(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2009/0258865 A1
`Cartt et al.
`(43) Pub. Date:
`Oct. 15, 2009
`
`US 20090258865A1
`
`(54) ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`(75) Inventors:
`
`Steve Cartt, Union City, CA (U S);
`David Medeims, South San
`giadlsrihomas
`Andrew LoXley, Philadelphia, PA
`(Pg
`Hale,
`San Diego, CA (US)
`
`Correspondence Addressi
`WILSON, SONSINI, GOODRICH & ROSATI
`650 PAGE MILL ROAD
`PALO ALTO, CA 94304-1050 (US)
`
`(73) Assigneej
`
`HALE BIOPH ARM A
`VENTURES, LLC, Encinitas, CA
`(Us)
`
`(21) Appl. No.:
`
`12/413,439
`
`(22) Filed:
`
`Mar. 27, 2009
`
`Related US. Application Data
`(60) ggrgoéiggosnal application No. 61/040,558, ?led on Mar.
`’
`'
`
`Publication Classi?cation
`
`(51) IIlt- Cl
`(2006.01)
`A61K 31/5513
`(52) us. Cl. ...................................................... .. 514/221
`
`(57)
`
`ABSTRACT
`
`The invention relates to pharmaceutical compositions com
`prising one or more benZodiaZepine drugs for nasal adminis
`tration, methods for producing and for using such composi
`tions.
`
`AQUESTIVE EXHIBIT 1010 page 0000
`
`

`

`US 2009/0258865 A1
`
`Oct. 15, 2009
`
`ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`[0001] This application claims priority under 35 U.S.C. §
`1 19(e) from US. provisional patent application No. 61/040,
`558, Which Was ?led on Mar. 28, 2008, and Which is incor
`porated herein in its entirety.
`
`FIELD OF THE INVENTION
`
`[0002] This application relates to the nasal administration
`of benZodiaZepine drugs and combinations thereof.
`
`BACKGROUND OF THE INVENTION
`
`[0003] By Way of non-limiting example, the benZodiaZ
`epine family consists of drugs such as diaZepam, loraZepam,
`and medaZepam. The drugs in this family have been observed
`as possessing sedative, tranquiliZing and muscle relaxing
`properties. They are frequently classi?ed as an anxiolytic and
`skeletal muscle relaxants. They are thought to be useful in
`preventing, treating, or ameliorating the symptoms of anxi
`ety, insomnia, agitation, seiZures (such as those caused by
`epilepsy), muscle spasms and rigidity (Which can be caused
`by tetanus), the symptoms of drug WithdraWal associated With
`the continuous abuse of central nervous system depressants,
`and exposure to nerve agents.
`[0004] BenZodiaZepines are thought to act by binding to the
`GABAA receptor of a neuron, possibly causing the receptor to
`change shape and making it more accessible to gama-ami
`nobutyric acid (GABA).
`[0005] GABA is an inhibitory neurotransmitter that, When
`bound to the GABAA receptor, facilitates Cl- ions ?ooding
`into the neuron to Which the receptor is bound. The increase in
`C1“ ions hyperpolariZes the membrane of the neuron. This
`completely or substantially reduces the ability of the neuron
`to carry an action potential. Targeting this receptor is particu
`larly useful in treating many disorders, such as tetanus and
`epilepsy, Which may result from too many action potentials
`proceeding through the nervous system.
`[0006] Current formulations of benZodiaZepine drugs can
`be administered orally, rectally, or parenterally. The ability to
`utiliZe these and other types of formulations has been signi?
`cantly limited due, in many cases, to solubility challenges.
`[0007] The oral route of administration may be considered
`sub-optimal due to several disadvantages. For example, the
`amount of time required for an orally administered benZodi
`aZepine drug to reach therapeutically relevant concentrations
`in blood plasma may be rather long, such as an hour or more.
`Moreover, as benZodiaZepine drugs pass through the liver a
`signi?cant amount may be metaboliZed. Thus, it may require
`large doses to achieve therapeutic plasma levels. Further
`more, due to the nature of seiZures and muscle spasms, it can
`be extremely dif?cult for either a patient or a care-giver to
`administer the benZodiaZepine drug orally.
`[0008] Intravenous administration perhaps provides a
`faster route of administration. HoWever intravenous admin
`istration is generally limited to trained health care profession
`als in tightly controlled clinical settings. Additionally, steril
`ity must be maintained. Furthermore, administering any drug
`intravenously can be painful and is likely impractical for
`patients suffering from a phobia of needles.
`[0009] Suppository compositions of benZodiaZepine drugs
`can have a rapid onset of action. 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 patient’s profes
`sional medical caretakers.
`
`SUMMARY OF THE INVENTION
`
`[0010] In some embodiments, the pharmaceutical compo
`sition for nasal administration comprises: a benZodiaZepine
`drug; one or more natural or synthetic tocopherols or tocot
`rienols, or any combinations thereof, in an amount from about
`30% to about 95% (W/W); and one or more alcohols or gly
`cols, or any combinations thereof, in an amount from about
`5% to about 70% (W/W), preferably about 10% to about 70%
`(W/W) in a pharmaceutically-acceptable formulation for
`administration to one or more nasal mucosal membranes of
`the patient. In some embodiments the benZodiaZepine drug is
`dissolved in the one or more natural or synthetic tocopherols
`or tocotrienols, or any combinations thereof, in an amount
`from about 30% to about 95% (W/W); and the one or more
`alcohols or glycols, or any combinations thereof, in an
`amount from about 5% to about 70% (W/W), preferably about
`10% to about 70% (W/W). In some embodiments, the benZo
`diaZepine drug is dissolved in a carrier system. In some
`embodiments, at least part of the benZodiaZepine drug is in a
`form comprising benZodiaZepine microparticles, nanopar
`ticles or combinations thereof. In some embodiments, the
`composition is substantially free of benZodiaZepine micro
`particles, nanoparticles or combinations thereof.
`[0011] In some embodiments, the benZodiaZepine drug is
`selected from the group consisting of: alpraZolam, broti
`Zolam, chlordiaZepoxide, clobaZam, clonaZepam, clo
`raZepam, demoxaZepam, diaZepam, ?umaZenil, ?uraZepam,
`halaZepam,
`midaZolam,
`nordaZepam,
`medaZepam,
`nitraZepam, oxaZepam, medaZepam, loraZepam, praZepam,
`quaZepam, triaZolam, temaZepam, lopraZolam, any pharma
`ceutically-acceptable salts thereof, and any combinations
`thereof. In some embodiments, the benZodiaZepine drug is
`diaZepam, or a pharmaceutically-acceptable salt thereof. In
`some embodiments, the benZodiaZepine drug comprises ben
`ZodiaZepine microparticles, nanoparticles, or combinations
`thereof. In some embodiments, the benZodiaZepine nanopar
`ticles have an effective average particle siZe of less than about
`5000 nm. In some embodiments, the benZodiaZepine drug is
`substantially free of benZodiaZepine microparticles, nanopar
`ticles or combinations thereof.
`[0012] In some embodiments, the one or more natural or
`synthetic tocopherols or tocotrienols are selected from the
`group consisting of: ot-tocopherol, [3-tocopherol, y-toco
`pherol, o-tocopherol, ot-tocotrienol, [3-tocotrienol, y-tocot
`rienol, o-tocotrienol, tocophersolan, any isomers thereof, any
`esters thereof, any analogs or derivatives thereof, and any
`combinations thereof. In some embodiments, a synthetic
`tocopherol can include Vitamin E TPGS (Vitamin E polyeth
`ylene glycol succinate). In some embodiments, on the other
`hand, synthetic tocopherols exclude tocopherols covalently
`bonded or linked (eg through a diacid linking group) to a
`glycol polymer, such as polyethylene glycol). Thus, in some
`embodiments, the compositions described herein exclude
`Vitamin E TPGS.
`[0013] In some embodiments, one or more alcohols are
`selected from the group consisting of: ethanol, propyl alco
`hol, butyl alcohol, pentanol, benZyl alcohol, any isomers
`thereof, or any combinations thereof. In some embodiments,
`the one or more glycols are selected from the group consisting
`
`AQUESTIVE EXHIBIT 1010 page 0001
`
`

`

`US 2009/0258865 A1
`
`Oct. 15, 2009
`
`of: ethylene glycol, propylene glycol, butylene glycol, pen
`tylene glycol, any isomers thereof, and any combinations
`thereof. In some preferred embodiments, the glycols exclude
`glycol polymers. In some preferred embodiments, the glycols
`exclude glycol polymers having an average molecular Weight
`of greater than 200. In some embodiments, the glycols
`exclude polyethylene glycol having an average molecular
`Weight of greater than about 200.
`[0014] In some embodiments, the benZodiaZepine drug is
`present in the carrier system in a concentration from about 1
`mg/mL to about 600 mg/mL. In some embodiments, the
`benZodiaZepine drug is present in a carrier system in a con
`centration from about 10 mg/mL to about 250 mg/mL. In
`some embodiments, the benZodiaZepine is present in a carrier
`system in a concentration from about 20 mg/mL to about 50
`mg/mL.
`[0015] In some embodiments, the carrier system comprises
`one or more natural or synthetic tocopherols or tocotrienols,
`or any combinations thereof, in an amount from about 45% to
`about 85% (W/W). In some embodiments, the carrier system
`comprises one or more natural or synthetic tocopherols or
`tocotrienols, or any combinations thereof, in an amount from
`about 60% to about 75% (W/W). In some embodiments, the
`carrier system comprises one or more natural or synthetic
`tocopherols or tocotrienols, or any combinations thereof, in
`an amount of about 70% (W/W).
`[0016] In some embodiments, the carrier system comprises
`one or more alcohols or glycols, or any combinations thereof,
`in an amount from about 10% to about 70% (W/W). In some
`embodiments, the carrier system comprises one or more alco
`hols or glycols, or any combinations thereof, in an amount
`from about 15% to about 55% (W/W).
`[0017] In some embodiments, the carrier system comprises
`one or more alcohols or glycols, or any combinations thereof,
`in an amount from about 25% to about 40% (W/W). In some
`embodiments, the carrier system comprises one or more alco
`hols or glycols, or any combinations thereof, in an amount of
`about 30% (W/W).
`[0018] In some embodiments, the composition comprises
`at least one additional ingredient selected from the group
`consisting of: active pharmaceutical ingredients; enhancers;
`excipients; and agents used to adjust the pH, buffer the com
`position, prevent degradation, and improve appearance, odor,
`or taste.
`[0019] In some embodiments, the composition comprises
`one or more additional excipients, such as one or more para
`bens, one or more povidones, and/or one or more alkyl gly
`cosides.
`[0020] The invention also discloses a method of treating a
`patient With a disorder that may be treatable With a benZodi
`aZepine drug. In some embodiments, the patient is a human.
`In some embodiments, the method comprises: administering
`to one or more nasal mucosal membranes of a patient a
`pharmaceutical composition for nasal administration com
`prising a benZodiaZepine drug; one or more natural or syn
`thetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from about 30% to about 95% (W/W);
`and one or more alcohols or glycols, or any combinations
`thereof, in an amount from about 5% to about 70%, preferably
`about 10% to about 70% (W/W). In some embodiments, the
`benZodiaZepine is dissolved in the one or more natural or
`synthetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from about 30% to about 95% (W/W);
`and the one or more alcohols or glycols, or any combinations
`
`thereof, in an amount from about 5% to about 70%, preferably
`about 10% to about 70% (W/W). In some embodiments, the
`benZodiaZepine drug is dissolved in a carrier system. In some
`embodiments, the benZodiaZepine drug includes benZodiaZ
`epine microparticles, nanoparticles, or combinations thereof.
`In some embodiments, the composition is substantially free
`of benZodiaZepine microparticles, nanoparticles or combina
`tions thereof.
`[0021] In some embodiments, the benZodiaZepine drug is
`selected from the group consisting of: alpraZolam, broti
`Zolam, chlordiaZepoxide, clobaZam, clonaZepam, clo
`raZepam, demoxaZepam, diaZepam, ?umaZenil, ?uraZepam,
`halaZepam,
`midaZolam,
`nordaZepam,
`medaZepam,
`nitraZepam, oxaZepam, medaZepam, loraZepam, praZepam,
`quaZepam, triaZolam, temaZepam, lopraZolam, or any phar
`maceutically-acceptable salts thereof, and any combinations
`thereof. In some embodiments, the benZodiaZepine drug is
`diaZepam, or a pharmaceutically-acceptable salt thereof. In
`some embodiments, the benZodiaZepine drug is fully dis
`solved in a single phase comprising one or more one or more
`natural or synthetic tocopherols or tocotrienols and one or
`more alcohols or glycols. In some embodiments, the benZo
`diaZepine drug comprises benZodiaZepine microparticles,
`nanoparticles, or combinations thereof. In some such
`embodiments, the composition further comprises Water. In
`some embodiments, the benZodiaZepine nanoparticles have
`an effective average particle siZe of less than about 5000 nm.
`In some embodiments, the composition is substantially free
`of benZodiaZepine microparticles, nanoparticles or combina
`tions thereof.
`[0022] In some embodiments, the one or more natural or
`synthetic tocopherols or tocotrienols are selected from the
`group consisting of: ot-tocopherol, [3-tocopherol, y-toco
`pherol, o-tocopherol, ot-tocotrienol, [3-tocotrienol, y-tocot
`rienol, o-tocotrienol, tocophersolan, any isomers thereof, any
`esters thereof, any analogs or derivatives thereof, and any
`combinations thereof.
`[0023] In some embodiments, the one or more alcohols are
`selected from the group consisting of: ethanol, propyl alco
`hol, butyl alcohol, pentanol, benZyl alcohol, any isomers
`thereof, and any combinations thereof. In some embodi
`ments, the one or more glycols are selected from the group
`consisting of: ethylene glycol, propylene glycol, butylene
`glycol, pentylene glycol, any isomers thereof, and any com
`binations thereof. In some embodiments, the alcohol or gly
`col is free of Water (dehydrated, USP). In some embodiments,
`the alcohol is ethanol (dehydrated, USP).
`[0024] In some embodiments, the benZodiaZepine drug is
`present in the carrier system in a concentration from about 1
`mg/mL to about 600 mg/mL. In some embodiments, the
`benZodiaZepine drug is present in the carrier system in a
`concentration of from about 10 mg/mL to about 250 mg/mL.
`In some embodiments, the benZodiaZepine drug is present in
`the carrier system in a concentration of from about 20 mg/mL
`to about 50 mg/mL.
`[0025] In some embodiments, the carrier system comprises
`one or more natural or synthetic tocopherols or tocotrienols,
`or any combinations thereof, in an amount from about 45% to
`about 85% (W/W). In some embodiments, the carrier system
`comprises one or more natural or synthetic tocopherols or
`tocotrienols, or any combinations thereof, in an amount from
`about 60% to about 75% (W/W). In some embodiments, the
`carrier system comprises one or more natural or synthetic
`
`AQUESTIVE EXHIBIT 1010 page 0002
`
`

`

`US 2009/0258865 A1
`
`Oct. 15, 2009
`
`tocopherols or tocotrienols, or any combinations thereof, in
`an amount of about 70% (W/W).
`[0026] In some embodiments, the carrier system comprises
`one or more alcohols or glycols, or any combinations thereof,
`in an amount from about 15% to about 55% (W/W). In some
`embodiments, the carrier system comprises one or more alco
`hols or glycols, or any combinations thereof, in an amount
`from about 25% to about 40% (W/W). In some embodiments,
`the carrier system comprises one or more alcohols or glycols,
`or any combinations thereof, in an amount from about 30%
`(W/W).
`[0027] In some embodiments, the composition comprises
`at least one additional ingredient selected from the group
`consisting of: active pharmaceutical ingredients; enhancers;
`excipients; and agents used to adjust the pH, buffer the com
`position, prevent degradation, and improve appearance, odor,
`or taste.
`[0028] In some embodiments, the composition is in a phar
`maceutically-acceptable spray formulation, and further com
`prising administering the composition to one or more nasal
`mucosal membranes of the patient. In some embodiments, the
`therapeutically effective amount is from about 1 mg to about
`20 mg of the benZodiaZepine. In some embodiments, the
`pharmaceutical composition is in a pharmaceutically-accept
`able spray formulation having volume from about 10 [LL to
`200 ML.
`[0029] In some embodiments, the administration of the
`composition comprises spraying at least a portion of the
`therapeutically effective amount of the composition into at
`least one nostril. In some embodiments, the administration of
`the composition comprises spraying at least a portion of the
`therapeutically effective amount of the composition into each
`nostril. In some embodiments, the administration of the com
`position comprises spraying a ?rst quantity of the composi
`tion into the ?rst nostril, spraying a second quantity of the
`composition into a second nostril, and optionally after a pre
`selected time delay, spraying a third quantity of the compo
`sition into the ?rst nostril. Some embodiments further com
`prise,
`optionally after a pre-selected time delay,
`administering at least a fourth quantity of the composition to
`the second nostril.
`[0030] In some embodiments, the administration of the
`composition begins at any time before or after onset of symp
`toms of a disorder Which may be treatable With the composi
`tion.
`[0031] Additional embodiments, uses, and advantages of
`the invention Will become apparent to the person skilled in the
`art upon consideration of the disclosure set forth herein.
`
`INCORPORATION BY REFERENCE
`
`[0032] All publications, patents, and patent applications
`mentioned in this speci?cation are herein incorporated by
`reference to the same extent as if each individual publication,
`patent, or patent application Was speci?cally and individually
`indicated to be incorporated by reference.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0033] Provided herein are pharmaceutical compositions
`of one or more benZodiaZepine drugs and methods of using
`such pharmaceutical compositions. Such pharmaceutical
`compositions are administered nasally.
`[0034] In some embodiments, the pharmaceutical compo
`sition for nasal administration comprises: a benZodiaZepine
`
`drug; one or more natural or synthetic tocopherols or tocot
`rienols, or any combinations thereof, in an amount from about
`30% to about 95% (W/W); and one or more alcohols or gly
`cols, or any combinations thereof, in an amount from about
`10% to about 70% (W/W) in a pharmaceutically-acceptable
`formulation for administration to one or more nasal mucosal
`membranes of the patient. In some embodiments the benZo
`diaZepine drug is dissolved in the one or more natural or
`synthetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from about 30% to about 95% (W/W);
`and the one or more alcohols or glycols, or any combinations
`thereof, in an amount from about 10% to about 70% (W/W). In
`some embodiments, the benZodiaZepine drug is dissolved in a
`carrier system. In some embodiments, at least part of the
`benZodiaZepine drug is in a form of microparticles, nanopar
`ticles, or combinations thereof. In some embodiments, the
`composition is substantially free of benZodiaZepine micro
`particles, nanoparticles or combinations thereof.
`[0035] In some embodiments, the pharmaceutical compo
`sition for nasal administration comprises: a benZodiaZepine
`drug; one or more natural or synthetic tocopherols or tocot
`rienols, or any combinations thereof, in an amount from about
`30% to about 95% (W/W); and one or more alcohols or gly
`cols, or any combinations thereof, in an amount from about
`5% to about 70% (W/W) in a pharmaceutically-acceptable
`formulation for administration to one or more nasal mucosal
`membranes of the patient. In some embodiments the benZo
`diaZepine drug is dissolved in the one or more natural or
`synthetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from about 30% to about 95% (W/W);
`and the one or more alcohols or glycols, or any combinations
`thereof, in an amount from about 5% to about 70% (W/W). In
`some embodiments, the benZodiaZepine drug is dissolved in a
`carrier system. In some embodiments, at least part of the
`benZodiaZepine drug is in a form of microparticles, nanopar
`ticles, or combinations thereof. In some embodiments, the
`composition is substantially free of benZodiaZepine micro
`particles, nanoparticles or combinations thereof.
`[0036] In some embodiments, the benZodiaZepine drug is
`selected from the group consisting of: alpraZolam, broti
`Zolam, chlordiaZepoXide, clobaZam, clonaZepam, clo
`raZepam, demoXaZepam, diaZepam, ?umaZenil, ?uraZepam,
`halaZepam,
`midaZolam,
`nordaZepam,
`medaZepam,
`nitraZepam, oxaZepam, medaZepam, loraZepam, praZepam,
`quaZepam, triaZolam, temaZepam, lopraZolam, any pharma
`ceutically-acceptable salts thereof, and any combinations
`thereof. In some embodiments, the benZodiaZepine drug is
`diaZepam, or a pharmaceutically-acceptable salt thereof. In
`some embodiments, the benZodiaZepine drug comprises ben
`ZodiaZepine microparticles, nanoparticles, or combinations
`thereof. In some embodiments, the benZodiaZepine nanopar
`ticles have an effective average particle siZe of less than about
`5000 nm. In some embodiments, the composition is substan
`tially free of benZodiaZepine microparticles, nanoparticles or
`combinations thereof.
`[0037] In some embodiments, the one or more natural or
`synthetic tocopherols or tocotrienols are selected from the
`group consisting of: ot-tocopherol, [3-tocopherol, y-toco
`pherol, o-tocopherol, ot-tocotrienol, [3-tocotrienol, y-tocot
`rienol, o-tocotrienol, tocophersolan, any isomers thereof, any
`esters thereof, any analogs or derivatives thereof, and any
`combinations thereof. In some embodiments, the carrier sys
`tem includes one or more synthetic tocopherols having a
`polymer glycol covalently bonded or linked to a tocopherol
`
`AQUESTIVE EXHIBIT 1010 page 0003
`
`

`

`US 2009/0258865 A1
`
`Oct. 15, 2009
`
`core, such as Vitamin E TPGS, Which is described in Us. Pat.
`No. 6,193,985, Which is incorporated herein by reference in
`its entirety.
`[0038] In particular, it has been found that in some particu
`late suspensions of benZodiaZepines, Wherein the benZodiaZ
`epine is not dissolved in a tocopherol phase, Vitamin E TPGS
`can be a desirable excipient for stabilizing the particulate
`(microparticle, nanoparticle or combination) suspension. In
`some embodiments, on the other hand, the carrier system
`speci?cally excludes synthetic tocopherols having a polymer
`glycol covalently bonded or linked to a tocopherol core, such
`as Vitamin E TPGS, Which is described in Us. Pat. No.
`6,193,985, Which is incorporated herein by reference in its
`entirety.
`[0039] In some embodiments, one or more alcohols are
`selected from the group consisting of: ethanol, propyl alco
`hol, butyl alcohol, pentanol, benZyl alcohol, any isomers
`thereof, or any combinations thereof. In some embodiments,
`the alcohol is ethanol (dehydrated, USP). In some embodi
`ments, the one or more glycols are selected from the group
`consisting of: ethylene glycol, propylene glycol, butylene
`glycol, pentylene glycol, any isomers thereof, and any com
`binations thereof. In some embodiments, the glycol is propy
`lene glycol USP. In some embodiments, a synthetic toco
`pherol can include Vitamin E TPGS (Vitamin E polyethylene
`glycol succinate). In some embodiments, on the other hand,
`synthetic tocopherols exclude tocopherols covalently bonded
`or linked (eg through a diacid linking group) to a glycol
`polymer, such as polyethylene glycol). Thus, in some
`embodiments, the compositions described herein exclude
`Vitamin E TPGS.
`[0040] In some embodiments, the benZodiaZepine drug is
`present in the carrier system in a concentration from about 1
`mg/mL to about 600 mg/mL. In some embodiments, the
`benZodiaZepine drug is present in a carrier system in a con
`centration from about 10 mg/mL to about 250 mg/mL. In
`some embodiments, the benZodiaZepine is present in a carrier
`system in a concentration from about 20 mg/mL to about 50
`mg/mL.
`[0041] In some embodiments, the carrier system comprises
`one or more natural or synthetic tocopherols or tocotrienols,
`or any combinations thereof, in an amount from about 45% to
`about 85% (W/W). In some embodiments, the carrier system
`comprises one or more natural or synthetic tocopherols or
`tocotrienols, or any combinations thereof, in an amount from
`about 60% to about 75% (W/W). In some embodiments, the
`carrier system comprises one or more natural or synthetic
`tocopherols or tocotrienols, or any combinations thereof, in
`an amount of about 70% (W/W). In some embodiments, a
`synthetic tocopherol can include Vitamin E TPGS (Vitamin E
`polyethylene glycol succinate). In some embodiments, on the
`other hand, synthetic tocopherols exclude tocopherols
`covalently bonded or linked (eg through a diacid linking
`group) to a glycol polymer, such as polyethylene glycol).
`Thus, in some embodiments, the compositions described
`herein exclude Vitamin E TPGS.
`[0042] In some embodiments, the carrier system comprises
`one or more alcohols or glycols, or any combinations thereof,
`in an amount from about 10% to about 55%, about 10% to
`about 40%, about 10% to about 35%, about 12% to about
`55%, about 12% to about 40%, about 12% to about 35%,
`about 15% to about 55%, about 15% to about 40%, about 15%
`to about 35%, about 10%, about 12.5%, about 15%, about
`17.5%, about 20%, about 22.5%, about 25%, about 27.5%,
`
`about 30%, about 32.5%, about 35%, about 37.5%, about
`40%, about 42.5%, about 45%, about 47.5%, about 50%,
`about 52.5% or about 55% (W/W). In some embodiments, the
`carrier system comprises one or more alcohols or glycols, or
`any combinations thereof, in an amount from about 25% to
`about 40% (W/W). In some embodiments, the carrier system
`comprises one or more alcohols or glycols, or any combina
`tions thereof, in an amount of about 30% (W/W). In some
`embodiments, the alcohol is ethanol or contains ethanol. In
`some preferred embodiments, the glycols exclude glycol
`polymers. In some preferred embodiments, the glycols
`exclude glycol polymers having an average molecular Weight
`of greater than 200. In some embodiments, the glycols
`exclude polyethylene glycol having an average molecular
`Weight of greater than about 200.
`[0043] In some embodiments, the carrier system comprises
`one or more alcohols or glycols, or any combinations thereof,
`in an amount from about 15% to about 55% (W/W). In some
`embodiments, the carrier system comprises one or more alco
`hols or glycols, or any combinations thereof, in an amount
`from about 25% to about 40% (W/W). In some embodiments,
`the carrier system comprises one or more alcohols or glycols,
`or any combinations thereof, in an amount of about 30%
`(W/W).
`[0044] In some embodiments, the composition comprises
`at least one additional ingredient selected from the group
`consisting of: active pharmaceutical ingredients; enhancers;
`excipients; and agents used to adjust the pH, buffer the com
`position, prevent degradation, and improve appearance, odor,
`or taste.
`[0045] In some embodiments, the compositions comprise
`at least one alkyl glycoside. In some embodiments, the at least
`one alkyl glycoside is one described in Us. Pat. No. 5,661,
`130, Which is incorporated by reference herein.
`[0046] In some embodiments, the composition comprises a
`benZodiaZepine drug that is fully dissolved in a solvent com
`prising a natural or synthetic tocopherol or tocotrienol, and an
`alcohol or glycol. In some embodiments, the composition
`comprises a benZodiaZepine drug that is fully dissolved in a
`solvent comprising a natural or synthetic tocopherol or tocot
`rienol and an alcohol or glycol, Wherein the solution is at least
`substantially free of Water. (In some embodiments, “substan
`tially free of Water” indicates that the solution contains less
`than about 1%, less than about 0.5%, less than about 0.25% or
`less than about 0.1% Water.) In some embodiments, the com
`position consists essentially of a benZodiaZepine drug that is
`fully dissolved in a solvent consisting of one or more natural
`or synthetic tocopherols or tocotrienols, one or more alcohols
`or glycols, and optionally one or more alkyl glycosides. In
`some embodiments, the composition consists essentially of a
`benZodiaZepine drug that is fully dissolved in a solvent con
`sisting of one or more natural or synthetic tocopherols or
`tocotrienols, one or more alcohols or glycols, and optionally
`one or more alkyl glycosides Wherein the solution is at least
`substantially free of Water. (In some embodiments, “substan
`tially free of Water” indicates that the solution contains less
`than about 1%, less than about 0.5%, less than about 0.25% or
`less than about 0.1% Water.) In some embodiments, the com
`position consists of a benZodiaZepine dissolved in a solvent
`consisting of one or more natural or synthetic tocopherols or
`tocotrienols, one or more alcohols or glycols, and optionally
`one or more alkyl glycosides. In some embodiments, the
`composition consists of a benZodiaZepine dissolved in a sol
`vent consisting of one or more natural or synthetic toco
`
`AQUESTIVE EXHIBIT 1010 page 0004
`
`

`

`US 2009/0258865 A1
`
`Oct. 15, 2009
`
`pherols or tocotrienols, one or more alcohols or glycols, and
`optionally one or more alkyl glycosides, wherein the solution
`is at least substantially free of Water. (In some embodiments,
`“substantially free of Water” indicates that the solution con
`tains less than about 1%, less than about 0.5%, less than about
`0.25% or less than about 0.1% Water.)
`[0047] In some embodiments, the composition comprises a
`benZodiaZepine drug that is fully dissolved in a solvent com
`prising a natural or synthetic tocopherol or tocotrienol, and an
`alcohol or glycol. Thus, in some embodiments, the composi
`tion is substantially free of benZodiaZepine microparticles,
`nanoparticles or combinations thereof. In some embodi
`ments, the composition comprises a benZodiaZepine drug that
`is fully dissolved in a solvent comprising a natural or syn
`thetic tocopherol or tocotrienol and an alcohol or glycol,
`Wherein the solution is at least substantially free of Water. (In
`some embodiments, “substantially free of Water” indicates
`that the solution contains less than about 1%, less than about
`0.5%, less than about 0.25% or less than about 0.1% Water.) In
`some embodiments, the composition consists essentially of a
`benZodiaZepine drug that is fully dissolved in a solvent con
`sisting of one or more natural or synthetic tocopherols or
`tocotrienols, one or more alcohols or glycols, and optionally
`one or more alkyl glycosides. In some embodiments, the
`composition consists essentially of a benZodiaZepine drug
`that is fully dissolved in a solvent consisting of one or more
`natural or synthetic tocopherols or tocotrienols, one or more
`alcohols or glycols, and optionally one or more alkyl glyco
`sides Wherein the solution is at least substantially free of
`Water. (In some embodiments, “substantially free of Water”
`indicates that the solution contains less than about 1%, less
`than about 0.5%, less than about 0.25% or less than about
`0.1% Water.) In some embodiments, the composition consists
`of a benZodiaZepine dissolved in a solvent consisting of one
`or more natural or synthetic tocopherols, one or more alco
`hols or glycols, and optionally one or more alkyl glycosides.
`In some embodiments, the composition consists of a benZo
`diaZepine dissolved in a solvent consisting of one or more
`natural or synthetic tocopherols, one or more alcohols or
`glycols, and optionally one or more alkyl glycosides, Wherein
`the solution is at least substantially free of Water. (In some
`embodiments, “substantially free of Water” indicates that the
`solution contains less than about 1%, less than about 0.5%,
`less than about 0.25% or less than about 0.1% Water.)
`[0048] In some embodiments, the composition contains a
`benZodiaZepine drug that at least partially in a particulate
`form suspended in a carrier system containing a natural or
`synthetic tocopherol or tocotrienol and one or more alcohols
`or glycols. In some embodiments, substantially all the ben
`ZodiaZepine drug is in a particulate form. In some embodi
`ments, at least part of the benZodiaZepine drug is in a micro