Intranasal adrenaline preparation and the method for treating disease

文档序号：1745347 发布日期：2019-11-26 浏览：25次中文

阅读说明：本技术 鼻内肾上腺素制剂及治疗疾病的方法 (Intranasal adrenaline preparation and the method for treating disease ) 是由理查德·洛温塔尔 E·T·马乔罗伯特·G·贝尔普拉蒂克·沙阿于 2019-02-06 设计创作，主要内容包括：提供了包含具有肾上腺素的制剂的适合于鼻腔递送的药物产品,以及包含这样的制剂的装置。还提供了用肾上腺素产品治疗过敏反应的方法。(It provides comprising the drug products for being suitable for nasal delivery with adrenergic preparation, and the device comprising such preparation.It additionally provides and treats anaphylactoid method with adrenaline product.)

1. a kind of nasal spray pharmaceutical preparation, comprising about 0.40mg to about in the nasal spray pharmaceutical preparation of single dose The adrenaline of 2.4mg or its salt.

2. preparation as described in claim 1, wherein to the nasal spray pharmaceutical preparation of subject's intranasal administration single dose It provides for treating the acute effective plasma epinephrine concentration of hypersensitivity.

3. the preparation as described in claim 1 or claim 2, wherein the nasal spray pharmaceutical preparation is aqueous solution, water Property suspension, water-based emulsion, non-aqueous solution, non-aqueous suspensions, non-aqueous lotion or dry powder.

4. preparation as claimed in any one of claims 1-3, wherein being sprayed to the nasal cavity of subject's intranasal administration single dose Mist pharmaceutical preparation provides the pharmacokinetics when intramuscular (IM) injection is given in big leg outer side similar to IM injection, or is similar to The subcutaneously absorption of (SC) or therebetween.

5. preparation as claimed in any one of claims 1-3, wherein being sprayed to the nasal cavity of subject's intranasal administration single dose Mist pharmaceutical preparation provides the absorption for being similar to subcutaneous (SC), and SC pharmacokinetics spectrum has at least C of 100pg/mL_maxWith The AUC of 150h*pg/mL_0-240min。

6. preparation as claimed in any one of claims 1-3, wherein being sprayed to the nasal cavity of subject's intranasal administration single dose Mist pharmaceutical preparation provides the absorption for being similar to intramuscular (IM) injection.

7. preparation as claimed in any one of claims 1-3, wherein being sprayed to the nasal cavity of subject's intranasal administration single dose Mist pharmaceutical preparation provides one of following Pharmacokinetic Characteristics or a variety of:

Average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.3mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；

Average C_maxThe C generated for 0.3mg intramuscular injection_maxAt least 80% and be no more than the Cmax 150%；

Average t_maxLess than 45 minutes；And

The absorption that IM injection is similar under the conditions of most preferably administration in thigh.

8. preparation as claimed in any one of claims 1-3, wherein being sprayed to the nasal cavity of subject's intranasal administration single dose Mist pharmaceutical preparation provides one of following Pharmacokinetic Characteristics or a variety of:

Average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.15mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；

Average C_maxThe C generated for 0.15mg intramuscular injection_maxAt least 80% and be no more than the Cmax 150%；

Average t_maxLess than 45 minutes；And

The absorption that IM injection is similar under the conditions of most preferably administration in thigh.

9. preparation as claimed in any one of claims 1-3, wherein being sprayed to the nasal cavity of subject's intranasal administration single dose Mist pharmaceutical preparation provides one of following Pharmacokinetic Characteristics or a variety of:

Average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.5mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；

Average C_maxThe C generated for 0.5mg intramuscular injection_maxAt least 80% and be no more than the Cmax 150%；

Average t_maxLess than 45 minutes；And

The absorption that IM injection is similar under the conditions of most preferably administration in thigh.

10. preparation as claimed in any one of claims 1-9 wherein, wherein the nasal spray pharmaceutical preparation of single dose includes about The adrenaline or its salt of 0.5mg to about 2.0mg.

11. preparation as claimed in any one of claims 1-9 wherein, wherein the nasal spray pharmaceutical preparation of single dose includes about The adrenaline or its salt of 0.5mg to about 1.5mg.

12. preparation as claimed in any one of claims 1-9 wherein, wherein the nasal spray pharmaceutical preparation of single dose includes about The adrenaline or its salt of 0.5mg to about 0.7mg.

13. preparation as claimed in any one of claims 1-9 wherein, wherein the nasal spray pharmaceutical preparation of single dose includes about The adrenaline of 1.0mg or its salt.

14. preparation as claimed in any one of claims 1-9 wherein, wherein the nasal spray pharmaceutical preparation of single dose includes about The adrenaline or its salt of 1.3mg to about 1.5mg.

15. the preparation as described in any one of claim 1-14, wherein the nasal spray pharmaceutical preparation includes a kind of or more Kind sorbefacient；And optional one or more medicaments selected from the following: isotonic agent；Stabilizer；Preservative；Odor mask； Viscosity improver；Antioxidant；Buffer and pH adjusting agent；Wherein the pH of the nasal spray pharmaceutical preparation is about 2.0 to about Between 6.0.

16. the preparation as described in any one of claim 1-15, wherein the pH of the nasal spray pharmaceutical preparation about 3.0 to Between about 5.0.

17. the preparation as described in any one of claim 1-15, wherein the pH of the nasal spray pharmaceutical preparation is about 4.0.

18. the preparation as described in any one of claim 15-17, wherein the nasal spray pharmaceutical preparation is adjusted comprising pH Agent.

19. preparation as claimed in claim 18, wherein the pH adjusting agent is acid, alkali, buffer or combinations thereof.

20. preparation as claimed in claim 19, in which:

The acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid；

The alkali is sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate；And

The buffer is phosphate buffer, acetate buffer or citrate buffer agent.

21. preparation as claimed in claim 15, wherein the nasal spray pharmaceutical preparation includes relative to every mole of adrenal gland The acid of plain about 0.5 to about 1.1 molar equivalent.

22. preparation as claimed in claim 21, wherein the acid is hydrochloric acid.

23. the preparation as described in any one of claim 15-22, wherein the preparation includes one or more absorption enhancements Agent, the sorbefacient are selected from ethyl alcohol, Aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetyl chloride pyrrole Pyridine, chitosan, cyclodextrin, deoxycholic acid, capryl, dimethyl sulfoxide, Monoolein, glycogen, glycogen, glycosyl Change sphingol, enoxolone, 2-HP-BETA-CD, laureth -9, lauric acid, Laurylcarnitine, hemolytic phosphatidyl Choline, menthol, poloxamer188 or F68, poly-L-arginine, polyoxyethylene -9- laurel ether, isopropyl myristate, palm fibre Palmitic acid isopropyl propionate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid or its salt, oleyl alcohol, Palmitinic acid, polysorbate 20, polyoxyethylene sorbitan monoleate, propylene glycol, polyoxyethylene alkyl ether, polyoxyglyceride, pyrrolidones, Quillaia saponaria soap Glycosides, salicylic acid, sodium salt, cupreol β-D- glucoside, lauryl sodium sulfate, sucrose cocounut oil acid esters, taurocholate, ox sulphur are de- Oxycholic acid, ox sulphur dihydro fusidinic acid, Thymol, tricaprylin, triolein and alkyl sugar.

24. the preparation as described in any one of claim 15-22, wherein the preparation includes one or more absorption enhancements Agent, the sorbefacient are selected from Lauryl.beta.-maltoside, benzalkonium chloride, oleic acid or its salt, polysorbate 20, polysorbate 80 and lauryl sodium sulfate.

25. the preparation as described in any one of claim 15-22, wherein one or more sorbefacients are:

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside；Or

About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；Or

About 0.001 (w/v) is to about 1% (w/v) oleic acid or its salt；Or

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) benzene Prick the combination of oronain；Or

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) oil The combination of acid or its salt；Or

About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt group It closes.

26. the preparation as described in any one of claim 15-22, wherein one or more sorbefacients are:

About 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride；Or

About 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or

About 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride；

Wherein the benzalkonium chloride is unique sorbefacient in the preparation, or with one or more other absorption enhancements Agent is present in together in the preparation.

27. the preparation as described in any one of claim 15-26, wherein the nasal spray pharmaceutical preparation includes stabilizer.

28. preparation as claimed in claim 27, wherein the stabilizer is ethylenediamine tetra-acetic acid (EDTA) or its salt.

29. preparation as claimed in claim 28, wherein the EDTA is EDETATE SODIUM.

30. preparation as claimed in claim 29, wherein the preparation includes about 0.001% (w/v's) to about 1% (w/v) EDETATE SODIUM.

31. the preparation as described in any one of claim 15-30, wherein the preparation includes preservative.

32. preparation as claimed in claim 31, wherein the preservative is benzalkonium chloride.

33. the preparation as described in any one of claim 15-32, wherein the nasal spray pharmaceutical preparation includes isotonic agent.

34. preparation as claimed in claim 33, wherein the isotonic agent is glucose, glycerol, mannitol, potassium chloride or chlorination Sodium.

35. preparation as claimed in claim 33, wherein the isotonic agent is sodium chloride.

36. a kind of method for treating the patient's condition mediated by adrenergic receptor comprising intranasal administration such as claim 1-35 Any one of described in preparation.

37. method as claimed in claim 36, wherein the patient's condition is selected from 1 type hypersensitivity (whole body allergy), acute Asthma attack, cardiac arrest and Stokes-Adams syndrome.

38. method as claimed in claim 37, wherein the patient's condition is 1 type hypersensitivity (whole body allergy).

39. method as claimed in claim 38, wherein the 1 type hypersensitivity be selected from allergic asthma, allergic conjunctivitis, Allergic rhinitis, allergic reaction, angioedema, nettle rash, eosinophilia, drug allergy and food allergies are anti- It answers.

40. method as claimed in claim 39, wherein the drug allergy is antibiotic allergy.

41. a kind of nasal spray pharmaceutical preparation comprising adrenaline or its salt, wherein to subject's intranasal administration single dose The nasal spray pharmaceutical preparation provides one of following Pharmacokinetic Characteristics or a variety of:

Average AUC_0-20minWith average AUC_0-tIt is the average AUC that 0.3mg intramuscular injection provides_0-20minWith average AUC_0-t's At least 80%；

Average C_maxThe C provided for 0.3mg intramuscular injection_maxAt least 80% and be no more than the Cmax 150%；

Average t_maxLess than 45 minutes；And

The absorption that intramuscular (IM) injection is similar under the conditions of most preferably administration in thigh.

42. a kind of nasal spray pharmaceutical preparation comprising adrenaline or its salt, wherein to subject's intranasal administration single dose The nasal spray pharmaceutical preparation provides one of following Pharmacokinetic Characteristics or a variety of:

Average AUC_0-20minWith average AUC_0-tIt is the average AUC that 0.15mg intramuscular injection provides_0-20minWith average AUC_0-t's At least 80%；

Average C_maxThe C provided for 0.15mg intramuscular injection_maxAt least 80% and be no more than the C_max150%；

Average t_maxLess than 45 minutes；And

The absorption that intramuscular (IM) injection is similar under the conditions of most preferably administration in thigh.

43. a kind of nasal spray pharmaceutical preparation comprising adrenaline or its salt, wherein to subject's intranasal administration single dose The nasal spray pharmaceutical preparation provides one of following Pharmacokinetic Characteristics or a variety of:

Average AUC_0-20minWith average AUC_0-tIt is the average AUC that 0.5mg intramuscular injection provides_0-20minWith average AUC_0-t's At least 80%；

Average C_maxThe C provided for 0.5mg intramuscular injection_maxAt least 80% and be no more than the C_max150%；

Average t_maxLess than 45 minutes；And

The absorption that intramuscular (IM) injection is similar under the conditions of most preferably administration in thigh.

44. the preparation as described in any one of claim 41-43, wherein to the nasal cavity of subject's intranasal administration single dose Sprayable pharmaceutical preparation provides the absorption for being similar to intramuscular (IM) injection.

45. the preparation as described in any one of claim 41-44, wherein to the nasal cavity of subject's intranasal administration single dose Sprayable pharmaceutical preparation is provided for treating the acute effective plasma epinephrine concentration of hypersensitivity.

46. the preparation as described in any one of claim 41-45, wherein the nasal spray pharmaceutical preparation of single dose includes The adrenaline or its salt of about 0.5mg to about 2.0mg.

47. the preparation as described in any one of claim 41-45, wherein the nasal spray pharmaceutical preparation of single dose includes The adrenaline or its salt of about 0.5mg to about 1.5mg.

48. the preparation as described in any one of claim 42,44 and 45, the wherein nasal spray pharmaceutical preparation of single dose Include about 0.5mg to the adrenaline of about 0.7mg or its salt.

49. the preparation as described in any one of claim 41,44 and 45, the wherein nasal spray pharmaceutical preparation of single dose Adrenaline comprising about 1.0mg or its salt.

50. the preparation as described in any one of claim 43-45, wherein the nasal spray pharmaceutical preparation of single dose includes The adrenaline or its salt of about 1.3mg to about 1.5mg.

51. the preparation as described in any one of claim 41-50, wherein the preparation is aqueous solution, aqueous suspension, water Property lotion, non-aqueous solution, non-aqueous suspensions, non-aqueous lotion, pressurized metered dose inhaler or dry powder.

52. the preparation as described in any one of claim 41-51, wherein the nasal spray pharmaceutical preparation includes a kind of or more Kind sorbefacient；And optional one or more medicaments selected from the following: isotonic agent；Stabilizer；Preservative；Odor mask； Viscosity improver；Antioxidant；Buffer and pH adjusting agent；Wherein the pH of the nasal spray pharmaceutical preparation is about 2.0 to about Between 6.0.

53. the preparation as described in any one of claim 41-52, wherein the pH of the nasal spray pharmaceutical preparation is about 3.0 To between about 5.0.

54. the preparation as described in any one of claim 41-52, wherein the pH of the nasal spray pharmaceutical preparation is about 4.0.

55. the preparation as described in any one of claim 52-54, wherein the nasal spray pharmaceutical preparation is adjusted comprising pH Agent.

56. preparation as claimed in claim 55, wherein the pH adjusting agent is acid, alkali, buffer or combinations thereof.

57. preparation as claimed in claim 56, in which:

The acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid；

The alkali is sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate；And

The buffer is phosphate buffer, acetate buffer or citrate buffer agent.

58. the preparation as described in any one of claim 52-57, wherein the preparation includes one or more absorption enhancements Agent, the sorbefacient are selected from ethyl alcohol, Aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, cetyl chloride pyrrole Pyridine, chitosan, cyclodextrin, deoxycholic acid, capryl, dimethyl sulfoxide, Monoolein, glycogen, glycogen, glycosyl Change sphingol, enoxolone, 2-HP-BETA-CD, laureth -9, lauric acid, Laurylcarnitine, hemolytic phosphatidyl Choline, menthol, poloxamer188 or F68, poly-L-arginine, polyoxyethylene -9- laurel ether, isopropyl myristate, palm fibre Palmitic acid isopropyl propionate, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid or its salt, oleyl alcohol, Palmitinic acid, polysorbate 20, polyoxyethylene sorbitan monoleate, propylene glycol, polyoxyethylene alkyl ether, polyoxyglyceride, pyrrolidones, Quillaia saponaria soap Glycosides, salicylic acid, sodium salt, cupreol β-D- glucoside, lauryl sodium sulfate, sucrose cocounut oil acid esters, taurocholate, ox sulphur are de- Oxycholic acid, ox sulphur dihydro fusidinic acid, Thymol, tricaprylin, triolein and alkyl sugar.

59. the preparation as described in any one of claim 52-57, wherein the preparation includes one or more absorption enhancements Agent, the sorbefacient are selected from Lauryl.beta.-maltoside, benzalkonium chloride, oleic acid or its salt, polysorbate 20, polysorbate 80 and lauryl sodium sulfate.

60. the preparation as described in any one of claim 52-57, wherein one or more sorbefacients are:

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside；Or

About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；Or

About 0.001 (w/v) is to about 1% (w/v) oleic acid or its salt；Or

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) benzene Prick the combination of oronain；Or

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) oil The combination of acid or its salt；Or

About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt group It closes.

61. the preparation as described in any one of claim 52-57, wherein one or more sorbefacients are:

About 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride；Or

About 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or

About 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride；

Wherein the benzalkonium chloride is unique sorbefacient in the preparation, or with one or more other absorption enhancements Agent is present in together in the preparation.

62. the preparation as described in any one of claim 52-61, wherein the nasal spray pharmaceutical preparation includes stabilizer.

63. preparation as claimed in claim 62, wherein the stabilizer is ethylenediamine tetra-acetic acid (EDTA) or its salt.

64. the preparation as described in claim 63, wherein the EDTA is EDETATE SODIUM.

65. the preparation as described in claim 64, wherein the preparation includes about 0.001% (w/v's) to about 1% (w/v) EDETATE SODIUM.

66. the preparation as described in any one of claim 52-65, wherein the preparation includes preservative.

67. the preparation as described in claim 66, wherein the preservative is benzalkonium chloride.

68. the preparation as described in any one of claim 52-67, wherein the nasal spray pharmaceutical preparation includes isotonic agent.

69. preparation as recited in claim 68, wherein the isotonic agent is glucose, glycerol, mannitol, potassium chloride or chlorination Sodium.

70. preparation as recited in claim 68, wherein the isotonic agent is sodium chloride.

71. a kind of method for treating the patient's condition mediated by adrenergic receptor comprising intranasal administration such as claim 41-70 Any one of described in preparation.

72. the method as described in claim 71, wherein the patient's condition is selected from 1 type hypersensitivity (whole body allergy), acute Asthma attack, cardiac arrest and Stokes-Adams syndrome.

73. the method as described in claim 72, wherein the patient's condition is 1 type hypersensitivity (whole body allergy).

74. the method as described in claim 73, wherein the 1 type hypersensitivity be selected from allergic asthma, allergic conjunctivitis, Allergic rhinitis, allergic reaction, angioedema, nettle rash, eosinophilia, drug allergy and food allergies are anti- It answers.

75. the method as described in claim 74, wherein the drug allergy is antibiotic allergy.

76. a kind of treat anaphylactoid method comprising to be less than about the adrenergic nasal cavity medicine of amount intranasal administration of 2.0mg Object preparation.

77. the method as described in claim 76, wherein the nasal cavity medicine preparation includes on the kidney of about 0.5mg to about 1.5mg Parathyrine or its salt.

78. the method as described in claim 76, wherein the nasal cavity medicine preparation includes on the kidney of about 0.5mg to about 0.7mg Parathyrine or its salt.

79. the method as described in claim 76, wherein the nasal cavity medicine preparation include about 1.0mg adrenaline or its Salt.

80. the method as described in claim 76, wherein the nasal cavity medicine preparation includes on the kidney of about 1.3mg to about 1.5mg Parathyrine or its salt.

81. the method as described in any one of claim 76-80, wherein the intranasal preparation includes:

One or more sorbefacients；

Isotonic agent；

Stabilizer；

Optional antioxidant；

Optional buffer；

Preservative；And

Optional pH adjusting agent.

82. the method as described in claim 81, wherein one or more sorbefacients are selected from:

Lauryl.beta.-maltoside；

Benzalkonium chloride；

Oleic acid or its salt；

The combination of Lauryl.beta.-maltoside and benzalkonium chloride；

The combination of Lauryl.beta.-maltoside and oleic acid or its salt；And

The combination of benzalkonium chloride and oleic acid or its salt.

83. the method as described in claim 81, wherein one or more sorbefacients are selected from:

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside；

About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；

About 0.001 (w/v) is to about 1% (w/v) oleic acid or its salt；

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) benzene Prick the combination of oronain；

About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) oil The combination of acid or its salt；Or

About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt group It closes.

84. the method as described in any one of claim 81-83, wherein the preparation includes:

About 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride；

About 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or

About 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride；

Wherein the benzalkonium chloride is unique sorbefacient in the preparation, or together with one or more sorbefacients It is present in the preparation.

85. the method as described in any one of claim 81-84, in which:

The isotonic agent is sodium chloride.

86. the method as described in any one of claim 81-85, in which:

The stabilizer is EDTA.

87. the method as described in any one of claim 81-85, in which:

The stabilizer is the EDTA of the amount of about 0.001% (w/v) to about 1% (w/v).

88. the method as described in any one of claim 81-87, in which:

The preservative is benzalkonium chloride.

89. the method as described in any one of claim 81-87, in which:

The preservative is the benzalkonium chloride of the amount of about 0.001% (w/v) to about 1% (w/v).

Invention field

This document describes intranasal (IN) adrenaline preparation and use such preparation for treating patient's condition or the method for disease.

Background of invention

Allergic reaction is a kind of condition, it may be necessary to recovery measure, such as airway management, supplemental oxygen, a large amount of Venous transfusion and closely monitoring.Application adrenaline is the selection for the treatment of.Need to give adrenergic needleless and Noninvasive Method.There is provided herein method, preparation and the devices for treating allergic reaction and other patient's condition.

Summary of the invention

Disclosed herein is method, adrenergic pharmaceutical preparation and its for treating such as 1 type hypersensitivity, (whole body is abnormal Reaction), the methods of the patient's condition such as asthma and cardiac arrest.

Allergic reaction is the 1 type hypersensitivity (whole body allergy) of serious, possible threat to life, influences many bodies System system is usually intravenously being exposed to average about 5 to 30 minutes after antigen and about 2 hours quick hairs after the exposure of oral cavity Make.Allergic reaction is caused by the inflammatory mediator and cell factor discharged from mast cell and basophilic granulocyte, and the release is logical Normally due to immune response, but sometimes due to nonimmune mechanism.The most common impacted body region includes: skin (80- 90%), respiratory tract (70%), gastrointestinal tract (30-45%), heart and vascular system (10-45%) and central nervous system (10-15%), usual single episode are related to two or more regions.

Allergic reaction is a kind of condition, it may be necessary to recovery measure, such as airway management, supplemental oxygen, a large amount of Venous transfusion and closely monitoring.Application adrenaline is the selection for the treatment of, and antihistaminic and steroids (for example, dexamethasone) are normal As adjuvant.Due to worrying two stages allergic reaction, it is generally necessary to be observed in 2 to 24 hours institutes after people restores normal Phase.

Adrenaline (adrenaline, (R) -4- (1- hydroxyl -2- (methylamino) ethyl) benzene -1,2- glycol) is allergic reaction Primary treatments, be used for not absolute contraindication.Currently, adrenaline as by the solution given of injection into Row application, it is preferable that once suspecting there is allergic reaction, be injected into outer middle side part before thigh immediately.It, can if response is insufficient Every duplicate injection in 5 to 15 minutes.The breaking-out of 16-35% needs to be administered for second, but seldom needs to be more than to be administered twice.Intramuscular way Diameter is better than subcutaneous administration, because the latter may have the adrenaline of delay to absorb.However, although only reporting by adrenaline Caused slight adverse reaction (is trembled, anxiety, headache and palpitaition), but there are many reports to claim, and the exposure of injection product is high What degree can be changed, depending on the position (intramuscular or subcutaneous) of injection and other factors such as body mass index (BMI).

Exploitation is highly desirable in medical field will may consequently contribute to improve the anaphylactoid product of clinical management under institute's external environment. Although adrenaline is that effectively, disclosed evidence shows that pharmacokinetics is that height can when being delivered by intramuscular injection Become, depends on injection site (intramuscular or subcutaneous).Using the approved automatic injector of complex technology, there is also significant Product quality problem causes U.S. FDA many times to recall these products.Adrenaline automatic injector is such asIt is also difficult to carry, and needs the trained and time that could suitably apply in the case where possible threat to life.

To for give it is adrenergic substitution, needleless and Noninvasive method demand be it will be apparent that because Many patients fear to inject and be therefore unwilling using any kind of automatic injector.In addition, automatic injector is big and heavy, because This many patient in need is without carrying always epinephrine injection device.It is unwilling in public environment self-administering dosage It is obvious.

Therefore, it is necessary in case of emergency give adrenergic improvement or substitution method, and improve or substitute Preparation and device.Desired improvement individually and in combination includes: conveniently (intranasally with intramuscular), more rapidly to apply, more reliable, more Consistent dosage, needleless is more discrete to be administered in public, and can be applied by unbred individual or layman With.

Therefore, there is provided herein method, preparation and the devices for treating allergic reaction and other patient's condition, including use small Type compressed unit dosage spraying device applies adrenergic intranasal preparation.

In one aspect, this document describes nasal spray pharmaceutical preparations, and it includes about 0.40mg to the adrenal gland of about 2.4mg Element or its salt.On the other hand, this document describes nasal spray pharmaceutical preparations, in the nasal spray pharmaceutical preparation of single dose In include about 0.40mg to about 2.4mg adrenaline or its salt.On the other hand, this document describes nasal spray drug systems Agent includes the adrenaline or its salt of about 0.40mg to about 2.4mg in single dose nasal spray pharmaceutical preparation.In some realities It applies in scheme, the nasal spray pharmaceutical preparation includes the adrenaline or its salt of about 0.40mg to about 2.0mg.In some implementations In scheme, the nasal spray pharmaceutical preparation includes the adrenaline or its salt of about 0.40mg to about 1.8mg.In some embodiment party In case, the nasal spray pharmaceutical preparation of single dose includes the adrenaline or its salt of about 0.5mg to about 2.0mg.Some In embodiment, the nasal spray pharmaceutical preparation of single dose includes the adrenaline or its salt of about 0.5mg to about 1.5mg. In some embodiments, the nasal spray pharmaceutical preparation of single dose include about 0.5mg to about 0.7mg adrenaline or Its salt.In some embodiments, the nasal spray pharmaceutical preparation of single dose include about 1.0mg adrenaline or its Salt.In some embodiments, the nasal spray pharmaceutical preparation of single dose includes the adrenal gland of about 1.3mg to about 1.5mg Element or its salt.In some embodiments, to the offer pair of the nasal spray pharmaceutical preparation of subject's intranasal administration single dose In the acute effective plasma epinephrine concentration of hypersensitivity for the treatment of.In some embodiments, the nasal spray drug system Agent is aqueous solution, aqueous suspension, water-based emulsion, non-aqueous solution, non-aqueous suspensions, non-aqueous lotion or dry powder.

In one aspect, this document describes nasal spray preparation, it includes the every dosage about 0.40mg distributed from device to The adrenaline of about 2.4mg or its salt.In some embodiments, this document describes nasal spray preparation, it includes from device The adrenaline or its salt of every dosage about 0.5mg to about 2.0mg of distribution；The every dosage about 0.5mg distributed from device is to about The adrenaline of 1.5mg or its salt；The adrenaline or its salt of the every dosage about 0.5mg to about 0.7mg distributed from device；From dress Set the adrenaline or its salt of every dosage about 1.0mg of distribution；Or the every dosage about 1.3mg distributed from device is to about 1.5mg's Adrenaline or its salt.In some embodiments, when intranasal administration, the nasal spray preparation of single dose is provided for treatment The acute effective plasma epinephrine concentration of hypersensitivity.In some embodiments, the adrenaline or its salt with for It treats acute hypersensitivity and effectively measures and be present in the pharmaceutical preparation.In some embodiments, the nasal spray system Agent is aqueous solution, aqueous suspension, water-based emulsion, non-aqueous solution, non-aqueous suspensions or non-aqueous lotion.

In some embodiments, the nasal spray preparation includes on the kidney of every dosage about 1mg/mL to about 40mg/mL Parathyrine or its salt.In some embodiments, the nasal spray preparation includes the kidney of every dosage about 5mg/mL to about 40mg/mL Upper parathyrine or its salt.In some embodiments, the nasal spray preparation includes every dosage about 1mg/mL to about 20mg/mL's Adrenaline or its salt.In some embodiments, the nasal spray preparation includes every dosage about 3mg/mL to about 20mg/mL Adrenaline or its salt.In some embodiments, the nasal spray preparation includes every dosage about 3mg/mL to about 15mg/ The adrenaline of mL or its salt.In some embodiments, the nasal spray preparation includes every dosage about 3mg/mL, about 4mg/ ML, about 5mg/mL, about 6mg/mL, about 7mg/mL, about 8mg/mL, about 9mg/mL, about 10mg/mL, about 11mg/mL, about 12mg/ ML, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/mL, about 19mg/mL or about The adrenaline of 20mg/mL or its salt.In some embodiments, the dosage of the nasal spray preparation includes about 100 μ L's Nasal spray adrenaline preparation as described herein.

In some embodiments, nasal spray preparation as described herein includes on the kidney of about 1mg/mL to about 40mg/mL Parathyrine or its salt.In some embodiments, nasal spray preparation as described herein includes the kidney of about 1mg/mL to about 20mg/mL Upper parathyrine or its salt.In some embodiments, nasal spray preparation as described herein includes about 1mg/mL to about 18mg/mL's Adrenaline or its salt.In some embodiments, nasal spray preparation as described herein include about 1mg/mL, about 2mg/mL, About 3mg/mL, about 4mg/mL, about 5mg/mL, about 6mg/mL, about 7mg/mL, about 8mg/mL, about 9mg/mL, about 10mg/mL, about 11mg/mL, about 12mg/mL, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/ The adrenaline of mL, about 19mg/mL or about 20mg/mL or its salt.In some embodiments, nasal spray system as described herein Agent includes about 3mg/mL, about 5mg/mL, about 6mg/mL, about 6.5mg/mL, about 7mg/mL, about 7.5mg/mL, about 8mg/mL, about 8.5mg/mL, about 9mg/mL, about 9.5mg/mL, about 10mg/mL, about 10.5mg/mL, about 11mg/mL, about 11.5mg/mL, about 12mg/mL, about 12.5mg/mL, about 13mg/mL, about 13.5mg/mL, about 14mg/mL, about 14.5mg/mL or about 15mg/mL's Adrenaline or its salt.In some embodiments, nasal spray preparation as described herein includes the adrenaline of about 10mg/mL Or its salt.In some embodiments, nasal spray preparation as described herein includes the adrenal gland of about 6mg/mL to about 8mg/mL Element or its salt.In some embodiments, nasal spray preparation as described herein includes the kidney of about 13mg/mL to about 15mg/mL Upper parathyrine or its salt.In some embodiments, the dosage of the nasal spray preparation includes the nose as described herein of about 100 μ L Chamber is sprayed adrenaline preparation.

In some embodiments, the nasal spray preparation as described herein of the dosage of about 100 μ L includes 1mg/mL to about The adrenaline of 40mg/mL or its salt.In some embodiments, the nasal spray system as described herein of the dosage of about 100 μ L Agent includes 1mg/mL to the adrenaline of 20mg/mL or its salt.In some embodiments, this paper institute of the dosage of about 100 μ L The nasal spray preparation stated include 3mg/mL, 3.5mg/mL, 4mg/mL, 4.5mg/mL, 5mg/mL, 6mg/mL, 6.5mg/mL, 7mg/mL、7.5mg/mL、8mg/mL、8.5mg/mL、9mg/mL、9.5mg/mL、10mg/mL、10.5mg/mL、11mg/mL、 The kidney of 11.5mg/mL, 12mg/mL, 12.5mg/mL, 13mg/mL, 13.5mg/mL, 14mg/mL, 14.5mg/mL or 15mg/mL Upper parathyrine or its salt.

In some embodiments, the nasal spray preparation includes one or more sorbefacients.

In some embodiments, the nasal spray preparation provides the class when intramuscular (IM) injection is given in big leg outer side It is similar to the pharmacokinetics of IM injection, or similar to the subcutaneously absorption of (SC) or therebetween.

In some embodiments, the nasal spray preparation provides the absorption for being similar to intramuscular (IM) injection.

In some embodiments, the nasal spray preparation provides the absorption for being similar to subcutaneous (SC), and SC medicine generation Kinetic spectrum has at least C of 100pg/mL_maxWith the AUC of 150h*pg/mL_0-240min。

In some embodiments, it is provided to the nasal spray pharmaceutical preparation of subject's intranasal administration single dose similar In the absorption of intramuscular (IM) injection.

In some embodiments, when being applied to subject, the nasal spray preparation generates following pharmacokinetics One of feature is a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.3mg intramuscular injection generates_0-20minAnd AUC_0-t's At least 80%；Average C_maxThe C generated for 0.3mg intramuscular injection_maxAt least 80% and be no more than the C_max150%；It is average t_maxLess than 45 minutes；Or the absorption that IM injection is similar under the conditions of most preferably administration in thigh.In some embodiments In, when being applied to subject, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.3mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；Average C_maxFor 0.3mg The C that intramuscular injection generates_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；And in thigh In best administration under the conditions of be similar to the absorption of IM injection.

In some embodiments, when being applied to subject, the nasal spray preparation generates following pharmacokinetics One of feature is a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.15mg intramuscular injection generates_0-20minAnd AUC_0-t At least 80%；Average C_maxThe C generated for 0.15mg intramuscular injection_maxAt least 80% and be no more than the C_max150%；It is flat Equal t_maxLess than 45 minutes；Or the absorption that IM injection is similar under the conditions of most preferably administration in thigh.In some embodiments In, when being applied to subject, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.15mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；Average C_maxFor The C that 0.15mg intramuscular injection generates_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；And The absorption that IM injection is similar under the conditions of most preferably administration in thigh.

In some embodiments, when being applied to subject, the nasal spray preparation generates following pharmacokinetics One of feature is a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.5mg intramuscular injection generates_0-20minAnd AUC_0-t's At least 80%；Average C_maxThe C generated for 0.5mg intramuscular injection_maxAt least 80% and be no more than the C_max150%；It is average t_maxLess than 45 minutes；Or the absorption that IM injection is similar under the conditions of most preferably administration in thigh.In some embodiments In, when being applied to subject, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.5mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；Average C_maxFor 0.5mg The C that intramuscular injection generates_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；And in thigh In best administration under the conditions of be similar to the absorption of IM injection.

In some embodiments, the nasal spray preparation includes relative to every mole of adrenaline about 0.5 to about 1.1 The acid of molar equivalent.In some embodiments, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphorus Acid, propionic acid, sulfuric acid or tartaric acid.In some embodiments, the acid is hydrochloric acid.In some embodiments, in the nose Alkali is not added thereto during the preparation of chamber spray formulation.In some embodiments, the pH of the nasal spray preparation is about Between 2.0 to about 6.0.In some embodiments, the pH of the nasal spray preparation is about 4.0.

In some embodiments, the nasal spray preparation includes on the kidney of every dosage about 5mg/mL to about 40mg/mL Parathyrine or its salt.In some embodiments, the nasal spray preparation includes every dosage about 0.9mg for distributing from device to about The adrenaline of 2.40mg or its salt.In some embodiments, the nasal spray preparation includes every dose distributed from device Measure the adrenaline or its salt of about 0.5mg to about 2.0mg.In some embodiments, the nasal spray preparation includes from dress Set the adrenaline or its salt of every dosage about 0.9mg to about 1.5mg of distribution.In some embodiments, the nasal spray Preparation includes the adrenaline or its salt of the every dosage about 0.75mg to about 1.5mg distributed from device.In some embodiments, The nasal spray preparation includes the adrenaline or its salt of the every dosage about 0.45mg to about 1.15mg distributed from device.One In a little embodiments, the nasal spray preparation includes the adrenaline of the every dosage about 1.0mg to about 2.0mg distributed from device Or its salt.In some embodiments, the nasal spray preparation includes every dosage about 0.5mg for distributing from device to about The adrenaline of 2.0mg or its salt.In some embodiments, the nasal spray preparation includes the every dosage distributed from device The adrenaline or its salt of about 0.5mg to about 1.5mg.In some embodiments, the nasal spray preparation includes from device The adrenaline or its salt of every dosage about 0.5mg to about 0.7mg of distribution.In some embodiments, the nasal spray system Agent includes the adrenaline or its salt of the every dosage about 1.0mg distributed from device.In some embodiments, the nasal spray Preparation includes the adrenaline or its salt of the every dosage about 1.3mg to about 1.5mg distributed from device.

In some embodiments, the pH of the nasal spray pharmaceutical preparation is between about 3.0 to about 5.0.In some realities It applies in scheme, the pH of the nasal spray pharmaceutical preparation is about 4.0.In some embodiments, the nasal spray drug system Agent includes pH adjusting agent.In some embodiments, the pH adjusting agent is acid, alkali, buffer or combinations thereof.In some implementations In scheme, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid；Institute Stating alkali is sodium hydroxide, sodium citrate, sodium bicarbonate, sodium carbonate；And the buffer is that phosphate buffer, acetate are slow Electuary or citrate buffer agent.In some embodiments, the nasal spray pharmaceutical preparation includes relative to every mole of kidney The acid of about 0.5 to about 1.1 molar equivalent of upper parathyrine.In some embodiments, the acid is hydrochloric acid.

In some embodiments, the nasal spray preparation includes one or more sorbefacients, and the absorption promotees Lauryl.beta.-maltoside, benzalkonium chloride, oleic acid or its salt, polysorbate 20, polyoxyethylene sorbitan monoleate and dodecyl are selected from into agent Sodium sulphate.

In some embodiments, the preparation includes one or more sorbefacients, and the sorbefacient is selected from Ethyl alcohol, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, hexadecylpyridinium chloride, chitosan, cyclodextrin, takes off Aprotinin Oxycholic acid, capryl, dimethyl sulfoxide, Monoolein, glycogen, glycogen, glycosylation sphingol, enoxolone, 2- Hydroxypropyl-β-cyclodextrin, laureth -9, lauric acid, Laurylcarnitine, lysophosphatidyl choline, menthol, poloxamer It is 407 or F68, poly-L-arginine, polyoxyethylene -9- laurel ether, isopropyl myristate, isopropyl palmitate, lanolin, light Matter mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid or its salt, palmitinic acid, polysorbate 20, gather oleyl alcohol Sorb ester 80, propylene glycol, polyoxyethylene alkyl ether, polyoxyglyceride, pyrrolidones, quillaja saponin, salicylic acid, sodium salt, β-paddy Sterol β-D- glucoside, lauryl sodium sulfate, sucrose cocounut oil acid esters, taurocholate, tauroursodeoxycholic acid, ox sulphur dihydro shuttle chain Spore acid, Thymol, tricaprylin, triolein and alkyl sugar.

In some embodiments, the preparation includes one or more sorbefacients, and the sorbefacient is selected from Lauryl.beta.-maltoside, benzalkonium chloride, oleic acid or its salt, polysorbate 20, polyoxyethylene sorbitan monoleate and lauryl sodium sulfate.

In some embodiments, one or more sorbefacients are: about 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；Or about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt；Or about 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/ V) to the combination of about 1% (w/v) benzalkonium chloride；Or about 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside with About 0.001 (w/v) to about 1% (w/v) oleic acid or its salt combination；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride with About 0.001 (w/v) to about 1% (w/v) oleic acid or its salt combination.

In some embodiments, one or more sorbefacients are: about 0.005% (w/v) to about 0.08% (w/v) benzalkonium chloride；Or about 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or about 0.01% (w/v) to about 0.04% (w/v) benzalkonium chloride；Wherein benzalkonium chloride is unique sorbefacient in the preparation, or with it is one or more another Outer sorbefacient is present in together in the preparation.

In some embodiments, the preparation includes preservative.In some embodiments, the preservative is that benzene is pricked Oronain.

In some embodiments, the nasal spray pharmaceutical preparation includes isotonic agent.In some embodiments, described Isotonic agent is glucose, glycerol, mannitol, potassium chloride or sodium chloride.In some embodiments, the isotonic agent is chlorination Sodium.

In some embodiments, the nasal spray preparation extraly includes stabilizer.In some embodiments, institute Stating stabilizer is ethylenediamine tetra-acetic acid (EDTA) or its salt.In some embodiments, the EDTA is EDETATE SODIUM.Some In embodiment, the nasal spray preparation includes the EDETATE SODIUM of about 0.001% (w/v) to about 1% (w/v).

In some embodiments, the nasal spray preparation extraly includes preservative.In some embodiments, institute Stating preservative is benzalkonium chloride.

In some embodiments, the nasal spray preparation includes one or more sorbefacients, and the absorption promotees Alkyl glycosides, benzalkonium chloride, oleic acid or its salt, polysorbate 20, polysorbate ester 80, dodecyl sulphate are selected from into agent It is sodium, cyclodextrin, medium chain fatty acid and long chain fatty acids or its salt, saturated fatty acid and unsaturated fatty acid or its salt, ethyl alcohol, sweet Oil, propylene glycol, PEG 300/400 and benzyl alcohol.

In some embodiments, the nasal spray preparation further includes antioxidant.In some embodiments, The nasal spray preparation further includes antioxidant, and the antioxidant is selected from alpha tocopherol, arachidonic acid, Vitamin C Acid, ascorbyl palmitate, benzethonium chloride, benzyl rope bromine ammonium, benzalkonium chloride, fourth hydroxyanisol (BHA), fourth hydroxyl first Benzene (BHT), capric acid, caproic acid, carbon dioxide, hexadecylpyridinium chloride, chelating agent, chitosan derivatives, Citric Acid Mono, The third dodecyl gallate of dimethylamino, enanthic acid, arabo-ascorbic acid, ethyl oleate, fumaric acid, glyceryl oleate, glycerol list stearoyl Ester, lauric acid, limonene, linolenic acid, lysine, malic acid, menthol, methionine, single thioglycerin, myristic acid, oleic acid, Palmitinic acid, n-nonanoic acid, peppermint oil, phosphoric acid, polysorbate, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sulfurous Sour hydrogen sodium, sodium caprate, NaTDC, deoxygenated ethanol acid sodium, sodium formaldehyde sulphoxylate, NaGC, (2-hydroxybenzoyl) Base aminocaprylic acid sodium, lauryl sodium sulfate, sodium pyrosulfite, sodium sulfite, natrium taurocholicum, sodium thiosulfate, stearic acid, Sulfur dioxide and combinations thereof.

In some embodiments, the nasal spray preparation further includes the synergy together with the antioxidant Agent, the synergist are selected from Citric Acid Mono, tartaric acid, Thymol, tocopherol (alpha tocopherol), tocopherasol, dimension life Plain E and vitamin E polyethylene glycol succinic acid ester and combinations thereof.

In some embodiments, the nasal spray preparation further includes penetration enhancers, the penetration enhancers Selected from ethyl alcohol, arachidonic acid, benzethonium chloride, benzyl rope bromine ammonium, benzalkonium chloride, capric acid, caproic acid, carvol, cetyl chloride Pyridine, chitosan, citric acid, 6- cyclohexyl -1- hexyl-β-D- pyrans maltoside, positive decyl-β-D- pyrans maltose Glycosides, dimethyl sulfoxide, the third dodecyl gallate of dimethylamino, 1-O- dodecyl-β-D- pyrans maltoside, dodecyl are poly- Glycol ether, natrium adetate dihydrate, enanthic acid, Monoolein, glyceryl monostearate, glycogen, myristic acid Isopropyl ester, isopropyl palmitate, n-nonanoic acid, lanolin, lauric acid, light mineral oil, limonene, linoleic acid, lysine, peppermint Alcohol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitinic acid, peppermint oil, polyoxyethylene alkyl ether, polyoxyglyceride, poly- sorb Ester, pyrrolidones, sodium caprate, NaTDC, deoxygenated ethanol acid sodium, NaGC, hydroxybenzoylamino Sodium Caprylate, Lauryl sodium sulfate, natrium taurocholicum, stearic acid, Thymol, tricaprylin, triolein, undecenoic acid and combinations thereof.

In some embodiments, the nasal spray preparation includes: about 0.005% (w/v) to about 2.5% (w/v) ten Dialkyl group maltoside；About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；About 0.001 (w/v) to about 1% (w/v) oleic acid Or its salt；About 0.005% (w/v) is to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) The combination of benzalkonium chloride；About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) are to about The combination of 1% (w/v) oleic acid or its salt；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about The combination of 1% (w/v) oleic acid or its salt；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about The combination of 1% (w/v) oleic acid or its salt and 0.001% to 1% sodium pyrosulfite；Or about 0.001 (w/v) to about 1% (w/v) Benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt and about 0.001% to 10% polyoxyethylene sorbitan monoleate and The combination of 0.001% to 1% sodium pyrosulfite；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) To about 1% (w/v) oleic acid or its salt and about 0.001% to 10% polyoxyethylene sorbitan monoleate and 0.001% to 1% sodium pyrosulfite and The combination of 0.001% to 1% citric acid.

In some embodiments, the nasal spray preparation includes: about 0.005% (w/v) to about 0.08% (w/v) benzene Prick oronain；About 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or about 0.01% (w/v) to about 0.04% (w/v) benzene Prick oronain；Wherein benzalkonium chloride is unique sorbefacient in the nasal spray preparation, or with it is one or more other Sorbefacient is present in together in the preparation.

In some embodiments, the nasal spray preparation includes: about 0.001% to 1% it is as described herein any A kind of combination of antioxidant or any antioxidant as described herein.

In some embodiments, the nasal spray preparation includes buffer.Buffer include but is not limited to adipic acid, Boric acid, calcium carbonate, calcium hydroxide, calcium lactate, tertiary calcium phosphate, Citric Acid Mono, disodium hydrogen phosphate, diethanol amine, glycine, Maleic acid, malic acid, methionine, sodium dihydrogen phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, carbon Sour hydrogen sodium, Boratex, sodium carbonate, Trisodium citrate dihydrate, sodium hydroxide, sodium lactate and triethanolamine.

In one aspect, the method for the patient's condition mediated there is provided herein treatment by adrenergic receptor, the method packet Include intranasal administration any preparation as described herein.In some embodiments, the patient's condition is selected from 1 type hypersensitivity (whole body allergy), acute asthmatic attack, cardiac arrest and Stokes-Adams syndrome.In some embodiments, institute Stating the patient's condition is 1 type hypersensitivity (whole body allergy).In some embodiments, the 1 type hypersensitivity is selected from allergia Asthma, allergic conjunctivitis, allergic rhinitis, allergic reaction, angioedema, nettle rash, eosinophilia, drug become State reaction and food allergy.In some embodiments, the drug allergy is antibiotic allergy.

In one aspect, this document describes the nasal spray preparation comprising adrenaline or its salt, when being applied to subject When, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: average AUC_0-20minAnd AUC_0-t The AUC generated for 0.3mg intramuscular injection_0-20minAnd AUC_0-tAt least 80%；Average C_maxIt is generated for 0.3mg intramuscular injection C_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；Or medicinal strip is most preferably given in thigh The absorption of IM injection is similar under part.On the other hand, this document describes the nasal spray systems comprising adrenaline or its salt Agent, when being applied to subject, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: average AUC_0-20minAnd AUC_0-tIt is the AUC that 0.3mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；Average C_maxFor 0.3mg The C that intramuscular injection generates_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；And in thigh In best administration under the conditions of be similar to the absorption of IM injection.

On the other hand, tested when being applied to this document describes the nasal spray preparation comprising adrenaline or its salt When person, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: average AUC_0-20minAnd AUC_0-t It is the AUC that 0.15mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；Average C_maxFor 0.15mg intramuscular injection generation C_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；Or the best administration in thigh Under the conditions of be similar to IM injection absorption.On the other hand, this document describes the nasal sprays comprising adrenaline or its salt Preparation, when being applied to subject, the nasal spray preparation generates one of following Pharmacokinetic Characteristics or a variety of: flat Equal AUC_0-20minAnd AUC_0-tIt is the AUC that 0.15mg intramuscular injection generates_0-20minAnd AUC_0-tAt least 80%；Average C_maxFor The C that 0.15mg intramuscular injection generates_maxAt least 80% and be no more than the C_max150%；Average t_maxLess than 45 minutes；And The absorption that IM injection is similar under the conditions of most preferably administration in thigh.

In some embodiments, the nasal spray preparation is pharmaceutical preparation.

In some embodiments, the adrenaline or its salt are effectively to measure presence for treating acute hypersensitivity In the nasal spray preparation.

In some embodiments, it provides to the nasal spray pharmaceutical preparation of subject's intranasal administration single dose for treatment The acute effective plasma epinephrine concentration of hypersensitivity.In some embodiments, the nasal spray drug of single dose Preparation includes the adrenaline or its salt of about 0.5mg to about 2.0mg.In some embodiments, the nasal cavity spray of single dose Mist pharmaceutical preparation includes the adrenaline or its salt of about 0.5mg to about 1.5mg.In some embodiments, single dose is described Nasal spray pharmaceutical preparation includes the adrenaline or its salt of about 0.5mg to about 0.7mg.In some embodiments, single dose The nasal spray pharmaceutical preparation include about 1.0mg adrenaline or its salt.In some embodiments, the institute of single dose State the adrenaline or its salt that nasal spray pharmaceutical preparation includes about 1.3mg to about 1.5mg.In some embodiments, described Preparation is aqueous solution, aqueous suspension, water-based emulsion, non-aqueous solution, non-aqueous suspensions, non-aqueous lotion, pressurizes and determine Measure inhalator or dry powder.

In some embodiments, the nasal spray preparation be aqueous solution, it is aqueous suspension, water-based emulsion, non-aqueous Property solution, non-aqueous suspensions or non-aqueous lotion.

In some embodiments, the nasal spray preparation has the class when intramuscular (IM) injection is given in big leg outer side It is similar to the pharmacokinetics of IM injection, or similar to the subcutaneously absorption of (SC) or therebetween.

In some embodiments, the nasal spray preparation has the absorption for being similar to subcutaneous (SC), and SC medicine generation Kinetic spectrum has at least C of 100pg/mL_maxWith the AUC of 150h*pg/mL_0-240min。

In some embodiments, the nasal spray preparation has the absorption for being similar to intramuscular (IM) injection.

In some embodiments, the nasal spray preparation includes sorbefacient.

In some embodiments, the nasal spray pharmaceutical preparation includes one or more sorbefacients；And appoint One or more medicaments selected from the following of choosing: isotonic agent；Stabilizer；Preservative；Odor mask；Viscosity improver；Antioxidant； Buffer and pH adjusting agent；Wherein the pH of the nasal spray pharmaceutical preparation is between about 2.0 to about 6.0.In some embodiment party In case, the pH of the nasal spray pharmaceutical preparation is between about 3.0 to about 5.0.In some embodiments, the nasal spray The pH of pharmaceutical preparation is about 4.0.

In some embodiments, the nasal spray pharmaceutical preparation includes pH adjusting agent.In some embodiments, institute Stating pH adjusting agent is acid, alkali, buffer or combinations thereof.In some embodiments, the acid is adipic acid, ammonium chloride, lemon Acid, acetic acid, hydrochloric acid, lactic acid, phosphoric acid, propionic acid, sulfuric acid or tartaric acid；The alkali be sodium hydroxide, sodium citrate, sodium bicarbonate, Sodium carbonate；And the buffer is phosphate buffer, acetate buffer or citrate buffer agent.

In some embodiments, the nasal spray preparation includes relative to every mole of adrenaline about 0.5 to about 1.1 The acid of molar equivalent.In some embodiments, the acid is adipic acid, ammonium chloride, citric acid, acetic acid, hydrochloric acid, lactic acid, phosphorus Acid, propionic acid, sulfuric acid or tartaric acid.In some embodiments, the acid is hydrochloric acid.In some embodiments, in the system Alkali is not added thereto during the preparation of agent.In some embodiments, the pH of the nasal spray preparation is about 2.0 to about Between 6.0.In some embodiments, the pH of the nasal spray preparation is about 4.0.

In some embodiments, the nasal spray preparation includes one or more sorbefacients, and the absorption promotees Into agent be selected from ethyl alcohol, Aprotinin, benzalkonium chloride, benzyl alcohol, capric acid, ceramide, hexadecylpyridinium chloride, chitosan, Cyclodextrin, capryl, dimethyl sulfoxide, Monoolein, glycogen, glycogen, glycosylates sphingol, is sweet deoxycholic acid Careless hypo acid, 2-HP-BETA-CD, laureth -9, lauric acid, Laurylcarnitine, lysophosphatidyl choline, peppermint Alcohol, poloxamer188 or F68, poly-L-arginine, polyoxyethylene -9- laurel ether, isopropyl myristate, palmitinic acid isopropyl Ester, lanolin, light mineral oil, linoleic acid, menthol, myristic acid, myristyl alcohol, oleic acid, oleyl alcohol, palmitinic acid, poly- sorb Ester 20, polyoxyethylene sorbitan monoleate, propylene glycol, polyoxyethylene alkyl ether, polyoxyglyceride, pyrrolidones, quillaja saponin, salicylic acid, sodium Salt, cupreol β-D- glucoside, lauryl sodium sulfate, sucrose cocounut oil acid esters, taurocholate, tauroursodeoxycholic acid, ox sulphur Dihydro fusidinic acid, Thymol, tricaprylin, triolein and alkyl sugar.

In some embodiments, the nasal spray preparation includes: about 0.005% (w/v) to about 2.5% (w/v) ten Dialkyl group maltoside；About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；About 0.001 (w/v) to about 1% (w/v) oleic acid Or its salt；About 0.005% (w/v) is to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) The combination of benzalkonium chloride；About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) are to about The combination of 1% (w/v) oleic acid or its salt；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt and about 0.001% to 1% antioxidant (such as sodium pyrosulfite) combination.In some realities It applies in scheme, the nasal spray preparation includes: about 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside；About 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；About 0.001 (w/v) is to about 1% (w/v) oleic acid or its salt；About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride combination； About 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) oleic acid or The combination of its salt；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or The combination of its salt.In some embodiments, the nasal spray preparation includes: about 0.005% (w/v) to about 0.08% (w/ V) benzalkonium chloride；About 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or about 0.01% (w/v) to about 0.04% (w/ V) benzalkonium chloride；Wherein benzalkonium chloride is unique sorbefacient in the nasal spray preparation, or with it is one or more another Outer sorbefacient is present in together in the preparation.

In some embodiments, the nasal spray preparation extraly includes stabilizer.In some embodiments, institute Stating stabilizer is ethylenediamine tetra-acetic acid (EDTA) or its salt.In some embodiments, the EDTA is EDETATE SODIUM.Some In embodiment, the EDTA exists with the amount of about 0.001% to about 1%.

In some embodiments, the nasal spray preparation extraly includes preservative.In some embodiments, institute Stating preservative is benzalkonium chloride.

In one aspect, the method for the patient's condition mediated this document describes treatment by adrenergic receptor, the method packet Include intranasal administration any preparation as described herein.In some embodiments, it is (complete to be selected from 1 type hypersensitivity for the patient's condition Body allergy), acute asthmatic attack, cardiac arrest and Stokes-Adams syndrome.In some embodiments, the disease Condition is 1 type hypersensitivity (whole body allergy).In some embodiments, the 1 type hypersensitivity be selected from allergic asthma, Allergic conjunctivitis, allergic rhinitis, allergic reaction, angioedema, nettle rash, eosinophilia, drug are abnormal anti- Should and food allergy.In some embodiments, the drug allergy is antibiotic allergy.

On the other hand, anaphylactoid method is treated this document describes a kind of comprising to be less than about the amount of 2.0mg The adrenergic intranasal preparation of intranasal administration.In some embodiments, the nasal cavity medicine preparation includes about 0.5mg to about The adrenaline of 1.5mg or its salt.In some embodiments, the nasal cavity medicine preparation includes about 0.5mg to about 0.7mg's Adrenaline or its salt.In some embodiments, the nasal cavity medicine preparation includes the adrenaline or its salt of about 1.0mg. In some embodiments, the nasal cavity medicine preparation includes the adrenaline or its salt of about 1.3mg to about 1.5mg.

In some embodiments of the treatment method, the intranasal preparation includes: one or more sorbefacients； Isotonic agent；Stabilizer；Preservative；Optional antioxidant；And optional pH adjusting agent.In some realities of the treatment method It applies in scheme, one or more sorbefacients are selected from: Lauryl.beta.-maltoside；Benzalkonium chloride；Oleic acid or its salt；Ten Sodium dialkyl sulfate；The combination of Lauryl.beta.-maltoside and benzalkonium chloride；Lauryl.beta.-maltoside and oleic acid or its salt Combination；And the combination of benzalkonium chloride and oleic acid or its salt.In some embodiments of the treatment method, it is described a kind of or A variety of sorbefacients are selected from: about 0.005% (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside；About 0.001 (w/v) To about 1% (w/v) benzalkonium chloride；About 0.001 (w/v) is to about 1% (w/v) oleic acid or its salt；About 0.005% (w/v) is to about The combination of 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride；About 0.005% The group of (w/v) to about 2.5% (w/v) Lauryl.beta.-maltoside and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt It closes；Or about 0.001 (w/v) to about 1% (w/v) benzalkonium chloride and about 0.001 (w/v) to about 1% (w/v) oleic acid or its salt group It closes.In some embodiments of the treatment method, the preparation includes: about 0.005% (w/v) to about 0.08% (w/v) Benzalkonium chloride；About 0.01% (w/v) to about 0.06% (w/v) benzalkonium chloride；Or about 0.01% (w/v) to about 0.04% (w/v) Benzalkonium chloride；Wherein benzalkonium chloride is unique sorbefacient in the preparation, or is promoted with one or more other absorptions It is present in the preparation together into agent.In some embodiments of the treatment method, the isotonic agent is sodium chloride.In In some embodiments of the treatment method, the stabilizer is EDTA.In some embodiments of the treatment method, The stabilizer is the EDTA of the amount of about 0.001% (w/v) to about 1% (w/v).In some embodiments of the treatment method In, the preservative is benzalkonium chloride.In some embodiments of the treatment method, the preservative is about 0.001% (w/v) to about 1% (w/v) amount benzalkonium chloride.

Provide product comprising packaging material, the nasal spray preparation as described herein in the packaging material, with And show the nasal spray preparation for treating the label of any patient's condition (such as allergic reaction) as described herein.

According to detailed description below, other purposes, the feature and advantage of composition as described herein and method will become Obviously.It is to be understood, however, that the detailed description and specific embodiment are when pointing out specific embodiment only with explanation Mode provide because variations and modifications within the spirit and scope of this disclosure will become from the detailed description It is apparent to those skilled in the art.

Detailed description of the invention

Fig. 1 is shown such as in Srisawat et al., " A preliminary study of intranasal epinephrine administration as a potential route for anaphylaxis treatment,” Asian Pac J Allergy Immunol, in March, 2016；34 (1): disclosed in 38-43, in various dose and administration The time 0-120 minute (AUC that adrenaline absorbs under approach_0-120min) plasma concentration v. time area under a curve, below Middle discussion.

Fig. 2 shows as disclosed in Srisawat et al., IN salt water, IN adrenaline 5mg and IM kidney are being applied Plasma epinephrine concentration-time profile after upper parathyrine 0.3mg.

Fig. 3 shows the first item described in the embodiment 2A for being compared 0.3mg adrenaline IM and IN and faces The average blood plasma Adrenaline Concentration (pg/mL) higher than baseline-time (min) curve of bed research；Curve with square It indicates IM, there is circular curve to indicate IN.

Fig. 4 is shown second described in the embodiment 2B for being compared 0.5,1.0 and 2.0mg adrenaline IN The average blood plasma Adrenaline Concentration (pg/mL) higher than baseline-time (min) curve of item clinical research.With circular song Line indicates 0.5mg；Curve with triangle indicates 1.0mg, and there is the curve of square to indicate 2.0mg.

Fig. 5 is shown described in the embodiment 2B for being compared 0.5,1.0 and 2.0mg IN adrenaline First 30 minutes of the average blood plasma Adrenaline Concentration (pg/mL) higher than baseline of binomial clinical research-time (min) curve. 0.5mg is indicated with circular curve；Curve with triangle indicates 1.0mg, and there is the curve of square to indicate 2.0mg。

Fig. 6 repeats the data from Fig. 4, and by the IM kidney of itself and the first item clinical research described in the embodiment 2A The mean plasma concentration of upper parathyrine-time graph superposition.

Fig. 7 repeats the data from Fig. 5, and by the IM kidney of itself and the first item clinical research described in the embodiment 2A It is superimposed within mean plasma concentration-time graph of upper parathyrine first 30 minutes.

Fig. 8 shows being higher than for the relative bioavailability part of the Section 2 clinical research described in the embodiment 2B 1.0mg adrenaline IN (is had circle by the average blood plasma Adrenaline Concentration (pg/mL) of baseline-time (min) curve Curve) with 0.3mg adrenaline IM (adrenaline automatic injector, with triangle curve) be compared.

Fig. 9 shows being higher than for the relative bioavailability part of the Section 2 clinical research described in the embodiment 2B The average blood plasma Adrenaline Concentration (pg/mL) of baseline was to first 30 minutes of time (min) curve, by 1.0mg adrenaline IN (there is circular curve) and 0.3mg adrenaline IM (Curve with triangle) it is compared.

Specific embodiment

Disclosed herein is the method and formulations for treating allergic reaction He other patient's condition, including the adrenergic nose of application Interior preparation.Additionally provide the device being suitable for patient's intranasal delivery pharmaceutical preparation, the delivering include single dose, dose double and Multi-dose delivering, the pharmaceutical preparation include the adrenaline and its pharmaceutically acceptable salt of therapeutically effective amount.

Intranasal adrenaline, which is used as decongestant and vasoconstrictor with low dosage, to have a long history, usually It is prepared with anaesthetic combination, is used for nasal sinus and surgery of nasal cavity.In history, adrenaline is difficult to be configured to the nose for systemic delivery Interior solution.See, for example, Srisawat C et al., " A preliminary study of intranasal epinephrine administration as a potential route for anaphylaxis treatment,”Asian Pac J Allergy Immunol, in March, 2016；34(1):38-43.Srisawat explanation, is only observed at 5mg via IN approach Adrenergic significant systemic Absorption (referring to Fig. 1), and even if at 5mg, the adrenergic pharmacokinetic parameter of IN and IM The pharmacokinetic parameter of adrenaline group is also not significantly different (referring to table 1, as follows).

The adrenergic intramuscular and intranasal administration of table 1. (comes from Srisawat (2016)).

Fig. 1 is to replicate from Srisawat C et al., and prove, Srisawat et al. is in intranasal dose level 2.5mg and it is following when do not observe the adrenaline of blood level.

In addition, Fig. 2 is shown, even if Srisawat can not also be prepared can be before about 60 minutes under the dosage of 5mg Any time point reaches the intranasal preparation of plasma concentration more higher than the intramuscular adrenaline delivered by automatic injector, therefore When needing quickly to absorb to prevent whole body allergy (allergic reaction), it is delayed by the absorption of crucial earlier time points. This may be in the serious conditions such as allergic reaction it is harmful, these patient's condition need to treat and therefore need similar immediately In the pharmacokinetics of injection.In view of the more vascular distribution of leg muscle allows adrenaline faster to absorb and divide Cloth is injected to provide the quickling increase quickly to terminate allergic reaction than other methods of application of blood plasma level to thigh IM PK compose optimal medication be considered by document.Fig. 2 is also shown, with the intramuscular adrenaline delivered by automatic injector It compares, the 5mg preparation of Srisawat is almost fully erased from blood plasma in about 2 hours.Finally, known adrenaline is intramuscular Inject down to 0.3 to 0.5mg dosage when it is related to dose-dependent cardiac side effects (including myocardial infarction)；Therefore, if In the presence of the nasal cavity patient's condition that may allow taken in excess, then up to there may be risks for the dosage of 5mg in general population.Therefore, excellent Choosing can avoid the low dose formulation of this kind of risk as safer nasal cavity preparation.

Disclosed herein is adrenergic intranasal preparation and comprising the nasal cavity spray apparatus of said preparation, which solve taste in the past The problem of examination.Many aspects can help to the success of preparation, device and application method disclosed herein.

For example, in certain embodiments, being suitably added to every mole of the adrenal gland in the acid by molar equivalent Preparing adrenaline in the case where element in aqueous solution helps to dissolve and stablize adrenaline.This allows preparation from using It is usually used in the buffer of injection aqueous pharmaceutical compositions, including phosphate buffer, acetate buffer and citrate delay Electuary is avoided sometimes in nasal cavity preparation disclosed herein using these buffers.Other adrenergic salt, such as acetic acid kidney Upper parathyrine, adrenalin hydrochloride, Adrenaline Tartrate, adrenaline acid tartrate, epinephrine bitartrate and boric acid Adrenaline can also be used for preparing adrenergic aqueous solution.

Certain embodiments offer of preparation, device and application method disclosed herein is better than the kidney otherwise prepared The advantages of upper parathyrine.Adrenaline is considered as a kind of narrow therapeutic index drug.As sympathetic transmitter releasers catecholamine, on kidney Parathyrine has relatively narrow therapeutic index, and the serious adverse reaction including cardiovascular response and cerebrovascular reaction may be with It uses related.Nevertheless, treating this indication using adrenaline still can save life, and use the good of it Place is greater than potential security risk.Because of content uniformity, delivering amount and the consistency of absorption, allow to and adrenaline via Injection mechanism is minimized using relevant serious adverse reaction (including the cardiovascular and cerebrovascular reacts), intranasal delivering and preparation Suitable for safety, painlessly deliver drug such as adrenaline.Injection weight has low changeability and consistently delivers marking agent Amount.

In one aspect, this document describes pharmaceutical composition, it includes: a) adrenaline；And b) alkyl glycosides；Wherein institute Pharmaceutical composition is stated to be prepared for being administered in the circulatory system of subject via intranasal, sucking or pulmonary administration approach.In In some embodiments, this document describes pharmaceutical composition, it includes: a) adrenaline；And b) alkyl glycosides；The wherein medicine Compositions are the liquid for being formulated for intranasal delivery.

In some embodiments, alkyl glycosides has the alkyl chain comprising 8 to 20 carbon.In some embodiments, Alkyl glycosides is selected from undecyl maltoside, Lauryl.beta.-maltoside, tridecyl maltoside, myristyl maltose Glycosides, sucrose list dodecylate, sucrose list tridecanoate and sucrose list myristate.In some embodiments, alkyl Glucosides is dodecyl-β-D-Maltose glycosides.In some embodiments, alkyl glycosides concentration is about 0.001% to 10.0% (w/v).In some embodiments, alkyl glycosides concentration is about 0.05% to 0.5% (w/v).

In some embodiments, composition further includes film penetration enhancer.In some embodiments, film permeates Promotor be surfactant, bile salt, phosphatide, ethyl alcohol, enamine, long-chain amphipathic molecule, small hydrophobic molecule, sodium salicylate or Salicyclic acid derivatives, the glyceride of acetoacetate, cyclodextrin, middle chain or long chain fatty acids, chelating agent, amino acid or its salt, enzyme Or their combination.In some embodiments, film penetration enhancer is selected from citric acid, sodium citrate, propylene glycol, glycerol, resists Bad hematic acid, sodium pyrosulfite, ethylenediamine tetra-acetic acid (EDTA) disodium, benzalkonium chloride, hydroxy quinolone, sodium hydroxide and its group It closes.In some embodiments, film penetration enhancer is selected from citric acid, sodium citrate, propylene glycol, glycerol, ascorbic acid, Jiao Ya Sodium sulphate, ethylenediamine tetra-acetic acid (EDTA) disodium, benzalkonium chloride, sodium hydroxide and combinations thereof.In some embodiments, film seeps Saturating promotor is benzalkonium chloride, EDTA or combinations thereof.

In some embodiments, with without alkyl glycosides application compared with, composition provided in subject about 2 times or Bigger adrenaline Cmax.

In some embodiments, compared with the application without alkyl glycosides, composition provides about two points in subject One of or smaller adrenaline Tmax.

In some embodiments, composition provides about 0.3 hour or shorter adrenaline Tmax in subject.

In some embodiments, the pH of composition is about 2.0 to 6.0.In some embodiments, the pH of composition is About 2.0 to 5.0.

On the other hand, this document describes the methods for increasing adrenergic bioavilability in subject comprising It include the pharmaceutical composition of adrenaline and alkyl glycosides to subject's application, to increase adrenergic in the subject Bioavilability；Wherein described pharmaceutical composition is prepared for being administered to via intranasal, sucking or pulmonary administration approach tested In the circulatory system of person.In some embodiments, this document describes increase adrenergic bioavilability in subject Method comprising include the pharmaceutical composition of adrenaline and alkyl glycosides to subject's application, to increase the subject In adrenergic bioavilability；Wherein described pharmaceutical composition is the liquid for being formulated for intranasal delivery.

In some embodiments, increasing adrenergic bioavilability allows the adrenaline of relatively low-dose intranasal It delivers and effective for treatment allergic reaction.In some embodiments, the adrenaline for being exposed to larger dose can lead to Adrenaline overdose.The interest and demand of developing such Noninvasive adrenaline dosage form substituted are increasingly increased, Its comparable adrenaline blood plasma concentration of adrenaline blood plasma concentration for providing and being obtained by adrenaline automatic injector, can It is used under a variety of dosage, there is the longer shelf-life, and there is no needle anxiety, avoid application mistake, unexpected injection and damage A possibility that.Adrenaline intranasal dosage form as described herein is provided as urgent for anaphylactoid first aid in community environment The potentiality of the user-friendly Noninvasive substitute for the treatment of.

In some embodiments, composition further includes film penetration enhancer.In some embodiments, film permeates Promotor be surfactant, bile salt, phosphatide, ethyl alcohol, enamine, middle chain and/or long-chain amphipathic molecule, small hydrophobic molecule, Sodium salicylate or salicyclic acid derivatives, the glyceride of acetoacetate, cyclodextrin, middle chain or long chain fatty acids, chelating agent, amino acid Or its salt, enzyme or their combination.In some embodiments, film penetration enhancer is selected from citric acid, sodium citrate, the third two Alcohol, glycerol, ascorbic acid, sodium pyrosulfite, ethylenediamine tetra-acetic acid (EDTA) disodium, benzalkonium chloride, sodium hydroxide and combinations thereof. In some embodiments, film penetration enhancer is benzalkonium chloride, EDTA or combinations thereof.

In some embodiments, with without alkyl glycosides application compared with, composition provided in subject about 2 times or Bigger adrenaline Cmax.

In some embodiments, compared with the application without alkyl glycosides, composition provides about two points in subject One of or smaller adrenaline Tmax.

In some embodiments, composition provides about 0.3 hour or shorter adrenaline Tmax in subject.

In some embodiments, the pH of composition is about 2.0 to 6.0.In some embodiments, the pH of composition is About 2.0 to 5.0.

In some embodiments, compositions described herein is suitable for the liquid composition of intranasal administration.

In one aspect, the present invention provides increased and applying composition via intranasal, sucking or pulmonary delivery approach Add adrenaline to the method for the absorption in the circulatory system of subject, the composition includes: (a) adrenaline；(b) increase The suitable nontoxic nonionic alkyl glycoside of the amount of absorption has the hydrophobic alkyl base for passing through keyed engagement with hydrophily sugar Group；And (c) mucosal delivery promotor.

Term " mucosal delivery promotor " includes the release or solubility of enhancing compound (for example, bioactive compound) (for example, from formulation delivered medium), diffusion rate, penetrating power and time of penetration, demurrage, stability, effectively partly decline at intake Phase, peak value or continuous concentration are horizontal, remove and the mucosal delivery feature needed for other is (for example, such as in site of delivery or selected Targeted activity site as measured at blood flow or central nervous system) medicament.The enhancing of mucosal delivery can be by more Any one of kind mechanism occurs, and increases diffusion, conveying, persistence or the stability of compound including for example passing through, and increases The availability or effect of membrane fluidity, the ion for adjusting in calcium and other regulating cells or penetrating by cell, dissolve the film of mucous membrane Component (for example, lipid) changes nonprotein and protein sulfhydryl level in mucosal tissue, it is logical to increase the water across mucomembranous surface Amount, adjust epithelium engage physiology, reduce covering mucous epithelium mucus viscosity, reduce mucociliary clearance rate and other Mechanism.

Exemplary mucosal delivery promotor includes following medicament and any combination thereof:

(a) agglutination inhibitor；

(b) charge modifiers；

(d) degradation enzyme inhibitor；

(e) mucolysis or mucus clearance agent；

(f) ciliostatic factors；

(g) film penetration enhancer selected from the following:

(i) surfactant；

(ii) bile salt；

(ii) phosphatide additive, mixed micelle, liposome or carrier；

(iii) ethyl alcohol；

(iv) enamine

(v) NO compound donator；

(vi) long-chain amphipathic molecule；

(vii) small hydrophobicity penetration enhancer；

(viii) sodium salicylate or salicyclic acid derivatives；

(ix) glyceride of acetoacetate；

(x) cyclodextrin or beta-cyclodextrin derivative；

(xi) medium chain fatty acid；

(xii) chelating agent；

(xiii) amino acid or its salt；

(xiv) N- acetylamino acid or its salt；

(xv) enzyme for making selected membrane component degrade；

(ix) fatty acid synthetic inhibitor；

(x) inhibitors of cholesterol synthesis；And

(xi) any combination for the film penetration enhancer enumerated in (i)-(x)；

(h) regulator of epithelium engagement physiology；

(i) vasodilator；

(j) selectivity conveying promotor；And

(k) stabilized delivery medium, carrier, mucoadhesive, support or formed compound substance, compound with it is described Substance is effectively combined, associates, includes, encapsulates or is combined, and causes the stabilisation of compound with the nasal mucosal delivery for enhancing, Wherein the compound formulation with intranasal delivery promotor provides compound increased bioavilability in subject's blood plasma.

Other mucosal delivery promotor includes for example, citric acid, sodium citrate, propylene glycol, glycerol, ascorbic acid (example Such as, L-AA), sodium pyrosulfite, ethylenediamine tetra-acetic acid (EDTA) disodium, benzalkonium chloride, sodium hydroxide and its mixture. For example, using the EDTA or its salt (example of based on the weight of the composition containing alkyl sugar preservative about 0.01% to 2% amount Such as, sodium salt or sylvite).

On the other hand, this document describes one kind, and there is suitable nontoxic nonionic alkyl glycoside and mucosal delivery to promote Into the pharmaceutical composition of agent, the alkyl glycosides has the hydrophobic alkyl group for passing through keyed engagement with hydrophily sugar, described viscous Film delivering promotor is selected from:

(a) agglutination inhibitor；

(b) charge modifiers；

(d) degradation enzyme inhibitor；

(e) mucolysis or mucus clearance agent；

(f) ciliostatic factors；

(g) film penetration enhancer selected from the following:

(i) surfactant；

(ii) bile salt；

(ii) phosphatide additive, mixed micelle, liposome or carrier；

(iii) ethyl alcohol；

(iv) enamine

(v) NO compound donator；

(vi) long-chain amphipathic molecule；

(vii) small hydrophobicity penetration enhancer；

(viii) sodium salicylate or salicyclic acid derivatives；

(ix) glyceride of acetoacetate；

(x) cyclodextrin or beta-cyclodextrin derivative；

(xi) chain or long chain fatty acids in；

(xii) chelating agent；

(xiii) amino acid or its salt；

(xiv) N- acetylamino acid or its salt；

(xv) enzyme for making selected membrane component degrade；

(ix) fatty acid synthetic inhibitor；

(x) inhibitors of cholesterol synthesis；And

(xi) any combination for the film penetration enhancer enumerated in (i)-(x)；

(h) regulator of epithelium engagement physiology；

(i) vasodilator；

(j) selectivity conveying promotor；And

It in another embodiment, is about 12 to about this document describes the long alkyl chains by applying therapeutically effective amount At least one alkyl glycosides of 14 carbon atoms, at least one sugar and adrenal gland with antibacterial activity usually apply alkyl The method of glycoside composition.

In one aspect, there is provided herein the alkyl sugar composites of antibacterial comprising dodecyl -4-O- α-D- pyrans Glucityl-β-D- glucopyranoside or n-tetradecane base -4-O- α-D- glycopyranosyl-β-D- glucopyranoside.

Therefore, there is provided herein embodiments 1, and a kind of nasal spray preparation, it includes the every dosage distributed from device about The adrenaline or its salt of 0.40mg to about 2.40mg.Alternate embodiment 1, a kind of nasal spray preparation, it includes from dress Set the adrenaline or its salt of every dosage about 0.40mg to about 2.0mg of distribution.

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