Intranasal delivery of olanzapine by precision nasal device
阅读说明:本技术 通过精密鼻装置的奥氮平的鼻内递送 (Intranasal delivery of olanzapine 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 于 2019-01-04 设计创作,主要内容包括:提供了用于躁动的急性治疗的方法,该躁动包括患有精神分裂症或双相障碍的患者中的躁动,所述方法包括向具有躁动的受试者施用有效剂量的包含奥氮平的干燥药物组合物,其中所述剂量通过鼻内递送装置施用,所述装置在鼻内施用后提供(a)至少30ng/mL的平均峰值血浆奥氮平浓度(C<Sub>max</Sub>)和(b)短于0.5小时的达到奥氮平的C<Sub>max</Sub>的平均时间(T<Sub>max</Sub>)。提供了适于奥氮平的鼻内递送的干燥药物组合物和装置。(Methods for acute treatment of agitation are providedComprising agitation in a patient suffering from schizophrenia or bipolar disorder, comprising administering to the subject with agitation an effective dose of a dry pharmaceutical composition comprising olanzapine, wherein the dose is administered by an intranasal delivery device that provides, following intranasal administration, (a) a mean peak plasma olanzapine concentration (Cmax) of at least 30ng/mL max ) And (b) C to olanzapine in less than 0.5 hour max Average time (T) of max ). Dry pharmaceutical compositions and devices suitable for intranasal delivery of olanzapine are provided.)
1. A method for acute treatment of agitation in a subject, comprising:
intranasally administering to a subject exhibiting agitation an effective dose of a dry pharmaceutical composition comprising olanzapine.
2. The method of claim 1, wherein the dry pharmaceutical composition is a powder.
3. The method of claim 2, wherein the powder comprises olanzapine in crystalline or amorphous form.
4. The method of claim 3, wherein the olanzapine is an amorphous solid obtained by spray drying.
5. The method of any one of claims 2-4, wherein the dry pharmaceutical composition comprises olanzapine in a partially crystalline and partially amorphous form.
6. The method of any one of claims 2-5, wherein the powder has a median diameter (D50) of the particle size distribution of olanzapine between 1 μm and 100 μm, between 1 μm and 50 μm, or between 1 μm and 15 μm.
7. The method of claim 6, wherein the olanzapine particle size distribution has a median diameter (D50) between 7.5 μm and 15 μm.
8. The method of any one of claims 1-70, wherein the dry pharmaceutical composition comprises no more than 70% olanzapine by weight.
9. The method of claim 8, wherein the dry pharmaceutical composition comprises no more than 60% olanzapine by weight.
10. The method of claim 9, wherein the dry pharmaceutical composition comprises 10-60% olanzapine by weight.
11. The method of claim 10, wherein the dry pharmaceutical composition comprises 25-55% olanzapine by weight.
12. The method of claim 11, wherein the dry pharmaceutical composition comprises 30-50% olanzapine by weight.
13. The method of claim 12, wherein the dry pharmaceutical composition comprises 40-50% olanzapine by weight.
14. The method of any one of claims 8-13, wherein the dry pharmaceutical composition further comprises a stabilizer, wherein the stabilizer is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), vinyl pyrrolidine-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolidine K30(Kollidon K30), polyvinylpyrrolidone K90(Kollidon K90), hydroxypropyl cellulose (HPC), hydroxypropyl β -cyclodextrin (HPBCD), mannitol, and lactose monohydrate.
15. The method of claim 14, wherein the stabilizer is Hydroxypropylmethylcellulose (HPMC).
16. The method of any one of claims 8-15, wherein the dry pharmaceutical composition further comprises a penetration enhancer, wherein the penetration enhancer is selected from the group consisting of: n-tridecyl- β -D-maltoside, n-dodecyl- β -D-maltoside, 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and polyethylene glycol (15) hydroxystearate.
17. The method of claim 16, wherein the penetration enhancer is 1, 2-distearoyl-sn-glycerol-3-phosphocholine (DSPC).
18. The method of any one of claims 8-17, wherein the dry pharmaceutical composition further comprises an antioxidant, wherein the antioxidant is selected from the group consisting of: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, bronopol, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylenediaminetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
19. The method of any one of claims 1-18, wherein the dried pharmaceutical composition comprises less than 3%, less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight water.
20. The method of any one of claims 8-19, wherein the dry pharmaceutical composition consists essentially of:
50% by weight olanzapine;
42% by weight of HPMC; and
8% by weight of DSPC.
21. The method of any one of claims 1-20, wherein the dose is administered by an intranasal delivery device.
22. The method of claim 21, wherein the intranasal delivery device is a hand-held, manually-actuated, metered dose intranasal administration device.
23. The method of claim 21, wherein the intranasal delivery device is a hand-held, manually-actuated, propellant-driven, metered dose intranasal administration device.
24. The method of any one of claims 21-23, wherein the dry pharmaceutical composition is encapsulated within a capsule located within the device prior to device actuation.
25. The method of any one of claims 21-23, wherein the dry pharmaceutical composition is stored within a dosage container that is removably coupled to the device prior to device actuation.
26. The method of any one of claims 21-25, wherein the intranasal delivery device is capable of delivering the dry pharmaceutical composition to the upper nasal cavity.
27. The method of any one of claims 1-26, wherein the effective dose of the dry pharmaceutical composition comprises olanzapine in an amount effective to reduce agitation within 30 minutes.
28. The method of claim 27, wherein the effective dose of the dry pharmaceutical composition comprises 1-30mg olanzapine.
29. The method of claim 28, wherein the effective dose comprises 2-20mg olanzapine.
30. The method of claim 29, wherein the effective dose comprises 5-15mg olanzapine.
31. The method of claim 30, wherein the effective dose comprises 5mg olanzapine.
32. The method of claim 30, wherein the effective dose comprises 10mg olanzapine.
33. The method of claim 30, wherein the effective dose comprises 15mg olanzapine.
34. The method of any one of claims 27-33, wherein the effective dose is administered as a single undivided dose.
35. The method of any one of claims 27-33, wherein the effective dose is administered in multiple divided sub-dose forms.
36. The method of any one of claims 1-35, wherein the subject has schizophrenia.
37. The method of any one of claims 1-35, wherein the subject has bipolar disorder, optionally bipolar I disorder.
38. The method of any one of claims 1-35, wherein the patient has autism, dementia, PTSD, intoxication or drug-induced psychotic state.
39. The method of any one of claims 1-38, wherein the intranasal administration provides:
(a) a mean peak plasma olanzapine concentration (C) of at least 20ng/mLmax) And are and
(b) c to olanzapine in less than 1.5 hoursmaxAverage time (T) ofmax)。
40The method of claim 39, wherein said intranasal administration provides: c to olanzapine in less than 1.0 hourmaxAverage time (T) ofmax)。
41. The method of claim 40, wherein the intranasal administration provides: c to olanzapine in less than 0.75 hoursmaxAverage time (T) ofmax)。
42. The method of claim 41, wherein the intranasal administration provides: c to olanzapine in less than 0.50 hoursmaxAverage time (T) ofmax)。
43. The method of claim 40, wherein the intranasal administration provides: c to olanzapine in less than 0.25 hoursmaxAverage time (T) ofmax)。
44. The method of any one of claims 39-43, wherein the intranasal administration provides: a mean peak plasma olanzapine concentration (C) of at least 30ng/mLmax)。
45. The method of claim 44, wherein the intranasal administration provides: a mean peak plasma olanzapine concentration (C) of at least 40ng/mLmax)。
46. The method of claim 45, wherein the intranasal administration provides: a mean peak plasma olanzapine concentration (C) of at least 50ng/mLmax)。
47. The method of claim 46, wherein the intranasal administration provides: a mean peak plasma olanzapine concentration (C) of at least 60ng/mLmax)。
48. The method of claim 47, wherein the intranasal administration provides: a mean peak plasma olanzapine concentration (C) of at least 70ng/mLmax)。
49. The method of claim 48, wherein said intranasal administration provides: a mean peak plasma olanzapine concentration (C) of at least 80ng/mLmax)。
50. A dry pharmaceutical composition suitable for intranasal administration comprising:
olanzapine, and
at least one excipient.
51. The dry pharmaceutical composition of claim 50, wherein the composition is a powder.
52. The dry pharmaceutical composition of claim 51, wherein the composition comprises olanzapine in a crystalline or amorphous form.
53. The dry pharmaceutical composition of claim 51, wherein the composition comprises olanzapine in an amorphous form.
54. The dry pharmaceutical composition of claim 53, wherein the amorphous olanzapine is obtained by spray drying.
55. The dry pharmaceutical composition of any one of claims 52-54, wherein the composition comprises olanzapine in a partially crystalline and partially amorphous form.
56. The dry pharmaceutical composition of any one of claims 52-55, wherein the median diameter (D50) of the particle size distribution of olanzapine in the powder is between 1 μm and 100 μm, between 1 μm and 50 μm, or between 1 μm and 15 μm.
57. The dry pharmaceutical composition of claim 56, wherein the olanzapine particle size distribution has a median diameter (D50) between 7.5 μm and 15 μm.
58. The dry pharmaceutical composition of any one of claims 50-57, wherein the dry pharmaceutical composition comprises no more than 70% olanzapine by weight.
59. The dry pharmaceutical composition of claim 58, wherein the dry pharmaceutical composition comprises no more than 60% olanzapine by weight.
60. The dry pharmaceutical composition of claim 59, wherein the dry pharmaceutical composition comprises 10-60% olanzapine by weight.
61. The dry pharmaceutical composition of claim 60, wherein the dry pharmaceutical composition comprises 25-55% olanzapine by weight.
62. The dry pharmaceutical composition of claim 61, wherein the dry pharmaceutical composition comprises 30-50% olanzapine by weight.
63. The dry pharmaceutical composition of claim 62, wherein the dry pharmaceutical composition comprises 30-40% olanzapine by weight.
64. The dry pharmaceutical composition of claim 62, wherein the dry pharmaceutical composition comprises 40-50% olanzapine by weight.
65. The dry pharmaceutical composition of any one of claims 50-64, further comprising a stabilizer, wherein the stabilizer is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), polyvinylpyrrolidone K30(Kollidon K30), polyvinylpyrrolidone K90(Kollidon K90), hydroxypropyl cellulose (HPC), hydroxypropyl β -cyclodextrin (HPBCD), mannitol, and lactose monohydrate.
66. The dry pharmaceutical composition of claim 65, wherein the stabilizer is Hydroxypropylmethylcellulose (HPMC).
67. The dry pharmaceutical composition of any one of claims 50-66, further comprising a penetration enhancer, wherein the penetration enhancer is selected from the group consisting of: n-tridecyl- β -D-maltoside, n-dodecyl- β -D-maltoside, 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and polyethylene glycol (15) hydroxystearate.
68. The dry pharmaceutical composition of claim 67, wherein the penetration enhancer is 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC).
69. The dry pharmaceutical composition of any one of claims 50-68, further comprising an antioxidant, wherein the antioxidant is selected from the group consisting of: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, bronopol, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylenediaminetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
70. The dry pharmaceutical composition of any one of claims 50-69, wherein the dry pharmaceutical composition comprises less than 3%, less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight water.
71. The dry pharmaceutical composition of any one of claims 50-70, wherein the dry pharmaceutical composition consists essentially of:
50% by weight olanzapine;
42% by weight of HPMC; and
8% by weight of DSPC.
72. A unit dosage form comprising a dry pharmaceutical composition according to any one of claims 50-71.
73. The unit dosage form of claim 72, wherein the unit dosage form contains 1-30mg olanzapine.
74. The unit dosage form of claim 73, wherein the unit dosage form contains 2-20mg olanzapine.
75. The unit dosage form of claim 74, wherein the unit dosage form contains 5-15mg olanzapine.
76. The unit dosage form of claim 75, wherein the unit dosage form contains 5mg olanzapine.
77. The unit dosage form of claim 75, wherein the unit dosage form contains 10mg of olanzapine.
78. The unit dosage form of claim 75, wherein the unit dosage form contains 15mg of olanzapine.
79. The unit dosage form of any one of claims 72-78, wherein the unit dosage form is a capsule encapsulating the dry pharmaceutical composition.
80. The unit dosage form of any one of claims 72-78, wherein the unit dosage form is a dosage container storing the dry pharmaceutical composition, wherein the dosage container is configured to be removably coupled to an intranasal delivery device.
Background
In 1.3 million U.S. emergency room visits per year, it is estimated that 170 million patients are involved in agitation, including patients whose agitation is a manifestation of schizophrenia or bipolar disorder.
The current standard of care for treating acute and exacerbating manic events in schizophrenia or bipolar I mania is by administering 5mg, 7.5mg or 10mg olanzapine (an atypical antipsychotic) by intramuscular Injection (IM). Although olanzapine IM is characterized by a rapid onset (reaching mean maximum plasma concentrations within 15 to 45 minutes), this route of administration is characterized by several injection-related acute side effects including injection site pain, excessive sedation, extrapyramidal syndrome and akathisia (Atkins et al, BMC Psychiatry 14,7 (2014); Battaglia et al, am.j.emerg.med.21: 192-charge 198 (2003); Kishi et al, j.psychiatr.res.68: 198-charge 209 (2015)). Moreover, the invasive intramuscular injection procedure may cause emotional trauma to the patient, whether collaborative or uncooperative, and may result in physical attack on hospital personnel attempting to inject. In addition, IM injections are contraindicated in cooperative patients (Nordstrom et al, west.j.emerg.med.13(1):3-10 (2012)).
Oral administration of olanzapine in standard tablets or orally disintegrating tablets has been approved for acute treatment of mania or mixed episodes associated with bipolar 1 disorder and does not suffer from many of the disadvantages of intramuscular injections in this patient population; however, there is a significant lag before effective blood levels are reached and agitation is reduced.
Pulmonary delivery of the typical antipsychotic drug loxapine by oral inhalation has been approved in 2017 for acute treatment of agitation associated with schizophrenia or bipolar 1 disorder in adults. However, the product label contains a black box warning: administration may cause bronchospasm, which may lead to respiratory distress and cessation (adasvre FDA product label, 8 months 2017), and the product is only available under risk assessment and mitigation strategies (REMS).
An effective non-invasive treatment of acute agitation can divert treatment from the emergency room to the "community" early in the onset of the agitation, with obvious benefits, including reduced emergency department visits and health economic burdens. Thus, there is a need for acute treatment of agitation, including agitation associated with schizophrenia and manic depression, which is rapid in onset and does not require parenteral injection.
Disclosure of Invention
We have developed a dry powder formulation of olanzapine suitable for intranasal delivery by a hand-held, manually actuated, propellant driven, metered dose intranasal applicator. After a single dose PK study in cynomolgus monkeys and rodents, we performed a phase I trial in healthy human subjects. In this phase I study, intranasal delivery of olanzapine formulations yielded similar or slightly higher plasma exposure (AUC) and maximum C compared to olanzapine administered IM at the same dosemax. In addition, median T after intranasal delivery of the formulationmax-three test doses in the range of 0.16-0.17 hours-significantly shorter than the median T measured for intramuscular and oral administrationmaxShows that the olanzapine can be quickly and effectively absorbed across nasal epithelial cells。
Three standardized behavioral tests were used to measure pharmacodynamic effects. Behavioral testing has shown that intranasal administration of olanzapine produces similar or better sedation than IM or oral administration of olanzapine. Consistent with pharmacokinetic data, behavioral effects of olanzapine were observed significantly earlier in the group of subjects treated with intranasal olanzapine (INP105) than in the group of subjects treated with oral olanzapine (Zyprexa Zydis). These results indicate that intranasal delivery of olanzapine may be an effective method for acute treatment of agitation.
Thus, in a first aspect, a method for acute treatment of agitation is presented. The method comprises intranasally administering to a subject exhibiting agitation an effective dose of a dry pharmaceutical composition comprising olanzapine.
In typical embodiments, the dry pharmaceutical composition is a powder. In some embodiments, the powder comprises olanzapine in crystalline or amorphous form. In some embodiments, olanzapine is an amorphous solid obtained by spray drying. In some embodiments, the dry pharmaceutical composition comprises olanzapine in a partially crystalline and partially amorphous form.
In some embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the powder is between 1 μm and 100 μm, between 1 μm and 50 μm, or between 1 μm and 15 μm, as measured by a laser diffraction particle size analyzer, such as a Malvern panalytical mastersizer 3000. In some embodiments, the olanzapine particle size distribution has a median diameter (D50) between 7.5 μm and 15 μm.
In some embodiments, the dose is administered by an intranasal delivery device. In some embodiments, the intranasal delivery device is a hand-held, manually-actuated, metered dose intranasal administration device. In some embodiments, the intranasal delivery device is a hand-held, manually-actuated, propellant-driven, metered dose intranasal administration device.
In some embodiments, the dry pharmaceutical composition is encapsulated within a capsule located 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.
In some embodiments, the intranasal delivery device is capable of delivering the dry pharmaceutical composition to the upper nasal cavity.
In some embodiments, the dry pharmaceutical composition comprises no more than 70% by weight, or no more than 60% by weight olanzapine. In some embodiments, the dry pharmaceutical composition comprises 10-60% olanzapine by weight, 20-60% olanzapine by weight, 25-55% olanzapine by weight, 30-50% olanzapine by weight, or 40-50% olanzapine by weight.
In some embodiments, the dry pharmaceutical composition further comprises a stabilizing agent, wherein the stabilizing agent is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), vinyl pyrrolidine-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolidine K30(Kollidon K30), polyvinylpyrrolidone K90(Kollidon K90), hydroxypropyl cellulose (HPC), hydroxypropyl β -cyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is Hydroxypropylmethylcellulose (HPMC).
In some embodiments, the dry pharmaceutical composition further comprises a penetration enhancer, wherein the penetration enhancer is selected from the group consisting of: n-tridecyl- β -D-maltoside, n-dodecyl- β -D-maltoside, 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and polyethylene glycol (15) hydroxystearate. In some embodiments, the penetration enhancer is 1, 2-distearoyl-sn-glycerol-3-phosphocholine (DSPC).
In some embodiments, the dry pharmaceutical composition further comprises an antioxidant, wherein the antioxidant is selected from the group consisting of: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, bronopol Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylenediaminetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
In some embodiments, the dry pharmaceutical composition comprises less than 3%, less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight water.
In some embodiments, the dry pharmaceutical composition consists essentially of: 50% by weight olanzapine; 42% by weight of HPMC; and 8 wt% DSPC.
In some embodiments, the effective dose is a dose of olanzapine effective to reduce agitation within 60 minutes. In some embodiments, an effective dose of the dry pharmaceutical composition comprises 1-30mg olanzapine; 2-20mg olanzapine; 5-15mg olanzapine; 5mg olanzapine; 10mg olanzapine; or 15mg olanzapine.
In some embodiments, the effective dose is administered as a single undivided dose. In some embodiments, the effective dose is administered in multiple aliquots of sub-dose forms.
In some embodiments, the subject has schizophrenia. In some embodiments, the subject has bipolar disorder, optionally bipolar I disorder. In some embodiments, the subject has autism, dementia, PTSD, intoxication or drug-induced psychotic state.
In some embodiments, intranasal administration provides: (a) a mean peak plasma olanzapine concentration (C) of at least 20ng/mLmax) And (b) C to olanzapine in less than 1.5 hoursmaxAverage time (T) ofmax)。
In some embodiments, intranasal administration provides: c to olanzapine in less than 1.0 hourmaxAverage time (T) ofmax) (ii) a C to olanzapine in less than 0.75 hoursmaxAverage time (T) ofmax) (ii) a C to olanzapine in less than 0.50 hoursmaxAverage time (T) ofmax) Or less than 0.25 hours to reach olanzapine CmaxAverage time (T) ofmax)。
In some embodiments, intranasal administration provides: average of at least 40ng/mLPeak plasma olanzapine concentration (C)max) (ii) a A mean peak plasma olanzapine concentration (C) of at least 50ng/mLmax) (ii) a A mean peak plasma olanzapine concentration (C) of at least 60ng/mLmax) (ii) a A mean peak plasma olanzapine concentration (C) of at least 70ng/mLmax) (ii) a Or a mean peak plasma olanzapine concentration (C) of at least 80ng/mLmax)。
In another aspect, the present invention provides a dry pharmaceutical composition suitable for intranasal administration comprising: olanzapine and at least one excipient.
In some embodiments, the composition is a powder. In some embodiments, the composition comprises olanzapine in a crystalline or amorphous form. In some embodiments, the composition comprises olanzapine in an amorphous form. In some embodiments, the amorphous olanzapine is obtained by spray drying. In some embodiments, the composition comprises olanzapine in a partially crystalline and partially amorphous form.
In some embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the powder is between 1 μm and 100 μm, between 1 μm and 50 μm, or between 1 μm and 15 μm. In some embodiments, the olanzapine particle size distribution has a median diameter (D50) between 7.5 μm and 15 μm.
In some embodiments, the dry pharmaceutical composition comprises no more than 70% olanzapine by weight, or no more than 60% olanzapine by weight. In some embodiments, the dry pharmaceutical composition comprises 10-60% olanzapine by weight, 20-60% olanzapine by weight, 25-55% olanzapine by weight, 30-50% olanzapine by weight, 30-40% olanzapine by weight, or 40-50% olanzapine by weight.
In some embodiments, the dry pharmaceutical composition further comprises a stabilizing agent, wherein the stabilizing agent is selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), polyvinylpyrrolidone K30(Kollidon K30), polyvinylpyrrolidone K90(Kollidon K90), hydroxypropyl cellulose (HPC), hydroxypropyl β -cyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is Hydroxypropylmethylcellulose (HPMC).
In some embodiments, the dry pharmaceutical composition further comprises a penetration enhancer, wherein the penetration enhancer is selected from the group consisting of: n-tridecyl- β -D-maltoside, n-dodecyl- β -D-maltoside, 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and polyethylene glycol (15) hydroxystearate. In some embodiments, the penetration enhancer is 1, 2-distearoyl-sn-glycerol-3-phosphocholine (DSPC).
In some embodiments, the dry pharmaceutical composition further comprises an antioxidant, wherein the antioxidant is selected from the group consisting of: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, bronopol Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylenediaminetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
In some embodiments, the dry pharmaceutical composition comprises less than 3%, less than 2%, less than 1.5%, less than 1%, or less than 0.5% by weight water.
In some embodiments, the dry pharmaceutical composition consists essentially of: 50% by weight olanzapine; 42% by weight of HPMC; and 8 wt% DSPC.
In yet another aspect, the present invention provides a unit dosage form containing a dry pharmaceutical composition provided herein.
In some embodiments, the unit dosage form contains 1-30mg olanzapine; 2-20mg olanzapine; 5-15mg olanzapine; 5mg olanzapine; 10mg olanzapine; or 15mg olanzapine.
In some embodiments, the unit dosage form is a capsule encapsulating the dry pharmaceutical composition. In some embodiments, the unit dosage form is a dosage container storing a dry pharmaceutical composition, wherein the dosage container is configured to be removably coupled to an intranasal delivery device.
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 intramuscular administration (IM) followed by or using precision nasal deliveryDevice mean plasma olanzapine levels in non-human primates (NHPs) after intranasal administration of three different dry powder formulations of olanzapine as a function of time.
Fig. 2 shows an image of an NHP-POD device for administering olanzapine to NHPs as described in examples 1 and 2.
Figure 3 shows the change in plasma olanzapine concentration over time (time shown is 0-2 hours) after administration of a nasal powder formulation of olanzapine (F-OLZ #1-6) delivered to a non-human primate (NHP) by an NHP-POD device.
Fig. 4 shows the change in plasma olanzapine concentration over time (time shown is 0-24 hours) after administration of a nasal powder formulation of olanzapine (F-OLZ #1-6) delivered to NHPs by an NHP-POD device.
Fig. 5A is an intranasal drug delivery device according to one or more embodiments.
Fig. 5B 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. 5C is a perspective view of a tip and capsule according to one or more embodiments.
Fig. 5D is a cross-sectional view of a tip and a capsule coupled to a device according to one or more embodiments.
Fig. 5E is an exploded view of a tip and capsule according to one or more embodiments.
Fig. 5F is a perspective view of a tip with a capsule attached thereto according to one or more embodiments.
Fig. 5G is a cross-sectional view of a tip with a capsule attached according to one or more embodiments.
Fig. 5H is a cross-sectional view of a tip according to one or more embodiments.
Fig. 5I is a cross-sectional view of a tip according to one or more embodiments.
Fig. 5J is a cross-sectional view of an inlet interface with a capsule-attached tip according to one or more embodiments.
Fig. 5K-5N are perspective views of a tip of a device according to one or more embodiments.
Fig. 5O is a perspective view of a tip according to one or more embodiments.
Fig. 5P is a perspective view of a tip according to one or more embodiments.
Fig. 5Q is a perspective view of a tip coupled to a device according to one or more embodiments.
Fig. 5R is a cross-sectional view of a tip coupled to a device according to one or more embodiments.
Fig. 5S is an enlarged view of a capsule-attached inlet interface according to one or more embodiments.
Fig. 5T is a perspective view of a second embodiment of a tip according to one or more embodiments.
Fig. 5U is a perspective view of the tip of fig. 5T with a capsule attached according to one or more embodiments.
Fig. 5V is a perspective view of a piercing member according to one or more embodiments.
Fig. 5W is a perspective view of a piercing member according to one or more embodiments.
Fig. 5X illustrates a flow path of a second embodiment of a piercing member according to one or more embodiments.
Fig. 6 illustrates an example of a non-human primate precision nasal delivery device according to one or more embodiments.
Fig. 7A illustrates another example of a non-human primate precision nasal delivery device according to one or more embodiments.
Fig. 7B illustrates a side view and a cross-sectional view of an actuator body of the inter-nasal device of fig. 7A, according to one or more embodiments.
Fig. 7C illustrates a side view of an extension tube of the intranasal device of fig. 7A according to one or more embodiments.
Fig. 7D illustrates an enlarged view of two embodiments of a connection interface at the end of the extension tube of fig. 7C according to one or more embodiments.
Fig. 7E illustrates a side view and a cross-sectional view of the tip of the inter-nasal device of fig. 7A, according to one or more embodiments.
Figures 8A-C show intranasal administration of 5mg, 10mg, or 15mg olanzapine (INP105) in a human subject; intramuscular administration of 5mg or 10mg olanzapine (Zyprexa IM); or the mean plasma concentration-time curve measured after oral administration of 10mg olanzapine (Zyprexa Zydis). Data were obtained from the
Figure 9 shows intranasal administration of 5mg, 10mg, or 15mg olanzapine (INP105) in a human subject; intramuscular administration of 5mg or 10mg olanzapine (Zyprexa IM); or to three categories after oral administration of 10mg olanzapine (Zyprexa Zydis): change from baseline in maximum VAS scores measured by alertness/dull, confusion/waking and energetic/not conscious. Data were obtained from the study described in example 3 and plotted with error bars.
Figure 10 shows intranasal administration of 5mg, 10mg, or 15mg olanzapine (INP105) in a human subject; intramuscular administration of 5mg or 10mg olanzapine (Zyprexa IM); or the change from baseline in the maximum ACES score measured after oral administration of 10mg olanzapine (Zyprexa Zydis). Data were obtained from the study described in example 3 and plotted with error bars.
Figures 11A-B show intranasal administration of 5mg, 10mg, or 15mg olanzapine (INP105) in a human subject; intramuscular administration of 5mg or 10mg olanzapine (Zyprexa IM); or the average ACES score-time curve measured after oral administration of 10mg olanzapine (Zyprexa Zydis). Data were obtained from the study described in example 3, with FIG. 11A plotting results for longer PK time points (0-8 hours) and FIG. 11B plotting results for shorter PK time points (0-1 hour).
Figure 12 shows intranasal administration of 5mg, 10mg, or 15mg olanzapine (INP105) in a human subject; intramuscular administration of 5mg or 10mg olanzapine (Zyprexa IM); or the change from baseline in the maximum DSST score measured after oral administration of 10mg olanzapine (Zyprexa Zydis). Data were obtained from the study described in example 3 and plotted with error bars.
Figures 13A-B show intranasal administration of 5mg, 10mg, or 15mg olanzapine (INP105) in a human subject; intramuscular administration of 5mg or 10mg olanzapine (Zyprexa IM); or the average DSST score-time curve measured after oral administration of 10mg olanzapine (Zyprexa Zydis). Data were obtained from the study described in example 3, with FIG. 13A plotting results for longer PK time points (0-4 hours) and FIG. 13B plotting results for shorter PK time points (0-1 hour).
Figures 14A-F show average DSST score-time curves and average plasma concentration-time curves measured after intramuscular administration of 5mg olanzapine (figure 14A), intramuscular administration of 10mg olanzapine (figure 14B), oral administration of 10mg olanzapine (figure 14C), intranasal administration of 5mg olanzapine (figure 14D), intranasal administration of 10mg olanzapine (figure 14E), or intranasal administration of 15mg olanzapine (figure 14F) in a human subject. Data were obtained from the study described in example 3, with results plotted for longer PK time points (0-12 hours).
Figures 15A-F show the mean DSST score-time curves and mean plasma concentration-time curves measured after intramuscular administration of 5mg olanzapine (figure 15A), intramuscular administration of 10mg olanzapine (figure 15B), oral administration of 10mg olanzapine (figure 15C), intranasal administration of 5mg olanzapine (figure 15D), intranasal administration of 10mg olanzapine (figure 15E), or intranasal administration of 15mg olanzapine (figure 15F) in a human subject. Data were obtained from the study described in example 3, with results plotted for shorter PK time points (0-1 hour).
Figures 16A-F show the average ACES score-time curve and average plasma concentration-time curve measured after intramuscular administration of 5mg olanzapine (figure 16A), intramuscular administration of 10mg olanzapine (figure 16B), oral administration of 10mg olanzapine (figure 16C), intranasal administration of 5mg olanzapine (figure 16D), intranasal administration of 10mg olanzapine (figure 16E), or intranasal administration of 15mg olanzapine (figure 16F) in a human subject. Data were obtained from the study described in example 3, with results plotted for longer PK time points (0-12 hours).
Figures 17A-F show average ACES score-time curves and average plasma concentration-time curves measured after intramuscular administration of 5mg olanzapine (figure 17A), intramuscular administration of 10mg olanzapine (figure 17B), oral administration of 10mg olanzapine (figure 17C), intranasal administration of 5mg olanzapine (figure 17D), intranasal administration of 10mg olanzapine (figure 17E), or intranasal administration of 15mg olanzapine (figure 17F) in a human subject. Data were obtained from the study described in example 3, with results plotted for shorter PK time points (0-1 hour).
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.
A pharmaceutical composition is "dry" if its residual moisture content does not exceed 5%.
Other understanding conventions
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 performed two single dose PK studies in cynomolgus monkeys to examine the pharmacokinetics following administration of a multi-powder olanzapine formulation delivered by the intranasal route using a non-human primate precision nasal delivery ("nhpPOD" or "NHP-POD") device. The formulations examined included unmodified crystalline powder, formulations containing HPMC and 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and formulations containing HPMC and Pluronic F68. A placebo control also delivered intranasally by the nhpPOD device was microcrystalline cellulose.
PK results indicate that intranasal delivery of olanzapine formulations containing HPMC and DSPC using an nhpPOD device resulted in similar plasma exposure (AUC) and T as intramuscular administration of olanzapinemax. The formulated (HPMC/DSPC) powder produced 1.7 times higher AUC and 2.8 times shorter T compared to unformulated olanzapine (Cipla API)max。
To further optimize Olanzapine (OLZ) formulation, approximately thirty different formulations were designed and manufactured for upper nasal delivery via the POD device. Formulations were tested, characterized and optimized for POD device compatibility. Stabilizers, penetration enhancers, particle size and manufacturing processes were also screened as part of the formulation development process.
In total twenty formulations were evaluated in a single dose PK study in rats (data not shown) and non-human primates (NHPs). The results show that administration of formulations F-
The pharmacodynamic effects of each nasal olanzapine formulation administered to NHPs were collected throughout each study. For TmaxThe shorter lead formulation, with visible sedation observed in NHP by 7 min blood draw, but not over-sedation, and this effect lasted 24 hours. This reported sedative effect was observed in all groups receiving nasal olanzapine, but with a delayed onset of action and less pronounced in the group with slower time to peak plasma concentrations and lower peak exposure.
The pharmacokinetic and pharmacodynamic effects of the intranasally administered formulation F-OLZ #2 (olanzapine formulation with HPMC and DSPC (INP105)) were further tested in a
Three standardized behavioral tests were used to measure pharmacodynamic effects — Visual Analog Scale (VAS); restlessness/calm rating scale (ACES); and digital sign replacement testing (DSST). These tests all show that intranasal olanzapine administration produces similar or better sedation than IM or oral administration of olanzapine. Furthermore, the behavioral effects of olanzapine were observed significantly earlier in the group of subjects treated with intranasal olanzapine (INP105) or IM olanzapine (Zyprexa IM) compared to the group of subjects treated with oral olanzapine (Zyprexa Zydis). This is consistent with pharmacokinetic results where it was found that intranasal delivery of olanzapine had a significantly shorter median T compared to IM or oral deliverymax. These results indicate that intranasal delivery of olanzapine may be an effective method for acute treatment of agitation.
Method for treating agitation
Accordingly, in a first aspect, a method is provided for acute treatment of agitation. The method comprises intranasally administering to a subject exhibiting agitation an effective dose of a dry pharmaceutical composition comprising olanzapine.
Dry powder composition
In typical embodiments, the dry pharmaceutical composition is a powder.
In typical embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the powder is from 1 μm to 500 μm as measured by a laser diffraction particle size analyzer such as a Malvern Panalytical Mastersizer 3000. In some embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the powder is from 1 μm to 250 μm, from 1 μm to 100 μm, from 1 μm to 75 μm, from 1 μm to 50 μm, from 1 μm to 25 μm, from 1 μm to 20 μm, from 1 μm to 15 μm, or from 2 μm to 15 μm. In certain embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the composition is from 2 μm to 5 μm or from 7.5 μm to 15 μm.
In some embodiments, the powder comprises olanzapine in crystalline form. In some embodiments, the powder comprises olanzapine in an amorphous form. In some embodiments, the dry pharmaceutical composition comprises olanzapine in both crystalline and amorphous forms. In some embodiments, the dry pharmaceutical composition comprises olanzapine in a partially crystalline and partially amorphous form. In a particular embodiment olanzapine is an amorphous solid obtained by spray drying.
In various embodiments, the dry powder composition comprises no more than 70% olanzapine by weight. In some embodiments, the dry pharmaceutical composition comprises no more than 60% olanzapine by weight. In some embodiments, the composition comprises 10-70% olanzapine by weight, 20-70% olanzapine by weight, 10-60% olanzapine by weight, 20-60% olanzapine by weight, 25-55% olanzapine by weight, 30-50% olanzapine by weight, 30-40% olanzapine by weight, or 40-50% olanzapine by weight.
In some embodiments, the dry powder composition further comprises a stabilizer selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), vinyl pyrrolidine-vinyl acetate copolymer (Kollidon VA64), polyvinyl pyrrolidine K30(Kollidon K30), polyvinylpyrrolidone K90(Kollidon K90), hydroxypropyl cellulose (HPC), hydroxypropyl β -cyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is Hydroxypropylmethylcellulose (HPMC).
In some embodiments, the dry powder composition further comprises a penetration enhancer selected from the group consisting of: n-tridecyl- β -D-maltoside, n-dodecyl- β -D-maltoside, 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and polyethylene glycol (15) hydroxystearate. In some embodiments, the penetration enhancer is 1, 2-distearoyl-sn-glycerol-3-phosphocholine (DSPC).
In some embodiments, the dry powder composition comprises both HPMC and DSPC.
In various embodiments, the dry powder 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 powder composition from 0.1 to 10 weight percent, more typically from 1 to 5 weight percent. In a particular embodiment, the nonionic surfactant is present at 1% by weight.
In some embodiments, the nonionic surfactant is Pluronic PF 68. In some embodiments, the nonionic surfactant is present in the dry powder composition from 20 to 40 weight percent, more typically from 25 to 35 weight percent. In a particular embodiment, the nonionic surfactant is present at 31 wt%.
In some embodiments, the dry powder composition further comprises an antioxidant selected from the group consisting of: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, bronopol Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylenediaminetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
In some embodiments, the dry powder composition further comprises an acid. In certain embodiments, the acid is citric acid. In some embodiments, the acid is present in the dry powder composition at 10 to 20 wt.%, more typically 15 to 20 wt.%. In a particular embodiment, the citric acid is present at 18% by weight.
In various embodiments, the dry powder 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 some embodiments, the dry powder composition comprises less than 3 wt.%, less than 2.5 wt.%, less than 2 wt.%, less than 1.5 wt.%, less than 1 wt.%, less than 0.9 wt.%, less than 0.8 wt.%, less than 0.7 wt.%, less than 0.6 wt.%, or less than 0.5 wt.% water.
In a currently preferred embodiment, the dry powder composition comprises 50% olanzapine by weight, 42% HPMC by weight and 8% DSPC. In some embodiments, the dry powder composition is a spray-dried composition comprising amorphous olanzapine. In some embodiments, olanzapine is spray dried in the presence of HPMC and/or DSPC. In other embodiments, HPMC and/or DSPC is added after spray drying of olanzapine.
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.
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 dose container that is removably coupled to the device prior to actuation of the device. For example, the dosage container may be inserted into a portion of the device or may be coupled to the device such that the dosage 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 typical embodiments, the intranasal delivery device is capable of delivering the dry pharmaceutical composition to the upper nasal cavity.
Nasal drug delivery device
In various embodiments, the intranasal applicator device is a non-human primate precision nasal delivery ("nhpPOD") device described in fig. 7A-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.
An example nhpPOD apparatus is shown in figure 6.
Referring to fig. 6, a Metered Dose Inhaler (MDI)
Medical unit dose container
In various embodiments, the intranasal administration device is a medical unit dose container as described in US 2016/0101245a1, 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. 5A and 5B, the
Fig. 5B illustrates a partial cross-sectional view of a
As shown in fig. 5B, the
The
The
The
Fig. 5C is a perspective view of a
As shown in fig. 5F, 5G, and 5J, the
In use, propellant released from the
In one example of use of the
Generally, any shrinkage joint will cause powder blockage when accelerating the powder formulation through the restrictive orifice. Since the powder administered by the
A
The
In one example,
The
Fig. 5T and 5U illustrate perspective views of a
Fig. 5V and 5W illustrate perspective views of a piercing member 542 that can be used with the
As an alternative to a capsule being manually separated prior to placement on the
By allowing the propellant flow path to be created by the inline piercing motion, as shown in fig. 5X, loading of the
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. 7A illustrates another example of a non-human primate precision nasal delivery device 700, and fig. 7B illustrates a side view and a cross-sectional view of an actuator body 710 of the inter-nasal device 700 of fig. 7A. The device 700 may deliver the compound as a liquid, a powder, or some combination thereof. The device 700 includes a propellant canister 705, an actuator body 710, an extension tube 715 and a
Figure 7C illustrates a side view of the extension tube 715 of the inter-nasal device 700 of figure 7A. The extension tube 715 is a tube that includes an internal passage that creates fluid communication between the actuator body 710 and the
Figure 7E illustrates a side view and a cross-sectional view of the
Effective dose
In the methods described herein, an effective dose is a dose of a dry powder composition comprising olanzapine in an amount effective to reduce agitation. In some embodiments, the effective dose is a dose comprising olanzapine in an amount effective to reduce agitation within 60 minutes, within 50 minutes, within 40 minutes, within 30 minutes, within 20 minutes, or within 10 minutes.
In some embodiments, an effective dose of the dried pharmaceutical composition comprises 1-30mg, 2-20mg, 5-15mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 19,15mg, 16mg, 17mg, 18mg, 19mg, or 20mg olanzapine.
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.
Patient's health
In the methods described herein, intranasal administration of olanzapine is used for the acute treatment of agitated patients. In some embodiments, the patient is a restless emergency department patient.
In some embodiments, the patient has schizophrenia, bipolar disorder, dementia, or autism. In some embodiments, the patient has bipolar I disorder. In some embodiments, the patient has acute agitation not associated with schizophrenia, bipolar disorder, or autism. In certain embodiments, the patient has refractory panic disorder, post-traumatic stress disorder, agitation associated with dementia, agitation associated with drug-induced psychotic states, intoxication, or agitation/aggression plus mental disability.
PK
In various embodiments of the methods described herein, intranasal administration provides (a) a mean peak plasma olanzapine concentration (C) of at least 20ng/mLmax) And (b) C to olanzapine in less than 1.5 hoursmaxAverage time (T) ofmax)。
In some embodiments, the intranasal administration provides a mean peak plasma olanzapine concentration (Cmax) of at least 25ng/mL, at least 30ng/mL, at least 40ng/mL, at least 50ng/mL, at least 60ng/mL, at least 70ng/mL, or at least 80ng/mLmax)。
In some embodiments, the intranasal administration provides a C to olanzapine of less than 1.0 hour, less than 0.75 hour, less than 0.50 hour, or less than 0.25 hourmaxAverage time (T) ofmax)。
In a currently preferred embodiment, the intranasal administration provides a mean peak plasma olanzapine concentration of at least 40ng/mL and a Cmax of less than 30 minutes, or more preferably less than 20 minutesmaxAverage time (T) ofmax)。
Dry pharmaceutical composition
In another aspect, a dry pharmaceutical composition suitable for intranasal administration is provided. The composition comprises olanzapine and at least one excipient.
In typical embodiments, the dry pharmaceutical composition is a powder.
In some embodiments, the composition comprises olanzapine in crystalline form. In some embodiments, the composition comprises olanzapine in an amorphous form. In some embodiments, the composition comprises olanzapine in a partially crystalline and partially amorphous form. In a particular embodiment olanzapine is an amorphous solid obtained by spray drying. In some embodiments, the composition comprises olanzapine in a crystalline form and an amorphous form.
In typical embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the powder is from 1 μm to 500 μm as measured by a laser diffraction particle size analyzer such as a Malvern Panalytical Mastersizer 3000. In some embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the powder is from 1 μm to 250 μm, from 1 μm to 100 μm, from 1 μm to 75 μm, from 1 μm to 50 μm, from 1 μm to 25 μm, from 1 μm to 20 μm, from 1 μm to 15 μm, or from 2 μm to 15 μm. In certain embodiments, the median diameter (D50) of the particle size distribution of olanzapine in the composition is from 2 μm to 5 μm or from 7.5 μm to 15 μm.
In various embodiments, the dry pharmaceutical composition comprises no more than 70% olanzapine by weight. In some embodiments, the composition comprises no more than 60% olanzapine by weight. In some embodiments, the composition comprises 10-70% olanzapine by weight, 20-70% olanzapine by weight, 10-60% olanzapine by weight, 20-60% olanzapine by weight, 25-55% olanzapine by weight, 30-50% olanzapine by weight, 30-40% olanzapine by weight, or 40-50% olanzapine by weight.
In some embodiments, the pharmaceutical composition further comprises a stabilizer selected from the group consisting of: hydroxypropyl methylcellulose (HPMC), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), vinylpyrrolidone-vinyl acetate copolymer (Kollidon VA64), polyvinylpyrrolidone K30(Kollidon K30), polyvinylpyrrolidone K90(Kollidon K90), hydroxypropyl cellulose (HPC), hydroxypropyl β -cyclodextrin (HPBCD), mannitol, and lactose monohydrate. In some embodiments, the stabilizer is Hydroxypropylmethylcellulose (HPMC).
In some embodiments, the dry pharmaceutical composition further comprises a penetration enhancer selected from the group consisting of: n-tridecyl- β -D-maltoside, n-dodecyl- β -D-maltoside, 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1, 2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), propylene glycol, disodium EDTA, PEG400 monostearate, polysorbate 80, and polyethylene glycol (15) hydroxystearate. In some embodiments, the penetration enhancer is 1, 2-distearoyl-sn-glycerol-3-phosphocholine (DSPC).
In some embodiments, the dry pharmaceutical composition comprises both HPMC and DSPC.
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 powder composition from 0.1 to 10 weight percent, more typically from 1 to 5 weight percent. In a particular embodiment, the nonionic surfactant is present at 1% by weight. In some embodiments, the nonionic surfactant is Pluronic PF 68. In some embodiments, the nonionic surfactant is present in the dry powder composition from 20 to 40 weight percent, more typically from 25 to 35 weight percent. In a particular embodiment, the nonionic surfactant is present at 31 wt%.
In some embodiments, the pharmaceutical composition further comprises an antioxidant selected from the group consisting of: alpha-tocopherol, ascorbic acid, ascorbyl palmitate, bronopol Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), citric acid monohydrate, sodium ascorbate, ethylenediaminetetraacetic acid, fumaric acid, malic acid, methionine, propionic acid, sodium metabisulfite, sodium sulfite, sodium thiosulfate, thymol, and vitamin E polyethylene glycol succinate.
In some embodiments, the dry pharmaceutical composition further comprises an acid. In certain embodiments, the acid is citric acid. In some embodiments, the acid is present in the dry powder composition at 10 to 20 wt.%, more typically 15 to 20 wt.%. In a particular embodiment, the citric acid is present at 18% by weight.
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 some embodiments, the dry pharmaceutical composition further comprises less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, or less than 0.5% by weight water.
In a currently preferred embodiment, the dry pharmaceutical composition comprises 50% olanzapine by weight, 42% HPMC by weight and 8% DSPC. In some embodiments, the dry pharmaceutical composition is a spray-dried composition comprising amorphous olanzapine. In some embodiments, olanzapine is spray dried in the presence of HPMC and/or DSPC. In other embodiments, HPMC and/or DSPC is added after spray drying of olanzapine.
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 5.5.
In typical embodiments, the unit dosage form contains 1-30mg olanzapine. In some embodiments, the unit dosage form contains 2 to 20mg olanzapine. In some embodiments, the unit dosage form contains 5-15mg olanzapine. In some embodiments, the unit dosage form contains 5mg olanzapine. In some embodiments, the unit dosage form contains 10mg olanzapine. In some embodiments, the unit dosage form contains 15mg olanzapine.
In some embodiments, the unit dosage form is a capsule encapsulating the dry pharmaceutical composition. In some embodiments, the capsule is a hard capsule. In some embodiments, the hard capsule is an HPMC hard capsule.
In some embodiments, the unit dosage form is a dosage container storing a dry pharmaceutical composition, wherein the dosage container is 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.