阅读说明：本技术 通过精密鼻装置的左旋多巴粉末的鼻内递送 (Intranasal delivery of levodopa powder by precision nasal device ) 是由 J·D·赫克曼 K·H·萨特利 I·达舍夫斯基 A·R·达斯 S·B·什雷斯布里 于 2019-01-04 设计创作，主要内容包括：提供了用于治疗帕金森氏病或帕金森综合征患者中的OFF事件的方法,其包括向正经历OFF事件的患有帕金森氏病或帕金森综合征的受试者施用有效剂量的包含L-DOPA的干燥药物组合物,其中所述剂量通过鼻内递送装置施用,其在鼻内施用后提供(a)至少200ng/mL的平均峰值血浆左旋多巴浓度(C<Sub>max</Sub>)和(b)短于或等于60分钟的达到左旋多巴C<Sub>max</Sub>的平均时间(T<Sub>max</Sub>)。还提供了适合于鼻内施用的左旋多巴干燥药物组合物和包含所述干燥药物组合物的单位剂型。(Provided are methods for treating an OFF event in a parkinson's disease or parkinsonian syndrome patient comprising administering to a subject suffering from parkinson's disease or parkinsonian syndrome experiencing an OFF event an effective dose of a dry pharmaceutical composition comprising L-DOPA wherein the dose is administered by an intranasal delivery device which provides, following intranasal administration, (a) at least 200ng/mL of a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically acceptable carrierMean peak plasma levodopa concentration (C) max ) And (b) less than or equal to 60 minutes of levodopa C achievement max Average time (T) of max ). Also provided are dry pharmaceutical compositions of levodopa suitable for intranasal administration and unit dosage forms comprising the dry pharmaceutical compositions.)

1. A method of treating an OFF event in a Parkinson's Disease (PD) or parkinsonian patient, the method comprising:

administering to a subject suffering from Parkinson's disease or Parkinson's syndrome experiencing an OFF event an effective dose of a dry pharmaceutical composition comprising levodopa (L-DOPA),

wherein the dose is administered by an intranasal delivery device that provides following intranasal administration

(a) Average peak plasma levodopa concentration (C) of at least 200ng/mL_max) And are and

(b) a mean time to levodopa Cmax (Tmax) of less than or equal to 60 minutes.

2. The method of claim 1, wherein the mean peak plasma levodopa concentration (C) provided by said dose_max) Is at least 400 ng/mL.

3. The method of any one of claims 1-2, wherein the intranasal administration of levodopa is adjunctive to oral administration of DDI.

4. The method of claim 3, wherein the intranasal administration of levodopa is adjunctive to oral treatment with DDI and oral treatment with levodopa.

5. The method of claim 4, wherein the intranasal administration of levodopa is adjunctive to oral therapy with an oral dosage form comprising a fixed dose combination of DDI and levodopa.

6. The method of any of claims 3-5, wherein the oral DDI is benserazide or carbidopa.

7. The method of claim 6, wherein the oral DDI is benserazide.

8. The method of claim 6, wherein the oral DDI is carbidopa.

9. The method of any one of claims 1-8, wherein the patient has PD.

10. The method of any one of claims 1-8, wherein the patient has parkinsonism selected from the group consisting of: postencephalitic parkinsonism, symptomatic parkinsonism after carbon monoxide poisoning, or symptomatic parkinsonism after manganese poisoning.

11. The method of any one of claims 1-10, wherein the dry pharmaceutical composition is a powder.

12. The method of claim 11, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is 5 μ ι η -500 μ ι η or 5 μ ι η -250 μ ι η.

13. The method of claim 12, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μ ι η to 100 μ ι η.

14. The method of claim 13, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is 5 μ ι η -75 μ ι η.

15. The method of claim 14, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μ ι η to 50 μ ι η.

16. The method of claim 15, wherein the median diameter (D50) of the levodopa particle size distribution in the composition is from 10 μ ι η to 50 μ ι η.

17. The method of claim 16, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is 20 μ ι η -40 μ ι η.

18. The method of any one of claims 1-17, wherein the dry pharmaceutical composition comprises levodopa in a crystalline or amorphous form.

19. The method of claim 18, wherein the dry pharmaceutical composition comprises levodopa in an amorphous form.

20. The method of claim 19, wherein the amorphous levodopa is obtained by spray drying.

21. The method of any one of claims 1-20, wherein the dry pharmaceutical composition comprises levodopa in a partially crystalline and partially amorphous form.

22. The method of any one of claims 1-21, wherein the dry pharmaceutical composition comprises no more than 80% by weight levodopa.

23. The method of claim 22, wherein the composition comprises 50-80% by weight levodopa.

24. The method of claim 23, wherein the composition comprises 50-70% by weight levodopa.

25. The method of claim 24, wherein the composition comprises 65-70% by weight levodopa.

26. The method of any one of claims 1-25, wherein the dry pharmaceutical composition further comprises a non-ionic surfactant.

27. The method of claim 26, wherein the non-ionic surfactant is an alkyl maltoside.

28. The method of claim 27, wherein the alkyl maltoside is n-dodecyl β -D-maltoside.

29. The method of any one of claims 26-28, wherein the nonionic surfactant is present at 0.1-10 wt%.

30. The method of claim 29, wherein the nonionic surfactant is present at 1-5% by weight.

31. The method of claim 30, wherein the nonionic surfactant is present at 1% by weight.

32. The method of any one of claims 1-31, wherein the dry pharmaceutical composition further comprises HPMC.

33. The method of any one of claims 1-32, wherein the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation.

34. The method of claim 33, wherein the salt is NaCl.

35. The method of claim 34, wherein the composition comprises 1-5 wt% NaCl.

36. The method of claim 35, wherein the composition comprises 2-4 wt% NaCl.

37. The method of any one of claims 1-36, wherein the dry pharmaceutical composition comprises 68% by weight levodopa, 2% by weight NaCl, 29% by weight HPMC, and 1% by weight n-dodecyl β -D-maltoside.

38. The method of claim 37, wherein the composition is a spray-dried composition.

39. The method of any one of claims 1-38, wherein the effective dose is a dose of a dry pharmaceutical composition comprising levodopa in an amount effective to reverse an OFF event within 60 minutes.

40. The method of claim 39, wherein the effective dose of levodopa is 25-150 mg.

41. The method of claim 40, wherein said effective dose of levodopa is 35-140 mg.

42. The method of claim 41, wherein the effective dose of levodopa is 35 mg.

43. The method of claim 41, wherein the effective dose of levodopa is 70 mg.

44. The method of claim 41, wherein the effective dose of levodopa is 105 mg.

45. The method of claim 41, wherein the effective dose of levodopa is 140 mg.

46. The method of any one of claims 1-45, wherein the effective dose is administered as a single undivided dose.

47. The method of any one of claims 1-45, wherein the effective dose is administered in multiple divided sub-dose forms.

48. The method of any one of claims 1-47, wherein the intranasal delivery device is a hand-held, manually-actuated, metered dose intranasal administration device.

49. The method of claim 48, wherein the device is a manually actuated, propellant driven, metered dose intranasal administration device.

50. The method of claim 48 or 49, wherein the levodopa composition is encapsulated within a capsule present in the device prior to device actuation.

51. The method of claim 48 or 49, wherein the levodopa composition is stored within a dosage container that is removably coupled to the device prior to device actuation.

52. A dry pharmaceutical composition suitable for intranasal administration comprising:

levodopa, and

at least one excipient.

53. The dry pharmaceutical composition of claim 52, wherein the composition is a powder.

54. The powder of claim 53, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μm to 500 μm.

55. The powder of claim 54, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μm to 250 μm.

56. The powder of claim 55, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μm to 100 μm.

57. The powder of claim 56, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μm to 75 μm.

58. The powder of claim 57, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 5 μm to 50 μm.

59. The powder of claim 58, wherein the median diameter (D50) of the levodopa particle size distribution in the composition is from 10 μm to 50 μm.

60. The powder of claim 59, wherein the median diameter (D50) of the levodopa particle size distribution in the powder is from 20 μm to 40 μm.

61. The dry pharmaceutical composition of any one of claims 52-60, wherein the composition comprises levodopa in a crystalline or amorphous form.

62. The dry pharmaceutical composition of claim 61, wherein the composition comprises levodopa in an amorphous form.

63. The dry pharmaceutical composition of claim 62, wherein the amorphous levodopa is obtained by spray drying.

64. The dry pharmaceutical composition of any one of claims 52-60, wherein the composition comprises levodopa in a partially crystalline and partially amorphous form.

65. The dry pharmaceutical composition of any one of claims 52-64, wherein the dry pharmaceutical composition comprises no more than 80% by weight levodopa.

66. The dry pharmaceutical composition of claim 65, wherein the composition comprises 50-80% by weight levodopa.

67. The dry pharmaceutical composition of claim 66, wherein the composition comprises 50-70% by weight levodopa.

68. The dry pharmaceutical composition of claim 67, wherein the composition comprises 65-70% by weight levodopa.

69. The dry pharmaceutical composition of any one of claims 52-68, wherein the dry pharmaceutical composition further comprises a non-ionic surfactant.

70. The dry pharmaceutical composition of claim 69, wherein the non-ionic surfactant is an alkyl maltoside.

71. The dry pharmaceutical composition of claim 70, wherein the alkyl maltoside is n-dodecyl β -D-maltoside.

72. The dry pharmaceutical composition of any one of claims 69-71, wherein the non-ionic surfactant is present at 0.1-10% by weight.

73. The dry pharmaceutical composition of claim 72, wherein the non-ionic surfactant is present at 1-5% by weight.

74. The dry pharmaceutical composition of claim 72, wherein the non-ionic surfactant is present at 1% by weight.

75. The dry pharmaceutical composition of any one of claims 52-74, wherein the dry pharmaceutical composition further comprises HPMC.

76. The dry pharmaceutical composition of any one of claims 52-75, wherein the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation.

77. The dry pharmaceutical composition of claim 76, wherein the salt is NaCl.

78. The dry pharmaceutical composition of claim 77, wherein the composition comprises 1-5% by weight NaCl.

79. The dry pharmaceutical composition of claim 78, wherein the composition comprises 2-4% NaCl by weight.

80. The dry pharmaceutical composition of any one of claims 52-79, wherein the dry pharmaceutical composition comprises 68% by weight levodopa, 2% by weight NaCl, 29% by weight HPMC, and 1% by weight n-dodecyl β -D-maltoside.

81. The dried pharmaceutical composition of claim 80, wherein the composition is a spray-dried composition.

82. A unit dosage form containing a dry pharmaceutical composition according to any one of claims 52-81.

83. The unit dosage form of claim 82, wherein the unit dosage form contains 25-150mg levodopa.

84. The unit dosage form of claim 83, wherein the unit dosage form contains 35-140mg levodopa.

85. The unit dosage form of claim 84, wherein the unit dosage form contains 35mg of levodopa.

86. The unit dosage form of claim 85, wherein the unit dosage form contains 70mg of levodopa.

87. The unit dosage form of any one of claims 82-86, wherein the unit dosage form is a capsule encapsulating the dry pharmaceutical composition.

88. The unit dosage form of any one of claims 82-86, wherein the unit dosage form is a dosage container configured to be removably coupled to an intranasal delivery device.

Background

In patients with Parkinson's disease, OFF events (OFF episodies) occur when levodopa (L-DOPA) levels are sub-therapeutic and may occur at early morning awakenings or sporadically throughout the day. A fast reduction of OFF events will provide improved quality of life and activities of daily living by allowing more ON time.

However, existing treatments for OFF events are inadequate. While alternatives to the OFF event have emerged, these new alternatives may not be optimal for various subtypes of parkinson's disease patients. For example, the FDA recently approved orally inhaled levodopa (INBRIJA) for the treatment of parkinson's disease OFF events. However, dose-to-dose consistency may be difficult to achieve given the common age-related complications. In addition, reported side effects include coughing and upper respiratory tract infections in patients with limited mobility. Sublingual apomorphine, also under development, has the ability to address OFF events, but due to the high incidence of induced nausea, tolerability problems can arise and patients can be difficult to manage.

Therefore, new methods of treating OFF events in Parkinson's disease patients are needed.

Disclosure of Invention

In a first aspect, a method for treating an OFF event in a Parkinson's disease patient is presented. The method comprises administering to a Parkinson's disease subject experiencing an OFF event an effective dose of a dry pharmaceutical composition comprising L-DOPA, wherein the dose is administered by an intranasal delivery device that, upon intranasal administration, provides (a) a mean peak plasma levodopa concentration (Cmax) of at least 200ng/mL_max) And (b) less than or equal to 60 minutes of levodopa C achievement_maxAverage time (T) of_max). In particular embodiments, the mean peak plasma levodopa concentration (C) provided by the dose_max) Is at least 400 ng/mL.

In various embodiments, the dry pharmaceutical composition is a powder. In certain embodiments, the powder comprises L-DOPA in crystalline form. In certain embodiments, the powder comprises L-DOPA in an amorphous, amorphous form. In certain embodiments, the powder comprises L-DOPA in a partially crystalline, partially amorphous form. In a particular embodiment, L-DOPA is an amorphous solid obtained by spray drying.

In various embodiments, the dry pharmaceutical composition further comprises HPMC. In some embodiments, the dry pharmaceutical composition further comprises maltoside.

In typical embodiments, the method further comprises administering to the subject a peripherally acting DOPA Decarboxylase Inhibitor (DDI). In particular embodiments, (DDI) is administered orally.

Other features and advantages of the present disclosure will become apparent from the following detailed description, including the drawings. However, it should be understood that the detailed description and specific examples are provided for illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Drawings

Figure 1 shows the mean plasma concentration-time curve following intranasal administration of a specified amount of L-DOPA powder delivered by a non-human primate precision nasal delivery ("nhpPOD") device. Data were obtained in study number 2037-003 described in example 1 below.

Figure 2 shows the mean plasma concentration-time curves after intranasal administration of 20mg of L-DOPA (various formulations) delivered by the nhpPOD device in cynomolgus monkeys previously given oral administration of the DOPA decarboxylase inhibitor benserazide. Data were obtained in study 2037-. 20mg bulk LDOPA (black line) data were extracted from study 2037-003 and shown to compare plasma levels measured in the absence of oral benserazide.

Figures 3A and 3B show mean plasma concentration-time profiles following intranasal administration of 20mg of L-DOPA (various formulations) delivered intranasally by an nhpPOD device in monkeys pre-dosed with oral benserazide. Data were obtained in study 2037-006 as described in example 1, with the results without error bars plotted in fig. 3A and error bars included in fig. 3B for clarity. The line labeled "bulk sieved 20-40 μm L-Dopa" shows the results for bulk sieved L-DOPA with intranasal administration particle diameters in the range of 20-40 μm (data from study 2037-. The line labeled "bulk L-Dopa API" shows the results of intranasal administration of bulk L-DOPA (data from study 2037-.

FIGS. 4A-4C the data obtained from study 2037-; for clarity, fig. 4B plots the results without error bars for shorter PK time points (0-150 min); figure 4C plots the results without error bars for still shorter PK time points (0-45 min). FIGS. 4A-4C also provide data from previous studies for comparison, such as (i)52F (group 4 in Table 9), (ii) bulk sieving of 20-40um crystalline L-Dopa (group 2 in Table 7), (iii)70A-L-Dopa: NaCl: HPMC: DSPC (68:2:16:14) (group 1 in Table 9); and (iv)70B-L-Dopa NaCl: HPMC: DSPC (68:2:23:7) (group 2 in Table 9).

Figures 5A-5E the data obtained from the study 2037-. Figure 5A plots data for four individual animals in group 1 (male 1001, male 1002, female 1501, female 1502); FIG. 5B plots data for four individual animals in group 2 (male 2001, male 2002, female 2501, female 2502); fig. 5C plots data for four individual animals in group 3 (male 3001, male 3002, female 3501, female 3502); figure 5D plots data for four individual animals in group 4 (male 4001, male 4002, female 4501, female 4502); and figure 5E plots data for four individual animals in group 5 (male 5001, male 5002, female 5501, female 5502). As provided in table 9, L-DOPA was administered to the animals in each group.

Fig. 6 illustrates an example nhpPOD device for administering levodopa to a non-human primate (NHP).

Fig. 7A is an intranasal drug delivery device according to one or more embodiments.

Fig. 7B illustrates a partial cross-sectional view of the intranasal delivery device with a removable tip attached thereto and an isolated perspective view of the removable tip in its detached state according to one or more embodiments.

Fig. 7C is a perspective view of a tip and a capsule according to one or more embodiments.

Fig. 7D is a cross-sectional view of a tip and a capsule coupled to a device according to one or more embodiments.

Fig. 7E is an exploded view of a tip and capsule according to one or more embodiments.

Fig. 7F is a perspective view of a tip with a capsule attached thereto according to one or more embodiments.

Fig. 7G is a cross-sectional view of a tip with a capsule attached according to one or more embodiments.

Fig. 7H is a cross-sectional view of a tip according to one or more embodiments.

Fig. 7I is a cross-sectional view of a tip according to one or more embodiments.

Fig. 7J is a cross-sectional view of an inlet interface with a capsule-attached tip according to one or more embodiments.

Fig. 7K-7N are perspective views of a tip of a device according to one or more embodiments.

Fig. 7O is a perspective view of a tip according to one or more embodiments.

Fig. 7P is a perspective view of a tip according to one or more embodiments.

Fig. 7Q is a perspective view of a tip coupled to a device according to one or more embodiments.

Fig. 7R is a cross-sectional view of a tip coupled to a device according to one or more embodiments.

Fig. 7S is an enlarged view of a capsule-attached inlet interface according to one or more embodiments.

Fig. 7T is a perspective view of a second embodiment of a tip according to one or more embodiments.

Fig. 7U is a perspective view of the tip of fig. 7T with a capsule attached thereto according to one or more embodiments.

Fig. 7V is a perspective view of a piercing member according to one or more embodiments.

Fig. 7W is a perspective view of a piercing member according to one or more embodiments.

Fig. 7X illustrates a flow path of a second embodiment of a piercing member according to one or more embodiments.

Fig. 8 illustrates an example of a non-human primate precision nasal delivery device according to one or more embodiments.

FIG. 9A illustrates another example of a non-human primate precision nasal delivery device used in the study 2037-.

Fig. 9B illustrates a side view and a cross-sectional view of an actuator body of the inter-nasal device of fig. 9A, according to one or more embodiments.

Fig. 9C illustrates a side view of an extension tube of the intranasal device of fig. 9A according to one or more embodiments.

Fig. 9D illustrates an enlarged view of two embodiments of a connection interface at the end of the extension tube of fig. 9C according to one or more embodiments.

Fig. 9E illustrates a side view and a cross-sectional view of the tip of the inter-nasal device of fig. 9A, according to one or more embodiments.

Fig. 10 is a graph illustrating metaphase PK data from cohorts 1 and 2 of the human phase IIa clinical trial described in example 2, according to one or more embodiments.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

An "OFF" event is defined as a period of time in which the UPDRS III motor score is greater than or equal to 30 for a Parkinson's Disease (PD) or parkinsonian patient undergoing anti-Parkinson treatment.

"Maltoside" refers to N-dodecyl- β -D-maltopyranoside (N-dodecyl- β -D-maltoside).

A pharmaceutical composition is "dry" if its residual moisture content does not exceed 10%.

Intranasal administration of levodopa is "adjunctive (adjuvant to)" to oral treatment with a decarboxylase inhibitor when levodopa is administered intranasally sufficiently close in time to the previous oral administration of the decarboxylase inhibitor because of the plasma C of the intranasally administered levodopa_maxAnd (4) rising.

Other understanding conventions

Particle size is the size reported by a Mastersizer 3000 laser diffraction particle size analyzer apparatus (Malvern Panalytical).

The range is as follows: throughout this disclosure, various aspects of the present invention are presented in a range format. Ranges are inclusive of the recited endpoints. It is to be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have explicitly disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, a description of a range such as 1 to 6 should be read as having explicitly disclosed sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the like, as well as individual numbers within that range, such as 1,2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

The term "or" as used herein is to be understood as being inclusive, unless specified otherwise or apparent from the context.

The terms "a", "an" and "the" as used herein are to be construed as singular or plural unless specifically stated or apparent from the context. That is, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

In this disclosure, "comprise," "include," "contain," "have," "include," and variants thereof have the meaning attributed to them in U.S. patent law, permitting the presence of additional components beyond those expressly recited.

Unless specifically stated or otherwise apparent from the context, the term "about" as used herein is to be understood as being within the normal tolerance of the art, e.g., within 2 standard deviations of the mean, and is intended to encompass variations of ± 20% or ± 10%, more preferably ± 5%, even more preferably ± 1%, and still more preferably ± 0.1% from the stated value.

Summary of Experimental observations

We have conducted four single dose PK studies in cynomolgus monkeys to examine PK following intranasal administration of levodopa (L-DOPA) multi-powder formulations delivered using a hand-held, manually actuated, metered dose intranasal administration device nhpPOD device suitable for use in non-human primates. The formulations examined included unmodified crystalline powder (median particle size 50 μm), a sieved formulation containing crystalline L-DOPA particles in the size range 20-40 μm, and a spray-dried formulation containing L-DOPA alone or NaCl with and without HPMC, 1, 2-distearoyl-sn-glycerol-3-phosphocholine (DSPC) or maltoside. We found that spray-dried amorphous L-DOPA formulated in powder with HPMC and maltoside when delivered intranasally to a non-human primate with our intranasal delivery device will rapidly provide blood levels of levodopa that are higher than levels known to be associated with improving OFF events in human patients.

Interim analysis of two of the cohorts enrolled in phase IIa clinical trials in parkinson's disease patients showed that the spray-dried formulations containing L-DOPA: NaCl: HPMC: maltoside in a ratio of 68:2:29:1 (wt%) delivered by a precision nasal delivery device were well tolerated. Interim pharmacokinetic data for cohort 1(35mg) and cohort 2(70mg) show that administration of the 70mg dose achieved blood concentrations within the range effective to treat the OFF event, with a mean time to Cmax (Tmax) of 30-60 minutes.

Methods of treating Parkinson's disease OFF events

Thus, in a first aspect, there is provided a method for treating an OFF event in a parkinson's disease or parkinsonian syndrome patient comprising administering to a parkinson's disease or parkinsonian syndrome patient experiencing an OFF event an effective dose of a dry pharmaceutical composition comprising levodopa (L-DOPA), wherein the dose is administered by an intranasal delivery device which provides (a) a mean peak plasma levodopa concentration (C) of at least 200ng/mL following intranasal administration_max) And (b) less than or equal to 60 minutes of levodopa C achievement_maxAverage time (T) of_max). In particular embodiments, the mean peak plasma levodopa concentration (C) provided by the dose_max) Is at least 400 ng/mL.

Patient's health

In the methods described herein, intranasal administration of levodopa is used to treat OFF events that occur despite oral administration of anti-parkinson treatment.

In typical embodiments, intranasal administration of levodopa is supplemented with oral administration of a DOPA decarboxylase inhibitor ("DDI"). In typical embodiments, intranasal administration of levodopa is adjunctive to oral treatment with DDI and oral treatment with levodopa. In some embodiments, intranasal administration of levodopa is complementary to oral treatment with an oral dosage form containing a fixed dose combination of DDI and levodopa. In various embodiments, the oral DDI is benserazide or carbidopa. In some embodiments, the oral DDI is benserazide. In some embodiments, the oral DDI is carbidopa.

In some embodiments, the patient has parkinson's disease ("PD").

In some embodiments, the patient has parkinsonism. In various embodiments, parkinsonism is selected from post-encephalitic parkinsonism, symptomatic parkinsonism after carbon monoxide poisoning, or symptomatic parkinsonism after manganese poisoning.

Effective dose

In the methods described herein, an effective dose is a dose of levodopa that is effective to reverse an OFF event within 60 minutes.

In some embodiments, the effective dose of levodopa is 25-150mg or 35-140 mg. In certain embodiments, the effective dose of levodopa is 35mg, 70mg, 105mg, or 140 mg.

In some embodiments, the effective dose is administered as a single undivided dose. In some embodiments, the effective dose is administered in multiple divided sub-doses.

Dry powder composition

In various embodiments, the dry pharmaceutical composition is a powder.

In typical embodiments, the median diameter of the particle size distribution of levodopa (D50) in the powder is from 5 μm to 500 μm. In some embodiments, the median diameter of the particle size distribution of levodopa (D50) in the powder is from 5 μm to 250 μm, 5 μm to 100 μm, 5 μm to 75 μm, or 5 μm to 50 μm. In certain embodiments, the median diameter of the particle size distribution of levodopa (D50) in the composition is from 10 μm to 50 μm or from 20 μm to 40 μm.

Typically, the dry pharmaceutical composition comprises levodopa in crystalline or amorphous form. In some embodiments, the dry pharmaceutical composition comprises levodopa in both crystalline and amorphous forms. In some embodiments, the dry pharmaceutical composition comprises levodopa in an amorphous form. In a particular embodiment, amorphous levodopa is obtained by spray drying.

In various embodiments, the dry pharmaceutical composition comprises no more than 80% by weight levodopa. In some embodiments, the composition comprises 50-80% by weight levodopa, 50-70% by weight levodopa, 65-70% by weight levodopa.

In various embodiments, the dry pharmaceutical composition further comprises a nonionic surfactant. In certain embodiments, the nonionic surfactant is an alkyl maltoside. In a particular embodiment, the alkyl maltoside is n-dodecyl β -D-maltoside.

In some embodiments, the nonionic surfactant is present in the dry pharmaceutical composition from 0.1 to 10% by weight, more typically from 1 to 5% by weight. In a particular embodiment, the nonionic surfactant is present at 1% by weight.

In various embodiments, the dry pharmaceutical composition further comprises HPMC.

In various embodiments, the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation. Typically, the salt is NaCl. In some embodiments, the composition comprises 1-5% by weight NaCl or 2-4% by weight NaCl.

In a currently preferred embodiment, the dry pharmaceutical composition comprises 68% by weight levodopa, 2% by weight NaCl, 29% by weight HPMC and 1% by weight n-dodecyl β -D-maltoside, and is a spray-dried composition comprising amorphous levodopa. In some embodiments, the L-DOPA is spray dried in the presence of HPMC and/or maltoside. In other embodiments, the HPMC and/or maltoside is added after spray drying of L-DOPA.

Device for measuring the position of a moving object

In the methods described herein, the dose is administered by an intranasal delivery device that delivers the powder to the nasal cavity.

Nasal drug delivery device

In various embodiments, the intranasal administration device is a nasal drug delivery device as described in U.S. patent No. 9,550,036, the disclosure of which is incorporated herein by reference in its entirety.

In some embodiments, the intranasal delivery device is a hand-held, manually-actuated, metered dose intranasal administration device. In certain embodiments, the device is a manually actuated, propellant driven, metered dose intranasal administration device. In particular embodiments, the dry pharmaceutical composition is encapsulated within a capsule present within the device prior to actuation of the device. In some embodiments, the dry pharmaceutical composition is stored within a dosage container that is removably coupled to the device prior to actuation of the device. For example, the dose container may be inserted into a portion of the device or may be coupled to the device such that the dose container is in fluid communication with the device.

In various embodiments, the intranasal delivery device includes a housing body, a propellant canister contained within the housing body, a compound chamber containing a drug compound or designed to receive a drug compound, a channel in fluid communication with the propellant canister and the compound chamber, and an outlet orifice at a distal end of the channel. In this configuration, the propellant released from the canister travels through the channel, contacts the drug compound in the compound chamber, and pushes the drug compound out of the outlet orifice for delivery into the upper nasal cavity.

In various embodiments, the intranasal applicator device is a non-human primate precision nasal delivery ("nhpPOD") device described in fig. 9A-E, also described in U.S. patent No. 9,550,036, which is incorporated herein by reference in its entirety. In one embodiment, the intranasal device is one of the embodiments of fig. 1,2 and 9 of U.S. patent No. 9,550,036. In these embodiments, the pharmaceutical compound is loaded directly into the compound chamber.

Fig. 6 illustrates an example nhpPOD device 600 for administering levodopa to a NHP. Similar to the device embodiments described above, the device 600 includes a housing body 602, a propellant canister 604, a compound chamber (not shown), a channel 606, and an outlet orifice 608.

Another embodiment of the nhpPOD apparatus is shown in figure 8.

Referring to fig. 8, a Metered Dose Inhaler (MDI) canister 802 that dispenses 25 μ Ι of hydrofluoroalkane is attached to a plastic actuator 804. The actuator is in gas communication with a polytetrafluoroethylene filter cartridge (frit)806 having a pore size of 50 μm. The filter cartridge 806 communicates with a dose holding cylinder 810, which is placed inside the body 812 of the POD to generate the aerosolized flow. Upon actuation, the HFA propellant 802 is converted to a gas by passing through the filter element material 806, which then mixes with the dose 810 and the dose and propellant mixture exits from a 23 gauge stainless steel tube nozzle 814 covered with a fluorinated ethylene-propylene liner that is placed over the outside of the metal tip to protect the nasal epithelium from damage by the nozzle 814 during use. In one embodiment, the dose 810 is loaded directly into the body 812 without a holding cylinder.

Medical unit dose container

In various embodiments, the intranasal administration device is a medical unit dose container as described in US 2016/0101245 a1, the disclosure of which is incorporated herein by reference in its entirety.

Intranasal device with access port

In various embodiments, the intranasal applicator is a medical unit dose container as described in U.S. application No. 16/198,312 filed on 21.11.2018, the disclosure of which is incorporated by reference herein in its entirety and repeated below for completeness.

As shown in fig. 7A and 7B, the intranasal device 700 is designed to deliver consistent quality of compound into the nasal cavity. For example, but not limited to, the compound may be an intranasal formulation in the form of a powder. The device 700 targets specific regions of the nasal cavity with a narrow targeted delivery plume. Specifically, device 700 provides the compound to the upper third of the nasal cavity. In one embodiment, device 700 is used to administer a compound into the upper nasal cavity of a human. The upper nasal cavity includes the olfactory region and the middle and upper turbinate regions. In another embodiment, device 700 is used to administer a compound into the upper nasal cavity of a non-human primate. Device 700 is also designed to simplify loading of compounds into device 700 by a clinician and use thereof. The device 700 can be reused to administer several doses of the compound.

Fig. 7B illustrates a partial cross-sectional view of a device 700 for intranasal delivery of a compound. In the embodiment of fig. 7B, the device 700 includes an actuator body 702, a propellant canister 704, and a tip 706. The tip 706 includes an outer wall 708 and an inner wall 710, an outlet passage 712, an inlet interface 714, one or more grooves 728 (shown in fig. 7C), an outlet orifice 716, and a nozzle 718. Fig. 7B illustrates a compound container 720 coupled to an inlet interface 714. The compound contained in the compound container 720 may be a liquid or a powder. In the embodiment of fig. 7B, the compound is a powder.

As shown in fig. 7B, the device 700 includes a propellant canister 704 located within an actuator body 702. The propellant canister 704 contains a propellant. In one embodiment, the propellant may be pressurized. The propellant is a fluid, e.g., a liquid or a gas. In one aspect, the propellant is a liquid. In another aspect, the propellant is a gas. The propellant includes a pharmaceutically suitable propellant. Some examples of pharmaceutically suitable propellants include Hydrofluoroalkanes (HFAs), including but not limited to HFA, HFA 227, HFA134a, HFA-FP, HFA-BP, and similar HFAs. In one aspect, the propellant is a liquid HFA. In another aspect, the propellant is gaseous HFA. Additional examples of suitable propellants include nitrogen or chlorofluorocarbons (CFCs). Additionally, the propellant may be pressurized air (e.g., ambient air). The canister 704 may be a Metered Dose Inhaler (MDI) device that includes a pressurized canister and a metering valve 722 (including a valve stem) to meter propellant upon actuation. In one embodiment, a pump valve (not shown) secures the metering valve 722 to the canister 704 and holds the two components in place during use of the device 700. A range of embodiments of the pump fitting include a fixed interface that retains the pump fitting within the actuator body 702, provides vertical displacement, and prevents rotation during installation of the canister 704.

The propellant canister 704 may have the ability to dispense propellant for a certain number of doses. In one embodiment, the device 700 may be shipped without the canister 704 and the canister 704 may be loaded into the actuator body 702 by a user. In some embodiments, the propellant canister may be replaced with a new propellant canister so that the device 700 may be reused. In one aspect, when the MDI device is actuated, a discrete amount of pressurized HFA fluid will be released. The MDI may contain between about 30 and about 300 actuations, inclusive, of the HFA propellant. The amount of fluid propellant released upon actuation may be between about 20 microliters (μ l) to about 200 μ l of liquid propellant, inclusive.

The actuator body 702 includes a propellant channel 724 that is in fluid communication with the propellant canister 704. Propellant channel 724 is in fluid communication with inlet interface 714, which is configured to be coupled to compound container 720 such that propellant released from propellant canister 704 may be introduced into compound container 720 via one or more grooves 728 on inlet interface 714. In the embodiment of fig. 7B, propellant channel 724 includes a port 726 at a distal end to receive tip 706. In this configuration, the tip 706 can be coupled to the actuator body 702 and decoupled from the actuator body 702 by inserting the tip 706 into the port 726. In other embodiments, the port 726 may be inserted into the tip 706. In some embodiments, the port 726 and/or the tip 706 may include a sealed interface that creates a hermetic seal between the propellant channel 724 and the tip 706 such that propellant released from the canister 704 does not escape the propellant channel 724 but is directed toward the inlet interface 714.

The tip 706 can be coupled to the actuator body 702 and decoupled from the actuator body 702, which enables a user to load and unload the compound container 720 to and from the inlet interface 714. The tip 706 includes an outer wall 708 and an inner wall 710, wherein the inner wall forms an outlet passage 712 extending between the proximal and distal ends of the tip 706. An inlet interface 714 is positioned about the distal end of the outer wall 708, the inlet interface 714 coupling a compound container 720. In the embodiment of fig. 7B, the inlet interface 714 is a collar that is insertable into the compound container 720. In other embodiments, the inlet interface 714 can be a ring, band, port, or band that interfaces with the compound container 720. The inlet interface 714 includes one or more grooves 728 (shown in fig. 7C) to direct propellant released from the canister 704 into the compound container 720 coupled to the inlet interface 714. The released propellant then contacts the compound within the compound container 720, agitating and entraining the compound and pushing the compound through the outlet channel 712 and out of the outlet orifice 716 located at the distal end of the outlet channel 712. In the embodiment of fig. 7B, the tip 706 includes a nozzle at the distal end of the outlet channel 712 to direct the released propellant and compound out of the outlet orifice in a narrow plume.

Fig. 7C is a perspective view of the tip 706 and a compound container according to one or more embodiments. In the embodiment of fig. 7C, the compound container 720 is a capsule. The capsule may be made of two parts that fit together. When separated, a portion of the capsule (e.g., a half-capsule, as shown in fig. 7E-7G) can be coupled to the tip 706. In use, the compound container 720 may contain a compound within a capsule. In one example, the compound is a powder. As shown in fig. 7E, the half-capsule includes an outlet opening 732 of the compound reservoir 720. The outlet opening 732 may be coupled to the inlet interface 714, as shown in fig. 7F-7G. In the embodiment of fig. 7F-7G, the inlet interface 714 is inserted into the outlet opening 732, and the compound container 720 can be secured to the inlet interface 714 via an interference fit. In an alternative embodiment, the outlet opening 732 may be inserted into the inlet interface 714. As shown in fig. 7G-7H, the tip 706 has an outer wall 708 and an inner wall 710, with an outlet passage 712 formed by a bore or lumen through the inner wall 710. An outlet opening 732 fits around the inlet interface 714, placing the compound container 720 and the outlet channel 712 in fluid communication.

As shown in fig. 7F, 7G, and 7J, the inlet interface 714 is, for example, a ring, band, port, collar, or band that interfaces with the compound container 720. As shown in fig. 7C, 7E, 7F, 7K, 7L, 7M, 7N, 7O, and 7P, one or more grooves 728 are located on the inlet interface 714 and create a flow path for propellant released from the propellant canister 704 to travel into the compound container 720. Examples of grooves 728 include, but are not limited to, channels, slots, radial ports, or passages. The groove 728 provides a path through the inlet interface 714 through which propellant flows into the compound container 720. In one example, there are a plurality of grooves 728. The grooves 728 may be equally spaced around the inlet interface 714. The grooves 728 may be of equal size to each other or may be of different sizes. The grooves 728 extend along the length of the inlet interface 714 such that when the compound container 720 is coupled to the inlet interface 714, a first portion of each groove 728 is exposed within the propellant channel 724 and a second portion of each groove 728 is positioned within the compound container 720. As shown in fig. 7C, the inlet interface 714 includes a ledge 730 designed to abut the compound container 720 when coupled to the inlet interface 714 and the groove 728 extends beyond the ledge 730 such that the groove 728 is not completely covered by the compound container 720.

In use, propellant released from the canister 704 flows through the propellant channel 724 and into the compound container 720 via the groove 728, as shown by the direction of the arrows in fig. 7D. The outlet passage 712 is aligned with the outlet opening 732 of the compound container 720. Propellant flows into the compound container 720 in the groove 728 of the inlet port 714 to agitate the powder, and powder and propellant exit the compound container 720 via the outlet opening 732 corresponding to the outlet channel 712. The propellant and powder mixture is carried through the outlet channel 712 through the nozzle 718 and exits the device 700 at the outlet orifice 716. In one example, the tip 706 can have one or more outlet orifices. The plume exiting the outlet orifice 716 has a narrow spray plume.

In one example of use of the device 700, at the time of use, the user divides the pre-filled capsule in half. In one example, the capsule is pre-filled with a powdered compound. The half-capsule is coupled to the tip 706 via an inlet interface 714. As shown in fig. 7P and 7Q, the tip 706 is then coupled to the actuator body 702. Propellant gas, for example from a refrigerant or compressed gas source, is directed through propellant channel 724 and toward the filled powder capsule. Grooves 728 around the inlet interface 714 of the tip 706 introduce high velocity jets of propellant gas that agitate the dry powder into suspension within the propellant gas (data not shown, but confirmed by high speed close-up video). The grooves 728, which introduce gas tangentially to the hemispherical bottom of the compound vessel 720, create jets that will enhance powder agitation and entrainment. Once the powder is suspended, it is evacuated through the outlet opening 732 into the outlet channel 712 and out of the outlet orifice 716 of the device 700.

Generally, any shrinkage joint will cause powder blockage when accelerating the powder formulation through the restrictive orifice. Since the powder administered by the device 700 is suspended in the propellant gas prior to evacuation, it can be further throttled and directed without clogging the device. Thus, much greater mass of powder can be delivered through a much smaller exit orifice without the device 700 being too long. The time from propellant actuation to the end of compound delivery is less than 1 second.

A groove 728 in the proximal end of the tip 706 will facilitate the flow of gas into the compound container 720. In one example, HFA gas is directed at the surface of the powder dose present in the compound container 720 (e.g., orthogonally or near orthogonally), which results in rapid agitation and entrainment of the powder. The hemispherical shape of the compound container 720 will facilitate redirection of the gas to the outlet channel 712 of the tip 706, as shown in fig. 7D. The arrows in fig. 7B and 7D illustrate the direction of propellant flow after the device 700 is actuated.

The actuator body 702 is attached and sealed to a propellant canister 704 and a tip 706, creating a pressurized flow path for the propellant gas. In certain aspects, the actuator body 702 is a reusable component. In certain aspects, the canister 704 is a reusable component.

In one example, the compound container 720 is a standard size 3 drug capsule, but one skilled in the art would know how to use other sized drug capsules and modify the device 700 to fit it. Additionally, in another example, the compound container 720 may not be a capsule, but another container capable of holding a compound, such as, but not limited to, an ampoule. In one example, the ampoule may be made of plastic, and in one example, it may be a blow-filled ampoule. To load the device 700, the user or clinician detaches the capsule containing the pre-filled formulation, discards the cap, and mounts the capsule over the tip 706. The empty compound container 720 may also be filled by a clinician at the time of use, and the compound container 720 then mounted to the tip 706. In certain examples, the capsule is a disposable component.

The tip 706 receives the compound container 720 during loading and then couples to the actuator body 702 prior to use. When the propellant canister 704 is actuated, expanding propellant gas is introduced into the compound container 720 via the groove 728 around the inlet interface 714 of the nib 706. The resulting jet of propellant gas agitates and entrains the powder formulation within the compound container 720 which then exits through the outlet passage 712 and the outlet orifice 716 of the tip 706. In one example, the tip 706 is a disposable component. FIG. 7K illustrates an example measurement of the tip 706 in inches. In the embodiment of fig. 7N, the inlet interface 714 can include a radius along the bottom edge 222 to aid in placement of the compound container 720 onto the tip 706. The radius of curvature may range between about 0.007 inches and 0.027 inches, inclusive.

Fig. 7T and 7U illustrate perspective views of a second embodiment 734 of a tip. Similar to the tip 706, the tip 734 can be coupled to the actuator body 702 and decoupled from the actuator body 702, which enables a user to load and unload a compound container 736 to the tip 734 and from the tip 734 for delivery to the user's upper nasal cavity using the device 700. As shown in fig. 7T and 7U, compound container 736 is a capsule. In one example, the compound container 736 can contain a powder. In the embodiment of fig. 7T and 7U, tip 734 includes an inlet interface 738 for coupling with a compound container 736, wherein inlet interface 738 has a piercing member 740. Piercing member 740 is designed to pierce compound container 736 to create an opening in compound container 736. Piercing member 740 may include a sharp point, a sharp corner, a knife-like edge, or other suitable geometry for piercing compound container 736. In one embodiment, inlet interface 738 comprises more than one piercing member 740, wherein each piercing member 740 is designed to pierce compound container 736. The piercing members 740 may be positioned in a symmetrical or random pattern around the portal 738. In one embodiment, in use, a user can remove the nib 734 from the actuator body 702, load the compound container 736 into the port 726 of the propellant channel 724, and then insert the nib 734 back into the port 726. With the tip 734 coupled to the actuator body 702, the piercing member 740 pierces the capsule. In this configuration, as shown in fig. 7U, the pierced capsule fits around piercing member 740. In an alternative embodiment, piercing member 742 may comprise a plurality of piercing points 744 that each pierce compound container 736. The plurality of puncture points 744 can be spaced about the puncture member 742.

Fig. 7V and 7W illustrate perspective views of a piercing member 742 that can be used with the tip 734 according to one or more embodiments. As shown in fig. 7V, piercing member 742 can be a loop, ring, band, port, or band that couples with the pierced compound container 736. Piercing member 742 comprises one or more piercing grooves 746, similar to grooves 728, that form a flow path between propellant channel 724 and compound container 736. Propellant from the propellant canister 704 enters via one or more piercing indentations 746 of the piercing member 742, flows along the piercing indentations 746 and into the pierced compound container 736. As shown in fig. 7V and 7W, the puncturing member 742 comprises a plurality of puncturing openings 748. In the embodiment of fig. 7V, 7W, 7X, the piercing opening 748 is in fluid communication with the outlet channel 712. Propellant from the propellant canister 704 flows into the piercing indentation 746, mixes with the powder in the pierced compound container 736, and flows into the piercing opening 744 to the outlet passage 712. The arrows in fig. 7X illustrate the flow path of the propellant. The outlet channel 712 provides a path for propellant and powder to the nozzle 718 and outlet orifice 716. The mixture of propellant and powder exits the device 700 via the outlet orifice 716. The plume exiting the device 700 is a narrow spray plume. In this embodiment, the piercing member 742 may be integrally molded as a single piece or may be comprised of two or more pieces. In one example, piercing member 742 may be a separate molding that acts in association with inlet interface 738 (where the capsule is attached). In some embodiments, the inlet interface can include more than one piercing member 742.

As an alternative to a capsule being manually separated prior to placement on the tip 734, the tip 734 may include an integral piercing member 742 and piercing indentation 746, as shown in fig. 7V and 7W. To create repeatable puncturing of compound container 736, piercing member 742 forms a single point, piercing point 744. In one example, the puncture site 744 includes puncture openings 746 radially spaced about the puncture site 744. Piercing opening 746 is in fluid communication with outlet passage 712 to evacuate powder from compound container 736.

By allowing the propellant flow path to be created by the inline piercing motion, as shown in fig. 7X, loading of the compound container 736 onto the nib 734 will be simplified for the user because the compound container 736 does not require manual manipulation and separation. In one example, the piercing member 742 is integrally formed with the tip 734. In one example, the filled compound container 736 can be filled and installed into the actuator body 702 or tip 734 during the manufacture of the device 700. In use, a user may apply linear motion to drive the piercing member 742 into the pre-filled compound container 736, thereby creating a complete gas flow path for metering prior to propellant actuation.

The present invention is further described in the following examples, which are not intended to limit the scope of the present invention.

Powder capsule

In one embodiment, a device was constructed and tested. The residual powder in the compound container after actuation was tested. When 2 or more but less than 6 grooves are used on the inlet interface, the device has comparable powder delivery performance as measured by the residue after actuation. In this example, the groove was combined with 63mg HFA propellant and the.040 "outlet orifice of the nozzle. Four grooves (every 90 degrees) were found to provide uniform gas delivery.

Dose mass

A dose mass reproducibility test was performed. The standard deviation of dose delivery indicates that the device is capable of delivering consistent dose quality. The average residual dose amount remaining in the device was < 5%, indicating that very little dose was lost in the device.

Intranasal devices with multiple cartridges

FIG. 9A illustrates another example of a non-human primate precision nasal delivery device 800 used in the study 2037-. The device 900 may deliver the compound as a liquid, a powder, or some combination thereof. The device 900 includes a propellant canister 905, an actuator body 910, an extension tube 915, and a tip 920. Similar to the device 1, the propellant canister 905 is in fluid communication with the actuator body 910 such that propellant released from the propellant canister 905 travels through the actuator body 910, through the extension tube 915, through the nib 920, and out of the outlet opening 925 of the nib 920. The compound may be loaded into the tip 920 such that as the propellant travels through the tip 920, the propellant contacts the compound and propels the compound to the outlet opening 925, where the propellant and compound exit in a plume.

Figure 9C illustrates a side view of the extension tube 915 of the inter-nasal device 900 of figure 9A. The extension tube 915 is a tube that includes an internal passage that creates fluid communication between the actuator body 910 and the tip 920. In the embodiment of fig. 9A-9D, a first end 930 of the extension tube 915 is coupled to the actuator body 910, while a second end 935 of the extension tube 915 is coupled to the tip 920, each of which is coupled via a respective connection interface 940a, 940b (collectively "940"). The connection hub 940 includes a luer lock having a male or female end on each side of the luer lock. In the embodiment of fig. 9A-9D, each connection interface 940 includes a luer lock having two male ends. Thus, the male ends of the connection hub 940a are inserted into the actuator body 910 and the first end 930, respectively, and the male ends of the connection hub 940b are inserted into the tip 920 and the second end 935, respectively. As illustrated in fig. 9C, the second end 935 may include a plurality of cartridges 945 positioned within the internal passage of the luer lock. The filter element 945 may be configured to convert liquid propellant to gas as the propellant passes through the filter element 945. Alternatively, extension tube 915 in fig. 9B may be configured to convert the liquid propellant to a gas. The filter element 945 can be composed of a porous material. The number of filter elements 945 can vary in different embodiments. As the number of filter elements increases, the intensity of the plume may decrease, for example, in terms of its impact force, velocity, plume width, other similar criteria, or some combination thereof. Similarly, the length of extension tube 915 may be adjusted so that the propellant travels a longer or shorter distance. Calibrating the intensity of the plume may enable the device 900 to accurately deliver the compound to the nasal cavity. Fig. 9D illustrates an enlarged view of the connection interface 940b at the second end 935 of the extension tube 915 of fig. 9C — the first example embodiment 950 includes a single cartridge 945 and the second example embodiment 955 includes three cartridges 945 stacked in series. The number of cartridges 945 can be selected based on the type of compound. For example, a single filter element 945 may be used for powder compounds while three filter elements 945 may be used for liquid compounds, or vice versa.

Fig. 9E illustrates a side view and a cross-sectional view of the tip 920 of the inter-nasal device of fig. 9A. The tip 920 is designed to be inserted into a nostril. The tip 920 includes an internal passage 960 and an outlet opening 925 for delivering the compound to the nasal cavity. In the embodiment of fig. 9E, the tip 920 includes a filter element 945 positioned within the internal passage 960. The filter element 945 may be configured to convert liquid propellant to gas as the propellant passes through the filter element 945. The filter element 945 can be composed of a porous material. In the embodiment of fig. 9E, the tip 920 also includes a nozzle 965 at the distal end of the tip 920 near the outlet opening 925. The nozzles 965 can enhance deposition of the compound within the nasal cavity, such as to the upper olfactory region of the user. In some embodiments, nozzle 965 can include a single orifice, while in alternative embodiments, nozzle 965 can include multiple orifices (e.g., between 2 and 11 orifices). In some embodiments, the tip 920 may not include a nozzle. Different embodiments of the tip may be used based on the different types of compounds to be delivered to the nasal cavity of the user. For example, a tip for delivering a powder compound may not include a nozzle, while a tip for delivering a liquid compound may include a nozzle, or vice versa. In addition, the number of orifices in the nozzle may similarly vary based on the type of compound. A compound may be loaded into the tip 920 such that the compound is contained within the internal passage 960. In the embodiment of fig. 9E, compound is loaded into the tip 920 through an opening 990 at the proximal end of the tip 920 prior to disposing the filter element 945 within the inner channel 960. The cartridge 945 is then inserted to contain the compound inside the tip 920. In an alternative embodiment, such as one in which the tip 920 does not include a nozzle 965, the compound can be loaded into the tip through the outlet opening 925. In the configuration of fig. 9E, propellant travels from the propellant canister 905, through the actuator body 910 and extension tube 915, through the tip 920 and contacts the filter element 945, and then contacts the compound within the internal passage 960, thereby pushing the compound through the outlet opening 925 where the propellant and compound exit in a plume that is delivered within the nasal cavity of the user.

Dry pharmaceutical composition

In another aspect, a dry pharmaceutical composition suitable for intranasal administration is provided. The composition comprises levodopa and at least one excipient.

In typical embodiments, the dry pharmaceutical composition is a powder.

In some embodiments, the median diameter of the levodopa particle size distribution (D50) in the powder is from 5 μm to 500 μm, from 5 μm to 250 μm, from 5 μm to 100 μm, or from 5 μm to 75 μm. In some embodiments, the median diameter of the particle size distribution of levodopa (D50) in the powder is from 5 μm to 50 μm, from 10 μm to 50 μm, or from 20 μm to 40 μm.

In various embodiments, the composition comprises levodopa in a crystalline or amorphous form. In some embodiments, the composition comprises levodopa in an amorphous form. In some embodiments, the composition comprises levodopa in a partially crystalline and partially amorphous form. In certain embodiments, amorphous levodopa is obtained by spray drying. In some embodiments, the composition comprises levodopa in a crystalline form and an amorphous form.

In various embodiments, the dry pharmaceutical composition comprises no more than 85% by weight levodopa or no more than 80% by weight levodopa. In certain embodiments, the composition comprises 50-80% by weight levodopa, 50-70% by weight levodopa, or 65-70% by weight levodopa.

In typical embodiments, the dry pharmaceutical composition further comprises a non-ionic surfactant. In some embodiments, the nonionic surfactant is an alkyl maltoside, and in a currently preferred embodiment, the alkyl maltoside is n-dodecyl β -D-maltoside.

In some embodiments, the nonionic surfactant is present at 0.1 to 10 wt%, more preferably 1 to 5 wt%. In a particular embodiment, the nonionic surfactant is present at 1% by weight.

In various embodiments, the dry pharmaceutical composition further comprises Hydroxypropylmethylcellulose (HPMC).

In various embodiments, the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation. In typical embodiments, the salt is NaCl. In certain embodiments, the composition comprises 1-5 wt% NaCl, or more preferably 2-4 wt% NaCl.

In a currently preferred embodiment, the dry pharmaceutical composition comprises 68% by weight levodopa, 2% by weight NaCl, 29% by weight HPMC and 1% by weight n-dodecyl β -D-maltoside. In a particularly preferred embodiment, the composition is a spray-dried composition comprising levodopa in amorphous form.

Unit dosage form

In another aspect, a unit dosage form is provided. The unit dosage form contains a dry pharmaceutical composition as described above in section 5.4.

In typical embodiments, the unit dosage form contains 25-150mg levodopa. In certain embodiments, the unit dosage form contains 35-140mg levodopa. In particular embodiments, 35mg of levodopa or 70mg of levodopa is contained.

In some embodiments, the unit dosage form is a capsule encapsulating the dry pharmaceutical composition. In certain embodiments, the capsule is a hard capsule. In a particular embodiment, the hard capsule is an HPMC hard capsule.

In some embodiments, the unit dosage form is a dosage container configured to be removably coupled to an intranasal delivery device. In particular embodiments, the dose container is a tip configured to be removably coupled to an intranasal delivery device.

Experimental examples

The invention is further described by reference to the following experimental examples. These embodiments are provided for illustrative purposes only and are not intended to be limiting.