`
`
`PATENT APPLICATION
`
`
`
`Administration of Benzodiazepine
`TRAN S M ITTAL
`
`
`Compositions
`
`
`(Only for new nonprovls/ona/ applications under 37 CFR 1. 53(b))
`
`June 13, 2012
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`Electronically Filed
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`4950654_I .DOC
`
`AQUESTIVE EXHIBIT 1004
`
`AQUESTIVE EXHIBIT 1004 page 0001
`
`page 0001
`
`

`

`WSGR Docket No. 35401-716501
`
`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 States of America
`
`East Hampton, New York
`
`David Hale
`Citizen of The United States of America
`
`San Diego, CA
`
`Edward T. Maggio
`Citizen of The United States of America
`
`San Diego, CA
`
`Assignee:
`
`Hale BioPharma Ventures, LLC
`
`. ‘
`
`. "I“MIR
`
`VWi. is 0 r1 Sm‘mini Goodrich '5." Rosari
`FREE}? E3581 UN v"
`(TOR E’OR:‘:'1‘§CF~"4
`
`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 using the EFS 4 Web patent filing system and addressed to
`
`/Linda Anders/
`
`Date: June 13, 2012
`
`Commissioner for Patents, PO. Box 1450, Alexandria, VA 22313-1450. By:
`
`AQUESTIVE EXHIBIT 10|4
`
`AQUESTIVE EXHIBIT 1004 page 0002
`
`page 0002
`
`

`

`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[001] This application is a Continuation-in-Part of United States Patent Application 12/413,439, filed
`
`3/27/2009, published as US 2009/0258865 on October 15, 2009, which is incorporated herein by
`
`reference in its entirety; this application also claims priority to United States provisional application
`
`61/040,558, filed March 28, 2008, United States provisional application 61/497,017, filed June 14, 2011
`
`and United States provisional application 61/570,110, filed December 13, 2011, each of which is
`
`incorporated herein by reference 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 midazolam. The drugs in this family have been observed as possessing sedative,
`
`tranquilizing and muscle relaxing properties. They are frequently classified as 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, 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 usefill in treating many disorders, such as tetanus
`
`and epilepsy, which may result from too many action potentials proceeding through the nervous system.
`
`-1-
`
`WSGR Docket No. 35401—716501
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`AQUESTIVE EXHIBIT 1004
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`AQUESTIVE EXHIBIT 1004 page 0003
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`page 0003
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`

`

`[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 of the drug may be
`
`metabolized. Thus, large doses may be required 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 and care-givers may be reluctant to place their hands
`
`in patients’ mouths.
`
`[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. 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. In
`
`addition, intravenous administration of benzodiazepines is associated with respiratory depression. Thus,
`
`use of intravenous benzodiazepines is limited to professional health care environments.
`
`[009] Rectal suppository compositions of benzodiazepine drugs can have a rapid onset of action.
`
`However, the inconvenience of rectally administered drug 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 care-givers.
`
`SUMMARY OF THE INVENTION
`
`[010]
`
`In some embodiments,
`
`there are provided (non-aqueous) pharmaceutical solutions for nasal
`
`administration consisting of: (a) a benzodiazepine drug; (b) one or more natural or synthetic tocopherols
`
`or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (W/W); (c) one
`
`or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70%
`
`(W/W); and (d) an alkyl glycoside, in a pharmaceutically-acceptable solution for administration to one or
`
`more nasal mucosal membranes of a 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
`
`-2-
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`AQUESTIVE EXHIBIT 1004 page 0004
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`page 0004
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`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,
`
`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 solution contains about 1 to about 20 % (W/v) of benzodiazepine,
`
`e.g. about
`
`1
`
`to about 20 % (W/v) of diazepam. In some embodiments, the one or more natural or
`
`synthetic tocopherols or tocotrienols are selected from the group consisting of: u-tocopherol, B-
`
`tocopherol, y-tocopherol, S-tocopherol, u-tocotrienol, B-
`
`tocotrienol, y-
`
`tocotrienol, 5-
`
`tocotrienol,
`
`tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any
`
`combinations thereof In some embodiments, the 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 solution contains two or more alcohols, such as
`
`ethanol (1-25 % (w/v)) and benzyl alcohol (1-25 % (W/v)), or ethanol (10-225 % (W/v)) and benzyl
`
`alcohol (7.5-12.5 % (W/v)). In some embodiments, the benzodiazepine is present in the pharmaceutical
`
`composition in a concentration from about 20 mg/mL to about 200 mg/mL. In some embodiments, the
`
`one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof,
`
`is in an
`
`amount from about 45% to about 85% (W/W). In some embodiments, the one or more natural or
`
`synthetic tocopherols or tocotrienols, or any combinations thereof, is in an amount from about 50% to
`
`about 75% (W/W). In some embodiments, the one or more alcohols or glycols, or any combinations
`
`thereof, is in an amount from about 15% to about 55% (W/W), e.g. about 25% to about 40% (W/W). In
`
`some embodiments, the solution consists of diazepam (5-l5 % (W/v)), alkyl glycoside (0.01-l % (W/v)),
`
`vitamin E (45-65 % (w/v)), ethanol (10-25 % (W/v)) and benzyl alcohol (5-l5 % (W/v)). In some
`
`embodiments, the solution comprises at least about 0.01% (W/W) of an alkyl glycoside, e. g. about 0.01%
`
`to l% (W/W) of an alkyl glycoside, such as dodecyl maltoside. In some embodiments, the solution
`
`consists of diazepam (5-l5 % (W/v)), dodecyl maltoside (0.01-l % (W/v)), vitamin E (45-65 % (W/v)),
`
`ethanol (10-25 % (W/v)) and benzyl alcohol (5-l5 % (W/v)); more particularly the solution may consist
`
`of diazepam (9-ll % (W/v)), dodecyl maltoside (0.l-0.5 % (W/v)), vitamin E (50-60 % (W/v)), ethanol
`
`(l5-22.5 % (W/v)) and benzyl alcohol (7.5-12.5 % (W/v)); and even more particularly, the solution may
`
`consist of diazepam (10 % (W/v)), dodecyl maltoside (0.l5-0.3 % (W/v)), vitamin E (50-60 % (W/v)),
`
`ethanol (17-20 % (w/v)) and benzyl alcohol (10-12 % (W/v)).
`
`-3-
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`WSGR Docket No. 35401—716501
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`AQUESTIVE EXHIBIT 1004
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`AQUESTIVE EXHIBIT 1004 page 0005
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`page 0005
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`

`

`[011] Some embodiments described herein provide a method of treating a patient with a disorder which
`
`may be treatable with a benzodiazepine drug, comprising: administering to one or more nasal mucosal
`
`membranes of a patient
`
`a pharmaceutical
`
`solution for nasal administration consisting of 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); one or more alcohols or glycols, or any
`
`combinations thereof, in an amount from about 10% to about 70% (w/w); and an alkyl glycoside. 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 selected from the group
`
`consisting of:
`
`alprazolam,
`
`brotizolam,
`
`chlordiazepoxide,
`
`clobazam,
`
`clonazepam,
`
`clorazepam,
`
`demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam,
`
`nitrazepam, oxazepam,
`
`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 solution contains about 1 to about 20 % (w/v) of benzodiazepine, e.g. about 1 to about 20 % (w/v) of
`
`diazepam. 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, S-tocopherol,
`
`0L-
`
`tocotrienol, [3- tocotrienol, y- tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters
`
`thereof, any analogs or derivatives thereof, and any combinations thereof In some embodiments, the 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
`
`solution contains two or more alcohols, such as ethanol (l-25 % (w/v)) and benzyl alcohol (l-25 %
`
`(w/v)), or ethanol (10-225 % (w/v)) and benzyl alcohol (7.5-125 % (w/v)). In some embodiments, the
`
`benzodiazepine is present in the pharmaceutical composition in a concentration from about 20 mg/mL to
`
`about 200 mg/mL.
`
`In some embodiments,
`
`the one or more natural or synthetic tocopherols or
`
`tocotrienols, or any combinations thereof, is in an amount from about 45% to about 85% (w/w). In some
`
`embodiments, the one or more natural or synthetic tocopherols or tocotrienols, or any combinations
`
`thereof, is in an amount from about 50% to about 75% (w/w). In some embodiments, the one or more
`
`alcohols or glycols, or any combinations thereof, is in an amount from about 15% to about 55% (w/w),
`
`e.g. about 25% to about 40% (w/w). In some embodiments, the solution consists of diazepam (5-15 %
`
`(w/v)), alkyl glycoside (0.01-1 % (w/v)), vitamin E (45-65 % (w/v)), ethanol (10-25 % (w/v)) and
`
`-4-
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`WSGR Docket No. 35401—716501
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`AQUESTIVE EXHIBIT 1004
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`AQUESTIVE EXHIBIT 1004 page 0006
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`page 0006
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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 glycoside, e. g. about 0.01% to 1% (w/w) of an alkyl glycoside, such as dodecyl maltoside. In
`
`some embodiments, the solution consists of diazepam (5-15 % (w/v)), dodecyl maltoside (0.01-1 %
`
`(w/v)), vitamin E (45-65 % (w/v)), ethanol (10-25 % (w/v)) and benzyl alcohol (5-15 % (w/v)); more
`
`particularly the solution may consist of diazepam (9-ll % (w/v)), dodecyl maltoside (0.1-0.5 % (w/v)),
`
`vitamin E (50-60 % (w/v)), ethanol (15-225 % (w/v)) and benzyl alcohol (7.5-12.5 % (w/v)); and even
`
`more particularly, the solution may consist of diazepam (10 % (w/v)), dodecyl maltoside (0.15-03 %
`
`(w/v)), vitamin E (50-60 % (w/v)), ethanol (17-20 % (w/v)) and benzyl alcohol (10-12 % (w/v)). In
`
`some embodiments, the patient is human. In some embodiments, the benzodiazepine is administered in a
`
`therapeutically effective amount
`
`from about
`
`1 mg to about 20 mg.
`
`In some embodiments,
`
`the
`
`benzodiazepine is administered as in a dosage volume from about 10 uL to about 200 uL. In some
`
`embodiments,
`
`the administration of the pharmaceutical composition comprises spraying at
`
`least a
`
`portion of the therapeutically effective amount of the benzodiazepine into at least one nostril. In some
`
`embodiments,
`
`the administration of the pharmaceutical composition comprises spraying at
`
`least a
`
`portion of the therapeutically effective amount of the benzodiazepine into each nostril.
`
`In some
`
`embodiments, administration of the pharmaceutical composition comprises spraying a first quantity of
`
`the pharmaceutical composition into the first nostril, spraying a second quantity of the pharmaceutical
`
`composition into a second nostril, and optionally after a pre-selected time delay, spraying a third
`
`quantity of the pharmaceutical composition into the first nostril. In some embodiments, the method
`
`filrther comprises, optionally after a pre-selected time delay, administering at least a fourth quantity of
`
`the pharmaceutical composition to the second nostril. In some embodiments, nasal administration of the
`
`pharmaceutical composition begins at any time before or after onset of symptoms of a disorder which
`
`may be treatable with the pharmaceutical composition. In some embodiments, the treatment achieves
`
`bioavailability that
`
`is from about 80-125% (e.g. about 90-llO%, or more particularly about 92.5-
`
`107.5%) of that achieved with the same benzodiazepine administered intravenously, e. g. In this context,
`
`it
`
`is intended that bioavailability be determined by a suitable pharmacodynamic method, such as
`
`comparison of area under the blood plasma concentration curve (AUC) for the nasally and intravenously
`
`administered drug. It is fiarther understood that the percent bioavailability of the nasally administered
`
`benzodiazepine may be determined by comparing the area under the blood plasma concentration curve
`
`obtained with one dose of the benzodiazepine (e.g. 10 mg of nasal diazepam) with another dose of the
`
`same benzodiazepine administered intravenously (e. g. 5 mg of iv. diazepam), taking into consideration
`
`the difference in dose. Thus, for the sake of illustration, a 10 mg nasal diazepam dose that achieves an
`
`-5-
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`WSGR Docket No. 35401—716501
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`AQUESTIVE EXHIBIT 1004
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`AQUESTIVE EXHIBIT 1004 page 0007
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`page 0007
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`

`AUC that is precisely half of the AUC obtained with 5 mg of iv. diazepam would have a bioavailability
`
`of 100%. In some embodiments, the disorder to be treated is a seizure, such as an epileptic seizure, a
`
`breakthrough seizure, or other seizure. In some embodiments,
`
`the solution and treatment with the
`
`solution are substantially non-irritating and well-tolerated.
`
`[012]
`
`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
`
`[013]
`
`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, 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.
`
`[014]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`
`selected from the group consisting of:
`
`(X-tOCOthI‘Ol, B-tocopherol, y-tocopherol, S-tocopherol,
`
`0L-
`
`tocotrienol, [3- tocotrienol, y- tocotrienol, 5- 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
`
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`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.
`
`[015]
`
`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.
`
`[016]
`
`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.
`
`[017]
`
`In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols
`
`or tocotrieno ls, 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).
`
`[018]
`
`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).
`
`[019]
`
`In some embodiments, the composition comprises at least one additional ingredient selected
`
`from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used
`
`to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
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`[020]
`
`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.
`
`[021] 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 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
`
`[022]
`
`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,
`
`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 fillly 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 fiarther 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
`
`[023]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`
`selected from the group consisting of: u-tocopherol, B-tocopherol, y-tocopherol, 8-tocopherol,
`
`0L-
`
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`tocotrienol, [3- tocotrienol, y- tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters
`
`thereof, any analogs or derivatives thereof, and any combinations thereof
`
`[024]
`
`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).
`
`[025]
`
`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.
`
`[026]
`
`In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols
`
`or tocotrieno ls, 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).
`
`[027]
`
`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).
`
`[028]
`
`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.
`
`[029]
`
`In some embodiments, the composition is in a pharmaceutically-acceptable spray formulation,
`
`and fiarther comprising administering the composition to one or more nasal mucosal membranes of the
`
`patient. In some embodiments