Compositions, devices and methods for treating or preventing headache

Abstract

Disclosed herein are pharmaceutical compositions, devices, combinations thereof, and their use in, for example, the treatment or prevention of headache. The present disclosure provides a novel method of medical treatment or prevention (e.g., headache) that results in unexpectedly superior pharmacokinetics compared to conventional methods. In some cases, the methods herein may produce unique pharmacokinetic profiles of metabolites.

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of December 11, 2019, an application number of 201980091853.1, and an invention title of "Compositions, Devices, and Methods for Treating or Preventing Headaches" (the corresponding PCT application has an application date of December 11, 2019 and an application number of PCT / US2019 / 065647).

[0002] Cross-reference

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 778,158, filed on December 11, 2018, U.S. Provisional Patent Application No. 62 / 799,635, filed on January 31, 2019, and U.S. Provisional Patent Application No. 62 / 847,607, filed on May 14, 2019, the content of each application being incorporated herein by reference in its entirety.

[0004] Incorporated by reference

[0005] All publications, patents, and patent applications disclosed herein are incorporated by reference to the extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If there is a conflict between the terms disclosed herein and the terms in the incorporated references, the terms herein shall prevail. SUMMARY OF THE INVENTION

[0006] The inventive embodiments provided in this summary are for illustrative purposes only and provide an overview of alternative embodiments disclosed herein. The illustrative and alternative summaries do not limit the scope of any claims, do not provide the entire scope of the inventive embodiments disclosed or contemplated herein, and should not be construed as limiting or restricting the scope of this disclosure or any claimed inventive embodiment.

[0007] In some aspects of many aspects, provided herein is a method of treatment or prevention, comprising administering to a human subject a powdered pharmaceutical composition comprising an active agent selected from a compound having the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs, its ion pairs, and any combination thereof:

[0008]

[0009] wherein the method results in a time to peak plasma concentration (T max ) of 90 minutes or longer for a metabolite of the active agent in the human subject, as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography-tandem mass spectrometry, and wherein:

[0010] R1 is hydrogen, (C1-C4) alkyl, or (C1-C4) perfluoroalkyl;

[0011] Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ;

[0012] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

[0013] R5, R6, and R7 are independently hydrogen, (C1-C3) alkyl, or (C1-C3) perfluoroalkyl;

[0014] R8 and R9 are independently hydrogen, (C1-C4) alkyl, or benzyl;

[0015] R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, —CO2R 108 or —CONR 109 R 110 ;

[0016] R 13 is hydrogen or halogen;

[0017] R 101 -R 110 is independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl, or heteroaralkyl;

[0018] k is 0, 1, or 2; and

[0019] n is 0, 1, 2, or 3.

[0020] In some cases, the T max is at least about 2 hours. In some cases, the peak plasma concentration (C max ) of the metabolite is less than about 250 pg / ml, such as less than about 150 pg / ml. In some cases, the peak plasma concentration (C max ) of the metabolite is less than the C max of the active agent measured after the administration to the human subject.about 15%, such as less than about 10%. In some cases, the plasma concentration of the metabolite is less than about 5% of the plasma concentration of the active agent measured within about 30 minutes after the administration to the human subject. In some cases, the plasma concentration of the metabolite is less than about 2% of the plasma concentration of the active agent measured within about 15 minutes after the administration to the human subject. In some cases, the reduced presence of the metabolite results in a reduced pharmacological effect of the metabolite in the human subject. In some cases, the reduced pharmacological effect is less than 20% of the binding activity to adrenergic receptors (e.g., α1 [non-specific], α2A, α2B, α2C, β), dopaminergic receptors (e.g., D: D1, D2, D3), or serotonergic receptors (e.g., 5-HT receptor or subtypes: 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 2A , 5-HT 2C , 5-HT3, 5-HT4, 5-HT 5A , 5-HT6, 5-HT7) measured by radioligand competitive binding assay. In some cases, the reduced pharmacological effect in the human subject is In some cases, the reduced pharmacological effect in the human subject is manifested as a reduced transcutaneous O2 partial pressure measured on the dorsum of the foot, a reduced venous constriction effect determined using a venous occlusion mercury strain gauge, a reduced diameter or compliance of the smaller brachial artery wall, a reduced human coronary artery, meningeal artery, or saphenous vein constriction effect, a reduced smaller venous diameter at a fixed occlusion pressure, a change in peripheral circulation volume, or any combination thereof. In some cases, both R3 and R4 are hydrogen. In some cases, the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the metabolite is of formula (I) and wherein the R 12is -OH. In some cases, the metabolite is 8'-hydroxy dihydroergotamine. In some cases, the pharmaceutical composition comprises: about 1 mg to about 6 mg of the active agent, about 12 mg to about 19 mg of microcrystalline cellulose, about 0.1 mg to about 0.6 mg of a thickening agent, and about 6 mg to about 7 mg of a sugar alcohol. In some cases, the thickening agent is present in an amount of about 10% by weight of the active agent. In some cases, the thickening agent comprises hydroxypropyl methylcellulose. In some cases, the thickening agent comprises hydroxypropyl cellulose. In some cases, the thickening agent comprises carboxymethyl cellulose. In some cases, the thickening agent is present in a spray-dried particle dispersion. In some cases, the sugar alcohol comprises mannitol. In some cases, the sugar alcohol comprises sorbitol. In some cases, the sugar alcohol comprises galactitol. In some cases, the active agent is present in a spray-dried particle dispersion. In some cases, about 3 mg to about 13 mg of the microcrystalline cellulose is present in a spray-dried particle dispersion. In some cases, the microcrystalline cellulose is at least partially coated with the active agent. In some cases, the active agent is in an amorphous form. In some cases, the active agent is dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the pharmaceutical composition comprises the pharmaceutically acceptable salt of dihydroergotamine, namely dihydroergotamine mesylate. In some cases, the pharmaceutical composition is a powder pharmaceutical composition. In some cases, the administration is intranasal administration. In some cases, the human subject begins to experience relief of migraine symptoms (pain, photophobia, phonophobia, nausea, or any combination thereof) or cranial autonomic symptoms (conjunctival injection, eyelid edema, miosis, ptosis, lacrimation, nasal congestion, rhinorrhea, forehead / facial sweating, or any combination thereof) within about 2 hours after the administration and the relief persists for up to 5 days. In some cases, the human subject begins to experience the relief within about 45 minutes, about 30 minutes, or less after the administration. In some cases, after the symptoms begin to relieve after the administration, the human subject experiences the relief for up to 2 to 24 hours, 48 hours, 96 hours, or longer. In some cases, the human subject is in a recumbent position. In some cases, the human subject is in a supine position. In some cases, the human subject is in a recovery position. In some cases, the human subject is in an upright position. In some cases, the method treats headache. In some cases, the headache includes migraine.In some cases, the headache includes migraine with aura, migraine without aura, cluster migraine, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, intractable migraine, migraine attack (optionally a migraine attack treated starting at least 1 - 24 hours (e.g., 2 hours, 3 hours) after the onset of the attack), a migraine attack when treatment is initiated at the earliest aura sign or symptom, pediatric migraine, status migraine, chronic daily headache, migraine attack with allodynia, menstruation-related migraine, menstrual migraine, migraine upon awakening or rapidly developing migraine. In some cases, at T. 0分钟 From T 15分钟 to T, the administration provides a dC / dT value that is at least about 10% higher compared to the dihydroergotamine liquid dosage form. In some cases, at T 0分钟 to T 15分钟During the period of time, the administration provides a dC / dT value of at least about 1000 (pg / mL) / hour. In some cases, the pharmaceutical composition is provided in a device configured for administering the same to the human subject. In some cases, the device does not need to be filled or is a pre-filled device. In some cases, the device can be actuated with one hand. In some cases, before actuating the device, the device is stored at about 20°C to about 25°C and at a relative humidity of about 60% for about twelve months or less. In some cases, the reservoir containing the pharmaceutical composition in the device does not contain metal or glass. In some cases, the device does not contain metal or glass. In some cases, the administration takes less than about: 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent. In some cases, the pharmaceutical composition is a single unit dose. In some cases, at least about 80% of the active agent is stable at room temperature, outside the container at one atmosphere and a relative humidity of less than about 50%, in a light-resistant airtight container, for a storage period of at least about 60 days to about 3 years, as measured by liquid chromatography. In some cases, the storage period is at least about 1 year. In some cases, the administration is repeated about every 2 - 8 hours. In some cases, the administration is repeated about every 2 - 6 hours. In some cases, the administration is repeated over a period of 1, 2, 3, 4 or 5 days. In some cases, the method further comprises monitoring the vital signs of the human subject. In some cases, the vital signs are at least one of blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation or electrocardiogram. In some cases, the human subject performs the monitoring. In some cases, the monitoring includes using an electronic device. In some cases, the electronic device is portable. In some cases, the electronic device is wearable. In some cases, the administration includes delivering two doses or more of the pharmaceutical composition to the human subject, such as for treating cluster headache or cluster migraine. In some cases, the administration includes delivering two doses or more of the pharmaceutical composition to the human subject in two or more of the devices. In some cases, each of the devices contains a single unit dose of the pharmaceutical composition. In some cases, two doses or more are administered to the human subject in one of the devices. In some cases, the two doses or more are delivered successively to one or both nostrils of the human subject. In some cases, the first dose of the two doses or more is immediately sequentially administered to two different nostrils of the human subject. In some cases, the sequential administrations are separated by about 15 to about 60 seconds.In some cases, the first dose and the second dose of the two doses or more are spaced apart by about: 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours or longer.

[0021] In some aspects, provided herein is a method of treatment or prevention comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from the group consisting of a compound having the following formula, stereoisomers thereof, pharmaceutically acceptable salts thereof, complexes thereof, chelates thereof, hydrates thereof, polymorphs thereof, ion pairs thereof, and any combination thereof:

[0022]

[0023] wherein the method produces in the human subject:

[0024] 1) a C of about 1 to about 2.5 ng / ml max , or a plasma concentration of at least 1 ng / mL is produced in about 10 minutes or less,

[0025] 2) a T of about 30 minutes or less max , and

[0026] 3) an AUC value selected from: an AUC of about 500 to about 1000 h*pg / ml 0-30分钟 , an AUC of about 1000 to about 2000 h*pg / ml 0-60分钟 , an AUC of about 2000 to about 3000 h*pg / ml 0-120分钟 , an AUC of about 10000 to about 12000 h*pg / ml 0-inf and any combination thereof, as determined by measuring the human plasma concentration of the active agent by automated extraction liquid chromatography-tandem mass spectrometry, and

[0027] wherein:

[0028] R1 is hydrogen, (C1-C4)alkyl, or (C1-C4)perfluoroalkyl;

[0029] each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ;

[0030] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxyl or methoxy;

[0031] R5, R6 and R7 are independently hydrogen, (C1-C3) alkyl or (C1-C3) perfluoroalkyl;

[0032] R8 and R9 are independently hydrogen, (C1-C4) alkyl or benzyl;

[0033] R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, -CO2R 108 or—CONR 109 R 110 ;

[0034] R 13 is hydrogen or a halogen;

[0035] R 101 -R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl;

[0036] k is 0, 1, or 2; and

[0037] n is 0, 1, 2 or 3.

[0038] In some cases, the method further provides a half-life of the active agent of about 12 hours to about 13 hours. In some cases, both R3 and R4 are hydrogen. In some cases, the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, wherein R 12It is -OH. In some cases, the pharmaceutical composition comprises: about 1 mg to about 6 mg of the active agent, about 12 mg to about 19 mg of microcrystalline cellulose, about 0.1 mg to about 0.6 mg of a thickening agent, and about 6 mg to about 7 mg of a sugar alcohol. In some cases, the thickening agent is present in an amount of about 10% by weight of the weight of the active agent. In some cases, the thickening agent comprises hydroxypropyl methylcellulose. In some cases, the thickening agent comprises hydroxypropyl cellulose. In some cases, the thickening agent comprises carboxymethyl cellulose. In some cases, the thickening agent is present in a spray-dried particle dispersion. In some cases, the sugar alcohol comprises mannitol. In some cases, the sugar alcohol comprises sorbitol. In some cases, the sugar alcohol comprises galactitol. In some cases, the active agent is present in a spray-dried particle dispersion. In some cases, about 3 mg to about 13 mg of the microcrystalline cellulose is present in a spray-dried particle dispersion. In some cases, the microcrystalline cellulose is at least partially coated with the active agent. In some cases, the active agent is in an amorphous form. In some cases, the active agent is dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the pharmaceutical composition comprises the pharmaceutically acceptable salt of dihydroergotamine, namely dihydroergotamine mesylate. In some cases, the pharmaceutical composition is a powder pharmaceutical composition. In some cases, the administration is intranasal administration. In some cases, the human subject begins to experience relief of migraine symptoms (pain, photophobia, phonophobia, nausea, or any combination thereof) or cranial autonomic symptoms (conjunctival injection, eyelid edema, miosis, ptosis, lacrimation, nasal congestion, rhinorrhea, forehead / facial sweating, or any combination thereof) within about 2 hours after the administration and the relief persists for up to 5 days. In some cases, the human subject begins to experience the relief within about 45 minutes, about 30 minutes, or less after the administration. In some cases, after the symptoms begin to relieve after the administration, the human subject experiences the relief for up to 2 to 24 hours, 48 hours, 96 hours, or longer. In some cases, the human subject is in a recumbent position. In some cases, the human subject is in a supine position. In some cases, the human subject is in a recovery position. In some cases, the human subject is in an upright position. In some cases, the method treats headache. In some cases, the headache includes migraine.In some cases, the headache includes migraine with aura, migraine without aura, cluster migraine, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, intractable migraine, migraine attacks (optionally migraine attacks treated starting at least 1 - 24 hours (e.g., 2 hours, 3 hours) after the onset of the attack), migraine attacks when treatment is initiated at the earliest aura sign or symptom, pediatric migraine, persistent migraine, chronic daily headache, migraine attacks with allodynia, menstruation-related migraine, menstrual migraine, migraine upon awakening or rapidly developing migraine. In some cases, at T. 0分钟 to T 15分钟 The administration provides a dC / dT value that is at least about 10% higher compared to the dihydroergotamine liquid dosage form over the time period. In some cases, at T 0分钟 to T 15分钟During the time period, the administration provides a dC / dT value of at least about 1000 (pg / mL) / hour. In some cases, the pharmaceutical composition is provided in a device configured for performing the administration to the human subject. In some cases, the device does not need to be filled or is a pre-filled device. In some cases, the device can be actuated with one hand. In some cases, the device is stored at about 20°C to about 25°C and about 60% relative humidity for about twelve months or less before actuating the device. In some cases, the reservoir containing the pharmaceutical composition in the device does not contain metal or glass. In some cases, the device does not contain metal or glass. In some cases, the administration takes less than about: 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent. In some cases, the pharmaceutical composition is a single unit dose. In some cases, at least about 80% of the active agent, as measured by liquid chromatography, is stable at room temperature, outside the container at one atmosphere pressure and relative humidity less than about 50%, in a light-resistant airtight container, for a storage time period of at least about 60 days to about 3 years. In some cases, the storage time period is at least about 1 year. In some cases, the administration is repeated about every 2 - 8 hours. In some cases, the administration is repeated about every 2 - 6 hours. In some cases, the administration is repeated over a time period of 1, 2, 3, 4 or 5 days. In some cases, the method further comprises monitoring the vital signs of the human subject. In some cases, the vital signs are at least one of blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation or electrocardiogram. In some cases, the human subject performs the monitoring. In some cases, the monitoring comprises using an electronic device. In some cases, the electronic device is portable. In some cases, the electronic device is wearable. In some cases, the administration comprises delivering two doses or more of the pharmaceutical composition to the human subject, such as for treating cluster headache or cluster migraine. In some cases, the administration comprises delivering two doses or more of the pharmaceutical composition to the human subject in two or more of the devices. In some cases, each of the devices contains a single unit dose of the pharmaceutical composition. In some cases, two doses or more are administered to the human subject in one of the devices. In some cases, the two doses or more are delivered successively to one or two nostrils of the human subject. In some cases, the first dose of the two doses or more is immediately sequentially administered to two different nostrils of the human subject. In some cases, the sequential administrations are spaced about 15 to about 60 seconds apart.In some cases, the first dose and the second dose of the two doses or more are spaced apart by about: 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours or longer.

[0039] In some aspects, provided herein is a method of treatment or prophylaxis comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from compounds having the formula below, stereoisomers thereof, pharmaceutically acceptable salts thereof, complexes thereof, chelates thereof, hydrates thereof, polymorphs thereof, ion pairs thereof, and any combination thereof:

[0040]

[0041] wherein after said administration to said human subject, the method yields an apparent clearance (CL / F) value of the active agent of about 100 L / hour to about 1000 L / hour, and wherein:

[0042] R1 is hydrogen, (C1-C4)alkyl, or (C1-C4)perfluoroalkyl;

[0043] Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ;

[0044] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

[0045] R5, R6, and R7 are independently hydrogen, (C1-C3)alkyl, or (C1-C3)perfluoroalkyl;

[0046] R8 and R9 are independently hydrogen, (C1-C4)alkyl, or benzyl;

[0047] R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4)alkyl, —CO2R 108 or —CONR 109 R 110 ;

[0048] R 13 is hydrogen or halogen;

[0049] R 101 -R 110 independently is hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl;

[0050] k is 0, 1 or 2; and

[0051] n is 0, 1, 2 or 3.

[0052] In some cases, the CL / F value of the active agent is about 540 L / hour. In some cases, both R3 and R4 are hydrogen. In some cases, the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, wherein the R 12It is -OH. In some cases, the pharmaceutical composition comprises: about 1 mg to about 6 mg of the active agent, about 12 mg to about 19 mg of microcrystalline cellulose, about 0.1 mg to about 0.6 mg of a thickening agent, and about 6 mg to about 7 mg of a sugar alcohol. In some cases, the thickening agent is present in an amount of about 10% by weight of the weight of the active agent. In some cases, the thickening agent comprises hydroxypropylmethylcellulose. In some cases, the thickening agent comprises hydroxypropylcellulose. In some cases, the thickening agent comprises carboxymethylcellulose. In some cases, the thickening agent is present in a spray-dried particle dispersion. In some cases, the sugar alcohol comprises mannitol. In some cases, the sugar alcohol comprises sorbitol. In some cases, the sugar alcohol comprises galactitol. In some cases, the active agent is present in a spray-dried particle dispersion. In some cases, about 3 mg to about 13 mg of the microcrystalline cellulose is present in a spray-dried particle dispersion. In some cases, the microcrystalline cellulose is at least partially coated with the active agent. In some cases, the active agent is in an amorphous form. In some cases, the active agent is dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the pharmaceutical composition comprises the pharmaceutically acceptable salt of dihydroergotamine, namely dihydroergotamine mesylate. In some cases, the pharmaceutical composition is a powdered pharmaceutical composition. In some cases, the administration is intranasal administration. In some cases, the human subject begins to experience relief from migraine symptoms (pain, photophobia, phonophobia, nausea, or any combination thereof) or cranial autonomic symptoms (conjunctival injection, eyelid edema, miosis, ptosis, lacrimation, nasal congestion, rhinorrhea, forehead / facial sweating, or any combination thereof) within about 2 hours after the administration and the relief persists for up to 5 days. In some cases, the human subject begins to experience the relief within about 45 minutes, about 30 minutes, or less after the administration. In some cases, after the symptoms begin to resolve after the administration, the human subject experiences the relief for up to 2 to 24 hours, 48 hours, 96 hours, or longer. In some cases, the human subject is in a recumbent position. In some cases, the human subject is in a supine position. In some cases, the human subject is in a recovery position. In some cases, the human subject is in an upright position. In some cases, the method treats headache. In some cases, the headache includes migraine.In some cases, the headache includes migraine with aura, migraine without aura, cluster migraine, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, intractable migraine, migraine attacks (optionally migraine attacks treated starting at least 1 - 24 hours (e.g., 2 hours, 3 hours) after the onset of the attack), migraine attacks when treatment is initiated at the earliest prodromal sign or symptom, pediatric migraine, persistent migraine, chronic daily headache, migraine attacks with allodynia, menstruation-related migraine, menstrual migraine, migraine upon awakening or rapidly developing migraine. In some cases, at T. 0分钟 to T 15分钟 During the time period, the administration provides a dC / dT value that is at least about 10% higher compared to a dihydroergotamine liquid dosage form. In some cases, at T 0分钟 to T 15分钟During the time period, the administration provides a dC / dT value of at least about 1000 (pg / mL) / hour. In some cases, the pharmaceutical composition is provided in a device configured for administering the same to the human subject. In some cases, the device does not need to be filled or is a pre-filled device. In some cases, the device is actuatable with one hand. In some cases, the device is stored at about 20°C to about 25°C and at about 60% relative humidity for about twelve months or less before actuating the device. In some cases, the reservoir containing the pharmaceutical composition in the device does not contain metal or glass. In some cases, the device does not contain metal or glass. In some cases, the administration takes less than about: 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent. In some cases, the pharmaceutical composition is a single unit dose. In some cases, at least about 80% of the active agent, as measured by liquid chromatography, is stable at room temperature, outside the container at one atmosphere and with a relative humidity of less than about 50%, in a light-resistant airtight container, for a storage period of at least about 60 days to about 3 years. In some cases, the storage period is at least about 1 year. In some cases, the administration is repeated about every 2 - 8 hours. In some cases, the administration is repeated about every 2 - 6 hours. In some cases, the administration is repeated over a period of 1, 2, 3, 4 or 5 days. In some cases, the method further comprises monitoring the vital signs of the human subject. In some cases, the vital signs are at least one of blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation or electrocardiogram. In some cases, the human subject performs the monitoring. In some cases, the monitoring comprises using an electronic device. In some cases, the electronic device is portable. In some cases, the electronic device is wearable. In some cases, the administration comprises delivering two doses or more of the pharmaceutical composition to the human subject, such as for treating cluster headache or cluster migraine. In some cases, the administration comprises delivering two doses or more of the pharmaceutical composition to the human subject in two or more of the devices. In some cases, each of the devices contains a single unit dose of the pharmaceutical composition. In some cases, two doses or more are administered to the human subject in one of the devices. In some cases, the two doses or more are delivered successively to one or two nostrils of the human subject. In some cases, the first dose of the two doses or more is immediately sequentially administered to two different nostrils of the human subject. In some cases, the sequential administrations are separated by about 15 to about 60 seconds.In some cases, the first dose and the second dose of the two doses or more doses are spaced apart by about: 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours or longer.

[0053] In some aspects, provided herein is a method of treatment or prevention, comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from a compound having the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs, its ion pairs, and any combination thereof:

[0054]

[0055] wherein when measured within 24 hours after said administering to said human subject, the method produces a visual analog scale score for measuring nasal symptoms of less than about 20, wherein the visual analog scale score is measured on a scale of 0 (no symptoms) to 100 (worst imaginable) based on each of the following nasal symptoms: nasal discomfort, nasal burning, nasal itching, nasal pain, nasal congestion, dysgeusia, rhinorrhea, and sneezing, and

[0056] wherein:

[0057] R1 is hydrogen, (C1-C4)alkyl, or (C1-C4)perfluoroalkyl;

[0058] each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 、—OR 101 、—NR 102 R 103 、—CONR 104 R 105 、—CO2R 106 or —CO2R 107 ;

[0059] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

[0060] R5, R6, and R7 are independently hydrogen, (C1-C3)alkyl, or (C1-C3)perfluoroalkyl;

[0061] R8 and R9 are independently hydrogen, (C1-C4)alkyl, or benzyl;

[0062] R 10 、R 11 、R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4)alkyl, —CO2R 108or —CONR 109 R 110 ;

[0063] R 13 is hydrogen or a halogen;

[0064] R 101 -R 110 are independently hydrogen, a halogen, an alkyl group, an acyl group, an aryl group, an aralkyl group, a heteroalkyl group, a heteroaryl group or a heteroaralkyl group;

[0065] k is 0, 1 or 2; and

[0066] n is 0, 1, 2 or 3.

[0067] In some cases, the methods herein do not result in clinically significant changes in vital signs, nasal mucosal integrity and nasal irritation in healthy normal subjects. In some cases, the visual analogue scale score is measured at about 4 hours after the administration. In some cases, the visual analogue scale score is measured at about 1 hour after the administration. In some cases, the visual analogue scale score is measured at about 15 minutes after the administration. In some cases, the visual analogue scale score is measured at about 5 minutes after the administration. In some cases, the visual analogue scale score is less than about 10. In some cases, the visual analogue scale score is less than about 5. In some cases, the visual analogue scale score is 0. In some cases, both R3 and R4 are hydrogen. In some cases, the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, wherein the R 12It is -OH. In some cases, the pharmaceutical composition comprises: about 1 mg to about 6 mg of the active agent, about 12 mg to about 19 mg of microcrystalline cellulose, about 0.1 mg to about 0.6 mg of a thickening agent, and about 6 mg to about 7 mg of a sugar alcohol. In some cases, the thickening agent is present in an amount of about 10% by weight of the weight of the active agent. In some cases, the thickening agent comprises hydroxypropyl methylcellulose. In some cases, the thickening agent comprises hydroxypropyl cellulose. In some cases, the thickening agent comprises carboxymethyl cellulose. In some cases, the thickening agent is present in a spray-dried particle dispersion. In some cases, the sugar alcohol comprises mannitol. In some cases, the sugar alcohol comprises sorbitol. In some cases, the sugar alcohol comprises galactitol. In some cases, the active agent is present in a spray-dried particle dispersion. In some cases, about 3 mg to about 13 mg of the microcrystalline cellulose is present in a spray-dried particle dispersion. In some cases, the microcrystalline cellulose is at least partially coated with the active agent. In some cases, the active agent is in an amorphous form. In some cases, the active agent is dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the pharmaceutical composition comprises the pharmaceutically acceptable salt of dihydroergotamine, namely dihydroergotamine mesylate. In some cases, the pharmaceutical composition is a powdered pharmaceutical composition. In some cases, the administration is intranasal administration. In some cases, the human subject begins to experience relief from migraine symptoms (pain, photophobia, phonophobia, nausea, or any combination thereof) or cranial autonomic symptoms (conjunctival injection, eyelid edema, miosis, ptosis, lacrimation, nasal congestion, rhinorrhea, forehead / facial sweating, or any combination thereof) within about 2 hours after the administration and the relief persists for up to 5 days. In some cases, the human subject begins to experience the relief within about 45 minutes, about 30 minutes, or less after the administration. In some cases, after the symptoms begin to subside after the administration, the human subject experiences the relief for up to 2 to 24 hours, 48 hours, 96 hours, or longer. In some cases, the human subject is in a recumbent position. In some cases, the human subject is in a supine position. In some cases, the human subject is in a recovery position. In some cases, the human subject is in an upright position. In some cases, the method treats headache. In some cases, the headache includes migraine.In some cases, the headache includes migraine with aura, migraine without aura, cluster migraine, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, intractable migraine, migraine attacks (optionally migraine attacks treated starting at least 1 - 24 hours (e.g., 2 hours, 3 hours) after the onset of the attack), migraine attacks when treatment is started at the earliest aura sign or symptom, childhood migraine, persistent migraine, chronic daily headache, migraine attacks with allodynia, menstruation-related migraine, menstrual migraine, migraine upon awakening or rapidly developing migraine. In some cases, at T. 0分钟 to T 15分钟 During the time period, the administration provides a dC / dT value that is at least about 10% higher compared to the dihydroergotamine liquid dosage form. In some cases, at T 0分钟 to T 15分钟During the time period, the administration provides a dC / dT value of at least about 1000 (pg / mL) / hour. In some cases, the pharmaceutical composition is provided in a device configured for the administration to the human subject. In some cases, the device does not need to be filled or is a pre-filled device. In some cases, the device can be actuated with one hand. In some cases, before actuating the device, the device is stored at about 20°C to about 25°C and about 60% relative humidity for about twelve months or less. In some cases, the reservoir containing the pharmaceutical composition in the device does not contain metal or glass. In some cases, the device does not contain metal or glass. In some cases, the administration takes less than about: 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent. In some cases, the pharmaceutical composition is a single unit dose. In some cases, at least about 80% of the active agent is stable at room temperature, outside the container at one atmosphere and relative humidity less than about 50%, in a light-resistant airtight container, for a storage time period of at least about 60 days to about 3 years, as measured by liquid chromatography. In some cases, the storage time period is at least about 1 year. In some cases, the administration is repeated about every 2 - 8 hours. In some cases, the administration is repeated about every 2 - 6 hours. In some cases, the administration is repeated over a time period of 1, 2, 3, 4 or 5 days. In some cases, the method further comprises monitoring the vital signs of the human subject. In some cases, the vital signs are at least one of blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation or electrocardiogram. In some cases, the human subject performs the monitoring. In some cases, the monitoring comprises using an electronic device. In some cases, the electronic device is portable. In some cases, the electronic device is wearable. In some cases, the administration comprises delivering two doses or more of the pharmaceutical composition to the human subject, such as for treating cluster headache or cluster migraine. In some cases, the administration comprises delivering two doses or more of the pharmaceutical composition to the human subject in two or more of the devices. In some cases, each of the devices contains a single unit dose of the pharmaceutical composition. In some cases, two doses or more are administered to the human subject in one of the devices. In some cases, the two doses or more are delivered successively to one or two nostrils of the human subject. In some cases, the first dose of the two doses or more is immediately sequentially administered to two different nostrils of the human subject. In some cases, the sequential administrations are spaced about 15 to about 60 seconds apart.In some cases, the first dose and the second dose of the two doses or more are spaced apart by approximately: 1 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 5 hours, 6 hours or longer. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also referred to herein as "FIGURES"), in which:

[0069] Figure 1A An exemplary device filled with a powder formulation is shown. Figure 1B Different graphical styles of components of an exemplary device without formulation are shown.

[0070] Figure 2A , 2B and 2C show cross-sectional views of additional exemplary delivery devices.

[0071] Figure 3 The operating principle of an exemplary device for intranasal delivery of, for example, dihydroergotamine mesylate intranasal powder is shown. The device is optionally stored in a package, such as a foil package. The foil package is opened and the device is removed from the foil package. The device optionally has a protective cap, for example, the protective cap is removed from the device before use. While holding the device in one hand, the pull tab is also held and bent or twisted back and forth to break it. The nozzle is inserted as deeply as possible into one nostril, as long as it can be inserted comfortably, while avoiding squeezing the pump. After inserting the device into the nostril, the pump is quickly and fully squeezed between the fingers and thumb until the two sides of the pump are pressed into or close to each other. The squeezing step is repeated twice, for a total of three squeezes into one nostril.

[0072] Figure 4A and 4B show linear graphs ( Figure 4A ) of the mean plasma concentrations of dihydroergotamine mesylate (DHE) and the metabolite 8'-hydroxydihydroergotamine (8'-OH-DHE) over time for 48 hours during the treatment of Part 1 of the Phase 1 clinical study described in Example 4 Figure 4B ) and logarithmic-linear graphs (

[0073] Figures 5A to 5D show linear graphs ( Figure 5A ) of the mean plasma concentration of 8'-OH-DHE over time during the treatment of Part 2 of the Phase 1 clinical study described in Example 4 for a 24-hour time course Figure 5B ) and for a logarithmic-linear graph for a 48-hour time course ( Figure 5B ) and for a linear graph for a 0 - 4 hour time course (Figure 5C ) and a log-linear plot over a time course of 0 - 4 hours ( Figure 5D ).

[0074] Figure 6 Shows the results of a Phase 1 study of the DHE plasma concentration of the dihydroergotamine mesylate intranasal powder formulation compared to other DHE formulations (0 - 2 hour data).

[0075] Figure 7 Shows a comparison of the AUC - time curves of dihydroergotamine mesylate (6 mg strength) intranasal powder, MIGRANAL (an intranasal liquid dihydroergotamine mesylate), and SEMPRANA (an oral pulmonary dihydroergotamine mesylate).

[0076] Figure 8 Shows the CV% (variability) comparison of C max and AUC results of dihydroergotamine mesylate (6 mg strength) intranasal powder compared to other DHE formulations.

[0077] Figure 9 Shows an exemplary visual analog scale (VAS) for evaluating post - treatment symptoms.

[0078] Figure 10 Shows the mean VAS scores of all subjects administered an intranasal powder formulation containing 6 mg of dihydroergotamine mesylate (Parts 1 and 2, n = 41).

[0079] Figure 11 Shows the individual VAS scores (including scores for dysgeusia or taste alteration) of all subjects who reported local or nasal - related adverse events (AEs) (including dysgeusia) and were administered an intranasal powder formulation containing 6 mg of dihydroergotamine mesylate (n = 12).

[0080] Figure 12 Shows a pharmacokinetic data model of different strength pharmaceutical compositions disclosed herein, the pharmaceutical compositions containing 3.9 mg or 5.2 mg (free base weight) of dihydroergotamine administered as a single dose or 2 doses with no delay or a 2 - hour delay. Detailed Description

[0081] The present disclosure provides new methods for medical treatment or prevention (e.g., headache) that produce unexpectedly superior pharmacokinetics compared to conventional methods. In some cases, the methods herein can produce unique pharmacokinetic profiles of metabolites. In some cases, the methods herein can employ a drug-device combination, such as for intranasal delivery. In some cases, the method can include delivering one dose, two doses, or more doses of a pharmaceutical composition to a subject using a device disclosed herein. In some cases, such a drug-device combination can consistently deliver a clinical dose and have an optimal aerodynamic particle size for nasal deposition, while the respirable fine particle fraction that can be deposited in the lungs is negligible. In some cases, such a drug-device combination can produce a consistent and robust delivery even in the case of suboptimal actuation. In some cases, the device for delivery does not require filling or pre-filling of the device. In some cases, the methods herein provide consistent and robust drug delivery performance. In some cases, the present disclosure further includes monitoring the vital signs of a subject receiving treatment or prevention and the subject himself / herself can perform such monitoring, e.g., using a portable or wearable electronic device. The present disclosure also provides new pharmaceutical compositions, such as an active agent (such as dihydroergotamine mesylate) and a selected excipient of a specific weight. In some cases, the methods and / or compositions herein can meet the unmet need for a reliable parenteral-free form of dihydroergotamine.

[0082] Unless otherwise defined, 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. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the compositions or unit doses herein, some methods and materials are now described. Unless otherwise noted, the techniques employed or contemplated herein are standard methods. The materials, methods, and examples are illustrative only and not limiting.

[0083] Details of one or more instances of the invention are set forth in the figures, claims, and description herein. Other instances, features, objects, and advantages of the invention instances disclosed and contemplated herein can be combined with any other instance, unless explicitly excluded.

[0084] Unless otherwise indicated, open-ended terms such as "contain / containing", "include / including", etc. mean "comprising".

[0085]

[0086] Unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" as used herein include plural references. Accordingly, unless otherwise indicated, the numerical parameters set forth in this application are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

[0087] Unless otherwise indicated, some examples herein contemplate numerical ranges. When a numerical range is provided, unless otherwise indicated, the range includes the endpoints of the range. Unless otherwise indicated, a numerical range includes all values and sub-ranges therein as if expressly written out. Unless otherwise indicated, any numerical range and / or value herein may be 80 - 120% of a numerical range and / or value. For example, the term "about" may mean plus or minus 20% of the reference numerical indication.

[0088] As used herein, the term "subject" may refer to a mammal (e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, or baboon). In some cases, the subject is a human subject. In some cases, the subject is a healthy human subject. In some cases, the subject is a person in need of treatment or prevention of a condition or disorder.

[0089] In some cases, the improvement is calculated as follows:

[0090] Improvement = (|I - C| / C) x D I / D c x 100%

[0091] I = the improvement value of the current composition

[0092] C = the control value from a comparator or conventional composition

[0093] D I = the dose of the current composition

[0094] D c = the dose of the comparator or conventional composition

[0095] Unless otherwise indicated, the relative bioavailability (rBA) is equal to [((AUC of the formulation with the amorphous active pharmaceutical ingredient / dose of the formulation with the amorphous) / (AUC of the formulation with 100% crystalline / dose of the formulation with 100% crystalline)) x 100%].

[0096] As used herein, the term "dC / dT" may refer to the change in the concentration of the active agent in plasma over time or the change in the plasma concentration of the active agent during the period or interval. It is calculated as dC / dT = (plasma concentration at T2 - plasma concentration at T1) / (time point T2 - time point T1).

[0097] As used herein, the term "pre-primed" can refer to a device such as a nasal delivery device that is capable of delivering a nasal dosage form to a human subject in need thereof without assembling the device, or that is capable of delivering a nasal dosage form to a human subject in need thereof upon first actuating the pump of the device, i.e., without filling (pumping a nasal spray or mist) the pump prior to administration.

[0098] The pharmacokinetic data (e.g., C max , T max , AUC 0-t , AUC 0-180分钟 , AUC 0-inf , T 1 / 2 ) disclosed herein can be measured in a primate (e.g., a monkey such as a cynomolgus monkey) after administering a composition disclosed herein. Alternatively, the pharmacokinetic data (e.g., C max , T max , AUC 0-t , AUC 0-180分钟 , AUC 0-inf , T 1 / 2 ) disclosed herein can be measured in a human subject after administering a composition disclosed herein. In some cases, the rate of administration of an active agent (such as dihydroergotamine or a complex, chelate, salt, hydrate, polymorph, or ion pair thereof) is such that the mean peak plasma concentration (C max ) of 8-hydroxy-dihydroergotamine is greater than 10,000 pg / ml, the mean time (T max ) for 8-hydroxy-dihydroergotamine to reach C max is 90 minutes or longer, or a combination thereof.

[0099] In some cases, the term "substantially" can refer to 80 - 100% of the subject matter recited.

[0100] In some cases, an aggregate can refer to a loose packing of discrete particles held together by weak physical forces.

[0101] In some cases, an agglomerate can refer to a dense cluster of discrete particles held together by strong chemical or sintering forces.

[0102] As used herein, intranasal administration can refer to administration of at least 90 ± 10% (e.g., 95 ± 5%) of a composition to the nasal cavity as analyzed by the Multipath Particle Dosimetry (MPPD) model (a computational model for estimating particle dose in the human airway) or measured via an Andersen Cascade Impactor.

[0103] In a Markush group, any combination of the members of the Markush group is contemplated.

[0104] Unless otherwise specified, the term "thickening agent" can refer to an excipient that increases the particle size of the active agent and / or the viscosity of the composition. In some cases, the thickening agents disclosed herein bind to the active agent and / or the carrier through non-covalent interactions (e.g., hydrogen bonds or van der Waals forces).

[0105] Unless otherwise specified, "average particle size" can refer to the particle size distribution of a powder in its non-aggregated state. In some cases, average particle size can refer to the mean particle size, for example calculated as the sum of the size measurements of all measurable particles divided by the total number of particles measured. In some cases, average particle size can refer to the median particle size, for example indicating that the particle size of approximately 50% of all measurable particles measured is less than a defined median particle size value, and the particle size of approximately 50% of all measurable particles measured is greater than the defined median particle size value. In some cases, average particle size can refer to the mode particle size, for example indicating the most frequently occurring particle size value. In some cases, for spherical particles, average particle size can be a measure of the particle diameter. In some cases, for non-spherical particles, average particle size can be a measure of the longest or shortest diameter, perimeter, projected area, or equivalent spherical diameter. In some cases, the average particle diameter can be determined using a laser diffraction particle size analyzer. In some cases, the particle size analyzer can be a Mastersizer 2000 manufactured by Malvern Instruments Limited. In some cases, the average particle diameter can be, for example, the aerodynamic particle diameter measured by a Next Generation Impactor or a Mercer Cascade Impactor.

[0106] Active agents and compositions

[0107] In some cases, the active agents disclosed herein can be non-peptide / non-protein drugs. In some cases, the active agent can be selected from ergot alkaloids, serotonin 1 (5-HT1) receptor agonists, CGRP antagonists, NK-1 receptor antagonists, antihistamines, antiemetics, decongestants, opioid receptor agonists, antibiotics, antifungals, sulfonamides, antituberculosis drugs, antimicrobials, antiviral agents, hypnotic sedatives, antiepileptic drugs, narcotic analgesics, non-narcotic analgesics, sedatives, psychotherapeutic agents, muscle relaxants, antiallergic agents, antirheumatic drugs, cardiotonic agents, antiarrhythmic agents, antihypertensive agents, diuretics, coronary vasodilators, antidementia drugs, brain activators, cerebral circulation improvers, antiparkinsonian drugs, antihyperlipidemic drugs, antiulcer drugs, obesity drugs, diabetes drugs, hemostatic drugs, antithrombotic drugs, migraine drugs, antitussives, expectorants, respiratory stimulants, asthma drugs, antidiarrheal drugs, non-steroidal anti-inflammatory drugs, gout drugs, therapeutic agents for urinary system diseases, drugs for improving sexual function, drugs for the uterus, steroids, prostaglandins, vitamins, antidotes, therapeutic agents for heavy metal poisoning, smoking cessation agents, antiallergic drugs, antitumor drugs, immunostimulants, immunosuppressive drugs, and any combination thereof. In some cases, the active agent can be selected from didanosine, zidovudine, lamivudine, atazanavir, nelfinavir, stavudine, emtricitabine, polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir, peramivir, laninamivir, favipiravir, amantadine, amphotericin B, miconazole, fluconazole, itraconazole, ketoconazole, ketamine, sodium pentobarbital, thiamylal, amobarbital, cyclohexenobarbital, lidocaine, triazolam, zopiclone, zolpidem, eszopiclone, etizolam, chlortetracycline, bromazepam, clorazepate, estazolam, midazolam, nitrazepam, flunitrazepam, diazepam, chlordiazepoxide hydrochloride, alprazolam, lorazepam, clorazepate ethyl ester, bromazepam, limazafone, chloral hydrate, carbamazepine, clonazepam, zonisamide, sodium valproate, phenytoin, phenobarbital, primidone, gabapentin, opium, morphine, ethylmorphine, oxycodone, hydrocodone, codeine, dihydrocodeine, fentanyl, remifentanil, droperidol, levorphanol, methadone, meperidine, pethidine, buprenorphine, butorphanol, tramadol, tapentadol, nalflurafine, pentazocine, nalbuphine hydrochloride, nalorphine, etazocine, levallorphan, metamizole sodium, aspirin, acetaminophen, ergotamine, dihydroergotamine, sumatriptan, eletriptan, zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan, oxazepam, ticazepam, donepezil, succinylcholine, pancuronium bromide, sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine, homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine, thioridazine, acetylpromazine,Digoxin, methyl digoxin, isosorbide, nitroglycerin, quinidine, disopyramide, dopamine, dobutamine, epinephrine, etilefrine, norepinephrine, phenylephrine, dimoxamine, doxapram, naloxone, flumazenil, tepafibrate, dextromethorphan, ambroxol, bromhexine, salbutamol, terbutaline, procaterol, theophylline, ephedrine, sodium cromoglycate, ketotifen, oxatomide, tranilast, granisetron, azasetron, ramosetron, tropisetron, indisetron, palonosetron, cisapride, domperidone, metoclopramide, trimebutine, loperamide, mefenamic acid, indometacin, sulindac, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenic acid, tiaramide, carbazochrome sulfonate, tranexamic acid, pralidoxime methyl iodide, progesterone, testosterone, dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine, folinic acid, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone, risperidone, olanzapine, thalidomide, zucapsaicin (civamide), acyclovir, valacyclovir, famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine, idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin, carmustine (carmustin), beraprost sodium and any combination thereof.

[0108] In some cases, the active agent can be, for example, a small molecule drug having a molecular weight of less than about 1000 grams per mole (g / mol), about 750 g / mol or about 500 g / mol. In some cases, the active agent can be an anti-migraine drug. In some cases, the active agent can be an ergot alkaloid. In some cases, the active agent can be dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof (e.g., DHE mesylate). In some cases, the active agent can be indometacin, midazolam or phenobarbital. In some cases, the active agent can be indometacin or a pharmaceutically acceptable salt thereof. In some cases, the active agent can be testosterone or a pharmaceutically acceptable salt thereof.

[0109] In some cases, the active agents disclosed herein can be peptides or peptide-related compounds, wherein the peptide or peptide-related compound can have a molecular weight of about 10,000 Daltons (Da) or less, about 20,000 (Da) or less, about 30,000 (Da) or less, about 40,000 (Da) or less, or about 50,000 Daltons or less. In some cases, the active agent can be selected from insulin, human growth hormone, calcitonin, glucagon, parathyroid hormone, parathyroid hormone (1-34), glucagon-like peptide-1, interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony-stimulating factor, parathyroid hormone, thyrotropin-releasing hormone, angiotensin, prolactin, luteinizing hormone, gastric inhibitory polypeptide (GIP), C-peptide, cyclosporine, FK-506, octreotide, carperitide, pramlintide, lanreotide, eptifibatide, albiglutide, pasireotide, teriparatide, exenatide, liraglutide, enfuvirtide, ziconotide, exenatide-4, metreleptin, nesiritide, peglinesatide, afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide, cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide, peptide analogs thereof, and any combination thereof.

[0110] In some cases, the active agents disclosed herein can be selected from compounds having the following formula, stereoisomers thereof, pharmaceutically acceptable salts thereof, complexes thereof, chelates thereof, hydrates thereof, polymorphs thereof, ion pairs thereof, and any combination thereof:

[0111]

[0112] And

[0113] Wherein:

[0114] R1 is hydrogen, (C1-C4) alkyl, or (C1-C4) perfluoroalkyl;

[0115] Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 Or —CO2R 107 ;

[0116] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxyl or methoxy;

[0117] R5, R6 and R7 are independently hydrogen, (C1-C3) alkyl (e.g., methyl) or (C1-C3) perfluoroalkyl;

[0118] R8 and R9 are independently hydrogen, (C1-C4) alkyl or benzyl;

[0119] R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, -CO2R 108 or—CONR 109 R 110 ;

[0120] R 13 is hydrogen or a halogen;

[0121] R 101 -R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl;

[0122] k is 0, 1, or 2; and

[0123] n is 0, 1, 2 or 3.

[0124] In some cases, when present, each chiral center can independently be R, S or racemic. In some cases, the R1 is hydrogen. In some cases, the R2 is hydrogen, or n is 0. In some cases, the R3 and the R4 are both hydrogen. In some cases, the R6 is hydrogen. In some cases, the R5 and the R7 are both methyl. In some cases, the R8 is hydrogen, and the R9 is benzyl. In some cases, R 10 , R 11 and R 12 are independently hydrogen or both are hydrogen. 13 is hydrogen. In some cases, the R 14 is hydrogen. In some cases, the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the metabolite is of formula (I) and wherein R 12 is -OH. In some cases, the pharmacologically active metabolite is 8'-hydroxydihydroergotamine. In some cases, the metabolite is pharmacologically active.

[0125] In some cases, the pharmaceutical compositions disclosed herein can be powder pharmaceutical compositions. In some cases, the pharmaceutical compositions disclosed herein can be liquids. In some cases, the pharmaceutical compositions disclosed herein can be aerosols.

[0126] In some cases, the pharmaceutical composition comprises: about 0.5 mg to about 10 or about 20 mg (e.g., about 1 mg to about 6 mg) of the active agent, about 12 mg to about 19 mg of microcrystalline cellulose, about 0.1 mg to about 0.6 mg of a thickening agent, and about 6 mg to about 7 mg of a sugar alcohol. In some cases, the thickening agent may be present in an amount of about: 20%, 15%, 10%, or 5% by weight of the active agent. In some cases, the thickening agent comprises hydroxypropyl methylcellulose. In some cases, the thickening agent comprises hydroxypropyl cellulose. In some cases, the thickening agent comprises carboxymethyl cellulose. In some cases, the thickening agent may be present in a spray-dried particle dispersion. In some cases, the sugar alcohol comprises mannitol. In some cases, the sugar alcohol comprises sorbitol. In some cases, the sugar alcohol comprises galactitol. In some cases, the active agent may be present in a spray-dried particle dispersion. In some cases, about 3 mg to about 13 mg of the microcrystalline cellulose may be present in a spray-dried particle dispersion. In some cases, the microcrystalline cellulose may be at least partially coated with the active agent. In some cases, the active agent may be in an amorphous form. In some cases, the active agent may be dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the pharmaceutical composition comprises the pharmaceutically acceptable salt of dihydroergotamine, which pharmaceutically acceptable salt may be dihydroergotamine mesylate. In some cases, the dihydroergotamine or its pharmaceutically acceptable salt may be present in an amount of about 0.5 or about 1 mg to about 10 or about 20 mg, such as about 3 mg to about 5.5 mg, for example about 3.9 mg to about 4.5 mg, the microcrystalline cellulose may be present in an amount of about 15 mg to about 16 mg, the hydroxypropyl methylcellulose may be present in an amount of about 0.4 mg to about 0.5 mg, and the mannitol may be present in an amount of about 6 mg. In some cases, the dihydroergotamine or its pharmaceutically acceptable salt, the hydroxypropyl methylcellulose, and about 8 mg to about 9 mg of the microcrystalline cellulose are present in a spray-dried particle dispersion. In some cases, the dihydroergotamine or its pharmaceutically acceptable salt may be present in an amount of about 0.5 or about 1 mg to about 10 or about 20 mg, such as about 4 mg to about 7 mg, for example about 5.2 mg to about 6 mg, the microcrystalline cellulose may be present in an amount of about 18 mg to about 19 mg, the hydroxypropyl methylcellulose may be present in an amount of about 0.6 mg, and the mannitol may be present in an amount of about 6 mg. In some cases, the dihydroergotamine or its pharmaceutically acceptable salt, the hydroxypropyl methylcellulose, and about 10 mg to about 13 mg of the microcrystalline cellulose are present in a spray-dried particle dispersion.

[0127] In some cases, the pharmaceutical compositions disclosed herein can comprise one dose, two doses, three doses or more doses of an active agent (e.g., dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof) and one or more excipients, the excipient(s) being present in an amount of at least about 0.1 mg per dose or in total, such as at least about: 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.3 mg, 1.5 mg, 2 mg, 2.5 mg, 2.6 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.2 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or 10 mg.The composition may comprise dihydroergotamine or a pharmaceutically acceptable salt thereof and one or more excipients in an amount of about 10 - 20 mg, about 20 - 30 mg, about 10 - 30 mg, about 1 - 20 mg, about 1 - 15 mg, about 0.1 - 20 mg per dose or in total, for example, about 0.1 - 10 mg, about 0.1 - 9 mg, about 0.1 - 8 mg, about 0.1 - 7 mg, about 0.1 - 6 mg, about 0.1 - 5 mg, about 0.1 - 4 mg, about 0.1 - 3 mg, about 0.1 - 2 mg, about 0.1 - 1 mg, about 0.1 - 0.8 mg, about 0.1 - 0.6 mg, about 0.1 - 0.5 mg, about 0.2 - 10 mg, about 0.2 - 9 mg, about 0.2 - 8 mg, about 0.2 - 7 mg, about 0.2 - 6 mg, about 0.2 - 5 mg, about 0.2 - 4 mg, about 0.2 - 3 mg, about 0.2 - 2 mg, about 0.2 - 1 mg, about 0.2 - 0.5 mg, about 0.5 - 10 mg, about 0.5 - 9 mg, about 0.5 - 8 mg, about 0.5 - 7 mg, about 0.5 - 6 mg, about 0.5 - 5 mg, about 0.5 - 4 mg, about 0.5 - 3 mg, about 0.5 - 2 mg, about 0.5 - 1 mg, about 1 - 10 mg, about 1 - 5 mg, about 1 - 4 mg, about 1 - 3 mg, about 1 - 2 mg, about 1.5 - 6 mg, about 1.3 - 5.2 mg, about 2 - 10 mg, about 2 - 9 mg, about 2 - 8 mg, about 2 - 7 mg, about 2 - 6 mg, about 2 - 5 mg, about 2 - 4 mg, about 2 - 3 mg, about 3 - 8 mg, about 3 - 9 mg, about 4 - 7 mg, about 4 - 8 mg, about 5 - 10 mg, about 5 - 9 mg, about 5 - 8 mg, about 5 - 7 mg, about 5 - 6 mg, about 6 - 10 mg, about 6 - 9 mg, about 6 - 8 mg, about 6 - 7 mg, about 7 - 10 mg, about 7 - 9 mg, about 7 - 8 mg, about 8 - 10 mg, about 8 - 9 mg, about 9 - 10 mg, about 10 - 15 mg, about 11 - 19 mg, about 12 - 18 mg, about 13 - 17 mg, about 14 - 16 mg, about 10 - 25 mg, about 5 - 15 mg, about 5 - 20 mg or about 5 - 25 mg.

[0128] In some aspects, the present disclosure provides a pharmaceutical composition comprising: about 1 mg to about 6 mg of dihydroergotamine or a pharmaceutically acceptable salt thereof, about 12 mg to about 19 mg of microcrystalline cellulose, about 0.1 mg to about 0.6 mg of a thickening agent, and about 6 mg to about 7 mg of a sugar alcohol. In some cases, the pharmaceutical composition can be a powdered pharmaceutical composition. In some cases, the thickening agent can be present in an amount of about 10% by weight of the weight of the dihydroergotamine or the pharmaceutically acceptable salt thereof. In some cases, the thickening agent comprises hydroxypropyl methylcellulose. In some cases, the thickening agent comprises hydroxypropyl cellulose. In some cases, the thickening agent comprises carboxymethyl cellulose. In some cases, the thickening agent can be present in a spray-dried particle dispersion. In some cases, the sugar alcohol comprises mannitol. In some cases, the sugar alcohol comprises sorbitol. In some cases, the sugar alcohol comprises galactitol. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof can be present in a spray-dried particle dispersion. In some cases, about 3 mg to about 13 mg of the microcrystalline cellulose can be present in a spray-dried particle dispersion. In some cases, the microcrystalline cellulose can be at least partially coated with the dihydroergotamine or the pharmaceutically acceptable salt thereof. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof can be in an amorphous form. In some cases, the pharmaceutical composition comprises a pharmaceutically acceptable salt of dihydroergotamine, and the pharmaceutically acceptable salt can be dihydroergotamine mesylate. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof can be present in an amount of about 1.3 mg to about 1.5 mg, the microcrystalline cellulose can be present in an amount of about 12 mg, the hydroxypropyl methylcellulose can be present in an amount of about 0.1 mg to about 0.2 mg, and the mannitol can be present in an amount of about 6 mg. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof, the hydroxypropyl methylcellulose, and about 2 - 4 mg of the microcrystalline cellulose are present in a spray-dried particle dispersion. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof can be present in an amount of about 2.6 mg to about 3 mg, the microcrystalline cellulose can be present in an amount of about 13 mg, the hydroxypropyl methylcellulose can be present in an amount of about 0.3 mg, and the mannitol can be present in an amount of about 6 mg. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof, the hydroxypropyl methylcellulose, and about 4 mg to about 7 mg of the microcrystalline cellulose are present in a spray-dried particle dispersion. In some cases, the dihydroergotamine or the pharmaceutically acceptable salt thereof can be present in an amount of about 3.9 mg to about 4.5 mg, the microcrystalline cellulose can be present in an amount of about 15 mg to about 16 mg, the hydroxypropyl methylcellulose can be present in an amount of about 0.4 mg to about 0.5 mg, and the mannitol can be present in an amount of about 6 mg.In some cases, the dihydroergotamine or its pharmaceutically acceptable salt, the hydroxypropyl methylcellulose, and about 8 mg to about 9 mg of the microcrystalline cellulose are present in the spray-dried particle dispersion. In some cases, the dihydroergotamine or its pharmaceutically acceptable salt may be present in an amount of about 5.2 mg to about 6 mg, the microcrystalline cellulose may be present in an amount of about 18 mg to about 19 mg, the hydroxypropyl methylcellulose may be present in an amount of about 0.6 mg, and the mannitol may be present in an amount of about 6 mg. In some cases, the dihydroergotamine or its pharmaceutically acceptable salt, the hydroxypropyl methylcellulose, and about 10 mg to about 13 mg of the microcrystalline cellulose are present in the spray-dried particle dispersion. In some cases, at least about 80% of the dihydroergotamine or its pharmaceutically acceptable salt may be stable at room temperature, at one atmosphere outside the container and at a relative humidity of less than about 50%, in a light-resistant airtight container, for a storage period of at least about 60 days to about 3 years. In some cases, the storage period may be at least about 1 year.

[0129] In some cases, the pharmaceutical compositions disclosed herein comprise: about 1.5 - 6 mg of dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof, about 12 - 18 mg of microcrystalline cellulose (MCC), about 0.1 - 0.6 mg of hydroxypropyl methylcellulose (HPMC), and about 6 - 8 mg of mannitol. In some cases, DHE or a pharmaceutically acceptable salt thereof may be present in particulate form, 90% of which has an aerodynamic particle size (APS) greater than 10 microns as measured, for example, by a Next Generation Impactor or a Mercer Cascade Impactor. In some cases, DHE or a pharmaceutically acceptable salt thereof may be present in particulate form, 95% of which has an aerodynamic particle size (APS) greater than 5 microns as measured, for example, by a Next Generation Impactor or a Mercer Cascade Impactor. In some cases, DHE or a pharmaceutically acceptable salt thereof may be in an amorphous form. In some cases, DHE or a pharmaceutically acceptable salt thereof may be present in a spray-dried dispersion. In some cases, the pharmaceutically acceptable salt of DHE may be DHE mesylate. In some cases, about 2 - 10 mg of microcrystalline cellulose (MCC) may be present in the spray-dried dispersion. In some cases, MCC may be coated with DHE or a pharmaceutically acceptable salt thereof. In some cases, HPMC may be present in the spray-dried dispersion. In some cases, the spray-dried dispersion comprises about 25 - 40% w / w of the pharmaceutical composition, such as about: 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, or 39%. In some cases, the spray-dried dispersion comprises about 45 - 60% w / w of the pharmaceutical composition, such as about: 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, or 59%. In some cases, by weight, HPMC may be present in an amount of about 20 wt%, 15 wt%, 10 wt%, or 5 wt% of DHE or a pharmaceutically acceptable salt thereof, such as about 10 wt%. In some cases, the pharmaceutical composition comprises: about 1.5 mg of dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof (e.g., about 1.3 mg DHE or about 1.5 mg DHE mesylate), about 12 mg of microcrystalline cellulose (MCC), about 0.15 mg of hydroxypropyl methylcellulose (HPMC), and about 6 mg of mannitol. In some cases, DHE or a pharmaceutically acceptable salt thereof, HPMC, and about 2.5 mg of MCC are present in the spray-dried dispersion.In some cases, the pharmaceutical composition comprises: about 3 mg of dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof (e.g., about 2.6 mg DHE or about 3 mg DHE mesylate), about 13 mg of microcrystalline cellulose (MCC), about 0.3 mg of hydroxypropyl methylcellulose (HPMC), and about 6 mg of mannitol. In some cases, DHE or a pharmaceutically acceptable salt thereof, HPMC, and about 5 mg of MCC are present in a spray-dried dispersion. In some cases, the pharmaceutical composition comprises: about 6 mg of dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof (e.g., about 5.2 mg DHE or about 6 mg DHE mesylate), about 17.5 mg of microcrystalline cellulose (MCC), about 0.6 mg of hydroxypropyl methylcellulose (HPMC), and about 6 mg of mannitol. In some cases, DHE or a pharmaceutically acceptable salt thereof, HPMC, and about 10 mg of MCC are present in a spray-dried dispersion. In some cases, the pharmaceutical composition can be delivered using a device disclosed herein, for example. Figure 1A , 1B , any of the devices shown in 2A, 2B, or 2C. In some cases, even when the actuation speed is reduced, e.g., reduced to 50% of the optimal value, greater than about 90%-95% of the target amount can be delivered. In vitro delivery characterization using the devices herein demonstrated an average delivery dose of about 90% to about 100% (e.g., about: 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%), with a relative standard deviation of about 0.1% to about 7% (e.g., about: 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, or 6.5%).

[0130] The methods and compositions provided herein can utilize active agents in the form of free base, salts, hydrates, polymorphs, isomers, diastereoisomers, prodrugs, metabolites, ion pair complexes, or chelates. Pharmaceutically acceptable non-toxic acids or bases (including inorganic or organic acids or bases) can be used to form the active agent. In some cases, the active agent used in combination with the methods and compositions provided herein can be a pharmaceutically acceptable salt derived from an acid including, but not limited to, the following acids: acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, or p-toluenesulfonic acid. In some cases, the active agent can be a salt of methanesulfonic acid. An alternative nomenclature for DHE mesylate can be DHE mesylate.

[0131] In some cases, the average particle size of the active agent or composition disclosed herein can be from about 10 to about 100 micrometers (μm), for example, about: 95μm, 90μm, 85μm, 80μm, 75μm, 70μm, 65μm, 60μm, 55μm, 50μm, 45μm, 40μm, 35μm, 30μm, 25μm, 20μm, 15μm, 10μm, 5μm or smaller. In some cases, the average particle size of the active agent or composition disclosed herein can be greater than 10μm, for example, 250μm, 200μm, 190μm, 180μm, 170μm, 160μm, 150μm, 140μm, 130μm, 120μm, 110μm, 100μm, 95μm, 90μm, 85μm, 80μm, 75μm, 70μm, 65μm, 60μm, 55μm, 50μm, 45μm, 40μm, 35μm, 30μm, 25μm, 20μm or 15μm. In some cases, the particle size of the active agent or composition can be about: 20 - 100μm, 25 - 150μm, 25 - 175μm, 25 - 200μm, 25 - 250μm, 25 - 300μm, 50 - 150μm, 50 - 175μm, 50 - 200μm, 50 - 250μm, 50 - 300μm, 10 - 100μm, for example, about: 15 - 90μm, 15 - 80μm, 15 - 70μm, 15 - 60μm, 15 - 50μm, 15 - 40μm, 15 - 30μm, 15 - 20μm, 15 - 20μm, 10 - 90μm, 10 - 80μm, 10 - 70μm, 10 - 60μm, 10 - 50μm, 10 - 40μm, 10 - 30μm, 10 - 20μm, 20 - 90μm, 20 - 80μm, 20 - 70μm, 20 - 60μm, 20 - 50μm, 20 - 40μm, 20 - 30μm, 30 - 90μm, 30 - 80μm, 30 - 70μm, 30 - 60μm, 30 - 50μm, 30 - 40μm, 40 - 90μm, 40 - 80μm, 40 - 70μm, 40 - 60μm, 40 - 50μm, 50 - 90μm, 50 - 80μm, 50 - 70μm, 50 - 60μm, 60 - 90μm, 60 - 80μm, 60 - 70μm, 70 - 90μm, 70 - 80μm or 80 - 90μm.In some cases, the average particle size of the active agent or composition can be about: 5.0 μm, 5.5 μm, 6.0 μm, 6.5 μm, 7.0 μm, 7.5 μm, 8.0 μm, 8.5 μm, 9.0 μm, 9.5 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm or 100 μm. In some cases, at least 90% of the compositions provided herein have a particle size less than 150 μm, and no more than 5% of the particles have a diameter less than 5 μm. In some cases, the overall average particle size of the compositions provided herein is about 15 μm to about 30 μm, about 18 μm to about 25 μm, about 18 μm to about 20 μm or about 20 μm to about 23 μm. In some cases, the aerodynamic particle size (APS) of the powder composition can be large enough to minimize potential lung deposition; for example, as measured by a Next Generation Impactor or a Mercer Cascade Impactor, less than 10% of the DHE particles have an APS < 10 μm and less than 5% of the DHE particles have an APS < 5 μm.

[0132] In some cases, the total weight of the composition comprises about 0.4% to about 46%, or about 0.4% to about 23%, or about 0.4% to about 9%, or about 2% to about 9%, or about 4% to about 9% of the active agent. In some cases, the total weight of the composition comprises about 0.3% to about 37%, or about 0.3% to about 18%, or about 0.3% to about 7%, or about 2% to about 7%, or about 3% to about 9% of the active agent or its pharmaceutically acceptable salt.

[0133] In some cases, the compositions disclosed herein may further include additional active agents such as: adenosine receptor antagonists, phosphodiesterase inhibitors, acetylcholinesterase inhibitors, vasodilators, xanthines, caffeine, paraxanthine, theobromine, and theophylline. In some cases, for example, the method and compositions further comprise caffeine. In some cases, the additional active agent (e.g., caffeine) may be at least about 1% of the total weight of the composition, such as about: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or more of the total weight of the composition. In some cases, the additional active agent (e.g., caffeine) may be about 1% to 60% of the total weight of the composition, such as about: 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-20%, 1%-10%, 1%-5%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 30%-60%, 30%-50%, 30%-40%, 40%-60%, 40%-50% or 50%-60% of the total weight of the composition. In some cases, the composition comprises about 5% to 10% of the additional active agent (e.g., caffeine). In some cases, the caffeine may be anhydrous caffeine. In some cases, the composition comprises about 10% to 15% of the additional active agent (e.g., caffeine).

[0134] In some cases, the present disclosure provides an intranasal pharmaceutical composition comprising particles that contain an active agent and at least one member selected from the group consisting of a thickening agent, a carrier, a pH regulator, a sugar alcohol, and any combination thereof, wherein: at least about 10%, about 20%, about 30%, about 40%, or about 50% by weight of the active agent can be amorphous as determined by X-ray diffraction; or when the intranasal pharmaceutical composition can be administered, the pharmacokinetic parameters of the active agent are increased by at least about 15% compared to when administering a corresponding composition containing the crystalline form of the active agent. In some cases, the pharmaceutical composition further comprises particles that contain the active agent and do not contain a thickening agent, a carrier, a pH regulator, a sugar alcohol, or a combination thereof. In some cases, the active agent can be a non-peptide / non-protein drug. In some cases, the particles have an average particle size of about 15 to about 100 μm as measured by laser diffraction. In some cases, the particles have an average particle size of about 20 to about 50 μm as measured by laser diffraction. In some cases, the particles are spray-dried. In some cases, the active agent can be spray-dried onto a carrier, a thickening agent, a pH regulator, a sugar alcohol, or a combination thereof to form particles. In some cases, solubility can be measured at a pH of about 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.8, 7.9, 7.10, such as about 6.8 to about 7.4. In some cases, the particles contain a carrier that is at least partially insoluble in water at 37 ± 0.5 °C. In some cases, water insolubility can be measured at a pH of about 6.8 to about 7.4. In some cases, the particles further contain a thickening agent, and wherein the carrier can have lower water solubility than the thickening agent. In some cases, the particles contain a carrier that is capable of at least partially adhering to mucus. In some cases, the particles contain a carrier that comprises an oligosaccharide, a polysaccharide, or any combination thereof. In some cases, the carrier comprises microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, starch, chitosan, β-cyclodextrin, or any combination thereof. In some cases, the particles can contain a carrier that has an average particle size of about 10 to about 100 μm as measured by laser diffraction. In some cases, the carrier has an average particle size of about 20 μm as measured by laser diffraction. In some cases, the particles contain a thickening agent that is at least partially soluble in water at 37 ± 0.5 °C. In some cases, water solubility can be measured at a pH of about 6.8 to about 7.4. In some cases, the particles further contain a carrier, and wherein the thickening agent can have higher water solubility than the carrier. In some cases, the particles contain the thickening agent bound to the active agent. In some cases, the particles further contain a carrier, and wherein the thickening agent is bound to the active agent and the carrier.In some cases, the particles comprise a thickening agent, and the thickening agent comprises a polysaccharide. In some cases, the thickening agent comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, sodium alginate, xanthan gum, gum arabic, guar gum, locust bean gum, tragacanth gum, starch, carbopol, methylcellulose, polyvinylpyrrolidone, or any combination thereof. In some cases, the particles comprise a thickening agent and have an average particle size of from about 10 to about 50 μm or from about 15 - 200 microns as measured by laser diffraction. In some cases, as measured by laser diffraction, the particles have an average particle size of about 15 μm or from about 50 - 150 microns. In some cases, the particles comprise a thickening agent and a carrier and have an average particle size of from about 10 to about 50 μm as measured by laser diffraction. In some cases, as measured by laser diffraction, the particles have an average particle size of about 20 or about 23 μm. In some cases, the pharmaceutical composition further comprises a fluidizing agent. In some cases, the fluidizing agent comprises tribasic calcium phosphate. In some cases, when compared to administering the corresponding composition comprising the active agent in crystalline form, administering the pharmaceutical composition increases the pharmacokinetic parameters of the active agent by at least about: 20%, 25%, 30%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, or 500%. In some cases, the increased pharmacokinetic parameters include a greater relative bioavailability (rBA) from 0 minutes to 15 minutes. 0-15分钟 ), a greater relative bioavailability (rBA) from 0 minutes to 30 minutes 0-30分钟 ), a greater relative bioavailability (rBA) from 0 minutes to 60 minutes 0-60分钟 ), or any combination thereof. In some cases, the increased pharmacokinetic parameters include an average rBA 0-15分钟 , and the increase can be at least about 100%, for example, at least about: 115% or 150%. In some cases, the average rBA in the subject's serum 0-15分钟 can be from about 150% to 1500%. In some cases, the increased pharmacokinetic parameters include an average rBA 0-30分钟 , and the increase can be at least about 80%, for example, at least about: 115%. In some cases, the increase can be about 400%. In some cases, the increased pharmacokinetic parameters include an average rBA 0-60分钟 , and the increase can be at least 100%, for example, at least about: 115%. In some cases, the increase can be about 200%. In some cases, the increased pharmacokinetic parameters include a higher maximum blood concentration (C max)。In some cases, the improved pharmacokinetic parameters include a shorter time to reach maximum blood concentration (Tmax). In some cases, the improved pharmacokinetic parameters include an increased area under the plasma concentration-time curve (AUC). In some cases, the pharmaceutical composition further comprises an additional active agent. In some cases, the additional active agent includes caffeine, which can be amorphous, crystalline, at least 20% by weight of the caffeine is amorphous, or any combination thereof. In some cases, at least about: 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% by weight of the active agent can be amorphous. In some cases, the pharmaceutical composition retains at least about: 80%, 85%, 90% or 95% by weight of the active agent in a sealed container after a period of at least about: 30, 60, 120, 180, 360, 720 or 1080 days. In some cases, at one atmosphere and a relative humidity of about 50% to about 75%, the container can be stored at about 15°C, about 20°C, about 30°C, about 40°C, about 50°C, about 60°C or about 70°C, such as about 20°C to about 40°C. For example, the relative humidity can be about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80% or about 85%. In some cases, at one atmosphere and a relative humidity of about 50%, the container can be stored at about 25°C. In some cases, the crystalline form includes polymorphs. In some cases, as measured by liquid chromatography, at least about: 80%, 85%, 90%, 95% of the active agent can be stable at room temperature, outside the container at one atmosphere and a relative humidity of less than about 50%-60%, in a light-resistant sealed container, for a storage period of at least about (60 days, 3 months, 6 months, 1 year or 2 years) to about 3 years. In some cases, the storage period can be at least about 1 year.

[0135] In some cases, based on the weight of the particles or the pharmaceutical composition, the active agent can be present in an amount of about: 2-4%, 1-5%, 1-10%, 1-15%, 1-20%, 1-25%, 1-30%, 1-40%, 10-50%, 10-40%, 10-30% or 15-25% by weight, such as about: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45% or 50% by weight.

[0136] In some cases, the particle size of each active agent, excipient, and powder formulation was determined by a laser diffraction system (Mastersizer 2000, Malvern Instruments Ltd.) under dry powder dispersion conditions.

[0137] In some cases, the present disclosure provides compositions comprising one or more of the following: active agents (e.g., DHE, indomethacin, testosterone); microcrystalline cellulose components (e.g., CEOLUS PH-F20JP, having a particle size of about 20 - 23 microns, or a mixture of CEOLUS PH-F20JP and CEOLUS PH-301); thickening agents (e.g., HPMC); d) sugar alcohols (e.g., mannitol, having a particle size of about 53 - 300 microns); optionally, pH regulators (e.g., ascorbic acid); optionally, fluidizing agents (e.g., tribasic calcium phosphate); and optionally, additional active agents disclosed herein (e.g., caffeine, such as anhydrous caffeine). Examples of the powder compositions disclosed herein are shown in Table 1.

[0138] In some cases, the compositions can be prepared by fluidized bed granulation of all of their components. In some cases, the pharmaceutical compositions comprise an active agent, a thickening agent, a carrier, and a sugar alcohol. In some cases, the active agent can be amorphous, e.g., at least 20% amorphous. In some cases, the active agent can be spray dried, for example, with the thickening agent. In some cases, the thickening agent can be a low viscosity grade binder, such as HPMC. In some cases, the sugar alcohol can be mannitol. In some cases, the sugar alcohol can have a particle size diameter of about 53 to about 300 microns. In some cases, all components are agglomerated together sufficiently to withstand delivery from the device and ensure deposition at the same location. In some cases, the agglomerates can be loose enough to immediately break down into individual components upon deposition on the mucosa. In some cases, the particle size diameter of the composition can be from about 50 microns to about 150 microns, e.g., about 150 microns. In some cases, the composition can have an angle of repose of less than 55°, e.g., less than: 50°, 45°, 40°, 35°, 30°, or 25°. In some cases, the composition can be free of fluidizing agents. In some cases, the compositions disclosed herein can have an angle of repose of about 53° or less, e.g., about: 53°, 52°, 51°, 50°, 48°, 46°, 44°, 42°, 40°, 38°, 36°, 34°, 32°, 30°, 28°, 26°, 24°, 22°, 20°, or less.

[0139] Pharmacokinetics

[0140] In some cases, the methods disclosed herein can produce a time to peak plasma concentration (T max) as determined, for example, by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography-tandem mass spectrometry. In some cases, the metabolite has pharmacological activity. In some cases, the T max can be at least about 2 hours. In some cases, the peak plasma concentration (C max ) of the metabolite can be less than about 500 pg / ml. In some cases, the C max of the metabolite can be less than about 250 pg / ml. In some cases, the active agent includes dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, the metabolite can be 8'-hydroxydihydroergotamine.

[0141] In some cases, the methods disclosed herein produce in human subjects: a C max of about 1 to about 2.5 ng / ml or a plasma concentration of at least 1 ng / mL within about 10 minutes or less, a T max of less than 30 minutes, and an AUC value selected from: an AUC 0-30分钟 of about 500 to about 1000 h*pg / ml, an AUC 0-60分钟 of about 1000 to about 2000 h*pg / ml, an AUC 0-120分钟 of about 2000 to about 3000 h*pg / ml, and an AUC 0-inf of about 10000 to about 12000 h*pg / ml, as determined by measuring the human plasma concentration of the active agent herein by automated extraction liquid chromatography-tandem mass spectrometry. In some cases, the method further provides a half-life of the active agent of about 12 hours to about 13 hours. In some cases, the active agent includes dihydroergotamine or a pharmaceutically acceptable salt thereof. In some cases, after said administration to the human subject, the methods disclosed herein produce an apparent clearance (CL / F) value of the active agent in the human subject of about 50 L / hour to about 1500 L / hour, such as about 100 L / hour to about 1000 L / hour. In some cases, the CL / F value of the active agent can be about 500 to about 600 L / hour, about 400 to about 700 L / hour, about 300 to about 800 L / hour, or about 200 to about 900 L / hour. In some cases, the CL / F value of the active agent can be about 540 L / hour. In some cases, the active agent includes dihydroergotamine or a pharmaceutically acceptable salt thereof.

[0142] In some cases, when measured within 24 hours after said administration to the human subject, the methods disclosed herein produce in the human subject a Visual Analogue Scale score (for measuring nasal symptoms) of less than about: 65, 50, 40, 30, or 20, wherein the Visual Analogue Scale score can be measured on a scale of 0 (asymptomatic) to 100 (worst imaginable) based on each of the following nasal symptoms: nasal discomfort, nasal burning, nasal itching, nasal pain, nasal congestion, dysgeusia or taste alteration, rhinorrhea, and sneezing. In some cases, the Visual Analogue Scale score can be measured about 4 hours after said administration. In some cases, the Visual Analogue Scale score can be measured about 1 hour after said administration. In some cases, the Visual Analogue Scale score can be measured about 15 minutes after said administration. In some cases, the Visual Analogue Scale score can be measured about 5 minutes after said administration. In some cases, the Visual Analogue Scale score can be less than about 10. In some cases, the Visual Analogue Scale score can be less than about 5. In some cases, the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof.

[0143] In some cases, between T 0分钟 and T 15分钟 the administration provides a dC / dT value that is at least about 10% higher compared to a liquid formulation of dihydroergotamine. In some cases, between T 0分钟 and T 15分钟 the administration provides a dC / dT value of at least about 1000 (pg / mL) / hour.

[0144] In some cases, the therapeutic or prophylactic methods disclosed herein can include administering to a human subject a powder composition comprising an active agent, and producing a lower C max and / or AUC value of the metabolite of the active agent as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography-tandem mass spectrometry, compared to a liquid formulation administered by the same route. In some cases, the same route for administration can be the intranasal route. In some cases, the C max and / or AUC value of the metabolite can be about 10 - 50% (e.g., about 10 - 20%, 10 - 30%, 20 - 30%, or 20 - 40%) of the C max and / or AUC value produced by a liquid formulation administered by the same route. In some other cases, the therapeutic or prophylactic methods disclosed herein can include administering to a human subject a powder composition comprising an active agent, and as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography-tandem mass spectrometry, the C maxHigher C of metabolites of the active agent (e.g., pharmacokinetically activated) compared to the C and / or AUC value max and / or AUC value. In some cases, the same route for administration can be the intranasal route. In some cases, the C max and / or AUC value of the metabolite can be about 1.5 to about 5 times (e.g., about 2, 3, or 4 times) the C max and / or AUC value produced by administering a liquid formulation via the same route. In some cases, the AUC value can be AUC 0-30分钟 、AUC 0-60分钟 、AUC 0-90分钟 、AUC 0-2h 、AUC 0-3h 、AUC 0-4h 、AUC 0-24h 、AUC 0-48h 、AUC 0-inf or any combination thereof. In some cases, the active agent includes dihydroergotamine, and the metabolite includes or can be 8'-hydroxy-dihydroergotamine. In some cases, when the method produces 8'-hydroxy-dihydroergotamine as one of multiple metabolites, the ratio of the human plasma concentration of 8'-hydroxy-dihydroergotamine to the human plasma concentration of one or more other metabolites of dihydroergotamine can be higher than the ratio produced by administering a liquid formulation via the same route. In some cases, the liquid formulation has the same dose of the active agent as the compositions disclosed herein. In some other cases, the liquid formulation has pharmacokinetic values (e.g., the same or substantially similar) of the active agent that are comparable to those of the compositions herein containing different doses (e.g., 4.5 or 6 mg of the same active agent, or about 2 - 4 times the strength in the liquid composition).

[0145] In some cases, the therapeutic or prophylactic methods disclosed herein can include intranasally administering to a human subject a powder composition comprising an active agent, and producing a lower C max of the metabolite of the active agent compared to a liquid formulation administered via a different route (e.g., intramuscular, subcutaneous, intravenous), as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography - tandem mass spectrometry. In some cases, the C max and / or AUC value of the metabolite can be the C maxand / or 10 - 50% of the AUC value (e.g., about 10 - 20%, 10 - 30%, 20 - 30% or 20 - 40%). In some other cases, the therapeutic or prophylactic methods disclosed herein may include intranasal administration to a human subject of a powdered composition comprising an active agent, and produce a higher C of a metabolite (e.g., pharmacokinetically activated) of the active agent compared to a liquid formulation administered by a different route (e.g., intramuscular, subcutaneous, intravenous). max , as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography - tandem mass spectrometry. In some cases, the C max and / or AUC value of the metabolite may be about 1.5 to about 5 times (e.g., about 2, 3 or 4 times) the C max and / or AUC value produced by administering the liquid formulation by a different route. In some cases, the AUC value may be AUC 0-30分钟 , AUC 0-60分钟 , AUC 0-90分钟 , AUC 0-2h , AUC 0-3h , AUC 0-4h , AUC 0-24h , AUC 0-48h , AUC 0-inf or any combination thereof. In some cases, the active agent comprises dihydroergotamine, and the metabolite may be or comprise 8'-hydroxy - dihydroergotamine. In some cases, when the method produces 8'-hydroxy - dihydroergotamine as one of a plurality of metabolites, the ratio of the human plasma concentration of 8'-hydroxy - dihydroergotamine to the human plasma concentration of one or more other metabolites of dihydroergotamine may be higher than the ratio produced by intranasal administration of the liquid formulation. In some cases, the liquid formulation has the same dose of the active agent as the composition disclosed herein. In some other cases, the liquid formulation has pharmacokinetic values (e.g., the same or substantially similar) of the active agent comparable to those of the present composition comprising a different dose (e.g., about 4.5 or 6 mg of the same active agent, or about 2 - 4 times the strength in the liquid composition).

[0146] In some cases, the peak plasma concentration (C max ) of the metabolite may be less than about 250 pg / ml, e.g., less than about: 200, 150, 100, 50 or 10 pg / ml. In some cases, the peak plasma concentration (C max ) of the metabolite may be less than the C max of the active agent measured after the administration to the human subject.about 20%, such as less than about: 15%, 10%, 5% or 1%. In some cases, the plasma concentration of the metabolite can be less than about 5% of the plasma concentration of the active agent measured within about: 30, 25, 20, 15, 10 or 5 minutes after the administration to the human subject. In some cases, the plasma concentration of the metabolite can be less than about 2% of the plasma concentration of the active agent measured within about: 15, 10 or 5 minutes after the administration to the human subject.

[0147] In some cases, the reduced presence of the metabolite can result in a reduced pharmacological effect of the metabolite in the human subject. In some cases, the reduced pharmacological effect is a binding activity to adrenergic receptors (e.g., α1 [non-specific], α2A, α2B, α2C, β), dopaminergic receptors (e.g., D: D1, D2, D3) or serotonergic receptors (e.g., 5-HT receptor or subtypes: 5-HT 1A 、5-HT 1B 、5-HT 1D 、5-HT 2A 、5-HT 2C 、5-HT3, 5-HT4, 5-HT 5A 、5-HT6, 5-HT7) as measured by a radioligand competitive binding assay that is less than 20%. In some cases, the reduced pharmacological effect is less in the human subject than in a non-human animal. In some cases, the reduced pharmacological effect in the human subject is manifested as a reduced transcutaneous O2 partial pressure measured on the dorsum of the foot, a reduced venous constriction as determined using a venous occlusion mercury strain gauge, a reduced diameter or compliance of the smaller brachial artery wall, a reduced human coronary, meningeal artery or saphenous vein constriction, a reduced smaller venous diameter at a fixed occlusion pressure, a change in peripheral circulation volume, or any combination thereof.

[0148] In some cases, the methods and compositions herein can include the average T of the active agent at least about 1 minute, such as at least about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 60 minutes, 90 minutes or 120 minutes after administering the composition. max In some cases, the average T of the active agent after administering the composition maxIt can be about 1 to about 120 minutes, for example, about 1 - 120 minutes, about 1 - 90 minutes, about 1 - 60 minutes, about 1 - 50 minutes, 1 - 40 minutes, 1 - 30 minutes, 1 - 20 minutes, 1 - 10 minutes, 1 - 5 minutes, about 1 - 2 minutes, about 5 - 120 minutes, about 5 - 90 minutes, about 5 - 60 minutes, about 5 - 50 minutes, 5 - 40 minutes, 5 - 30 minutes, 5 - 25 minutes, 5 - 20 minutes, 5 - 10 minutes, about 10 - 120 minutes, about 10 - 90 minutes, about 10 - 60 minutes, about 10 - 50 minutes, 10 - 40 minutes, 10 - 30 minutes, 10 - 20 minutes, about 20 - 120 minutes, about 20 - 90 minutes, about 20 - 60 minutes, about 20 - 50 minutes, 20 - 40 minutes, 20 - 30 minutes, about 30 - 120 minutes, about 30 - 90 minutes, about 30 - 60 minutes, about 30 - 50 minutes, 30 - 40 minutes, about 40 - 120 minutes, about 40 - 90 minutes, about 40 - 60 minutes, 40 - 50 minutes, about 50 - 120 minutes, about 50 - 90 minutes, about 50 - 60 minutes, about 60 - 120 minutes, about 60 - 90 minutes or about 90 - 120 minutes. In some cases, the average T after administering the composition max can be measured from a primate (e.g., a monkey such as a cynomolgus monkey). In some cases, the average T after administering the composition max can be measured from a human subject.

[0149] In some cases, the methods and compositions herein can include the average C of the active agent after administering the composition maxis at least about 0.01 nanogram per milliliter (ng / mL), for example, at least about 0.01 ng / mL, 0.1 ng / mL, 0.2 ng / mL, 0.3 ng / mL, 0.4 ng / mL, 0.5 ng / mL, 0.6 ng / mL, 0.7 ng / mL, 0.8 ng / mL, 0.9 ng / mL, 1 ng / mL, 1.5 ng / mL, 2 ng / mL, 2.5 ng / mL, 3 ng / mL, 3.5 ng / mL, 4 ng / mL, 4.5 ng / mL, 5 ng / mL, 5.5 ng / mL, 6 ng / mL, 6.5 ng / mL, 7 ng / mL, 7.5 ng / mL, 8 ng / mL, 8.5 ng / mL, 9 ng / mL, 9.5 ng / mL, 10 ng / mL, 11 ng / mL, 12 ng / mL, 13 ng / mL, 14 ng / mL, 15 ng / mL, 16 ng / mL, 17 ng / mL, 18 ng / mL, 19 ng / mL, 20 ng / mL, 25 ng / mL, 30 ng / mL, 35 ng / mL, 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, 75 ng / mL, 80 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, 100 ng / mL, 110 ng / mL, 120 ng / mL, 130 ng / mL, 140 ng / mL or 150 ng / mL. In some cases, the average C of the active agent after administering the composition maxIt can be about 0.1 to about 150 ng / mL, for example, about 0.1 - 150 ng / mL, 0.1 - 130 ng / mL, 0.1 - 110 ng / mL, 0.1 - 90 ng / mL, 0.1 - 70 ng / mL, 0.1 - 50 ng / mL, 0.1 - 30 ng / mL, 0.1 - 10 ng / mL, 0.1 - 5 ng / mL, 0.1 - 1.0 ng / mL, 0.1 - 0.5 ng / mL, 1 - 150 ng / mL, 1 - 130 ng / mL, 1 - 110 ng / mL, 1 - 90 ng / mL, 1 - 70 ng / mL, 1 - 50 ng / mL, 1 - 30 ng / mL, 1 - 10 ng / mL, 1 - 5 ng / mL, 5 - 150 ng / mL, 5 - 130 ng / mL, 5 - 110 ng / mL, 5 - 90 ng / mL, 5 - 70 ng / mL, 5 - 50 ng / mL, 5 - 30 ng / mL, 5 - 10 ng / mL, 10 - 150 ng / mL, 10 - 130 ng / mL, 10 - 110 ng / mL, 10 - 90 ng / mL, 10 - 70 ng / mL, 10 - 50 ng / mL, 10 - 30 ng / mL, 30 - 150 ng / mL, 30 - 130 ng / mL, 30 - 110 ng / mL, 30 - 90 ng / mL, 30 - 70 ng / mL, 30 - 50 ng / mL, 50 - 150 ng / mL, 50 - 130 ng / mL, 50 - 110 ng / mL, 50 - 90 ng / mL, 50 - 70 ng / mL, 70 - 150 ng / mL, 70 - 130 ng / mL, 70 - 110 ng / mL, 70 - 90 ng / mL, 90 - 150 ng / mL, 90 - 130 ng / mL, 90 - 110 ng / mL, 110 - 150 ng / mL, 110 - 130 ng / mL or 130 - 150 ng / mL. In some cases, the average C after administering the composition max can be measured from a primate (e.g., a monkey, such as a cynomolgus monkey). In some cases, the average C after administering the composition max can be measured from a human subject.

[0150] In some cases, the methods and compositions herein can include the average AUC of the active agent after administering the composition 0-infis at least about 0.5 nanogram - hour / milliliter (ng·h / mL), for example, at least about 0.5 ng·h / mL, 1 ng·h / mL, 2 ng·h / mL, 3 ng·h / mL, 4 ng·h / mL, 5 ng·h / mL, 6 ng·h / mL, 7 ng·h / mL, 8 ng·h / mL, 9 ng·h / mL, 10 ng·h / mL, 20 ng·h / mL, 30 ng·h / mL, 40 ng·h / mL, 50 ng·h / mL, 60 ng·h / mL, 70 ng·h / mL, 80 ng·h / mL, 90 ng·h / mL, 100 ng·h / mL, 200 ng·h / mL, 300 ng·h / mL, 400 ng·h / mL, 500 ng·h / mL, 600 ng·h / mL, or 700 ng·h / mL. In some cases, the average AUC of the active agent after administering the composition 0-infIt can be about 0.5 to about 700 ng·h / mL. For example, about 0.5 - 700 ng·h / mL, 0.5 - 500 ng·h / mL, 0.5 - 300 ng·h / mL, 0.5 - 100 ng·h / mL, 0.5 - 80 ng·h / mL, 0.5 - 60 ng·h / mL, 0.5 - 40 ng·h / mL, 0.5 - 20 ng·h / mL, 0.5 - 10 ng·h / mL, 0.5 - 5 ng·h / mL, 0.5 - 2 ng·h / mL, 0.5 - 1 ng·h / mL, 1 - 700 ng·h / mL, 1 - 500 ng·h / mL, 1 - 300 ng·h / mL, 1 - 100 ng·h / mL, 1 - 80 ng·h / mL, 1 - 60 ng·h / mL, 1 - 40 ng·h / mL, 1 - 20 ng·h / mL, 1 - 10 ng·h / mL, 1 - 5 ng·h / mL, 10 - 700 ng·h / mL, 10 - 500 ng·h / mL, 10 - 300 ng·h / mL, 10 - 100 ng·h / mL, 10 - 80 ng·h / mL, 10 - 60 ng·h / mL, 10 - 40 ng·h / mL, 10 - 20 ng·h / mL, 20 - 700 ng·h / mL, 20 - 500 ng·h / mL, 20 - 300 ng·h / mL, 20 - 100 ng·h / mL, 20 - 80 ng·h / mL, 20 - 60 ng·h / mL, 20 - 40 ng·h / mL, 40 - 700 ng·h / mL, 40 - 500 ng·h / mL, 40 - 300 ng·h / mL, 40 - 100 ng·h / mL, 40 - 80 ng·h / mL, 40 - 60 ng·h / mL, 60 - 700 ng·h / mL, 60 - 500 ng·h / mL, 60 - 300 ng·h / mL, 60 - 100 ng·h / mL, 60 - 80 ng·h / mL, 80 - 700 ng·h / mL, 80 - 500 ng·h / mL, 80 - 300 ng·h / mL, 80 - 100 ng·h / mL, 100 - 700 ng·h / mL, 100 - 500 ng·h / mL, 100 - 300 ng·h / mL, 300 - 700 ng·h / mL, 300 - 500 ng·h / mL or 500 - 700 ng·h / mL. In some cases, the average AUC after administering the composition 0-inf can be measured from a primate (e.g., a monkey, such as a cynomolgus monkey). In some cases, the average AUC after administering the composition 0-inf can be measured from a human subject.

[0151] In some cases, the methods and compositions herein can include the average AUC of the active agent after administering the composition 0-tis at least about 0.5 ng·h / mL, for example, at least about 0.5 ng·h / mL, 1 ng·h / mL, 2 ng·h / mL, 3 ng·h / mL, 4 ng·h / mL, 5 ng·h / mL, 6 ng·h / mL, 7 ng·h / mL, 8 ng·h / mL, 9 ng·h / mL, 10 ng·h / mL, 20 ng·h / mL, 30 ng·h / mL, 40 ng·h / mL, 50 ng·h / mL, 60 ng·h / mL, 70 ng·h / mL, 80 ng·h / mL, 90 ng·h / mL, 100 ng·h / mL, 200 ng·h / mL, 300 ng·h / mL, 400 ng·h / mL, 500 ng·h / mL, 600 ng·h / mL or 700 ng·h / mL. In some cases, the average AUC of the active agent after administering the composition 0-infcan be from about 0.5 to about 700 ng·h / mL, for example, about 0.5 - 700 ng·h / mL, 0.5 - 500 ng·h / mL, 0.5 - 300 ng·h / mL, 0.5 - 100 ng·h / mL, 0.5 - 80 ng·h / mL, 0.5 - 60 ng·h / mL, 0.5 - 40 ng·h / mL, 0.5 - 20 ng·h / mL, 0.5 - 10 ng·h / mL, 0.5 - 5 ng·h / mL, 0.5 - 2 ng·h / mL, 0.5 - 1 ng·h / mL, 1 - 700 ng·h / mL, 1 - 500 ng·h / mL, 1 - 300 ng·h / mL, 1 - 100 ng·h / mL, 1 - 80 ng·h / mL, 1 - 60 ng·h / mL, 1 - 40 ng·h / mL, 1 - 20 ng·h / mL, 1 - 10 ng·h / mL, 1 - 5 ng·h / mL, 10 - 700 ng·h / mL, 10 - 500 ng·h / mL, 10 - 300 ng·h / mL, 10 - 100 ng·h / mL, 10 - 80 ng·h / mL, 10 - 60 ng·h / mL, 10 - 40 ng·h / mL, 10 - 20 ng·h / mL, 20 - 700 ng·h / mL, 20 - 500 ng·h / mL, 20 - 300 ng·h / mL, 20 - 100 ng·h / mL, 20 - 80 ng·h / mL, 20 - 60 ng·h / mL, 20 - 40 ng·h / mL, 40 - 700 ng·h / mL, 40 - 500 ng·h / mL, 40 - 300 ng·h / mL, 40 - 100 ng·h / mL, 40 - 80 ng·h / mL, 40 - 60 ng·h / mL, 60 - 700 ng·h / mL, 60 - 500 ng·h / mL, 60 - 300 ng·h / mL, 60 - 100 ng·h / mL, 60 - 80 ng·h / mL, 80 - 700 ng·h / mL, 80 - 500 ng·h / mL, 80 - 300 ng·h / mL, 80 - 100 ng·h / mL, 100 - 700 ng·h / mL, 100 - 500 ng·h / mL, 100 - 300 ng·h / mL, 300 - 700 ng·h / mL, 300 - 500 ng·h / mL or 500 - 700 ng·h / mL. In some cases, the average AUC after administering the composition 0-inf can be measured from a primate (e.g., a monkey, such as a cynomolgus monkey). In some cases, the average AUC after administering the composition 0-infCan be measured from human subjects. In some cases, the measurement can be performed for 5 minutes, 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes, 360 minutes, 420 minutes, or 480 minutes, or any combination thereof.

[0152] In some cases, the methods and compositions herein can include the average T of the active agent after administering the composition 1 / 2 To be at least about 10 minutes, such as at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 120 minutes, 150 minutes, 200 minutes, 250 minutes, or 300 minutes. In some cases, the average T of the active agent after administering the composition 1 / 2 Can be from about 10 to about 300 minutes, for example, about 10 - 300 minutes, 10 - 250 minutes, 10 - 200 minutes, 10 - 150 minutes, 10 - 120 minutes, 10 - 100 minutes, 10 - 80 minutes, 10 - 60 minutes, 10 - 40 minutes, 10 - 20 minutes, 20 - 300 minutes, 20 - 250 minutes, 20 - 200 minutes, 20 - 150 minutes, 20 - 120 minutes, 20 - 100 minutes, 20 - 80 minutes, 20 - 60 minutes, 20 - 40 minutes, 40 - 300 minutes, 40 - 250 minutes, 40 - 200 minutes, 40 - 150 minutes, 40 - 120 minutes, 40 - 100 minutes, 40 - 80 minutes, 40 - 60 minutes, 60 - 300 minutes, 60 - 250 minutes, 60 - 200 minutes, 60 - 150 minutes, 60 - 120 minutes, 60 - 100 minutes, 60 - 80 minutes, 80 - 300 minutes, 80 - 250 minutes, 80 - 200 minutes, 80 - 150 minutes, 80 - 120 minutes, 80 - 100 minutes, 100 - 300 minutes, 100 - 250 minutes, 100 - 200 minutes, 100 - 150 minutes, 100 - 120 minutes, 120 - 300 minutes, 120 - 250 minutes, 120 - 200 minutes, 120 - 150 minutes, 150 - 300 minutes, 150 - 250 minutes, 150 - 200 minutes, 200 - 300 minutes, 200 - 250 minutes, or 250 - 300 minutes. In some cases, for example, the average T of the active agent after administering the composition 1 / 2 Can be from about 100 to about 300 minutes. In some cases, the average T after administering the composition 1 / 2 Can be measured from monkeys (e.g., cynomolgus monkeys). In some cases, the average T after administering the composition 1 / 2 Can be measured from human subjects.

[0153] In some cases of the active agent, the average Tmax may be from about 10 to about 30 minutes, average C max may be from about 0.5 to about 6 ng / mL, average AUC 0-inf may be 1 to about 15 ng·h / mL, and average T 1 / 2 may be 100 to about 300 minutes. In other cases, average T max may be from about 10 to about 50 minutes, average C max may be from about 1 to about 15 ng / mL, average AUC 0-inf may be 10 to about 50 ng·h / mL, and average T 1 / 2 may be 100 to about 300 minutes. In another case of the active agent, average T max may be from about 10 to about 50 minutes, average C max may be from about 2 to about 20 ng / mL, average AUC 0-inf may be 15 to about 110 ng·h / mL, and average T 1 / 2 may be 100 to about 300 minutes. In another case of the active agent, average T max may be from about 10 to about 50 minutes, average C max may be from about 2 to about 50 ng / mL, average AUC 0-inf may be 15 to about 200 ng·h / mL, and average T 1 / 2 may be 100 to about 300 minutes. In some cases, average T after administering the composition max 、C max 、AUC 0-inf and / or T 1 / 2 may be measured from a primate (e.g., a monkey, such as a cynomolgus monkey). In some cases, average T after administering the composition may be measured from a human subject max 、C max 、AUC 0-inf and / or T 1 / 2 .

[0154] In some cases, the methods herein acutely treat migraine with or without aura and include administering to a subject suffering from migraine an effective dose of a pharmaceutical composition comprising dihydroergotamine (DHE) or a salt thereof, wherein the effective dose may be administered via an intranasal delivery device that provides, after intranasal administration, (a) an average peak plasma DHE concentration (C max ) of at least 750 pg / ml, (b) an average time (T max ) for DHE to reach C max of less than 45 minutes, and (c) an average plasma AUC of DHE of at least 2500 pg*hour / ml 0-inf. In some cases, the pharmaceutical composition can be a powder or a liquid.

[0155] In some cases, the kits herein can acutely treat migraine with or without aura and comprise a vial in which at least one effective dose of a pharmaceutical composition comprising dihydroergotamine (DHE) or a salt thereof is sealed, wherein after intranasal administration via an intranasal delivery device, the effective dose provides (a) an average peak plasma DHE concentration (C max ) of at least 750 pg / ml, (b) an average time (T max ) for DHE to reach C max of less than 45 minutes, and (c) an average plasma AUC of DHE of at least 2500 pg*hour / ml 0-inf . In some cases, the pharmaceutical composition can be a powder or a liquid.

[0156] In some cases, the compositions disclosed herein can be administered such that the inter-subject variability of the active agent C max can be less than 50%. In some cases, for example, the inter-subject variability of the active agent C max can be less than 50%, 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the compositions can be administered such that the inter-subject variability of the active agent T max can be less than 30%. In some cases, for example, the inter-subject variability of the active agent T max can be less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the compositions can be administered such that the inter-subject variability of DHE AUC 0-inf can be less than 30%. In some cases, for example, the inter-subject variability of the active agent AUC 0-inf can be less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, the compositions can be administered such that the inter-subject variability of the active agent T 1 / 2 can be less than 30%. In some cases, for example, the inter-subject variability of the active agent T 1 / 2 can be less than 30%, 25%, 20%, 15%, 10%, or 5%. In some cases, after administering the compositions, the inter-subject variability of the active agent T max , C max , AUC 0-inf and / or T 1 / 2 can be measured from primates (e.g., monkeys such as cynomolgus monkeys). In some cases, after administering the compositions, the inter-subject variability of the active agent T max , C max , AUC 0-inf and / or T 1 / 2Inter-subject variability can be measured from human subjects.

[0157] In some cases, the pharmacokinetic parameters disclosed herein can be determined by analyzing blood samples or plasma samples collected at one or more time points of about: 2, 5, 10, 15, 20, 30, 45, 60, 120, or 180 minutes after intranasal administration. In some cases, the analysis includes measuring the plasma concentration of the active agent (e.g., DHE or metabolite (e.g., 8’-hydroxy-DHE) or a combination thereof) in the blood sample or plasma sample. In some cases, the analysis can be performed using liquid chromatography (LC), mass spectrometry (MS), or a combination thereof. In some cases, the LC / MS / MS method or liquid chromatography-tandem mass spectrometry with manual or automated extraction can be used for the analysis.

[0158] Excipient

[0159] In some cases, the compositions disclosed herein can contain one or more excipients, e.g., different substances, or the same substances of different sizes. In some cases, the excipient includes a carrier, e.g., a water-insoluble polysaccharide or oligosaccharide. In some cases, the carrier can be selected from cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, chitosan, β-cyclodextrin, ethyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), microcrystalline cellulose, starch, and any combination thereof. In some cases, the excipient includes a thickening agent, e.g., a water-soluble polysaccharide. In some cases, the thickening agent can be selected from hydroxypropyl methylcellulose (HPMC), gum arabic, alginic acid, colloidal silica, calcium carboxymethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl cellulose (hydroxypropylmethylcellulose), methylcellulose, sucrose, sodium alginate, sodium carboxymethylcellulose, and any combination thereof. In some cases, the excipient includes a first excipient (any excipient disclosed herein) and a second excipient (any excipient disclosed herein). In some cases, the excipient includes a carrier (e.g., microcrystalline cellulose) and a thickening agent (e.g., HPMC). In some cases, the compositions disclosed herein include sugar alcohols. In some cases, the sugar alcohol can be selected from mannitol, glycerol, galactitol, fucitol, inositol, heptitol, maltotriitol, maltotetritol, dextran, erythritol, threitol, ribitol, arabitol, xylitol, allitol, galactitol, glucitol, sorbitol, adonitol, iditol, maltitol, lactitol, isomaltulose, and any combination thereof. In some cases, the sugar alcohol can have 3, 4, 5, 6, 7, 12, 18, or 24 carbons. In some cases, the compositions disclosed herein contain a propellant suitable for pharmaceutical use, e.g., a hydrofluoroalkane, such as hydrofluoroalkane-134a. In some cases, the compositions disclosed herein can be propellant-free, e.g., without hydrofluoroalkane.

[0160] In some cases, the particles may contain a thickening agent, and based on the weight of the active agent or pharmaceutical composition, the thickening agent may be present in an amount of about: 0.1 - 0.5%, 0.05 - 1%, 0.05 - 2%, 0.05 - 3%, 0.05 - 4%, 0.05 - 5%, 4 - 6%, 3 - 7%, 2 - 8%, 1 - 10% or 1 - 20% by weight, such as about: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% by weight. In some cases, the particles contain microcrystalline cellulose, and based on the weight of the active agent or pharmaceutical composition, the microcrystalline cellulose may be present in an amount of about: 10 - 95%, 10 - 75%, 15 - 55%, 20 - 75%, 35 - 75% or 40 - 75% by weight, such as about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95% by weight. In some cases, the particles contain sugar alcohol, and based on the weight of the active agent or pharmaceutical composition, the sugar alcohol may be present in an amount of about: 10 - 95%, 10 - 75%, 15 - 55%, 20 - 75%, 35 - 75% or 40 - 75% by weight, such as about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90% or 95% by weight. In some cases, the particles contain a pH regulator, and based on the weight of the active agent or pharmaceutical composition, the pH regulator may be present in an amount of about: 10 - 20%, 20 - 30%, 5 - 25%, 15 - 35% or 5 - 40% by weight, such as about: 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35% or 40% by weight.

[0161] In some cases, the particulate or pharmaceutical compositions disclosed herein may include a pH regulator. In some cases, the pH regulator may be selected from ascorbic acid, sodium ascorbate, tartaric acid, sodium tartrate, potassium tartrate, calcium tartrate, lithium tartrate, citric acid, sodium citrate, potassium citrate, calcium citrate, lithium citrate, phosphoric acid, sodium dihydrogen phosphate, sodium hydrogen phosphate, lithium phosphate, potassium phosphate, calcium phosphate, sodium carbonate, sodium bicarbonate, lactic acid, sodium lactate, potassium lactate, calcium lactate, acetic acid, sodium acetate, potassium acetate, calcium acetate, propionic acid, sulfuric acid, sodium sulfate, potassium sulfate, boric acid, sodium borate, maleic acid, lithium maleate, sodium maleate, potassium maleate, calcium maleate, succinic acid, lithium succinate, sodium succinate, potassium succinate, calcium succinate, fumaric acid, glutamic acid, formic acid, malic acid, hydrochloric acid, nitric acid, sodium hydroxide, potassium hydroxide, triethanolamine, diisopropanolamine, ammonia solution, monoethanolamine, diethanolamine, triethanolamine meglumine, sodium citrate, sodium bicarbonate, potassium bicarbonate, and any combination thereof. In some cases, the pH regulator disclosed herein may be acetic acid; adipic acid; ammonium aluminum sulfate; ammonium bicarbonate; ammonium carbonate; ammonium dibasic citrate; ammonium monobasic citrate; ammonium hydroxide; ammonium dibasic phosphate; ammonium monobasic phosphate; calcium acetate; calcium acid pyrophosphate; calcium carbonate; calcium chloride; calcium citrate; calcium fumarate; calcium gluconate; calcium hydroxide; calcium lactate; calcium oxide; calcium dibasic phosphate; calcium monobasic phosphate; calcium tribasic phosphate; calcium sulfate; carbon dioxide; citric acid; tartar; fumaric acid; gluconic acid; glucono-δ-lactone; hydrochloric acid; lactic acid; magnesium carbonate; magnesium citrate; magnesium fumarate; magnesium hydroxide; magnesium oxide; magnesium phosphate; magnesium sulfate; malic acid; manganese sulfate; metatartaric acid; phosphoric acid; potassium tartrate; potassium aluminum sulfate; potassium bicarbonate; potassium carbonate; potassium chloride; potassium citrate; potassium fumarate; potassium hydroxide; potassium lactate; potassium dibasic phosphate; potassium tribasic phosphate; potassium sulfate; potassium bitartrate; potassium tripolyphosphate; sodium acetate; sodium acid pyrophosphate; sodium hydrogen tartrate; sodium aluminum phosphate; sodium aluminum sulfate; sodium bicarbonate; sodium bisulfate; sodium carbonate; sodium citrate; sodium fumarate; sodium gluconate; sodium hexametaphosphate; sodium hydroxide; sodium lactate; sodium dibasic phosphate; sodium monobasic phosphate; sodium tribasic phosphate; sodium potassium hexametaphosphate; sodium potassium tartrate; sodium potassium tripolyphosphate; sodium tetrabasic pyrophosphate; sodium tripolyphosphate; sulfuric acid; sulfurous acid; tartaric acid; or any combination thereof.

[0162] In some cases, the buffering agent may be selected from sodium phosphate, sodium hydrogen phosphate, anhydrous sodium dihydrogen phosphate, crystalline sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, sodium acetate, citric acid, citric anhydride, sodium citrate, sodium glutamate, creatinine, and phosphate buffered saline.

[0163] In some cases, the composition may further comprise a fluidizing agent. For example, the fluidizing agent may be a metal salt (e.g., calcium salt) or a phosphate. In some cases, the fluidizing agent may be a calcium phosphate salt, such as tribasic calcium phosphate. In some cases, tribasic calcium phosphate may be from about 0.1% to about 5.0% of the total weight of the composition, such as about 0.1%-5%, 0.1%-4%, 0.1%-3%, 0.1%-2%, 0.1%-1%, 0.1%-0.5%, 0.5%-5%, 0.5%-4%, 0.5%-3%, 0.5%-2%, 0.5%-1%, 1%-5%, 1%-4%, 1%-3%, 1%-2%, 2%-5%, 2%-4%, 2%-3%, 3%-5%, 3%-4% or 4%-5% of the total weight of the composition. In some cases, tribasic calcium phosphate may be from about 0.5% to about 1.0% of the total weight of the composition. In some cases, tribasic calcium phosphate may be from about 0.5% to about 1.5% of the total weight of the composition. In some cases, tribasic calcium phosphate may be about 0.8% of the total weight of the composition. The fluidizing agent may include but is not limited to tribasic calcium phosphate, hydrous silica, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, calcium silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, talc, corn starch, magnesium metasilicate aluminate, anhydrous calcium hydrogen phosphate, synthetic hydrotalcite and magnesium metasilicate aluminate. In some cases, the fluidizing agent may be tribasic calcium phosphate. In some cases, tribasic calcium phosphate accounts for about 0.5-1.0% of the total weight of the composition. In a specific case of the method for treating migraine, tribasic calcium phosphate accounts for about 0.8% of the total weight of the composition.

[0164] In some cases, the excipient can have an average particle size of about 100 μm or less, for example, an average particle size of about 95 μm, 90 μm, 85 μm, 80 μm, 75 μm, 70 μm, 65 μm, 60 μm, 55 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm, 20 μm, 15 μm, 10 μm, 5 μm or less. In some cases, the compositions herein can include a first excipient having an average particle diameter of about 30 μm or less and a second excipient having an average particle diameter of about 30 to about 100 μm. In some cases, the first excipient can have an average particle diameter of about 30 μm or less, for example, an average particle diameter of about 30 - 25 μm, 30 - 20 μm, 30 - 15 μm, 30 - 10 μm, 30 - 5 μm, 25 - 20 μm, 25 - 15 μm, 25 - 10 μm, 25 - 5 μm, 20 - 15 μm, 20 - 10 μm, 20 - 5 μm, 15 - 10 μm, 15 - 5 μm or 10 - 5 μm. In some cases, the first excipient can have an average particle diameter of about 15 - 30 μm. In some cases, the first excipient can have an average particle diameter of about 18 - 20 μm. In some cases, the first excipient can have an average particle diameter of about 20 μm. In some cases, the second excipient can have an average particle diameter of about 30 to about 100 μm, for example, an average particle diameter of about 30 - 90 μm, 30 - 80 μm, 30 - 70 μm, 30 - 60 μm, 30 - 50 μm, 30 - 40 μm, 40 - 90 μm, 40 - 80 μm, 40 - 70 μm, 40 - 60 μm, 40 - 50 μm, 50 - 90 μm, 50 - 80 μm, 50 - 70 μm, 50 - 60 μm, 60 - 90 μm, 60 - 80 μm, 60 - 70 μm, 70 - 90 μm, 70 - 80 μm or 80 - 90 μm. In some cases, the second excipient can have an average particle diameter of about 45 - 65 μm. In some cases, the second excipient can have an average particle diameter of about 45 - 55 μm. In some cases, the second excipient can have an average particle diameter of about 50 - 55 μm. In some cases, the second excipient can have an average particle diameter of about 50 μm. In some cases, the first excipient can have an average particle diameter of about 15 to about 30 μm and the second excipient can have an average particle diameter of about 45 to about 65 μm. In some cases, the first excipient can have an average particle diameter of about 20 μm and the second excipient can have an average particle diameter of about 50 to about 55 μm. In some cases, the first excipient can have an average particle diameter of about 20 μm and the second excipient can have an average particle diameter of about 50 μm. In some cases, the excipient can be substantially free of particles having an average particle size of about 31 to about 44 μm. In some cases, the excipient can be substantially free of particles having an average particle size of about 31 to about 49 μm.In some cases, substantially free of particles of a certain average particle size means that less than 15%, 10%, 5% or 2% of all the particles fall within a given range.

[0165] In some cases, one or more excipients (e.g., microcrystalline cellulose, HPMC, mannitol, TCP) can account for at least about 5% of the total weight of the composition, e.g., at least about: 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98% of the total weight of the composition. In some cases, the excipient can account for about 15% to about 99% of the total weight of the composition, e.g., about: 15%-99%, 20%-99%, 30%-99%, 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, 15%-90%, 20%-90%, 30%-90%, 40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 15%-80%, 20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70-80%, 15%-70%, 20%-70%, 30%-70%, 40-70%, 50-70%, 60-70%, 15%-60%, 20%-60%, 30%-60%, 40-60%, 50-60%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 15%-40%, 20%-40%, 30%-40%, 15%-30%, 20%-30% or 15-20% of the total weight of the composition. In some cases, the first excipient accounts for about 10 to about 90% of the total weight of the composition, e.g., about: 10%-90%, 15%-90%, 20%-90%, 30%-90%, 40-90%, 50-90%, 60-90%, 70-90%, 80-90%, 10%-80%, 15%-80%, 20%-80%, 30%-80%, 40-80%, 50-80%, 60-80%, 70-80%, 10%-70%, 15%-70%, 20%-70%, 30%-70%, 40-70%, 50-70%, 60-70%, 10%-60%, 15%-60%, 20%-60%, 30%-60%, 40-60%, 50-60%, 10%-50%, 15%-50%, 20%-50%, 30%-50%, 40-50%, 10%-40%, 15%-40%, 20%-40%, 30%-40%, 10%-30%, 15%-30%, 20%-30%, 10%-20%, 15-20% or 10%-15% of the total weight of the composition. In some cases, the first excipient accounts for about 70% to about 90% of the total weight of the composition. In some cases, the first excipient accounts for about 70% to about 90% of the total weight of the composition.In some cases, the second excipient accounts for about 5% to about 15% of the total weight of the composition, for example, about 5%-15%, 5%-10% or 10%-15% of the total weight of the composition. In some cases, the second excipient accounts for about 10% of the total weight of the composition. In some cases, for example, the first excipient accounts for about 8% to about 90% of the total weight of the composition, and the second excipient accounts for about 10% of the total weight of the composition. In some cases, the first excipient can be about 5% to about 90% of the total weight of the composition, and the second excipient can be about 10% of the total weight of the composition.

[0166] In some cases regarding the microcrystalline cellulose component of the compositions provided herein, generally, acceptable microcrystalline cellulose can include microcrystalline cellulose obtained by decomposing a cellulose material such as pulp by one or both of acid hydrolysis and base hydrolysis, then purifying the hydrolysis product, and comminuting or grinding it before, during or after drying. In some cases, for example, by appropriate processing, such as by fine grinding and size sorting using a high-speed rotary impact mill or an air mill as needed, microcrystalline cellulose with a selected average particle size can be obtained. In some cases, the microcrystalline cellulose component that is part of the microcellulose of the compositions provided herein can include products obtainable under the following trade names: PH-F20JP (for example, average particle size of about 20-23 microns, bulk density of about 0.23 g / cm 3 , angle of repose not less than 60 degrees), PH-301 (for example, average particle size of about 50 microns, bulk density of about 0.41 g / cm 3 , angle of repose of about 41 degrees), PH-101 (for example, average particle size of about 50 microns, bulk density of about 0.29 g / cm 3 , angle of repose of about 45 degrees), PH-102 (for example, average particle size of about 90 microns, bulk density of about 0.3 g / cm 3 , angle of repose of about 42 degrees) and PH-302 (obtainable from Asahi Kasei Corporation, for example, average particle size of about 90 microns, bulk density of about 0.43 g / cm 3 , angle of repose of about 38 degrees) and PH-105 (for example, average particle size of about 20 microns, bulk density of about 0.20-0.30 g / cm 3 ), PH-101 (for example, average particle size of about 50 microns, bulk density of about 0.26-0.31 g / cm 3 ), PH-102 (e.g., having an average particle size of about 100 microns and a bulk density of about 0.28 - 0.33 g / cm 3 ), PH-301 (e.g., having an average particle size of about 50 microns and a bulk density of about 0.34 - 0.45 g / cm 3 ) and PH-302 (obtainable from FMC Biopolymer Corporation, e.g., having an average particle size of about 100 microns and a bulk density of about 0.35 - 0.46 g / cm 3 ). In some cases, the compositions that can be used in combination with the methods and compositions provided herein may include PH-F20JP and PH-301.

[0167] In some cases, standard techniques (e.g., by a laser diffraction particle size distribution analyzer or by a sieving method) can be used to determine the average particle diameter (e.g., the average particle diameter of the microcrystalline portion of the compositions described herein). In some cases, the average particle diameter refers to the diameter that divides the particles into two equal groups: the group with the larger diameter and the group with the smaller diameter. In some cases, the average particle diameter determined using a laser diffraction particle size distribution analyzer corresponds to 50% volume in the determined cumulative particle size distribution curve. In some cases, the average particle diameter corresponding to 50% (W / W) on the cumulative particle size distribution curve can be determined, for example, by a sieving method, by sieving an appropriate amount of the particles to be evaluated on an electromagnetic vibrating sieve for an appropriate time (e.g., 10 minutes), using standard sieves and weighing the remaining samples on each sieve, and the cumulative particle size distribution curve can be obtained.

[0168] In some cases, the microcrystalline cellulose component of the composition comprises a first microcrystalline cellulose portion having an average particle size of about 30 μm or less, and a second microcrystalline cellulose portion having an average particle size of about 30 - 100 μm. In some cases, the first microcrystalline cellulose portion may have an average particle size of about 15 - 30 μm. In some cases, the first microcrystalline cellulose portion may have an average particle size of about 18 - 20 μm. In some cases, the first microcrystalline cellulose portion may have an average particle size of about 20 μm. In some cases, the second microcrystalline cellulose portion may have an average particle size of about 45 - 65 μm. In some cases, the second microcrystalline cellulose portion may have an average particle size of about 45 - 55 μm. In some cases, the second microcrystalline cellulose portion may have an average particle size of about 50 - 55 μm. In some cases, the second microcrystalline cellulose portion may have an average particle size of about 50 μm. In some cases, the first microcrystalline cellulose portion may have an average particle size of about 20 μm, and the second microcrystalline cellulose portion may have an average particle size of about 50 μm. In some cases, the first microcrystalline cellulose portion may have an average particle size of about 30 μm or less, e.g., an average particle size of about 15 - 30 μm, about 18 - 20 μm, or about 20 μm, and the second microcrystalline cellulose portion may have an average particle size of about 45 - 65 μm, about 45 - 55 μm, about 50 - 55 μm, or about 50 μm.

[0169] In some cases, the microcrystalline cellulose component of the composition accounts for about 10 to about 99% of the total weight of the composition, for example, about 15 to about 99%. In some cases, the microcrystalline cellulose component of the composition accounts for about 53 to about 99%, about 76 to about 99%, about 76 to about 97%, about 90 to about 97%, or about 90 to about 95% of the total weight of the composition. In some cases, the microcrystalline cellulose component of the composition accounts for about 10 to about 98%, about 18 to about 98%, about 18 to about 91%, about 67 to about 91%, or about 67 to about 83%. In some cases, the microcrystalline cellulose component of the composition accounts for about 53%, about 76%, about 90%, about 95%, about 97%, or about 99% of the total weight of the composition. In some cases, the microcrystalline cellulose component of the composition accounts for about 10%, about 18%, about 66%, about 83%, about 91%, or about 98% of the total weight of the composition. In some cases, the first microcrystalline cellulose portion accounts for about 3.0 to about 90% of the total weight of the composition, for example, about 8.0 to about 90%, and the second microcrystalline cellulose portion accounts for about 10% of the total weight of the composition. In some cases, the first microcrystalline cellulose portion accounts for about 43 to about 89%, about 66 to about 89%, about 66 to about 87%, about 80 to about 87%, or about 80 to about 85% of the total weight of the composition, and the second microcrystalline cellulose portion accounts for about 10% of the total weight of the composition. In some cases, the microcrystalline cellulose component of the composition accounts for about 1 to about 88%, about 8 to about 88%, about 8 to about 81%, about 57 to about 81%, or about 57 to about 83%, and the second microcrystalline cellulose portion accounts for about 10% of the total weight of the composition. In some cases, the microcrystalline cellulose component of the composition accounts for about 43%, about 66%, about 80%, about 85%, about 87%, or about 89% of the total weight of the composition, and the second microcrystalline cellulose portion accounts for about 10% of the total weight of the composition. In some cases, the microcrystalline cellulose component of the composition accounts for about 1%, about 8%, about 57%, about 73%, about 81%, or about 88% of the total weight of the composition, and the second microcrystalline cellulose portion accounts for about 10% of the total weight of the composition.

[0170] In some cases, with respect to tribasic calcium phosphate (also known as hydroxyapatite), any pharmaceutically acceptable tribasic calcium phosphate can be used in combination with the methods and compositions provided herein. In some cases, the tribasic calcium phosphate utilized can have an average particle size of about 10 - 100 μm, for example, about 10 - 75 μm, about 10 - 50 μm, about 10 - 30 μm, or about 10 μm. In some cases, no less than 90% of the tribasic calcium phosphate particles in the compositions provided herein have a diameter less than 150 μm, and no more than 5% of the particles in the composition have a diameter less than 10 μm. In some cases, the overall average particle size of the tribasic calcium phosphate particles in the compositions provided herein can include about 15 to about 30 μm, about 18 to about 25 μm, about 18 to about 20 μm, or about 20 μm.

[0171] In some cases, greater than or equal to about 90% of the tribasic calcium phosphate particles have a diameter less than 150 μm. In some cases, the overall average particle size of the tribasic calcium phosphate particles can include from about 15 to about 30 μm, from about 18 to about 25 μm, from about 18 to about 20 μm, or about 20 μm. In some cases, less than or equal to about 5% of the tribasic calcium phosphate particles have a diameter less than 10 μm. In some cases, for the tribasic calcium phosphate particles, greater than or equal to about 90% of the particles can include a diameter less than 150 μm; and the overall average particle size can be from about 15 to about 30 μm, from about 18 to about 25 μm, from about 18 to about 20 μm, or about 20 μm; and less than or equal to about 5% of the particles have a diameter less than 10 μm.

[0172] In some cases, the tribasic calcium phosphate accounts for at least: about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, 2.0% of the total weight of the composition, for example, 0.5 - 1.0%. In some specific cases of a method for treating headaches including migraines, the tribasic calcium phosphate accounts for about 0.8% of the total weight of the composition.

[0173] Dosage

[0174] In some cases, the total dose of the administered composition can be at least about 0.1 mg, for example, at least about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg. In some cases, the total dose of the administered composition can be from about 0.1 to about 50 mg, for example, about 0.1 - 50.0 mg, about 0.1 - 25.0 mg, about 0.1 - 20.0 mg, about 0.1 - 15.0 mg, about 0.1 - 10.0 mg, about 0.1 - 5.0 mg, about 0.1 - 2.0 mg, about 0.1 - 1.0 mg, about 0.1 - 0.5 mg, about 0.2 - 50.0 mg, about 0.2 - 25.0 mg, about 0.2 - 20.0 mg, about 0.2 - 15.0 mg, about 0.2 - 10.0 mg, about 0.2 - 5.0 mg, about 0.2 - 2.0 mg, about 0.2 - 1.0 mg, about 0.2 - 0.5 mg, about 0.5 - 55.0 mg, 0.5 - 25.0 mg, about 0.5 - 20.0 mg, about 0.5 - 15.0 mg, about 0.5 - 10.0 mg, about 0.5 - 5.0 mg, about 0.5 - 2.0 mg, about 0.5 - 1.0 mg, about 1.0 - 25.0 mg, about 1.0 - 50.0 mg, about 1.0 - 20.0 mg, about 1.0 - 15.0 mg, about 1.0 - 10.0 mg, about 1.0 - 5.0 mg, about 1.0 - 2.0 mg, about 2.0 - 50.0 mg, about 2.0 - 25.0 mg, about 2.0 - 20.0 mg, about 2.0 - 15.0 mg, about 2.0 - 10.0 mg, about 2.0 - 5.0 mg, about 5.0 - 25.0 mg, about 5.0 - 20.0 mg, about 5.0 - 15.0 mg, about 5.0 - 10.0 mg, about 10.0 - 50.0 mg, about 0.5 - 25.0 mg, about 10.0 - 20.0 mg, about 10.0 - 15.0 mg, about 15.0 - 25.0 mg, about 15.0 - 20.0 mg, about 20 - 40 mg or about 25 - 35 mg. In some cases, for example, the total dose of the administered composition can be about 25 - 35 mg.

[0175] In some cases, the composition comprises a total dose of active agent administered at at least about 0.1 mg, for example, at least about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg or about 10 mg. In some cases, the composition may comprise a total dose of active agent administered at about 0.1 to about 10.0 mg, for example, about 0.1 - 10.0 mg, about 0.1 - 9.0 mg, about 0.1 - 8.0 mg, about 0.1 - 7.0 mg, about 0.1 - 6.0 mg, about 0.1 - 5.0 mg, about 0.1 - 4.0 mg, about 0.1 - 3.0 mg, about 0.1 - 2.0 mg, about 0.1 - 1.0 mg, about 0.1 - 0.5 mg, about 0.2 - 10.0 mg, about 0.2 - 9.0 mg, about 0.2 - 8.0 mg, about 0.2 - 7.0 mg, about 0.2 - 6.0 mg, about 0.2 - 5.0 mg, about 0.2 - 4.0 mg, about 0.2 - 3.0 mg, about 0.2 - 2.0 mg, about 0.2 - 1.0 mg, about 0.2 - 0.5 mg, about 0.5 - 10.0 mg, about 0.5 - 9.0 mg, about 0.5 - 8.0 mg, about 0.5 - 7.0 mg, about 0.5 - 6.0 mg, about 0.5 - 5.0 mg, about 0.5 - 4.0 mg, about 0.5 - 3.0 mg, about 0.5 - 2.0 mg, about 0.5 - 1.0 mg, about 1.0 - 10.0 mg, about 1.0 - 5.0 mg, about 1.0 - 4.0 mg, about 1.0 - 3.0 mg, about 1.0 - 2.0 mg, about 2.0 - 10.0 mg, about 2.0 - 9.0 mg, about 2.0 - 8.0 mg, about 2.0 - 7.0 mg, about 2.0 - 6.0 mg, about 2.0 - 5.0 mg, about 2.0 - 4.0 mg, about 2.0 - 3.0 mg, about 5.0 - 10.0 mg, about 5.0 - 9.0 mg, about 5.0 - 8.0 mg, about 5.0 - 7.0 mg, about 5.0 - 6.0 mg, about 6.0 - 10.0 mg, about 6.0 - 9.0 mg, about 6.0 - 8.0 mg, about 6.0 - 7.0 mg, about 7.0 - 10.0 mg, about 7.0 - 9.0 mg, about 7.0 - 8.0 mg, about 8.0 - 10.0 mg, about 8.0 - 9.0 mg or about 9.0 - 10.0 mg. In some cases, for example, the total dose administered may comprise about 0.5 mg. In some cases, the total dose administered may comprise about 0.1 - 5 mg. In some cases, the total amount administered may comprise about 0.5 - 5 mg.In some cases, the total amount administered can include from about 0.5 - 3 mg. In some cases, the total amount administered can include from about 1 - 2 mg.

[0176] Method for preparing the composition

[0177] In some cases, the present disclosure provides methods for preparing the compositions herein, including mixing, grinding, granulating, spray drying, freeze drying, and / or melt extrusion.

[0178] In some cases, the present disclosure provides methods for preparing intranasal pharmaceutical compositions, including spray drying / freeze drying / melt extruding an active agent and at least one selected from thickeners, carriers, pH adjusters, sugar alcohols, and any combination thereof to produce particles, wherein: the particles can contain the active agent; at least about 20% by weight of the active agent in the particles can be amorphous as determined by X-ray diffraction. In some cases, the active agents disclosed herein can be suspended in methanol prior to spray drying. In some cases, the particles can contain the active agent and a thickener. In some cases, the particles can contain the active agent and a carrier. In some cases, the particles contain the active agent, a carrier, and a thickener. In some cases, the method further includes mixing the particles with an additional amount of the carrier. In some cases, the method further includes mixing the particles with an additional carrier, an additional thickener, or any combination thereof. In some cases, the particles can contain the active agent and be free of a thickener, a carrier, or a combination thereof. In some cases, solubility can be measured at a pH of about 6.8 to about 7.4. In some cases, the particles can contain a carrier that is at least partially insoluble in water at 37 ± 0.5 °C. In some cases, water insolubility can be measured at a pH of about 6.8 to about 7.4. In some cases, the particles further contain a thickener, and wherein the carrier can have lower water solubility than the thickener. In some cases, the particles contain a carrier that is capable of at least partially adhering to mucus. In some cases, the particles contain a carrier that includes oligosaccharides, polysaccharides, or any combination thereof. In some cases, the carrier can include microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, starch, chitosan, β-cyclodextrin, or any combination thereof. In some cases, the particles can have an average particle size of about 15 to about 100 μm as measured by laser diffraction. In some cases, the carrier can have an average particle size of about 20 to about 50 μm as measured by laser diffraction. In some cases, the particles can contain a thickener that is at least partially soluble in water at 37 ± 0.5 °C. In some cases, water solubility can be measured at a pH of about 6.8 to about 7.4. In some cases, the particles can further contain a carrier, and wherein the thickener can have higher water solubility than the carrier. In some cases, the particles can contain a thickener bound to the active agent. In some cases, the particles can further contain a carrier, and wherein the thickener is bound to the active agent and the carrier. In some cases, the particles can contain a thickener that can include a polysaccharide.In some cases, the thickening agent includes hydroxypropyl methylcellulose (HPMC), HPMC acetate succinate, hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium alginate, xanthan gum, gum arabic, guar gum, locust bean gum, tragacanth gum, starch, carbomer, methyl cellulose, polyvinylpyrrolidone, or any combination thereof. In some cases, the particles contain a thickening agent and can have an average particle size of from about 10 to about 50 μm, as measured by laser diffraction. In some cases, the particles can have an average particle size of about 15 μm, as measured by laser diffraction. In some cases, the particles contain a thickening agent and a carrier and have an average particle size of from about 10 to about 50 μm, as measured by laser diffraction. In some cases, the particles have an average particle size of about 20 μm, as measured by laser diffraction.

[0179] In some cases, provided herein are methods for producing a composition, including spray drying / freeze drying / melt extrusion of an active agent optionally with a water-insoluble polysaccharide mucoadhesive carrier (e.g., MCC), a sugar alcohol (such as mannitol), and / or a water-soluble polysaccharide thickening agent (e.g., HPMC). In some cases, the active agent can be produced by grinding, evaporation, spraying, or freeze drying. In some cases, the preparation method further includes physically mixing the active agent with an additional mucoadhesive carrier (e.g., MCC) and / or a fluidizing agent (e.g., tribasic calcium phosphate). In some cases, provided herein are methods for preparing spray-dried particles (SDRP) having an active agent and a mucoadhesive carrier (e.g., MCC) without a thickening agent (e.g., HPMC). In some cases, provided herein are methods for preparing spray-dried particles (SDRP) having an active agent and a thickening agent (e.g., HPMC) without a mucoadhesive carrier (e.g., MCC). In some cases, provided herein are methods for preparing spray-dried particles (SDRP) having only an active agent without a mucoadhesive carrier (e.g., MCC) or a thickening agent (e.g., HPMC).

[0180] In some cases, the compositions described herein can be prepared using standard techniques. In some cases, for example, the components of the composition can be mixed while applying a shear force (e.g., by a high-shear mixer / stirrer). Alternatively, for example, the components of the composition can be uniformly mixed using, for example, a mortar or a V-blender.

[0181] In some cases, the compositions provided herein can be encapsulated in a capsule prior to administration. For example, the compositions provided herein can be encapsulated in a capsule in unit dosage form. In some cases, the encapsulated composition can be released from the capsule prior to administration. In some cases, the composition can be released from the capsule upon administration. In some cases, for example, the composition can be administered intranasally using a device designed to receive and deliver an encapsulatable composition. In some cases, the fill weight of the capsule includes a suitable excess of the composition such that a desired dose can be administered taking into account the selected administration device utilized.

[0182] device

[0183] Also provided herein are devices for intranasal delivery. The intranasal delivery devices can be used to administer the compositions to a subject in need of treatment or prophylaxis. Delivery of the composition can be performed by a medical professional and / or the subject in need of treatment or prophylaxis (e.g., a human subject). As described herein, the device can be pre-loaded with a single dose of the composition. In some cases, the device can be a disposable device. In some cases, the device can be pre-filled or need not be filled prior to administration. Also disclosed herein are methods for treating or preventing a condition or disease (e.g., migraine), including actuating a device comprising the composition disclosed herein. In some cases, administration of the composition takes less than about 20, 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent. In some cases, the method optionally includes visually inspecting the amount of composition remaining in the reservoir and repeating the method (e.g., repeating more than 1 - 2 times) until a sufficient dose can be delivered. In some cases, the device can be one of the devices described in US 2019 / 0091424, US2011 / 0045088 or WO 2012 / 105236, each of which is incorporated herein by reference and which disclose devices that can be used to administer formulations intranasally to a primate (e.g., a human). In some cases, the device for administering the composition disclosed herein can be a Fit-lizer TM (SNBL, LTD) intranasal dispenser device.

[0184] In some cases, the pharmaceutical composition may be provided in a device configured for such administration to the human subject. In some cases, the device may not need to be filled or may be a pre-filled device. In some cases, the reservoir containing the pharmaceutical composition in the device may be free of metal or glass. In some cases, the device may be free of metal or glass. In some cases, the administration takes less than about 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent. In some cases, the pharmaceutical composition may be a single unit dose. In some cases, the device may be actuated with one hand. In some cases, the device may be stored at about 20°C to about 25°C and about 60% relative humidity for about twelve months or less before actuation of the device. In some cases, the device may be adapted to deliver at least about 85% (e.g., about 90%, 95%, 98% or 100%) of the composition into the nostrils of the subject after actuation of the manual air pump once, twice or three times, e.g., about 90 - 95% or more in a single spray delivery. In some cases, at least about 90% of the composition may be delivered into the nostrils of the subject after actuation of the manual air pump once, twice or three times.

[0185] In some cases, the devices described herein may include at least four components, e.g., a nozzle, a holder, a lift valve and a pump. In some cases, the composition may be introduced into the nozzle of the device, which may serve as a reservoir. In some cases, the nozzle may be coupled to the pump. In some cases, the devices described herein may provide complete delivery of the composition and minimal composition remaining in the device after actuation of the device. In certain cases, the lift valve may be adapted to regulate the airflow from the pump to the nozzle upon actuation of the device. In some cases, the lift valve may be adapted to prevent the composition from moving from the reservoir upstream of the device into the pump of the device. In some cases, the lift valve may include a slit (channel or groove) which may be used to create a vortex in the reservoir for effective delivery of the composition. In some cases, the groove in the lift valve may be positioned to allow laminar air flow in the reservoir. In some cases, the groove in the lift valve may be positioned to create a swirling air flow in the reservoir upon actuation of the pump.

[0186] In some cases, the present disclosure provides a device for administering a composition disclosed herein, the device can include: a nozzle having a reservoir disposed therein, a lift valve at least partially mounted in the reservoir, a holder that is hollow and for fixing the lift valve, and a manual air pump (e.g., operatively connected to the upstream end of the nozzle and the downstream end of the holder), wherein the lift valve can have one or more contact points with the holder. In some cases, one or more of the contact points are one or more internal ribs. In some cases, the holder can have an internal circumferential groove based on the upstream end of the holder. In some cases, the edge of the circumferential groove of the holder can contact one or more contact points of the lift valve. In some cases, the holder fixes the lift valve. In some cases, when the device is actuated, a portion of the air from the pump flows along the circumferential groove into the holder and through the surface grooves of the holder to create a vortex in the reservoir. In some cases, one or more air intake holes of the holder allow external air to enter the pump after the device is actuated. In some cases, the reservoir houses the composition. In some cases, the device is adapted to deliver at least about 85% (e.g., about 90%, 95%, 98% or 100%) of the composition into the nostrils of a subject after one, two or three actuations of the manual air pump, e.g., a single squeeze delivers about 90 - 95% or more. In some cases, at least about 90% of the composition can be delivered into the nostrils of a subject after one, two or three actuations of the manual air pump. In some cases, the composition can be present in an amount of about 1 to about 30 mg. In some cases, the composition can be present in an amount of about 20 mg. In some cases, the nozzle further includes a frangible tab located at the downstream end of the nozzle. In some cases, the device can be a disposable device. In some cases, the lift valve further includes a conical top portion. In some cases, the conical top portion can be connected to a first shelf, the first shelf can be connected to a first cylindrical portion. In some cases, the first cylindrical portion can be connected to a second shelf, the second shelf can be connected to a second cylindrical portion. In some cases, the lift valve can have one or more surface grooves. In some cases, the lift valve can have about 3 to about 20 surface grooves, e.g., about 8 surface grooves. In some cases, when the device is actuated, one or more surface grooves create a vortex in the reservoir. In some cases, one or more surface grooves are present on the second shelf. In some cases, the lift valve can have about 2 to about 10 internal ribs. In some cases, the lift valve can have about 3 internal ribs. In some cases, the lift valve can be at least partially located inside the reservoir. In some cases, the lift valve can be at least partially located inside the manual air pump. In some cases, the lift valve contains a cavity. In some cases, the volume of the device can be less than about 100 cm 3 . In some cases, the volume of the device can be less than about 50 cm 3 . In some cases, the volume of the device can be about 30 cm3 . In some cases, the device can have a mass of less than about 20 grams. In some cases, the device can have a mass of less than about 10 grams. In some cases, the device can have a mass of about 6 - 7 grams. In some cases, the reservoir can have an inner diameter of less than about 10 mm. In some cases, the reservoir can have an outer diameter of about 8 to about 9 mm. In some cases, the outer diameter of the reservoir can be about 8.7 to about 8.9 mm. In some cases, the upstream end of the reservoir can have a smooth surface adapted to contact the lift valve. In some cases, the lift valve can have an outer diameter of about 7 to about 8 mm, such as about 7.7 to about 7.9 mm. In some cases, the opening of the manual air pump can be wider than the outer diameter of the lift valve. In some cases, the retainer includes an outer peripheral edge that can be wider than the opening of the manual air pump. In some cases, the retainer can have two air inlets. In some cases, one or more air inlets are about 0.2 - 0.4 mm wide. In some cases, the retainer can be at least partially assembled inside the manual air pump. In some cases, the length of the part of the lift valve assembled into the nozzle parallel to the upstream - to - downstream axis can be about 5 mm to about 6 mm, such as about 5.7 mm to about 5.9 mm. In some cases, the length of the nozzle parallel to the upstream - to - downstream axis can be about 5 mm to about 40 mm. In some cases, the nozzle of the device comprises a transparent, light - colored or translucent material.

[0187] Method of Use

[0188] . In some cases, the routes of administration of the pharmaceutical compositions disclosed herein include nasal, pulmonary, buccal or sublingual administration. In some cases, a method of intranasally delivering a composition to a subject in need using the device disclosed herein includes positioning at least a portion of the nozzle of the device into the subject's nostril and actuating the manual air pump, wherein the nozzle contains the composition. In some cases, the method treats a disease or condition of the subject, such as a headache, such as a migraine. In some cases, the composition contains an active agent disclosed herein, such as dihydroergotamine or a pharmaceutically acceptable salt thereof.

[0189] In some cases, the disease or condition can include pain, hormonal imbalance, headache, amyotrophic lateral sclerosis, Parkinson's disease, stress, anxiety, nausea, vomiting, aggressive behavior, pain, neuropathic pain, insomnia, insomnia disorder, restless legs syndrome, depression, or any combination thereof. In some cases, the disease or condition can include headache. In some cases, headache can include migraine, cluster headache, hemicrania continua, chronic headache, tension headache, chronic tension headache, or any combination thereof. In some cases, the headache can be migraine. In some cases, headache can include cluster migraine, cluster headache, post-traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, refractory migraine, migraine attack (optionally a migraine attack treated starting at least 1 - 3 hours (e.g., 2 hours) after the onset of the attack), migraine attack when treated at the earliest aura sign or symptom, pediatric migraine, persistent migraine, chronic daily headache, migraine attack with allodynia, menstrual-related migraine, menstrual migraine, migraine upon awakening, or rapidly developing migraine. In some cases, the headache can be migraine with aura. In some cases, the headache can be migraine without aura. In some cases, the headache can be moderate to severe. In some cases, the headache can be acute. In some cases, the pharmaceutical composition can be administered for at least one day, two days, three days, four days, five days, six days, one week, one month, or one year. In some cases, the administration of the pharmaceutical composition can be administered 1, 2, 3, 4, 5, 6, 7, or 8 times per day. In some cases, the pharmaceutical composition can be a single unit dose. In some cases, the pharmaceutical composition can be a unit dose of about 5 mg to about 50 mg. In some cases, the unit dose of the pharmaceutical composition contains about 0.5 mg to about 25 mg of the active agent. In some cases, the subject can be a primate. In some cases, the subject can be a human. In some cases, the subject can be a monkey.

[0190] In some cases, the administration disclosed herein can be intranasal administration. In some cases, the human subject begins to experience relief of migraine symptoms (e.g., pain, photophobia, phonophobia, nausea, or any combination thereof) within about 2 hours or about 1 hour after the administration. In some cases, the human subject experiences the relief within about 45, 30, or 15 minutes after the administration. In some cases, the human subject experiences the relief for 2 to 24 hours after the administration. In some cases, the method treats or prevents headache. In some cases, the second dose or more doses of the administration can be repeated at about every 24 hours or about every 1 - 12 hours, such as 2 - 8 hours or 2 - 24 hours (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, or 23 hours) after the administration of the first dose. In some cases, the administration can be repeated at about every 2 hours, every 2 - 6 hours, every 2 - 3 hours, every 2 - 4 hours, or every 4 - 6 hours. In some cases, the administration can be repeated over a period of 1, 2, 3, 4, or 5 days. In some cases, the administration can be repeated only 1, 2, or 3 times, i.e., a total of 2, 3, or 4 doses respectively (to the same nostril, or to different / alternating nostrils, e.g., the first dose to one nostril and then 1, 2, 3, or 4 hours later, the second dose to the other nostril to treat migraine).

[0191] In some cases, the administrations disclosed herein include delivering two or more doses (e.g., 2, 3, or 4 doses) of a pharmaceutical composition to the same human subject in two or more devices (e.g., prefilled devices, or 2, 3, or 4 devices). In some cases, the two or more doses are delivered sequentially to one or both nostrils of the human subject. In some cases, two doses of the pharmaceutical composition are delivered to a human subject via two of the devices, wherein a first dose is delivered to one nostril by a first device and then a second dose is delivered to the other nostril by a second device. In some cases, the deliveries are separated by about 1 to about 10 seconds (e.g., separated by about 2, 3, 4, 5, 6, 7, 8, or 9 seconds), by about 10 to about 60 seconds (e.g., separated by about 15, 20, 25, 30, 40, or 50 seconds), by at least about 30 to about 60 seconds, by about 2 to about 10 minutes (e.g., separated by about 3, 4, 5, 6, 7, 8, or 9 minutes), by no more than 1 - 14 minutes (e.g., separated by no more than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 minutes), by up to 24 hours or by at least about: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, or 24 hours, or any combination thereof. In some cases, the deliveries are for treating cluster headache. In some cases, the two doses are delivered simultaneously to both nostrils of the human subject. In some cases, each of the devices can be prefilled with a single dose unit of the pharmaceutical composition. In some cases, the pharmaceutical composition comprises dihydroergotamine or a pharmaceutically acceptable salt thereof, such as dihydroergotamine mesylate. In some cases, the dihydroergotamine mesylate can be present in an amount of about 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7.5 mg.

[0192] In some cases, the method further comprises monitoring the vital signs of the human subject. In some cases, the vital signs can be at least one of blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation, or electrocardiogram. In some cases, the human subject performs the monitoring. In some cases, the monitoring comprises using an electronic device, such as a smart phone or a watch. In some cases, the electronic device can be portable. In some cases, the electronic device can be wearable, such as a watch.

[0193] In some cases, the present disclosure provides methods of treating a disease or condition including pain, headache, or hormonal imbalance, including intranasal (e.g., via the nasal cavity) administration of a composition comprising an active agent. In some cases, other possible mucosal administration routes include conjunctival administration, buccal administration, and sublingual administration. In some cases, buccal and sublingual administration have the advantages of being user-friendly and non-invasive and can be self-administered. In some cases, another alternative route of administration may include transdermal delivery of the active agent through the skin of the patient. In some cases, another form of administration may include intradermal injection (administered to the dermis) and subcutaneous injection (administered to the fatty layer beneath the skin). In some cases, the composition comprises an active agent, microcrystalline cellulose having an average particle size of about 100 μm or less, and optionally tribasic calcium phosphate. In some cases, the composition comprises an active agent, a microcrystalline cellulose portion having an average particle size of about 50 - 55 μm (e.g., about 50 μm) (about 10% of the total weight of the composition), a microcrystalline cellulose portion having an average particle size of about 20 μm (about 3 to about 90% of the total weight of the composition, e.g., about 8 to about 90%), and optionally a fluidizing agent. In some cases, the composition used as part of the method may further comprise an active agent disclosed herein, e.g., caffeine, e.g., anhydrous caffeine.

[0194] "Treatment" as used with the methods disclosed herein refers to the improvement, alleviation, or elimination of at least one symptom of the disorder being treated. In some cases, a method for treating a headache or pain improves, alleviates, or eliminates at least one or more symptoms. Symptoms of a headache (e.g., cluster headache, chronic daily headache, or migraine) can include pain. Symptoms can include, for example, sinus headache, sinus pain, sinus pressure, nasal congestion, runny nose, watery eyes, nausea, vomiting, photophobia, phonophobia (aversion or allergy to sounds), osmophobia (aversion to odors), dizziness, and / or allodynia. One or more symptoms can be evaluated, for example, using the following four-point severity scale: 0 = no symptoms; 1 = mild symptoms that do not interfere with normal daily activities; 2 = moderate symptoms that cause some limitation of normal activities; 3 = severe, preventing normal daily activities. Alternatively or additionally, one or more symptoms (including the four listed above) can be evaluated using a four-point functional disability scale that assesses the degree of impairment of the symptoms on the patient's ability to perform daily activities, as follows: 0 = not impaired at all; 1 = mildly impaired; 2 = moderately impaired; 3 = severely or completely impaired. In some cases, a headache or pain can have a severity greater than any one of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 on a 0-to-10 scale. In some cases, the intensity of a headache or pain (e.g., pain associated with a migraine) can be measured according to a 4-point severity scale (0 = no pain, 1 = mild, 2 = moderate, 3 = severe). In some cases, the methods for treating a headache (e.g., migraine) proposed herein reduce the severity of the headache pain (e.g., pain associated with a migraine) by at least one point on such a 4-point severity scale. In some cases, the human subject can be in a recumbent position. In some cases, the human subject can be in a supine position. In some cases, the human subject can be in a recovery position. In some cases, the human subject can be in an upright position.

[0195] In some cases, for treating a disease or condition, the total amount of the composition administered to a single nostril or both nostrils can be about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In some cases, the total amount of the composition can be administered to a single nostril. In some cases, a portion of the total amount of the composition can be administered to each nostril. In some cases, about half of the total amount of the composition can be administered to one nostril and the remaining half to the other nostril. In some cases, the total dose of the active agent administered can be about 0.5 - 6.0 mg. In some cases, the total dose of the active agent administered can be about 1.0 - 6.0 mg. In some cases, the total dose of the active agent administered can be about 2.0 - 4.0 mg. In some cases, the total dose of the active agent administered can be about 0.1 mg, about 0.5 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 4.0 mg, about 5.0 mg, about 7.5 mg, or about 10.0 mg. In some cases, the total dose can be administered to a single nostril. In some cases, a portion of the total dose can be administered to each nostril. In some cases, about half of the total dose can be administered to one nostril and the remaining half to the other nostril.

[0196] Table 1. Composition components and their weights (approximate "about").

[0197]

[0198]

[0199]

[0200] The present invention provides, including but not limited to, the following embodiments:

[0201] 1. A method of treatment or prevention, comprising administering a powdered pharmaceutical composition to a human subject, the pharmaceutical composition comprising an active agent selected from compounds having the following formula, their stereoisomers, their pharmaceutically acceptable salts, their complexes, their chelates, their hydrates, their polymorphs, and their ion pairs:

[0202]

[0203] wherein the method results in a time (T max ) of 90 minutes or longer to reach peak plasma concentration of the metabolite of the active agent in the human subject, as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography - tandem mass spectrometry, and

[0204] wherein:

[0205] R1 is hydrogen, (C1-C4) alkyl, or (C1-C4) perfluoroalkyl;

[0206] Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ;

[0207] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

[0208] R5, R6, and R7 are independently hydrogen, (C1-C3) alkyl, or (C1-C3) perfluoroalkyl;

[0209] R8 and R9 are independently hydrogen, (C1-C4) alkyl, or benzyl;

[0210] R 10 R 11 R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, —CO2R 108 or —CONR 109 R 110 ;

[0211] R 13 is hydrogen or halogen;

[0212] R 101 -R 110 is independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl, or heteroaralkyl;

[0213] k is 0, 1, or 2; and

[0214] n is 0, 1, 2, or 3.

[0215] 2. The method according to embodiment 1, wherein the T max is at least about 2 hours.

[0216] 3. The method according to embodiment 1 or 2, wherein the peak plasma concentration (C max ) of the metabolite is less than about 250 pg / ml.

[0217] 4. The method according to embodiment 3, wherein the C maxLess than about 150 pg / ml.

[0218] 5. The method according to any one of embodiments 1-4, wherein the peak plasma concentration (C max ) of the metabolite is less than about 15% of the C max of the active agent measured after said administration to said human subject.

[0219] 6. The method according to embodiment 5, wherein the peak plasma concentration (C max ) of the metabolite is less than about 10% of the C max of the active agent measured after said administration to said human subject.

[0220] 7. The method according to any one of embodiments 1-6, wherein the plasma concentration of the metabolite is less than about 5% of the plasma concentration of the active agent measured within about 30 minutes after said administration to said human subject.

[0221] 8. The method according to any one of embodiments 1-7, wherein the plasma concentration of the metabolite is less than about 2% of the plasma concentration of the active agent measured within about 15 minutes after said administration to said human subject.

[0222] 9. The method according to any one of embodiments 1-8, wherein the reduced presence of the metabolite results in a reduced pharmacological effect of the metabolite in the human subject.

[0223] 10. The method according to embodiment 9, wherein the reduced pharmacological effect is less than 20% of the binding activity to adrenergic, dopaminergic, or 5-HT receptors or receptor subtypes measured by radioligand competitive binding assay.

[0224] 11. The method according to embodiment 9 or 10, wherein the reduced pharmacological effect is manifested as a reduced transcutaneous O2 partial pressure measured at the dorsum of the foot, a reduced venous constriction as determined using a venous occlusion mercury strain gauge, a reduced diameter or compliance of the smaller brachial artery wall, a reduced human coronary, meningeal artery, or saphenous vein constriction, a reduced diameter of the smaller vein at a fixed occlusion pressure, a change in peripheral circulation volume, or any combination thereof.

[0225] 12. A method of treatment or prophylaxis, comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from compounds having the following formula, their stereoisomers, their pharmaceutically acceptable salts, their complexes, their chelates, their hydrates, their polymorphs, and their ion pairs:

[0226]

[0227] Formula (I),

[0228] wherein the method produces in the human subject:

[0229] 1) about 1 to about 2.5 ng / ml of C max , or a plasma concentration of at least 1 ng / mL is produced in about 10 minutes or less,

[0230] 2) a T of about 30 minutes or less max , and

[0231] 3) an AUC value selected from: an AUC of about 500 to about 1000 h*pg / ml 0-30分钟 , an AUC of about 1000 to about 2000 h*pg / ml 0-60分钟 , an AUC of about 2000 to about 3000 h*pg / ml 0-120分钟 and an AUC of about 10000 to about 12000 h*pg / ml 0-inf ,

[0232] as determined by measuring the human plasma concentration of the active agent by automated extraction liquid chromatography - tandem mass spectrometry, and

[0233] wherein:

[0234] R1 is hydrogen, (C1 - C4) alkyl or (C1 - C4) perfluoroalkyl;

[0235] each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ;

[0236] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy or methoxy;

[0237] R5, R6 and R7 are independently hydrogen, (C1 - C3) alkyl or (C1 - C3) perfluoroalkyl;

[0238] R8 and R9 are independently hydrogen, (C1 - C4) alkyl or benzyl;

[0239] R 10 、R 11 、R 12 and R 14Independently hydrogen, halogen, -OH, (C1-C4)alkyl, —CO2R 108 or —CONR 109 R 110 ;

[0240] R 13 is hydrogen or halogen;

[0241] R 101 -R 110 Independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl;

[0242] k is 0, 1 or 2; and

[0243] n is 0, 1, 2 or 3.

[0244] 13. The method according to embodiment 12, further providing a half-life of said active agent of from about 12 hours to about 13 hours.

[0245] 14. The method according to embodiment 12 or 13, wherein the method produces a time to peak plasma concentration (T max ) of 90 minutes or longer for the metabolite of the active agent in the human subject, as determined by measuring the human plasma concentration of the metabolite by automated extraction liquid chromatography-tandem mass spectrometry.

[0246] 15. A method of treatment or prophylaxis comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from a compound having the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs and its ion pairs:

[0247]

[0248] wherein after said administration to the human subject, the method produces an apparent clearance (CL / F) value of the active agent of from about 100 L / hour to about 1000 L / hour, and

[0249] wherein:

[0250] R1 is hydrogen, (C1-C4)alkyl or (C1-C4)perfluoroalkyl;

[0251] Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R105 、 —CO2R 106 or —CO2R 107 ;

[0252] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy or methoxy;

[0253] R5, R6 and R7 are independently hydrogen, (C1-C3)alkyl or (C1-C3)perfluoroalkyl;

[0254] R8 and R9 are independently hydrogen, (C1-C4)alkyl or benzyl;

[0255] R 10 、R 11 、R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4)alkyl, —CO2R 108 or —CONR 109 R 110 ;

[0256] R 13 is hydrogen or halogen;

[0257] R 101 -R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl;

[0258] k is 0, 1 or 2; and

[0259] n is 0, 1, 2 or 3.

[0260] 16. The method according to embodiment 15, wherein the CL / F value of the active agent is about 540 L / hour.

[0261] 17. A method of treatment or prophylaxis comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from compounds of the formula below, their stereoisomers, pharmaceutically acceptable salts thereof, their complexes, their chelates, their hydrates, their polymorphs and their ion pairs:

[0262]

[0263] wherein the method produces a visual analogue scale score for measuring nasal symptoms of less than about 20 when measured within 24 hours after said administration to the human subject,

[0264] wherein the visual analogue scale score is measured on a scale of 0 (no symptoms) to 100 (the worst imaginable) for each of the following nasal symptoms: nasal discomfort, nasal burning, nasal itching, nasal pain, nasal congestion, dysgeusia, rhinorrhea, and sneezing, and

[0265] wherein:

[0266] R1 is hydrogen, (C1-C4)alkyl, or (C1-C4)perfluoroalkyl;

[0267] each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl, —NO2, —N3, —OH, —S(O) k R 100 、—OR 101 、—NR 102 R 103 、—CONR 104 R 105 、—CO2R 106 or —CO2R 107 ;

[0268] R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy;

[0269] R5, R6, and R7 are independently hydrogen, (C1-C3)alkyl, or (C1-C3)perfluoroalkyl;

[0270] R8 and R9 are independently hydrogen, (C1-C4)alkyl, or benzyl;

[0271] R 10 、R 11 、R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4)alkyl, —CO2R 108 or —CONR 109 R 110 ;

[0272] R 13 is hydrogen or halogen;

[0273] R 101 -R 110 are independently hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl, or heteroaralkyl;

[0274] k is 0, 1, or 2; and

[0275] n is 0, 1, 2, or 3.

[0276] 18. The method according to embodiment 17, wherein the visual analogue scale score is measured about 4 hours after the administration.

[0277] 19. The method according to embodiment 17 or 18, wherein the visual analogue scale score is measured about 1 hour after the administration.

[0278] 20. The method according to any one of embodiments 17-19, wherein the visual analogue scale score is measured about 15 minutes after the administration.

[0279] 21. The method according to any one of embodiments 17-20, wherein the visual analogue scale score is measured about 5 minutes after the administration.

[0280] 22. The method according to any one of embodiments 17-21, wherein the visual analogue scale score is less than about 10.

[0281] 23. The method according to embodiment 22, wherein the visual analogue scale score is less than about 5.

[0282] 24. The method according to embodiment 23, wherein the visual analogue scale score is 0.

[0283] 25. The method according to any one of embodiments 1-24, wherein both R3 and R4 are hydrogen.

[0284] 26. The method according to embodiment 25, wherein the active agent comprises dihydroergotamine or a pharmaceutically acceptable salt thereof.

[0285] 27. The method according to any one of embodiments 1-11 and 14, wherein the metabolite is of formula (I), and wherein R 12 is -OH.

[0286] 28. The method according to embodiment 27, wherein the metabolite is 8'-hydroxydihydroergotamine.

[0287] 29. The method according to any one of embodiments 1-28, wherein the pharmaceutical composition comprises:

[0288] about 1 mg to about 6 mg of the active agent,

[0289] about 12 mg to about 19 mg of microcrystalline cellulose,

[0290] about 0.1 mg to about 0.6 mg of a thickening agent, and

[0291] about 6 mg to about 7 mg of a sugar alcohol.

[0292] 30. The method according to embodiment 29, wherein the thickening agent is present in an amount of about 10% by weight of the active agent.

[0293] 31. The method according to embodiment 29 or 30, wherein the thickening agent comprises hydroxypropyl methylcellulose.

[0294] 32. The method according to any one of embodiments 29 - 31, wherein the thickening agent comprises hydroxypropyl cellulose.

[0295] 33. The method according to any one of embodiments 29 - 32, wherein the thickening agent comprises carboxymethyl cellulose.

[0296] 34. The method according to any one of embodiments 29 - 33, wherein the thickening agent is present in the spray - dried particle dispersion.

[0297] 35. The method according to any one of embodiments 29 - 34, wherein the sugar alcohol comprises mannitol.

[0298] 36. The method according to any one of embodiments 29 - 35, wherein the sugar alcohol comprises sorbitol.

[0299] 37. The method according to any one of embodiments 29 - 36, wherein the sugar alcohol comprises galactitol.

[0300] 38. The method according to any one of embodiments 29 - 37, wherein the active agent is present in the spray - dried particle dispersion.

[0301] 39. The method according to any one of embodiments 29 - 38, wherein about 3 mg to about 13 mg of the microcrystalline cellulose is present in the spray - dried particle dispersion.

[0302] 40. The method according to any one of embodiments 29 - 39, wherein the microcrystalline cellulose is at least partially coated with the active agent.

[0303] 41. The method according to any one of embodiments 1 - 40, wherein the active agent is in an amorphous form.

[0304] 42. The method according to any one of embodiments 1 - 41, wherein the active agent is dihydroergotamine or a pharmaceutically acceptable salt thereof.

[0305] 43. The method according to embodiment 42, wherein the pharmaceutical composition comprises the pharmaceutically acceptable salt of dihydroergotamine, namely dihydroergotamine mesylate.

[0306] 44. The method according to any one of embodiments 12 - 43, wherein the pharmaceutical composition is a powdered pharmaceutical composition.

[0307] 45. The method according to any one of embodiments 1 - 44, wherein the administration is intranasal administration.

[0308] 46. The method according to any one of embodiments 1 - 45, wherein the human subject experiences relief of migraine symptoms or cranial autonomic symptoms within about 2 hours after the administration.

[0309] 47. The method according to embodiment 46, wherein the migraine symptoms include pain, photophobia, phonophobia, nausea, or any combination thereof.

[0310] 48. The method according to embodiment 46 or 47, wherein the human subject begins to experience the relief within about 45 minutes, about 30 minutes, or less after the administration.

[0311] 49. The method according to any one of embodiments 46 - 48, wherein the human subject experiences the relief for up to about 2 to 96 hours after the administration.

[0312] 50. The method according to any one of embodiments 1 - 49, wherein the human subject is in a recumbent position.

[0313] 51. The method according to any one of embodiments 1 - 49, wherein the human subject is in a supine position.

[0314] 52. The method according to any one of embodiments 1 - 49, wherein the human subject is in a recovery position.

[0315] 53. The method according to any one of embodiments 1 - 49, wherein the human subject is in an upright position.

[0316] 54. The method according to any one of embodiments 1 - 53, wherein the method treats or prevents headache.

[0317] 55. The method according to embodiment 54, wherein the headache includes migraine.

[0318] 56. The method according to embodiment 54, wherein the headache includes migraine with aura, migraine without aura, cluster headache, post - traumatic headache, hemiplegic migraine, basilar migraine, episodic migraine, chronic migraine, intractable migraine, migraine attack (optionally a migraine attack treated at least 1 - 24 hours after the onset of the attack), a migraine attack when treated at the earliest aura sign or symptom, pediatric migraine, persistent migraine, chronic daily headache, migraine attack with allodynia, menstrual - related migraine, menstrual migraine, migraine upon awakening, rapidly - developing migraine, or any combination thereof.

[0319] 57. According to the method of any one of embodiments 1-56, wherein during the time period from T 0分钟 to T 15分钟 , the administration provides a dC / dT value that is at least about 10% higher than that of a dihydroergotamine liquid dosage form.

[0320] 58. According to the method of embodiment 57, wherein during the time period from T 0分钟 to T 15分钟 , the administration provides a dC / dT value of at least about 1000 (pg / mL) / hour.

[0321] 59. According to the method of any one of embodiments 1-58, wherein the administration comprises delivering two or more doses of the pharmaceutical composition to the human subject.

[0322] 60. According to the method of any one of embodiments 1-59, wherein the pharmaceutical composition is provided in a device configured for administering the same to the human subject.

[0323] 61. According to the method of embodiment 60, wherein the device does not require filling or is a pre-filled device.

[0324] 62. According to the method of embodiment 60 or 61, wherein the device is actuatable with one hand.

[0325] 63. According to the method of any one of embodiments 60-62, wherein the device is stored at about 20°C to about 25°C and about 60% relative humidity for about twelve months or less before actuation.

[0326] 64. According to the method of any one of embodiments 60-63, wherein the reservoir containing the pharmaceutical composition in the device does not contain metal or glass.

[0327] 65. According to the method of embodiment 64, wherein the device does not contain metal or glass.

[0328] 66. According to the method of any one of embodiments 60-65, wherein the administration comprises delivering two or more doses of the pharmaceutical composition to the human subject in two or more of the devices.

[0329] 67. According to the method of embodiment 66, wherein each of the devices contains a single unit dose of the pharmaceutical composition.

[0330] 68. The method according to any one of embodiments 60 - 65, wherein the administration comprises delivering two or more doses of the pharmaceutical composition to the human subject in one of the devices.

[0331] 69. The method according to any one of embodiments 66 - 68, wherein the two or more doses are successively delivered to one or both nostrils of the human subject.

[0332] 70. The method according to any one of embodiments 66 - 69, wherein the first dose of the two or more doses is immediately sequentially administered to two different nostrils of the human subject.

[0333] 71. The method according to embodiment 70, wherein the sequential administrations are spaced about 15 to about 60 seconds apart.

[0334] 72. The method according to any one of embodiments 66 - 71, wherein the first dose and the second dose of the two or more doses are spaced about 2 hours or more apart.

[0335] 73. The method according to any one of embodiments 1 - 72, wherein the administration takes less than about: 15, 10, 5, 4, 3, 2, 1, 0.5 or 0.25 minutes to deliver an effective dose of the active agent.

[0336] 74. The method according to any one of embodiments 1 - 73, wherein at least about 80% of the active agent is stable at room temperature, outside the container at one atmosphere pressure and a relative humidity of less than about 50%, in a light - resistant airtight container, for a storage period of at least about 60 days to about 3 years, as measured by liquid chromatography.

[0337] 75. The method according to embodiment 74, wherein the storage period is at least about 1 year.

[0338] 76. The method according to any one of embodiments 1 - 75, wherein the administration is repeated about every 2 - 8 hours.

[0339] 77. The method according to any one of embodiments 1 - 75, wherein the administration is repeated about every 2 - 6 hours.

[0340] 78. The method according to any one of embodiments 1 - 77, wherein the administration is repeated over a period of 1, 2, 3, 4 or 5 days.

[0341] 79. The method according to any one of embodiments 1 - 78, wherein the method further comprises monitoring the vital signs of the human subject.

[0342] 80. The method according to embodiment 79, wherein the vital sign is at least one of blood pressure, heart rate, body temperature, respiratory rate, oxygen saturation, or electrocardiogram.

[0343] 81. The method according to embodiment 79 or 80, wherein the human subject performs the monitoring.

[0344] 82. The method according to any one of embodiments 79 - 81, wherein the monitoring includes using an electronic device.

[0345] 83. The method according to embodiment 82, wherein the electronic device is portable.

[0346] 84. The method according to embodiment 82 or 83, wherein the electronic device is wearable.

[0347] 85. A pharmaceutical composition from Table 1.

[0348] 86. A delivery device comprising the pharmaceutical composition from Table 1.

[0349] Examples

[0350] Example 1 - Dihydroergotamine Mesylate Intranasal Powder Formulation and Device Combination

[0351] The drug - device combination product consists of a DHE mesylate powder formulation pre - filled into a disposable delivery device for intranasal administration. The intranasal powder formulation of dihydroergotamine mesylate is the drug component of the combination, and the intranasal device for dihydroergotamine mesylate is the device component of the combination.

[0352] Powder Formulation

[0353] The powder formulation is prepared using about 0.5 to 20 mg of one or more microcrystalline celluloses (MCC), about 1 - 15 mg of one or more sugar alcohols, and 0.05 - 5 mg of a thickening agent. The entire formulation is not too large for comfortable administration (e.g., < 50 mg). The particle size delivered from the device is large enough to minimize potential lung deposition.

[0354] The intranasal powder formulation of dihydroergotamine mesylate is a combination of dihydroergotamine mesylate, one or more sugar alcohols, and MCC.

[0355] Additional powder formulations are made at strengths of 4.5 mg of dihydroergotamine mesylate (3.9 mg of dihydroergotamine) and 6 mg of dihydroergotamine mesylate (5.2 mg of dihydroergotamine).

[0356] Device

[0357] Dihydroergotamine mesylate intranasal powder devices are air-driven and manually actuated. They are designed for intranasal delivery of powder formulations, such as dihydroergotamine mesylate intranasal powder formulations. The drug-device combination product may contain pre-filled single unit doses of dihydroergotamine mesylate intranasal powder formulations. The patient does not need to fill the device, and the device may be disposable. The instructions for use of the device are as Figure 3 shown.

[0358] Drawings of suitable devices are as Figure 1A shown, with 5 components: a cap, a nozzle, a lift valve, a holder, and a pump as Figure 1B shown. The powder formulation is contained in a drug reservoir located in the nozzle. The pull tab on the nozzle is broken off immediately before administration. The patient inserts the nozzle into one nostril and squeezes the pump, forcing air through the nozzle and expelling the powder formulation.

[0359] Figure 2A FIG. shows a cross-sectional view of a disposable intranasal delivery device. The intranasal delivery device (100) may include an air source, which may be a flexible vial (102). The flexible vial may be used as a manual air pump (104). The flexible vial may include an inlet (not shown) and an outlet (106). Optionally, the flexible vial does not need to include an inlet. The flexible vial may include a throat (108) located at the top of the flexible vial, and the top of the flexible vial has a diameter narrower than the bottom of the flexible vial (110). The throat (108) may contain an external thread (112) for connecting the nozzle (114). A one-way valve (116) may be located on the surface of the throat (108) of the flexible vial (102) and block the outlet (106) when the device is not actuated (e.g., when the manual air pump is not compressed). Placing the one-way valve (116) on the surface of the throat (108) may prevent the powdered therapeutic composition (M) from entering the flexible vial (102) when the device is not actuated. The one-way valve (116) may include a top portion (118), a first cylindrical portion (120), a first shelf (122), a second cylindrical portion (124), and a second shelf (126). The surface of the first shelf may have one or more slits (128). When the manual air pump (104) is compressed, the one or more slits (128) may allow air or gas to flow from the flexible vial (102) to the nozzle (114).

[0360] The nasal device (100) may further include a nozzle (114), which may include a nozzle tube (130) that may be inserted or partially inserted into the nasal cavity or nostril of a subject. The nozzle (114) may further include a nozzle orifice (132), a removable or frangible cap (134), and a reservoir (138) for a powdered therapeutic agent. The reservoir for the powdered therapeutic agent may contain a powdered therapeutic agent (M). The nozzle (114) may include a base (140), which may include an internal thread (142) for connection to a throat (108) of the flexible vial (102). The internal thread of the nozzle base may mate with the external thread of the vial throat.

[0361] Figure 2BThe cross-sectional view of a disposable intranasal delivery device is illustrated. The intranasal delivery device (900) may include an air source, which may be a flexible vial (902). The flexible vial may be used as a manual air pump (904). The flexible vial may include an outflow port (906) and not include an inflow port when a removable or frangible cap (934) has not been removed. The inflow port may include a nozzle hole (932), which may serve as an inflow port when the removable or frangible cap (934) has been removed. The flexible vial may include a throat (908) located at the top of the flexible vial, and the top of the flexible vial has a diameter narrower than the bottom of the flexible vial (910). The throat (908) may contain an external thread (912) for connecting the nozzle (914). A one-way valve (916) may be located on the surface of the throat (908) of the flexible vial (902) and block the outflow port (906) when the device is not actuated (e.g., when the manual air pump is not compressed). Placing the one-way valve (916) on the surface of the throat (908) can prevent the powdered therapeutic composition (M) from entering the flexible vial (902) when the device is not actuated. The one-way valve (916) may include an inner inlet portion, a valve cavity (946), a top portion (918), a first cylindrical portion (920), a first shelf (922), a second cylindrical portion (924), and a second shelf (926). In some cases, the top portion includes the inner inlet portion. In some cases, the valve does not include a top portion. The surface of the first shelf may have one or more slits (928). When the manual air pump (904) is compressed, the one or more slits (928) may allow air or gas to flow from the flexible vial (902) to the nozzle (914). The intranasal device (900) may also include a nozzle (914), which may include a nozzle tube (930) that may be inserted or partially inserted into the nasal cavity or nostril of a subject. The nozzle (914) may also include a removable or frangible cap (934), a nozzle hole (932) (which may act as an inflow port when the removable or frangible cap is removed), and a reservoir (938) for the powdered therapeutic formulation. The reservoir for the powdered therapeutic formulation may contain the powdered therapeutic composition (M). The nozzle (914) may include a base (940), which may include an internal thread (942) for connecting to the throat (908) of the flexible vial (902). The internal thread of the nozzle base may mate with the external thread of the vial throat.

[0362] Figure 2CIllustrated is another intranasal nebulizer device that can be used to deliver the pharmaceutical compositions described herein. The device (1) includes a deformable volume (2) and an inlet port (3b), which includes a manual air pump (3). The device (1) also includes a valve assembly (5), which includes a check valve (11) (which includes an outlet port (3a), a valve disc (15), a spring (14), a flow channel (7), and a lift valve (16) (which also includes a deflecting surface (17)). The lift valve (16) is disposed within the flow channel (7) and the throat (12), and the throat (12) communicates with the diffuser (13). The valve assembly also includes one or more engagement holes (5a) for attachment to the nozzle (6). The device also includes a nozzle (6), which includes a nozzle tube (4), which is adapted to be inserted or partially inserted into the nasal cavity or nostril of a subject. The nozzle also includes a flow restrictor (21), a frangible cap (22), and a powder formulation reservoir (23). The powder pharmaceutical reservoir contains a powdered therapeutic formulation (M). The nozzle (6) also includes one or more ratchets (6a) for attachment to the valve assembly (5). The devices disclosed herein can have any suitable size for administering the therapeutic composition contained therein. For example, the height of the device can be about 1-6 inches, such as about 1 inch, about 1.5 inches, about 2 inches, about 2.5 inches, about 3 inches, about 3.5 inches, about 4 inches, about 4.5 inches, about 5 inches, about 5.5 inches, or about 6 inches. The size of the device can be selected based on the amount of therapeutic composition to be delivered, ease of use, portability, or ease of manufacture.

[0363] Example 2 - Method for Preparing Intranasal Powder of Dihydroergotamine Mesylate

[0364] Method 1. DHE mesylate exists in crystalline or amorphous form (1.5, 3, and 6 mg DHE mesylate strengths). The formulation contains a thickening agent (about 20% to about 25% w / w of DHE). The DHE powder formulation is prepared by grinding DHE mesylate, the thickening agent, one or more sugar alcohols, and one or more microcrystalline celluloses in a mortar. The thickening agent can be carboxymethyl cellulose, polyvinylpyrrolidone, or hydroxypropylmethyl cellulose. The sugar alcohol can be trehalose, galactitol, mannitol, sorbitol, or any combination thereof.

[0365] Method 2. DHE mesylate exists in crystalline or amorphous form (1.5, 3, and 6 mg DHE mesylate strengths). The formulation contains a thickening agent (about 20% to about 25% w / w of DHE). The DHE powder formulation is prepared by fluidized bed granulation of DHE mesylate, the thickening agent, one or more sugar alcohols, and one or more microcrystalline celluloses. The thickening agent can be carboxymethyl cellulose, polyvinylpyrrolidone, or hydroxypropylmethyl cellulose. The sugar alcohol can be trehalose, galactitol, mannitol, sorbitol, or any combination thereof.

[0366] Method 3. DHE mesylate exists in crystalline or amorphous form (1.5, 3, and 6 mg DHE mesylate strengths). There is a thin coating of DHE on MCC. The formulation contains a thickening agent (about 10% to about 15% w / w of DHE). DHE mesylate, the thickening agent, one or more sugar alcohols, and one or more microcrystalline celluloses (wherein at least one has an average particle size of about 23 microns) are added to a hydroxy-containing compound for a spray drying process to obtain a spray-dried dispersion. Then the spray-dried dispersion is mixed and blended with MCC and one or more sugar alcohols to obtain a DHE powder formulation. The thickening agent can be carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl methyl cellulose, or any combination thereof. The sugar alcohol can be trehalose, galactitol, sorbitol, mannitol, or any combination thereof.

[0367] Method 4. DHE mesylate exists in crystalline or amorphous form (1.5, 3, and 6 mg DHE mesylate strengths). The formulation contains a thickening agent (about 5% to about 25% w / w of DHE). DHE mesylate, the thickening agent, one or more sugar alcohols, and one or more microcrystalline celluloses are mixed for about 10 - 60 minutes with vigorous shaking, optionally ground in a mortar, and sieved through a sieve to obtain a DHE powder formulation with an average particle size less than 100 μm. The thickening agent can be carboxymethyl cellulose, polyvinylpyrrolidone, or hydroxypropyl methyl cellulose. The sugar alcohol can be trehalose, galactitol, mannitol, sorbitol, or any combination thereof.

[0368] Example 3 - Characterization of Intranasal Powder of Dihydroergotamine Mesylate

[0369] In vitro delivery characterization using the pre-filled disposable device herein showed that the average delivery dose was about 96% with a relative standard deviation of 3.5%. Aerodynamic particle size analysis showed that about 1.3% of the delivered dose of DHE particles had an aerodynamic particle size less than 5 μm. Even when the actuation speed was reduced to about 50% of the optimal value, the powder formulation still showed delivery of more than about 95% of the target amount.

[0370] Example 4 - Phase 1 Clinical Study of the Formulation and Device

[0371] A randomized, open-label, two-part, phase 3 crossover study was conducted to evaluate the pharmacokinetics, bioavailability, dose proportionality, safety, and tolerability of single doses of dihydroergotamine mesylate intranasal powder, dihydroergotamine mesylate intramuscular injection, and dihydroergotamine mesylate intranasal spray in healthy adult subjects. This was a single-center, single-dose, open-label, two-part, phase 3 crossover (within each part), pharmacokinetic and safety study. Approximately thirty (30) healthy subjects (18 to 50 years of age) received study medication. In Part 1, approximately 15 subjects received three escalating doses of dihydroergotamine mesylate intranasal powder in a phase 3 crossover design. One dose strength of dihydroergotamine mesylate intranasal powder was selected for Part 2, in which approximately 15 subjects received dihydroergotamine mesylate intranasal powder, intranasal DHE spray, and intramuscular DHE injection in a random order. The treatment sequence is shown in Table 2. The total duration of the study was approximately 4 weeks.

[0372] Table 2. Randomization Schedule

[0373]

[0374] Treatment A = 1.5 mg DHE mesylate intranasal powder

[0375] Treatment B = 3.0 mg DHE mesylate intranasal powder

[0376] Treatment C = 6.0 mg DHE mesylate intranasal powder

[0377] Treatment D = 1 mg DHE intramuscular injection (D.H.E. or generic)

[0378] Treatment E = 2 mg DHE liquid intranasal spray ( or generic)

[0379] *One dose strength (A or B or C) was selected after Part 1

[0380] A sufficient number of volunteers were screened to enroll approximately 30 subjects in the study. Subjects who withdrew from the study, either actively or passively, after dosing were not replaced. Subjects were selected from the non-institutionalized members of the general community. The screening period was no more than 28 days. The treatment and follow-up period was approximately 22 days.

[0381] During each treatment period, subjects stay at the clinical research unit for approximately 48 hours. Subjects are admitted to the clinical research unit one day before drug administration in each treatment period and stay at the clinical research unit until approximately 24 hours after drug administration. The study drug is administered 60 minutes after a light standardized breakfast in the morning. Blood samples for pharmacokinetic analysis are collected at the following times (the allowed time deviation is in parentheses):

[0382] 0 (before drug administration)

[0383] 5, 10, 15 minutes (±2 minutes each),

[0384] 30, 45, 60, 90 minutes (±5 minutes each),

[0385] 2, 4, 6, 8 hours (±10 minutes each),

[0386] 12, 24, 36, and 48 hours after drug administration in each treatment period (±30 minutes each).

[0387] A standardized lunch is provided approximately 4 hours after drug administration. A standardized dinner is provided approximately 9 - 10 hours after drug administration, and a snack is provided approximately 12 - 13 hours after drug administration. There is a minimum washout period of 7 (+1) days between each consecutive study drug administration. The duration of the washout period is measured from the time of study drug administration in the previous period to the dosing day in the next period. Safety follow-up is conducted 7 ± 2 days after the last treatment period.

[0388] Part 1 of the study is to select the dose levels of dihydroergotamine mesylate nasal powder for further evaluation in Part 2. The secondary objectives of this study are to describe the pharmacokinetics of dihydroergotamine after single - dose administration of 1.5 mg, 3.0 mg, and 6.0 mg of dihydroergotamine mesylate nasal powder, to describe the pharmacokinetics of 8'-hydroxy - dihydroergotamine (8'OH - DHE) after single - dose administration of 1.5 mg, 3.0 mg, and 6.0 mg of dihydroergotamine mesylate nasal powder, and to evaluate the safety and tolerability of single - dose 1.5 mg, 3.0 mg, and 6.0 mg of dihydroergotamine mesylate nasal powder.

[0389] 4.1 Treatment groups

[0390] Part 1, Phases 1, 2, and 3: DHE and 8'OH - DHE concentration - time data

[0391] In Periods 1 and 2, 15 subjects received a single intranasal inhalation dose of dihydroergotamine mesylate intranasal powder. The dose level in Period 1 was 1.5 mg of dihydroergotamine mesylate intranasal powder, and all subjects returned for Period 2, where all subjects received a dose of 3.0 mg of dihydroergotamine mesylate intranasal powder. In Period 3, 14 subjects received a single intranasal inhalation dose of dihydroergotamine mesylate intranasal powder at a dose of 6.0 mg.

[0392] 4.2 Measured Parameters

[0393] Blood samples were planned to be collected before dosing and at 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours after administration. Using WinNonlin version 6.3 or higher was used to analyze the plasma concentration-time data with calibrated sampling times for calculating the standard pharmacokinetic (PK) parameters after intranasal administration. The concentration-time data for the 1.5 mg and 3.0 mg dose levels were available up to 48 hours, and the data for the 6.0 mg dose were available up to 24 hours.

[0394] 4.3 Administration Protocol

[0395] Intranasal Powder

[0396] The administration protocol is as Figure 3 shown. It is recommended that the user clean his / her nose by blowing it thoroughly before administration. Open the foil package and remove the delivery device from the package. Remove the protective cap from the device. While holding the device in one hand (e.g., by grasping the base of the nozzle), hold the tab with the other hand and bend it back and forth to break it off. Insert the nozzle into one nostril as comfortably as possible while avoiding squeezing the pump. While inhaling through the nose, squeeze the pump quickly and completely (e.g., between the fingers and thumb) until the sides of the pump are pressed together or the fingers touch. Optionally, repeat the squeezing step two more times, squeezing a total of three times into each nostril.

[0397] Liquid Intranasal Spray

[0398] The drug vial and pump need to be assembled before use. For example, for MIGRANAL. The full dose administration takes more than 15 minutes, for example, about 20 minutes. Pull the tab backward to bend the cap. Remove the cap and the metal seal completely by a circular motion as a whole. Remove the rubber stopper while keeping the vial upright. Then put the vial aside. Remove the plastic cap from the bottom of the pump unit. Insert the spray pump into the vial and turn clockwise until firmly fixed. Remove the cap from the spray unit. Before use, pump the nasal spray four times while holding the vial away from anyone's face. Insert the spray unit into each nostril and spray once each time. After fifteen minutes, spray each nostril again and dispose of the nasal spray pump with the vial.

[0399] Intramuscular liquid injection

[0400] Thoroughly wash the user's hands with soap and water. Check the dose of the drug. Check the ampoule to see if there is any liquid at the top of the ampoule. If there is, flick it with a finger to send all the liquid to the bottom of the ampoule. Hold the bottom of the ampoule with one hand. Clean the neck of the ampoule with an alcohol swab with the other hand. Then place the alcohol swab against the neck of the ampoule and break the ampoule with the pressure of the thumb. Administer subcutaneously to the middle of the patient's thigh, well above the knee.

[0401] 4.4 Evaluation criteria

[0402] Pharmacokinetic endpoints

[0403] 1. Area under the concentration-time curve (AUC0-∞; AUC0-30 minutes; AUC0-60 minutes; AUC0-2 hours; AUC0-24 hours; AUC0-48 hours)

[0404] 2. Observed maximum plasma concentration (Cmax)

[0405] 3. Time to reach Cmax (Tmax)

[0406] 4. Terminal phase half-life (T1 / 2)

[0407] 5. Terminal rate constant (kel)

[0408] 6. Extrapolated residual area ((1 - AUC0-t / AUC0-∞) * 100)

[0409] Safety

[0410] The following evaluations and measurements are performed regularly before and / or up to 48 hours after administration:

[0411] 1. Physical examination

[0412] 2. Vital signs and weight

[0413] 3. 12 - lead ECG

[0414] 4. Blood tests for hematological and biochemical analysis

[0415] 5. Urinalysis

[0416] 6. Adverse events (AE)

[0417] 7. Review of concomitant medications

[0418] 8. Subjective assessment of nasal irritation using a questionnaire, completed by the subjects

[0419] 9. Objective assessment of nasal irritation using a structured examination of nasal and mucosal integrity

[0420] Pharmacokinetics

[0421] The following pharmacokinetic parameters of DHE and its major metabolite 8'-hydroxy - dihydroergotamine (8'OH - DHE) were calculated using standard non - compartmental analysis:

[0422] 1. Area under the concentration - time curve (partial AUCs, AUC0 - ∞, and AUC0 - t)

[0423] 2. Observed maximum plasma concentration (Cmax)

[0424] 3. Time to reach Cmax (Tmax)

[0425] 4. Terminal - phase half - life (T1 / 2)

[0426] 5. Terminal rate constant (kel)

[0427] 6. Residual area ((1 - AUC0 - t / AUC0 - ∞)*100)

[0428] 7. CL / F

[0429] 8. Vz / F

[0430] 9. Ratio of AUC and Cmax of metabolite to parent

[0431] Where appropriate, plasma concentrations and pharmacokinetic parameters were descriptively summarized by treatment group and time point. All PK parameters were calculated using the blood sampling times after actual drug administration. Each time point was evaluated relative to the baseline value. PK parameters for each treatment group were summarized using descriptive statistics [N, arithmetic and geometric means, standard deviation (SD), minimum, median, maximum, and coefficient of variation (CV)].

[0432] The study variables were:

[0433] Part 1:

[0434] 1. Pharmacokinetics of DHE after administration of 1.5 mg, 3.0 mg, and 6.0 mg of dihydroergotamine mesylate intranasal powder (Treatments A, B, and C).

[0435] 2. Pharmacokinetics of 8’OH-DHE after administration of 1.5 mg, 3.0 mg, and 6.0 mg of dihydroergotamine mesylate intranasal powder (Treatments A, B, and C).

[0436] 3. Dose proportionality of 1.5 mg, 3.0 mg, and 6.0 mg of dihydroergotamine mesylate intranasal powder (Treatments A, B, and C) was determined using a power model by comparing AUC0-∞, AUC0-t, and Cmax estimated from the plasma DHE and 8’-β-OH-DHE concentration curves.

[0437] 4. Safety and tolerability of DHE after administration of dihydroergotamine mesylate intranasal powder (Treatments A, B, and C) in healthy adults.

[0438] Part 2:

[0439] 1. Pharmacokinetics of DHE after administration of selected dose levels of dihydroergotamine mesylate intranasal powder (A or B or C).

[0440] 2. Pharmacokinetics of DHE after administration of 1 mg of DHE intramuscular injection (Treatment D).

[0441] 3. Pharmacokinetics of DHE after administration of 2 mg of Migranal intranasal liquid spray (Treatment E).

[0442] 4. Pharmacokinetics of 8’OH-DHE after administration of selected dose levels of dihydroergotamine mesylate intranasal powder (A or B or C).

[0443] 5. Pharmacokinetics of 8’OH-DHE after administration of 1 mg of DHE intramuscular injection (Treatment D).

[0444] 6. Pharmacokinetics of 8’OH-DHE after administration of 2 mg of Migranal intranasal liquid spray (Treatment E).

[0445] The relative bioavailability of intranasal powder of dihydroergotamine mesylate (A or B or C) at the selected dose levels was determined by comparing the dose-adjusted DHE values of AUC0-t, AUC0-∞, and Cmax of the intranasal powder of dihydroergotamine mesylate with the dose-adjusted DHE values of AUC0-t, AUC0-∞, and Cmax of 1 mg DHE intramuscular injection (Treatment D) and 2 mg DHE Migranal intranasal liquid spray (Treatment E). The comparative bioavailability of intranasal powder of dihydroergotamine mesylate (A or B or C) at the selected dose levels was determined by comparing the DHE values of AUC0-t, AUC0-∞, and Cmax of the intranasal powder of dihydroergotamine mesylate with the DHE values of AUC0-t, AUC0-∞, and Cmax of 1 mg DHE intramuscular injection (Treatment D) and 2 mg DHE Migranal intranasal liquid spray (Treatment E). All safety measures (i.e., adverse events, vital signs, and laboratory parameters) were examined and reported for all treatments in this study. The relative bioavailability and comparative bioavailability of DHE after administration of intranasal powder of dihydroergotamine mesylate and IM DHE were determined by examining the 90% confidence interval (CI) of the mean of the selected dose strengths relative to the reference group mean (Treatment D) (derived from the analysis of ln-transformed dose-adjusted AUC0-t, AUC0-∞, and Cmax). The relative bioavailability and comparative bioavailability of DHE after administration of intranasal powder of dihydroergotamine mesylate and IN DHE were determined by examining the 90% confidence interval (CI) of the mean of the selected dose strengths relative to the reference group mean (Treatment E) (derived from the analysis of ln-transformed non-dose-adjusted AUC0-t, AUC0-∞, and Cmax). The Tmax data were analyzed using non-parametric statistical tests such as the wilcoxon test.

[0446] 4.5 Results of Part 1 of the clinical study

[0447] The mean maximum concentration of DHE for the 1.5 mg intranasal powder of dihydroergotamine mesylate was 608 pg / mL, 1140 pg / mL for the 3.0 mg dose, and increased to 1770 pg / mL for the 6.0 mg dose. For the 1.5 mg dose, Tmax occurred at 0.5 and 0.75 hours after dosing. For the 3.0 mg and 6.0 mg doses, Tmax was 0.5 hour. Fourteen out of 15 subjects had measurable DHE concentrations at 48 hours after dosing with 1.5 mg, with a mean concentration of 12.1 pg / mL at that time. All 15 subjects had measurable DHE concentrations at 48 hours after dosing with 3.0 mg, with a mean concentration of 19.9 pg / mL at that time.

[0448] The linear and log-linear plots of the mean plasma DHE and 8’OH-DHE concentration-time data separated by treatment are shown in Figure 4A and 4B . The concentration of 8’-OH-DHE was much lower than that of the parent drug. The mean maximum concentration of 8’-OH-DHE after administration of 1.5 mg dihydroergotamine mesylate nasal powder was 24.5 pg / mL, and the Tmax was 1.5 hours after dosing. For the 3.0 mg dose, the Tmax was 2 hours and the mean maximum concentration was 50.9 pg / mL. For the 6.0 mg dose, the Tmax was 1.5 hours, at which time the mean maximum concentration was 108 pg / mL. In most subjects, there was a lag time of 0.25 to 0.5 hours in the formation of 8’-OH-DHE. For the 1.5 mg dihydroergotamine mesylate nasal powder dose, one subject had no measurable concentration and another subject had a single measurable concentration of 8’-OH-DHE. Only 3 subjects had measurable concentrations 24 hours after dosing, and no measurable concentrations were observed at 36 or 48 hours. At the 3.0 mg dose level, 9 of 15 subjects had measurable concentrations at 24 hours. Measurable concentrations were observed in 4 of 15 subjects at 36 hours, and only 1 subject had a measurable concentration at 48 hours. At the 6.0 mg dose level, 14 of 15 subjects had measurable concentrations at 24 hours.

[0449] The mean Cmax for the 1.5 mg dose was 645 pg / mL, ranging from 111 to 2000 pg / mL, and the median Tmax was 0.75 hours. For the 3.0 mg dose, the mean Cmax was 1240 pg / mL, ranging from 607 to 2950 pg / mL, and the median Tmax was 0.50 hours. The mean Cmax for the 6.0 mg dose was 1870 pg / mL, ranging from 725 to 3880 pg / mL, and the median Tmax was 0.5 hours and the mean T max was 23 minutes. The variability of Cmax decreased continuously from 64.9% CV% for the 1.5 mg dose to 46.3% for the 3.0 mg and 44% for the 6.0 mg dose.

[0450] Plasma DHE concentrations showed a biexponential decay curve, and the mean terminal-phase half-life was 12.9 hours for the 1.5 mg dose, 12.6 hours for 3.0 mg, and 8.87 hours for the 6.0 mg dose. The geometric mean AUCinf was 3840 h*pg / mL for 1.5 mg, 6640 h*pg / mL for 3.0 mg, and 9060 h*pg / mL for 6.0 mg. As the dose increased from 1.5 mg to 3.0 mg to 6.0 mg, the variability of AUCinf decreased from a %CV of 44.6% to 36.4% and then increased slightly to 38.5%.

[0451] As demonstrated by the geometric means, the apparent clearance (CL / F) was as high as 391 L / h for the 1.5 mg dose, 452 L / h for 3.0 mg, and 662 L / h for 6.0 mg. The calculated volume of distribution (Vz / F) was large, with geometric means of 7210, 8200, and 8350 L, respectively.

[0452] The mean 8’-OH-DHE Cmax for the 1.5 mg dose of dihydroergotamine mesylate nasal powder was 27.8 pg / mL, and the mean doubled to 60.5 pg / mL for the 3.0 mg dose. The mean Cmax for the 6.0 mg dose of dihydroergotamine mesylate nasal powder was 127 pg / mL, almost twice that of the 3.0 mg dose. The median Tlag was 0.25 hours, indicating the lag time for metabolite formation. The median Tmax was 2 hours for dose levels 1.5 and 3.0 mg. The median Tmax was 1.5 hours for the 6.0 mg dose level. Based on available data from 11 of 15 subjects, the mean terminal-phase half-life was 13.4 hours for the 1.5 mg dose, 13.6 hours for the 3.0 mg dose using all subjects' data, and 12.3 hours for the 6.0 mg dose using all subjects' data. The geometric mean AUCinf was 454 h*pg / mL for the 1.5 mg dose, 675 h*pg / mL for the 3.0 mg dose, and 1170 h*pg / mL for the 6.0 mg dose.

[0453] The fraction of DHE converted to 8’OH-DHE was low and variable, with an arithmetic mean of 0.0552 (5.52%) for 1.5 mg, 0.0821 (8.21%) for 3.0 mg, and 0.115 (11.5%) for 6.0 mg, reflecting an increase in the percentage of conversion with increasing dose.

[0454] The results reflected a proportional increase in Cmax with increasing dose, while the increase in AUCinf was slightly less than proportional. A decrease in AUCinf / dose was reflected in some subjects, but the results also revealed a decrease in variability at higher dose levels.

[0455] 4.6 Results of the Clinical Study, Part 2

[0456] In Part 2, Phase 1, 27 subjects received a single intranasal inhalation dose of 6.0 mg of dihydroergotamine mesylate nasal powder (5.2 mg dihydroergotamine DHE), 25 subjects received 1 mg of intramuscular (IM) DHE, and 21 subjects received 2 mg of DHE administered as an intranasal liquid spray (Migranal). Blood samples were scheduled to be collected before dosing and at 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, and 48 hours after administration. Plasma concentration-time data were analyzed using WinNonlin version 6.3 or higher with calibrated sampling times to calculate standard pharmacokinetic (PK) parameters after intranasal administration.

[0457] The nasal powder showed rapid absorption with DHE plasma concentrations of 1230 and 1850 pg / mL at 5 and 10 minutes after administration, respectively. Compared to Migranal, the nasal powder showed approximately 2-fold higher Cmax (2180 vs 961 pg / mL), AUC 0-2h (2980 vs 1320 h*pg / mL), and AUC 0-inf (12000 vs 6360 h*pg / mL). The mean AUC 0-inf of the nasal powder was comparable to IM DHE (12000 vs 13600 h*pg / mL). Compared to Migranal, the nasal powder showed substantially lower variability in C max (41% vs 76%), AUC 0-2h (39% vs 75%), and AUC 0-inf (39% vs 56%). The nasal powder was well tolerated, and in Part 1, 60%, 33%, and 36% of the subjects reported treatment-emergent AEs (TEAEs) (all mild and transient) after administration of nasal powder at 1.3, 2.6, and 5.2 mg strengths (corresponding to 1.5, 3, and 6 mg DHE mesylate), respectively, and in Part 2, 41%, 15%, and 19% of the subjects reported treatment-emergent AEs after administration of the exemplary intranasal DHE powder, IM DHE, and Migranal, respectively.

[0458] The drug-device combination here showed rapid absorption, achieving effective DHE plasma concentrations within 5 - 10 minutes, and showed substantially higher C max , AUC 0-2h , AUC 0-infand lower variability, and shows an AUC comparable to that of IM DHE 0-inf This drug-device combination is a non-invasive acute migraine treatment, expected to have good tolerability and enable rapid, consistent relief from pain and related migraine symptoms without recurrence. Exemplary data are shown below.

[0459] Figure 6 Shows the DHE plasma concentration results of a Phase 1 study of dihydroergotamine mesylate intranasal powder compared to other DHE formulations (0 - 2 hour data). The DHE plasma concentration curve of dihydroergotamine mesylate intranasal powder is comparable to or better than other DHE formulations with proven efficacy.

[0460] Figure 7 Shows a comparison of the AUC-time curves of dihydroergotamine mesylate intranasal powder, MIGRANAL (an intranasal liquid dihydroergotamine mesylate), and SEMPRANA (an oral pulmonary dihydroergotamine mesylate). The AUC-time curve of dihydroergotamine mesylate intranasal powder predicts a potent curve superior to MIGRANAL and comparable to or better than SEMPRANA. The AUC values of the intranasal powder and SEMPRANA are comparable within 30 - 40 minutes, which can be interpreted as the clinical benefit taking effect within about 30 minutes as expected. The AUC0 - 2h of the intranasal powder is approximately 2 times that of SEMPRANA, which can be interpreted as the efficacy at 2 hours (the time point of the primary endpoint). The AUC0 - inf of the intranasal powder is approximately 2.7 times that of SEMPRANA, which can be interpreted as the sustained efficacy from 2 hours up to 24 - 48 hours.

[0461] Figure 8 Shows a comparison of the CV% (variability) of C max and AUC results for 6.0 mg dihydroergotamine mesylate intranasal powder compared to other DHE formulations. The CV% of Cmax and AUC for dihydroergotamine mesylate intranasal powder is superior to that of the DHE liquid nasal spray (MIGRANAL) and comparable to that of oral pulmonary DHE (SEMPRANA). Such low variability predicts consistent and reliable clinical efficacy.

[0462] Table 3 shows that this dihydroergotamine mesylate powder formulation has unexpectedly excellent pharmacokinetics compared to the MIGRANAL liquid spray. For example, based on the geometric mean, compared to the MIGRANAL liquid spray, the powder formulation provides an AUC0 - inf that is 2 times higher and a C max .

[0463] Table 3 - Comparative Bioavailability Assessment of This Powder Preparation and MIGRANAL Liquid Spray

[0464]

[0465]

[0466] Treatment: C = 6.0 mg dihydroergotamine mesylate nasal powder, D = 1 mg DHE (intramuscular injection), E = 2 mg DHE (MIGRANAL nasal liquid spray)

[0467] LS = Least Squares; CI = Confidence Interval

[0468] Linear mixed models for the natural logarithms of AUCinf, AUClast, and Cmax were performed with sequence, period, and treatment as fixed factors and subjects within sequence as random effects.

[0469] Table 4 shows that the pharmacokinetics of this dihydroergotamine mesylate powder preparation are comparable to those of the intramuscular liquid injection. For example, Table 4 shows that the AUC 0-inf is approximately 83%.

[0470] Table 4 - Comparative Bioavailability Assessment of This Powder Preparation and Intramuscular Liquid Injection

[0471]

[0472] Treatment: C = 6.0 mg dihydroergotamine mesylate nasal powder, D = 1 mg DHE (intramuscular injection), E = 2 mg DHE (Migranal nasal liquid spray)

[0473] LS = Least Squares; CI = Confidence Interval

[0474] Linear mixed models for the natural logarithms of AUCinf, AUClast, and Cmax were performed with sequence, period, and treatment as fixed factors and subjects within sequence as random effects.

[0475] Figures 5A to 5D Summarizes the concentration-time data of 8'-OH-DHE by treatment in Part 2. Figure 5A Shows grouped individual subject plots of linear-scale 8'-OH-DHE concentration-time data by treatment from Part 2. Figure 5B Contains data on log-linear scale from Part 2. Figure 5C and 5DShows 8’-OH-DHE concentration-time data from Part 2 plotted on linear and log-linear scales respectively over 0 - 4 hours after dosing. The concentration of 8’-OH-DHE was much lower than that of the parent drug. In Part 2, after administration of 1 mg intramuscular (IM) DHE, the mean maximum concentration C max of 8’-OH-DHE was 65.8 pg / mL - 68.84 pg / mL, and the mean Tmax was 1 - 1.14 hours after dosing. For a 2.0 mg liquid intranasal spray dose, the Tmax of 8’-OH-DHE was on average 2 - 2.29 hours, and the mean maximum concentration Cmax was 34.92 - 36.4 pg / mL. For a 6.0 mg dihydroergotamine mesylate intranasal powder dose, the Tmax of 8’-OH-DHE was on average 2 - 2.02 hours, at which time its mean maximum concentration C max was 110 - 125.98 pg / mL, almost twice that of the IM group and approximately three times that of the liquid spray group. In addition, in most subjects, there was a lag time of 0.25 to 0.5 hours in the formation of 8’-OH-DHE. For subjects receiving 1 mg IM DHE, only 4 subjects had measurable concentrations at 48 hours after dosing. At the 2.0 mg DHE intranasal spray dose level, 5 out of 21 subjects had measurable concentrations at 48 hours. At the 6.0 mg dihydroergotamine mesylate intranasal powder dose level, 16 out of 21 subjects had measurable concentrations at 48 hours. The mean 8’-OH-DHE Cmax for the 1 mg IM DHE dose was 69.3 pg / mL, and the mean 8’-OH-DHE Cmax for the 2.0 mg DHE intranasal spray dose decreased to 37.7 pg / mL on average. The C max mean for the 6.0 mg dihydroergotamine mesylate intranasal powder dose was 126 pg / mL, almost twice that of the 1 mg IM DHE dose. The median Tmax for 1 mg IM DHE and 2.0 mg DHE intranasal spray treatments were 1 hour and 2 hours respectively. The median Tmax at the 6.0 mg dihydroergotamine mesylate intranasal powder dose level was 2 hours.

[0476] The mean terminal phase half-life for the 1 mg IM DHE dose was 16.7 hours, for the 2.0 mg DHE intranasal spray dose was 22.1 hours, and for the 6.0 mg dihydroergotamine mesylate intranasal powder dose was 19.2 hours. The geometric mean AUCinf for the 1 mg IM DHE dose was 934 h*pg / mL, for the 2.0 mg DHE intranasal spray dose was 847 h*pg / mL, and for the 6.0 mg dihydroergotamine mesylate intranasal powder dose was 1570 h*pg / mL.

[0477] Table 5 summarizes the plasma DHE concentrations (pg / mL) statistical data of the pharmacokinetic population in Part 2 by scheduled time and treatment group. Table 6 summarizes the statistical data of the plasma DHE pharmacokinetic parameters of the pharmacokinetic population in Part 2 by three treatment groups. For example, Table 6 shows that the AUC 0-24h is approximately 82%.

[0478] Table 5 - Summary Statistics of Plasma DHE Concentrations (pg / mL) by Treatment Group and Scheduled Time - Pharmacokinetic Population in Part 2

[0479]

[0480] Treatment: C = 6.0 mg dihydroergotamine mesylate nasal powder, D = 1 mg DHE (intramuscular injection), E = 2 mg DHE (Migranal nasal liquid spray)

[0481] Table 6 - Summary Statistics of Plasma DHE Pharmacokinetic Parameters by Treatment Group - Pharmacokinetic Population in Part 2

[0482]

[0483]

[0484] Treatment: C = 6.0 mg dihydroergotamine mesylate nasal powder, D = 1 mg DHE (intramuscular injection), E = 2 mg DHE (Migranal nasal liquid spray)

[0485] Table 6. Continued

[0486]

[0487]

[0488] Treatment: C = 6.0 mg dihydroergotamine mesylate nasal powder, D = 1 mg DHE (intramuscular injection), E = 2 mg DHE (Migranal nasal liquid spray)

[0489] 4.7 Safety Analysis

[0490] A safety analysis was conducted on all subjects who received at least one dose of the study drug. All adverse events (AEs) and serious adverse events (SAEs) were collected starting from the time of the first entry into the clinical site (Phase 1; Day 1) until the end of the study, or, if the subject withdrew from the study prematurely, the last study visit, and were recorded on the CRF (including the time of occurrence of the adverse reaction - AE). All reported or observed adverse events were listed, documenting the course, severity, start and stop dates, possible relationship to the study drug, actions taken, and outcomes. The original terms were classified into preferred terms and relevant system organ classes using the MedDRA dictionary. The preferred terms and system organ classes were listed by treatment group. All recorded adverse events were summarized by the number of volunteers reporting the adverse event, system organ class, preferred term, severity, and relationship to the study drug. Safety laboratories included a complete blood count (CBC), chemistry, and urine analysis tabulated using descriptive statistics. Tables were provided of abnormal / out-of-range findings in the volunteers and changes in all laboratory variables from pre-dose to post-dose. Vital signs, nasal irritation, and nasal mucosal integrity assessments, as well as standard 12-lead ECGs, were tabulated using descriptive statistics. Tables were provided of abnormal / out-of-range findings in the volunteers and changes in the variables from pre-dose to post-dose. The study was designed to rigorously evaluate intranasal safety and tolerability. Frequent AE collection was combined with subjective nasal irritation / symptom assessments and nasal examinations at multiple time points.

[0491] Subjective evaluation of nasal symptoms

[0492] Participants were asked to rate the nasal symptoms:

[0493] 1) Nasal discomfort

[0494] 2) Nasal burning

[0495] 3) Nasal itching

[0496] 4) Nasal pain

[0497] 5) Nasal congestion

[0498] 6) Dysgeusia or taste alteration

[0499] 7) Rhinorrhea

[0500] 8) Sneezing

[0501] 9) Possible other symptoms such as ocular disorders (e.g., increased tearing), gastrointestinal disorders (e.g., abdominal pain), headache, vascular puncture / injection site reactions, and neurological disorders.

[0502] Participants rated symptoms on a 0 to 100 millimeter visual analogue scale (VAS), where 0 corresponded to "no symptoms" and 100 corresponded to "the worst imaginable". Each study subject answered questions at five time points after each dose: 5 minutes, 15 minutes, 1 hour, 4 hours, and 24 hours. The questionnaire used was as Figure 9 shown.

[0503] The results of the safety study were as Figure 10 and Table 7 show. 92% of the scores were reported as zero, 98.4% of the scores were less than 10, and 90% of all 41 subjects reported all scores less than 20. Figure 11 showed that subjects with local AEs tended to report higher symptom scores. 96% of the scores in all AE subjects were less than 20. Only 4 scores were greater than 50 (in a single subject). At a single time point, only one "pain" score exceeded 20 (27). Overall, the subjective assessment of the visual analogue scale data for nasal symptoms emphasized the good safety and tolerability profile of intranasal powder dihydroergotamine mesylate.

[0504] Table 7 - Drug-related adverse reactions of intranasal powder dihydroergotamine mesylate at different doses and other DHE drug delivery methods and compositions. Adverse reaction events occurred in at least 2 participants in any treatment group.

[0505]

[0506] All intranasal powder dihydroergotamine mesylate adverse events were mild, transient, and considered clinically irrelevant. No unexpected adverse events were reported. No nausea or "triptan-sensation" adverse events were reported. No clinically relevant findings were noted on nasal examination.

[0507] Example 5. Further study on the PK of cluster headache

[0508] The objectives of this example were 1) to evaluate the safety and pharmacokinetics (PK) of co-administering the drug compositions disclosed herein to both nostrils to support the potential indication of cluster headache, and 2) to evaluate the safety and PK of administering the drug compositions disclosed herein to both nostrils at 2-hour intervals.

[0509] It was found that certain drug compositions disclosed herein were bioequivalent to the injectable liquid dosage form (e.g., D.H.E. 45) approved for the cluster headache indication in terms of Cmax and AUC.

[0510] Figure 12Shown is a pharmacokinetic data model for different strengths of a pharmaceutical composition disclosed herein comprising 3.9 mg or 5.2 mg (free base weight) of dihydroergotamine administered in a single dose or in 2 doses with no delay or a 2 hour delay.

[0511] This clinical trial is a 4-phase crossover study with a one-week washout period between treatments, as shown in Table 8 below. The objectives are as follows:

[0512] To evaluate the pharmacokinetics of the drug after simultaneous administration to both nostrils

[0513] To evaluate the pharmacokinetics of the drug after administration to both nostrils at 2-hour intervals

[0514] Single-dose pharmacokinetics compared with intramuscular DHE

[0515] To assess the tolerability and safety of administration to both nostrils

[0516] Table 8. Clinical design.

[0517] Number of subjects Phase 1 treatment Phase 2 treatment Phase 3 treatment Phase 4 treatment 8 A B C D 8 B C D A 8 C D A B 8 D A B C

[0518] Treatment A: 2 x 3.9 mg of the present pharmaceutical composition (one dose per nostril, delivered to both nostrils without delay)

[0519] Treatment B: 2 x 5.2 mg of the present pharmaceutical composition (one dose per nostril, delivered to both nostrils without delay)

[0520] Treatment C: 5.2 mg of the present pharmaceutical composition + 5.2 mg of the present pharmaceutical composition (one dose per nostril; delivered to both nostrils at 2-hour intervals)

[0521] Treatment D: 1 mg DHE intramuscular injection (DHE45)

[0522] Endpoints measured included plasma levels of DHE and its metabolite (8'OH-DHE), C max ,t max , AUC 0-30分钟 , AUC 0-1 , AUC 0-2 , AUC 0-24 , AUC 0-48 , AUC 0-inf and t 1 / 2 , and adverse reactions.

[0523] The embodiments and situations described herein are for illustrative purposes only, and various modifications or changes suggested to those skilled in the art are intended to be included within the spirit and purview of this application and the scope of the appended claims.

Claims

1. A method of treatment or prophylaxis, comprising administering to a human subject a powdered pharmaceutical composition comprising an active agent selected from a compound having the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs, and its ion pairs: Among them, The method produces in the human subject a time to peak plasma concentration (Tmax) of 90 minutes or longer for a metabolite of the active agent, as determined by measuring the concentration of the metabolite in human plasma by automated extraction liquid chromatography - tandem mass spectrometry, and wherein: R1 is hydrogen, (C1 - C4)alkyl, or (C1 - C4)perfluoroalkyl; Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl —NO2, —N3, —OH, —S(O)kR100, —OR101, —NR102R103, —CONR104R105, —CO2R106, or —CO2R107; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy; R5, R6, and R7 are independently hydrogen, (C1 - C3)alkyl, or (C1 - C3)perfluoroalkyl; R8 and R9 are independently hydrogen, (C1 - C4)alkyl, or benzyl; R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, -CO2R 108 or—CONR 109 R 110 ; R 13 is hydrogen or a halogen; R 101 -R 110 independently is hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl; k is 0, 1, or 2; and n is 0, 1, 2, or 3.

2. The method according to claim 1, wherein said T max is at least about 2 hours.

3. The method according to claim 1 or 2, wherein the peak plasma concentration (C max ) of the metabolite is less than about 250 pg / ml.

4. The method according to claim 3, wherein the C of the metabolite max is less than about 150 pg / ml.

5. The method according to any one of claims 1 - 4, wherein the peak plasma concentration (C max ) of the metabolite is less than about 15% of the C max of the active agent measured after said administration to said human subject.

6. A method of treatment or prophylaxis, comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from a compound having the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs, and its ion pairs: wherein the method produces in the human subject: 1) C at about 1 to about 2.5 ng / ml max , or produce a plasma concentration of at least 1 ng / mL in about 10 minutes or less 2) A T of about 30 minutes or less max , and 3) An AUC value selected from the following: an AUC of about 500 to about 1000 h*pg / ml 0-30分钟 , an AUC of about 1000 to about 2000 h*pg / ml 0-60分钟 , an AUC of about 2000 to about 3000 h*pg / ml 0-120分钟 and an AUC of about 10000 to about 12000 h*pg / ml 0-inf , as determined by measuring the concentration of the active agent in human plasma by automated extraction liquid chromatography - tandem mass spectrometry, and wherein: R1 is hydrogen, (C1 - C4)alkyl, or (C1 - C4)perfluoroalkyl; Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl a group, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy; R5, R6, and R7 are independently hydrogen, (C1 - C3)alkyl, or (C1 - C3)perfluoroalkyl; R8 and R9 are independently hydrogen, (C1 - C4)alkyl, or benzyl; R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, -CO2R 108 or—CONR 109 R 110 ; R 13 is hydrogen or a halogen; R 101 -R 110 independently is hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl; k is 0, 1, or 2; and n is 0, 1, 2, or 3.

7. A method of treatment or prophylaxis, comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from a compound having the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs, and its ion pairs: wherein after said administration to the human subject, the method produces an apparent clearance (CL / F) value of the active agent of from about 100 L / hour to about 1000 L / hour, and wherein: R1 is hydrogen, (C1 - C4)alkyl, or (C1 - C4)perfluoroalkyl; Each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl Base, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy, or methoxy; R5, R6, and R7 are independently hydrogen, (C1 - C3)alkyl, or (C1 - C3)perfluoroalkyl; R8 and R9 are independently hydrogen, (C1-C4)alkyl or benzyl; R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, -CO2R 108 or—CONR 109 R 110 ; R 13 is hydrogen or a halogen; R 101 -R 110 independently is hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl; k is 0, 1 or 2; and n is 0, 1, 2 or 3.

8. A method of treatment or prophylaxis comprising administering to a human subject a pharmaceutical composition comprising an active agent selected from a compound of the following formula, its stereoisomers, its pharmaceutically acceptable salts, its complexes, its chelates, its hydrates, its polymorphs and its ion pairs: wherein when measured within 24 hours after said administration to said human subject, the method produces a visual analogue scale score for measuring nasal symptoms of less than about 20, wherein the visual analogue scale score is measured on a scale of 0 (no symptoms) to 100 (the worst imaginable) for each of the following nasal symptoms: nasal discomfort, nasal burning, nasal itching, nasal pain, nasal congestion, dysgeusia, rhinorrhea and sneezing, and wherein: R1 is hydrogen, (C1-C4)alkyl or (C1-C4)perfluoroalkyl; each R2 is independently hydrogen, halogen, alkyl, acyl, heteroalkyl a base, —NO2, —N3, —OH, —S(O) k R 100 , —OR 101 , —NR 102 R 103 , —CONR 104 R 105 , —CO2R 106 or —CO2R 107 ; R3 and R4 are independently hydrogen, deuterium, halogen, hydroxy or methoxy; R5, R6 and R7 are independently hydrogen, (C1-C3)alkyl or (C1-C3)perfluoroalkyl; R8 and R9 are independently hydrogen, (C1-C4)alkyl or benzyl; R 10 , R 11 , R 12 and R 14 are independently hydrogen, halogen, -OH, (C1-C4) alkyl, -CO2R 108 or—CONR 109 R 110 ; R 13 is hydrogen or a halogen; R 101 -R 110 independently is hydrogen, halogen, alkyl, acyl, aryl, aralkyl, heteroalkyl, heteroaryl or heteroaralkyl; k is 0, 1 or 2; and n is 0, 1, 2 or 3.

9. A pharmaceutical composition from Table 1.

10. A delivery device comprising a pharmaceutical composition from Table 1.

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