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`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`equired to respond to a collection of information unless it displays a valid OMB contro! number.
`
`Title
`
`Steve Cartt
`Administration of Benzodiazepine
`as
`Compositions
`
`0372772009
`
`ADDRESS TO: Fes for Patents
`Alexandria, VA 22313-1480
`ACCOMPANYING APPLICATION PARTS
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`3639110_1.DOC
`
`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 0001
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`WSGR Docket No. 35401-716.201
`
`PROVISIONAL PATENT APPLICATION
`
`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`Inventor(s):
`
`Steve Cartt
`Citizen of The United States of America
`San Carlos, CA
`
`David Medeiros
`Citizen of The United States of America
`South San Francisco, CA
`
`Garry Thomas Gwozdz
`Citizen of The United States of America
`Nazareth, Pennsylvania
`
`Andrew Loxley
`Citizen of Great Britain
`Philadelphia, PA
`
`Mark Mitchnick
`Citizen of the United Sates of America
`East Hampton, New York
`
`David Hale
`Citizen of the United States of America
`San Diego, CA
`
`Assignee:
`
`Hale BioPharma Ventures, LLC
`
`WR
`Wilson Sonsini Goodrich & Rosati
`PROFESSIONAL CORPORATION
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300
`(650) 493-6811
`
`Certificate of Electronic Filing
`
`Linda Anders
`
`I hereby certify that the attached Nonprovisional Application andall marked attachments are
`being deposited by Electronic Filing on March 27, 2009 by using the EFS -- Web patentfiling
`system and addressed to Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`
`By: lA WALL (wohus
`
`Date: March 27, 2009
`
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`[001]
`
`This application claimspriority under 35 U.S.C. § 119(e) from United States provisional patent
`
`application number 61/040,558, which wasfiled on March 28, 2008, and whichis incorporated herein in its
`
`entirety.
`
`[002]
`
`This application relates to the nasal administration of benzodiazepine drugs and combinationsthereof.
`
`FIELD OF THE INVENTION
`
`BACKGROUND OF THE INVENTION
`
`[003] By way of non-limiting example, the benzodiazepine family consists of drugs such as diazepam,
`
`lorazepam, and medazepam. Thedrugsin this family have been observedas possessing sedative, tranquilizing
`
`and muscle relaxing properties. They are frequently classified as an anxiolytic and skeletal muscle relaxants.
`
`They are thought to be useful in preventing, treating, or ameliorating the symptomsof anxiety, insomnia,
`
`agitation, seizures (such as those caused by epilepsy), muscle spasmsand 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.
`
`[004] Benzodiazepines are thought to act by binding to the GABAgreceptor of a neuron, possibly causing the
`
`receptor to change shape and making it more accessible to gama-aminobutyric acid (GABA).
`
`[005]
`
`GABAis an inhibitory neurotransmitter that, when bound to the GABAg receptor, facilitates CI ions
`
`flooding into the neuron to which the receptor is bound. The increase in CIions hyperpolarizes the membrane of
`
`the neuron. This completely or substantially reduces the ability of the neuron to carry an action potential.
`
`Targeting this receptoris particularly useful in treating many disorders, such as tetanus and epilepsy, which may
`
`result from too manyaction potentials proceeding through the nervous system.
`
`[006] Current formulations of benzodiazepine drugs can be administered orally, rectally, or parenterally. The
`
`ability to utilize these and other types of formulations has been significantly limited due, in many cases, to
`
`solubility challenges.
`
`[007]
`
`Theoral route of administration may be considered sub-optimal due to several disadvantages. For
`
`example, the amount of time required for an orally administered benzodiazepine drug to reach therapeutically
`
`relevant concentrations in blood plasma mayberather long, such as an hour or more. Moreover, as
`
`benzodiazepine drugs pass throughthe liver a significant amount may be metabolized. Thus, it may require large
`
`doses to achieve therapeutic plasma levels. Furthermore, due to the nature of seizures and muscle spasms,it can
`
`be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drugorally.
`
`[008]
`
`Intravenous administration perhaps provides a faster route of administration. However intravenous
`
`administration is generally limited to trained health care professionals in tightly controlled clinical settings.
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`Additionally, sterility must be maintained. Furthermore, administering any drug intravenously can be painful and
`
`is likely impractical for patients suffering from a phobia of needles.
`
`[009]
`
`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 professional medical caretakers.
`
`SUMMARYOF THE INVENTION
`
`[010]
`
`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), preferably about 10% to about 70% (w/w) ina
`
`pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranesofthe
`
`patient. In some embodiments the benzodiazepine drug is dissolved in the one or morenatural or synthetic
`
`tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and
`
`the one or morealcohols or glycols, or any combinationsthereof, 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 some embodiments,at least part of the benzodiazepine drug is in a form comprising
`
`benzodiazepine microparticles, nanoparticles or combinations thereof. In some embodiments, the composition is
`
`substantially free of benzodiazepine microparticles, nanoparticles or combinationsthereof.
`
`[011]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, 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 combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective
`
`average particle size of less than about 5000 nm. In some embodiments, the benzodiazepine drug is substantially
`
`free of benzodiazepine microparticles, nanoparticles or combinationsthereof.
`
`[012]
`
`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, 6- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinationsthereof. 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 bondedorlinked (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.
`
`-2-
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`[013]
`
`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 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 somepreferred
`
`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.
`
`[014]
`
`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/mLto about 250 mg/mL. In some embodiments, the benzodiazepine
`
`is present in a carrier system in a concentration from about 20 mg/mLto about 50 mg/mL.
`
`[015]
`
`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).
`
`[016]
`
`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 alcohols or glycols, or any combinationsthereof, in an amount from about 15% to 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 amount of about 30% (w/w).
`
`[017]
`
`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, ortaste.
`
`[018]
`
`In some embodiments, the composition comprises one or more additional excipients, such as one or more
`
`parabens, one or more povidones, and/or one or more alkyl] glycosides.
`
`[019]
`
`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 membranesofa 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
`
`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
`
`-3-
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`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 benzodiazepine
`
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the compositionis substantially
`
`free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`
`[020]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, 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-
`
`acceptable salt thereof. In some embodiments, the benzodiazepine drugis fully dissolved 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 benzodiazepine 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 combinationsthereof.
`
`[021]
`
`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.
`
`[022]
`
`In some embodiments, the one or more alcohols are selected from the group consisting of: ethanol, propyl
`
`alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any 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, the alcohol or glycol is free of water (dehydrated, USP). In some embodiments, the alcoholis
`
`ethanol (dehydrated, USP).
`
`[023]
`
`In some embodiments, the benzodiazepine drugis present in the carrier system in a concentration from
`
`about | 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.
`
`[024]
`
`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
`
`-4-
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`

`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).
`
`[025]
`
`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 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 combinationsthereof,
`
`in an amount from about 30% (w/w).
`
`[026]
`
`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, ortaste.
`
`[027]
`
`In some embodiments, the composition is in a pharmaceutically-acceptable spray formulation, and further
`
`comprising administering the composition to one or more nasal mucosal membranesofthe patient. In some
`
`embodiments, the therapeutically effective amountis from about | mg to about 20 mg of the benzodiazepine. In
`
`some embodiments, the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having
`
`volumefrom about 10 wL to 200 uL.
`
`[028]
`
`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 composition comprises
`
`spraying a first quantity of the composition into the first 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 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
`
`symptomsof a disorder which maybetreatable with the composition.
`
`[030] Additional embodiments, uses, and advantages of the invention will become apparentto the person skilled
`
`in the art upon consideration of the disclosure set forth herein.
`
`INCORPORATION BY REFERENCE
`
`[031] All publications, patents, and patent applications mentionedin this specification are herein incorporated
`
`by reference to the same extent as if each individual publication, patent, or patent application wasspecifically and
`
`individually indicated to be incorporated by reference.
`
`-5-
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`DETAILED DESCRIPTION OF THE INVENTION
`
`[032]
`
`Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and methods of
`
`using such pharmaceutical compositions. Such pharmaceutical compositions are administered nasally.
`
`[033]
`
`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 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for
`
`administration to one or more nasal mucosal membranesofthe patient. In some embodiments the benzodiazepine
`
`drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinationsthereof,
`
`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, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially
`
`free of benzodiazepine microparticles, nanoparticles or combinationsthereof.
`
`[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) in a pharmaceutically-acceptable formulation for
`
`administration to one or more nasal mucosal membranesofthe patient. In some embodiments the benzodiazepine
`
`drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinationsthereof,
`
`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, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially
`
`free of benzodiazepine microparticles, nanoparticles or combinationsthereof.
`
`[035]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, 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 combinations thereof. 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 combinationsthereof.
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`-6-
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`WSGRDocket No. 35401-716.201
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`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 0008
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`page 0008
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`[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, 6- 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 bondedor 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 referencein its entirety.
`
`In particular, it has been found that in some particulate suspensions of benzodiazepines, wherein the
`
`benzodiazepine is not dissolved in a tocopherol phase, Vitamin E TPGScanbea 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
`
`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 inits 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 consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any
`
`isomers thereof, and any combinationsthereof. 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
`
`bondedor 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/mLto about 250 mg/mL. In some embodiments, the benzodiazepine
`
`is present in a carrier system in a concentration from about 20 mg/mLto about 50 mg/mL.
`
`[039]
`
`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 bondedor 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.
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`-7-
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`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 0009
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`page 0009
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`[040]
`
`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
`
`combinations thereof, in an amount of about 30% (w/w). In some embodiments, the alcoholis 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.
`
`[041]
`
`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 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 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, ortaste.
`
`[043]
`
`In some embodiments, the compositions comprise at least one alkyl glycoside. In some 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 drug that is 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 alcoholor 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