 68B shows a representative ECG demonstrating AF persistence following IT instillation of vehicle.

Fig. 68C shows a representative ECG, which demonstrates AF prior to administration.

FIG. 68D shows a representative ECG demonstrating AF conversion to NSR after IT flecainide (0.75 mg/kg).

FIG. 69 shows blood pressure, ventricular rate and LV dP/dT when AF reverts to NSR following IV or IT administration of flecainide_max(maximum rate of rise of LV pressure).

Figure 70 shows the change in plasma concentration of flecainide in the Left Ventricle (LV), Pulmonary Artery (PA) and femoral Vein (VEN) based on the flecainide delivery routes (IT and IV). Note that after IV infusion, the concentration of flecainide in PA was briefly higher (2.1 to 3.5 times) than in LV. After IT instillation of flecainide, the concentration of flecainide in LV was transiently higher (1.4 to 3.2 times) than in PA (between 1 and 3 minutes after administration of flecainide).

Figure 71 shows the time course of the plasma concentration ratio of flecainide in the Pulmonary Artery (PA) and Left Ventricle (LV) after IV or IT administration.

FIGS. 72-87B refer to data obtained in human subjects. Fig. 72 shows the effect of posture change and inhaled flecainide or placebo (n-3) on Heart Rate (HR) at different time points.

Figure 73 shows the effect of intravenous delivery of (IV) flecainide on systolic blood pressure and heart rate for 6 subjects at different time points.

Figure 74 shows the effect of inhaled flecainide on systolic blood pressure and heart rate for 6 subjects at different time points.

Figure 75A shows the systolic and diastolic blood pressure after intravenous delivery of flecainide in 6 subjects.

Figure 75B shows systolic and diastolic blood pressure after administration of 6 subjects flecainide Inhalation (IH).

FIGS. 76A and 76B show the venous plasma concentration-time profiles after oral inhalation of 20, 40 and 60mg of eTLD flecainide in the protocol population and the post hoc population, respectively.

Figures 77A and 77B show the intravenous plasma concentration-time profiles after intravenous infusion and inhalation of flecainide, respectively.

Figure 78 shows the venous plasma concentration-time curves after flecainide IV infusion (normalized to 30mg eTLD dose) and oral inhalation.

Fig. 79 shows the time course of changes in QRS interval duration with flecainide or placebo.

Fig. 80A and 80B show the time course of changes in QRS interval duration after IV infusion and oral inhalation of flecainide, respectively.

FIG. 81 shows the time course of changes in duration of P-R intervals with flecainide or placebo.

FIGS. 82A and 82B show the time course of P-R interval changes following infusion of Flucanini IV and oral inhalation, respectively.

FIG. 83 shows the venous plasma peak concentration (C) of flecainide_max) The magnitude of the maximum QRS prolongation.

Figures 84A and 84B show the time course of the change in flecainide plasma concentration and QRS duration for flecainide IV infusion and oral inhalation, respectively.

Figure 85 shows the non-steady state relationship between the plasma concentration of flecainide and QRS duration after flecainide IV infusion and oral inhalation, respectively.

Figure 86 shows the non-steady state relationship between the plasma concentration of flecainide and QRS duration following IV infusion and oral inhalation of flecainide in subjects with approximately equal Δ QRS values.

Fig. 87A shows baseline (pre-dose) values of heart rate, systolic Blood Pressure (BP), and diastolic blood pressure for 6 subjects in study part B at time 1 and time 2.

Fig. 87B shows baseline (pre-dose) values of QRS complex and P-R interval for 6 subjects at time 1 and time 2 in part B study.

Detailed Description

It is to be understood that unless otherwise indicated, the invention is not limited to specific formulation components, drug delivery systems, manufacturing techniques, administration steps, etc., as these may vary. In this regard, unless otherwise indicated, reference to a compound or component includes the compound or component by itself, as well as the compound or component in combination with other compounds or components (e.g., mixtures of compounds).

Before further discussion, the following definitions of terms will aid in understanding the present invention.

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an "antiarrhythmic agent" includes not only a single active agent, but also a combination or mixture of two or more different active agents.

Reference herein to "one embodiment," "a form," or "an aspect" shall include one or more such embodiments, forms, or aspects unless the context clearly dictates otherwise.

As used herein, the term "solvate" is intended to include, but is not limited to, pharmaceutically acceptable solvates.

As used herein, the term "pharmaceutically acceptable solvate" is intended to mean a solvate that retains one or more biological activities and/or properties of the antiarrhythmic agent and is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable solvates include, but are not limited to, antiarrhythmic agents in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

As used herein, the term "salt" is intended to include, but is not limited to, pharmaceutically acceptable salts.

As used herein, the term "pharmaceutically acceptable salts" is intended to mean those salts that retain one or more of the biological activities and properties of the free acids and bases and are not biologically or otherwise undesirable. Illustrative examples of pharmaceutically acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, 1, 4-succinate, 1, 6-adipate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, dihydrogensulfate, metaphosphate, pyrophosphate, chloride, bromide, iodide, propionate, fumarate, caprylate, or caprylate, Lactate, gamma-hydroxybutyrate, glycolate, tartrate, mesylate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

If the antiarrhythmic agent is a base, the desired salt can be prepared by any suitable method known in the art, including treating the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosyl acids such as glucuronic acid and galacturonic acid, α -hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid and ethanesulfonic acid, and the like.

If the antiarrhythmic agent is an acid, the desired salt can be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali or alkaline earth metal hydroxide, and the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, as well as inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The term "about" in relation to a reference value may include a range of values plus or minus 10% from that value. For example, an amount of "about 10" includes amounts of 9 to 11, including reference numerals 9, 10, and 11. The term "about" in relation to a reference value may also include ranges of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value.

As used herein, "atrial arrhythmia" may refer to an arrhythmia that affects at least one atrium and does not include bradycardia. For example, atrial arrhythmias may originate from and affect at least one atrium.

As used herein, "tachycardia" may mean an arrhythmia that is too fast, e.g., faster than normal. For example, a tachycardia can include a resting heart rate that beats more than 100 times per minute, such as more than 110 beats per minute, more than 120 beats per minute, or more than 130 beats per minute.

As used herein, the term "cardiac rhythmic arrhythmia" may refer to an arrhythmia in which the heart beats irregularly.

As used herein, the "amount of at least one anti-arrhythmic agent in the blood of the coronary circulation of the heart" may be measured by extracting a sample from any vascular region of the coronary circulation of the heart (e.g. arteries, veins, including the coronary sinus) using a cannula. The amount of antiarrhythmic agent in the sample can then be determined by known methods, for example, bioanalytical techniques using analytical equipment such as LC-MS/MS. Thus, the amount of the antiarrhythmic agent in the blood of the heart can be measured at any particular time.

As used herein, the terms "treating …" and "treatment" refer to a reduction in the severity and/or frequency of symptoms, elimination of symptoms and/or underlying causes, a reduction in the likelihood of the appearance of symptoms and/or underlying causes, and/or repair of injury. Thus, "treating" a patient with an active agent as provided herein includes preventing a particular condition, disease, or disorder in a subject susceptible to disease as well as treating a clinically symptomatic subject.

As used herein, "nominal amount" may refer to the amount contained within the unit dose vessel being administered.

As used herein, "effective amount" may refer to an amount that encompasses both a therapeutically effective amount and a prophylactically effective amount.

As used herein, a "therapeutically effective amount" of an active agent refers to an amount effective to achieve the desired therapeutic result. The therapeutically effective amount of a given active agent will generally vary depending upon factors such as the type and severity of the condition or disease being treated, as well as the age, sex, and weight of the patient. In some cases, "inhalation" (e.g., "oral inhalation") may refer to inhalation delivery of a therapeutically effective amount of a medicament in one unit dose vessel, which in some cases may require one or more breaths, e.g., 1,2, 3,4, 5,6, 7, 8,9 or more breaths. For example, if the effective amount is 90mg and each unit dose vessel contains 30mg, delivery of the effective amount may require 3 inhalations.

Unless otherwise indicated, the term "therapeutically effective amount" may include a "prophylactically effective amount," e.g., an amount of an active agent effective to prevent the onset or recurrence of a particular condition, disease, or disorder in a subject susceptible to disease.

As used herein, the phrase "minimum effective amount" may refer to the minimum amount of an agent necessary to achieve an effective amount.

As used herein, "mass median diameter" or "MMD" may refer to the median diameter of a plurality of particles typically in a polydisperse population of particles, for example, made up of a series of particle size components. Unless the context indicates otherwise, the MMD values reported herein are determined by laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany). For example, for powders, the sample was added directly to the feeder funnel of a Sympatec RODOS dry powder dispersion device. This can be done manually or by mechanical agitation from the end of the VIBRI vibratory feeder element. The sample is dispersed into primary particles by applying compressed air (2 to 3bar) and the vacuum is reduced to a maximum (suction) at a given dispersion pressure. The dispersed particles were detected with a 632.8nm laser beam, which intersected the trajectory of the dispersed particles at right angles. The laser light scattered from the ensemble of particles is imaged onto a concentric array of photomultiplier tube detector elements using an inverse fourier lens assembly. Scattered light was collected in 5 millisecond time slices. The particle size distribution was back-calculated from the spatial/intensity distribution of the scattered light using a proprietary algorithm.

As used herein, "geometric diameter" may refer to the diameter of an individual particle as determined by microscopy, unless the context indicates otherwise.

As used herein, "mass median aerodynamic diameter" or "MMAD" may refer to the median of the aerodynamic size of a plurality of particles or particles, typically in a polydisperse population. The "aerodynamic diameter" may be the diameter of a unit density sphere that typically has the same settling velocity in air as a powder, and is therefore a useful method of characterizing aerosolized powders or other dispersed particles or particle formulations in terms of settling behavior. The aerodynamic diameter includes the shape, density, and physical size of the particle or granules. As used herein, MMAD refers to the median value of the aerodynamic diameter or particle size distribution of aerosolized particles determined by cascade collisions, unless the context indicates otherwise.

As used herein, the term "empty rate" or "ED" may refer to a representation of the delivery of particles from an aerosolization device following an actuation or dispersion event from a unit dose vessel or reservoir. ED is defined as the ratio of the dose delivered by the inhaler device to the nominal dose (e.g. the mass of powder or liquid per unit dose put into a suitable inhaler device before use). ED is an experimentally determined quantity that can be determined using an in vitro system that mimics patient dosing. For example, to determine the ED value of a dry powder, a nominal dose of the dry powder is placed

DPI device (PH)&T, Italy), as described in U.S. patent nos. 4,069,819 and 4,995,385, the entire contents of which are incorporated herein by reference. ActuationDPI to disperse the powder. The resulting aerosol cloud (30L/min) was drawn from the device by vacuum for 2.5 seconds after actuation, at which time it was captured on a tared glass fibre filter (Gelman, 47mm diameter) connected to the mouthpiece of the device. The amount of powder reaching the filter constitutes the delivered dose. For example, for a capsule containing 5mg of dry powder, capturing 4mg of powder on a tared filter would indicate an ED of 80% (═ 4mg (delivered dose)/5 mg (nominal dose)).

As used herein, "passive dry powder inhaler" may refer to an inhalation device that relies on the patient's inspiratory behavior to disperse and aerosolize a pharmaceutical composition contained in a reservoir or unit dose within the device, and does not include inhaler devices that include means for providing energy to disperse and aerosolize the pharmaceutical composition (e.g., pressurized gas and a vibrating or rotating element).

As used herein, "active dry powder inhaler" may refer to an inhalation device that does not rely solely on the inspiratory behavior of a patient to disperse and aerosolize a pharmaceutical composition contained in a reservoir or unit dose within the device, and includes inhaler devices that include means for providing energy to disperse and aerosolize the pharmaceutical composition (e.g., pressurized gas and a vibrating or rotating element).

A "pharmaceutically acceptable" component refers to a component that is not biologically or otherwise undesirable, e.g., the component may be incorporated into a pharmaceutical formulation of the present invention as described herein and administered to a patient without causing any significant undesirable biological effect and without deleterious interaction with any of the other components of the formulation in which it is contained. When the term "pharmaceutically acceptable" is used in reference to an excipient, it is generally meant that the component has met the required standards of toxicological and manufacturing testing, or is included in the inactive ingredient guide, written by the U.S. food and drug administration.

As used herein, "P-wave" may represent the wave generated by the electrical depolarizations of the atria (right and left), and is typically 0.08 to 0.1 seconds (80-100ms) in duration.

As used herein, "quality of life profile SF-36" may refer to a profile (SF-36) that investigates the health status of a patient (8 month update 2005). SF-36 consists of eight scale scores that are the sum of the questions of the part in which it is located. Assuming equal weight for each question, each scale is directly converted to a scale of 0-100. The eight parts are: (1) (ii) effort; (2) a physiological function; (3) somatic pain; (4) general health condition; (5) a physiological function; (6) emotional functions; (7) social functions; and (8) mental health. It may also refer to any quality of life questionnaire regarding AF symptoms.

As used herein, "preservative" may refer to cresols and benzoates. Thus, "substantially free of preservatives" may mean that the composition does not contain significant amounts of any cresols and/or benzoates. For example, a composition that is "substantially free of preservatives" can comprise less than 1 wt%, such as less than 0.5 wt%, less than 0.4 wt%, less than 0.3 wt%, less than 0.2 wt%, or less than 0.1 wt% preservatives. Of course, "preservative free" may mean that no preservative is present.

As used herein, "substantially tasteless" may refer to a composition that tastes little or no taste upon initial ingestion.

As an overview, the present invention relates to methods of treating atrial arrhythmias. The method may include administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent such that the at least one anti-arrhythmic agent enters the heart first through the pulmonary veins to the left atrium.

In one aspect, a method of treating atrial arrhythmia comprises administering to a patient in need thereof by inhalation an effective amount of at least one anti-arrhythmic agent, wherein the amount of the at least one anti-arrhythmic agent peaks in the coronary circulation within a time period ranging from 10 seconds to 30 minutes from administration.

In another aspect, the invention relates to a method of self-diagnosing and treating atrial arrhythmias. The method includes self-diagnosing atrial arrhythmia by detecting at least one of tachypnea, palpitations, and a higher than normal heart rate. The method further comprises self-administering an effective amount of at least one anti-arrhythmic agent by inhalation within two hours, one hour, 30 minutes, or 15 minutes of self-diagnosis. In some cases, the method comprises self-administering an effective amount of at least one anti-arrhythmic agent by inhalation within 15 minutes of self-diagnosis.

In another aspect, a method of treating atrial arrhythmia comprises administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation, wherein an electrophysiological effect is observed by electrocardiography within a time range of 10 seconds to 30 minutes from administration.

In another aspect, a method of treating atrial arrhythmia includes administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation, wherein a cardiac score from a monitor executing an arrhythmia detection algorithm indicates a transition from an arrhythmic state to a normal sinus rhythm in the patient within a time range of 10 seconds to 30 minutes from administration.

In another aspect, a method of treating atrial arrhythmia comprises administering to a patient in need thereof an effective amount of at least one anti-arrhythmic agent by inhalation, wherein the patient has an improved quality of life profile-36 score over a time period ranging from 10 seconds to 30 minutes from administration.

In another aspect, the unit dose comprises a unit dose vessel and the composition within the unit dose vessel. The composition comprises at least one antiarrhythmic agent in an amount less than or equal to the amount of the same at least one antiarrhythmic agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation, and a pharmaceutically acceptable excipient.

In another aspect, an aerosol comprises particles having a mass median aerodynamic diameter of less than 10 μm. The particles comprise at least one antiarrhythmic agent in an amount less than or equal to the amount of the same at least one antiarrhythmic agent administered intravenously in the arm to achieve a minimum effective amount in the coronary circulation, and a pharmaceutically acceptable excipient.

In another aspect, a kit includes a container containing at least one antiarrhythmic agent and an aerosolization device.

In certain embodiments, the invention includes "drug rescue therapy" to provide rapid cardioversion in patients with atrial arrhythmias such as paroxysmal ventricular tachycardia (PSVT) and Paroxysmal Atrial Fibrillation (PAF). Drug rescue therapy is generally intended to self-administer drugs by inhalation.

Inhalation is the shortest route for the drug to reach the heart, only after intracardiac injection, as shown in fig. 2A and 2B. Drugs delivered by inhalation often exhibit a short duration of high drug concentration, followed by dilution to sub-therapeutic levels of "pulsatile pharmacokinetics".

Thus, in some embodiments, the present invention relates to fast acting inhalation products that have a rapid onset of action compared to oral medications. The product is expected to be at least as fast as an intravenous medication. In some embodiments, the amount of the at least one anti-arrhythmic agent peaks in the coronary circulation of the heart within a time range from 10 seconds to 30 minutes, e.g., from 30 seconds to 20 minutes, from 1 minute to 10 minutes, from 2 minutes to 8 minutes, or from 2.5 minutes to 5 minutes from administration. In certain embodiments, the electrophysiological effect is observed by electrocardiography within a time range from 10 seconds to 30 minutes, e.g., from 30 seconds to 20 minutes, from 1 minute to 10 minutes, from 2 minutes to 8 minutes, or from 2.5 minutes to 5 minutes from administration. In some embodiments, the cardiac score from the device with arrhythmia detection algorithm shows that the patient transitioned from an arrhythmic state to normal sinus rhythm in a time range from 10 seconds to 30 minutes, e.g., 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes from administration. In some embodiments, the patient's quality of life profile-36 score increases over a time period ranging from 10 seconds to 30 minutes, e.g., from 30 seconds to 20 minutes, from 1 minute to 10 minutes, from 2 minutes to 8 minutes, or from 2.5 minutes to 5 minutes from administration. In certain embodiments, the patient has a normal sinus rhythm within 30 minutes, e.g., within 10 minutes, of the initial administration.

In some aspects, the invention relates to safe and effective low doses. Other aspects are generally related to lower premature metabolism and lower drug interactions.

The present invention includes non-invasive drug delivery to the heart. In addition to intracardiac injections, the lung is the shortest route for drugs to reach the heart with minimal dilution. Drugs delivered by the lung have a fast onset of action compared to drugs delivered by the oral route. Pipeline instruments, Antiarrhythmics, Datamonitor. Pulmonary drug delivery to the heart at least corresponds to a portable intravenous injection. Inhalation drugs (e.g., verapamil, diltiazem, lidocaine, ibutilide, procainamide, and propafenone) are expected to exhibit transiently high drug concentrations and then dilute to sub-therapeutic levels of "pulsatile pharmacokinetics".

Existing cardiovascular drugs tend to be small molecules with high lipid solubility. These lipid soluble molecules (e.g., diltiazem, verapamil, ibutilide, propafenone) are expected to have high pulmonary bioavailability and rapid pulmonary absorption. This ensures that they reach the heart through the pulmonary veins.

Pulsatile pharmacokinetic behavior of the drug indicates that the drug is diluted within a few seconds after reaching effective concentrations in the heart and to sub-therapeutic levels in the blood volume. This feature will minimize drug-drug interactions that produce a significant toxicological response that is normally observed at steady state.

Thus, in certain embodiments, the present invention relates to achieving a transiently high drug concentration in the heart that effects heart rate and rhythm changes in the heart over a short period of time, thereby enabling treatment of paroxysmal arrhythmias, such as paroxysmal atrial arrhythmias.

The results of the present invention are surprising and unexpected. In this regard, the antiarrhythmic agent passes rapidly through the lungs. For example, verapamil and diltiazem ionize if in salt form, and the base will pass rapidly through the lungs. In some aspects, the methods of the invention take advantage of rapid onset of action, high drug bioavailability, and rapid absorption through the lung. Most cardiovascular drugs are small molecules with high lipid solubility and are therefore expected to have high pulmonary bioavailability and rapid absorption rates. Figure 3 shows the log-p value and lipid solubility of exemplary cardiovascular molecules and their expected high lung bioavailability.

Another reason for the surprising and unexpected results of the present invention relates to the rate at which the anti-arrhythmic agent passes through the heart. Although the skilled artisan may consider the rate to be too fast, modeling indicates that the drug does not pass through the heart too fast. Thus, a therapeutic effect is obtained despite the rapid passage and despite only one passage at therapeutic levels.

In view of the above, in one or more embodiments of the invention, the composition comprises an antiarrhythmic agent examples of antiarrhythmic agents include, but are not limited to, class Ia (sodium channel blockers, moderate association/dissociation), class Ib (sodium channel blockers, fast association/dissociation), class Ic (sodium channel blockers, slow association/dissociation), class II (β receptor blockers), class III (potassium channel blockers), class IV (calcium channel blockers), and class V (mechanism unknown) antiarrhythmics.

Class Ia antiarrhythmic agents include, but are not limited to, quinidine, procainamide, and propiram, and pharmaceutically acceptable salts thereof. Class Ib antiarrhythmic agents include, but are not limited to, lidocaine, tocainide, phenytoin sodium, moraxezine and mexiletine, and pharmaceutically acceptable salts thereof. Class Ic antiarrhythmics include, but are not limited to, flecainide, propafenone, and moraxezine, and pharmaceutically acceptable salts thereof. Class II antiarrhythmics include, but are not limited to, propranolol, acebutolol, sotalol, esmolol, timolol, metoprolol, and atenolol, and pharmaceutically acceptable salts thereof. Class III antiarrhythmics include, but are not limited to amiodarone, sotalol, bromobenzylamine, ibutilide, E-4031 (methanesulfonamide), Vernakaline and dofetilide, and pharmaceutically acceptable salts thereof. Class IV antiarrhythmics include, but are not limited to, bepridil, nitrendipine, amlodipine, isradipine, nifedipine, nicardipine, verapamil and diltiazem, and pharmaceutically acceptable salts thereof. Class V antiarrhythmics include, but are not limited to, digoxin and adenosine, and pharmaceutically acceptable salts thereof.

The present invention also includes derivatives of the above antiarrhythmic agents, such as solvates, salts, solvated salts, esters, amides, hydrazides, N-alkyls, and/or N-aminoacylates. The derivative of the antiarrhythmic agent may be a pharmaceutically acceptable derivative. Examples of ester derivatives include, but are not limited to, methyl esters, choline esters, and dimethylaminopropyl esters. Examples of amide derivatives include, but are not limited to, primary amides, secondary amides, and tertiary amides. Examples of hydrazide derivatives include, but are not limited to, N-methylpiperazine hydrazide. Examples of N-alkylate derivatives include, but are not limited to, N ' -trimethyl derivatives of the methyl esters of the antiarrhythmic agents and N ', N ' -dimethylaminopropyl succinimidyl derivatives. Examples of N-aminoacyl derivatives include, but are not limited to, N-ornithine-, N-diaminopropionyl-, N-lysyl-, N-hexamethyllysyl, and N-piperidine-propionyl-or N ', N' -methyl-1-piperazine-propionyl-methyl antiarrhythmic agent.

The antiarrhythmic agents may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to fall within the scope of the present invention. These various forms of the compound may be isolated/prepared by methods known in the art.

The antiarrhythmic agents of the present invention can be prepared as a racemic mixture (e.g., a mixture of isomers) comprising more than 50%, preferably at least 75%, more preferably at least 90% of the desired isomer (e.g., 80% enantiomeric or diastereomeric excess). According to a particularly preferred embodiment, the compounds of the invention are such as to comprise at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), most preferably at least 99% (98% e.e. or d.e.) of the desired isomer. Compounds identified herein as single stereoisomers are intended to describe compounds used in a form that contains more than 50% of a single isomer. These compounds in any such form can be isolated by slightly varying the method of purification and/or isolation from the solvents used in the synthetic preparation of these compounds using known techniques.

Pharmaceutical compositions according to one or more embodiments of the invention may comprise one or more antiarrhythmic agents, optionally together with one or more other active ingredients and optionally one or more pharmaceutically acceptable excipients. For example, the pharmaceutical composition may comprise pure particles of the anti-arrhythmic agent (e.g. particles comprising only the anti-arrhythmic agent), may comprise pure particles of the anti-arrhythmic agent as well as other particles, and/or may comprise particles comprising the anti-arrhythmic agent and one or more active ingredients and/or one or more pharmaceutically acceptable excipients.

Thus, a pharmaceutical composition according to one or more embodiments of the present invention may comprise an antiarrhythmic agent in combination with one or more other active agents, as desired. Examples of other active agents include, but are not limited to, agents that can be delivered through the lungs.

Other active agents may include, for example, hypnotics and sedatives, psychostimulants, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, anti-parkinsonian agents (dopamine antagonists), analgesics, anti-inflammatories, anxiolytics (anxiolytics), appetite suppressants, anti-migraine agents, muscle contractants, other anti-infectives (antivirals, antifungals, vaccines), antiarthritics, antimalarials, antiemetics, antiepileptics, cytokines, growth factors, anticancer agents, antithrombotic agents, antihypertensive agents, cardiovascular agents, antiarrhythmics, antioxidants, anti-asthmatic agents, hormonal agents (including contraceptives), sympathomimetics, diuretics, lipid regulators, antiandrogens, antiparasitics, anticoagulants, neoplasms (neoplastics), antineoplastics, hypoglycemic agents, nutritional agents and supplements, hypnotics, Growth supplements, anti-inflammatory agents, vaccines, antibodies, diagnostic agents and contrast agents. When administered by inhalation, the other active agents may act locally or systemically.

Other active agents may belong to one of many structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting a physiological effect, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

Examples of other active agents suitable for use in the present invention include, but are not limited to, one or more of calcitonin, amphotericin B, Erythropoietin (EPO), factor VIII, factor IX, acalcicoside, imiridase, cyclosporine, Granulocyte Colony Stimulating Factor (GCSF), Thrombopoietin (TPO), α -1 protease inhibitor, elcatonin, Granulocyte Macrophage Colony Stimulating Factor (GMCSF), growth hormone, Human Growth Hormone (HGH), Growth Hormone Releasing Hormone (GHRH), heparin, Low Molecular Weight Heparin (LMWH), interferon α, interferon β, interferon gamma, interleukin 1 receptor, interleukin 2, interleukin 1 receptor antagonist, interleukin 3, interleukin 4, interleukin 6, Luteinizing Hormone Releasing Hormone (LHRH), factor IX, insulin, thymogen, insulin analogs thereof (e.g., such as those described in U.S. Pat. No. 5,922, insulin-acylated insulin intended for the purposes, such as described herein, pullulan, C-peptide, somatostatin, insulin, thymosin, insulin analogs thereof, insulin analogs thereof, such as cefalotin, ceftioxin, ceftioxacin, ceftioxin, and other pharmaceutically acceptable excipients, antibiotic, ceftioxacin, ceftiofur, ceftioxacin, ceftiofur, ceftioxacin, ceftioxin, ceftiofur, ceftioxacin, ceftioxin, ceftioxacin, ceftiofur, antibiotic, ceftiofur, antibiotic.

Other active agents useful in the present invention may further include nucleic acids, such as naked nucleic acid molecules, vectors, related viral particles, plasmid DNA or RNA or other types of nucleic acid constructs suitable for cell transfection or transformation, e.g., nucleic acid constructs suitable for gene therapy including anti-transcription therapy. In addition, the active agent may comprise live attenuated or inactivated viruses suitable for use as vaccines. Other useful drugs include those listed in the physicians' Desk Reference (latest edition), the entire contents of which are incorporated herein by Reference.

When a combination of active agents is used, the agents may be provided in combination in a single kind of pharmaceutical composition, or separately in different kinds of pharmaceutical compositions.

The amount of the antiarrhythmic agent in the pharmaceutical composition may vary. The amount of the antiarrhythmic agent is typically at least about 5 wt%, such as at least about 10 wt%, at least about 20 wt%, at least about 30 wt%, at least about 40 wt%, at least about 50 wt%, at least about 60 wt%, at least about 70 wt%, or at least about 80 wt% of the total amount of the pharmaceutical composition. The amount of the antiarrhythmic agent typically varies between about 0.1 wt% to 100 wt%, such as between about 5 wt% to about 95 wt%, between about 10 wt% to about 90 wt%, between about 30 wt% to about 80 wt%, between about 40 wt% to about 70 wt%, or between about 50 wt% to about 60 wt%.

As noted above, the pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients. Examples of pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, and the like, and combinations thereof.

Examples of lipids include, but are not limited to, phospholipids, glycolipids, gangliosides GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids with polymer chains, such as polyethylene glycol, chitin, hyaluronic acid or polyvinylpyrrolidone; lipids with sulfonated monosaccharides, disaccharides, and polysaccharides; fatty acids such as palmitic acid, stearic acid and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate.

In one or more embodiments, the phospholipid comprises a saturated phospholipid, such as one or more phosphatidylcholines. An exemplary length of the acyl chain is 16: 0 and 18: 0 (e.g., palmitoyl and stearoyl). Phospholipid content may be determined by the active agent activity, mode of delivery, and other factors.

Phospholipids from natural and synthetic sources can be used in varying amounts. When present, the phospholipid is typically present in an amount sufficient to coat the active agent with at least a monolayer of the phospholipid. Typically, the phospholipid content is about 5 wt% to about 99.9 wt%, such as about 20 wt% to about 80 wt%.

Generally, compatible phospholipids may include those having a gel to liquid crystal phase transition of greater than about 40 ℃, such as greater than about 60 ℃ or greater than about 80 ℃. The incorporated phospholipids may be relatively long-chain (e.g., C)₁₆-C₂₂) The saturated lipid of (4). Exemplary phospholipids that can be used in the present invention include, but are not limited to, phosphoglycerides such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidonoylphosphatidylcholine, docosacylphosphatidylcholine, diphosphatidylglycerol, short chain phosphatidylcholine, hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen, Germany), long chain saturated phosphatidylethanolamine, long chain saturated phosphatidylserine, long chain saturated phosphatidylglycerol, long chain saturated phosphatidylinositol, phosphatidic acid, phosphatidylinositol, and sphingomyelin.

Examples of metal ions include, but are not limited to, divalent cations including calcium, magnesium, zinc, iron, and the like. For example, when phospholipids are used, the pharmaceutical composition may also comprise multivalent cations, as disclosed in WO 01/85136 and WO01/85137, the entire contents of which are incorporated herein by reference. The multivalent cation may be present in an amount effective to increase the melting temperature (T) of the phospholipid_m) So that the pharmaceutical composition exhibits a T_mSpecific to its storage temperature (T)_m) At least about 20 c higher, such as at least about 40 c higher. The molar ratio of multivalent cations to phospholipids may be at least about 0.05: 1, such as about 0.05: 1 to about 2.0: 1, or about 0.25: 1 to about 1.0: 1. polyvalent cation: an example of a molar ratio of phospholipids is about 0.50: 1. when the multivalent cation is calcium, it may be in the form of calcium chloride. Although the phospholipids typically contain metal ions such as calcium, they are not required.

As noted above, the pharmaceutical composition may comprise one or more surfactants. For example, the one or more surfactants can be in the liquid phase, one or more of which are associated with solid particles or particles of the composition. Associated with means that the pharmaceutical composition may incorporate, adsorb, absorb, be coated with, or be formed from a surfactant. Surfactants include, but are not limited to, fluorinated and non-fluorinated compounds such as saturated and unsaturated lipids, nonionic detergents, nonionic block copolymers, ionic surfactants, and combinations thereof. It should be emphasized that in addition to the surfactants described above, suitable fluorinated surfactants are compatible with the teachings herein and can be used to provide the desired formulation.

Examples of non-ionic detergents include, but are not limited to, sorbitan esters, including sorbitan trioleate (Span)^TM85) Sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, glycerol esters and sucrose esters. Other suitable nonionic Detergents are readily identified using McCutcheon's Emulsifiers and Detergents (mcpublishingco., Glen Rock, n.j.), the entire contents of which are incorporated herein by reference.

Examples of block copolymers include, but are not limited to, diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic)^TMF-68), Poloxamer 407 (Pluronic)^TMF-127) and poloxamer 338.

Examples of ionic surfactants include, but are not limited to, sodium sulfosuccinate and fatty acid soaps.

Examples of amino acids include, but are not limited to, hydrophobic amino acids. The use of amino acids as pharmaceutically acceptable excipients is known in the art, as disclosed in WO 95/31479, WO 96/32096 and WO96/32149, the entire contents of which are incorporated herein by reference.

Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides, and polysaccharides. For example, monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose, and the like; disaccharides such as lactose, maltose, sucrose, trehalose, and the like; trisaccharides such as raffinose, etc.; and other carbohydrates such as starch (hydroxyethyl starch), cyclodextrin and maltodextrin.

Examples of buffers include, but are not limited to, tris or citrate.

Examples of acids include, but are not limited to, carboxylic acids.

Examples of salts include, but are not limited to, sodium chloride, carboxylic acid salts (e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, and the like), ammonium carbonate, ammonium acetate, ammonium chloride, and the like.

Examples of organic solids include, but are not limited to, camphor and the like.

The pharmaceutical composition of one or more embodiments of the present invention may also comprise a biocompatible polymer, such as a biodegradable polymer, copolymer, or mixtures or other combinations thereof. Polymers useful in this regard include polylactide, polylactide-glycolide, cyclodextrin, polyacrylate, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydrides, polylactams, polyvinylpyrrolidone, polysaccharides (dextran, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). One skilled in the art will appreciate that by selecting an appropriate polymer, the delivery efficiency of the composition and/or the stability of the dispersion can be adjusted to optimize the effectiveness of the anti-arrhythmic agent.

For solutions, the composition may comprise one or more osmolality adjusting agents, such as sodium chloride. For example, sodium chloride may be added to the solution to adjust the osmolality of the solution. In one or more embodiments, the aqueous composition consists essentially of the antiarrhythmic agent, the osmolality adjusting agent, and water.

The solution may also contain a buffer or pH adjuster, typically a salt prepared from an organic acid or base. Representative buffers include organic acid salts of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid, tris (hydroxymethyl) aminomethane, tromethamine hydrochloride or phosphate buffers. Thus, buffers include citrate, phosphate, phthalate and lactate.

In addition to the above pharmaceutically acceptable excipients, it may be desirable to add other pharmaceutically acceptable excipients to the pharmaceutical composition to improve rigidity, yield, evacuation rate and deposition, shelf life and patient acceptance of the particles. These optional pharmaceutically acceptable excipients include, but are not limited to: colorants, taste masking agents, buffers, moisture absorbers, antioxidants, and chemical stabilizers. In addition, various pharmaceutically acceptable excipients may be used to provide structure and form to the particulate composition (e.g., latex particles). In this regard, it should be understood that post-production techniques such as selective solvent extraction may be used to remove the hardening components.

The pharmaceutical composition of one or more embodiments of the present invention may lack taste. In this regard, although a taste-masking agent is optionally included in the composition, the composition typically does not include a taste-masking agent and lacks taste even without a taste-masking agent.

The pharmaceutical composition may also comprise a mixture of pharmaceutically acceptable excipients. For example, mixtures of carbohydrates and amino acids are within the scope of the invention.

The compositions of one or more embodiments of the present invention may take various forms, such as solutions, dry powders, reconstituted powders, suspensions, or dispersions containing a non-aqueous phase such as a propellant (e.g., chlorofluorocarbons, hydrofluoroalkanes).

The solutions of the invention are generally transparent. In this regard, many of the antiarrhythmic agents of the present invention are water soluble.

In some embodiments, the isotonicity of the solution is isotonic to physiological isotonicity. Physiological isotonicity is the isotonicity of physiological fluids.

The pH of the composition is typically from 3.5 to 8.0, for example from 4.0 to 7.5, or from 4.5 to 7.0, or from 5.0 to 6.5.

For dry powders, the moisture content is typically less than about 15 wt%, such as less than about 10 wt%, less than about 5 wt%, less than about 2 wt%, less than about 1 wt%, or less than about 0.5 wt%. Such powders are described in WO 95/24183, WO96/32149, WO99/16419, WO 99/16420 and WO 99/16422, the entire contents of which are incorporated herein by reference.

In one form, the pharmaceutical composition comprises an antiarrhythmic agent incorporated in a phospholipid matrix. The pharmaceutical composition may comprise a phospholipid matrix incorporating the active agent and being in the form of particles having a hollow and/or porous microstructure, as described in the above-mentioned WO99/16419, WO 99/16420, WO 99/16422, WO 01/85136 and WO01/85137, the entire contents of which are incorporated herein by reference. The hollow and/or porous microstructures can be used to deliver an antiarrhythmic agent to the lungs because of their density, size, and aerodynamic properties that facilitate delivery into the deep lungs during inhalation by the user. In addition, the phospholipid-based hollow and/or porous microstructure reduces the attractive forces between the particles, makes the pharmaceutical composition more susceptible to deagglomeration during aerosolization and improves the flowability of the pharmaceutical composition, making it easier to process.

In one form, the pharmaceutical composition is formulated with a bulk density of less than about 1.0g/cm³Less than about 0.5g/cm³Less than about 0.3g/cm³Less than about 0.2g/cm³Or less than about 0.1g/cm³A hollow and/or porous microstructure. By providing particles or granules of low bulk density, the minimum mass of powder that can be filled into a unit dose container is reduced, thereby eliminating the need for carrier particles. That is, the relatively low density of the powder of one or more embodiments of the present invention provides for reproducible administration of relatively low doses of the pharmaceutical compound. In addition, eliminating carrier particles would potentially reduce laryngeal deposition and any "vomiting" effect or coughing, as large carrier particles, such as lactose particles, can affect the larynx and upper respiratory tract due to their size.

In some aspects, the present invention relates to particles of high roughness. For example, the particles may have a roughness of greater than 2, such as greater than 3 or greater than 4, and the roughness may be in the range of 2 to 15, such as 3 to 10.

In one form, the pharmaceutical composition is in dry powder form and is contained in a unit dose vessel that can be inserted into or near an aerosolization device to aerosolize a unit dose of the pharmaceutical composition. This form is useful in that the dry powder form can be stably stored in its unit dose vessel for long periods of time. In some examples, the pharmaceutical compositions of one or more embodiments of the present invention may be stable for at least 2 years. In some forms, stability is achieved without refrigeration. In other forms, reduced temperatures, such as 2-8 ℃, may be used to extend stable storage. In many forms, storage stability allows aerosolization using an external power source.

It is to be understood that the pharmaceutical compositions disclosed herein may comprise a structural matrix exhibiting, defining, or comprising voids, pores, imperfections, hollows, spaces, interstices, voids, pores, perforations, or pores. The absolute shape (as opposed to morphology) of the apertured microstructures is generally not critical, and any overall configuration that provides the desired characteristics is considered to be within the scope of the present invention. Thus, some embodiments include an approximately spherical shape. However, collapsed, deformed or broken particles are also compatible.

In one form, the antiarrhythmic agent is incorporated into a matrix that forms discrete particles, and the pharmaceutical composition comprises a plurality of discrete particles. The discrete particles may be sized such that they are effectively administered and/or such that they are available when needed. For example, for an aerosolizable pharmaceutical composition, the particles should be of a size such that the particles are capable of being aerosolized and delivered to the respiratory tract of a user during inhalation by the user.

The matrix material may comprise a hydrophobic material or a partially hydrophobic material. For example, the matrix material may include a lipid, such as a phospholipid, and/or a hydrophobic amino acid, such as leucine or trileucine. Examples of phospholipid matrices are described in WO99/16419, WO 99/16420, WO 99/16422, WO 01/85136 and WO01/85137, U.S. patent nos. 5,874,064, 5,855,913, 5,985,309, 6,503,480 and 7,473,433, and U.S. published application No. 20040156792, the entire contents of which are incorporated herein by reference. Examples of hydrophobic amino acid matrices are described in U.S. patent nos. 6,372,258, 6,358,530, and 7,473,433, the entire contents of which are incorporated herein by reference.

When phospholipids are used as matrix material, the pharmaceutical composition may further comprise multivalent cations, as disclosed in WO 01/85136 and WO01/85137, the entire contents of which are incorporated herein by reference.

According to another embodiment, the release kinetics of the composition comprising the antiarrhythmic agent is controlled. According to one or more embodiments, the compositions of the present invention provide immediate release of the antiarrhythmic agent. Alternatively, the compositions of other embodiments of the present invention may be provided as a heterogeneous mixture of active agent incorporated into a matrix material and non-incorporated active agent to provide a desired release rate of the antiarrhythmic agent. According to this embodiment, the antiarrhythmic agents formulated using the emulsion-based manufacturing process of one or more embodiments of the present invention may be used for immediate release applications when administered to the respiratory tract. Rapid release is facilitated by: (a) high specific surface area of low density porous powder; (b) the small volume of drug crystals incorporated therein; and (c) low surface energy of the particles.

Alternatively, it may be desirable to engineer the particulate matrix to achieve extended release of the active agent. This may be particularly desirable when the active agent is rapidly cleared from the lung or sustained release is desired. For example, the nature of the phase behavior of phospholipid molecules is influenced by their chemical structure properties and/or the preparation method in the spray-drying raw material as well as the drying conditions and other composition components used. In the case of spray drying of active agents dissolved in small unilamellar liposomes (SUVs) or Multilamellar Liposomes (MLVs), the active agent is encapsulated in multiple bilayers and released over an extended period of time.

In contrast, according to the teachings herein, spray drying of a feedstock consisting of emulsion droplets and dispersed or dissolved active agent results in a phospholipid matrix with less remote order, thereby facilitating rapid release. While not being bound by any particular theory, it is believed that this is due in part to the fact that: the active agent is never formally encapsulated in the phospholipid, and the phospholipid is initially present as a monolayer (rather than a bilayer as in the case of liposomes) on the surface of the emulsion droplets. The spray-dried particles prepared by the emulsion-based manufacturing process of one or more embodiments of the present invention generally have a high degree of disorder. Also, spray dried particles typically have a low surface energy, where it is observed that this value for spray dried DSPC particles can be as low as 20mN/m (as determined by reverse phase gas chromatography). Small angle X-ray scattering (SAXS) studies with spray-dried phospholipid particles also showed high disorder, scattering peak dispersion, length scale extending in some cases only beyond a few nearest neighbors.

It should be noted that a matrix with a higher gel-to-liquid crystal phase transition temperature is not sufficient by itself to achieve sustained release of the active agent. For bilayer structures, it is also important to have sufficient order to achieve sustained release. To facilitate rapid release, emulsion systems with high porosity (high surface area) and minimal interaction between the drug and the phospholipid may be used. It is also contemplated that the pharmaceutical composition formation process may also include the addition of other composition components (e.g., small polymers such as Pluronic F-68; carbohydrates, salts, hydrotropes) to disrupt the bilayer structure.

To achieve sustained release, incorporation of phospholipids in bilayer form, particularly where the active agent is encapsulated, can be used. In this case, T of phospholipid is increased_mBenefits may be provided by the incorporation of a divalent counterion or cholesterol. Similarly, increasing the interaction between phospholipid and drug by forming ion pairs (negatively charged agent + stearylamine, positively charged agent + phosphatidylglycerol) tends to decrease the dissolution rate. If the active agent is amphiphilic, the surfactant/surfactant interaction may also slow the dissolution of the active.

Addition of a divalent counterion (e.g., calcium or magnesium) to long-chain saturated phosphatidylcholine results in negatively charged phosphorus for the zwitterionic head groupThe interaction between the acid radical and the positively charged metal ion. This results in displacement of the water of hydration and compression of the packing of the phospholipid lipid head group and acyl chain. Furthermore, this results in an increase in the Tm of the phospholipid. The reduction in head-based hydration can have a profound effect on the spreading properties of spray-dried phospholipid particles when contacted with water. A fully hydrated phosphatidylcholine molecule will diffuse very slowly into dispersed crystals by diffusion of the molecule in the aqueous phase. This process is extremely slow because the solubility of phospholipids in water is very low (DPPC solubility is about 10)^-10mol/L). Prior art attempts to overcome this phenomenon include homogenizing the crystals in the presence of phospholipids. In this case, the high shear and radius of curvature of the homogenized crystals favours the coating of the phospholipid on the crystals. In contrast, "dry" phospholipid powders according to one or more embodiments of the invention can rapidly spread when in contact with water, thereby encapsulating the dispersed crystals without the application of high energy.

For example, upon reconstitution, the surface tension of the spray-dried DSPC/Ca mixture at the air/water interface decreased to an equilibrium value (about 20mN/m) as fast as measurements could be made. In contrast, the surface tension of liposomes of DSPC decreases very little over a period of hours (about 50mN/m), and this decrease is most likely due to the presence of hydrolytic degradation products (e.g. free fatty acids) in the phospholipids. Single tail fatty acids diffuse to the air/water interface faster than the hydrophobic parent compound. Thus, the addition of calcium ions to phosphatidylcholine can facilitate more rapid encapsulation of crystalline drugs with less energy applied.

In another form, the pharmaceutical composition comprises low density particles obtained by co-spray drying nanocrystals with an aqueous emulsion of a perfluorocarbon. The nanocrystals can be formed by precipitation and can, for example, range in size from about 45 μm to about 80 μm. Examples of perfluorocarbons include, but are not limited to, perfluorohexane, perfluorooctylbromide, perfluorooctylethane, perfluorodecalin, perfluorobutylethane.

In accordance with the teachings herein, the particles may be provided in a "dry" state. That is, in one or more embodiments, the particles will have a moisture content that keeps the powder chemically and physically stable and dispersible during storage at ambient or reduced temperatures. In this regard, the primary particle size, content, purity, and aerodynamic particle size distribution are hardly or not changed at all.

Thus, the moisture content of the particles is typically less than about 10 wt%, such as less than about 6 wt%, less than about 3 wt%, or less than about 1 wt%. The moisture content is determined at least in part by the composition and is controlled by the process conditions employed, such as inlet temperature, feed concentration, pumping rate and blowing agent type, concentration and post-drying. The reduction in bound water results in a significant improvement in the dispersibility and flowability of the phospholipid-based powder, resulting in the potential for efficient delivery of powdered lung surfactant or particulate compositions comprising an active agent dispersed in a phospholipid. The improved dispersion allows simple passive DPI devices to deliver these powders efficiently.

Another form of drug composition includes a particle composition that may contain, or be partially or completely coated with, a charged species that extends the residence time at the point of contact or enhances permeation through the mucosa. For example, anionic charges are known to favor mucoadhesion, while cationic charges can be used to associate the formed particles with negatively charged bioactive agents, such as genetic material. The charge may be imparted by association or combination of polyanionic or polycationic materials such as polyacrylic acid, polylysine, polylactic acid, and chitosan.

In some forms, the pharmaceutical composition comprises particles having a mass median diameter of less than about 20 μm, for example less than about 10 μm, less than about 7 μm, or less than about 5 μm. The particles may have a mass median aerodynamic diameter of from about 1 μm to about 6 μm, for example from about 1.5 μm to about 5 μm or from about 2 μm to about 4 μm. If the particles are too large, a large fraction of the particles may not reach the lungs. If the particles are too small, a large portion of the particles may be exhaled.

A unit dose of the pharmaceutical composition may be placed in the container. Examples of containers include, but are not limited to, syringes, capsules, blow-fill containers (blister's), blisters, vials, ampoules, or container closure systems made of metal, polymers (e.g., plastics, elastomers), glass, and the like. For example, the vial may be a colorless type I borosilicate glass ISO 6R 10mL vial with a neoprene siliconized stopper and a tear-off aluminum cap with a colored plastic cover.

The container may be inserted into the aerosolization device. The container may be of a suitable shape, size and material to contain the pharmaceutical composition and provide the pharmaceutical composition in a usable state. For example, a capsule or blister may comprise a wall comprising a material that does not adversely react with the pharmaceutical composition. In addition, the wall may include a material that allows the capsule to be opened to allow the pharmaceutical composition to be aerosolized. In one form, the wall comprises one or more of gelatin, Hydroxypropylmethylcellulose (HPMC), polyethylene glycol complexed HPMC, hydroxypropylcellulose, agar, aluminum foil, and the like. In one form, the capsule may include telescopically adjoined portions, such as described in U.S. Pat. No. 4,247,066, the entire contents of which are incorporated herein by reference. The size of the capsule may be selected to adequately contain the dosage of the pharmaceutical composition. Sizes are typically # 5 to # 000, outer diameters from about 4.91mm to 9.97mm, heights from about 11.10mm to about 26.14mm, and volumes from about 0.13mL to about 1.37 mL. Suitable capsules are commercially available from Capsugel, e.g., Shionogi qualicates co, Nara, Japan and Greenwood, s.c. After filling, the top can be placed over the bottom to form a capsule shape and the powder contained in the capsule as described in U.S. patent nos. 4,846,876 and 6,357,490 and WO 00/07572, the entire contents of which are incorporated herein by reference. After placing the top over the bottom, the capsules may optionally be bundled.

For solutions, the amount of the composition per unit dose is typically from about 0.5ml to about 15ml, for example from about 2ml to about 15ml, from about 3ml to about 10ml, from about 4ml to about 8ml or from about 5ml to about 6 ml.

The compositions of the present invention may be prepared by any of a variety of methods and techniques known and available to those of skill in the art.

For example, the following procedure may be used to prepare solutions of the antiarrhythmic agents. Typically, the manufacturing equipment is sterilized prior to use. A portion of the final volume (e.g., 70%) of the solvent (e.g., water for injection) may be added to a suitable container. An antiarrhythmic agent may then be added. The antiarrhythmic agent may be mixed until dissolved. Additional solvent may be added to make up the final batch volume. The batch may be filtered, for example, through a 0.2 μm filter into a sterile receiving reservoir. The fill assembly may be sterilized and then used to fill batches into vials (e.g., 10ml vials).

As an example, the sterilization described above may include the following. The 5 liter type 1 glass bottles and caps can be placed in an autoclave bag and sterilized using an autoclave at elevated temperatures, e.g., 121 ℃, for 15 minutes. Similarly, vials may be placed on suitable racks, inserted into autoclave bags, and sterilized using an autoclave at elevated temperatures, e.g., 121 ℃, for 15 minutes. Similarly also, the stoppers may be placed in an autoclave bag and sterilized using an autoclave at elevated temperature, e.g. 121 ℃, for 15 minutes. Prior to sterilization, a sterilizing filter may be connected to a line, for example a 2mm long 7mm x 13mm silica gel line. The fill line may be prepared by placing the fill line into an autoclave bag and sterilizing using an autoclave at an elevated temperature, e.g., 121 ℃, for 15 minutes.

The filtering may involve filtering into a laminar flow work zone. The receiver flask and filter may be disposed in a laminar flow work zone.

The filling can also be carried out under laminar flow protection. The fill line can be opened and placed into a receiving bottle. The sterile vial and stopper may be opened under laminar flow protection. Each vial may be filled to a target fill level of, for example, 5g and stoppered. An inversion collar may be applied to each vial. The sealed vials can be checked for vial leakage, proper tip seals, and cracks.

In some cases, the antiarrhythmic agent may be in solution. In a particular example, the solution is an aqueous solution. In other examples, the anti-arrhythmic agent may be present in a concentration of about 1mg/mL to about 60mg/mL, e.g., 1mg/mL to 5mg/mL, 1mg/mL to 10mg/mL, 1mg/mL to 15mg/mL, 1mg/mL to 20mg/mL, 1mg/mL to 25mg/mL, 1mg/mL to 30mg/mL, 1mg/mL to 35mg/mL, 1mg/mL to 40mg/mL, 1mg/mL to 45mg/mL, 1mg/mL to 50mg/mL, 1mg/mL to 55mg/mL, 5mg/mL to 10mg/mL, 5mg/mL to 15mg/mL, 5mg/mL to 20mg/mL, 5mg/mL to 25mg/mL, 5mg/mL to 30mg/mL, or, 5mg/mL to 35mg/mL, 5mg/mL to 40mg/mL, 5mg/mL to 45mg/mL, 5mg/mL to 50mg/mL, 5mg/mL to 55mg/mL, 5mg/mL to 60mg/mL, 10mg/mL to 15mg/mL, 10mg/mL to 20mg/mL, 10mg/mL to 25mg/mL, 10mg/mL to 30mg/mL, 10mg/mL to 35mg/mL, 10mg/mL to 40mg/mL, 10mg/mL to 45mg/mL, 10mg/mL to 50mg/mL, 10mg/mL to 55mg/mL, 10mg/mL to 60mg/mL, 15mg/mL to 20mg/mL, 15mg/mL to 25mg/mL, 15mg/mL to 30mg/mL, or, 15mg/mL to 35mg/mL, 15mg/mL to 40mg/mL, 15mg/mL to 45mg/mL, 15mg/mL to 50mg/mL, 15mg/mL to 55mg/mL, 15mg/mL to 60mg/mL, 20mg/mL to 25mg/mL, 20mg/mL to 30mg/mL, 20mg/mL to 35mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 45mg/mL, 20mg/mL to 50mg/mL, 20mg/mL to 55mg/mL, 20mg/mL to 60mg/mL, 25mg/mL to 30mg/mL, 25mg/mL to 35mg/mL, 25mg/mL to 40mg/mL, 25mg/mL to 45mg/mL, 25mg/mL to 50mg/mL, 25mg/mL to 55mg/mL, 25mg/mL to 60mg/mL, 30mg/mL to 35mg/mL, 30mg/mL to 40mg/mL, 30mg/mL to 45mg/mL, 30mg/mL to 50mg/mL, 30mg/mL to 55mg/mL, 30mg/mL to 60mg/mL, 35mg/mL to 40mg/mL, 35mg/mL to 45mg/mL, 35mg/mL to 50mg/mL, 35mg/mL to 55mg/mL, 35mg/mL to 60mg/mL, 40mg/mL to 45mg/mL, 40mg/mL to 50mg/mL, 40mg/mL to 60mg/mL, 45mg/mL to 50mg/mL, 45mg/mL to 55mg/mL, or, 45mg/mL to 60mg/mL, 50mg/mL to 55mg/mL, 50mg/mL to 60mg/mL, or 55mg/mL to 60 mg/mL. In other embodiments, the antiarrhythmic agent is present at about 30mg/mL, 31mg/mL, 32mg/mL, 33mg/mL, 34mg/mL, 35mg/mL, 36mg/mL, 37mg/mL, 38mg/mL, 39mg/mL, 40mg/mL, 41mg/mL, 42mg/mL, 43mg/mL, 44mg/mL, 45mg/mL, 46mg/mL, 47mg/mL, 48mg/mL, 49mg/mL, 50mg/mL, 51mg/mL, 52mg/mL, 53mg/mL, 54mg/mL, or 55 mg/mL.

As another example, an antiarrhythmic drug may be prepared by lyophilizing the antiarrhythmic drug to form a powder for storage. The powder is then reconstituted prior to use. This technique can be used when the antiarrhythmic agent is unstable in solution.

In some cases, the lyophilized powder can be reconstituted in a suitable solvent such that the anti-arrhythmic agent is present in a concentration of about 1mg/mL to about 60mg/mL, e.g., 1mg/mL to 5mg/mL, 1mg/mL to 10mg/mL, 1mg/mL to 15mg/mL, 1mg/mL to 20mg/mL, 1mg/mL to 25mg/mL, 1mg/mL to 30mg/mL, 1mg/mL to 35mg/mL, 1mg/mL to 40mg/mL, 1mg/mL to 45mg/mL, 1mg/mL to 50mg/mL, 1mg/mL to 55mg/mL, 5mg/mL to 10mg/mL, 5mg/mL to 15mg/mL, 5mg/mL to 20mg/mL, 5mg/mL to 25mg/mL, or, 5mg/mL to 30mg/mL, 5mg/mL to 35mg/mL, 5mg/mL to 40mg/mL, 5mg/mL to 45mg/mL, 5mg/mL to 50mg/mL, 5mg/mL to 55mg/mL, 5mg/mL to 60mg/mL, 10mg/mL to 15mg/mL, 10mg/mL to 20mg/mL, 10mg/mL to 25mg/mL, 10mg/mL to 30mg/mL, 10mg/mL to 35mg/mL, 10mg/mL to 40mg/mL, 10mg/mL to 45mg/mL, 10mg/mL to 50mg/mL, 10mg/mL to 55mg/mL, 10mg/mL to 60mg/mL, 15mg/mL to 20mg/mL, 15mg/mL to 25mg/mL, or, 15mg/mL to 30mg/mL, 15mg/mL to 35mg/mL, 15mg/mL to 40mg/mL, 15mg/mL to 45mg/mL, 15mg/mL to 50mg/mL, 15mg/mL to 55mg/mL, 15mg/mL to 60mg/mL, 20mg/mL to 25mg/mL, 20mg/mL to 30mg/mL, 20mg/mL to 35mg/mL, 20mg/mL to 40mg/mL, 20mg/mL to 45mg/mL, 20mg/mL to 50mg/mL, 20mg/mL to 55mg/mL, 20mg/mL to 60mg/mL, 25mg/mL to 30mg/mL, 25mg/mL to 35mg/mL, 25mg/mL to 40mg/mL, 25mg/mL to 45mg/mL, 25mg/mL to 50mg/mL, 25mg/mL to 55mg/mL, 25mg/mL to 60mg/mL, 30mg/mL to 35mg/mL, 30mg/mL to 40mg/mL, 30mg/mL to 45mg/mL, 30mg/mL to 50mg/mL, 30mg/mL to 55mg/mL, 30mg/mL to 60mg/mL, 35mg/mL to 40mg/mL, 35mg/mL to 45mg/mL, 35mg/mL to 50mg/mL, 35mg/mL to 55mg/mL, 35mg/mL to 60mg/mL, 40mg/mL to 45mg/mL, 40mg/mL to 50mg/mL, 40mg/mL to 55mg/mL, 40mg/mL to 60mg/mL, 45mg/mL to 50mg/mL, or, 45mg/mL to 55mg/mL, 45mg/mL to 60mg/mL, 50mg/mL to 55mg/mL, 50mg/mL to 60mg/mL, or 55mg/mL to 60 mg/mL. In other embodiments, the anti-arrhythmic agent is present at about 30mg/mL, 31mg/mL, 32mg/mL, 33mg/mL, 34mg/mL, 35mg/mL, 36mg/mL, 37mg/mL, 38mg/mL, 39mg/mL, 40mg/mL, 41mg/mL, 42mg/mL, 43mg/mL, 44mg/mL, 45mg/mL, 46mg/mL, 47mg/mL, 48mg/mL, 49mg/mL, 50mg/mL, 51mg/mL, 52mg/mL, 53mg/mL, 54mg/mL, or 55mg/mL after reconstitution of the lyophilized powder.

The solvent for the solution to be lyophilized may include water. The solution may be excipient free. For example, the solution may be free of cryoprotectants.

In one or more embodiments, an appropriate amount of drug substance (e.g., 120g per liter of final solution) can be dissolved in, for example, about 75% of the theoretical total amount of water for injection under nitrogen sparging. The dissolution time can be recorded and the appearance can be assessed.

Dilution to the final volume can then be performed with WFI. The final volume can be checked. Density, pH, endotoxin, bioburden and content can be measured by UV before and after sterile filtration.

The solution may be filtered prior to lyophilization. For example, 0.22 μm filtration may be performed twice before filling. The integrity and bubble point of the filter can be tested before and after filtration.

The pre-washed and autoclaved vials can be aseptically filled to a target volume of 5ml per vial using an automated filling line and then partially stoppered. In the process, the fill volume can be checked by checking the fill weight every 15 minutes.

Lyophilization is typically performed within about 72 hours, e.g., within about 8 hours or within about 4 hours, after dissolution.

In one or more embodiments, lyophilization comprises freezing the solution to form a frozen solution. The frozen solution is typically maintained at an initial temperature in the range of about-40 ℃ to about-50 ℃, such as about-45 ℃. The pressure surrounding the frozen solution during the initial temperature period is typically atmospheric pressure. The initial temperature period is typically in the range of about 1 hour to about 4 hours, for example about 1.5 hours to about 3 hours, or about 2 hours.

Lyophilization may further include increasing the temperature of the frozen solution to a first predetermined temperature, which may be in the range of about 10 ℃ to about 20 ℃, for example about 15 ℃. The ramp time from the initial temperature to the first predetermined temperature is generally in the range of about 6 hours to about 10 hours, for example about 7 hours to about 9 hours.

In the first predetermined temperature period, the pressure around the solution is typically in the range of about 100 μ bar to about 250 μ bar, for example about 150 μ bar to about 225 μ bar. The solution may be maintained at the first predetermined temperature for a period in the range of about 20 hours to about 30 hours, for example about 24 hours.

Lyophilization may also include raising the temperature of the solution to a second predetermined temperature, which may be in the range of about 25 ℃ to about 35 ℃, e.g., about 30 ℃. In the second predetermined temperature period, the pressure around the frozen solution is typically in the range of about 100 μ bar to about 250 μ bar, for example about 150 μ bar to about 225 μ bar. The solution may be held at the second predetermined temperature for a period of time ranging from about 10 hours to about 20 hours.

In view of the above, the lyophilization cycle may include a temperature reduction, e.g., from 20 ℃ to-45 ℃ over 65 minutes, followed by a freeze soak, e.g., at-45 ℃ for 2 hours. Primary drying may be accomplished by raising the temperature from-45 ℃ to 15 ℃ for example within 8 hours and subsequently maintaining the temperature at e.g. 15 ℃ for 24 hours, for example under a pressure of 200 μ bar. The secondary drying can be accomplished by, for example, warming from 15 ℃ to 30 ℃ over 15 minutes and then holding at 30 ℃ for 15 hours under a pressure of 200 μ bar. At the end of the lyophilization cycle, the vacuum may be broken with sterile nitrogen and the vial may be automatically stoppered.

The water content of the lyophilized powder is typically less than about 7 wt%, e.g., less than about 5 wt%, less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, or less than about 1 wt%.

The powder is capable of being reconstituted with water in less than about 60 seconds, such as less than about 30 seconds, less than about 15 seconds, or less than about 10 seconds, at 25 ℃ and 1.0 atmosphere with manual agitation.

Powders generally have a large specific surface area which facilitates reconstitution. The specific surface area is usually about 5m²G to about 20m²G, e.g. about 8m²G to 15m²In the range of/g or about 10m²G to 12m²/g。

Upon reconstitution with water, the pH of the antiarrhythmic agent solution is typically from about 2.5 to about 7, for example from about 3 to about 6.

For dry powders, the composition can be formed by spray drying, lyophilization, milling (e.g., wet milling, dry milling), and the like.

In spray drying, the formulation or starting material to be spray dried may be any solution, coarse suspension, slurry, colloidal dispersion or paste that can be atomized using the selected spray drying equipment. In the case of insoluble reagents, the starting material may comprise a suspension as described above. Alternatively, a dilute solution and/or one or more solvents may be used in the starting material. In one or more embodiments, the feedstock will comprise a colloidal system, such as an emulsion, an inverse emulsion microemulsion, a multiple emulsion, a particle dispersion, or a slurry.

In one form, the antiarrhythmic agent and the matrix material are added to the aqueous feedstock to form a feedstock solution, suspension, or emulsion. The feedstock is then spray dried to produce dried particles comprising the matrix material and the antiarrhythmic agent. Suitable spray drying methods are known in the art, for example, as disclosed in WO99/16419 and U.S. patent nos. 6,077,543, 6,051,256, 6,001,336, 5,985,248, and 5,976,574, the entire contents of which are incorporated herein by reference.

Regardless of the components selected, the first step in the production of the particles generally involves the preparation of the starting materials. If the phospholipid-based particles are intended to be used as a carrier for an antiarrhythmic agent, the selected active agent may be introduced into a liquid, such as water, to produce a concentrated suspension. The concentration of the antiarrhythmic agent and optional active agent is typically dependent on the amount of agent desired in the final powder and the properties of the delivery device used (e.g., fine particle dose of a Metered Dose Inhaler (MDI) or Dry Powder Inhaler (DPI)).

Any other active agent may be incorporated into a single raw material formulation and spray dried to provide a single pharmaceutical composition species comprising multiple active agents. Conversely, individual active agents may be added to separate starting materials and separately spray dried to provide multiple pharmaceutical composition classes having different compositions. These individual substances may be added to the suspension medium or dry powder dispensing chamber in any desired ratio and placed in an aerosol delivery system as described below.

The multivalent cation may be combined with the antiarrhythmic agent suspension, with the phospholipid emulsion, or with the oil-in-water emulsion formed in a separate reservoir. The antiarrhythmic agent may also be dispersed directly in the emulsion.

For example, the multivalent cations and phospholipids may be homogenized for 2 to 5 minutes in hot distilled water (e.g., 70 ℃) at 8000rpm using a suitable high shear mechanical mixer (e.g., an Ultra-Turrax T-25 type mixer). Typically, 5 to 25g of the fluorocarbon is added dropwise to the dispersed surfactant solution while mixing. The resulting emulsion of the perfluorocarbon containing multivalent cations in water may then be treated using a high pressure homogenizer to reduce the particle size. Typically, the emulsion is treated in five discrete runs at 12,000 to 18,000PSI and maintained at about 50 ℃ to about 80 ℃.

When multivalent cations are combined with oil-in-water emulsions, the dispersion stability and dispersibility of spray-dried pharmaceutical compositions can be improved by the use of a foaming agent, as described in WO99/16419, the entire contents of which are incorporated herein by reference. The process forms an emulsion, optionally stabilized by an incorporated surfactant, typically comprising submicron droplets of a water-immiscible blowing agent dispersed in an aqueous continuous phase. The blowing agent may be a fluorinated compound (e.g., perfluorohexane, perfluorooctylbromide, perfluorooctylethane, perfluorodecalin, perfluorobutylethane) that evaporates during spray drying leaving aerodynamic light particles that are typically hollow and porous. Other suitable liquid blowing agents include non-fluorinated oils, chloroform, and mixtures thereof,

Fluorocarbon, ethyl acetate, alcohol, hydrocarbon, nitrogen, and carbon dioxide gas. The foaming agent may be emulsified with a phospholipid.

Although a foaming agent as described above may be used to form the pharmaceutical composition, it is to be understood that in some cases, no additional foaming agent is required and the aqueous dispersion of the antiarrhythmic agent and/or pharmaceutically acceptable excipients and surfactants is spray dried directly. In such cases, the pharmaceutical composition may have certain physicochemical properties (e.g., high crystallinity, elevated melting temperature, surface activity, etc.) that make it particularly suitable for use in such techniques.

A co-surfactant such as poloxamer 188 or span 80 can be dispersed into the additional solution as desired. In addition, pharmaceutically acceptable excipients, such as sugars and starches, may also be added.

The feedstock may then be fed into a spray dryer. Typically, the feedstock is sprayed into a stream of filtered warm air which evaporates the solvent and transports the dried product to a collector. The waste air is then exhausted with the solvent. Commercial spray dryers manufactured by Buchi ltd. or Niro corp. can be modified for use in the production of pharmaceutical compositions. Examples of spray drying methods and systems suitable for making dry powders of one or more embodiments of the present invention are disclosed in U.S. patent nos. 6,077,543, 6,051,256, 6,001,336, 5,985,248, and 5,976,574, the entire contents of which are incorporated herein by reference.

The operating conditions of the spray dryer, such as inlet and outlet temperatures, feed rates, atomization pressure, flow rate of the drying air, and nozzle configuration, can be adjusted to produce the desired particle size and yield of the resulting dry particles. Selection of appropriate equipment and processing conditions is within the ability of the skilled artisan in light of the teachings herein, and can be accomplished without undue experimentation. An exemplary setup is as follows: a gas inlet temperature between about 60 ℃ to about 170 ℃; the gas outlet temperature is between about 40 ℃ and about 120 ℃; a feed rate of between about 3mL/min to about 15 mL/min; the suction flow is about 300L/min; and the atomization air flow rate is between about 25L/min to about 50L/min. Of course, the settings will vary depending on the type of equipment used. In any event, the use of these and similar methods allows the formation of aerodynamically light particles with diameters suitable for aerosol deposition into the lungs.

Hollow and/or porous microstructures may be formed by spray drying, as disclosed in WO99/16419, which is incorporated herein by reference. The spray drying process can result in the formation of a pharmaceutical composition comprising particles having relatively thin porous walls defining larger internal voids. Spray drying methods are also generally preferred over other methods because the formed particles are less likely to break during processing or during deagglomeration.

Alternatively, pharmaceutical compositions useful in one or more embodiments of the present invention may be formed by lyophilization. Lyophilization is a freeze-drying process in which water sublimes from a composition upon freezing. Lyophilization is commonly used because biologics and pharmaceuticals, which are relatively unstable in aqueous solution, can be dried without exposure to high temperatures and then stored in a dried state where stability is less of a problem. With respect to one or more embodiments of the present invention, such techniques are particularly suitable for incorporating peptides, proteins, genetic material, and other natural and synthetic macromolecules into pharmaceutical compositions without compromising physiological activity. The lyophilized cake containing the fine-bubble structure can be micronized using techniques known in the art to provide particles of the desired size.

The compositions of one or more embodiments of the present invention may be administered by inhalation.

Furthermore, because the inhaled composition is effectively targeted to the heart, the dose of inhaled composition is generally much less than that required to be administered by other routes and achieve a similar effect.

In one or more embodiments of the invention, a pharmaceutical composition comprising an antiarrhythmic agent is administered to the lungs of a patient in need thereof. For example, the patient may have been diagnosed with an arrhythmia. Examples of cardiac arrhythmias include, but are not limited to, tachycardia, supraventricular tachycardia (SVT), paroxysmal supraventricular tachycardia (PSVT), Atrial Fibrillation (AF), Paroxysmal Atrial Fibrillation (PAF), persistent atrial fibrillation, permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, and isolated atrial fibrillation.

Accordingly, the pharmaceutical compositions of one or more embodiments of the present invention may be used to treat and/or provide prophylaxis to a wide range of patients. A patient suitable for receiving treatment and/or prevention as described herein is any mammalian patient in need thereof, preferably the mammal is a human. Examples of patients include, but are not limited to, pediatric patients, adult patients, and geriatric patients. In some embodiments, the composition is intended only for treatment for rapid relief of symptoms and restoration of normal sinus rhythm, and not as a prophylactic, e.g., when the patient is healthy, no medication is required — this increases the benefit-risk ratio and overall safety of the treatment as occasional or intermittent dosing and focus only on reducing symptoms of discomfort and restoration of sinus rhythm when needed.

The necessary dosage and frequency of administration of the anti-arrhythmic agent depends on the composition of the composition and the concentration of the anti-arrhythmic agent. In some cases, the dose is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of its normal intravenous dose. In some cases, the dose is about 5% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 95% of the intravenous dose. The lung dose is similar to the intracardiac dose. Inhalation avoids dilution of the drug in vivo, as compared to intravenous or oral administration.

In some cases, an effective dose for intravenous administration can be calculated based on the weight of the subject. For example, in some cases, an effective dose for intravenous administration to a subject weighing 70kg is 2mg/kg (i.e., 140 mg).

Inhalation may also avoid metabolism, such as hepatic metabolism. For example, calcium channel blockers such as diltiazem undergo significant hepatic metabolism when administered orally. Inhalation allows rapid delivery of the diltiazem parent compound to the heart as a single dose (bolus). Surprisingly, administration of diltiazem by inhalation via the inhalation route according to the present invention reverts atrial fibrillation to normal sinus rhythm and reduces the heart rate. Thus, administration of diltiazem by inhalation is useful in the treatment of atrial fibrillation and supraventricular tachycardia (SVT). In contrast, IV administration of diltiazem is generally only used to convert SVT to normal sinus rhythm and is used for atrial fibrillation to reduce heart rate (not for conversion to normal sinus rhythm).

Inhalation also avoids red blood cell metabolism. For example, the reduced dilution and short-range associated with inhalation reduces the red blood cell metabolism of esmolol.

For example, IV administration of β receptor blockers such as esmolol may reduce mean arterial blood pressure (MAP.) inhalation allows for rapid delivery of esmolol without reducing MAP, thus inhalation of β receptor blockers may result in a MAP that is 10 to 20mm Hg higher than that produced by IV administration of the same β receptor blocker.

With inhaled cardiac therapy, the drug reaches the heart from the lungs in a single dose. Thus, high concentrations are visible at the heart. The drug is rapidly diluted as it passes through the heart, but the exposure time is sufficient to achieve the desired pharmacological effect. Once the drug passes through the heart, the concentration of the drug in the systemic circulation (e.g., peripheral venous blood) is below the therapeutic concentration and is considered ineffective. The therapeutic window is the range of drug doses or their concentration in the body system that provides a safe and effective treatment. Any amount below the minimum amount is sub-therapeutic and therefore not effective at this concentration. Unnecessary side effects are minimized in view of dilution.

In one form, the antiarrhythmic agent may be administered daily. In this form, the daily dose of the antiarrhythmic agent ranges from about 0.1mg to about 600mg, such as from about 0.5mg to about 500mg, from about 1mg to about 400mg, from about 2mg to about 300mg, and from about 3mg to about 200 mg. The amount of the antiarrhythmic agent for treating arrhythmia may be at least about 0.1mg, such as at least about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, or 500 mg. The amount of the antiarrhythmic agent for the treatment of arrhythmia may be in the range of about 0.01-500mg, e.g., about 0.1-500, 0.1-450, 0.1-400, 0.1-350, 0.1-300, 0.1-250, 0.1-200, 0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10, 0.1-5, 0.1-1.0, 0.1-0.5, 1-500, 1-450, 1-400, 1-350, 1-300, 1-250, 1-200, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30, 1-10, 1-5, 5-500, 5-450, 5-400, 5-350, 5-300, 5-250, 5-200, 5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-500, 10-450, 10-400, 10-350, 10-300, 10-250, 10-200, 10-150, 10-130, 10-110, 10-90, 10-70, 10-50, 10-30, 30-500, 30-450, 30-400, 30-350, 30-300, 30-250, 30-200, 30-150, 30-130, 30-110, 30-90, 30-70, 30-50, 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-130, 50-110, 50-90, 50-70, 70-500, 70-450, 70-400, 70-350, 70-300, 70-250, 70-200, 70-150, 70-130, 70-110, 70-90, 90-500, 90-450, 90-400, 90-350, 90-300, 90-250, 90-200, 90-150, 90-130, 90-110, 110-500, 110-450, 110-400, 110-350, 110-300, 110-250, 110-200, 110-150, 110-130, 130-500, 130-450, 130-400, 130-350, 130-300, 110-90, 90-90, 110-90, 110-500, 110-450, 110-400-350, 110-130-300, 110-300-90, 130-250, 130-200, 130-150, 150-500, 150-450, 150-400, 150-350, 150-300, 150-250, 150-200, 200-500, 200-450, 200-400, 200-350, 200-300, 200-250, 250-500, 250-450, 250-300, 300-400, 300-350, 350-500, 350-450, 400-400, 400-450 or 450-500 mg. For example, the amount of the antiarrhythmic agent used to treat arrhythmia may be in the range of about 0.1 to about 5 mg.

The dose may be administered during a single inhalation or may be administered during several inhalations. Fluctuations in the concentration of the anti-arrhythmic agent may be reduced by administering the pharmaceutical composition more frequently, or may be increased by administering the pharmaceutical composition less frequently. Thus, administration of the pharmaceutical compositions of one or more embodiments of the present invention may be from about four times daily to about monthly, e.g., from about daily to about biweekly, from about biweekly to about weekly, and about weekly. The pharmaceutical composition may also be administered to the patient as needed.

For treating a patient suffering from an arrhythmia, the amount of the anti-arrhythmic agent administered per dose may be an amount effective to treat the arrhythmia. The amount of the antiarrhythmic agent used for the treatment of arrhythmia will generally be higher than the amount of the antiarrhythmic agent used for the prophylaxis, and is generally about 0.001mg/kg to 6mg/kg, for example about 0.002mg/kg to about 5mg/kg or about 0.005mg/kg to about 4 mg/kg. In an exemplary treatment regimen, a formulation according to one or more embodiments of the present invention can be administered from about 1 to about 4 times daily, for example from about 2 to about 3 times daily. Typically, the dose of the antiarrhythmic agent delivered to the patient ranges from about 0.1mg to about 600mg per day, for example from about 0.2mg to 500mg per day, depending on the condition being treated, the age and weight of the patient, and the like.

In some cases, the amount of the antiarrhythmic agent for the treatment of arrhythmia may be at least about 0.001mg/kg, such as at least about 0.001mg/kg, 0.002mg/kg, 0.003mg/kg, 0.004mg/kg, 0.005mg/kg, 0.01mg/kg, 0.02mg/kg, 0.04mg/kg, 0.06mg/kg, 0.08mg/kg, 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg, 1.5mg/kg, 2mg/kg, 2.5mg/kg, 3mg/kg, 3.5mg/kg, 4mg/kg, 4.5mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 15mg/kg or 20 mg/kg. The amount of the antiarrhythmic agent for the treatment of arrhythmia may range from about 0.001mg/kg to 20mg/kg, such as from about 0.001mg/kg to about 0.01mg/kg, from about 0.01mg/kg to about 0.05mg/kg, from about 0.05mg/kg to about 0.1mg/kg, from about 0.1mg/kg to about 0.2mg/kg, from about 0.5mg/kg to about 0.1mg/kg to about 1mg/kg, from about 0.1mg/kg to about 2mg/kg, from about 0.1mg/kg to about 3mg/kg, from about 0.3mg/kg to about 1mg/kg, from about 0.3mg/kg to about 2mg/kg, from about 0.3mg/kg to about 3mg/kg, from about 0.5mg/kg to about 1mg/kg, from about 0.5mg/kg to about 2mg/kg, from about 0.5mg/kg to about 3mg/kg, About 0.5mg/kg to about 6mg/kg, about 0.7mg/kg to about 1mg/kg, about 0.7mg/kg to about 2mg/kg, about 0.7mg/kg to about 4mg/kg, about 0.7mg/kg to about 6mg/kg, about 1mg/kg to about 2mg/kg, about 1mg/kg to about 4mg/kg, about 1mg/kg to about 6mg/kg, about 1mg/kg to about 8mg/kg, about 1mg/kg to about 10mg/kg, about 1mg/kg to about 15mg/kg, about 1mg/kg to about 20mg/kg, about 2mg/kg to about 3mg/kg, about 2mg/kg to about 4mg/kg, about 2mg/kg to about 6mg/kg, about 2mg/kg to about 8mg/kg, about 2mg/kg to about 10mg/kg, About 2mg/kg to about 15mg/kg, about 2mg/kg to about 20mg/kg, about 3mg/kg to about 4mg/kg, about 3mg/kg to about 5mg/kg, about 3mg/kg to about 6mg/kg, about 3mg/kg to about 8mg/kg, about 3mg/kg to about 10mg/kg, about 3mg/kg to about 15mg/kg, about 3mg/kg to about 20mg/kg, about 4mg/kg to about 5mg/kg, about 4mg/kg to about 6mg/kg, about 4mg/kg to about 8mg/kg, about 4mg/kg to about 10mg/kg, about 4mg/kg to about 15mg/kg, about 4mg/kg to about 20mg/kg, about 6mg/kg to about 8mg/kg, about 6mg/kg to about 10mg/kg, About 6mg/kg to about 15mg/kg, about 6mg/kg to about 20mg/kg, about 8mg/kg to about 10mg/kg, about 8mg/kg to about 15mg/kg, about 8mg/kg to about 20mg/kg, about 10mg/kg to about 15mg/kg, about 10mg/kg to about 20mg/kg, or about 15mg/kg to about 20 mg/kg.

For example, if cardioversion does not occur after an initial inhalation, the present invention may include a subsequent inhalation. Typically, if cardioversion does not occur within 30 minutes after the initial inhalation, the subsequent dose should be higher or the same as the initial dose.

Administration may be guided by the patient's experience. Also or alternatively, administration may be guided by use of a portable/mobile ECG device. For example, administration may be guided by using a Holter monitor.

In another form, the pharmaceutical composition is administered prophylactically to a patient who may develop an arrhythmia. For example, a patient with a history of arrhythmia may be treated prophylactically with a pharmaceutical composition comprising an antiarrhythmic agent to reduce the likelihood of developing an arrhythmia.

The pharmaceutical composition can be administered to the patient in any regimen effective to prevent arrhythmia. An exemplary prophylactic regimen includes administration of an anti-arrhythmic agent described herein 1 to 21 times per week.

While not wishing to be bound by theory, by providing an antiarrhythmic agent according to one or more embodiments of the present invention, systemic exposure to the antiarrhythmic agent may be reduced by avoiding initial dilution. As noted above, antiarrhythmic drugs undergo dilution both during and after passage through the heart. Thus, administration of antiarrhythmic agents by inhalation is considered safer than intravenous delivery.

In another aspect, methods of administration include administration to a free-breathing patient by an aerosol generator device and/or system for administering aerosolized medicaments, such as those disclosed in U.S. published application nos. 20050235987, 20050211253, 20050211245, 20040035413, and 20040011358, the disclosures of which are incorporated herein by reference in their entirety.

In one form, the pharmaceutical composition may be delivered to the lungs of the patient in the form of a dry powder. Thus, the pharmaceutical composition comprises a dry powder that can be effectively delivered to the deep lung or another target site. The pharmaceutical composition is in the form of a dry powder comprising particles having a size selected to allow penetration into the alveoli. In one form, the pharmaceutical composition may be delivered by extruding a liquid through micron or submicron sized orifices, followed by breaking the Rayleigh into fine droplets.

In some cases, it is desirable to deliver a unit dose, e.g., 0.1mg or 100mg or greater, of the antiarrhythmic agent to the lungs by a single inhalation. The above-described hollow and/or porous dry powder particles of phospholipids allow a dose of about 5mg or more, usually greater than about 10mg, sometimes greater than about 15mg, sometimes greater than about 20mg, sometimes greater than about 25mg, and sometimes greater than about 30mg to be delivered by a single inhalation and in an advantageous manner. Alternatively, the dose may be delivered over two or more inhalations, e.g., 1 to 6, 1 to 5, or 1 to 4 inhalations. For example, a 10mg dose may be delivered by providing two unit doses of 5mg each, and the two unit doses may be inhaled separately. In certain embodiments, the total dose of the antiarrhythmic agent is in the range of 0.1mg to 200mg, such as 0.5mg to 150mg or 1mg to 100 mg.

In some cases, a dose may be delivered over two or more inhalations, e.g., at least 2, 3,4, 5,6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 inhalations. The dose may also be delivered via 1 to 100 inhalations, e.g., 1-3, 1-4, 1-5, 1-6, 1-10, 1-20, 1-50, 1-80, 1-100, 2-5, 2-6, 2-10, 2-20, 2-50, 2-100, 5-10, 5-20, 5-50, 5-100, 10-20, 10-50, 10-100, 20-50, 20-100, or 50-100 inhalations. For example, a 10mg dose may be delivered by providing two unit doses of 5mg each, and the two unit doses may be inhaled separately. In certain embodiments, the total dose of the antiarrhythmic agent is about 0.01-500mg, e.g., about 0.1-500, 0.1-450, 0.1-400, 0.1-350, 0.1-300, 0.1-250, 0.1-200, 0.1-150, 0.1-130, 0.1-110, 0.1-90, 0.1-70, 0.1-50, 0.1-30, 0.1-10, 0.1-5, 0.1-1.0, 0.1-0.5, 1-500, 1-450, 1-400, 1-350, 1-300, 1-250, 1-200, 1-150, 1-130, 1-110, 1-90, 1-70, 1-50, 1-30, 1-10, 1-5, 5-500, 5-450, 5-350, 5-450, 5-350, 5-300, 5-250, 5-200, 5-150, 5-130, 5-110, 5-90, 5-70, 5-50, 5-30, 5-10, 10-500, 10-450, 10-400, 10-350, 10-300, 10-250, 10-200, 10-150, 10-130, 10-110, 10-90, 10-70, 10-50, 10-30, 30-500, 30-450, 30-400, 30-350, 30-300, 30-250, 30-200, 30-150, 30-130, 30-110, 30-90, 30-70, 30-50, 50-500, 50-450, 50-400, 50-350, 50-300, 50-250, 50-200, 50-150, 50-130, 50-110, 50-90, 50-70, 70-500, 70-450, 70-400, 70-350, 70-300, 70-250, 70-200, 70-150, 70-130, 70-110, 70-90, 90-500, 90-450, 90-400, 90-350, 90-300, 90-250, 90-200, 90-150, 90-130, 90-110, 110-500, 110-450, 110-400, 110-350, 110-300, 110-250, 110-200, 110-150, 110-130-500, 130-450, 130-400, 130-350, 130-300, 130-250, 110-200, 110-150, 110-130-500, 130-450, 130-400, 130-350, 130-300, 130-250-130-250, 130-200, 130-150, 150-500, 150-450, 150-400, 150-350, 150-300, 150-250, 150-200, 200-500, 200-450, 200-400, 200-350, 200-300, 200-250, 250-500, 250-450, 250-400, 250-300, 300-500, 300-450, 300-400, 300-350, 350-500, 350-450, 350-400, 400-450 or 450-500 mg. For example, the amount of the antiarrhythmic agent used to treat arrhythmia may be in the range of about 0.1 to about 5 mg. In some cases, the antiarrhythmic agent may be administered as needed to titrate to an effective dose.

The administration time is usually short. For nebulizers, the administration time is typically 1 minute to 20 minutes, for example 2 minutes to 15 minutes or 3 minutes to 10 minutes. With respect to dry powders, the total administration time is typically less than about 1 minute for a single capsule. Thus, the administration time may be less than about 5 minutes, such as less than about 4 minutes, less than about 3 minutes, less than about 2 minutes, or less than about 1 minute.

In certain embodiments, the invention relates to a method of diagnosing and then treating atrial arrhythmias by a health care provider. In certain embodiments, the present invention relates to a method for self-diagnosing and treating atrial arrhythmias. The method includes diagnosing or self-diagnosing atrial arrhythmia by detecting at least one of tachypnea, palpitations, and a higher than normal heart rate. The method further comprises self-administering by inhalation an effective amount of at least one anti-arrhythmic agent within two hours of self-diagnosis, for example within 1 hour, 30 minutes or 15 minutes.

In certain embodiments, the patient may self-titrate. For example, the patient may self-administer, such as by using a nebulizer, until the discomfort symptoms disappear. In some cases, self-administration may continue until the patient no longer feels palpitations, or until the patient detects restoration of a normal sinus rhythm using a portable/mobile ECG device (which may be worn by the patient, such as a watch; or otherwise carried by the patient, such as a skin patch or an implantable device connected to a smart phone or watch).

The onset of action is also generally short. For example, the patient may have a normal sinus rhythm within 20 minutes of the beginning of administration, such as within 15 minutes, within 10 minutes, or within 5 minutes of the beginning of administration. A rapid onset is advantageous because the longer a patient is suffering from an arrhythmia, the longer it will typically take to convert the patient to a normal sinus rhythm.

In some embodiments, the methods of the invention allow a patient to avoid other therapies, such as ablation and/or electrical cardioversion. In other embodiments, the methods of the invention are used in combination with other therapies, such as before or after electrical cardioversion and/or ablation therapies.

The dispersion or powder pharmaceutical composition may be administered using an aerosolization device. The aerosolization device may be a nebulizer, a metered dose inhaler, a liquid dose instillation device, or a dry powder inhaler. Aerosolization devices can include extrusion of a drug formulation through micron or submicron-sized orifices, followed by break-up of Rayleigh into fine droplets. The pharmaceutical compositions may be delivered by a nebulizer as described in WO 99/16420, a metered dose inhaler as described in WO 99/16422, a liquid dose instillation device as described in WO 99/16421, and a dry powder inhaler as described in U.S. published application nos. 20020017295 and 20040105820, WO99/16419, WO 02/83220, and U.S. patent No. 6,546,929, the entire contents of which are incorporated herein by reference. Thus, the inhaler may comprise a canister containing particles or particles and propellant, and wherein the inhaler comprises a metering valve in communication with the interior of the canister. The propellant may be a hydrofluoroalkane.

The formulations of the present invention may be administered with a nebulizer to provide an administerable aerosolized drug to the pulmonary airways of a patient in need thereof, for example the nebulizer disclosed in PCT WO 99/16420, the disclosure of which is incorporated herein by reference in its entirety. Nebulizers are known in the art and can be readily used to administer the claimed formulations without undue experimentation. Breath activated or breath actuated nebulizers, as well as nebulizers containing other types of modifications that have been or will be developed, are also compatible with the formulations of the present invention and are considered to be within the scope of the present invention.

In some cases, the nebulizer is a breath activated or breath actuated nebulizer. In some cases, the nebulizer is a handheld inhaler device (e.g., a nebulizer kit)

II Breath Actuated Nebulizer (BAN)). In some cases, the atomizer has a source of compressed air. In some cases, nebulizers convert liquid drugs into aerosols. In some cases, nebulizers convert liquid drugs into aerosols by extruding the drug formulation through micron or submicron sized orifices. In some cases, nebulizers convert liquid drugs into aerosols, which can thus be inhaled into the lungs. In some cases, the nebulizer is a small volume nebulizer. In some cases, the nebulizer is a small volume jet nebulizer. In some cases, the aerosolized drug is only generated when inhaled through the device. In some cases, the drug is contained in a cup between breaths or during an interruption of treatment. In some cases, the medicament will be contained in a cup until ready for useIs well inhaled.

The nebulizer imparts energy to the liquid drug formulation to aerosolize the liquid and allow delivery to the pulmonary system, e.g., lungs, of the patient. Nebulizers include liquid delivery systems, such as containers having a reservoir that contains a liquid drug formulation. Liquid pharmaceutical formulations typically comprise the active agent in solution or suspended in a liquid medium.

In one type of nebulizer, commonly referred to as a jet nebulizer, a compressed gas is forced through an orifice in a container. The compressed gas forces the liquid to be pushed out through the nozzle, and the pushed out liquid is mixed with the flowing gas to form aerosol droplets. A cloud of droplets is then administered to the respiratory tract of the patient.

In another type of atomizer, commonly referred to as a vibrating mesh atomizer, energy, such as mechanical energy, vibrates a screen. This vibration of the screen aerosolizes the liquid drug formulation, thereby creating an aerosol cloud that is administered to the patient's lungs. In another type of atomizer, atomization involves extrusion through micron or sub-micron sized orifices, followed by Rayleigh breakup into fine droplets.

Alternatively or additionally, the pharmaceutical formulation may be in liquid form and may be aerosolized using an inhaler as described in WO 2004/071368, which is incorporated by reference herein in its entirety, and U.S. published application nos. 2004/0011358 and 2004/0035413, which are incorporated by reference herein in their entirety. Other examples of inhalers include, but are not limited to, those available from Aerogen Ltd

Go or

A Pro atomizer; PARI eFlow and other PARI nebulizers available from PARI Respiratory Equipment, inc.of Midlothian, Va.; available from Lumiscope Company, inc

An atomizer 6600 or 6610; and can be selected fromOmron NE-U22 available from Omron Healthcare, inc. Other examples of nebulizers include devices manufactured by Medspray (enspeed, The Netherlands).

It has been found that atomizers of the vibrating mesh type, e.g. atomizers which form droplets without the use of compressed gas, e.g.

Pro, provides unexpected improvements in dose efficiency and consistency. By using a vibrating perforated or unperforated membrane to produce fine droplets, rather than by introducing compressed air, the aerosolized drug formulation may be introduced without substantially affecting flow characteristics. In addition, when this type of atomizer is used, the droplets produced are introduced at a low velocity, thereby reducing the likelihood that the droplets will be driven to undesired areas. It has been found that when using an atomiser of the extrusion/Rayleigh jet break up type, the droplets produced are also introduced at a low velocity, thereby reducing the likelihood of the droplets being driven to undesired regions.

In some cases, the atomizer may be of the vibrating mesh type. In some cases, the atomizer may be of the pressurized spray type. In some cases, the atomizer may be of the extrusion/Rayleigh break-up type. In some cases, the nebulizer is light in weight (up to 60 grams, up to 100 grams, up to 200 grams, up to 250 grams) and nearly silent. In some cases, the sound level of the nebulizer at 1 meter is less than 35A-weighted decibels (dBA). In some cases, the nebulizer has a cup capacity of 6 mL. In some cases, the residual volume of the nebulizer is less than 0.3 mL. In some cases, the atomizer produced an average flow rate of 0.4 mL/min. In some cases, the atomizer produced an average flow rate of 0.5 mL/min. In some cases, the atomizer produced an average flow rate of 0.6 mL/min. In some cases, the atomizer produced an average flow rate of 0.7 mL/min. In some cases, the atomizer produced an average flow rate of 0.8 mL/min. In some cases, the atomizer produced an average flow rate of 0.9 mL/min. In some cases, the atomizer produced an average flow rate of 1.0 mL/min. In some cases, the atomizer produced an average flow rate of 1.1 mL/min. In some cases, the atomizer produced an average flow rate of 1.2 mL/min. In some cases, the atomizer produced an average particle size of 3.0 μm MMAD. In some cases, the atomizer produces an average particle size of between 3.0 μm MMAD and 4.0 μm MMAD. In some cases, the atomizer produced an average particle size of 3.0 μm MMAD. In some cases, the atomizer produces an average particle size of between 3.0 μm MMAD and 5.0 μm MMAD. In some cases, the atomizer produced an average particle size of 3.0 μm MMAD. In some cases, the atomizer produces an average particle size of between 3.0 μm MMAD and 6.0 μm MMAD.

In another type of nebulizer, ultrasound is generated to directly vibrate and aerosolize a pharmaceutical formulation.

As mentioned above, the present invention may also include a dry powder inhaler. Particular forms of dry powder aerosolization apparatus are described in U.S. Pat. nos. 4,069,819 and 4,995,385, the entire contents of which are incorporated herein by reference. Another useful device is described in U.S. patent No. 3,991,761, which is incorporated herein by reference in its entirety, having a chamber sized and shaped to receive a capsule such that the capsule is orthogonal to the direction of inhalation. U.S. Pat. No. 3,991,761 also describes a piercing mechanism that can pierce both ends of the capsule. In another form, the chamber may receive the capsule in a manner that air flows through the capsule, such as described in U.S. Pat. nos. 4,338,931 and 5,619,985, which are incorporated herein by reference in their entirety. In another form, aerosolization of the pharmaceutical composition can be accomplished by pressurized gas flowing through the inlet, such as described in U.S. patent nos. 5,458,135, 5,785,049, and 6,357,233; or by a propellant, as described in WO 00/72904 and U.S. patent No. 4,114,615, which are incorporated herein by reference. These types of dry powder inhalers are commonly referred to as active dry powder inhalers.

Other dry powder inhalers include those available from Boehringer Ingelheim (e.g., Respimat inhaler), Hovione (e.g., FlowCaps inhaler), plasitiape (e.g., Osmohaler inhaler), and MicroDose. The present invention may also utilize a condensation aerosol device available from Alexza, Mountain View, calif. Another useful inhaler is disclosed in WO 2008/051621, the entire content of which is incorporated herein by reference.

The pharmaceutical formulations disclosed herein may also be administered to the lungs of a patient by aerosolization, for example, using a metered dose inhaler. The use of such formulations provides excellent dose reproducibility and improved pulmonary deposition, as disclosed in WO 99/16422, which is incorporated herein by reference in its entirety. MDI is known in the art and can be readily used to administer the claimed dispersions without undue experimentation. Breath activated or breath actuated MDIs and pressurized MDIs (pmdis), as well as modified MDIs comprising other types that have been or will be developed, are also compatible with the formulations of the present invention and are therefore considered to be within the scope of the present invention.

Together with DPIs, MDIs and nebulizers, it will be appreciated that the formulations of one or more embodiments of the present invention may be used in conjunction with liquid dose instillation or LDI techniques, for example as disclosed in WO 99/16421, the entire contents of which are incorporated herein by reference. Liquid dose instillation involves administering the formulation directly to the lungs. For LDI, the formulation is preferably used in combination with partial liquid aeration or full liquid aeration. In addition, one or more embodiments of the present invention can further comprise introducing a therapeutically beneficial amount of a physiologically acceptable gas (e.g., nitric oxide or oxygen) into the drug microdispersion before, during, or after administration.

The pharmaceutical compositions of one or more embodiments of the present invention generally have improved emptying rate efficiency. Thus, a variety of aerosolization devices and techniques can be used to deliver high doses of pharmaceutical compositions.

The particles of the present invention may have an empty rate (ED) of greater than about 30%, such as greater than about 40%, greater than about 50%, greater than about 60%, or greater than about 70%.

One or more embodiments relate to a kit. For example, the kit may include an aerosolization device and a container, such as a unit-dose vessel, containing an aerosolizable anti-arrhythmic agent, such as a liquid or a dry powder.

The kit may further comprise a package, such as a bag, comprising the aerosolization device and the container.

In view of the above, the present invention relates to a method of treating an arrhythmia acute episode and/or chronic arrhythmia. In certain embodiments, the treatment comprises an emergency treatment after the detection of the atrial arrhythmia.

This method of treatment results in pulsatile pharmacokinetic profiles and transient pharmacodynamic effects, similar to those of IV administration. This method can deliver high concentrations of drugs that are safe and effective for the heart, while distribution to other parts of the body results in the drug being diluted to sub-therapeutic levels. This approach is the shortest route of delivery to the heart, except for intracardiac injections. This provides the convenience of self-administration, similar to the "pill-in-the-pocket" method, but with the effectiveness and rapid onset of IV administration. Although the delivery of drugs via the lungs for systemic action is not fresh, it is generally believed that it has no effect on the heart because the drug passes rapidly through the heart. Animal and human PK/PD data from this study show that drug exposure at much lower doses is sufficient to achieve therapeutic effects compared to other routes of administration. This approach ensures that the drug concentration in total plasma is much lower than that achieved by the oral/IV route, thus minimizing drug-drug interactions and side effects.

In some cases, T of an antiarrhythmic agent administered by inhalation_maxMay be about 0.1 minute to about 30 minutes, for example, 0.1-0.5, 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5, 0.1-3, 0.1-3.5, 0.1-4, 0.1-4.5, 0.1-5, 0.1-6, 0.1-8, 0.1-10, 0.1-15, 0.1-20, 0.1-25, 0.1-30, 0.2-0.5, 0.2-1, 0.2-1.5, 0.2-2, 0.2-2.5, 0.2-3, 0.2-3.5, 0.2-4, 0.2-4.5, 0.2-5, 0.2-6, 0.2-8, 0.2-10, 0.2-15, 0.2-3.5, 0.2-3, 0.5-3, 0.2-3, 0.5, 0.2-3, 0.5-3, 0.1-3, 0.5, 0.1-3.5, 0.5, 0.1, 0.3-4, 0.3-4.5, 0.3-5, 0.3-6, 0.3-8, 0.3-10, 0.3-15, 0.3-20, 0.3-25, 0.3-30, 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5, 0.5-4, 0.5-4.5, 0.5-5, 0.5-6, 0.5-8, 0.5-10, 0.5-15, 0.5-20, 0.5-25, 0.5-30, 1-1.5, 1-2, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1-6, 1-8, 1-10,1-15, 1-20, 1-25, 1-30, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 1.5-6, 1.5-8, 1.5-10, 1.5-15, 1.5-20, 1.5-25, 1.5-30, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5, 2-5, 2-6, 2-8, 2-10, 2-15, 2-20, 2-25, 2-30, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 2.5-6, 2.5-8, 2.5-10, 2.5-15, 2.5-10, 2.5-3.5, 2.5-4, 2.5-5, 2.5-6, 2.5-8, 2.5-10, 2.5-15, 2.5-5, 3-3.5, 3-4, 3-4.5, 3-5, 3-6, 3-8, 3-10, 3-15, 3-20, 3-25, 3-30, 3.5-4, 3.5-4.5, 3.5-5, 3.5-6, 3.5-8, 3.5-10, 3.5-15, 3.5-20, 3.5-25, 3.5-30, 4-4.5, 4-5, 4-6, 4-8, 4-10, 4-15, 4-20, 4-25, 4-30, 4.5-5, 4.5-6, 4.5-8, 4.5-10, 4.5-15, 4.5-20, 4.5-25, 4.5-30, 5-6, 5-8, 5-10, 5-15, 5-20, 5-5, 5-25, 5-30, 5.5-6, 5.5-8, 5.5-10, 5.5-15, 5.5-20, 5.5-25, 5.5-30, 6-8, 6-10, 6-15, 6-20, 6-25, 6-30, 8-10, 8-15, 8-20, 8-25, 8-30, 10-15, 10-20, 10-25, 10-30, 15-20, 15-25, 15-30, 20-25, 20-30 or 25-30 minutes. Ranges given in this disclosure may be between two exact values, and in some cases, ranges in this disclosure may also refer to ranges between two approximate values. For example, "1-10" may mean "from 1 to 10" in some cases, and "1-10" may mean "from about 1 to about 10" in other cases. In some cases, T of an antiarrhythmic agent administered by inhalation_maxCan be 0.01-5, 0.02-5, 0.03-5, 0.04-5, 0.05-5, 0.06-5, 0.07-5, 0.08-5, 0.09-5, 0.12-5, 0.14-5, 0.15-5, 0.16-5, 0.18-5, 0.2-5, 0.24-5, 0.26-5, 0.28-5, 0.3-5, 0.35-5, 0.4-5, 0.5-5, 0.6-5, 0.7-5, 0.8-5, 0.9-5 or 1-5 minutes. In some cases, T of an antiarrhythmic agent administered by inhalation_maxAnd may be from about 0.1 to about 3 minutes. In some cases, T of an antiarrhythmic agent administered by inhalation_maxAnd may be from about 0.1 to about 5 minutes. In some cases, T of an antiarrhythmic agent (e.g., flecainide) administered by inhalation_maxAnd may be from about 0.2 to about 5 minutes. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, antiThe arrhythmia agents are class Ic antiarrhythmic agents. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

In some cases, T may be_maxCalculated as the amount of time that the maximum plasma concentration of the antiarrhythmic agent was observed. In some cases, T may be_maxCalculated as the amount of time to reach maximum plasma concentration after administration of the antiarrhythmic agent. In some cases, T may be_maxCalculated as the amount of time to reach maximum plasma concentration after the start of administration of the antiarrhythmic agent. In some cases, T may be_maxCalculated as the amount of time to reach maximum plasma concentration after completion of the administration of the antiarrhythmic agent. In some cases, T may be calculated from the plasma concentration of the antiarrhythmic agent measured in the left ventricle_max. In some cases, T may be calculated from the plasma concentration of the antiarrhythmic agent measured in the pulmonary artery_max. In some cases, T may be calculated from the plasma concentration of the antiarrhythmic agent measured in a vein (e.g., the femoral vein)_max. In some cases, T can be measured in human PK/PD studies_max. As used herein, the term "human PK/PD study" may refer to any setting in which a human subject receives administration of a single dose of an antiarrhythmic agent as provided herein and Pharmacokinetic (PK) or Pharmacodynamic (PD) parameters are measured from the human subject following administration of the antiarrhythmic agent. In some cases, a human PK/PD study provided herein may refer to a clinical study conducted in a clinic or hospital setting. In some cases, the human PK/PD study may be a single-center or multi-center study. Human PK/PD studies can be performed on healthy human subjects or human cardiovascular patients. In some cases, patients with cardiovascular disease experience arrhythmias as described herein. In some cases, the human PK/PD study may be a single dose study, in other cases, the human PK/PD study may be a multiple dose (e.g., ascending dose) study.

In some cases, C of an antiarrhythmic agent administered by inhalation_maxCan be from about 10ng/mL to about5000ng/mL, for example, about 10-30, 10-50, 10-70, 10-80, 10-90, 10-100, 10-110, 10-120, 10-130, 10-140, 10-150, 10-160, 10-170, 10-180, 10-190, 10-200, 10-250, 10-300, 10-350, 10-400, 10-450, 10-500, 10-550, 10-600, 10-650, 10-700, 10-800, 10-900, 10-1000, 10-1500, 10-2000, 10-3000, 10-4000, 10-5000, 20-30, 20-50, 20-70, 20-80, 20-90, 20-100, 20-110, 20-120, 20-130, 20-140, 20-150, 20-160, 20-170, 20-180, 20-190, 20-200, 20-250, 20-300, 20-350, 20-400, 20-450, 20-500, 20-550, 20-600, 20-650, 20-700, 20-800, 20-900, 20-1000, 20-1500, 20-2000, 20-3000, 20-4000, 20-5000, 30-50, 30-70, 30-80, 30-90, 30-100, 30-110, 30-120, 30-130, 30-140, 30-150, 30-160, 30-170, 30-180, 30-190, 30-200, 30-250, 30-300, 30-180, 30-350, 30-400, 30-450, 30-500, 30-550, 30-600, 30-650, 30-700, 30-800, 30-900, 30-1000, 30-1500, 30-2000, 30-3000, 30-4000, 30-5000, 50-70, 50-80, 50-90, 50-100, 50-110, 50-120, 50-130, 50-140, 50-150, 50-160, 50-170, 50-180, 50-190, 50-200, 50-250, 50-300, 50-350, 50-400, 50-450, 50-500, 50-550, 50-600, 50-650, 50-700, 50-800, 50-900, 50-1000, 50-1500, 50-2000, 50-3000, 50-4000, 50-5000, 70-80, 70-90, 70-100, 70-110, 70-120, 70-130, 70-140, 70-150, 70-160, 70-170, 70-180, 70-190, 70-200, 70-250, 70-300, 70-350, 70-400, 70-450, 70-500, 70-550, 70-600, 70-650, 70-700, 70-800, 70-900, 70-1000, 70-1500, 70-2000, 70-3000, 70-4000, 70-5000, 80-90, 80-100, 80-110, 80-120, 80-130, 80-140, 80-150, 80-160, 80-170, 80-180, 80-190, 80-200, 80-250, 80-300, 80-350, 80-400, 80-450, 80-500, 80-550, 80-600, 80-650, 80-700, 80-800, 80-900, 80-1000, 80-1500, 80-2000, 80-3000, 80-4000, 80-5000, 90-100, 90-110, 90-120, 90-130, 90-140, 90-150, 90-160, 90-170, 90-180, 90-190, 90-200, 90-250, 90-300, 90-350, 90-400, 90-450, 90-500, 90-550, 90-600, 90-650, 90-700, 90-800, 90-900, 90-1000, 90-1500, 90-2000, 90-3000, 90-4000, 90-5000, etc,100-110、100-120、100-130、100-140、100-150、100-160、100-170、100-180、100-190、100-200、100-250、100-300、100-350、100-400、100-450、100-500、100-550、100-600、100-650、100-700、100-800、100-900、100-1000、100-1500、100-2000、100-3000、100-4000、100-5000、110-120、110-130、110-140、110-150、110-160、110-170、110-180、110-190、110-200、110-250、110-300、110-350、110-400、110-450、110-500、110-550、110-600、110-650、110-700、110-800、110-900、110-1000、110-1500、110-2000、110-3000、110-4000、110-5000、120-130、120-140、120-150、120-160、120-170、120-180、120-190、120-200、120-250、120-300、120-350、120-400、120-450、120-500、120-550、120-600、120-650、120-700、120-800、120-900、120-1000、120-1500、120-2000、120-3000、120-4000、120-5000、130-140、130-150、130-160、130-170、130-180、130-190、130-200、130-250、130-300、130-350、130-400、130-450、130-500、130-550、130-600、130-650、130-700、130-800、130-900、130-1000、130-1500、130-2000、130-3000、130-4000、130-5000、140-150、140-160、140-170、140-180、140-190、140-200、140-250、140-300、140-350、140-400、140-450、140-500、140-550、140-600、140-650、140-700、140-800、140-900、140-1000、140-1500、140-2000、140-3000、140-4000、140-5000、150-160、150-170、150-180、150-190、150-200、150-250、150-300、150-350、150-400、150-450、150-500、150-550、150-600、150-650、150-700、150-800、150-900、150-1000、150-1500、150-2000、150-3000、150-4000、150-5000、160-170、160-180、160-190、160-200、160-250、160-300、160-350、160-400、160-450、160-500、160-550、160-600、160-650、160-700、160-800、160-900、160-1000、160-1500、160-2000、160-3000、160-4000、160-5000、170-180、170-190、170-200、170-250、170-300、170-350、170-400、170-450、170-500、170-550、170-600、170-650、170-700、170-800、170-900、170-1000、170-1500、170-2000、170-3000、170-4000、170-5000、180-190、180-200、180-250、180-300、180-350、180-400、180-450、180-500、180-550、180-600、180-650、180-700、180-800、180-900、180-1000、180-1500、180-2000、180-3000、180-4000、180-5000、190-200、190-250、190-300、190-350、190-400、190-450、190-500、190-550、190-600、190-650、190-700、190-800、190-900、190-1000、190-1500、190-2000、190-3000、190-4000、190-5000、200-250、200-300、200-350、200-400、200-450、200-500、200-550、200-600、200-650、200-700、200-800、200-900、200-1000、200-1500、200-2000、200-3000、200-4000、200-5000、250-300、250-350、250-400、250-450、250-500、250-550、250-600、250-650、250-700、250-800、250-900、250-1000、250-1500、250-2000、250-3000、250-4000、250-5000、300-350、300-400、300-450、300-500、300-550、300-600、300-650、300-700、300-800、300-900、300-1000、300-1500、300-2000、300-3000、300-4000、300-5000、350-400、350-450、350-500、350-550、350-600、350-650、350-700、350-800、350-900、350-1000、350-1500、350-2000、350-3000、350-4000、350-5000、400-450、400-500、400-550、400-600、400-650、400-700、400-800、400-900、400-1000、400-1500、400-2000、400-3000、400-4000、400-5000、450-500、450-550、450-600、450-650、450-700、450-800、450-900、450-1000、450-1500、450-2000、450-3000、450-4000、450-5000、500-550、500-600、500-650、500-700、500-800、500-900、500-1000、500-1500、500-2000、500-3000、500-4000、500-5000、550-600、550-650、550-700、550-800、550-900、550-1000、550-1500、550-2000、550-3000、550-4000、550-5000、600-650、600-700、600-800、600-900、600-1000、600-1500、600-2000、600-3000、600-4000、600-5000、650-700、650-800、650-900、650-1000、650-1500、650-2000、650-3000、650-4000、650-5000、700-800、700-900、700-1000、700-1500、700-2000、700-3000、700-4000、700-5000、800-900、800-1000、800-1500、800-2000、800-3000、800-4000、800-5000、900-1000、900-1500、900-2000、900-3000、900-4000、900-5000、1000-1500、1000-2000、1000-3000、1000-4000、1000-5000, 1500-2000, 1500-3000, 1500-4000, 1500-5000, 2000-3000, 2000-4000, 2000-5000, 3000-4000, 3000-5000 or 4000-5000 ng/mL. In some cases, C of an antiarrhythmic agent administered by inhalation_maxCan be about 20ng/mL to about 500ng/mL, such as 20-500, 30-500, 40-500, 50-500, 60-500, 70-500, 80-500, 90-500, 100-500, 150-500, 200-500, or 250-500 ng/mL. In some cases, C of an antiarrhythmic agent administered by inhalation_maxAnd may be about 50 to about 500 ng/mL. In some cases, C of an antiarrhythmic agent administered by inhalation_maxAnd may be about 100 to about 250 ng/mL. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic agent is a class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

In some cases, C may be_maxCalculated as the maximum plasma concentration of the observed antiarrhythmic agent. In some cases, C may be_maxCalculated as the peak plasma concentration achieved by the antiarrhythmic agent after drug administration. In some cases, Cc may be calculated from the plasma concentration of the antiarrhythmic agent measured in the left ventricle_max. In some cases, Cc may be calculated from the plasma concentration of the antiarrhythmic agent measured in the pulmonary artery_max. In some cases, Cc may be calculated from the plasma concentration of the antiarrhythmic agent measured in a vein (e.g., the femoral vein)_max. In some cases, C can be measured in human PK/PD studies_max。

In some cases, AUC of an antiarrhythmic agent administered by inhalation_LastCan be about 100hr ng/mL to about 10000hr ng/mL, such as 100-0-4500、100-5000、100-5500、100-6000、100-6500、100-7000、100-8000、100-9000、100-10000、200-300、200-400、200-420、200-440、200-460、200-480、200-500、200-520、200-540、200-560、200-580、200-600、200-620、200-640、200-660、200-680、200-700、200-800、200-900、200-1000、200-1500、200-2000、200-3000、200-3500、200-4000、200-4500、200-5000、200-5500、200-6000、200-6500、200-7000、200-8000、200-9000、200-10000、300-400、300-420、300-440、300-460、300-480、300-500、300-520、300-540、300-560、300-580、300-600、300-620、300-640、300-660、300-680、300-700、300-800、300-900、300-1000、300-1500、300-2000、300-3000、300-3500、300-4000、300-4500、300-5000、300-5500、300-6000、300-6500、300-7000、300-8000、300-9000、300-10000、400-420、400-440、400-460、400-480、400-500、400-520、400-540、400-560、400-580、400-600、400-620、400-640、400-660、400-680、400-700、400-800、400-900、400-1000、400-1500、400-2000、400-3000、400-3500、400-4000、400-4500、400-5000、400-5500、400-6000、400-6500、400-7000、400-8000、400-9000、400-10000、420-440、420-460、420-480、420-500、420-520、420-540、420-560、420-580、420-600、420-620、420-640、420-660、420-680、420-700、420-800、420-900、420-1000、420-1500、420-2000、420-3000、420-3500、420-4000、420-4500、420-5000、420-5500、420-6000、420-6500、420-7000、420-8000、420-9000、420-10000、440-460、440-480、440-500、440-520、440-540、440-560、440-580、440-600、440-620、440-640、440-660、440-680、440-700、440-800、440-900、440-1000、440-1500、440-2000、440-3000、440-3500、440-4000、440-4500、440-5000、440-5500、440-6000、440-6500、440-7000、440-8000、440-9000、440-10000、460-480、460-500、460-520、460-540、460-560、460-580、460-600、460-620、460-640、460-660、460-680、460-700、460-800、460-900、460-1000、460-1500、460-2000、460-3000、460-3500、460-4000、460-4500、460-5000、460-5500、460-6000、460-6500、460-7000、460-8000、460-9000、460-10000、480-500、480-520、480-540、480-560、480-580、480-600、480-620、480-640、480-660、480-680、480-700、480-800、480-900、480-1000、480-1500、480-2000、480-3000、480-3500、480-4000、480-4500、480-5000、480-5500、480-6000、480-6500、480-7000、480-8000、480-9000、480-10000、500-520、500-540、500-560、500-580、500-600、500-620、500-640、500-660、500-680、500-700、500-800、500-900、500-1000、500-1500、500-2000、500-3000、500-3500、500-4000、500-4500、500-5000、500-5500、500-6000、500-6500、500-7000、500-8000、500-9000、500-10000、520-540、520-560、520-580、520-600、520-620、520-640、520-660、520-680、520-700、520-800、520-900、520-1000、520-1500、520-2000、520-3000、520-3500、520-4000、520-4500、520-5000、520-5500、520-6000、520-6500、520-7000、520-8000、520-9000、520-10000、540-560、540-580、540-600、540-620、540-640、540-660、540-680、540-700、540-800、540-900、540-1000、540-1500、540-2000、540-3000、540-3500、540-4000、540-4500、540-5000、540-5500、540-6000、540-6500、540-7000、540-8000、540-9000、540-10000、560-580、560-600、560-620、560-640、560-660、560-680、560-700、560-800、560-900、560-1000、560-1500、560-2000、560-3000、560-3500、560-4000、560-4500、560-5000、560-5500、560-6000、560-6500、560-7000、560-8000、560-9000、560-10000、580-600、580-620、580-640、580-660、580-680、580-700、580-800、580-900、580-1000、580-1500、580-2000、580-3000、580-3500、580-4000、580-4500、580-5000、580-5500、580-6000、580-6500、580-7000、580-8000、580-9000、580-10000、600-620、600-640、600-660、600-680、600-700、600-800、600-900、600-1000、600-1500、600-2000、600-3000、600-3500、600-4000、600-4500、600-5000、600-5500、600-6000、600-6500、600-7000、600-8000、600-9000、600-10000、620-640、620-660、620-680、620-700、620-800、620-900、620-1000、620-1500、620-2000、620-3000、620-3500、620-4000、620-4500、620-5000、620-5500、620-6000、620-6500、620-7000、620-8000、620-9000、620-10000、640-660、640-680、640-700、640-800、640-900、640-1000、640-1500、640-2000、640-3000、640-3500、640-4000、640-4500、640-5000、640-5500、640-6000、640-6500、640-7000、640-8000、640-9000、640-10000、660-680、660-700、660-800、660-900、660-1000、660-1500、660-2000、660-3000、660-3500、660-4000、660-4500、660-5000、660-5500、660-6000、660-6500、660-7000、660-8000、660-9000、660-10000、680-700、680-800、680-900、680-1000、680-1500、680-2000、680-3000、680-3500、680-4000、680-4500、680-5000、680-5500、680-6000、680-6500、680-7000、680-8000、680-9000、680-10000、700-800、700-900、700-1000、700-1500、700-2000、700-3000、700-3500、700-4000、700-4500、700-5000、700-5500、700-6000、700-6500、700-7000、700-8000、700-9000、700-10000、800-900、800-1000、800-1500、800-2000、800-3000、800-3500、800-4000、800-4500、800-5000、800-5500、800-6000、800-6500、800-7000、800-8000、800-9000、800-10000、900-1000、900-1500、900-2000、900-3000、900-3500、900-4000、900-4500、900-5000、900-5500、900-6000、900-6500、900-7000、900-8000、900-9000、900-10000、1000-1500、1000-2000、1000-3000、1000-3500、1000-4000、1000-4500、1000-5000、1000-5500、1000-6000、1000-6500、1000-7000、1000-8000、1000-9000、1000-10000、1500-2000、1500-3000、1500-3500、1500-4000、1500-4500、1500-5000、1500-5500、1500-6000、1500-6500、1500-7000、1500-8000、1500-9000、1500-10000、2000-3000、2000-3500、2000-4000、2000-4500、2000-5000、2000-5500、2000-6000、2000-6500、2000-7000、2000-8000、2000-9000、2000-10000、2500-3000、2500-3500、2500-4000、2500-4500、2500-5000、2500-5500、2500-6000、2500-6500、2500-7000、2500-8000、2500-9000、2500-10000、3000-3500、3000-4000、3000-4500、3000-5000、3000-5500、3000-6000、3000-6500、3000-7000、3000-8000、3000-9000、3000-10000、3500-4000、3500-4500、3500-5000、3500-5500、3500-6000、3500-6500、3500-7000. 3500-8000, 3500-9000, 3500-10000, 4000-4500, 4000-5000, 4000-5500, 4000-6000, 4000-6500, 4000-7000, 4000-8000, 4000-9000, 4000-10000, 4500-5000, 4500-5500, 4500-6000, 4500-6500, 4500-7000, 4500-8000, 4500-9000, 4500-10000, 5000-5500, 5000-6000, 5000-7000, 5000-8000, 5000-6000, 5500-6500, 5500-7000, 6500, 8000-8000, 5500-9000, 6500-8000-7000, 8000-7000, 7000-charging 9000, 7000-charging 10000, 8000-charging 9000, 8000-charging 10000 or 9000-charging 10000hr ng/mL. In some cases, AUC of an antiarrhythmic agent administered by inhalation_LastMay be about 200 to about 2000hr ng/mL. In some cases, AUC of an antiarrhythmic agent administered by inhalation_LastMay be about 500 to about 800hr ng/mL. In some cases, AUC of an antiarrhythmic agent administered by inhalation_LastMay be about 400 to about 600hr ng/mL. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic agent is a class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

In some cases, the AUC may be_LastCalculated as the area under the concentration-time curve up to the last measurable concentration. In some cases, the AUC may be_LastCalculated as total drug exposure over time. In some cases, AUC can be calculated from the plasma concentration of the antiarrhythmic agent measured in the left ventricle_Last. In some cases, AUC can be calculated from plasma concentrations of the antiarrhythmic agent measured from pulmonary arteries_Last. In some cases, AUC can be calculated from plasma concentrations of the antiarrhythmic agent measured in veins (e.g., femoral vein)_Last. In some cases, AUC can be measured in human PK/PD studies_Last。

In some cases, antiarrhythmic agents administered by inhalationDistribution t of_1/2May be about 0.1 minute to about 15 minutes, for example, about 0.1-0.5, 0.1-1, 0.1-1.5, 0.1-2, 0.1-2.5, 0.1-2.6, 0.1-2.7, 0.1-2.8, 0.1-2.9, 0.1-3, 0.1-3.1, 0.1-3.2, 0.1-3.3, 0.1-3.4, 0.1-3.5, 0.1-3.6, 0.1-3.7, 0.1-3.8, 0.1-3.9, 0.1-4, 0.1-4.1, 0.1-4.2, 0.1-4.3, 0.1-4.4, 0.1-4.5, 0.1-5, 0.5, 0.1-4.1-1, 0.5, 0.1-1-4.1, 0.5, 0.1-1-4.5, 0.1-1, 0.5, 0.1-1, 0.5, 0.1-1-1.1, 0.5, 0.1-1-, 0.5-2.6, 0.5-2.7, 0.5-2.8, 0.5-2.9, 0.5-3, 0.5-3.1, 0.5-3.2, 0.5-3.3, 0.5-3.4, 0.5-3.5, 0.5-3.6, 0.5-3.7, 0.5-3.8, 0.5-3.9, 0.5-4, 0.5-4.1, 0.5-4.2, 0.5-4.3, 0.5-4.4, 0.5-4.5, 0.5-5, 0.5-5.5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 0.5-11, 0.5-12, 0.5-13, 1-1.5, 1-1.1-1, 1-1.5, 1-1.1, 1-2.1, 1-3.5, 1-1, 1-3.5, 1.3, 1-4, 1.5-4, 0.5-4, 1.5, 1-3.4, 1-3.5, 1-3.6, 1-3.7, 1-3.8, 1-3.9, 1-4, 1-4.1, 1-4.2, 1-4.3, 1-4.4, 1-4.5, 1-5, 1-5.5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1.5-2, 1.5-2.5, 1.5-2.6, 1.5-2.7, 1.5-2.8, 1.5-2.9, 1.5-3, 1.5-3.1, 1.5-3.2, 1.5-3.3, 1.5-3.4, 1.5-3.5, 1.5-3.6, 1.5-3.5, 1.5-3, 1.5-4.3, 1.5-4.4, 1.5-4.5, 1.5-5, 1.5-5.5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-14, 1.5-15, 2-2.5, 2-2.6, 2-2.7, 2-2.8, 2-2.9, 2-3, 2-3.1, 2-3.2, 2-3.3, 2-3.4, 2-3.5, 2-3.6, 2-3.7, 2-3.8, 2-3.9, 2-4, 2-4.1, 2-4.2, 2-4.3, 2-4.4, 2-4.5, 2-5.5, 2-5, 2-4.5, 2-5, 2-4.9, 2-4.1, 2-4.3, 2-4.4.3, 2-5, 2-10, 2, 2-11, 2-12, 2-13, 2-14, 2-15, 2.5-2.6, 2.5-2.7, 2.5-2.8, 2.5-2.9, 2.5-3, 2.5-3.1, 2.5-3.2, 2.5-3.3, 2.5-3.4, 2.5-3.5, 2.5-3.6, 2.5-3.7, 2.5-3.8, 2.5-3.9, 2.5-4, 2.5-4.1, 2.5-4.2, 2.5-4.3, 2.5-4.4, 2.5-4.5, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-4.5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-6, 2.6, 2.6.6, 2.5-6, 2.6.6, 2.6-3.6, 2.5-3.6, 2.6, 2.5-4.6, 2.6, 2.6.6.6, 2.6-3.3, 2.6-3.4, 2.6-3.5, 2.6-3.6, 2.6-3.7, 2.6-3.8, 2.6-3.9, 2.6-4, 2.6-4.1, 2.6-4.2, 2.6-4.3, 2.6-4.4,2.6-4.5、2.6-5、2.6-5.5、2.6-6、2.6-7、2.6-8、2.6-9、2.6-10、2.6-11、2.6-12、2.6-13、2.6-14、2.6-15、2.7-2.8、2.7-2.9、2.7-3、2.7-3.1、2.7-3.2、2.7-3.3、2.7-3.4、2.7-3.5、2.7-3.6、2.7-3.7、2.7-3.8、2.7-3.9、2.7-4、2.7-4.1、2.7-4.2、2.7-4.3、2.7-4.4、2.7-4.5、2.7-5、2.7-5.5、2.7-6、2.7-7、2.7-8、2.7-9、2.7-10、2.7-11、2.7-12、2.7-13、2.7-14、2.7-15、2.8-2.9、2.8-3、2.8-3.1、2.8-3.2、2.8-3.3、2.8-3.4、2.8-3.5、2.8-3.6、2.8-3.7、2.8-3.8、2.8-3.9、2.8-4、2.8-4.1、2.8-4.2、2.8-4.3、2.8-4.4、2.8-4.5、2.8-5、2.8-5.5、2.8-6、2.8-7、2.8-8、2.8-9、2.8-10、2.8-11、2.8-12、2.8-13、2.8-14、2.8-15、2.9-3、2.9-3.1、2.9-3.2、2.9-3.3、2.9-3.4、2.9-3.5、2.9-3.6、2.9-3.7、2.9-3.8、2.9-3.9、2.9-4、2.9-4.1、2.9-4.2、2.9-4.3、2.9-4.4、2.9-4.5、2.9-5、2.9-5.5、2.9-6、2.9-7、2.9-8、2.9-9、2.9-10、2.9-11、2.9-12、2.9-13、2.9-14、2.9-15、3-3.1、3-3.2、3-3.3、3-3.4、3-3.5、3-3.6、3-3.7、3-3.8、3-3.9、3-4、3-4.1、3-4.2、3-4.3、3-4.4、3-4.5、3-5、3-5.5、3-6、3-7、3-8、3-9、3-10、3-11、3-12、3-13、3-14、3-15、3.1-3.2、3.1-3.3、3.1-3.4、3.1-3.5、3.1-3.6、3.1-3.7、3.1-3.8、3.1-3.9、3.1-4、3.1-4.1、3.1-4.2、3.1-4.3、3.1-4.4、3.1-4.5、3.1-5、3.1-5.5、3.1-6、3.1-7、3.1-8、3.1-9、3.1-10、3.1-11、3.1-12、3.1-13、3.1-14、3.1-15、3.2-3.3、3.2-3.4、3.2-3.5、3.2-3.6、3.2-3.7、3.2-3.8、3.2-3.9、3.2-4、3.2-4.1、3.2-4.2、3.2-4.3、3.2-4.4、3.2-4.5、3.2-5、3.2-5.5、3.2-6、3.2-7、3.2-8、3.2-9、3.2-10、3.2-11、3.2-12、3.2-13、3.2-14、3.2-15、3.3-3.4、3.3-3.5、3.3-3.6、3.3-3.7、3.3-3.8、3.3-3.9、3.3-4、3.3-4.1、3.3-4.2、3.3-4.3、3.3-4.4、3.3-4.5、3.3-5、3.3-5.5、3.3-6、3.3-7、3.3-8、3.3-9、3.3-10、3.3-11、3.3-12、3.3-13、3.3-14、3.3-15、3.4-3.5、3.4-3.6、3.4-3.7、3.4-3.8、3.4-3.9、3.4-4、3.4-4.1、3.4-4.2、3.4-4.3、3.4-4.4、3.4-4.5、3.4-5、3.4-5.5、3.4-6、3.4-7、3.4-8、3.4-9、3.4-10、3.4-11、3.4-12、3.4-13、3.4-14、3.4-15、3.5-3.6、3.5-3.7、3.5-3.8, 3.5-3.9, 3.5-4, 3.5-4.1, 3.5-4.2, 3.5-4.3, 3.5-4.4, 3.5-4.5, 3.5-5, 3.5-5.5, 3.5-6, 3.5-7, 3.5-8, 3.5-9, 3.5-10, 3.5-11, 3.5-12, 3.5-13, 3.5-14, 3.5-15, 3.6-3.7, 3.6-3.8, 3.6-3.9, 3.6-4, 3.6-4.1, 3.6-4.2, 3.6-4.3, 3.6-4.4, 3.6-4.5, 3.6-5, 3.6-6, 3.6-4.6, 3.6-6, 3.6-4.5, 3.6-6, 3.6-4.6, 3.6-6, 3.6-4.5, 3.6-6, 3, 3.8-4, 3.8-4.1, 3.8-4.2, 3.8-4.3, 3.8-4.4, 3.8-4.5, 3.8-5, 3.8-5.5, 3.8-6, 3.8-7, 3.8-8, 3.8-9, 3.8-10, 3.8-11, 3.8-12, 3.8-13, 3.8-14, 3.8-15, 3.9-4, 3.9-4.1, 3.9-4.2, 3.9-4.3, 3.9-4.4, 3.9-4.5, 3.9-5, 3.9-5.5, 3.9-6, 3.9-7, 3.9-8, 3.9-9, 3.9-10, 3.9-11, 3.9-12, 3.9-5.5, 3.9-4.5, 4-4.9-6, 3.9-7, 3.9-8, 3.9-9, 3.9-10, 3.9-4.9, 3.9-4.9, 4.9-4.5, 3.4.9-4.4.5, 3.9, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14, 4-15, 4.1-4.2, 4.1-4.3, 4.1-4.4, 4.1-4.5, 4.1-5, 4.1-5.5, 4.1-6, 4.1-7, 4.1-8, 4.1-9, 4.1-10, 4.1-11, 4.1-12, 4.1-13, 4.1-14, 4.1-15, 4.2-4.3, 4.2-4.4, 4.2-4.5, 4.2-5, 4.2-5.5, 4.2-6, 4.2-7, 4.2-8, 4.2-9, 4.2-10, 4.2-11, 4.2-12, 4.2-5, 4.2-6, 4.2-7, 4.2-8, 4.2-9, 4.2-10, 4.2-11, 4.2-12, 4.2-5, 4.2-4.3, 4.1-13, 4.5, 4.1, 4.3-5, 4.3-5.5, 4.3-6, 4.3-7, 4.3-8, 4.3-9, 4.3-10, 4.3-11, 4.3-12, 4.3-13, 4.3-14, 4.3-15, 4.4-4.5, 4.4-5, 4.4-5.5, 4.4-6, 4.4-7, 4.4-8, 4.4-9, 4.4-10, 4.4-11, 4.4-12, 4.4-13, 4.4-14, 4.4-15, 4.5-5, 4.5-5.5, 4.5-6, 4.5-7, 4.5-8, 4.5-9, 4.5-10, 4.5-11, 4.5-12, 4.5-13, 4.5-5, 4.5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 4.5-12, 4.5-5-13, 5-5, 5-10, 5-5, 5-11, 5-12, 5-13, 5-14, 5-15, 5.5-6, 5.5-7, 5.5-8, 5.5-9, 5.5-10, 5.5-11, 5.5-12, 5.5-13, 5.5-14, 5.5-15, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14, 7-15, 8-9, 8-10, 8-11, 8-12, 8-13, 8-14, 8-15, 9-10, 9-11, 9-12, 9-13, 9-9, 6-7, 6-13, 6-9-10, 7-11, 7-13, 8-9, 9-14, 9-15, 10-11, 10-12, 10-13, 10-14, 10-15, 11-12, 11-13, 11-14, 11-15, 12-13, 12-14, 12-15, 13-14, 13-15, or 14-15 minutes. In some cases, the distribution t of the antiarrhythmic agent administered by inhalation_1/2May be aboutFrom 3 to about 5 minutes. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic agent is a class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

In some cases, the distribution t may be_1/2Calculated as the time at which the plasma level of the antiarrhythmic agent drops to half the level at equilibrium due to distribution in the systemic tissues. In some cases, the distribution t may be_1/2The time required for the antiarrhythmic agent to lose half of its pharmacological activity was calculated. In some cases, the profile t may be calculated from the plasma concentration of the antiarrhythmic agent measured in the left ventricle_1/2. In some cases, the profile t may be calculated from the plasma concentration of the antiarrhythmic agent measured from the pulmonary artery_1/2. In some cases, the profile t may be calculated from the plasma concentration of the antiarrhythmic agent measured in a vein (e.g., the femoral vein)_1/2. In some cases, profile t can be measured in human PK/PD studies_1/2。

In some cases, the elimination of antiarrhythmic agents administered by inhalation t_1/2May be about 1 hour to about 25 hours, for example about 1-3, 1-5, 1-7, 1-7.5, 1-8, 1-8.5, 1-8.7, 1-8.9, 1-9.1, 1-9.3, 1-9.5, 1-9.7, 1-9.9, 1-10.1, 1-10.3, 1-10.5, 1-10.7, 1-10.9, 1-11.1, 1-11.3, 1-11.5, 1-11.7, 1-11.9, 1-12.1, 1-12.5, 1-13, 1-13.5, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-25, 3-5, 3-7, 3-7.5, 3-8, 3-8.5, 3-8.7, 3-8.5, 3-8.9, 3-9.1, 3-9.3, 3-9.5, 3-9.7, 3-9.9, 3-10.1, 3-10.3, 3-10.5, 3-10.7, 3-10.9, 3-11.1, 3-11.3, 3-11.5, 3-11.7, 3-11.9, 3-12.1, 3-12.5, 3-13, 3-13.5, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-25, 5-7, 5-7.5, 5-8, 5-8.5, 5-8.7, 5-8.9, 5-9.1, 5-9.3, 5-9.5, 5-9.7, 5-9.9, 5-10.1, 5-10.5-10.7, 5-10.9, 5-10.1, 5-10.5-10.9.5, 5-10.9.7, 5-10.9, 3-9, 5-10.9, 5-11.1, 5-11.3, 5-11.5, 5-11.7, 5-11.9, 5-12.1, 5-12.5, 5-13, 5-13.5, 5-14, 5-15, 5-16, 5-17、5-18、5-19、5-20、5-25、7-7.5、7-8、7-8.5、7-8.7、7-8.9、7-9.1、7-9.3、7-9.5、7-9.7、7-9.9、7-10.1、7-10.3、7-10.5、7-10.7、7-10.9、7-11.1、7-11.3、7-11.5、7-11.7、7-11.9、7-12.1、7-12.5、7-13、7-13.5、7-14、7-15、7-16、7-17、7-18、7-19、7-20、7-25、7.5-8、7.5-8.5、7.5-8.7、7.5-8.9、7.5-9.1、7.5-9.3、7.5-9.5、7.5-9.7、7.5-9.9、7.5-10.1、7.5-10.3、7.5-10.5、7.5-10.7、7.5-10.9、7.5-11.1、7.5-11.3、7.5-11.5、7.5-11.7、7.5-11.9、7.5-12.1、7.5-12.5、7.5-13、7.5-13.5、7.5-14、7.5-15、7.5-16、7.5-17、7.5-18、7.5-19、7.5-20、7.5-25、8-8.5、8-8.7、8-8.9、8-9.1、8-9.3、8-9.5、8-9.7、8-9.9、8-10.1、8-10.3、8-10.5、8-10.7、8-10.9、8-11.1、8-11.3、8-11.5、8-11.7、8-11.9、8-12.1、8-12.5、8-13、8-13.5、8-14、8-15、8-16、8-17、8-18、8-19、8-20、8-25、8.5-8.7、8.5-8.9、8.5-9.1、8.5-9.3、8.5-9.5、8.5-9.7、8.5-9.9、8.5-10.1、8.5-10.3、8.5-10.5、8.5-10.7、8.5-10.9、8.5-11.1、8.5-11.3、8.5-11.5、8.5-11.7、8.5-11.9、8.5-12.1、8.5-12.5、8.5-13、8.5-13.5、8.5-14、8.5-15、8.5-16、8.5-17、8.5-18、8.5-19、8.5-20、8.5-25、8.7-8.9、8.7-9.1、8.7-9.3、8.7-9.5、8.7-9.7、8.7-9.9、8.7-10.1、8.7-10.3、8.7-10.5、8.7-10.7、8.7-10.9、8.7-11.1、8.7-11.3、8.7-11.5、8.7-11.7、8.7-11.9、8.7-12.1、8.7-12.5、8.7-13、8.7-13.5、8.7-14、8.7-15、8.7-16、8.7-17、8.7-18、8.7-19、8.7-20、8.7-25、8.9-9.1、8.9-9.3、8.9-9.5、8.9-9.7、8.9-9.9、8.9-10.1、8.9-10.3、8.9-10.5、8.9-10.7、8.9-10.9、8.9-11.1、8.9-11.3、8.9-11.5、8.9-11.7、8.9-11.9、8.9-12.1、8.9-12.5、8.9-13、8.9-13.5、8.9-14、8.9-15、8.9-16、8.9-17、8.9-18、8.9-19、8.9-20、8.9-25、9.1-9.3、9.1-9.5、9.1-9.7、9.1-9.9、9.1-10.1、9.1-10.3、9.1-10.5、9.1-10.7、9.1-10.9、9.1-11.1、9.1-11.3、9.1-11.5、9.1-11.7、9.1-11.9、9.1-12.1、9.1-12.5、9.1-13、9.1-13.5、9.1-14、9.1-15、9.1-16、9.1-17、9.1-18、9.1-19、9.1-20、9.1-25、9.3-9.5、9.3-9.7、9.3-9.9、9.3-10.1、9.3-10.3、9.3-10.5、9.3-10.7、9.3-10.9、9.3-11.1、9.3-11.3、9.3-11.5、9.3-11.7、9.3-11.9、9.3-12.1、9.3-12.5、9.3-13、9.3-13.5、9.3-14、9.3-15、9.3-16、9.3-17、9.3-18、9.3-19、9.3-20、9.3-25、9.5-9.7、9.5-9.9、9.5-10.1、9.5-10.3、9.5-10.5、9.5-10.7、9.5-10.9、9.5-11.1、9.5-11.3、9.5-11.5、9.5-11.7、9.5-11.9、9.5-12.1、9.5-12.5、9.5-13、9.5-13.5、9.5-14、9.5-15、9.5-16、9.5-17、9.5-18、9.5-19、9.5-20、9.5-25、9.7-9.9、9.7-10.1、9.7-10.3、9.7-10.5、9.7-10.7、9.7-10.9、9.7-11.1、9.7-11.3、9.7-11.5、9.7-11.7、9.7-11.9、9.7-12.1、9.7-12.5、9.7-13、9.7-13.5、9.7-14、9.7-15、9.7-16、9.7-17、9.7-18、9.7-19、9.7-20、9.7-25、9.9-10.1、9.9-10.3、9.9-10.5、9.9-10.7、9.9-10.9、9.9-11.1、9.9-11.3、9.9-11.5、9.9-11.7、9.9-11.9、9.9-12.1、9.9-12.5、9.9-13、9.9-13.5、9.9-14、9.9-15、9.9-16、9.9-17、9.9-18、9.9-19、9.9-20、9.9-25、10.1-10.3、10.1-10.5、10.1-10.7、10.1-10.9、10.1-11.1、10.1-11.3、10.1-11.5、10.1-11.7、10.1-11.9、10.1-12.1、10.1-12.5、10.1-13、10.1-13.5、10.1-14、10.1-15、10.1-16、10.1-17、10.1-18、10.1-19、10.1-20、10.1-25、10.3-10.5、10.3-10.7、10.3-10.9、10.3-11.1、10.3-11.3、10.3-11.5、10.3-11.7、10.3-11.9、10.3-12.1、10.3-12.5、10.3-13、10.3-13.5、10.3-14、10.3-15、10.3-16、10.3-17、10.3-18、10.3-19、10.3-20、10.3-25、10.5-10.7、10.5-10.9、10.5-11.1、10.5-11.3、10.5-11.5、10.5-11.7、10.5-11.9、10.5-12.1、10.5-12.5、10.5-13、10.5-13.5、10.5-14、10.5-15、10.5-16、10.5-17、10.5-18、10.5-19、10.5-20、10.5-25、10.7-10.9、10.7-11.1、10.7-11.3、10.7-11.5、10.7-11.7、10.7-11.9、10.7-12.1、10.7-12.5、10.7-13、10.7-13.5、10.7-14、10.7-15、10.7-16、10.7-17、10.7-18、10.7-19、10.7-20、10.7-25、10.9-11.1、10.9-11.3、10.9-11.5、10.9-11.7、10.9-11.9、10.9-12.1、10.9-12.5、10.9-13、10.9-13.5、10.9-14、10.9-15、10.9-16、10.9-17、10.9-18、10.9-19、10.9-20、10.9-25、11.1-11.3、11.1-11.5、11.1-11.7、11.1-11.9、11.1-12.1、11.1-12.5、11.1-13、11.1-13.5、11.1-14、11.1-15、11.1-16、11.117, 11.1-18, 11.1-19, 11.1-20, 11.1-25, 11.3-11.5, 11.3-11.7, 11.3-11.9, 11.3-12.1, 11.3-12.5, 11.3-13, 11.3-13.5, 11.3-14, 11.3-15, 11.3-16, 11.3-17, 11.3-18, 11.3-19, 11.3-20, 11.3-25, 11.5-11.7, 11.5-11.9, 11.5-12.1, 11.5-12.5, 11.5-13, 11.5-13.5, 11.5-14, 11.5-15, 11.5-16, 11.5-17, 11.5-18, 11.5-19, 11.5-20, 11.5-25, 11.5-14, 11.5-15, 11.5-16, 11.5-17, 11.5-18, 11.5-19, 11.5-20, 11.5-12.5-7.1, 11.1-11.1, 11.5-15, 11.7.1-13.7.7.7, 11.5-15, 11.1-13.7.7.1-15, 11.7.7.7., 11.7-18, 11.7-19, 11.7-20, 11.7-25, 11.9-12.1, 11.9-12.5, 11.9-13, 11.9-13.5, 11.9-14, 11.9-15, 11.9-16, 11.9-17, 11.9-18, 11.9-19, 11.9-20, 11.9-25, 12.1-12.5, 12.1-13, 12.1-13.5, 12.1-14, 12.1-15, 12.1-16, 12.1-17, 12.1-18, 12.1-19, 12.1-20, 12.1-25, 12.5-13, 12.5-13.5, 12.5-14, 12.5-15, 12.5-16, 12.5-17, 12.5-18, 12.5-19, 12.5-13, 12.5-13.5-13, 12.5-14, 12.5-15, 12.5-16, 12.5-17, 12.5-18, 12.5-13.5-13, 13, 13-19, 13-20, 13-25, 13.5-14, 13.5-15, 13.5-16, 13.5-17, 13.5-18, 13.5-19, 13.5-20, 13.5-25, 14-15, 14-16, 14-17, 14-18, 14-19, 14-20, 14-25, 15-16, 15-17, 15-18, 15-19, 15-20, 15-25, 16-17, 16-18, 16-19, 16-20, 16-25, 17-18, 17-19, 17-20, 17-25, 18-19, 18-20, 18-25, 19-20, 19-25 or 20-25 hours. In some cases, the elimination of antiarrhythmic agents administered by inhalation t_1/2And may be from about 8.5 hours to about 10.5 hours. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic agent is a class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

In some cases, t is eliminated_1/2It can be calculated as the time for the plasma level of the antiarrhythmic agent to drop to half the level at equilibrium due to metabolism and elimination. In some cases, the elimination t may be calculated from the plasma concentration of the antiarrhythmic agent measured in the left ventricle_1/2. In some cases, plasma concentration of the anti-arrhythmic agent may be measured in the pulmonary arteryDegree to calculate the elimination t_1/2. In some cases, the elimination t may be calculated from the plasma concentration of the antiarrhythmic agent measured in a vein (e.g., the femoral vein)_1/2. In some cases, abrogation of t can be measured in human PK/PD studies_1/2。

In some cases, the maximum change in duration of the QRS interval (Δ QRS) following administration of the antiarrhythmic agent by inhalation may be about 0.01 to about 100 milliseconds, e.g., about 0.01-0.1, 0.01-0.5, 0.01-1, 0.01-1.5, 0.01-2, 0.01-2.5, 0.01-3, 0.01-3.5, 0.01-4, 0.01-4.5, 0.01-5, 0.01-5.5, 0.01-6, 0.01-8, 0.01-10, 0.01-15, 0.01-20, 0.01-25, 0.01-30, 0.01-40, 0.01-50, 0.01-60, 0.01-70, 0.01-80, 0.01-90, 0.01-100, 0.01-1.5, 0.1-1.1, 0.5-1.5, 0.5-2.5, 0.5-2.5, 0.1-4.5, 0.1-5, 0.1-5.5, 0.1-6, 0.1-8, 0.1-10, 0.1-15, 0.1-20, 0.1-25, 0.1-30, 0.1-40, 0.1-50, 0.1-60, 0.1-70, 0.1-80, 0.1-90, 0.1-100, 0.5-1, 0.5-1.5, 0.5-2, 0.5-2.5, 0.5-3, 0.5-3.5, 0.5-4, 0.5-4.5, 0.5-5, 0.5-5.5, 0.5-6, 0.5-8, 0.5-10, 0.5-15, 0.5-20, 0.5-25, 0.5-30, 0.5-40, 0.5-5, 0.5-5, 0.90, 0.5-5, 0.5-5-1.5, 0.5-1, 0.5-1.5, 0.5-3, 0.5-5, 0.5-5, 1-2.5, 1-3, 1-3.5, 1-4, 1-4.5, 1-5, 1-5.5, 1-6, 1-8, 1-10, 1-15, 1-20, 1-25, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1.5-2, 1.5-2.5, 1.5-3, 1.5-3.5, 1.5-4, 1.5-4.5, 1.5-5, 1.5-5.5, 1.5-6, 1.5-8, 1.5-10, 1.5-15, 1.5-20, 1.5-25, 1.5-30, 1.5-40, 1.5-50, 1.5-60, 1.5-70, 1.5-90, 1.5-100, 1.5-5, 2-2.5, 2-3, 2-3.5, 2-4, 2-4.5, 2-5, 2-5.5, 2-6, 2-8, 2-10, 2-15, 2-20, 2-25, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-4.5, 2.5-5, 2.5-5.5, 2.5-6, 2.5-8, 2.5-10, 2.5-15, 2.5-20, 2.5-25, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 3.5-3.5, 3-4.5, 3-5, 3-4.5, 3-5, 3-5.5, 3-6, 3-8, 3-10, 3-15, 3-20, 3-25, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 3.5-4, 3.5-4.5, 3.5-5, 3.5-5.5, 3.5-6, 3.5-8, 3.5-10, 3.5-15, 3.5-3.20, 3.5-3.25, 3.5-3.30, 3.5-40, 3.5-50, 3.5-60, 3.5-70, 3.5-80, 3.5-90, 3.5-100, 4-4.5, 4-5, 4-5.5, 4-6, 4-8, 4-10, 4-15, 4-20, 4-5.5, 4-6, 4-5, 4-5-6, 4-10, 4-15, 3-5, 3.5-90, 3, 4-25, 4-30, 4-40, 4-50, 4-60, 4-70, 4-80, 4-90, 4-100, 4.5-5, 4.5-5.5, 4.5-6, 4.5-8, 4.5-10, 4.5-15, 4.5-20, 4.5-25, 4.5-30, 4.5-4.50, 4.5-50, 4.5-60, 4.5-70, 4.5-80, 4.5-90, 4.5-100, 5-5.5, 5-6, 5-8, 5-10, 5-15, 5-20, 5-25, 5-30, 5-40, 5-50, 5-60, 5-70, 5-80, 5-90, 5-100, 5.5-6, 5.5-8, 5.5-10, 5-5.5-5-60, 5-5, 5.5-15, 5.5-20, 5.5-25, 5.5-30, 5.5-40, 5.5-50, 5.5-60, 5.5-70, 5.5-80, 5.5-90, 5.5-100, 6-8, 6-10, 6-15, 6-20, 6-25, 6-30, 6-40, 6-50, 6-60, 6-70, 6-80, 6-90, 6-100, 8-10, 8-15, 8-20, 8-25, 8-30, 8-40, 8-50, 8-60, 8-70, 8-80, 8-90, 8-100, 10-15, 10-20, 10-25, 10-30, 10-40, 10-50, 10-60, 8-80, 8-90, 8-100, 10-15, 10-20, 10-25, 10-30, 10-40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 15-20, 15-25, 15-30, 15-40, 15-50, 15-60, 15-70, 15-80, 15-90, 15-100, 20-25, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 25-30, 25-40, 25-50, 25-60, 25-70, 25-80, 25-90, 25-100, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 50-60, 50-70, 50-80, 50-90, 50-100, 60-70, 60-80, 60-90, 60-100, 70-80, 70-90, 70-100, 80-90, 80-100, or 90-100 milliseconds. In some cases, the maximum change in QRS interval duration (Δ QRS) may be about 1 to about 10 milliseconds after administration of the antiarrhythmic agent by inhalation. In some cases, the maximum change in QRS interval duration (Δ QRS) may be about 5 to about 20 milliseconds after administration of the antiarrhythmic agent by inhalation. In some cases, Δ QRS can be measured in a human PK/PD study. In the present disclosure, the term "Δ QRS," if not related to the post-administration time of the antiarrhythmic drug, may be used interchangeably with the term "maximum Δ QRS," e.g., meaning the maximum change in QRS after administration of the antiarrhythmic drug provided herein. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic agent is a class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

In some cases, the time point for measuring the QRS interval after administration of the antiarrhythmic agent by inhalation to determine the QRS relative to Δ QRS prior to administration may be about 0.1 minute to about 450 minutes, e.g., about 0.1-1, 0.1-3, 0.1-5, 0.1-10, 0.1-15, 0.1-30, 0.1-45, 0.1-60, 0.1-90, 0.1-120, 0.1-150, 0.1-180, 0.1-210, 0.1-240, 0.1-270, 0.1-300, 0.1-330, 0.1-360, 0.1-390, 0.1-410, 0.1-450, 1-3, 1-5, 1-10, 1-15, 1-30, 1-45, 1-60, 1-90, 1-120, 1-150, 1-180, 1-210, 1-240, 1-270, 1-300, 1-330, 1-360, 1-390, 1-410, 1-450, 3-5, 3-10, 3-15, 3-30, 3-45, 3-60, 3-90, 3-120, 3-150, 3-180, 3-210, 3-240, 3-270, 3-300, 3-330, 3-360, 3-390, 3-410, 3-450, 5-10, 5-15, 5-30, 5-45, 5-60, 5-90, 5-120, 5-150, 5-180, 5-210, 5-240, 5-270, 5-300, 5-330, 5-360, 5-390, 5-90, 5-410, 5-450, 10-15, 10-30, 10-45, 10-60, 10-90, 10-120, 10-150, 10-180, 10-210, 10-240, 10-270, 10-300, 10-330, 10-360, 10-390, 10-410, 10-450, 15-30, 15-45, 15-60, 15-90, 15-120, 15-150, 15-180, 15-210, 15-240, 15-270, 15-300, 15-330, 15-360, 15-390, 15-410, 15-450, 30-45, 30-60, 30-90, 30-120, 30-150, 30-180, 30-210, 30-240, 30-270, 30-300, 30-330, 30-360, 30-390, 30-410, 30-450, 45-60, 45-90, 45-120, 45-150, 45-180, 45-210, 45-240, 45-270, 45-300, 45-330, 45-360, 45-390, 45-410, 45-450, 60-90, 60-120, 60-150, 60-180, 60-210, 60-240, 60-270, 60-300, 60-330, 60-360, 60-390, 60-410, 60-450, 90-120, 90-150, 90-180, 90-210, 90-240, 90-270, 90-300, 90-330, 90-360, 90-390, 90-410, 90-450, 120-150, 120-180, 120-210, 120-240, 120-270, 120-300, 120-330, 120-360, 120-390, 120-410, 120-450, 150-180, 150-210, 150-240, 150-270, 150-300, 150-330, 150-360, 150-390, 150-410, 150-450, 180-210, 180-240, 180-270, 180-300, 180-330, 180-360, 180-410, 180-450, 210-270, 210-300, 210-330, 210-360, 210-410, 240-270, 300-300, 210-180-210-180, 240-.

The antiarrhythmic activity of the agent may be correlated with QRS interval duration. In some examples, an antiarrhythmic agent administered by inhalation may have a higher antiarrhythmic activity than an antiarrhythmic agent administered by intravenous delivery (e.g., intravenous infusion). In some cases, higher maximum Δ QRS and C_maxThe ratio reflects this higher antiarrhythmic activity. For example, given the same C_maxFor example, peak plasma concentrations of an antiarrhythmic agent, inhaled delivery of an antiarrhythmic agent provided herein can have a higher maximum Δ QRS as compared to intravenous delivery of the same agent. In some cases, it may not be possible to compare between corresponding doses administered by two different routes, e.g., inhaling a first dose of an agent may have a first C _max(C_max1) And a first maximum Δ QRS (Δ QRS)_max1) And a second dose of the agent administered intravenously may have a second C_max(C_max2) And a second maximum Δ QRS (Δ QRS)_max2). In some cases, C_max1And C_max2May be similar. In other cases, C_max1And C_max2May be different. In some examples of the disclosure, Δ QRS_max1And C_max1The ratio of (A) to (B) may be higher than Δ QRS_max2And C_max2The ratio of (i.e., Δ QRS)_max1/C_max1＞ΔQRS_max2/C_max2. In some cases, Δ QRS_max1/C_max1Is Δ QRS_max2/C_max2At least 1.1 times, at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.2 times, at least 2.3 times, at least 2.4 times, at least,At least 2.5 times, at least 2.6 times, at least 2.7 times, at least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, at least 3.8 times, at least 3.9 times, at least 4.0 times, at least 4.2 times, at least 4.4 times, at least 4.6 times, at least 4.8 times, at least 5.0 times, at least 5.5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times, at least 20 times, at least 25 times, or at least 50 times. In some cases, Δ QRS_max1/C_max1Ratio Δ QRS_max2/C_max2At least 2 times greater. In one or more embodiments, the antiarrhythmic agent is a class I, class II, class III, or class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic agent is a class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic agent is flecainide or a pharmaceutically acceptable salt thereof.

The invention will be further illustrated by the following examples. These examples are non-limiting and do not limit the scope of the invention. Unless otherwise indicated, all percentages, parts, etc. given in the examples are by weight.

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