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`nostril, spraying a second quantity ofthe composition into a second nostril, and optionally after a pre-
`selected time delay, spraying a third quantity of the composition into the first nostril. Some
`embodiments further comprise, optionally after a pre-selected time delay, administering at least a
`fourth quantity of the composition to the second nostril.
`[029]
`In some embodiments,the administration of the composition begins at any time before or
`after onset of symptoms of a disorder which may be treatable with the composition.
`[030] Additional embodiments, uses, and advantagesof the invention will become apparent to the
`person skilled in the art upon considerationofthe disclosure set forth herein.
`
`INCORPORATION BY REFERENCE
`
`[031] All publications, patents, and patent applications mentioned in this specification are herein
`incorporated by reference to the same extent as if each individual publication, patent, or patent
`application was specifically and individually indicated to be incorporated by reference.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and
`[032]
`methods ofusing such pharmaceutical compositions. Such pharmaceutical compositions are
`administered nasally.
`
`In some embodiments, the pharmaceutical composition for nasal administration comprises: a
`[033}
`benzodiazepine drug; 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 one or more alcohols or
`
`glycols, 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 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 thercof, 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 ofthe benzodiazepine drug is in a form of
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is
`substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`[034]
`In some embodiments, the pharmaceutical composition for nasal administration comprises: a
`benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any
`combinationsthereof, 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% (w/w) ina
`pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes
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`of the patient. In some embodiments the benzodiazepine drugis dissolved in the one or more natural
`or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to
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`about 95% (w/w); and the one or more alcoholsor glycols, or any combinations thereof, in an amount
`from about 5% to about 70% (w/w). In some embodiments, the benzodiazepine drugis dissolved in a
`carrier system. In some embodiments,at least part ofthe benzodiazepine drug is in a form of
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is
`
`substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`[035]
`In some embodiments, the benzodiazepine drug is selected from the group consisting of:
`alprazolam, brotizolam, chiordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,
`diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam,
`oxazepam, medazepam, lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, any
`pharmaceutically-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 benzodiazepine microparticles, nanoparticles, or
`combinationsthereof. In some embodiments, the benzodiazepine nanoparticles have an effective
`average patticle size of less than about 5000 nm. In some embodiments, the composition is
`substantially free of benzodiazepine microparticles, nanoparticles or combinationsthereof.
`[036]
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`selected from the group consisting of: a-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol, a-
`tocotrienol, B- tocotrienol, ‘y- tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters
`thereof, any analogs or derivatives thereof, and any combinations thereof. In some embodiments, the
`carrier system includes one or more synthetic tocopherols having a polymer glycol covalently bonded
`or linked to a tocopherol core, such as Vitamin E TPGS, whichis described in United States Patent
`
`No.6,193,985, which is incorporated herein by reference in its entirety. In particular, it has been
`
`found that in some particulate suspensions of benzodiazepines, wherein the benzodiazepineis not
`dissotved in a tocopherol phase, Vitamin E TPGScan be a desirable excipient for stabilizing the
`particulate (microparticle, nanoparticle or combination) suspension. In some embodiments, on the
`
`other hand, the carrier system specifically excludes synthetic tocopherols having a polymer glycol
`covalently bondedor linked to a tocopherol core, such as Vitamin E TPGS, which is described in
`United States Patent No. 6,193,985, which is incorporated herein by reference in its entirety.
`[037}
`In some embodiments,one or more alcohols are selected from the group consisting of:
`ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any
`combinations thereof. In some embodiments, the alcohol is ethanol (dehydrated, USP). In some
`embodiments, the one or more glycols are selected from the group consistingof: ethylene glycol,
`propyleneglycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations
`thereof. In some embodiments, the glycol is propylene glycol USP. 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
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`or linked (e.g. 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.
`[038]
`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 concentration from about 10 mg/mL to about 250 mg/mL. In
`some embodiments, the benzodiazepineis present in a carrier system in a concentration from about 20
`mg/mL to about 50 mg/mL.
`[039]
`In some embodiments,the carrier system comprises one or more natural or synthetic
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`tocopherols or tacotrienols, 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 combinationsthereof, in an amount from about 60% to about 75%
`(w/w). In some embodiments, the carrier system comprises one or morenatural 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 orlinked (e.g. 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.
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`In some embodiments, the carrier system comprises one or more alcohols or glycols, or any
`[040]
`combinationsthereof, 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 combinationsthereof, 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 amountof about 30% (w/w). In some embodiments,the alcoholis
`
`ethanolor contains ethanol. In some preferred embodiments, the glycols exclude glycol polymers. In
`somepreferred 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.
`
`Insome embodiments,the carrier system comprises one or more alcohols or glycols, or any
`[041]
`combinations thereof, in an amount from about 15% to about 55% (w/w). In some embodiments, the
`carrier system comprises one or morealcohols or glycols, or any combinations thereof, in an amount
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`from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or
`
`more alcohols or glycols, or any combinationsthereof, in an amount of about 30% (w/w).
`[042]
`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 composition, prevent degradation, and improve appearance, odor, or
`taste.
`
`In some embodiments, the compositions comprise at least one alkyl glycoside. In some
`[@43}
`embodiments, the at least one alkyl glycoside is one described in United States Patent No. 5,661,130,
`which is incorporated by reference herein.
`[044]
`In some embodiments, the composition comprises a benzodiazepine drugthatis fully
`
`dissolved in a solvent comprising 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 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
`
`In some embodiments, the composition
`0.5%,less than about 0.25% orless than about 0.1% water.)
`consists essentially of a benzodiazepinedrugthat is fully dissolved in a solvent consisting of one or
`morenatural 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 drugthat 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 morealkyl
`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% orless than about 0.1% water.) In some embodiments, the composition
`consists of a benzodiazepinedissolved in a solvent consisting of one or more natural or synthetic
`tocopherols or tocotrienols, one or more alcohois or glycols, and optionally one or more alkyl
`glycosides. In some embodiments, the composition consists of a benzodiazepine dissolvedin a
`solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more
`alcohols or glycols, and optionally one or morealkyl 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.)
`
`In some embodiments, the composition comprises a benzodiazepinedrugthatis fully
`[945]
`dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and an alcohol or
`glycol. Thus, in some embodiments, the composition is substantially free of benzodiazepine
`microparticles, nanoparticles or combinations thereof. In some embodiments, the composition
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`comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic
`
`tocopherol or tocotrienol and an alcohol or glycol, wherein the solutionis 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% orless than about 0.1% water.)
`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 glycosides. In some embodiments, the
`composition consists essentially of a benzodiazepine drugthat 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 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 benzodiazepinedissolved 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. 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 alcohols or glycois,
`and optionally one or more alkyl glycosides, wherein the solution is at least substantially free of
`water. (In some embodiments,“substantially free ofwater”indicates that the solution contains less
`
`than about 1%, less than about 0.5%,less than about 0.25% orless than about 0.1% water.)
`[046]
`In some embodiments, the composition contains a benzodiazepine drug thatat least partially
`in a particulate form suspendedin a carrier system containing a natural or synthetic tocopherol or
`tocotrienol and one or more alcchols or glycols. In some embodiments, substantially all the
`benzodiazepine drugis in a particulate form. In some embodiments,at least part ofthe
`benzodiazepine drugis in a microparticulate or nanoparticulate form. The carrier system is one in
`which the amountofat least one benzodiazepine present in the composition exceeds its solubility in
`the carrier system. In some embodiments, a carrier system in such a composition includes water. In
`some embodiments, such a liquid carrier system contains water and one or more excipients. In some
`embodiments, one or more excipients are dissolved or suspendedin the carrier system. In some
`embodiments,at least one such excipient stabilizes the suspension of benzodiazepineparticulates in
`the carrier system. In some embodiments,the carrier system may contain varying concentrations of
`parabens (e.g. methylparaben, propylparaben, etc.), and/or varying amounts of one or more
`surfactants, such as povidone (polyvinyl! pyrrolidinone). In some embodiments, benzodiazepine
`particulate suspensions specifically exclude one or more polymeric glycols, such as polyethylene
`glycol. In some embodiments, benzodiazepine particulate suspensions specifically exclude one or
`more polymeric glycols having a molecular weight greater than about 200 g/mol. In some
`embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine
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`microparticles and/or nanoparticles suspended in a carrier system comprising synthetic tocopherol,
`one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
`In some
`embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine
`microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or
`both of methylparaben and propylparaben, at least one glycol, povidone and water. In some
`
`embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine
`microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS,
`methylparaben, propylparaben, propylene glycol, povidone and water. In some embodiments, the
`
`composition consists essentially of a benzodiazepine drug in a form including benzodiazepine
`microparticles and/or nanoparticles suspended in a carrier system consisting essentially ofa synthetic
`tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
`In some embodiments, the composition consists essentially of a benzodiazepine drug in a form
`including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting
`essentially of Vitamin E TPGS,oncor both ofmethylparaben and propylparaben, at least one glycol,
`povidone and water. In some embodiments, the composition consists essentially of a benzodiazepine
`drugin a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier
`system consisting essentially ofVitamin E TPGS, methylparaben, propylparaben, propylene glycol,
`
`povidone and water. In some embodiments, the composition consists of a benzodiazepine drug in a
`form including benzodiazepine microparticles and/or nanoparticles suspendedin a carrier system
`consisting of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or
`more surfactants and water.
`In some embodiments, the composition consists of a benzodiazepine
`drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system
`consisting of Vitamin E TPGS,oneor both of methylparaben and propylparaben,at least one glycol,
`povidone and water. In some embodiments, the composition consists of a benzodiazepine drug ina
`form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system
`consisting ofVitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
`[047]
`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, one or more alcohals or glycols, and an alkyl glycoside. In some embodiments,
`substantiallyall the benzodiazepine drugis in a particulate form. In some embodiments,at least part
`of the benzodiazepine drug is in a microparticulate or nanoparticulate form. The carrier system is one
`in which the amount ofat least one benzodiazepine present in the composition exceedsits solubility in
`the carrier system. In some embodiments, a carrier system in such a composition includes water. In
`some embodiments, such a liquid carrier system contains water and one or more excipients. In some
`embodiments, one or more excipients are dissolved or suspended in the carrier system. In some
`embodiments,at least one such excipient stabilizes the suspension of benzodiazepineparticulates in
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`the carrier system. In some embodiments,the carrier system may contain varying concentrations of
`parabens (e.g. methylparaben, propylparaben, etc.), and/or varying amounts of one or more
`surfactants, such as povidone (polyvinyl pyrrolidinone). In some embodiments, benzodiazepine
`particulate suspensionsspecifically exchide one or more polymeric glycols, such as polyethylene
`glycol. In some embodiments, benzodiazepine particulate suspensions specifically exclude one or
`more polymeric glycols having a molecular weight greater than about 200 g/mol. In some
`embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine
`microparticles and/or nanoparticles suspended in a carrier system comprising a synthetic tocopherol,
`one or more parabens, one or more alcohols or glycols, an alkyglycoside and water.
`In some
`
`embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine
`microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or
`both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside and water. In some
`embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine
`microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS,
`methylparaben, propylparaben, propylene glycol, an alkyl glycoside and water. In some
`embodiments, the composition consists essentially of a benzodiazepine drugin a form including
`benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting
`essentially of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyl
`glycoside, optionally a surfactant, and water.
`In some embodiments, the composition consists
`essentially of a benzodiazepine drug in a form including benzodiazepine microparticles or
`nanoparticles suspended in a carrier system consisting essentially ofVitamin E TPGS,one or both of
`
`methylparaben and propylparaben,at least one glycol, an alkyl glycoside, optionally a povidone and.
`water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form
`
`including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting
`essentially of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside,
`optionally a povidone, and water. In some embodiments, the composition consists of a
`benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles
`suspended in a carrier system consisting of a synthetic tocopherol, one or more parabens, one or more
`alcohols or glycols, an alkyl glycoside, optionally one or more surfactants, and water.
`In some
`
`embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine
`microparticles or nanoparticles suspended in a cartier system consisting ofVitamin E TPGS,oneor
`both of methylparaben and propyiparaben, at least one glycol, an alkyl glycoside, optionally a
`povidone and water. In some embodiments, the composition consists of a benzodiazepine drug ina
`form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system
`consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside,
`optionally a povidone and water.
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`[@48}] The invention also discloses a method oftreating a patient with a disorder that may be
`
`treatable with a benzodiazepine drug. In some embodiments, the patient is a human. In some
`embodiments, the method comprises: administering to one or more nasal mucosal membranes ofa
`patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug; 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 one or more alcoholsor 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 benzodiazepineis dissolved in the one or morenatural or synthetic
`tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 30% to about 95%
`(w/w); andthe 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
`benzodiazepine drugis dissolved in a carrier system. In other embodiments,at least part ofthe
`benzodiazepine drugis in a form including microparticles, nanoparticles, or combinations thereof. In
`some embodiments, the composition is substantially free of benzodiazepine microparticles,
`nanoparticles or combinations thereof.
`[049]
`In some embodiments, the benzodiazepine drugis selected from the group consisting of:
`alprazolam,brotizolam, chiordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,
`
`diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam,nitrazepam,
`oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any
`pharmaceutically-acceptable salts thereof, and any combinations thereof. In some embodiments, the
`benzodiazepine drug is diazepam, or a pharmaceutically-acceptablesalt thereof. In some
`embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or
`combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective
`average particle size of less than about 5000 om.
`
`[050]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`
`selected from the group consisting of: a-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol, a-
`tocotrienol, B- tocotrienol, y- tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters
`thereof, any analogs or derivatives thereof, and any combinationsthereof. A synthetic tocopherol may
`include a tocopherol that has been modified to include a hydrophilic group, such as a polyethylene
`glycol group, which may be directly covalently bonded to the tocopherol or may be linked to the
`tocopherol through a covalent linking group, such as a diacid. An exemplary synthetic tocopherol of
`this type is Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), although the person skilled
`in the art will be able to envision other synthetic tocopherols that have similar diacid and/or
`hydrophilic groups.
`
`In some embodiments, the one or morealcohols are selected from the group consisting of:
`[051]
`ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any
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`combinations thereof. In some embodiments, 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 combinations thereof. In some embodiments, one or more glycols specifically
`excludes polymeric glycols, such as polyethylene glycol. In some embodiments, one or more glycols
`specifically excludes a polymeric glycol having a molecular weight of greater than about 200 g/mol.
`[052]
`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 drugis present in the carrier system in a concentration of
`from about 20 mg/mL to about 50 mg/mL.
`
`In some embodiments, the carrier system comprises one or more natural or synthetic
`[053]
`tocopherols or tocotrienols, or any combinations thereof, in an amountfrom 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 combinationsthereof, in an amount from about 60% to about 75%
`(ww). 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, especially where particulate suspensions of a benzodiazepine drug are contemplated,
`
`the compositions may include a tocopherol, especially a synthetic tocopherol having a hydrophilic
`group covalently linked to a tocopherol. In other embodiments, especially where a solution of
`benzodiazepine drug is contemplated, the tocopherol is substantially or completely free of Vitamin E
`TPGS.
`
`In some embodiments, the carrier system comprises one or morealcohols or glycols, or any
`[054]
`combinationsthereof, in an amount from about 10% to 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 embcdiments, the carrier system comprises one or
`more alcoholsor glycols, or any combinations thereof, in an amount from about 30% (w/w). In some
`embodiments the amount of one or more alcohols or glycols in the carrier system is 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).
`[055]
`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 composition, prevent degradation, and improve appearance, odor, or
`taste.
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`In some embodiments, a composition comprises at least one penetration enhancer in addition
`[056]
`to a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol. In
`some embodiments,the penetration enhancer is an alkyl glycoside. In some embodiments, the alkyl
`glycosiderefers to any sugar joined to any hydrophobicalkyl, as described in United States patent
`number 5,661,130, which is incorporated herein by reference in its entirety. The hydrophobic alkyl
`can be anysuitable length, for example about 9 to about 24 carbons in length, especially about 10 to
`about 14 carbons in length. The hydrophobic alkyl can be branched and/orpartially or wholly
`unsaturated. The alkyl may be joined to the saccharide core for example through a carbonyl group,
`whereby an ester group may be formed. A suitable alkyi glycoside will have the characteristics of
`
`being nontoxic, nonionic, and capable of increasing the absorption of a benzodiazepine drug whenit is
`administered intranasally as described herein. Exemplary saccharides that may be covalentlyjoined
`to an alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose,
`
`sucrose and trehalose. Exemplary alkyl glycosides that may be employed include octyl-, nonyl-,
`decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl a- or B-D-maltoside, -glucoside
`or sucroside, In some embodiments, the preferred glycosides include maltose, sucrose or glucose
`linked by glycosidic linkage