CROSS-REFERENCE
[0001] The present application claims the benefit of U.S. Provisional Application Serial No. 62/371,298, filed August 5, 2016, which is incorporated herein by reference in its entirety.
INCORPORATION BY REFERENCE
[0002] All publications, patents, and patent applications disclosed herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term disclosed herein and a term in an incorporated reference, the term herein controls.

BRIEF SUMMARY

[0003] The inventive embodiments provided in this Brief Summary are meant to be illustrative only and to provide an overview of selective embodiments disclosed herein. The Brief Summary, being illustrative and selective, does not limit the scope of any claim, does not provide the entire scope of inventive embodiments disclosed or contemplated herein, and should not be construed as limiting or constraining the scope of this disclosure or any claimed inventive embodiment.

[0004] In some cases, the present disclosure provides for an intranasal pharmaceutical powder composition comprising particles that comprise an active agent and at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any combination thereof, wherein: at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction; when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C; the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction; and when the intranasal pharmaceutical powder composition is administered, a pharmacokinetic parameter of the active agent improves by at least about 15%, compared to a corresponding composition that comprises the active agent in a crystalline form when

intranasally administered, as measured by a same method. In some instances, the pharmaceutical powder composition comprises the active agent, the thickening agent, the carrier, and the sugar alcohol. In some instances, the pharmaceutical powder composition further comprises particles that comprise the active agent and are free from the thickening agent, the carrier, or a

combination thereof. In some instances, the active agent is a non-peptide/non-protein drug. In some instances, the active agent is selected from the group consisting of an ergot alkaloid, 5-hydroxytryptaminel (5-HT1) receptor agonist, CGRP antagonist, K-1 receptor antagonist, antihistamine, antiemetic agent, decongestant, opioid receptor agonist, antibiotic, antifungal agent, sulfa drug, antituberculosis drug, antimicrobial agent, antiviral agent, hypnotic sedative, antiepileptic agent, narcotic analgesic, nonnarcotic analgesic, sedative drug, psychotherapeutic agent, muscle relaxant, antiallergic agent, anti-rheumatic drug, cardiotonic drug, antiarrhythmic agent, antihypertensive agent, diuretic agent, coronary vasodilator, antidementia drug, brain activator, brain circulation ameliorating agent, antiparkinsonian agent, antihyperlipidemic drug, antiulcer drug, obesity drug, diabetic drug, hemostatic drug, antithrombotic agent, migraine drug, antitussive drug, expectorant, respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidal antiinflammatory agent, antipodagric, therapeutic agent for urinary disease, drug for improving sexual function, agent for the uterus, steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavy metal toxification, quit smoking agent, anti anaphylactic agent, antitumor agent, immunostimulator, immunosuppressive drug, and any combination thereof. In some instances, the active agent is selected from the group consisting of didanosine, zidovudine, lamivudine, acyatazanavir, nelfenavir, sanilvudine, emtncitabine, polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir, peramivir, laninamivir, favipiravir, amantadine, amphotericin B, miconazole, fluconazole, itraconazole, ketoconazole, ketamine, pentobarbital sodium, thiopental, amopentobarbital, hexobarbital, lidocaine, triazolam, zopiclone, Zolpidem, eszopiclone, etizolam, clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam, flunitrazepam, diazepam, chlordiazepoxide HC1, alprazolam, lorazepam, ethyl loflazepate, bromazepam, rilmazafone, 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, nalfurafine, pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine, levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine, dihydroergotamine (DHE), sumatriptan, eletriptan, zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan, olcegepant, telcagepant, donepezil, suxamethonium, pancuronium, sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine, homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine, thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide, nitroglycerin, quinidine, disopyramide, dopamine, dobutamine, epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine, doxapram, naloxone, flumazenil, tipepidine, 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, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenic acid, tiaramide, carbazochrome sulfonic acid, tranexamic acid, pralidoxime iodide methyl, progesterone, testosterone, dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine, leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone, risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir, famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine, idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin, carmustine, beraprost sodium, and any

combination thereof. In some instances, the active agent is a peptide or a peptide-related compound, wherein the peptide or peptide-related compound has a molecular weight of 50,000 Daltons or less. In some instances, the active agent is selected from the group consisting of 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 formation-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-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, emfuvirtide, ziconotide, ecallantide, mifamurtide, nesiritide, peglinesatide, afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide, cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide, a peptide analog thereof, and any combination thereof. In some instances, the active agent is a small molecule drug. In some instances, the active agent is an anti-migraine drug. In some instances, the active agent is an ergot alkaloid. In some instances, the active agent is DHE or a

pharmaceutically acceptable salt thereof. In some instances, the active agent is DHE mesylate. In some instances, the active agent is indomethacin, midazolam, phenobarbital, or a

pharmaceutically acceptable salt of any of the foregoing. In some instances, the active agent has an average particle size of about 5 microns or larger. In some instances, the particles have an average particle size of from about 15 to about 100 μιτι, or about 15-200 microns, as measured by laser diffraction. In some instances, the particles have an average particle size of from about 20 to about 50 μιτι, or about 50-150 microns, as measured by laser diffraction. In some instances, the particles are spray dried, freeze-dried, or melt-extruded. In some instances, the active agent is spray dried onto the carrier, the thickening agent, or a combination thereof. In some instances, the solubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles comprise the carrier that is at least partially water insoluble at 37± 0.5 °C. In some instances, the water insolubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the thickening agent, and wherein the carrier has lower water solubility than that of the thickening agent. In some instances, the particles comprise the carrier that is at least partially adhesive to mucus. In some instances, the particles comprise the carrier that comprises a polysaccharide, an oligosaccharide, or any combination thereof. In some instances, the carrier comprises microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate,

hydroxypropylmethylcellulose phthalate, starch, chitosan, β cyclodextrin, or any combination thereof. In some instances, the particles comprise the carrier that has an average particle size of from about 5 to about 100 μιτι, as measured by laser diffraction. In some instances, the carrier has an average particle size of about 20 or about 23 μιτι, as measured by laser diffraction. In some instances, the particles comprise the thickening agent that is at least partially water soluble at 37± 0.5 °C. In some instances, the water solubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the carrier, and wherein the thickening agent has higher water solubility than that of the carrier. In some instances, the particles comprise the thickening agent that binds to the active agent. In some instances, the particles further comprise the carrier, and wherein the thickening agent binds to the active agent and the carrier. In some instances, the particles comprise the thickening agent that comprises a polysaccharide. In some instances, the thickening agent comprises hydroxypropyl

methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, methylcellulose, polyvinylpyrrolidone, or any combination thereof. In some instances, the particles comprise the thickening agent and have an average particle size of from about 10 to about 50 μιτι, about 15 to about 200 microns, as measured by laser diffraction. In some instances, the particles have an average particle size of about 15 μιη, or about 50 to 150 microns, as measured by laser diffraction. In some instances, the particles comprise the thickening agent, the sugar alcohol, and the carrier and have an average particle size of from about 10 to about 50 μιτι, or about 15 to 200 microns, as measured by laser diffraction. In some instances, the particles have an average particle size of about 20 μιτι, or about 50 to 150 microns, as measured by laser diffraction. In some instances, the

pharmaceutical powder composition further comprises a fluidizing agent. In some instances, the fluidizing agent comprises a calcium phosphate. In some instances, the calcium phosphate comprises tribasic calcium phosphate. In some instances, when the intranasal pharmaceutical powder composition is administered to the subject, a pharmacokinetic parameter of the active agent improves by at least about: 20%, 25%, 30%, 40%, 45%, 50%, 60%, 70%, 80%, 90%,

100%, 150%, 200%, 250%, 300%, 400%, or 500%, compared to a corresponding composition that comprises the active agent in a crystalline form when administered. In some instances, the improved pharmacokinetic parameter comprises a greater relative bioavailability from 0 min to 15 min (rBA0-i5min), a greater relative bioavailability from 0 min to 30 min (rBA0-30min), a greater relative bioavailability from 0 min to 60 min (rBA0-60min), or any combination thereof. In some instances, the improved pharmacokinetic parameter comprises an average rBA0-i5min, and the improvement is at least about 100%, e.g., at least about 115% or 150%. In some instances, the average rBA0-i5min is about 150% to 1500%) in serum of the subject. In some instances, the improved pharmacokinetic parameter comprises an average rBA0-30min, and the improvement is at least about 80%, e.g., at least about 115%. In some instances, the improved pharmacokinetic parameter comprises an average rBA0-60min, and the improvement is at least 100%, e.g., at least about 115%). In some instances, the improved pharmacokinetic parameter comprises a higher maximum blood concentration (Cmax)- In some instances, the improved pharmacokinetic parameter comprises a shorter time to reach maximum blood concentration (Tmax)- In some instances, the improved pharmacokinetic parameter comprises an increased area under the curve (AUC) for blood concentration-time profile. In some instances, the pharmaceutical powder composition further comprises an additional active agent. In some instances, the additional active agent comprises caffeine, which is amorphous, crystalline, at least 20% of amorphous by weight of the caffeine, or any combination thereof. In some instances, 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 is amorphous. In some instances, the pharmaceutical powder composition retains at least about: 80%, 85%, 90%, or 95% by weight of the active agent in a closed container after a period of at least about: 30, 60, 120, 180, 360, 720, or 1080 days. In some instances, the container is kept at about 20°C to about 40°C at a standard atmosphere pressure with a relative humidity of about 50%) to about 75%. In some instances, the container is kept at about 25°C at a standard atmosphere pressure with a relative humidity of about 50%. In some instances, the crystalline form comprises a polymorph.

[0005] In some instances, the intranasal pharmaceutical powder composition comprises indomethacin or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and mannitol. In some instances, the intranasal pharmaceutical powder composition comprises indomethacin or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and tribasic calcium phosphate. In some instances, the indomethacin or a pharmaceutically acceptable salt thereof is in a freeze-dried form, amorphous, or a combination thereof. In some instances, the microcrystalline cellulose comprises a first microcrystalline cellulose that has an average particle size of about 20-23 μπι and a second microcrystalline cellulose has an average particle size of about 50 μιη. In some instances, the pharmaceutical powder composition comprises: indomethacin or a pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous, which is present in about 1-15% of a total weight of the pharmaceutical powder composition; a first microcrystalline cellulose that is present in about 70-95%) of the total weight of the pharmaceutical powder composition, wherein the first microcrystalline cellulose has an average particle size of about 20-23 μπι; a second microcrystalline cellulose that is present in about 1-20%) of the total weight of the pharmaceutical powder composition, wherein the second microcrystalline cellulose has an average particle size of about 50 μπι; and tribasic calcium phosphate that is present in about 0.5-5% of the total weight of the pharmaceutical powder composition. In some instances, the pharmaceutical powder composition comprises:

indomethacin or a pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous, which is present in about 5% of a total weight of the pharmaceutical powder composition; a first microcrystalline cellulose that is present in about 84%> of the total weight of the pharmaceutical powder composition, wherein the first microcrystalline cellulose has an average particle size of about 20-23 μπι; a second microcrystalline cellulose that is present in about 10%> of the total weight of the pharmaceutical powder composition, wherein the second microcrystalline cellulose has an average particle size of about 50 μπι; and tribasic calcium phosphate that is present in about 1%) of the total weight of the pharmaceutical powder composition. In some instances, the pharmaceutical powder composition comprises: about 0.5-5 mg of indomethacin or a

pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous; about 10-18 mg of microcrystalline cellulose that has an average particle size of about 20-23 μπι; about 1-10 mg of microcrystalline cellulose that has an average particle size of about 50 μπι; and about 0.1-2 mg of tribasic calcium phosphate. In some instances, the pharmaceutical powder composition comprises: about 1 mg of indomethacin or a pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous; about 16.8 mg of microcrystalline cellulose that has an average particle size of about 20-23 μπι; about 2 mg of microcrystalline cellulose that has an average particle size of about 50 μπι; and about 0.2 mg of tribasic calcium phosphate.

[0006] In some instances, the intranasal pharmaceutical powder composition comprises testosterone or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and mannitol. In some instances, the intranasal pharmaceutical powder composition comprises testosterone or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and tribasic calcium phosphate. In some instances, the indomethacin or a pharmaceutically acceptable salt thereof is a freeze-dried form, amorphous, or a combination thereof. In some instances, the microcrystalline cellulose comprises a first microcrystalline cellulose that has an average particle size of about 20-23 μπι and a second microcrystalline cellulose has an average particle size of about 50 μηι. In some instances, wherein the pharmaceutical powder composition comprises: testosterone or a pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous, which is present in about 1-20% of a total weight of the pharmaceutical powder composition; a first microcrystalline cellulose that is present in about 70-95%) of the total weight of the pharmaceutical powder composition, wherein the first microcrystalline cellulose has an average particle size of about 20-23 μπι; a second microcrystalline cellulose that is present in about 1-20% of the total weight of the pharmaceutical powder composition, wherein the second

microcrystalline cellulose has an average particle size of about 50 μπι; and tribasic calcium phosphate that is present in about 0.5-5% of the total weight of the pharmaceutical powder composition. In some instances, the pharmaceutical powder composition comprises: testosterone or a pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous, which is present in about 10%> of a total weight of the pharmaceutical powder composition; a first microcrystalline cellulose that is present in about 79% of the total weight of the pharmaceutical powder composition, wherein the first microcrystalline cellulose has an average particle size of about 20-23 μπι; a second microcrystalline cellulose that is present in about 10%> of the total weight of the pharmaceutical powder composition, wherein the second microcrystalline cellulose has an average particle size of about 50 μπι; and tribasic calcium phosphate that is present in about 1%) of the total weight of the pharmaceutical powder composition. In some instances, the pharmaceutical powder composition comprises: about 1-10 mg of testosterone or a

pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous; about 10-18 mg of microcrystalline cellulose that has an average particle size of about 20-23 μπι; about 1-10 mg of microcrystalline cellulose that has an average particle size of about 50 μπι; and about 0.1-2 mg of tribasic calcium phosphate. In some instances, wherein the pharmaceutical powder

composition comprises: about 2 mg of testosterone or a pharmaceutically acceptable salt thereof, e.g., freeze-dried and/or amorphous; about 15.8 mg of microcrystalline cellulose that has an average particle size of about 20-23 μπι; about 2 mg of microcrystalline cellulose that has an average particle size of about 50 μπι; and about 0.2 mg of tribasic calcium phosphate.

[0007] In some cases, the present disclosure provides for a method, comprising intranasally administering to a subject a pharmaceutical powder composition comprising particles that comprise an active agent and at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any combination thereof, wherein at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction; when the active agent has a crystalline form, a solubility of the active agent in a crystalline form ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C at a pH ranging from about 6.8 to about 7.4; the particles have an

average particle size of about 10 microns to about 300 microns, as measured by laser diffraction; and the intranasal administration of the pharmaceutical powder composition improves a pharmacokinetic parameter of the active agent by at least about 15%, when compared to an intranasal administration of a corresponding composition that comprises the active agent in a crystalline form, as measured by a same method. In some instances, the pharmaceutical powder composition comprises the active agent, the thickening agent, the carrier, and the sugar alcohol. In some instances, the pharmaceutical powder composition further comprises particles that comprise the active agent and are free from the thickening agent, the carrier, or a combination thereof. In some instances, the active agent is a non-peptide/non-protein drug. In some instances, the active agent is selected from the group consisting of ergot alkaloid, 5-hydroxytryptaminel (5-HT1) receptor agonist, CGRP antagonist, K-1 receptor antagonist, antihistamine, antiemetic agent, decongestant, opioid receptor agonist, antibiotic, antifungal agent, sulfa drug,

antituberculosis drug, antimicrobial agent, antiviral agent, hypnotic sedative, antiepileptic agent, narcotic analgesic, nonnarcotic analgesic, sedative drug, psychotherapeutic agent, muscle relaxant, antiallergic agent, anti -rheumatic drug, cardiotonic drug, antiarrhythmic agent, antihypertensive agent, diuretic agent, coronary vasodilator, antidementia drug, brain activator, brain circulation ameliorating agent, antiparkinsonian agent, antihyperlipidemic drug, antiulcer drug, obesity drug, diabetic drug, hemostatic drug, antithrombotic agent, migraine drug, antitussive drug, expectorant, respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidal antiinflammatory agent, antipodagric, therapeutic agent for urinary disease, drug for improving sexual function, agent for the uterus, steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavy metal toxification, quit smoking agent, anti anaphylactic agent, antitumor agent, immunostimulator, immunosuppressive drug, and any combination thereof. In some instances, the active agent is selected from the group consisting of didanosine, zidovudine, lamivudine, acyatazanavir, nelfenavir, sanilvudine, emtricitabine, polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir, peramivir, laninamivir, favipiravir, amantadine, amphotericin B, miconazole, fluconazole, itraconazole, ketoconazole, ketamine, pentobarbital sodium, thiopental, amopentobarbital, hexobarbital, lidocaine, triazolam, zopiclone, Zolpidem, eszopiclone, etizolam, clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam, flunitrazepam, diazepam, chlordiazepoxide HC1, alprazolam, lorazepam, ethyl loflazepate, bromazepam, rilmazafone, 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, nalfurafine, pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine, levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine, dihydroergotamine, sumatriptan, eletriptan, zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan, olcegepant, telcagepant, donepezil, suxamethonium, pancuronium, sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine, homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine, thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide, nitroglycerin, quinidine, disopyramide, dopamine, dobutamine, epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine, doxapram, naloxone, flumazenil, tipepidine, 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, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenic acid, tiaramide, carbazochrome sulfonic acid, tranexamic acid, pralidoxime iodide methyl, progesterone, testosterone, dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine, leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone, risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir, famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine, idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin, carmustin, beraprost sodium, and any combination thereof. In some instances, the active agent is a peptide or a peptide-related compound, wherein the peptide or peptide-related compound has a molecular weight of 50,000 Daltons or less. In some instances, the active agent is selected from the group consisting of 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 formation-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-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, emfuvirtide, ziconotide, ecallantide, mifamurtide, nesiritide, peglinesatide, afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide, cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide, a peptide analog thereof, and any combination thereof. In some instances, the active agent is a small molecule drug. In some instances, the active agent is an anti-migraine drug. In some instances, the active agent is an ergot alkaloid. In some instances, the active agent is dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof. In some instances, the active agent is dihydroergotamine mesylate. In some instances, the active agent is indomethacin, midazolam, phenobarbital, or a pharmaceutically acceptable salt of any of the foregoing. In some instances, the active agent has an average particle size of about 5 microns or larger. In some instances, the particles have an average particle size of from about 15 to about 100 μιη, or about 15-200 microns, as measured by laser diffraction. In some instances, the particles have an average particle size of from about 20 to about 50 μιτι, or about 50-150 microns, as measured by laser diffraction. In some instances, the particles are spray dried. In some instances, the active agent is spray dried onto the carrier, the thickening agent, or a combination thereof to form the particles. In some instances, the solubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles comprise the carrier that is at least partially water insoluble at 37± 0.5 °C. In some instances, the water insolubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the thickening agent, and wherein the carrier has lower water solubility than that of the thickening agent. In some instances, the particles comprise the carrier that is at least partially adhesive to mucus. In some instances, the particles comprise the carrier that comprises an oligosaccharide, a polysaccharide, or any combination thereof. In some instances, the carrier comprises

microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, starch, chitosan, β cyclodextrin, or any combination thereof. In some instances, the particles comprise the carrier that has an average particle size of from about 10 to about 100 μιτι, as measured by laser diffraction. In some instances, the carrier has an average particle size of about 20 or 23 μιτι, as measured by laser diffraction. In some instances, the particles comprise the thickening agent that is at least partially water soluble at 37± 0.5 °C. In some instances, the water solubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the carrier, and wherein the thickening agent has higher water solubility than that of the carrier. In some instances, the particles comprise that the thickening agent binds to the active agent. In some instances, the particles further comprise the carrier, and wherein the thickening agent binds to the active agent and the carrier. In some instances, the particles comprise the thickening agent that comprises a polysaccharide. In some instances, the thickening agent comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, methylcellulose, polyvinylpyrrolidone, or any combination thereof. In some instances, the particles comprise the thickening agent and have an average particle size of from about 10 to about 50 μιτι, as measured by laser diffraction. In some instances, the particles have an average particle size of about 15 μιτι, or about 50-150 microns, as measured by laser diffraction. In some instances, the particles comprise the thickening agent, the sugar alcohol, and the carrier and have an average particle

size of from about 10 to about 50 μπι, or about 15-200 microns, as measured by laser diffraction. In some instances, the particles have an average particle size of about 20 μπι, or about 50-150 microns, as measured by laser diffraction. In some instances, the pharmaceutical powder composition further comprises a fluidizing agent. In some instances, the fluidizing agent comprises a tribasic calcium phosphate. In some instances, the administration of the

pharmaceutical powder composition improves the pharmacokinetic parameter 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%, when compared to administration of the corresponding

composition that comprises the active agent in the crystalline form. In some instances, the improved pharmacokinetic parameter comprises a greater relative bioavailability from 0 min to 15 min (rBA0-i5min), a greater relative bioavailability from 0 min to 30 min (rBA0-3omin), a greater relative bioavailability from 0 min to 60 min (rBA0-60min), or any combination thereof. In some instances, the improved pharmacokinetic parameter comprises an average rBA0-i5min, and the improvement is at least about 100%, e.g., at least about: 115% or 150%. In some instances, the average rBAo-ismin is about 150% to 1500%) in serum of the subject. In some instances, the improved pharmacokinetic parameter comprises an average rBA0-30min, and the improvement is at least about 80%, e.g., at least about 115%. In some instances, the improvement is about 400%. In some instances, the improved pharmacokinetic parameter comprises an average rBA0-60min, and the improvement is at least 100%, e.g., at least about 115%. In some instances, the improvement is about 200%). In some instances, the improved pharmacokinetic parameter comprises a higher maximum blood concentration (Cmax)- In some instances, the improved pharmacokinetic parameter comprises a shorter time to reach maximum blood concentration (Tmax)- In some instances, the improved pharmacokinetic parameter comprises an increased area under the curve (AUC) for blood concentration-time profile. In some instances, the pharmaceutical powder composition further comprises an additional active agent. In some instances, the additional active agent comprises caffeine, which is amorphous, crystalline, at least 20% of amorphous by weight of the caffeine, or any combination thereof. In some instances, 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 is amorphous. In some instances, the pharmaceutical powder composition retains at least about: 80%, 85%, 90%, or 95% by weight of the active agent in a closed container after a period of at least about: 30, 60, 120, 180, 360, 720, or 1080 days. In some instances, the container is kept at about 20°C to about 40°C at a standard atmosphere pressure with a relative humidity of about 50%) to about 75%. In some instances, the container is kept at about 25°C at a standard atmosphere pressure with a relative humidity of about 50%. In some instances, the crystalline form comprises a polymorph. In some instances, the method is used in the treatment of a disease or a condition in the human subject. In some instances, the disease or condition is a headache, amyotrophic lateral sclerosis, Parkinson's disease, stress, anxiety, nausea, emesis, aggression, pain, neuropathic pain, sleeplessness, insomnia, restless leg syndrome, depression, or any combination thereof. In some instances, the disease or condition is a headache. In some instances, the headache is a migraine headache, a cluster headache, a hemicrania continua headache, a chronic headache, a tension headache, a chronic tension headache, or any combination thereof. In some instances, the headache is a migraine headache. In some instances, the headache is a migraine headache with aura. In some instances, the headache is a migraine headache without aura. In some instances, the headache is moderate to severe. In some instances, the headache is acute. In some instances, the pharmaceutical powder composition is 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 instances, the administration of the pharmaceutical powder composition is 1, 2, 3, 4, 5, 6, 7, or 8 times daily. In some instances, the pharmaceutical powder composition is in a single unit dose. In some instances, the pharmaceutical powder composition is a unit dose of from about 5 mg to about 50 mg, e.g., about 20 mg. In some instances, a unit dosage of the pharmaceutical powder composition contains about 0.1 mg to about 10 mg of the active agent, e.g., about 4 mg. In some instances, the subject is a primate. In some instances, the subject is a human. In some instances, the subject is a monkey.

[0008] In some cases, the present disclosure provides for a method of making an intranasal pharmaceutical powder composition, comprising spray drying, freeze-drying, or melt-extruding an active agent with at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any combination thereof, to produce particles, wherein: at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction; when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C; and the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction. In some instances, the particles comprise the active agent and the thickening agent. In some instances, the particles comprise the active agent and the carrier. In some instances, the particles comprise the active agent, the carrier, and the thickening agent. In some instances, the method further comprises blending the particles with an additional amount of the carrier. In some instances, the method further comprises blending the particles with an additional carrier, additional thickening agent, or any combination thereof. In some instances, the particles comprise the active agent and are free from the thickening agent, the carrier, or a combination thereof. In some instances, the solubility is measured at a pH ranging from about 6.8 to about 7.4.

In some instances, the particles comprise the carrier that is at least partially water insoluble at 37± 0.5 °C. In some instances, the water insolubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the thickening agent, and wherein the carrier has lower water solubility than that of the thickening agent. In some instances, the particles comprise the carrier that is at least partially adhesive to mucus. In some instances, the particles comprise the carrier that comprises an oligosaccharide, a polysaccharide, or any combination thereof. In some instances, the carrier comprises microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, starch, chitosan, β cyclodextrin, or any combination thereof. In some instances, the particles have an average particle size of from about 15 to about 100 μιτι, as measured by laser diffraction. In some instances, the carrier has an average particle size of about 20 to about 50 μιτι, as measured by laser diffraction. In some instances, the particles comprise the thickening agent that is at least partially water soluble 37± 0.5 °C. In some instances, the water solubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the carrier, and wherein the thickening agent has higher water solubility than that of the carrier. In some instances, the particles comprise the thickening agent that binds to the active agent. In some instances, the particles further comprise the carrier, and wherein the thickening agent binds to the active agent and the carrier. In some instances, the particles comprise thickening agent that comprises a polysaccharide. In some instances, the thickening agent comprises hydroxypropyl

methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, methylcellulose, polyvinylpyrrolidone, or any combination thereof. In some instances, the particles comprise the thickening agent and have an average particle size of from about 10 to about 50 μιτι, or about 15-200 microns, as measured by laser diffraction. In some instances, the particles have an average particle size of about 15 μιτι, or about 50-150 microns, as measured by laser diffraction. In some instances, the particles comprise the thickening agent, the sugar alcohol, and the carrier and have an average particle size of from about 10 to about 50 μιτι, as measured by laser diffraction. In some instances, the particles an average particle size of about 20 μιη-100 μιτι, 20-50 μιτι, or about 50-150 microns, as measured by laser diffraction. In some instances, the active agent is spray dried, freeze-dried, or melt-extruded with the thickening agent. In some instances, the method further comprises using a fluid bed granulation, e.g., after mixing all the components.

[0009] In some cases, the present disclosure provides for a use of an intranasal pharmaceutical powder composition disclosed herein in the treatment of a disease or condition. In some

instances, the disease or condition is a headache, amyotrophic lateral sclerosis (ALS),

Parkinson's disease, stress/anxiety, nausea, emesis, aggression, pain, neuropathic pain, sleeplessness, insomnia, restless leg syndrome, or depression. In some instances, the disease or condition is a headache. In some instances, the headache is a migraine headache, a cluster headache, a hemicrania continua headache, a chronic headache, a tension headache, a chronic tension headache, or any combination thereof. In some instances, the headache is a migraine headache. In some instances, the headache is a migraine headache with aura. In some instances, the headache is a migraine headache without aura. In some instances, the headache is moderate to severe. In some instances, the headache is acute. In some instances, the pharmaceutical powder composition is 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 instances, the intranasal

pharmaceutical powder composition is administered 1, 2, 3, 4, 5, 6, 7, or 8 times daily for the treatment. In some instances, the intranasal pharmaceutical powder composition is in a single unit dose, e.g., in an amount of about 5-50 mg or about 20 mg. In some instances, a unit dosage of the intranasal pharmaceutical powder composition contains about 0.1 mg to about 10 mg of the active agent, e.g., about 4 mg. In some instances, the subject is a primate. In some instances, the subject is a human. In some instances, the subject is a monkey.

[0010] In some cases, the present disclosure provides for a device that contains a pharmaceutical powder composition disclosed herein. In some instances, the device is for a single use.

[0011] In some cases, an active agent disclosed herein has an average particle size larger than 5 μπι.

[0012] In some cases, an active agent disclosed herein is suspended in methanol before spray drying or freeze-drying.

[0013] In some cases, an active agent is present in an amount of about 1-30% (e.g., 1-10%) by weight based on a weight of the particles or a pharmaceutical powder composition, for example about: 20%, or 3%.

[0014] In some cases, particles comprise a thickening agent that is present in an amount of about 0.05-2%) or about 0.05-10%) by weight based on a weight of the particles or a pharmaceutical powder composition, for example about 0.3%> or about 5%. In some instances, particles comprise a sugar alcohol that is present in an amount of about 20-95%> by weight based on a weight of the particles or a pharmaceutical powder composition, for example about: 20%, 25%, 40%), 60%), 25%, 50%), 75%o, or 90%. In some instances, particles comprise the pH adjusting agent that is present in an amount of about 1-40% by weight based on a weight of the particles or a pharmaceutical powder composition, for example about: 2.5%, 5%, 15%, or 25%.

[0015] In some cases, a particle or composition disclosed herein comprises a pH adjusting agent.

In some instances, the pH adjusting agent is selected from the group consisting of 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 dihydrogenphosphate, sodium monohydrogenphosphate, lithium phosphate, potassium phosphate, calcium phosphate, sodium carbonate, sodium hydrogencarbonate, lactic acid, sodium lactate, potassium lactate, calcium lactate, acetic acid, sodium acetate, potassium acetate, calcium acetate, propionic acid, sulphuric acid, sodium sulphate, potassium sulphate, 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, monoethanole amine, diethanoleamine, triethanoleamine meglumine, sodium citrate, sodium bicarbonate, potassium bicarbonate, and any combination thereof.

[0016] In some cases, a particle or composition disclosed herein comprises a sugar alcohol. In some instances, the sugar alcohol is selected from the group consisting of mannitol, glycerol, galactitol, fucitol, inositol, volemitol, maltotriitol, maltoetetraitol, polyglycitol, erythritol, threitol, ribitol, arabitol, xylitol, allitol, dulcitol, glucitol, sorbitol, altritol, iditol, maltitol, lactitol, isomalt, and any combination thereof.

[0017] In some cases, a pharmacokinetic parameter disclosed herein is determined with an analysis of a blood or plasma sample 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 instances, the analysis comprises a measurement of a plasma concentration of DHE, 8' -hydroxy -DHE, or a combination thereof in the blood or plasma sample. In some instances, the analysis is conducted with liquid chromatography (LC), mass spectrometry (MS), or a combination thereof. In some instances, the analysis is conducted with a LC/MS/MS method.

[0018] In some instances, the pharmaceutical powder composition disclosed herein comprises dihydroergotamine or a pharmaceutically acceptable salt thereof, mannitol, and microcrystalline cellulose. In some instances, the pharmaceutical powder composition further comprises HPMC. In some cases, the present disclosure provides a pharmaceutical powder composition that comprises: 1) about 1 -8 mg such as 4 mg of dihydroergotamine or a pharmaceutically

acceptable salt thereof; 2) about 5-15 mg such as 5 mg of mannitol; and 3) about 5-15 mg such as 11 mg of microcrystalline cellulose. In some instances, the pharmaceutical powder

composition has an average particle size diameter of about 20 to about 100 microns. In some instances, the pharmaceutical powder composition is for intransal administration. In some cases, the present disclosures provides a pharmaceutical powder composition that comprises: 1)

dihydroergotamine or a pharmaceutically acceptable salt thereof that is present in about 20% of a total weight of the pharmaceutical powder composition; optionally 2) HPMC that is present in about 5% of the total weight of the pharmaceutical powder composition; 3) mannitol that is present in about 25% of the total weight of the pharmaceutical powder composition; and 4) microcrystalline cellulose that is present in about 50% or 55% of the total weight of the pharmaceutical powder composition, and wherein the pharmaceutical powder composition have an average particle size diameter of about 50 to about 150 microns. In some instances, the pharmaceutical powder composition is for intransal administration. In some cases, the present disclosures provides a pharmaceutical powder composition that comprises: 1) about 4 mg of dihydroergotamine or a pharmaceutically acceptable salt thereof; 2) about 1 mg of HPMC; 3) about 5 mg of mannitol; and 4) about 10 mg of microcrystalline cellulose, and wherein the pharmaceutical powder composition have an average particle size diameter of about 50 to about 150 microns. In some instances, the pharmaceutical powder composition is for intransal administration.

[0019] In some cases, the present disclosure provides particles that comprise an active agent, a carrier, a sugar alcohol, or any combination thereof. In some instances, the particles further comprise a thickening agent. In some instances, the particles are substantially uniform. In some instances, at least about: 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% by weight of the particles are agglomerated, aggregated, or a combination thereof. In some instances, about: 10%-15%, 20%-30%, 40%-50%, 60%-70%, 80%-90%, 95%-99%, 10%-25%, 20%-40%, 40%-60%, 60%-80%, 80%-95%, 10%-30%, 10%-40%, 10%-50%, 30%-70%, 50%-90%, or 70%-99% by weight of the particles are agglomerated, aggregated, or a combination thereof. In some instances, the particles are substantially agglomerated, aggregated, or a combination thereof. In some instances, the active agent is aggregated or agglomerated, with the carrier, the sugar alcohol, or a combination thereof. In some instances, the sugar alcohol is aggregated or agglomerated, with the carrier. In some instances, the active agent is DHE or a pharmaceutically acceptable salt thereof. In some instances, the thickening agent is HPMC. In some instances, the carrier is microcrystalline cellulose. In some instances, the sugar alcohol is mannitol. In some instances, an average diameter of the particles is about 15 microns to about 200 microns, for example about 50 microns to about 150 microns, or about 20 microns to about 50 microns.

[0020] In some instances, the intranasal pharmaceutical powder composition disclosed herein comprises particles that have one or more following features: at least some of the particles disclosed herein substantially contain a single ingredient selected from the group consisting of an active agent, a thickening agent, a carrier, a pH adjusting agent, and a sugar alcohol; or at least some of the particles contain a single ingredient selected from the group consisting of the active agent, the thickening agent, the carrier, the pH adjusting agent, and the sugar alcohol; or at least some of the particles contain at least two ingredients selected from the group consisting of the active agent, the thickening agent, the carrier, the pH adjusting agent, and the sugar alcohol; or the intranasal pharmaceutical powder composition further comprises particles that comprise the active agent and are free from the thickening agent, the carrier, or a combination thereof; or at least some of the particles are aggregates; or at least some of the particles are agglomerates; or any combination thereof. In some cases, the present disclosure provides agglomerated particles that comprise an active agent, a thickening agent, a carrier, and a sugar alcohol. In some instances, the active agent is DHE or a pharmaceutically acceptable salt thereof. In some instances, the thickening agent is HPMC. In some instances, the carrier is microcrystalline cellulose. In some instances, the sugar alcohol is mannitol. In some instances, an average diameter of the agglomerated particles is about 15 microns to about 200 microns. In some instances, the average diameter of the agglomerated particles is about 50 microns to about 150 microns.

[0021] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different instances, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure.

Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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 present invention will be obtained by reference to the following detailed description that sets forth illustrative instances, in which the principles of the invention are utilized, and the accompanying drawings (also "figure" and "FIG." herein), of which:

[0023] FIGs. 1 A to IF are a group of line graphs comparing DUE pharmacokinetic profiles in monkeys from testing various DUE formulations, for 0-180 min.

[0024] FIGs. 2A and 2B are a group of bar graphs comparing AUC profiles of various DUE formulations, tested in monkeys.

[0025] FIGs. 3 A, 3B, and 3C are a group of X-ray diffraction spectra overlay comparing various DUE formulations.

[0026] FIG. 4 is a group of scanning electron microscope (SEM) scans of various DUE formulations.

[0027] FIG. 5 is a graph showing plasma indomethacin concentration-time profiles in monkeys.

[0028] FIG. 6 is a graph showing X-ray diffraction spectra of freeze-dried indomethacin and non-treated indomethacin.

[0029] FIG. 7 is a graph showing plasma testosterone concentration-time profiles in monkeys.

[0030] FIG. 8 is a graph comparing X-ray diffraction spectra of freeze-dried testosterone and non-treated testosterone.

DETAILED DESCRIPTION

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of the 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 mentioned otherwise, the techniques employed or

contemplated herein are standard methodologies. The materials, methods and examples are illustrative only and not limiting.

[0032] The details of one or more inventive instances are set forth in the accompanying drawings, the claims, and the description herein. Other features, objects, and advantages of the inventive instances disclosed and contemplated herein can be combined with any other instance unless explicitly excluded.

[0033] Unless otherwise indicated, open terms for example "contain," "containing," "include," "including," and the like mean comprising.

[0034] The singular forms "a", "an", and "the" are used herein to include plural references unless the context clearly dictates otherwise. Accordingly, unless the contrary is 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.

[0035] Unless otherwise indicated, some instances herein contemplate numerical ranges. When a numerical range is provided, unless otherwise indicated, the range includes the range endpoints. Unless otherwise indicated, numerical ranges include all values and subranges therein as if explicitly written out. Unless otherwise indicated, any numerical ranges and/or values herein can be at 80-125% of the numerical ranges and/or values.

[0036] A standard atmosphere (symbol: atm) is a unit of pressure defined as 101325 Pa (1.01325 bar), equivalent to 760 mmHg (torr), 29.92 inHg, or 14.696 psi.

[0037] In some instances, improvement is calculated as the following:

Improvement = (|I-C|/C) x Di/Dc x 100%

1= Improved value from a present composition

C= Control value from a comparator or conventional composition

Di= Dose of the present composition

Dc= Dose of the comparator or conventional composition

[0038] Unless otherwise indicated, relative bioavailability (rBA) is equal to [(AUC of preparation with amorphous API / Dose of preparation with amorphous) / (AUC of preparation with 100% crystal / Dose of preparation of 100% crystal) x 100%].

[0039] In some instances, a buffering agent is selected from the group consisting of sodium phosphate, sodium hydrogenphosphate, anhydrous sodium dihydrogenphosphate, crystalline sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, dipotassium phosphate, boric acid, borax, sodium acetate, citric acid, citric anhydride, sodium citrate, sodium glutamate, creatinine, and phosphate buffered saline.

[0040] Unless otherwise indicated, the term "thickening agent" refers to an excipient that increases a particle size of an active agent and/or viscosity of a composition. In some instances, a thickening agent disclosed herein binds to an active agent and/or a carrier via a non-covalent interaction, e.g., hydrogen bonding or van der Waals force.

[0041] Unless otherwise indicated, "average particle size" can refer to a particle size distribution of a powder in its non-aggregated state. In some instances, an average particle size refers to a mean particle size, for example calculated as a sum of size measurements of all measurable particles divided by a total number of particles measured. In some instances, an average particle size refers to a median particle size, for example indicating that about 50% of all measurable particles measured have a particle size less than the defined median particle size value, and that about 50% of all measurable particles measured have a particle size greater than the defined median particle size value. In some instances, an average particle size refers to a mode particle size, for example indicating the most frequently-occurring particle size value. In some instances, for spherical particles, an average particle size is a measurement of a particle' s diameter. In some instances, for non-spherical particles, an average particle size is a measurement of longest or shortest diameters, perimeter, projected area, or by an equivalent spherical diameter. Primary particle diameter can be determined using a laser-diffraction particle size analyzer. In some instances, the particle size analyzer can be Mastersizer 2000 manufactured by Malvern

Instruments Limited.

[0042] Pharmacokinetic data disclosed herein (e.g., Cmax, Tmax, AUC0-t, AUCo-iso minutes, AUCo-mf, T1/2) can be measured from a primate, preferably a monkey, and preferably a Cynomolgus monkey, after a powder composition disclosed herein is administered. Alternatively, the pharmacokinetic data disclosed herein (e.g., Cmax, Tmax, AUC0-t, AUCo-iso minutes, AUC0-mf, T1/2) can be measured from a human subject after a powder composition disclosed herein is administered. In some instances, an active agent such as dihydroergotamine, or a complex,

chelate, salt, hydrate, polymorph, or ion pair thereof is administered at a rate such that a mean peak plasma concentration (Cmax) of 8-hydroxy dihydroergotamine is higher than 10,000 pg/ml, and a mean time to Cmax (Tmax) of 8-hydroxy dihydroergotamine is longer than 45 minutes.

[0043] Presented herein are compositions, comprising an active agent. In some instances, the active agent is in a free base form. In some instances, the active agent is in a pharmaceutically acceptable salt form. In some instances, the term "substantially" can mean 80-100% of a referred subject matter. In some instances, agglomerate can mean a loose accumulation of separate particles bonded by weak physical forces. In some instances, aggregate can mean a dense cluster of separate particles bonded by strong chemical or sinter forces.

[0044] Intranasal administration, as used herein in the context of the powder compositions presented herein, unless otherwise noted, refers to administration whereby at least 95±5% of the powder composition is administered to the nasal cavity as measured by multiple path particle dosimetry (MPPD) model analysis, a computational model used to estimate human airway particle dosimetry (see, e.g., Anjilvel, S. and Asgharian, B. (1995) Fundam. Appl. Toxicol. 28, 41-50; and National Institute for Public Health and the Environment (RIVM) (2002) Multiple Path Particle Dosimetry Model (MPPD v 1.0): A Model for Human and Rat Airway Particle Dosimetry. Bilthoven, The Netherlands. RIVA Report 650010030), or via an Andersen Cascade Impactor.

[0045] In some instances, not less than 90% of the particles in the powder compositions presented herein have a diameter less than 150 μιτι, and not more than 5% of the particles in the powder compositions have a diameter less than 10 μιη. In some instances, the overall average particle size of the particles in the powder compositions presented herein is about 15 to about 30 μιη, about 18 to about 25 μιτι, about 18 to about 20 μιτι, or about 20 μιη.

[0046] In some instances, presented herein is a method of treating a disease or condition, e.g., pain, headache (e.g., migraine), hormone disorder, comprising intranasally administering to a human, a composition comprising an active agent, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, and tribasic calcium phosphate, wherein the composition is not a liquid solution or a liquid spray composition. Unless noted, such compositions are referred to herein as powder compositions. In some instances, a method disclosed herein comprises intranasally administering powder compositions comprising an active agent, microcrystalline cellulose with an average particle diameter size of about 100 μιη or less, and tribasic calcium phosphate. Throughout, unless otherwise noted, "about" means within ±10% of a value. For example, if it is stated that a component makes up "about 70%" of a mixture, it is implied that the component makes up within a range of 63% and 77% of the mixture. In addition, in instances wherein "about" is used, it is to be understood that instances involving the exact value associated with "about" are also contemplated. For example, when an instance recites "about 0.5 milligram (mg) of an active agent," an instance reciting "0.5 mg of an active agent" is also contemplated and is described herein.

[0047] In some cases, provided herein are methods of treating a disease or condition, e.g., pain, headache (e.g., migraine), hormone disorder, comprising intranasally administering powder compositions comprising an active agent, a microcrystalline cellulose portion with an average particle size diameter of about 50-55 μιτι, e.g., 50 μιτι, comprising about 10% of the total weight of the powder composition, a microcrystalline cellulose portion with an average particle size of about 20 μιη comprising about 3 to about 90%, e.g., 8 to about 90%, of the total weight of the powder composition and, optionally, a fluidizing agent. In some instances, the powder compositions utilized as part of the methods further comprise an active agent disclosed herein, e.g., caffeine, for example, anhydrous caffeine. Throughout, unless otherwise noted, percent (%) weight, in the context of the powder compositions presented herein, refers to weight per weight percent (%) (W/W%).

[0048] In some cases, presented herein are powder compositions that can be utilized in conjunction with the methods of treating a disease or condition, e.g., pain, headache (e.g., migraine), hormone disorder, wherein the powder compositions comprise an active agent or a pharmaceutically acceptable salt thereof. In some instances, provided herein are powder compositions comprising: a) an active agent b) microcrystalline cellulose, e.g., a

microcrystalline cellulose with an average particle diameter size of about 100 μιη or less; and c) tribasic calcium phosphate. In some instances, provided herein are powder compositions comprising an active agent, a microcrystalline cellulose portion with an average particle size diameter of about 50-55 μιτι, e.g., 50 μιτι, comprising about 10% of the total weight of the powder composition, a microcrystalline cellulose portion with an average particle size of about 20 μιη comprising about 3% to about 90%, e.g., about 8 to about 90%, of the total weight of the powder composition and, optionally, a fluidizing agent. In some instances, the powder compositions further comprise an active agent disclosed herein, e.g. caffeine, for example, anhydrous caffeine. In some instances, greater than or equal to about 90% of the particles in the powder composition have a diameter less than 150 μηι. In some instances, the overall average particle size of the composition is about 15 to about 30 μηι, about 18 to about 25 μηι, about 18 to about 20 μηι, or about 20 μηι. In some instances, less than or equal to about 5% of the particles in the powder composition have a diameter less than 10 μηι. In some instances, greater than or equal to about 90% of the particles in the powder composition have a diameter less than 150 μιη; and the overall average particle size of the composition is about 15 to about 30 μηι, about 18 to about 25 μηι, about 18 to about 20 μηι, or about 20 μιη; and less than or equal to about 5% of the particles in the powder composition have a diameter less than 10 μιη.

[0049] In some cases, a powder composition disclosed herein comprises an active agent, microcrystalline cellulose, and tribasic calcium phosphate. In some instances, the

microcrystalline cellulose comprises a first microcrystalline cellulose (e.g., average particle size of about 20 μπι) and a second microcrystalline cellulose (e.g., average particle size of about 50 μιη).

[0050] In some cases, a powder composition disclosed herein has an angle of repose about 53° or less, for example, about 53°, 52°, 51°, 50°, 48°, 46°, 44°, 42°, 40°, 38°, 36°, 34°, 32°, 30°, 28°, 26°, 24°, 22°, 20° or less.

[0051] In some cases, presented herein are methods and compositions used for treating a disease or a condition, e.g., headache, pain, or hormone disorder. For example, the methods and compositions are used for treating migraine. In some instances, the methods of treating migraine are methods for the acute treatment of migraine headaches with or without aura. In some instances, at least a portion of the powder composition is administered to a single nostril of the human. In some instances, at least a portion of the powder composition is administered to each nostril of the human. For example, in some instances of the method, about half of the

composition is administered to one nostril and about half of the composition is administered to the other nostril of the human.

[0052] In some cases, the present disclosure provides for a device that contains a pharmaceutical powder composition disclosed herein. In some instances, the device is for a single use.

Active Agents and Compositions

[0053] In some cases, an active agent disclosed herein is a non-peptide/non-protein drug. In some instances, the active agent is selected from the group consisting of ergot alkaloid, 5-hydroxytryptaminel (5-HT1) receptor agonist, CGRP antagonist, K-1 receptor antagonist, antihistamine, antiemetic agent, decongestant, opioid receptor agonist, antibiotic, antifungal agent, sulfa drug, antituberculosis drug, antimicrobial agent, antiviral agent, hypnotic sedative, antiepileptic agent, narcotic analgesic, nonnarcotic analgesic, sedative drug, psychotherapeutic agent, muscle relaxant, antiallergic agent, anti-rheumatic drug, cardiotonic drug, antiarrhythmic agent, antihypertensive agent, diuretic agent, coronary vasodilator, antidementia drug, brain activator, brain circulation ameliorating agent, antiparkinsonian agent, antihyperlipidemic drug, antiulcer drug, obesity drug, diabetic drug, hemostatic drug, antithrombotic agent, migraine drug, antitussive drug, expectorant, respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidal antiinflammatory agent, antipodagric, therapeutic agent for urinary disease, drug for improving sexual function, agent for the uterus, steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavy metal toxification, quit smoking agent, anti anaphylactic agent, antitumor agent, immunostimulator, immunosuppressive drug, and any combination thereof. In some instances, the active agent is selected from the group consisting of didanosine, zidovudine, lamivudine, acyatazanavir, nelfenavir, sanilvudine, emtncitabine, polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir, peramivir, laninamivir, favipiravir, amantadine, amphotericin B, miconazole, fluconazole, itraconazole, ketoconazole, ketamine, pentobarbital sodium, thiopental, amopentobarbital, hexobarbital, lidocaine, triazolam, zopiclone, Zolpidem, eszopiclone, etizolam, clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam, flunitrazepam, diazepam, chlordiazepoxide HC1, alprazolam, lorazepam, ethyl loflazepate, bromazepam, rilmazafone, 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, nalfurafine, pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine, levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine, dihydroergotamine, sumatriptan, eletriptan, zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan, olcegepant, telcagepant, donepezil, suxamethonium, pancuronium, sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine, homatropine methylbromide, chlorpromazine, digitoxin, levomepromazine, thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide, nitroglycerin, quinidine, disopyramide, dopamine, dobutamine, epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine, doxapram, naloxone, flumazenil, tipepidine, 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, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenic acid, tiaramide, carbazochrome sulfonic acid, tranexamic acid,

pralidoxime iodide methyl, progesterone, testosterone, dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine, leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone, risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir,

famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine, idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin, carmustin, beraprost sodium, and any combination thereof.

[0054] In some instances, the active agent is a small molecule drug, e.g., having a molecular weight of less than about 1000 grams/mole (g/mol), about 750 g/mol, or about 500 g/mol. In some instances, the active agent is an anti-migraine drug. In some instances, the active agent is an ergot alkaloid. In some instances, the active agent is dihydroergotamine (DHE) or a

pharmaceutically acceptable salt thereof, e.g., DHE mesylate. In some instances, the active agent is indomethacin, midazolam, or phenobarbital. In some instances, the active agent is indomethacin or a pharmaceutically acceptable salt thereof. In some instances, the active agent is testosterone or a pharmaceutically acceptable salt thereof.

[0055] In some cases, an active agent disclosed herein is a peptide or a peptide-related

compound, wherein the peptide or peptide-related compound has 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 instances, the active agent is selected from the group consisting of 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 formation-stimulating factor, parathyroid hormone, thyroid-stimulating hormone-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, emfuvirtide, ziconotide, ecallantide, mifamurtide, nesiritide, peglinesatide, afamelanotide, linaclotide, lixisenatide, teduglutide, bentiromide, cureletide diethylamine, degarelix, ghrelin, atrial natriuretic peptide, a peptide analog thereof, and any combination thereof.

[0056] Methods and compositions presented herein can utilize an active agent in a freebase, salt, hydrate, polymorph, isomer, diastereomer, prodrug, metabolite, ion pair complex, or chelate form. An active agent can be formed using a pharmaceutically acceptable non-toxic acid or base, including an inorganic acid or base, or an organic acid or base. In some instances, an active agent that can be utilized in connection with the methods and compositions presented herein is a pharmaceutically acceptable salt derived from acids including, but not limited to, the following: acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, or /?-toluenesulfonic acid. In some instances, the active agent is a salt of

methanesulfonic acid. An alternative nomenclature of the methanesulfonic acid salt of DHE is DHE mesylate. For further description of pharmaceutically acceptable salts that can be used in the methods described herein see, for example, S.M. Barge et al., "Pharmaceutical Salts," 1977, J. Pharm. Sci. 66: 1-19, which is incorporated herein by reference in its entirety.

[0057] In some cases, an average particle size of an active agent or a composition disclosed herein can be less than about 100 micrometer (μιη), for example, about: 95 μιτι, 90 μιτι, 85 μιτι, 80 μιη, 75 μιη, 70 μιτι, 65 μιτι, 60 μιτι, 55 μιτι, 50 μιτι, 45 μm, 40 μm, 35 μιτι, 30 μm, 25 μιτι, 20 μm, 15 μm, 10 μιτι, 5 μm or less. In some instances, an average particle size of an active agent or a composition disclosed herein can be larger than 10 μιτι, for example, more than about: 250 μιη, 200 μιη, 190 μιη, 180 μιη, 170 μιη, 160 μιη, 150 μιη, 140 μιη, 130 μιη, 120 μm, 1 10 μm, 100 μιη, 95 μm, 90 μιτι, 85 μm, 80 μm, 75 μιτι, 70 μm, 65 μιτι, 60 μm, 55 μm, 50 μιτι, 45 μm, 40 μιη, 35 μm, 30 μm, 25 μιτι, 20 μm, or 15 μιη. The particle size of an active agent or a powder composition can be about: 20-100 microns, 25-150 microns, 25-175 microns, 25-200 microns, 25-250 microns, 25-300 microns, 50-150 microns, 50-175 microns, 50-200 microns,50-250 microns, 50-300 microns, 10-100 μιτι, for example, about: 15-90 μιτι, 15-80 μιτι, 15-70 μιτι, 15-60 μιη, 15-50 μιη, 15-40 μιη, 15-30 μιη, 15-20 μιη, 15-20 μm, 10-90 μιη, 10-80 μm, 10-70 μm, 10-60 μιη, 10-50 μm, 10-40 μιη, 10-30 μm, 10-20 μm, 20-90 μιη, 20-80 μm, 20-70 μιη, 20-60 μm, 20-50 μm, 20-40 μιη, 20-30 μm,30-90 μm, 30-80 μιη, 30-70 μm, 30-60 μιη, 30-50 μm, 30-40 μιη, 40-90 μm, 40-80 μm, 40-70 μιη, 40-60 μm, 40-50 μιη, 50-90 μm, 50-80 μm, 50-70 μιη, 50-60 μm, 60-90 μιη, 60-80 μm, 60-70 μm, 70-90 μιη, 70-80 μm, or 80-90 μιη. The average particle size of the active agent or the composition can be about: 5.0 μιτι, 5.5 μιτι, 6.0 μιτι, 6.5 μιτι, 7.0 μιη, 7.5 μm, 8.0 μm, 8.5 μιτι, 9.0 μm, 9.5 μιτι, 10 μm, 1 1 μm, 12 μιτι, 13 μm, 14 μιτι, 15 μm, 16 μm, 17 μιτι, 18 μm, 19 μιτι, 20 μm, 25 μm, 30 μιτι, 35 μm, 40 μιτι, 45 μm, 50 μm, 55 μιτι, 60 μm, 65 μιτι, 70 μm, 75 μm, 80 μιτι, 85 μm, 90 μιτι, 95 μm, or 100 μιη. In some instances, not less than 90% of the powder compositions presented herein have a particle diameter less than 150 μιτι, and not more than 5% of the particles have a diameter less than 5 μιη. In some instances, the overall average particle size of the powder compositions presented herein are about 15 μιη to about 30 μιη, about 18 μιη to about 25 μιτι, about 18 μιη to about 20 μιτι, or about 20 μιη.

[0058] In some cases, a total weight of a powder 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 an active agent. In some instances, the total weight of the powder 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 an active agent or a

pharmaceutically acceptable salt thereof.

[0059] In some cases, a composition disclosed herein further comprises an additional active agent, for example: an adenosine receptor antagonist, a phosphodiesterase inhibitor,

an acetylcholinesterase inhibitor, a vasodilator, xanthine, caffeine, paraxanthine, theobromine, and theophylline. For example, the methods and compositions further comprise caffeine. The additional active agent (e.g., caffeine) can be at least about 1% of the total weight of the powder

composition, for example 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 powder composition. The additional active agent (e.g., caffeine) can be about 1% to 60% of the total weight of the powder composition, for example, about: l%-60%, l%-50%, l%-40%, l%-30%, l%-20%, 1%-10%, l%-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 powder composition. In some instances, the powder composition comprises about 5% to 10% of an additional active agent (e.g., caffeine). In some instances, the caffeine is anhydrous caffeine. In some instances, the powder composition comprises about 10% to 15%) of an additional active agent (e.g., caffeine).

[0060] In some cases, the present disclosure provides for an intranasal pharmaceutical powder composition comprising particles that comprise an active agent and at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, 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 in the particles is amorphous as determined by X-ray diffraction; when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 milligram/milliliter (mg/mL) in water at a temperature of 37± 0.5 °C; the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction; and when the intranasal pharmaceutical powder composition is administered, a pharmacokinetic parameter of the active agent improves by at least about 15%, compared to a corresponding composition that comprises the active agent in a crystalline form when administered. In some instances, the pharmaceutical powder composition further comprises particles that comprise the active agent and are free from the thickening agent, the carrier, the pH adjuster, the sugar alcohol, or a combination thereof. In some instances, the active agent is a non-peptide/non-protein drug. In some instances, the particles have an average particle size of from about 15 to about 100 μηι, as measured by laser diffraction. In some instances, the particles have an average particle size of from about 20 to about 50 μηι, as measured by laser diffraction. In some instances, the particles are spray dried. In some instances, the active agent is spray dried onto the carrier, the thickening agent, the pH adjuster, the sugar alcohol or a combination thereof to form the particles. In some instances, the solubility is 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, for example, ranging from about 6.8 to about 7.4. In some instances, the particles comprise the carrier that is at least partially water insoluble at 37± 0.5 °C. In some instances, the water insolubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the thickening agent, and wherein the carrier has lower

water solubility than that of the thickening agent. In some instances, the particles comprise the carrier that is at least partially adhesive to mucus. In some instances, the particles comprise the carrier that comprises an oligosaccharide, a polysaccharide, or any combination thereof. In some instances, the carrier comprises microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate,

hydroxypropylmethylcellulose phthalate, starch, chitosan, β cyclodextrin, or any combination thereof. In some instances, the particles comprise the carrier that has an average particle size of from about 10 to about 100 μιτι, as measured by laser diffraction. In some instances, the carrier has an average particle size of about 20 μιτι, as measured by laser diffraction. In some instances, the particles comprise the thickening agent that is at least partially water soluble at 37± 0.5 °C. In some instances, the water solubility is measured at a pH ranging from about 6.8 to about 7.4. In some instances, the particles further comprise the carrier, and wherein the thickening agent has higher water solubility than that of the carrier. In some instances, the particles comprise that the thickening agent binds to the active agent. In some instances, the particles further comprise the carrier, and wherein the thickening agent binds to the active agent and the carrier. In some instances, the particles comprise the thickening agent that comprises a polysaccharide. In some instances, the thickening agent comprises hydroxypropyl methylcellulose (HPMC),

CLAIMS
WHAT IS CLAIMED IS:
An intranasal pharmaceutical powder composition, wherein the intranasal pharmaceutical powder composition comprises particles that comprise an active agent and at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any combination thereof, wherein:

at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction;

when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C;

the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction; and

when the intranasal pharmaceutical powder composition is administered, a

pharmacokinetic parameter of the active agent improves by at least about 15%, compared to a corresponding composition that comprises the active agent in a crystalline form when administered intranasally, as measured by a same method.

The intranasal pharmaceutical powder composition of claim 1, wherein the intranasal pharmaceutical powder composition comprises the active agent, the carrier, and the sugar alcohol.

The intranasal pharmaceutical powder composition of claim 1, wherein the intranasal pharmaceutical powder composition comprises the active agent, the thickening agent, the carrier, and the sugar alcohol.

The intranasal pharmaceutical powder composition of any one of claims 1-3, wherein: at least some of the particles substantially contain a single ingredient selected from the group consisting of the active agent, the thickening agent, the carrier, the pH adjusting agent, and the sugar alcohol; or

at least some of the particles contain a single ingredient selected from the group consisting of the active agent, the thickening agent, the carrier, the pH adjusting agent, and the sugar alcohol; or

at least some of the particles contain at least two ingredients selected from the group consisting of the active agent, the thickening agent, the carrier, the pH adjusting agent, and the sugar alcohol; or

the intranasal pharmaceutical powder composition further comprises particles that comprise the active agent and are free from the thickening agent, the carrier, or a combination thereof; or

at least some of the particles are aggregates; or

at least some of the particles are agglomerates; or

any combination thereof.

The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is a non-peptide/non-protein drug.

The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is selected from the group consisting of an ergot alkaloid, 5-hydroxytryptaminel (5-HTi) receptor agonist, CGRP antagonist, K-1 receptor antagonist, antihistamine, antiemetic agent, decongestant, opioid receptor agonist, antibiotic, antifungal agent, sulfa drug, antituberculosis drug, antimicrobial agent, antiviral agent, hypnotic sedative, antiepileptic agent, narcotic analgesic, nonnarcotic analgesic, sedative drug, psychotherapeutic agent, muscle relaxant, antiallergic agent, anti-rheumatic drug, cardiotonic drug, antiarrhythmic agent, antihypertensive agent, diuretic agent, coronary vasodilator, antidementia drug, brain activator, brain circulation ameliorating agent, antiparkinsonian agent, antihyperlipidemic drug, antiulcer drug, obesity drug, diabetic drug, hemostatic drug, antithrombotic agent, migraine drug, antitussive drug, expectorant, respiratory stimulant, asthma drug, antidiarrheal drug, nonsteroidal antiinflammatory agent, antipodagric, therapeutic agent for urinary disease, drug for improving sexual function, agent for the uterus, steroid, prostaglandin, vitamin, antidote, therapeutic agent for heavy metal toxification, quit smoking agent,

anti anaphylactic agent, antitumor agent, immunostimulator, immunosuppressive drug, and any combination thereof.

The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is selected from the group consisting of didanosine, zidovudine, lamivudine, acyatazanavir, nelfenavir, sanilvudine, emtricitabine, polyinosinic-polycytidylic acid, oseltamivir, zanamivir, valganciclovir, peramivir, laninamivir, favipiravir, amantadine, amphotericin B, miconazole, fluconazole, itraconazole, ketoconazole, ketamine, pentobarbital sodium, thiopental, amopentobarbital, hexobarbital, lidocaine, triazolam, zopiclone, Zolpidem, eszopiclone, etizolam, clotiazepam, brotizolam, lormetazepam, estazolam, midazolam, nitrazepam, flunitrazepam, diazepam, chlordiazepoxide HC1, alprazolam, lorazepam, ethyl loflazepate, bromazepam, rilmazafone, 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, nalfurafine, pentazocine, nalbuphine hydrochloride, nalorphine, eptazocine, levallorphan, sulpyrine, aspirin, acetaminophen, ergotamine, dihydroergotamine (DHE), sumatriptan, eletriptan, zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan, avitriptan, lasmiditan, olcegepant, telcagepant, donepezil, suxamethonium, pancuronium, sildenafil, vardenafil, apomorphine, tadalafil, atropine, scopolamine, homatropine methylbromide,

chlorpromazine, digitoxin, levomepromazine, thioridazine, acepromazine, digoxin, methyldigoxin, isosorbide, nitroglycerin, quinidine, disopyramide, dopamine,

dobutamine, epinephrine, etilefrine, norepinephrine, phenylephrine, dimorpholamine, doxapram, naloxone, flumazenil, tipepidine, 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, indomethacin, sulindac, ibuprofen, ketoprofen, naproxen, pranoprofen, loxoprofen, diclofenac, tiaprofenic acid, tiaramide, carbazochrome sulfonic acid, tranexamic acid, pralidoxime iodide methyl, progesterone, testosterone,

dehydroepiandrosterone, estrogen, estradiol, levonorgestrel, protamine, leucovorin, dimercaprol, deferoxamine, sodium thiosulfate, mifepristone, risperidone, olanzapine, thalidomide, civamide, acyclovir, valacyclovir, famciclovir, penciclovir, lopinavir, ritonavir, saquinavir, vidarabine, idoxuridine, nifedipine, nimodipine, amiodarone, loratadine, tretinoin, carmustine, beraprost sodium, and any combination thereof.

8. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is a small molecule drug.

9. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is an anti-migraine drug.

10. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is an ergot alkaloid.

11. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is DHE or a pharmaceutically acceptable salt thereof.

12. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is DHE mesylate.

13. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is indomethacin or a pharmaceutically acceptable salt thereof.

14. The intranasal pharmaceutical powder composition of any of claims 1-4, wherein the active agent is testosterone or a pharmaceutically acceptable salt thereof.

15. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles have an average particle size of from about 15 to about 200 μιτι, as measured by laser diffraction.

16. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles have an average particle size of from about 20 to about 50 μιτι, as measured by laser diffraction.

17. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles are spray dried, freeze-dried, or melt-extruded.

18. The intranasal pharmaceutical powder composition of any preceding claim, wherein the active agent is spray dried onto the carrier, the thickening agent, or a combination thereof.

19. The intranasal pharmaceutical powder composition of any preceding claim, wherein the solubility is measured at a pH ranging from about 6.8 to about 7.4.

20. The intranasal pharmaceutical powder composition of any preceding claim, wherein the active agent is present in an amount of about 1-30% by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

21. The intranasal pharmaceutical powder composition of any preceding claim, wherein the active agent is present in an amount of about 20% by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

22. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent that is present in an amount of about 0.05-10%) by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

23. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent that is present in an amount of about 5% by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

24. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the sugar alcohol that is present in an amount of about 10-75% by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

25. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the sugar alcohol that is present in an amount of about: 20%, 25%,

40%, or 60% by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

26. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the pH adjusting agent that is present in an amount of about 1-40% by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

27. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the pH adjusting agent that is present in an amount of about: 2.5% or 5%) by weight based on a weight of the particles or the intranasal pharmaceutical powder composition.

28. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the carrier that is at least partially water insoluble at 37± 0.5 °C.

29. The intranasal pharmaceutical powder composition of any preceding claim, wherein the water insolubility is measured at a pH ranging from about 6.8 to about 7.4.

30. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles further comprise the thickening agent, and wherein the carrier has lower water solubility than that of the thickening agent.

31. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the carrier that is at least partially adhesive to mucus.

32. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the carrier that comprises a polysaccharide, an oligosaccharide, or any combination thereof.

33. The intranasal pharmaceutical powder composition of any preceding claim, wherein the carrier comprises microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate,

hydroxypropylmethylcellulose phthalate, starch, chitosan, β cyclodextrin, or any combination thereof.

34. The intranasal pharmaceutical powder composition of any preceding claim, wherein the carrier comprises microcrystalline cellulose that has an average particle size of about 20 μιη.

35. The intranasal pharmaceutical powder composition of any preceding claim, wherein the carrier comprises a first microcrystalline cellulose that has an average particle size of about 20 μπι, as measured by laser diffraction, and a second microcrystalline cellulose that has an average particle size of about 50 μπι, as measured by laser diffraction.

36. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the carrier that has an average particle size of from about 5 to about 100 μιη, as measured by laser diffraction.

37. The intranasal pharmaceutical powder composition of any preceding claim, wherein the carrier has an average particle size of about 23 μιτι, as measured by laser diffraction.

38. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent that is at least partially water soluble at 37± 0.5 °C.

39. The intranasal pharmaceutical powder composition of any preceding claim, wherein the water solubility is measured at a pH ranging from about 6.8 to about 7.4.

40. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles further comprises the carrier, and wherein the thickening agent has higher water solubility than that of the carrier.

41. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent that binds to the active agent.

42. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles further comprise the carrier, and wherein the thickening agent binds to the active agent and the carrier.

43. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent that comprises a polysaccharide.

44. The intranasal pharmaceutical powder composition of any preceding claim, wherein the thickening agent comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose calcium, sodium

carboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, methylcellulose, polyvinylpyrrolidone, or any combination thereof.

45. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent and have an average particle size of from about 15 to about 200 μιτι, as measured by laser diffraction.

46. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the thickening agent, the sugar alcohol, and the carrier and have an average particle size of from about 15 to about 200 μιτι, as measured by laser diffraction.

47. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles have an average particle size of about 50 to about 150 μιτι, as measured by laser diffraction.

48. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles have an average particle size of about 20 to about 30 μιτι, as measured by laser diffraction.

49. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition further comprises a fluidizing agent.

50. The intranasal pharmaceutical powder composition of any preceding claim, wherein the fluidizing agent comprises a calcium phosphate.

51. The intranasal pharmaceutical powder composition of any preceding claim, wherein the calcium phosphate comprises tribasic calcium phosphate.

52. The intranasal pharmaceutical powder composition of any preceding claim, wherein when the intranasal pharmaceutical powder composition is administered to the subject, a pharmacokinetic parameter of the active agent improves by at least about: 20%, 25%, 30%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 400%, or 500%), compared to a corresponding composition that comprises the active agent in a crystalline form when administered intranasally.

53. The intranasal pharmaceutical powder composition of any preceding claim, wherein the pharmacokinetic parameter is determined with an analysis of a blood or plasma sample collected at one or more time points of 2, 5, 10, 15, 20, 30, 45, 60, 120, or 180 minutes after the intranasal administration.

54. The intranasal pharmaceutical powder composition of any preceding claim, wherein the analysis measures a plasma concentration of DHE, 8' -hydroxy -DHE, or a combination thereof in the blood or plasma sample.

55. The intranasal pharmaceutical powder composition of any preceding claim, wherein the analysis is conducted with liquid chromatography (LC), mass spectrometry (MS), or a combination thereof.

56. The intranasal pharmaceutical powder composition of any preceding claim, wherein the analysis is conducted with a LC/MS/MS method.

57. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises a greater relative bioavailability from 0 min to 15 min (rBAo-ismin), a greater relative bioavailability from 0 min to 30 min (rBAo- 30min), a greater relative bioavailability from 0 min to 60 min (rB A0-60min), or any combination thereof.

58. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises an average rBA0-i5min, and the improvement is at least about 100%.

59. The intranasal pharmaceutical powder composition of any preceding claim, wherein the average rBAo-ismin is about 120% to 1500%) in serum of the subject.

60. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises an average rBA0-30min, and the

improvement is at least about 80%>.

61. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises an average rBA0-60min, and the

improvement is at least 60%>.

62. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises a higher maximum blood concentration

63. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises a shorter time to reach maximum blood concentration (Tmax)- 64. The intranasal pharmaceutical powder composition of any preceding claim, wherein the improved pharmacokinetic parameter comprises an increased area under the curve (AUC) for blood concentration-time profile.

65. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition further comprises an additional active agent.

66. The intranasal pharmaceutical powder composition of any preceding claim, wherein the additional active agent comprises caffeine, which is amorphous, crystalline, at least 20% of amorphous by weight of the caffeine, or any combination thereof.

67. The intranasal pharmaceutical powder composition of any preceding claim, wherein 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 is amorphous.

68. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition retains at least about: 80%>, 85%>, 90%, or 95%) by weight of the active agent in a closed container after a period of at least about: 30, 60, 120, 180, 360, 720, or 1080 days.

69. The intranasal pharmaceutical powder composition of any preceding claim, wherein the container is kept at about 20°C to about 40°C at a standard atmosphere pressure with a relative humidity of about 50% to about 75%.

70. The intranasal pharmaceutical powder composition of any preceding claim, wherein the container is kept at about 25°C at a standard atmosphere pressure with a relative humidity of about 50%.

71. The intranasal pharmaceutical powder composition of any preceding claim, wherein the active agent has an average particle size of about 5 μιη or larger.

72. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the pH adjusting agent.

73. The intranasal pharmaceutical powder composition of any preceding claim, wherein the particles comprise the sugar alcohol.

74. The intranasal pharmaceutical powder composition of any preceding claim, wherein the sugar alcohol is selected from the group consisting of mannitol, glycerol, galactitol, fucitol, inositol, volemitol, maltotriitol, maltoetetraitol, polyglycitol, erythritol, threitol, ribitol, arabitol, xylitol, allitol, dulcitol, glucitol, sorbitol, altritol, iditol, maltitol, lactitol, isomalt, and any combination thereof.

75. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition comprises the active agent, the carrier that is microcrystalline cellulose, and the sugar alcohol that is mannitol.

76. The intranasal pharmaceutical powder composition of claim 75, wherein the intranasal pharmaceutical powder composition comprises dihydroergotamine or a pharmaceutically acceptable salt thereof, mannitol, and microcrystalline cellulose.

77. The intranasal pharmaceutical powder composition of claim 75 or 76, wherein the

intranasal pharmaceutical powder composition further comprises the thickening agent that is HPMC.

78. The intranasal pharmaceutical powder composition of claim 75,

wherein the intranasal pharmaceutical powder composition comprises:

1) dihydroergotamine or a pharmaceutically acceptable salt thereof that is

present in about 20% of a total weight of the intranasal pharmaceutical powder composition;

2) mannitol that is present in about 25% of the total weight of the intranasal pharmaceutical powder composition; and

3) microcrystalline cellulose that is present in about 55% of the total weight of the intranasal pharmaceutical powder composition, and

wherein the intranasal pharmaceutical powder composition have an average particle size diameter of about 20 to about 100 microns.

79. The intranasal pharmaceutical powder composition of claim 75,

wherein the intranasal pharmaceutical powder composition comprises:

1) dihydroergotamine or a pharmaceutically acceptable salt thereof that is

present in about 20% of a total weight of the intranasal pharmaceutical powder composition;

2) HPMC that is present in about 5% of the total weight of the intranasal

pharmaceutical powder composition;

3) mannitol that is present in about 25% of the total weight of the intranasal pharmaceutical powder composition; and

4) microcrystalline cellulose that is present in about 50% of the total weight of the intranasal pharmaceutical powder composition, and

wherein the intranasal pharmaceutical powder composition have an average particle size diameter of about 20 to about 100 microns.

80. The intranasal pharmaceutical powder composition of claim 75,

wherein the intranasal pharmaceutical powder composition comprises:

1) About 1 to about 8 mg of dihydroergotamine or a pharmaceutically acceptable salt thereof;

2) About 5 to about 15 mg of mannitol; and

3) About 5 to about 15 mg of microcrystalline cellulose.

81. The intranasal pharmaceutical powder composition of claim 75,

wherein the intranasal pharmaceutical powder composition comprises:

1) About 4 mg of dihydroergotamine or a pharmaceutically acceptable salt

thereof;

2) About 5 mg of mannitol; and

3) About 11 mg of microcrystalline cellulose, and

wherein the intranasal pharmaceutical powder composition have an average particle size diameter of about 20 to about 100 microns.

82. The intranasal pharmaceutical powder composition of claim 75,

wherein the intranasal pharmaceutical powder composition comprises:

1) About 4 mg of dihydroergotamine or a pharmaceutically acceptable salt

thereof;

2) About 1 mg of HPMC;

3) About 5 mg of mannitol; and

4) About 10 mg of microcrystalline cellulose, and

wherein the intranasal pharmaceutical powder composition have an average particle size diameter of about 20 to about 100 microns.

83. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition comprises indomethacin or a

pharmaceutically acceptable salt thereof, microcrystalline cellulose, and mannitol.

84. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition comprises indomethacin or a

pharmaceutically acceptable salt thereof, microcrystalline cellulose, and tribasic calcium phosphate.

85. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition comprises testosterone or a

pharmaceutically acceptable salt thereof, microcrystalline cellulose, and mannitol.

86. The intranasal pharmaceutical powder composition of any preceding claim, wherein the intranasal pharmaceutical powder composition comprises testosterone or a

pharmaceutically acceptable salt thereof, microcrystalline cellulose, and tribasic calcium phosphate.

87. A method, comprising intranasally administering to a subject an intranasal

pharmaceutical powder composition of any preceding claim.

88. The method of claim 87, wherein the method is used in the treatment or prevention of a disease or a condition in the human subject.

89. The method of claim 88, wherein the disease or condition is a headache, pain, hormone disorder, amyotrophic lateral sclerosis, Parkinson's disease, stress, anxiety, nausea, emesis, aggression, pain, neuropathic pain, sleeplessness, insomnia, restless leg syndrome, depression, or any combination thereof.

90. The method of claim 88 or 89, wherein the treatment lasts for at least one day, two days, three days, four days, five days, six days, one week, one month, or one year.

91. The method of any one of claims 87-90, wherein the administration occurs 1, 2, 3, 4, 5, 6, 7, or 8 times daily.

92. The method of any one of claims 87-91, wherein the intranasal pharmaceutical powder composition is in a single unit dose.

93. The method of any one of claims 87-92, wherein the intranasal pharmaceutical powder composition is a unit dose of from about 5 mg to about 50 mg.

94. The method of claim 93, wherein the unit dose is about 20 mg to about 30 mg.

95. The method of claim 93, wherein a unit dosage of the intranasal pharmaceutical powder composition contains about 0.1 mg to about 10 mg of the active agent.

96. The method of claim 95, wherein the active agent is present in an amount of about 4 mg.

97. The method of any one of claims 87-96, wherein the subject is a primate.

98. The method of claim 97, wherein the subject is a human.

99. The method of claim 97, wherein the subject is a monkey.

100. A method of making an intranasal pharmaceutical powder composition, comprising

spray-drying an active agent with at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any

combination thereof, to produce particles, wherein:

at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction;

when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C; and

the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction.

101. A method of making an intranasal pharmaceutical powder composition, comprising

freeze-drying an active agent with at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any

combination thereof, to produce particles, wherein:

at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction;

when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C; and

the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction.

102. A method of making an intranasal pharmaceutical powder composition, comprising melt- extruding an active agent with at least one member selected from the group consisting of a thickening agent, a carrier, a pH adjusting agent, a sugar alcohol, and any combination thereof, to produce particles, wherein:

at least about 20 percent by weight of the active agent in the particles is amorphous as determined by X-ray diffraction;

when the active agent has a crystalline form, a solubility of the active agent in a crystalline form in an aqueous liquid ranges from about 0.1 μg/mL to about 1 mg/mL in water at a temperature of 37± 0.5 °C; and

the particles have an average particle size of about 10 microns to about 300 microns, as measured by laser diffraction.

103. The method of any one of claims 100, wherein the particles comprise the active agent and the thickening agent.

104. The method of any one of claims 100 to 102, wherein the particles comprise the active agent and the carrier.

105. The method of any one of claims 100 to 102, wherein the particles comprise the active agent, the carrier, and the sugar alcohol.

106. The method of any one of claims 100 to 102, wherein the particles comprise the active agent, the carrier, and the thickening agent.

107. The method of any one of claims 100 to 105, further comprising blending the particles with an additional amount of the carrier.

108. The method of any one of claims 100 to 107, further comprising blending the particles with an additional carrier, additional thickening agent, or any combination thereof.

109. The method of any one of claims 100 to 108, wherein the particles comprise the active agent and are free from the thickening agent, the carrier, or a combination thereof.

110. The method of any one of claims 100 to 109, wherein the particles have an average

particle size of about 20 to about 50 μιτι, as measured by laser diffraction.

111. The method of any one of claims 100 to 110, wherein the particles comprise the carrier that is at least partially water insoluble at 37± 0.5 °C.

112. The method of claim 111, wherein the water insolubility is measured at a pH ranging from about 6.8 to about 7.4.

113. The method of claim 111 or 112, wherein the particles further comprise the thickening agent, and wherein the carrier has lower water solubility than that of the thickening agent.

114. The method of any one of claims 100 to 113, wherein the particles comprise the carrier that is at least partially adhesive to mucus.

115. The method of any one of claims 100 to 114, wherein the particles comprise the carrier that comprises an oligosaccharide, a polysaccharide, or any combination thereof.

116. The method of claim 115, wherein the carrier comprises microcrystalline cellulose, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, starch, chitosan, β cyclodextrin, or any combination thereof.

117. The method of any one of claims 100 to 116, wherein the particles have an average

particle size of from about 15 to about 200 μιτι, as measured by laser diffraction.

118. The method of claim 117, wherein the carrier has an average particle size of about 50 to about 150 μιη, as measured by laser diffraction.

119. The method of any one of claims 100 to 118, wherein the particles comprise the thickening agent that is at least partially water soluble 37± 0.5 °C.

120. The method of claim 119, wherein the water solubility is measured at a pH ranging from about 6.8 to about 7.4.

121. The method of claim 119 or 120, wherein the particles further comprise the carrier, and wherein the thickening agent has higher water solubility than that of the carrier.

122. The method of any one of claims 100 to 121, wherein the particles comprise the

thickening agent that binds to the active agent.

123. The method of claim 122, wherein the particles further comprise the carrier, and wherein the thickening agent binds to the active agent and the carrier.

124. The method of any one of claims 100 to 123, wherein the particles comprise thickening agent that comprises a polysaccharide.

125. The method of claim 124, wherein the thickening agent comprises hydroxypropyl

methylcellulose (HPMC), hydroxypropyl cellulose, methyl cellulose,

carboxymethylcellulose calcium, sodium carboxymethylcellulose, sodium alginate, xanthan gum, acacia, guar gum, locust bean gum, gum tragacanth, starch, carbopols, methylcellulose, polyvinylpyrrolidone, or any combination thereof.

126. The method of any one of claims 100 to 125, wherein the particles comprise the

thickening agent and have an average particle size of from about 15 to about 200 μιτι, as measured by laser diffraction.

127. The method of claim 126, wherein the particles have an average particle size of about 50 to about 150 μιτι, as measured by laser diffraction.

128. The method of any one of claims 100 to 127, wherein the active agent is suspended in methanol before the spray drying or freeze-drying.

129. The method of any one of claims 100 to 128, wherein the active agent has an average particle size of about 5 μιη or larger.

130. The method of any one of claims 100 to 129, wherein the particles comprise a pH

adjusting agent.

131. The method of any one of claims 100 to 130, wherein the particles comprise a sugar alcohol.

132. The method of claim 131, wherein the sugar alcohol is selected from the group consisting of mannitol, glycerol, galactitol, fucitol, inositol, volemitol, maltotriitol, maltoetetraitol, polyglycitol, erythritol, threitol, ribitol, arabitol, xylitol, allitol, dulcitol, glucitol, sorbitol, altritol, iditol, maltitol, lactitol, isomalt, and any combination thereof.

133. The method of any one of claims 100 to 102, wherein the intranasal pharmaceutical powder composition comprises the active agent, the thickening agent, the carrier, and the sugar alcohol.

134. A device that contains the intranasal pharmaceutical powder composition as recited in any preceding claim.

135. The device of claim 134 that is for a single use.

136. Particles, wherein the particles comprise an active agent, a carrier, a sugar alcohol, or any combination thereof.

137. The particles of claim 136, wherein the particles further comprise a thickening agent.

138. The particles of claim 136 or 137, wherein the particles are substantially uniform.

139. The particles of claim 136 or 137, wherein at least about: 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% by weight of the particles are agglomerated, aggregated, or a combination thereof.

140. The particles of claim 139, wherein the particles are substantially agglomerated,

aggregated, or a combination thereof.

141. The particles of claim 139, wherein the active agent is aggregated or agglomerated, with the carrier, the sugar alcohol, or a combination thereof.

142. The particles of claim 139, wherein the sugar alcohol is aggregated or agglomerated, with the carrier.

143. The particles of any one of claims 136 to 142, wherein the active agent is DHE or a

pharmaceutically acceptable salt thereof.

144. The particles of any one of claims 136 to 137, wherein the thickening agent is HPMC.

145. The particles of any one of claims 136 to 144, wherein the carrier is microcrystalline cellulose.

146. The particles of any one of claims 136 to 145, wherein the sugar alcohol is mannitol.

147. The particles of any one of claims 136 to 146, wherein an average diameter of the

particles is about 15 microns to about 200 microns.

148. The particles of claim 147, wherein the average diameter of the particles is about 50 microns to about 150 microns.

149. The particles of claim 147, wherein the average diameter of the particles is about 20 microns to about 50 microns.

150. The particles of any one of claims 136 to 149, wherein:

at least some of the particles substantially contain a single ingredient selected from the group consisting of the active agent, the thickening agent, the carrier, and the sugar alcohol; or

at least some of the particles contain a single ingredient selected from the group consisting of the active agent, the thickening agent, the carrier, and the sugar alcohol; or at least some of the particles contain at least two ingredients selected from the group consisting of the active agent, the thickening agent, the carrier, and the sugar alcohol; or the intranasal pharmaceutical powder composition further comprises particles that comprise the active agent and are free from the thickening agent, the carrier, or a combination thereof; or

at least some of the particles are aggregates; or

at least some of the particles are agglomerates; or

any combination thereof.

The intranasal pharmaceutical powder composition or particles recited in any preceding claim, wherein the active agent is in a freebase form, a salt form, or any combination thereof.