(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0279784 A1
`Cartt et al.
`(43) Pub. Date:
`NOV. 13, 2008
`
`US 20080279784A1
`
`(54) NASAL ADMINISTRATION OF
`BENZODIAZEPINES
`
`(75) Inventors:
`
`Steve Cartt, Union City, CA (U S);
`David Medeil‘os, South San
`Francisco, CA (US)
`
`Correspondence Address:
`WILSON SONSINI GOODRICH & ROSATI
`
`PALO ALTO, CA 94304-1050 (US)
`
`(73) Assignee:
`
`QUESTCOR
`PHARMACEUTICALS, INC.,
`Union City, CA (US)
`
`(21) Appl. No.:
`
`12/116,842
`
`(
`)
`22
`
`Filed;
`
`y ,
`Ma 7 2008
`
`Related US. Application Data
`
`(60) Provisional application No. 60/916,550, ?led on May
`7’ 2007'
`
`Publication Classi?cation
`
`(5 1) Int. Cl.
`A61K 9/12
`A61K 31/5513
`
`(200601)
`(2006-01)
`
`(2006-01)
`A61K 31/5517
`(52) US. Cl. .......... .. 424/43; 514/221; 514/220; 514/219
`57
`ABSTRACT
`(
`)
`Particulate formulations of benZodiaZepines, such as diaZ
`epam, are used for nasal administration of diaZepine drugs to
`patients. Multimodal particulate formulations of benZodiaZ
`epines and methods for their use, e. g. by nasal administration
`f h
`f '
`l
`p
`'d d
`ort e treatment 0 seizure, are a so rovi e .
`
`AQUESTIVE EXHIBIT 1015 page 0000
`
`

`

`US 2008/0279784 A1
`
`Nov. 13, 2008
`
`NASAL ADMINISTRATION OF
`BENZODIAZEPINES
`
`[0001] This application claims bene?t of priority of provi
`sional application U.S. Ser. No. 60/916,550, ?led on May 7,
`2007, the entire contents of Which are incorporated herein by
`reference.
`
`FIELD OF THE INVENTION
`
`[0002] This application relates to the administration of ben
`ZodiaZepine drugs, and in particular to the nasal administra
`tion 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 classi?ed as anxiolytic, sedative and/or
`hypnotic. The class of benZodiaZepines are minor tranquiliZ
`ers possessing varying hypnotic, sedative, anxiolytic, anti
`convulsant, muscle relaxant and amnesic properties. Various
`benZodiaZepines are useful in treating anxiety, insomnia, agi
`tation, seiZures, and muscle spasms, as Well as alcohol With
`draWal. They can also be used before certain medical proce
`dures 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.
`[0004] As anti-convulsants, benZodiaZepines may be used
`separately or in adjunctive therapy. Various formulations for
`treatment of seiZure With benZodiaZepines have been devel
`oped. 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 longias
`much as an hour. Moreover, some benZodiaZepines, such as
`diaZepam, have poor oral bioavailability and/or suffer from
`signi?cant ?rst-pass liver effects. Alternatives to oral dosing
`of benZodiaZepines, including diaZepam, have been devel
`oped.
`[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 benZodiaZepines for acute treatment of sei
`Zure 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 sup
`positories is an obvious impediment to their being adminis
`tered by anyone outside a very small group of the patient’s
`intimate acquaintances and the 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 con
`trolled 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 fast achievement of pharma
`ceutically 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 [11, preferably
`less than 150 [1.1, and ideally from 25 to 100 [1.1, since admin
`istration of larger volumes usually exceeds the capacity of the
`nasal sinuses and results in volumes in excess of about 250 pl
`bypassing the sinuses and ?oWing doWn the back of the throat
`Where it is sWalloWed. As smaller dose volumes are preferred
`for nasal administration, poor Water solubility of benZodiaZ
`epines limits the effective dose that may be administered to a
`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 suf?cient
`quantity of benZodiaZepine 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 mucosa. There is also a need
`for methods of treating a variety of disorders, including anxi
`ety 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 effec
`tive 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 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 embodi
`ments of the present invention, Which provide a composition
`for nasal administration of a medicament, comprising a ?rst
`population of particles having a ?rst effective mean particle
`diameter and a second population of particles having a second
`effective mean particle diameter, Wherein the ?rst 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.
`[0010] The foregoing and further needs are met by embodi
`ments of the present invention, Which provide a composition
`for nasal administration of a medicament, comprising a ?rst
`population of particles having a ?rst effective mean particle
`diameter and a second population of particles having a second
`effective mean particle diameter, Wherein the ?rst effective
`mean particle diameter is at least tWice that of the second
`effective mean particle diameter.
`[0011] The foregoing and further needs are met by embodi
`ments of the present invention, Which provide a method of
`using a composition for nasal administration of a medica
`ment, comprising a ?rst population of particles having a ?rst
`effective mean particle diameter and a second population of
`particles having a second effective mean particle diameter,
`Wherein the ?rst 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. The method comprises administering an effective
`
`AQUESTIVE EXHIBIT 1015 page 0001
`
`

`

`US 2008/0279784 A1
`
`Nov. 13, 2008
`
`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 embodi
`ments of the present invention, Which provide a method of
`using a composition for nasal administration of a medica
`ment, comprising a ?rst population of particles having a ?rst
`effective mean particle diameter and a second population of
`particles having a second effective mean particle diameter,
`Wherein the ?rst 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.
`[0013] The foregoing and further needs are met by embodi
`ments of the present invention, Which provide a pharmaceu
`tical particulate composition for nasal delivery of a medica
`ment comprising particulates having a multimodal particle
`siZe distribution.
`[0014] The foregoing and further needs are met by embodi
`ments of the present invention, Which provide a method of
`using a pharmaceutical particulate composition for nasal
`delivery of a medicament comprising particulates having a
`multimodal particle siZe distribution, comprising administer
`ing an effective amount of the composition to the nose by
`administering a therapeutically effective amount of the com
`position to at least one nostril.
`[0015] The foregoing and further needs are further met by
`embodiments of the present invention, Which provide an aero
`sol composition of an aqueous suspension or dispersion of
`nanoparticulate benZodiaZepine particles, Wherein: the drop
`lets of the aerosol have a mass median aerodynamic diameter
`(MMAD) less than or equal to about 1000 um and the nano
`particulate benZodiaZepine particles have an effective aver
`age 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 sus
`pension or dispersion of nanoparticulate benZodiaZepine par
`ticles, Wherein: the droplets of the aerosol have a mass median
`aerodynamic diameter (MMAD) less than or equal to about
`1000 um 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 thera
`peutically effective amount of the composition into at least
`one nostril.
`[0017] The foregoing and further needs are met by embodi
`ments 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 dis
`persion of nanoparticulate benZodiaZepine particles,
`Wherein: the droplets of the aerosol have a mass median
`aerodynamic diameter (MMAD) less than or equal to about
`1000 um and the nanoparticulate benZodiaZepine particles
`have an effective 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 method of
`administering a pharmaceutical composition for nasal admin
`istration of benZodiaZepine comprising benZodiaZepine par
`ticles and one or more non-cationic surface active agents
`adsorbed to a surface thereof, the method comprising admin
`istering an effective amount of the composition to the nose by
`administering a therapeutically effective amount of the com
`position to at least one nostril.
`[0020] The foregoing and further needs are met by embodi
`ments of the present invention, Which provide a method of
`administering a benZodiaZepine drug to a patient, comprising
`administering to the patient’s nose or nasal cavity a pharma
`ceutical composition comprising particles of a benZodiaZ
`epine drug having a surface active agent adsorbed to a surface
`thereof.
`[0021] The foregoing and further needs are met by embodi
`ments of the present invention, Which provide a non-aqueous
`dispersion or suspension of nanoparticulate benZodiaZepine
`particles.
`[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 suspen
`sion of nanoparticulate benZodiaZepine particles, the method
`comprising administering an effective amount of the disper
`sion or suspension to the nose by administering a therapeuti
`cally 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 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 dis
`persion or suspension of nanoparticulate benZodiaZepine par
`ticles.
`[0024] The foregoing and additional needs are further met
`by embodiments of the invention, Which provide a nanopar
`ticulate composition comprising: (a) a benZodiaZepine hav
`ing an effective average particle siZe of less than about 2000
`nm, Wherein the benZodiaZepine is selected from the group
`consisting of alpraZolam, brotiZolam, chlordiaZepoXide, clo
`baZam, clonaZepam, cloraZepam, demoXaZepam, ?umaZenil,
`?uraZepam,
`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 ionic surfactant, a cationic surfactant, an anionic surfac
`tant, and a ZWitterionic surfactant.
`[0025] The foregoing and additional needs are further met
`by a method of treating a subject in need comprising admin
`istering to the subject a nanoparticulate benZodiaZepine com
`position comprising: (a) a benZodiaZepine having an effective
`average particle siZe of less than about 2000 nm, Wherein the
`benZodiaZepine is selected from the group consisting of
`alpraZolam, brotiZolam, chlordiaZepoXide, clobaZam, clon
`aZepam, cloraZepam, demoXaZepam, ?umaZenil, ?uraZepam,
`halaZepam, midaZolam, nordaZepam, medaZepam, diaZ
`epam, 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
`
`AQUESTIVE EXHIBIT 1015 page 0002
`
`

`

`US 2008/0279784 A1
`
`Nov. 13, 2008
`
`some embodiments, the surface stabilizer is selected from the
`group consisting of a nonionic surfactant, an 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 speci?cation are herein incorporated by reference to
`the same extent as if each individual publication or patent
`application Was speci?cally and individually indicated to be
`incorporated by reference.
`
`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, comprising nasally administer
`ing 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 sei
`Zure. In some embodiments, the invention further provides
`methods of administering a benZodiaZepine to a patient, com
`prising nasally administering an effective amount of the ben
`ZodiaZepine to the patient, Wherein the effective 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 synony
`mous, unless otherWise stated. As used herein, the phrase
`“effective mean particle diameter” is intended to by synony
`mous 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 meth
`ods. Redispersibility can be tested eg as set forth in the
`examples of Us. Pat. No. 6,375,986, Which is incorporated
`herein by reference.
`[0030] In some embodiments, the invention provides a
`composition for nasal administration of a medicament com
`prising a ?rst population of particles having a ?rst effective
`mean particle diameter and a second population of particles
`having a second effective mean particle diameter, Wherein the
`?rst 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, atleast 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. In some
`embodiments, the invention provides a composition for nasal
`administration of a medicament comprising a ?rst population
`of particles having a ?rst effective mean particle diameter and
`a second population of particles having a second effective
`
`mean particle diameter, Wherein the ?rst effective mean par
`ticle diameter is at least tWice that of the second effective
`mean particle diameter. In some embodiments, the ?rst popu
`lation of particles comprises a ?rst active ingredient. In some
`embodiments, the ?rst population of particles and the second
`population of particles both comprise the ?rst active ingredi
`ent. In some embodiments, the second population of particles
`comprises a second active ingredient. In some embodiments,
`the ?rst population of particles, the second population of
`particles or both the ?rst and second populations of particles
`comprise a ?rst active ingredient and a second active ingre
`dient. In some embodiments, the medicament comprises a
`benZodiaZepine. In some embodiments, the medicament
`comprises a benZodiaZepine selected from the group consist
`ing of: alpraZolam, brotiZolam, chlordiaZepoxide, clobaZam,
`clonaZepam, cloraZepam, demoxaZepam, ?umaZenil, ?u
`raZepam, 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 com
`prises at least one member of the group consisting of alpra
`Zolam, diaZepam, ?uraZepam, loraZepam, medaZepam, mex
`aZolam, midaZolam, temaZepam and pharmaceutically
`acceptable salts and combinations thereof. In some embodi
`ments, 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 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 sur
`factant, an anionic surfactant, a surface active biological
`modi?er 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, cetyltrimethylammonium bromide,
`chitosans, lauryldimethylbenZylammonium chloride, acyl
`carnitine hydrochlorides, dimethyldioctadecylammomium
`bromide (DDAB), dioleyoltrimethylammonium propane
`(DOTAP),
`dimyri stoyltrimethylammonium
`propane
`(DMTAP), dimethylaminoethanecarbamoyl cholesterol
`(DC-Chol), 1,2-diacylglycero-3-(O-alkyl)phosphocholine,
`O-alkylphosphatidylcholine, alkyl pyridinium halides, and
`long-chain alkyl amines such as, for example, n-octylamine
`and oleylamine. In some embodiments, at least one surface
`acting agent is an anionic surface active agent selected from
`the group consisting of natural anionic phospholipids, syn
`thetic 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, carbopol 980, carbopol 974 P, carbopol 971 P, poly
`carbophil, sodium carboxymethylcellulose, sodium hyalur
`onate or combinations thereof. In some embodiments, at least
`one 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 poly
`carbophil-cysteine), thiolated sodium carboxymethylcellu
`
`AQUESTIVE EXHIBIT 1015 page 0003
`
`

`

`US 2008/0279784 A1
`
`Nov. 13, 2008
`
`lose, chitosan modi?ed With 2-iminothiolate (e.g. chitosan
`4-thiobutylamidine conjugates, chitosan-thioglycolic acid
`conjugates, chitosan-cysteine conjugates). In some embodi
`ments, at least one surface acting agent is selected from the
`group consisting of polymeric mucilaginous polysaccha
`rides. In some embodiments, the polymeric mucilaginous
`polysaccharide is from the aloe vera plant. In some embodi
`ments, 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 differ
`ent from the ?rst and second populations of particles. In some
`embodiments, the composition further comprises one or more
`additional ingredient selected from active pharmaceutical
`ingredients and enhancers. In some embodiments, the ?rst
`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 ?rst 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 in the range of about 1000 nm to about 10,000
`nm. In some embodiments, the ?rst 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 ?rst popula
`tion of particles is smaller than the mean particle diameter of
`the second population of particles. In some embodiments, the
`?rst population of particles has a mean diameter in the range
`of about 50 to about 500 nm and the second population of
`particles has a mean diameter in the range of about 2000 to
`about 10,000 nm. In some embodiments, the difference
`betWeen the mean particle siZe of the ?rst and second popu
`lations is greater than about 100 nm, greater than about 200
`nm, greater than about 500 nm, greater than about 1000 nm,
`greater than about 2000 nm, greater than about 3000 nm,
`greater than about 4000 nm, greater than about 5000 nm,
`greater than about 6000 nm, greater than about 7000 nm,
`greater than about 8000 nm, greater than about 9000 nm or
`greater than about 10,000 nm. In some embodiments, the
`difference betWeen the mean particle siZe of the ?rst and
`second particle populations is greater than about 10%, greater
`than about 20% or greater than about 30% of the mean par
`ticle diameter of the second population of particles. In some
`embodiments, the benZodiaZepine particles do not contain
`solvent residues resulting from solvent extraction or solvent
`precipitation.
`[0031] In some embodiments, the invention provides a
`method of using a composition for nasal administration of a
`medicament, the composition comprising a ?rst population of
`particles having a ?rst effective mean particle diameter and a
`second population of particles having a second effective mean
`particle diameter. In some embodiments, the ?rst 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, comprising administering
`an effective amount of the composition to the nose by admin
`istering a therapeutically effective amount of the composition
`to at least one nostril. In some embodiments, the ?rst effective
`mean particle diameter is at least tWice that of the second
`effective mean particle diameter, comprising administering
`
`an effective amount of the composition to the nose by admin
`istering a therapeutically effective amount of the composition
`to at least one nostril. In some embodiments, at least a portion
`of the therapeutically effective amount of the composition to
`each nostril. In some embodiments, the method comprises
`administering a ?rst quantity of the composition to a ?rst
`nostril, administering a second quantity of the composition to
`a second nostril, and optionally after a pre-selected time
`delay, administering a third quantity of the composition to the
`?rst nostril. In some embodiments, the method further com
`prises optionally after a pre-selected time delay, administer
`ing at least a fourth quantity of the composition to the second
`nostril. In some embodiments, the effective amount of the
`composition is effective to treat seiZure, protect against sei
`Zure, reduce or ameliorate the intensity of seiZure, reduce or
`ameliorate the frequency of seiZure, and/or prevent occur
`rence or re-occurrence of seiZure. In some embodiments, the
`effective amount of the composition is effective to provide a
`therapeutic effect selected from an anxiolytic effect, an anti
`convulsant effect, a sedative effect, a skeletal muscle relaxant
`effect, an amnesic effect or combinations thereof. In some
`embodiments, a therapeutically effective plasma level of ben
`ZodiaZepine drug is obtained Within about 1 hours of admin
`istration to the patient. In some embodiments, the therapeu
`tically effective plasma level of the benZodiaZepine drug is
`obtained Within about 30 minutes of administration of the
`composition to the patient. In some embodiments, the thera
`peutically effective plasma level of the benZodiaZepine is
`obtained Within about 15 minutes of administration of the
`composition to the patient. In some embodiments, the thera
`peutically effective plasma level of benZodiaZepine drug is
`obtained Within about 10 minutes of administration of the
`composition to the patient. In some embodiments, the thera
`peutically effective plasma level of benZodiaZepine drug is
`obtained Within about 5 minutes of administration of the
`composition to the patient. In some embodiments, a maxi
`mum (peak) plasma concentration (Cmax) is obtained for the
`benZodiaZepine drug at a time (Tmax) less than about 1 hour
`after administration of the composition to a patient. In some
`embodiments, Tmax is less than about 30 minutes after admin
`istration of the composition to the patient. In some embodi
`ments, Tmax is less than about 15 minutes after administration
`of the composition to the patient. In some embodiments, Tmax
`is less than about 12 minutes after administration of the com
`position to the patient. In some embodiments, a benZodiaZ
`epine plasma concentration curve having a ?rst benZodiaZ
`epine plasma concentration maximum (Cmaxl) and a second
`benZodiaZepine plasma concentration maximum (Cmax2) is
`obtained. In some embodiments, the ?rst 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 administra
`tion 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, Cmax1 and
`Cmax2 are obtained at times Tmax1 and Tmax2 that are at
`least about 5 minutes, at least about 10 minutes, at least about
`20 minutes or at least about 30 minutes apart. In some
`embodiments, Cmax1 is obtained at time Tmax1 and Cmax2
`is obtained at time Tmax2, Wherein a difference betWeen
`Tmax1 and Tmax2 is from 5 to 360, from 10 to 240, from 15
`to 120 or from 20 to 60 minutes. In some embodiments, a
`
`AQUESTIVE EXHIBIT 1015 page 0004
`
`

`

`US 2008/0279784 A1
`
`Nov. 13, 2008
`
`benZodiaZepine plasma concentration curve having a plasma
`benZodiaZepine concentration maximum (Cmax) and a shoul
`der (Cshoulder) is obtained. In some embodiments, the shoul
`der occurs Within about 1 minute, Within about 5 minutes,
`Within about 10 minutes, Within about 15 minutes or Within
`about 30 minutes of time (Tmax) When the concentration
`maximum (Cmax) occurs. In some embodiments, a benZodi
`aZepine plasma concentration curve having a single plasma
`benZodiaZepine concentration maximum (Cmax) is obtained.
`In some embodiments, Cmax is obtained Within about 5 min
`utes, Within about 10 minutes, Within about 20 minutes,
`Within about 30 minutes or Within about 60 minutes of admin
`istering the medicament to the patient. in some embodiments,
`the plasma benZodiaZepine concentration is in the range of 5
`to 95% of Cmax from 30 to 720 minutes after the time (Tmax)
`When Cmax is obtained. In some embodiments, the plasma
`benZodiaZepine concentration is in the range of 5 to 95% of
`C from 30 to 360 minutes after the time (Tmax) When Cmax
`ismgbtained. In some embodiments, the plasma benZodiaZ
`epine concentration is in the range of 10 to 90 of Cmax from 30
`to 720 minutes after the time (Tmax) When Cmax is obtained. In
`some embodiments, the plasma benZodiaZepine concentra
`tion is in the range of 10 to 90 of Cmax from 60 to 360 minutes
`after the time (Tmax) When Cmax is obtained. In some embodi
`ments, the plasma benZodiaZepine concentration is in the
`range of 15 to 60% of Cmax from 30 to 720 minutes after the
`time (Tmax) When Cmax is obtained. In some embodiments, the
`plasma benZodiaZepine concentration is in the range of 15 to
`60% of Cmax from 60 to 360 minutes after the time (Tmax)
`When Cmax is obtained. In some embodiments, the plasma
`benZodiaZepine concentration is in the range of 20 to 55% of
`Cmax from 30 to 720 minutes after the time (Tmax) When Cmax
`is obtained. In some embodiments, the plasma benZodiaZ
`epine concentration is in the range of 20 to 55% of Cmax from
`60 to 360 minutes after the time (Tmax) When Cmax is obtained.
`[0032] In some embodiments, the invention provides a
`pharmaceutical particulate composition for nasal delivery of
`a medica