(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERA TION TREATY (PCT)
`
`(19) World Intellectual
`Property Organization
`International Bureau
`
`( 43) International Publication Date
`
`
`PCT
`13 November 2008 (13.11.2008)
`
`(51) International
`Patent Classification:
`A61K 31155 (2006.01)
`
`Publication Number
`
`111111 11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`(10) International
`
`WO 2008/137960 Al
`(74) Agents: GRUMBLING, Matthew, V. eta!.; Wilson Son­
`sini Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA
`94304-1050 (US).
`(21) International Application Number:
`(81) Designated States (unless
`otherwise indicated, for every
`
`PCT/US2008/062961
`
`
`kind of national protection available):
`AE, AG, AL, AM,
`
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, B Y, BZ, CA,
`(22) International
`Filing Date: 7 May 2008 (07.05.2008)
`
`CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`
`EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN,
`MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
`
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`SY, TJ, TM, TN, TR, T T, TZ, UA, UG, US, UZ, V C, V N,
`ZA, ZM,ZW.
`
`7 May 2007 (07.05.2007) US
`(84) Designated States (unless
`otherwise indicated, for every
`
`
`(71) Applicant (for all designated
`
`
`kind of regional protection available):
`ARIPO (BW, GH,
`States except US):
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`QUESTOR PHARMACEU TICALS, INC. [US/US];
`(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`ZW), Eurasian
`3260 Whipple Road, Union City, CA 94587 (US).
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`
`FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL,
`
`NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`(25) Filing Language:
`
`(26) Publication
`Language:
`
`(30) Priority Data:
`60/916,550
`
`English
`
`English
`
`(72) Inventors; and
`(75) Inventors/Applicants
`(for US only): CARTT, Steve
`[US/US]; 3260 W hipple Road, Union City, CA 94587
`(US). MEDEIROS, David [US/US]; 212 Crown Circle,
`Published:
`
`So. San Francisco, CA 94080 (US).
`
`with international search report
`
`--
`
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`
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`-
`
`== -
`
`--
`
`!!!!!!!!
`iiiiiiii
`iiiiiiii
`
`----
`
`0
`\0
`0\
`t--­
`�
`,..-.!
`..........
`QO ____________________________________________________________________ __
`
`g (54) Title: NASAL ADMINISTRATION OF BENZODIAZEPINES
`M
`0 (57) Abstract: Particulate
`> to patients.
`� treatment
`
`formulations ofbenzodiazepines, such as diazepam, are used for nasal administration of diazepine drugs
`
`
`
`
`
`
`
`
`Multimodal particulate formulations of benzodiazepines and methods for their use, e.g. by nasal administration for the
`
`of seizure, are also provided.
`
`AQUESTIVE EXHIBIT 1017 page 0000
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`

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`wo 2008/137960
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`PCT/US2008/062961
`
`NASAL ADMINISTRATION OF BENZODIAZEPINES
`
`[0001] This application claims benefit of priority of provisional application United States serial number
`
`60/916,550, filed on May 7, 2007, the entire contents of which are incorporated herein by reference.
`
`5
`
`[0002] This application relates to the administration of benzodiazepine drugs, and in particular to the nasal
`
`FIELD OF THE INVENTION
`
`administration of benzodiazepine drugs.
`
`BACKGROUND OF THE INVENTION
`
`[0003] Benzodiazepines, such as diazepam, lorazepam and medazepam, make up a class of psychoactive drugs.
`
`Most benzodiazepines are classified as anxiolytic, sedative and/or hypnotic. The class of benzodiazepines are
`
`10
`
`minor tranquilizers possessing varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and
`
`amnesic properties. Various benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and
`
`muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as
`
`endoscopies, dental work, or other medical procedures where tension and anxiety are present, and prior to some
`
`medical procedures in order to induce amnesia.
`
`15
`
`[0004] As anti-convulsants, benzodiazepines may be used separately or in adjunctive therapy. Various
`
`formulations for treatment of seizure with benzodiazepines have been developed. Generally speaking, the oral
`
`route of administration is considered sub-optimal for acute treatment of seizures, as the amount of time require
`
`for the drug to reach therapeutically relevant concentrations in the blood plasma is rather long- as much as an
`
`hour. Moreover, some benzodiazepines, such as diazepam, have poor oral bioavailability and/or suffer from
`
`20
`
`significant first-pass liver effects. Alternatives to oral dosing of benzodiazepines, including diazepam, have been
`
`developed.
`
`[0005] These alternatives include intravenous, suppository and intranasal formulations. The intravenous route
`
`provides perhaps the fastest route of administration to date; however intravenous administration is generally
`
`limited to trained health care professionals (e.g. nurses). Thus, the intravenous administration of
`
`25
`
`benzodiazepines for acute treatment of seizure is limited to tightly controlled clinical settings, such as emergency
`
`rooms and in-patient hospital and/or hospice care.
`
`[0006] Suppository formulations of benzodiazepines have a rapid onset of action and require little professional
`
`expertise for their administration. However, the inconvenience of suppositories is an obvious impediment to
`
`their being administered by anyone outside a very small group of the patient's intimate acquaintances and the
`
`30
`
`patient's professional medical caretakers. Thus, while suppository formulations have found some success in the
`
`treatment of children by their parents or guardians, they are unlikely to gain widespread acceptance as a means
`
`for acute treatment of seizure in adults outside controlled clinical environments.
`
`[0007] Nasal formulations of benzodiazepines have been suggested for the acute treatment of seizure.
`
`Benzodiazepines are quickly absorbed and transported across the mucosa of the nasal sinuses, which results in
`
`35
`
`fast achievement of pharmaceutically effective plasma levels. However, the utility of the existing nasal
`
`benzodiazepine formulations has been limited to a degree by the poor solubility of such benzodiazepines as
`
`diazepam. Nasal preparations are generally administered in metered sprays having volumes of less than 250 !J-l,
`
`- 1 -
`
`AQUESTIVE EXHIBIT 1017 page 0001
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`

`

`wo 2008/137960
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`PCT/US2008/062961
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`preferably less than 150 111, and ideally from 25 to 100 111, since administration of larger volumes usually exceeds
`
`the capacity of the nasal sinuses and results in volumes in excess of about 250 111 bypassing the sinuses and
`
`flowing down the back of the throat where it is swallowed. As smaller dose volumes are preferred for nasal
`
`administration, poor water solubility of benzodiazepines limits the effective dose that may be administered to a
`
`5
`
`patient at any given time. This in turn limits the clinical effectiveness of nasally-administered benzodiazepines
`
`for the acute treatment of seizure.
`
`[0008] There is a need for benzodiazepine formulations that are capable of providing to the nasal mucosa
`
`sufficient quantity ofbenzodiazepine in a small enough volume to provide therapeutically effective blood plasma
`
`concentration of benzodiazepine within a short period after administration of the formulation to the nasal
`
`1 0
`
`mucosa. There is also a need for methods of treating a variety of disorders, including anxiety and seizure, by
`
`administering a therapeutically effective amount of a benzodiazepine drug to the nasal mucosa. In particular,
`
`there is a need for an intranasal formulation of diazepam that is capable of producing anticonvulsant effective
`
`blood plasma levels within a short period after having been administered to a patient. There is also a need for a
`
`method of providing acute relief from seizure to a patient within a short period after administering a
`
`1 5
`
`benzodiazepine, such as diazepam, to the patient. These and other objects and advantages are provided by the
`
`invention described herein.
`
`SUMMARY OF THE INVENTION
`
`[0009] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`20
`
`composition for nasal administration of a medicament, comprising a ftrst population of particles having a ftrst
`
`effective mean particle diameter and a second population of particles having a second effective mean particle
`
`diameter, wherein the ftrst effective mean particle diameter is at least 1.5 times, at least 1.6 times, at least 1.7
`
`times, at least 1.8 times, at least 1.9 times, at least 2 times, at least 2.5 times or at least 3 times that of the second
`
`effective mean particle diameter.
`
`25
`
`(0010] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`composition for nasal administration of a medicament, comprising a ftrst population of particles having a ftrst
`
`effective mean particle diameter and a second population of particles having a second effective mean particle
`
`diameter, wherein the ftrst effective mean particle diameter is at least twice that of the second effective mean
`
`particle diameter.
`
`30
`
`[0011] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`method of using a composition for nasal administration of a medicament, comprising a ftrst population of
`
`particles having a first effective mean particle diameter and a second population of particles having a second
`
`effective mean particle diameter, wherein the ftrst effective mean particle diameter is at least 1.5 times, at least
`
`1.6 times, at least 1. 7 times, at least 1. 8 times, at least 1.9 times, at least 2 times, at least 2.5 times or at least 3
`
`35
`
`times that of the second effective mean particle diameter. The method comprises administering an effective
`
`amount of the composition to the nose by administering a therapeutically effective amount of the composition to
`
`at least one nostril.
`
`[0012] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`method of using a composition for nasal administration of a medicament, comprising a ftrst population of
`
`40
`
`particles having a rrrst effective mean particle diameter and a second population of particles having a second
`
`-2-
`
`AQUESTIVE EXHIBIT 1017 page 0002
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`

`

`wo 2008/137960
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`PCT/US2008/062961
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`effective mean particle diameter, wherein the flrst effective mean particle diameter is at least twice that of the
`
`second effective mean particle diameter. The method comprises administering an effective amount of the
`
`composition to the nose by administering a therapeutically effective amount of the composition to at least one
`
`nostril.
`
`5
`
`[0013] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`pharmaceutical particulate composition for nasal delivery of a medicament comprising particulates having a
`
`multimodal particle size distribution.
`
`[0014] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`method of using a pharmaceutical particulate composition for nasal delivery of a medicament comprising
`
`1 0
`
`particulates having a multimodal particle size distribution, comprising administering an effective amount of the
`
`composition to the nose by administering a therapeutically effective amount of the composition to at least one
`
`nostril.
`
`[0015] The foregoing and further needs are further met by embodiments of the present invention, which
`
`provide an aerosol composition of an aqueous suspension or dispersion of nanoparticulate benzodiazepine
`
`1 5
`
`particles, wherein: the droplets of the aerosol have a mass median aerodynamic diameter (MMAD) less than or
`
`equal to about 1000 f.liD and the nanoparticulate benzodiazepine particles have an effective average particle size
`
`of less than about 5000 nm.
`
`[0016] The foregoing and further needs are further met by embodiments of the present invention, which
`
`provide a method of using an aerosol composition of an aqueous suspension or dispersion of nanoparticulate
`
`20
`
`benzodiazepine particles, wherein: the droplets of the aerosol have a mass median aerodynamic diameter
`
`(MMAD) less than or equal to about 1000 !lm and the nanoparticulate benzodiazepine particles have an effective
`
`average particle size of less than about 5000 nm, the method comprising administering an effective amount of
`
`the composition to the nose by spraying a therapeutically effective amount of the composition into at least one
`
`nostril.
`
`25
`
`[0017] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`method of administering a benzodiazepine drug to a patient, comprising administering to the nose or nasal cavity
`
`an effective amount of an aerosol composition of an aqueous suspension or dispersion of nanoparticulate
`
`benzodiazepine particles, wherein: the droplets of the aerosol have a mass median aerodynamic diameter
`
`(MMAD) less than or equal to about 1000 !lm and the nanoparticulate benzodiazepine particles have an effective
`
`30
`
`average particle size of less than about 5000 nm.
`
`[0018] The foregoing and further needs are additionally met by embodiments of the present invention, which
`
`provide a pharmaceutical composition for nasal administration of benzodiazepine comprising benzodiazepine
`
`particles and one or more non-cationic surface active agents adsorbed to a surface thereof.
`
`[0019] The foregoing and further needs are further met by embodiments of the invention, which provides a
`
`35
`
`method of administering a pharmaceutical composition for nasal administration of benzodiazepine comprising
`
`benzodiazepine particles and one or more non-cationic surface active agents adsorbed to a surface thereof, the
`
`method comprising administering an effective amount of the composition to the nose by administering a
`
`therapeutically effective amount of the composition to at least one nostril.
`
`[0020] The foregoing and further needs are met by embodiments of the present invention, which provide a
`
`40
`
`method of administering a benzodiazepine drug to a patient, comprising administering to the patient's nose or
`
`-3-
`
`AQUESTIVE EXHIBIT 1017 page 0003
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`

`

`wo 2008/137960
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`PCT/US2008/062961
`
`nasal cavity a pharmaceutical composition comprising particles of a benzodiazepine drug having a surface active
`
`agent adsorbed to a surface thereof.
`
`[0021] The foregoing and further needs are met by embodiments of the present invention, which provide a non­
`
`aqueous dispersion or suspension of nanoparticulate benzodiazepine particles.
`
`5
`
`[0022] The foregoing and additional needs are further met by embodiments of the present invention, which
`
`provide a method of administering a non-aqueous dispersion or suspension of nanoparticulate benzodiazepine
`
`particles, the method comprising administering an effective amount of the dispersion or suspension to the nose
`
`by administering a therapeutically effective amount of the composition to at least one nostril.
`
`[0023] The foregoing and further needs are additionally met by embodiments of the present invention, which
`
`1 0
`
`provide, a method of administering a benzodiazepine drug to a patient, comprising administering to the patient's
`
`nose or nasal cavity a pharmaceutical composition comprising a non-aqueous dispersion or suspension of
`
`nanoparticulate benzodiazepine particles.
`
`[0024] The foregoing and additional needs are further met by embodiments of the invention, which provide a
`
`nanoparticulate composition comprising: (a) a benzodiazepine having an effective average particle size of less
`
`1 5
`
`than about 2000 nm, wherein the benzodiazepine is selected from the group consisting of alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam,
`
`halazepam, midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, midazepam, lorazepam,
`
`prazepam, quazepam, triazolam, temazepam, loprazolam, pharmaceutically acceptable salts and esters thereof,
`
`and mixtures thereof; and (b) at least one surface stabilizer. In some embodiments, the surface stabilizer is
`
`20
`
`selected from the group consisting of a nonionic surfactant, an ionic surfactant, a cationic surfactant, an anionic
`
`surfactant, and a zwitterionic surfactant.
`
`[0025] The foregoing and additional needs are further met by a method of treating a subject in need comprising
`
`administering to the subject a nanoparticulate benzodiazepine composition comprising: (a) a benzodiazepine
`
`having an effective average particle size of less than about 2000 nm, wherein the benzodiazepine is selected
`
`25
`
`from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam,
`
`demoxazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, diazepam,
`
`nitrazepam, oxazepam, midazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam,
`
`pharmaceutically acceptable salts and esters thereof, and mixtures thereof; and (b) at least one surface stabilizer.
`
`In some embodiments, the surface stabilizer is selected from the group consisting of a nonionic surfactant, an
`
`30
`
`ionic surfactant, a cationic surfactant, an anionic surfactant, and a zwitterionic surfactant.
`
`[0026] These and further advantages and characteristics of the present invention will become apparent to the
`
`person skilled in the art upon consideration of the description and claims.
`
`INCORPORATION BY REFERENCE
`
`[0027] All publications and patent applications mentioned in this specification are herein incorporated by
`
`35
`
`reference to the same extent as if each individual publication or patent application was specifically and
`
`individually indicated to be incorporated by reference.
`
`-4-
`
`AQUESTIVE EXHIBIT 1017 page 0004
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`PCT/US2008/062961
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0028] The present invention provides nasal formulations for administering benzodiazepine drugs, such as
`
`diazepam, lorazepam or midazolam, to a patient in need of therapeutic treatment with a benzodiazepine drug. In
`
`some embodiments, the invention further provides methods of administering a benzodiazepine to a patient,
`
`5
`
`comprising nasally administering an effective amount of the benzodiazepine to the patient, wherein the effective
`
`amount of the composition is effective to treat seizure, protect against seizure, reduce or ameliorate the intensity
`
`of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
`
`In some embodiments, the invention further provides methods of administering a benzodiazepine to a patient,
`
`comprising nasally administering an effective amount of the benzodiazepine to the patient, wherein the effective
`
`1 0
`
`amount of the composition is effective to provide a therapeutic effect selected from an anxiolytic effect, an
`
`anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations
`
`thereof.
`
`[0029] As used herein, the terms "average" and "mean" are synonymous, unless otherwise stated. As used
`
`herein, the terms "particle size" and "particle diameter" are synonymous, unless otherwise stated. As used
`
`15
`
`herein, the pharase "effective mean particle diameter" is intended to by synonymous with "effective average
`
`particle size" as used in United States pre-grant publication number 2006-0198896, which is incorporated herein
`
`by reference in its entirety. Effective mean particle diameter (effective average particle size) may be measured
`
`by an art-recognized method, such as by light-scattering methods, microscopy, or other appropriate methods.
`
`Redispersibility can be tested e.g. as set forth in the examples of U.S. Pat. No. 6,375,986, which is incorporated
`
`20
`
`herein by refemce.
`
`[0030]
`
`In some embodiments, the invention provides a composition for nasal administration of a medicament
`
`comprising a first population of particles having a first effective mean particle diameter and a second population
`
`of particles having a second effective mean particle diameter, wherein the first effective mean particle diameter
`
`is at least 1.5 times, at least 1.6 times, at least 1. 7 times, at least 1.8 times, at least 1.9 times, at least 2 times, at
`
`25
`
`least 2.5 times or at least 3 times that of the second effective mean particle diameter. In some embodiments, the
`
`invention provides a composition for nasal administration of a medicament comprising a first population of
`
`particles having a first effective mean particle diameter and a second population of particles having a second
`
`effective mean particle diameter, wherein the first effective mean particle diameter is at least twice that of the
`
`second effective mean particle diameter. In some embodiments, the first population of particles comprises a first
`
`30
`
`active ingredient. In some embodiments, the first population of particles and the second population of particles
`
`both comprise the first active ingredient. In some embodiments, the second population of particles comprises a
`
`second active ingredient. In some embodiments, the first population of particles, the second population of
`
`particles or both the first and second populations of particles comprise a first active ingredient and a second
`
`active ingredient. In some embodiments, the medicament comprises a benzodiazepine. In some embodiments,
`
`35
`
`the medicament comprises a benzodiazepine selected from the group consisting of: alprazolam, brotizolam,
`
`chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, flumazenil, flurazepam, halazepam,
`
`midazolam, nordazepam, medazepam, diazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam,
`
`quazepam, triazolam, temazepam, loprazolam, and pharmaceutically acceptable salts and combinations thereof.
`
`In some embodiments, the benzodiazepine comprises at least one member of the group consisting of alprazolam,
`
`40
`
`diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically
`
`-5-
`
`AQUESTIVE EXHIBIT 1017 page 0005
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`PCT/US2008/062961
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`acceptable salts and combinations thereof. In some embodiments, the benzodiazepine comprises one or more
`
`members of the group consisting of: diazepam, lorazepam, midazolam and pharmaceutically acceptable salts
`
`thereof. In some embodiments, the particles in the medicament have a mean diameter of greater than about 500
`
`nm, greater than about 1000 nm, greater than about 2000 nm, greater than about 4000 nm or greater than about
`
`5
`
`5000 nm. In some embodiments, the second population of particles or both are coated with at least one surface
`
`acting agent. In some embodiments, at least one surface acting agent is a cationic surfactant, a non-ionic
`
`surfactant, an anionic surfactant, a surface active biological modifier or a zwitterionic surfactant. In some
`
`embodiments, at least one surface acting agent is a cationic surfactant selected from the group consisting of
`
`natural phospholipids, synthetic phospholipids, quaternary ammonium compounds, benzalkonium chloride,
`
`1 0
`
`cetyltrimethylammonium bromide, chitosans, lauryldimethylbenzylammonium chloride, acyl camitine
`
`hydrochlorides, dimethyldioctadecylammomium bromide (DDAB), dioleyoltrimethylammonium propane
`
`(DOTAP), dimyristoyltrimethylammonium propane (DMTAP), dimethylaminoethanecarbamoyl cholesterol
`
`(DC-Chol), 1 ,2-diacylglycero-3-(0-alkyl)phosphocholine, 0-alkylphosphatidylcholine, alkyl pyridinium halides,
`
`and long-chain alkyl amines such as, for example, n-octylamine and oleylamine. In some embodiments, at least
`
`1 5
`
`one surface acting agent is an anionic surface active agent selected from the group consisting of natural anionic
`
`phospholipids, synthetic anionic phospholipids and anionic polymers. In some embodiments, the natural anionic
`
`phospholipids, synthetic anionic phospholipids and anionic polymers are selected from the group consisting of
`
`polyacrylic acid, carrageenan k type II, carbopol980, carbopol 974 P, carbopol971 P, polycarbophil, sodium
`
`carboxymethylcellulose, sodium hyaluronate or combinations thereof. In some embodiments, at least one
`
`20
`
`surface acting agent is selected from the group consisting of thiolated polymers. In some embodiments, the
`
`thiolated polymer is selected from the group consisting of cysteine conjugates of polyacrylic acid, polycarbophil
`
`(thiomer polycarbophil-cysteine), thiolated sodium carboxymethylcellulose, chitosan modified with 2-
`
`iminothiolate (e.g. chitosan-4-thiobutylamidine conjugates, chitosan-thioglycolic acid conjugates, chitosan­
`
`cysteine conjugates). In some embodiments, at least one surface acting agent is selected from the group
`
`25
`
`consisting of polymeric mucilaginous polysaccharides. In some embodiments, the polymeric mucilaginous
`
`polysaccharide is from the aloe vera plant. In some embodiments, at least one surface acting agent is
`
`methylcellulose, ethylcellulose, hydroxypropylmethylcellulose (HPMC) or a mixture of two or more thereof. In
`
`some embodiments, the composition comprises a third population of benzodiazepine particles having a third
`
`mean particle size distribution different from the first and second populations of particles. In some
`
`30
`
`embodiments, the composition further comprises one or more additional ingredient selected from active
`
`pharmaceutical ingredients and enhancers. In some embodiments, the first population of particles has a mean
`
`diameter in the range of about 25 to about 4000 nm and the second population of particles has a mean diameter
`
`in the range of about 500 to about 10,000 nm. In some embodiments, the first population of particles has a mean
`
`diameter in the range of about 50 to about 2000 nm and the second population of particles has a mean diameter
`
`35
`
`in the range of about 1000 nm to about 10,000 nm. In some embodiments, the frrst population of particles has a
`
`mean diameter in the range of about 50 to about 1000 nm and the second population of particles has a mean
`
`diameter in the range of about 1000 nm to about 10,000 nm. In some embodiments, the mean particle diameter
`
`of the frrst population of particles is smaller than the mean particle diameter of the second population of
`
`particles. In some embodiments, the first population of particles has a mean diameter in the range of about 50 to
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`40
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`about 500 nm and the second population of particles has a mean diameter in the range of about 2000 to about
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`10,000 nm. In some embodiments, the difference between the mean particle size of the ftrst and second
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`populations is greater than about 100 nm, greater than about 200 nm, greater than about 500 nm, greater than
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`about 1000 nm, greater than about 2000 nm, greater than about 3000 nm, greater than about 4000 nm, greater
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`than about 5000 nm, greater than about 6000 nm, greater than about 7000 nm, greater than about 8000 nm,
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`5
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`greater than about 9000 nm or greater than about 10,000 nm. In some embodiments, the difference between the
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`mean particle size of the ftrst and second particle populations is greater than about 10%, greater than about 20%
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`or greater than about 30% of the mean particle diameter of the second population of particles. In some
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`embodiments, the benzodiazepine particles do not contain solvent residues resulting from solvent extraction or
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`solvent precipitation.
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`1 0
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`[0031]
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`In some embodiments, the invention provides a method of using a composition for nasal administration
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`of a medicament, the composition comprising a ftrst population of particles having a ftrst effective mean particle
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`diameter and a second population of particles having a second effective mean particle diameter. In some
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`embodiments, the ftrst effective mean particle diameter is at least 1.5 times, at least 1.6 times, at least 1.7 times,
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`at least 1.8 times, at least 1.9 times, at least 2 times, at least 2.5 times or at least 3 times that of the second
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`15
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`effective mean particle diameter, comprising administering an effective amount of the composition to the nose
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`by administering a therapeutically effective amount of the composition to at least one nostril. In some
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`embodiments, the ftrst effective mean particle diameter is at least twice that of the second effective mean particle
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`diameter, comprising administering an effective amount of the composition to the nose by administering a
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`therapeutically effective amount of the composition to at least one nostril. In some embodiments, at least a
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`20
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`portion of the therapeutically effective amount of the composition to each nostril. In some embodiments, the
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`method comprises administering a ftrst quantity of the composition to a ftrst nostril, administering a second
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`quantity of the composition to a second nostril, and optionally after a pre-selected time delay, administering a
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`third quantity of the composition to the ftrst nostril. In some embodiments, the method further comprises
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`optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the
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`25
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`second nostril. In some embodiments, the effective amount of the composition is effective to treat seizure,
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`protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of
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`seizure, and/or prevent occurrence or re-occurrence of seizure. In some embodiments, the effective amount of
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`the composition is effective to provide a therapeutic effect selected from an anxiolytic effect, an anticonvulsant
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`effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations thereof. In some
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`30
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`embodiments, a therapeutically effective plasma level of benzodiazepine drug is obtained within about 1 hours
`
`of administration to the patient. In some embodiments, the therapeutically effective plasma level of the
`
`benzodiazepine drug is obtained within about 30 minutes of administration of the composition to the patient. In
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`some embodiments, the therapeutically effective plasma level of the benzodiazepine is obtained within about 15
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`minutes of administration of the composition to the patient. In some embodiments, the therapeutically effective
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`35
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`plasma level of benzodiazepine drug is obtained within about 10 minutes of administration ofthe composition to
`
`the patient. In some embodiments, the therapeutically effective plasma level of benzodiazepine drug is obtained
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`within about 5 minutes of administration of the composition to the patient. In some embodiments, a maximum
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`(peak) plasma concentration (Cmax) is obtained for the benzodiazepine drug at a time (Tmax) less than about 1
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`hour after administration of the composition to a patient. In some embodiments, T max is less than about 30
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`40
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`minutes after administration of the composition to the patient. In some embodiments, Tmax is less than about 15
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`minutes after administration of the composition to the patient. In some embodiments, Tmax is less than about 12
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`minutes after administration of the composition to the patient. In some embodiments, a benzodiazepine plasma
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`concentration curve having a ftrst benzodiazepine plasma concentration maximum ( Cmax 1) and a second
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`benzodiazepine plasma concentration maximum (Cmax2) is obtained. In some embodiments, the ftrst
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`5
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`benzodiazepine plasma concentration maximum (Cmaxl) is obtained from 1 to 30 minutes after administration
`
`of the composition and the second benzodiazepine plasma concentration maximum (Cmax2) is obtained from 5
`
`to 360 minutes after administration of the composition. In some embodiments, Cmax1 is obtained from 5 to 20
`
`minutes after administration of the composition and Cmax2 is obtained from 10 to 60 minutes after
`
`administration. In some embodiments, Cmax l and Cmax2 are obtained at times Tmaxl and Tmax2 that are at
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`1 0
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`least about 5 minutes, at least about 10 minutes, at least about 20 minutes or at least about 30 minutes apart. In
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`some embodiments, Cmaxl is obtained at time Tmaxl and Cmax2 is obtained at time Tmax2, wherein a
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`difference between Tmax1 and Tmax2 is from 5 to 360, from 10 to 240, from 15 to