WSGRDocket No. 35401-716.102
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`PROVISIONAL PATENT APPLICATION
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
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`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
`
`WagR
`Wilson Sonsint Goodrich & Rosati
`
`TORO PESSPONAL CO borg ATI
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300
`(650) 493-6811
`
`Certificate of Electronic Filing
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`Date: June 14, 2011
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`[herebycertify that the attached Nonprovisional Application andall marked attachments are
`being deposited by Electronic Filing on June 14, 2011 by using the EFS — Webpatentfiling
`system and addressed to Commissioner for Patents, P.O. Box 1450, Alexandria, VA 22313-1450.
`
`By:
`
`/Misty Elam/
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`AQUESTIVE EXHIBIT 1005
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
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`[001]
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`This application relates to the nasal administration of benzodiazepine drugs and combinationsthereof.
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`FIELD OF THE INVENTION
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`BACKGROUND OF THE INVENTION
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`[002] By way of non-limiting example, the benzodiazepine family consists of drugs such as diazepam,
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`lorazepam, and medazepam. The drugsin this family have been observed as possessing sedative, tranquilizing
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`and muscle relaxing properties. They are frequently classified as an anxiolytic and skeletal muscle relaxants.
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`They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, insomnia,
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`agitation, seizures (such as those caused by epilepsy), muscle spasms andrigidity (which can be caused by
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`tetanus), the symptoms of drug withdrawalassociated with the continuous abuse of central nervous system
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`depressants, and exposure to nerve agents.
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`[003] Benzodiazepines are thought to act by binding to the GABAgreceptor of a neuron, possibly causing the
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`receptor to change shape and making it more accessible to gama-aminobutyric acid (GABA).
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`[004]
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`GABAis an inhibitory neurotransmitter that, when bound to the GABA,receptor, facilitates CI ions
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`flooding into the neuron to which the receptor is bound. The increase in CI ions hyperpolarizes the membrane of
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`the neuron. This completely or substantially reduces the ability of the neuron to carry an action potential.
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`Targeting this receptoris particularly useful in treating many disorders, such as tetanus and epilepsy, which may
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`result from too many action potentials proceeding through the nervous system.
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`[005] Current formulations of benzodiazepine drugs can be administered orally, rectally, or parenterally. The
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`ability to utilize these and other types of formulations has been significantly limited due, in many cases, to
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`solubility challenges.
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`[006]
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`The oral route of administration may be considered sub-optimal due to several disadvantages. For
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`example, the amount of time required for an orally administered benzodiazepine drug to reach therapeutically
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`relevant concentrations in blood plasma maybe rather long, such as an hour or more. Moreover, as
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`benzodiazepine drugs pass throughthe liver a significant amount may be metabolized. Thus, it may require large
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`doses to achieve therapeutic plasma levels. Furthermore, due to the nature of seizures and muscle spasms,it can
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`be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drugorally.
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`[007]
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`Intravenous administration perhaps provides a faster route of administration. However intravenous
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`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
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`is likely impractical for patients suffering from a phobia of needles.
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`[008]
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`Suppository compositions of benzodiazepine drugs can have a rapid onset of action. However, the
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`inconvenience of suppositories is an obvious impediment to their being administered by anyone outside a very
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`small group of the patient’s intimate acquaintances andthe patient’s professional medical caretakers.
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`SUMMARYOF THE INVENTION
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`[009]
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`Insome embodiments, there are provided (non-aqueous) pharmaceutical solutions for nasal
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`administration consisting of: (a) a benzodiazepine drug; (b) one or more natural or synthetic tocopherols or
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`tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); (c) one or more
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`alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w); and (d) an
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`alkyl glycoside, in a pharmaceutically-acceptable solution for administration to one or more nasal mucosal
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`membranes of a patient. In some embodiments, the benzodiazepine drug is dissolved in the one or more natural
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`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
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`about 70% (w/w). In some embodiments, the benzodiazepine drug is selected from the group consisting of:
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`alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam,
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`flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam,
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`lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaccutically-acceptable salts
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`thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a
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`pharmaceutically-acceptable salt thereof. In some embodiments, the solution contains about | to about 20 Y%ow/v
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`of benzodiazepine, e.g. about 1 to about 20 %w/v of diazepam. In some embodiments, the one or more natural or
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`synthetic tocopherols or tocotrienols are selected from the group consisting of: a-tocopherol, B-tocopherol, y-
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`tocopherol, 5-tocopherol, a-tocotrienol, B- tocotrienol, y- tocotrienol, 6- tocotrienol, tocophersolan, any isomers
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`thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. In some
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`embodiments, the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl
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`alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof. In some embodiments, the
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`solution contains two or more alcohols, such as ethanol (1-25 %ow/v) and benzyl alcohol (1-25 % w/v), or ethanol
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`(10-22.5 %w/v) and benzyl alcohol(7.5-12.5 % w/v). In some embodiments, the benzodiazepine is present in the
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`pharmaceutical composition in a concentration from about 20 mg/mL to about 200 mg/mL. In some
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`embodiments, the one or more natural or synthetic tocopherols or tocotrienols, or any combinationsthereof, is in
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`an amount from about 45% to about 85% (w/w). In some embodiments, the one or more natural or synthetic
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`tocopherols or tocotrienols, or any combinations thereof, is in an amount from about 50% to about 75% (w/w).
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`In
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`some embodiments, the one or more alcohols or glycols, or any combinations thereof, is in an amount from about
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`15% to about 55% (w/w), e.g. about 25% to about 40% (w/w). In some embodiments, the solution consists of
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`diazepam (5-15 %w/v), alkyl glycoside (0.01-1 Yow/v), vitamin E (45-65 w%/v), ethanol (10-25 w%/v) and
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`benzyl alcohol (5-15 %w/v). In some embodiments, the solution comprises at least about 0.01% (w/w)of an alkyl
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`-2-
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`glycoside, e.g. about 0.01% to 1% (w/w) of an alkyl glycoside, such as dodecyl maltoside. In some embodiments,
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`the solution consists of diazepam (5-15 %w/v), dodecyl maltoside (0.01-1 %w/v), vitamin E (45-65 w%/v),
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`ethanol (10-25 w%/v) and benzyl alcohol (5-15 %ow/v); more particularly the solution may consist of diazepam
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`(9-11 %w/v), dodecyl maltoside (0.1-0.5 %w/v), vitamin E (50-60 w%/v), ethanol (15-22.5 w%/v) and benzyl
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`alcohol (7.5-12.5 Yow/v); and even moreparticularly, the solution may consist of diazepam (10 %w/v), dodecyl
`
`maltoside (0.15-0.3 Y%ow/v), vitamin E (50-60 w%/v), ethanol (17-20 w%/v) and benzyl alcohol (10-12 “w/v).
`
`[010]
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`Some embodiments described herein provide a methodoftreating a patient with a disorder which may be
`
`treatable with a benzodiazepine drug, comprising: administering to one or more nasal mucosal membranesof a
`
`patient a pharmaceutical solution for nasal administration consisting of a benzodiazepine drug, one or more
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`natural or synthetic tocopherols or tocotrienols, or any combinationsthereof, in an amount from about 30% to
`
`about 95% (w/w); one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to
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`about 70% (w/w); and an alkyl glycoside. In some embodiments, the benzodiazepine drugis 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
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`from about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drugis selected from the group
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`consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,
`
`diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,
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`medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaccutically-
`
`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 solution contains about 1 to
`
`about 20 %w/v of benzodiazepine, e.g. about 1 to about 20 Y%w/v of diazepam. In some embodiments, the one or
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`more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: a-tocopherol, B-
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`tocopherol, y-tocopherol, 5-tocopherol, a-tocotrienol, B- tocotrienol, y- tocotrienol, 6- tocotrienol, tocophersolan,
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`any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. In some
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`embodiments, the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl
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`alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof. In some embodiments, the
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`solution contains two or morealcohols, such as ethanol (1-25 %ow/v) and benzyl alcohol (1-25 % w/v), or ethanol
`
`(10-22.5 %w/v) and benzyl alcohol (7.5-12.5 % w/v). In some embodiments, the benzodiazepineis present in the
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`pharmaceutical composition in a concentration from about 20 mg/mL to about 200 mg/mL. In some
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`embodiments, the one or morenatural or synthetic tocopherols or tocotrienols, or any combinationsthereof, is in
`
`an amount from about 45% to about 85% (w/w). In some embodiments, the one or more natural or synthetic
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`tocopherols or tocotrienols, or any combinations thereof, is in an amount from about 50% to about 75% (w/w).
`
`In
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`some embodiments, the one or more alcohols or glycols, or any combinations thereof, is in an amount from about
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`15% to about 55% (w/w), e.g. about 25% to about 40% (w/w). In some embodiments, the solution consists of
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`diazepam (5-15 %w/v), alkyl glycoside (0.01-1 Yow/v), vitamin E (45-65 w%/v), ethanol (10-25 w%/v) and
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`benzyl alcohol (5-15 %w/v). In some embodiments, the solution comprisesat least about 0.01% (w/w)of an alkyl
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`glycoside, e.g. about 0.01% to 1% (w/w) of an alkyl glycoside, such as dodecyl maltoside. In some embodiments,
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`the solution consists of diazepam (5-15 %w/v), dodecyl maltoside (0.01-1 %w/v), vitamin E (45-65 w%/v),
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`ethanol (10-25 w%/v) and benzyl alcohol (5-15 %ow/v); more particularly the solution may consist of diazepam
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`(9-11 %w/v), dodecyl maltoside (0.1-0.5 %w/v), vitamin E (50-60 w%/v), ethanol (15-22.5 w%/v) and benzyl
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`alcohol (7.5-12.5 %ow/v); and even moreparticularly, the solution may consist of diazepam (10 %w/v), dodecyl
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`maltoside (0.15-0.3 “ow/v), vitamin E (50-60 w%/v), ethanol (17-20 w%/v) and benzyl alcohol (10-12 “ow/v). In
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`some embodiments, the patient is human. In some embodiments, the benzodiazepine is administered in a
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`therapeutically effective amount from about 1 mg to about 20 mg. In some embodiments, the benzodiazepineis
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`administered as in a dosage volumefrom about 10 wL to about 200 wL. In some embodiments, the administration
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`of the pharmaceutical composition comprises spraying at least a portion of the therapeutically effective amount of
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`the benzodiazepineinto at least one nostril. In some embodiments, the administration of the pharmaceutical
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`composition comprises spraying at least a portion of the therapeutically effective amount of the benzodiazepine
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`into each nostril. In some embodiments, administration of the pharmaceutical composition comprises spraying a
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`first quantity of the pharmaceutical composition into the first nostril, spraying a second quantity of the
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`pharmaceutical composition into a second nostril, and optionally after a pre-selected time delay, spraying a third
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`quantity of the pharmaceutical composition into thefirst nostril. In some embodiments, the method further
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`comprises, optionally after a pre-selected time delay, administering at least a fourth quantity of the pharmaceutical
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`composition to the second nostril. In some embodiments, nasal administration of the pharmaceutical composition
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`begins at any time before or after onset of symptomsof a disorder which may be treatable with the pharmaceutical
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`composition. In some embodiments, the treatment achieves bioavailability that is from about 80-125% (e.g. about
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`90-110%, or moreparticularly about 92.5-107.5%) of that achieved with the same benzodiazepine administered
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`intravenously, e.g. In this context, it is intended that bioavailability be determined by a suitable pharmacodynamic
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`method, such as comparison of area under the blood plasma concentration curve (AUC)for the nasally and
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`intravenously administered drug. It is further understood that the percent bioavailability of the nasally
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`administered benzodiazepine may be determined by comparing the area under the blood plasma concentration
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`curve obtained with one dose of the benzodiazepine (e.g. 10 mg of nasal diazepam) with another dose of the same
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`benzodiazepine administered intravenously (e.g. 5 mg of i.v. diazepam), taking into consideration the difference
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`in dose. Thus, for the sake of illustration, a 10 mg nasal diazepam dose that achieves an AUCthatis precisely
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`half of the AUC obtained with 5 mg of i.v. diazepam would havea bioavailability of 100%. In some
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`embodiments, the disorder to be treated is a seizure, such as an epileptic seizure, a breakthrough seizure, or other
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`seizure. In some embodiments, the solution and treatment with the solution are substantially non-irritating and
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`well-tolerated.
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`[011]
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`Insome embodiments, the pharmaceutical composition for nasal administration comprises: a
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`benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in
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`an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations
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`thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w) ina
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`pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes ofthe
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`patient. In some embodiments the benzodiazepine drugis dissolved in the one or more natural or synthetic
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`tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and
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`the one or morealcohols 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
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`a carrier system. In some embodiments, at least part of the benzodiazepine drug is in a form comprising
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`benzodiazepine microparticles, nanoparticles or combinations thereof. In some embodiments, the composition is
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`substantially free of benzodiazepine microparticles, nanoparticles or combinationsthereof.
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`[012]
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`Insome embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
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`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 pharmacceutically-acceptable salts thereof, and any
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`combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaccutically-
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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 benzodiazepine drug is substantially
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`free of benzodiazepine microparticles, nanoparticles or combinations thereof.
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`[013]
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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: a-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol, a-tocotrienol, B- tocotrienol, y-
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`tocotrienol, 6- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
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`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 bondedor linked (e.g. through a diacid linking group) to a glycol polymer, such as
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`polyethylene glycol). Thus, in some embodiments, the compositions described herein exclude Vitamin E TPGS.
`
`[014]
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`Insome 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 one or more glycols are selected from the group consisting of: ethylene glycol, propylene
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`glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. In some preferred
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`embodiments, the glycols exclude glycol polymers. In some preferred embodiments, the glycols exclude glycol
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`polymers having an average molecular weight of greater than 200. In some embodiments, the glycols exclude
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`polyethylene glycol having an average molecular weight of greater than about 200.
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`[015]
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`Insome embodiments, the benzodiazepine drugis 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 drugis 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.
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`[016]
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`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
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`embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any
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`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).
`
`[017]
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`In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations
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`thereof, in an amount from about 10% to about 70% (w/w). In some embodiments, the carrier system comprises
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`one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w).
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`In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinationsthereof,
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`in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or
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`more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w).
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`[018]
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`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.
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`[019]
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`Insome embodiments, the composition comprises one or more additional excipients, such as one or more
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`parabens, one or more povidones, and/or one or morealkyl glycosides.
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`[020]
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`The invention also discloses a methodoftreating a patient with a disorder that may betreatable with a
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`benzodiazepine drug. In some embodiments, the patient is a human. In some embodiments, the method
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`comprises: administering to one or more nasal mucosal membranesofa patient a pharmaceutical composition for
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`nasal administration comprising a benzodiazepine drug; one or morenatural or synthetic tocopherols or
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`tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more
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`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 benzodiazepineis dissolved in the one or more natural or
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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
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`about 70%, preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is
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`dissolved in a carrier system. In some embodiments, the benzodiazepine drug includes benzodiazepine
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`microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially
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`free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`
`[021]
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`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
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`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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`-6-
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`prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and
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`any 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 drugis fully dissolved in a single phase
`
`comprising one or more one or more natural or synthetic tocopherols or tocotrienols and one or morealcohols or
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`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
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`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.
`
`[022]
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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: 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.
`
`[023]
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`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 glycolis free of water (dehydrated, USP). In some embodiments, the alcoholis
`
`ethanol (dehydrated, USP).
`
`[024]
`
`In some embodiments, the benzodiazepine drugis present in the carrier system in a concentration from
`
`about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drugis 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.
`
`[025]
`
`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).
`
`[026]
`
`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).
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`-7-
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`AQUESTIVE EXHIBIT 1005
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`AQUESTIVE EXHIBIT 1005 page 0008
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`page 0008
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`[027]
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`Insome 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.
`
`[028]
`
`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
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`embodiments, the therapeutically effective amount is from about | 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 wL to 200 wL.
`
`[029]
`
`In some embodiments, the administration of the composition comprises spraying at least a portion of the
`
`therapeutically effective amount of the composition intoat least one nostril. In some embodiments, the
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`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 secondnostril.
`
`[030]
`
`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.
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`[031] 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
`
`[032] 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.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[033]
`
`Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and methods of
`
`using such pharmaceutical compositions. Such pharmaceutical compositions are administered nasally.
`
`[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 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
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`AQUESTIVE EXHIBIT 1005
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`AQUESTIVE EXHIBIT 1005 page 0009
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`page 0009
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`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.
`
`[035]
`
`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 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 combinations thereof.
`
`[036]
`
`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 combinations thereof.
`
`[037]
`
`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- tocotrieno