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`Document Description: Provisional Cover Sheet (8816)
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`Provisional Application for Patent Cover Sheet
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`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c)
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`generated within this form by selecting the Add button.
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`Title of Invention
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
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`‘
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`Attorney Docket Number (if applicable)
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`35401-716103
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`Correspondence Address
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`© The address corresponding to Customer Number
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`EFS - Web1.0.1
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`0 Firm or Individual Name
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`AQUESTIVE EXHIBIT 1006 page 0001
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`AQUESTIVE EXHIBIT 1006
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`page 0001
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`Doc Code: TR.PROV
`Document Description: Provisional Cover Sheet (8816) V
`
`PTO/SB/16 (11-08)
`
`Approved for use through 01/31/2014 OMB 0651-0032
`US Patent and Trademark Office: US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number
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`Customer Number
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`021971
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`The invention was made by an agency of the United States Government or under a contract with an agency ofthe United
`States Government.
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`6) No.
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`0 Yes, the name of the US. Government agency and the Government contract number are:
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`EFS - Web 1.0.1
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0002
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`page 0002
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`

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`Doc Code: TR.PROV
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`Document Description: Provisional Cover Sheet (8816)
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`PTO/SBI16 (11-08)
`
`Approved for use through 01/31/2014 OMB 0651-0032
`US, Patent and Trademark Office: US. DEPARTMENT OF COMMERCE
`Under the Paperwork Reduction Act of 1995, no persons are required to respond to a collection of information unless it displays a valid OMB control number
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`,
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`Entity Status
`Applicant claims small entity status under 37 CFR 1.27
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`O No
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`Petitioner/applicant is cautioned to avoid submitting personal information in documents filed in a patent application that may
`contribute to identity theft. Personal information such as social security numbers, bank account numbers, or credit card
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` (9 Yes, applicant qualifies for small entity status under 37 CFR 1.27
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`Please see37 CFR 1 4(d) for the form of the signature
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`Signature
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`lMatthew Grumbling/
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`Date (YYYY-MM-DD)
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`2011-12-13
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`First Name
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`Matthew
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`Last Name
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`Grumbling
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`Registration Number
`(If appropriate)
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`44427
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`This collection of information is required by 37 CFR 1.51. The information is required to obtain or retain a benefit by the public which is to
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`form can only be used when in conjunction with EFS-Web. If this form is mailed to the USPTO, it may cause delays in handling
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0003
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`page 0003
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`Privacy Act Statement
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0004
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`page 0004
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`WSGR Docket No. 35401-716103
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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
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`San Carlos, CA
`
`David Medeiros
`Citizen of The United States of America
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`South San Francisco, CA
`
`Garry Thomas Gwozdz
`Citizen of The United States of America
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`Nazareth, Pennsylvania
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`Andrew Loxley
`Citizen of Great Britain
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`Philadelphia, PA
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`Mark Mitchnick
`Citizen of the United Sates of America
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`East Hampton, New York
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`David Hale
`Citizen of the United States of America
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`San Diego, CA
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`Assignee:
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`Hale BioPharma Ventures, LLC
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`Wilson Snnsini Goodrich 5.5 Read
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`:9 3’. 0. 1w,LBSEUNAL CUR E‘O R l-X'l'l ON‘
`
`
`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
`Commissioner for Patents, PO. Box 1450, Alexandria, VA 22313-1450.
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`Date: December 13, 2011
`
`By:
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`/Linda Anders/
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0005
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`page 0005
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
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`FIELD OF THE INVENTION
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`[001]
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`This application relates to the nasal administration of benzodiazepine drugs and combinations thereof.
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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 drugs in 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 and rigidity (Which can be caused by
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`tetanus), the symptoms of drug Withdrawal associated 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 GABAA receptor 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] GABA is an inhibitory neurotransmitter that, When bound to the GABAA receptor, facilitates Cl' ions
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`flooding into the neuron to Which the receptor is bound. The increase in C1' 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 receptor is 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 may be rather long, such as an hour or more. Moreover, as
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`benzodiazepine drugs pass through the 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 drug orally.
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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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`-1-
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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 and the patient’s professional medical caretakers.
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`SUMMARY OF THE INVENTION
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`[009]
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`In some 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%
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`(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 pharmaceutically—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 1 to about 20 %W/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: (x-tocopherol, B-tocopherol, y-
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`tocopherol, 8-tocopherol, (x-tocotrienol, B- tocotrienol, y- tocotrienol, 8- 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 %W/v) and benzyl alcohol (1-25 % W/v), or ethanol
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`(lo-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 combinations thereof, 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).
`
`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 %W/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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`WSGR Docket No. 35401—716103
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0007
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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 %W/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 %W/v); and even more particularly, the solution may consist of diazepam (10 %W/v), dodecyl
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`maltoside (0.15-0.3 %W/v), vitamin E (50-60 W%/v), ethanol (17-20 W%/v) and benzyl alcohol (10-12 %W/v).
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`[010]
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`Some embodiments described herein provide a method of treating a patient With a disorder which may be
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`treatable With a benzodiazepine drug, comprising: administering to one or more nasal mucosal membranes of a
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`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 combinations thereof, in an amount from about 30% to
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`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 drug is dissolved in the one
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`or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about
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`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 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-
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`acceptable salts thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is
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`diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the solution contains about 1 to
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`about 20 %W/v of benzodiazepine, e. g. about 1 to about 20 %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: (x-tocopherol, B-
`
`tocopherol, y-tocopherol, 8-tocopherol, (x-tocotrienol, B- tocotrienol, y- tocotrienol, 8- 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 more alcohols, such as ethanol (1-25 %W/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
`
`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
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`diazepam (5-15 %W/v), alkyl glycoside (0.01-1 %W/v), vitamin E (45-65 W%/v), ethanol (10-25 W%/v) and
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`-3-
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`WSGR Docket No. 35401—716103
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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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`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),
`
`ethanol (10-25 W%/v) and benzyl alcohol (5-15 %W/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 (15-225 W%/v) and benzyl
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`alcohol (7.5 -12.5 %W/v); and even more particularly, the solution may consist of diazepam (10 %W/v), dodecyl
`
`maltoside (0.15-0.3 %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
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`therapeutically effective amount from about 1 mg to about 20 mg. In some embodiments, the benzodiazepine is
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`administered as in a dosage volume from about 10 uL to about 200 uL. 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 benzodiazepine into 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 the first 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 symptoms of 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 more particularly 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 iv. 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 AUC that is precisely
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`half of the AUC obtained With 5 mg of iv. diazepam would have a 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.
`
`[011]
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`In some 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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`-4-
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`WSGR Docket No. 35401—716103
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0009
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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) in a
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`pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the
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`patient. In some embodiments the benzodiazepine drug is 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 more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%
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`(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 combinations thereof
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`[012]
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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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`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 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: (x-tocopherol, B-tocopherol, y-tocopherol, 8-tocopherol, (x-tocotrienol, B- tocotrienol, y-
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`tocotrienol, 5- 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
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`TPGS (Vitamin E polyethylene glycol succinate). In some embodiments, on the other hand, synthetic tocopherols
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`exclude tocopherols covalently bonded or 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.
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`[014]
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`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 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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`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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`-5-
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`WSGR Docket No. 35401—716.103
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0010
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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).
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`[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 combinations thereof,
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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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`In some 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 more alkyl glycosides.
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`[020]
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`The invention also discloses a method of treating a patient With a disorder that may be treatable 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 membranes of a patient a pharmaceutical composition for
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`nasal administration comprising a benzodiazepine drug; 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); 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
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`10% to about 70% (W/W). In some embodiments, the benzodiazepine is 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%
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`(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
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`[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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`WSGR Docket No. 35401—716.103
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`AQUESTIVE EXHIBIT 1006
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`AQUESTIVE EXHIBIT 1006 page 0011
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`page 0011
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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 drug is fully dissolved in a single phase
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`comprising one or more one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols or
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`glycols. In some embodiments, t