Under the Pa - '
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`Approved for use through 06/301‘2010. OMB 0651-0032
`U.S. Patent and Trademark Office. U.S. DEPARTMENT OF COMMERCE
`ired to ac - nd to a collection of information unless it di - la - a valid OMB control number.
`
`35401-716201
`
`UTILITY
`PATENT APPLICATION
`TRANSMITTAL
`(Oniyjbr new nonprovtliional applications under 37 CPR 1.530))
`
`Steve Cartt
`Administration ofBenzodiazepine
`Composmons
`03/27/2009
`
`Electronicallyfiled on.
`
`APPLICATION ELEMENTS
`See MPEP chapter 600 concerning utiIity patent application contents.
`
`ADDRESS T0:
`_
`
`§?$:?:;5 for Patents
`Alex-ml.” VA ”313-1450
`
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`(when there is 0" assignee)
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`D Information Disclosure (PTO/SENS or PTO-1449)
`I D Copies of citations attached
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`(Should be spectficat'ly itemized)
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`0"or continuation/divisional with Box 18 completed)
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`Signed statement attached deleting inventor(s)
`named in the prior application, see 37 CFR
`1.63(d)(2) and 1.3303).
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`
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`If a CONTINUING APPLICATION, check appropriate box, and supply the requisite information below in thefirst sentence ofthe specification
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`19. CORRESPONDENCE ADDRESS
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`This collection of information is required by 37 CFR 1.530)). The information is required to obtain or retain a benefit by the public which is to file (and by the USPTO to process) an application.
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`3639110_1.DOC
`
`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 0001
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`page 0001
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`WSGR Docket No. 35401 -71 6.201
`
`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
`
`WfiR
`
`Wilson Sonsini Goodrich 86 Rosati
`PROFESSIONAL CORPORATION
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300
`(650) 493-6811
`
`Certificate of Electronic Filing
`
`I hereby certify that the attached Nonprovisional Application and all marked attachments are
`being deposited by Electronic Filing on March 27, 2009 by using the EFS w Web patent filing
`system and addressed to Commissioner for Patents, PO. Box 1450, Alexandria, VA 22313-1450.
`
`Linda Anders
`
`By: é: Max: (ILALQM
`
`Date: March 27,2009
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 0002
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`page 0002
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`

`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`[001]
`
`This application claims priority under 35 U.S.C. § 119(e) from United States provisional patent
`
`application number 61/040,558, which was filed on March 28, 2008, and which is incorporated herein in its
`
`entirety.
`
`FIELD OF THE INVENTION
`
`[002]
`
`This application relates to the nasal administration of benzodiazepine drugs and combinations thereof.
`
`BACKGROUND OF THE INVENTION
`
`[003] By way of non-limiting example, the benzodiazepine 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 classified as an anxiolytic and skeletal muscle relaxants.
`
`They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, 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.
`
`[004] 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-aminobutyric acid (GABA).
`
`[005] GABA is an inhibitory neurotransmitter that, when bound to the GABAA receptor, facilitates Cl" ions
`
`flooding 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 particularly useful in treating many disorders, such as tetanus and epilepsy, which may
`
`result from too many action 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]
`
`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 benzodiazepine 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 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 drug orally.
`
`[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.
`-1-
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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.
`
`SUMMARY OF 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 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% (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 benzodiazepine drug is 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 combinations thereof.
`
`[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 combinations thereof
`
`[012]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from
`
`the group consisting of: (x-tocopherol, B-tocopherol, y-tocopherol, 8-tocopherol, (x—tocotrienol, B- tocotrienol, y-
`
`tocotrienol, 8- 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 polyethylene glycol succinate). In some embodiments, on the other hand, synthetic tocopherols
`
`exclude tocopherols covalently bonded 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.
`
`-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 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.
`
`[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/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.
`
`[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 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 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, or taste.
`
`[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 of treating 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 of a 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 composition is 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 drug is 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 combinations thereof.
`
`[021]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from
`
`the group consisting of: (x-tocopherol, B-tocopherol, y-tocopherol, 8-tocopherol, (x—tocotrienol, B- tocotrienol, y-
`
`tocotrienol, 8- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinations thereof.
`
`[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 alcohol is
`
`ethanol (dehydrated, USP).
`
`[023]
`
`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.
`
`[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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`WSGR Docket No. 35401—716201
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`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 0006
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`page 0006
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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 combinations thereof,
`
`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, or taste.
`
`[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 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-acceptable spray formulation having
`
`volume from about 10 [LL 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
`
`symptoms of a disorder which may be treatable with the composition.
`
`[030] 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
`
`[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.
`
`-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 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
`
`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 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 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% (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). 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 combinations thereof
`
`[035]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil,
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`flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam,
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`prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any
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`combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-
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`acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles,
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`nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective
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`average particle size of less than about 5000 nm. In some embodiments, the composition is substantially free of
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`benzodiazepine microparticles, nanoparticles or combinations thereof
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`-6-
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`WSGR Docket No. 35401—716201
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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]
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`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from
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`the group consisting of: (x-tocopherol, B-tocopherol, y-tocopherol, 8-tocopherol, (x—tocotrienol, B- tocotrienol, y-
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`tocotrienol, 8- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
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`thereof, and any combinations thereof. In some embodiments, the carrier system includes one or more synthetic
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`tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS,
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`which is described in United States Patent No. 6,193,985, which is incorporated herein by reference in its entirety.
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`In particular, it has been found that in some particulate suspensions of benzodiazepines, wherein the
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`benzodiazepine is not dissolved in a tocopherol phase, Vitamin E TPGS can be a desirable excipient for
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`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, 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
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`alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof In some
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`embodiments, the alcohol is ethanol (dehydrated, USP). In some embodiments, the one or more glycols are
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`selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any
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`isomers thereof, and any combinations thereof In some embodiments, the glycol is propylene glycol USP. In
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`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
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`bonded or linked (e. g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol). Thus, in
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`some embodiments, the compositions described herein exclude Vitamin E TPGS.
`
`[038]
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`In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration from
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`about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in a carrier
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`system in a concentration from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine
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`is 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 tocopherols or
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`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
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`system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an
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`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 (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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`[040]
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`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
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`12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to
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`about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about
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`22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%,
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`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 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
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`embodiments, the glycols exclude polyethylene glycol having an average molecular weight of greater than about
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`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 5 5% (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).
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`In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof,
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`in an amount of about 30% (w/w).
`
`[042]
`
`In some embodiments, the composition comprises at least one additional ingredient selected from the
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`group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH,
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`buffer the composition, prevent degradation, and improve appearance, odor, or taste.
`
`[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 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 consisting of one
`
`or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or