`
`PROVISIONAL PATENT APPLICATION
`
`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`Inventor(s):
`
`Steve Cartt
`Citizen of The United States of America
`
`San Carlos, CA
`
`David Medeiros
`Citizen of The United States of America
`
`South San Francisco, CA
`
`Garry Thomas Gwozdz
`Citizen of The United States of America
`
`Nazareth, Pennsylvania
`
`Andrew Loxley
`Citizen of Great Britain
`
`Philadelphia, PA
`
`Mark Mitchnick
`Citizen of the United Sates of America
`
`East Hampton, New York
`
`Assignee:
`
`Questcor Pharmaceuticals, Inc.
`
`WK
`
`Wilson Sonsini Goodrich 86 Rosati
`PROFESSIONAL CORPORATION
`
`650 Page Mill Road
`Palo Alto, CA 94304
`
`(650) 493-93 00
`(650) 493-6811
`
`Electronically Filed on March 28, 2008
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`AQUESTIVE EXHIBIT 1008
`
`AQUESTIVE EXHIBIT 1008 page 0001
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`page 0001
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`
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`FIELD OF THE INVENTION
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`[001] This application relates to the nasal administration of benzodiazepine drugs and combinations thereof.
`
`BACKGROUND OF THE INVENTION
`
`[002] By way of non-limiting example, the benzodiazepine family consists of drugs such as diazepam,
`
`lorazepam, and medazepam. The drugs in this family have been observed as possessing sedative, tranquilizing
`
`and muscle relaxing properties. They are frequently classified as an anxiolytic and skeletal muscle relaxants.
`
`They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, insomnia,
`
`agitation, seizures (such as those caused by epilepsy), muscle spasms and rigidity (which can be caused by
`
`tetanus), the symptoms of drug withdrawal associated with the continuous abuse of central nervous system
`
`depressants, and exposure to nerve agents.
`
`[003] 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).
`
`[004] GABA is an inhibitory neurotransmitter that, when bound to the GABAA receptor, facilitates (31' ions
`
`flooding into the neuron to which the receptor is bound. The increase in CT ions hyperpolarizes the membrane of
`
`the neuron. This completely or substantially reduces the ability of the neuron to carry an action potential.
`
`Targeting this receptor is particularly useful in treating many disorders, such as tetanus and epilepsy, which may
`
`result from too many action potentials proceeding through the nervous system.
`
`[005] 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.
`
`{006] The oral route of administration may be considered sub-optimal due to several disadvantages. For
`
`example, the amount of time required for an orally administered benzodiazepine drug to reach therapeutically
`
`relevant concentrations in blood plasma may be rather long, such as an hour or more. Moreover, as
`
`benzodiazepine drugs pass through the liver a significant amount may be metabolized. Thus, it may require large
`
`doses to achieve therapeutic plasma levels. Furthermore, due to the nature of seizures and muscle spasms, it can
`
`be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drug orally.
`
`[007]
`
`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 fiom a phobia of needles.
`
`-1-
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`WSGRDocket No. 32103-716.101
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`AQUESTIVE EXHIBIT 1008
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`AQUESTIVE EXHIBIT 1008 page 0002
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`page 0002
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`
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`[008]
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`Suppository compositions of benzodiazepine drugs can have a rapid onset of action. However, the
`
`inconvenience of suppositories is an obvious impediment to their being administered by anyone outside a very
`
`small group of the patient’s intimate acquaintances and the patient’s professional medical caretakers.
`
`SUMMARY OF THE INVENTION
`
`[009]
`
`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 phannaceutically—acceptable formulation for
`
`administration to one or more nasal mucosal membranes of the patient. In some embodiments the benzodiazepine
`
`drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof,
`
`in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations
`
`thereof, in an amount from about 5% to about 70% (w/w). In some embodiments, the benzodiazepine drug is
`
`dissolved in a carrier system.
`
`[010]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diacham, flumazenil,
`
`flurazepam, halazeparn, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam,
`
`prazepam, quazepam, triazolam, temazepam, Ioprazolam, any phannaceutically-acceptable salts thereof, and any
`
`combinations thereof. In some embodiments, the benzodiazepine drug is diacham, or a pharmaceutically-
`
`acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine,
`
`microparticics, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles
`
`have an effective average particle size of less than about 5000 nm.
`
`[011]
`
`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, S-tocopherol, a-tocotrienol, B— tocotrienol, y-
`
`tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinations thereof.
`
`{012]
`
`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.
`
`[013]
`
`In some embodiments, the benzodiaaepine 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.
`
`-2-
`
`WSGR Docket No. 321035716101
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`AQUESTIVE EXHIBIT 1008
`
`AQUESTIVE EXHIBIT 1008 page 0003
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`page 0003
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`
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`[014]
`
`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).
`
`[015]
`
`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 canier 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% (wfw).
`
`[016]
`
`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.
`
`[017] 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 mucosa] 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% (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% (wfw); 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.
`
`[018]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flnmazenil,
`
`flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam,
`
`prazepam, quazepam, triazolam, temazepam, loprazolam, or any phannaceutically—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,
`
`microparticies, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles
`
`have an effective average particle size of less than about 5000 11m.
`
`[019]
`
`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, S-tocopherol, d—tocon'ienol, [3- tocotrienol, 7-
`
`-3-
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`WSGR Docket No. 32103-716101
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`AQUESTIVE EXHIBIT 1008
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`AQUESTIVE EXHIBIT 1008 page 0004
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`page 0004
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`
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`tocotrienol, 8- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinations thereof.
`
`[020]
`
`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.
`
`[021]
`
`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 benzodiaaepine 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.
`
`[022]
`
`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).
`
`[023]
`
`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% (wfw). 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).
`
`[024]
`
`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.
`
`[025]
`
`In some embodiments, the composition is in a phannaceutically-acceptable spray formulation, and further
`
`comprising administering the composition to one or more nasal mucosal membranes of the patient. In some
`
`embodiments, the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine. In
`
`some embodiments, the pharmaceutical composition is in a phannaceutically—acceptable spray formulation having
`
`volume from about 10 uL to 200 uL.
`
`[026]
`
`In some embodiments, the administration of the composition comprises spraying at least a portion of the
`
`therapeutically effective amount of the composition into at least one nostril. In some embodiments, the
`
`administration of the composition comprises spraying at least a portion of the therapeutically effective amount of
`
`the composition into each nostril. In some embodiments, the administration of the composition comprises
`
`spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition
`
`-4-
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`WSGR Docket No. 32103-71610]
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`AQUESTIVE EXHIBIT 1008
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`AQUESTIVE EXHIBIT 1008 page 0005
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`page 0005
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`into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition
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`into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay,
`
`administering at least a fourth quantity of the composition to the second nostril.
`
`[027]
`
`In some embodiments, the administration ofthe composition begins at any time before or after onset of
`
`symptoms of a disorder which may be treatable with the composition.
`
`[028] 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.
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`INCORPORATION BY REFERENCE
`
`[029] All publications, patents, and patent applications mentioned in this specification are herein incorporated
`
`by reference to the same extent as if each individual publication, patent, or patent application was specifically and
`
`individually indicated to be incorporated by reference.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[030]
`
`Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and methods of
`
`using such pharmaceutical compositions. Such pharmaceutical compositions are administered nasally.
`
`[031]
`
`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 fiom about 30% to about 95% (w/w); and one or more alcohols or glycois, or any combinations
`
`thereof, in an amount from about 5% to about 70% (w/w) in a pharmaceutically-acceptable formulation for
`
`administration to one or more nasal mucosal membranes of the patient. In some embodiments the benzodiazepine
`
`drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof,
`
`in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations
`
`thereof, in an amount from about 5% to about 70% (w/w). In some embodiments, the benzodiazepine drug is
`
`dissolved in a carrier system.
`
`[032]
`
`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, tn'azolam, temazepam, Ioprazolam, any pharmaceutically—acceptable salts thereof, and any
`
`combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceuticaily-
`
`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.
`
`[033]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from
`
`the group consisting of: a-tocopherol, fi-tocopherol, y-tocopherol, B—tocopherol, d—tocotrienol, B- tocotrienol, 7-
`
`-5-
`
`WSGR Docket No. 32103-716101
`
`AQUESTIVE EXHIBIT 1008
`
`AQUESTIVE EXHIBIT 1008 page 0006
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`page 0006
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`
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`tocotrienol, 5— tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinations thereof.
`
`[034]
`
`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.
`
`[035]
`
`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.
`
`[036]
`
`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% (wr'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).
`
`[037]
`
`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).
`
`[038]
`
`In some embodiments, the composition comprises at least one additional ingredient selected from the
`
`group consisting of: active pharmaceuticaI ingredients; enhancers; excipients; and agents used to adjust the pH,
`
`buffer the composition, prevent degradation, and improve appearance, odor, or taste.
`
`[039] 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 mucosa] 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% (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% (w/w). In some embodiments,
`
`the benzodiazepine drug is dissolved in a carrier system.
`
`-6-
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`WSGR Docket No. 32103-716101
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`AQUESTIVE EXHIBIT 1008
`
`AQUESTIVE EXHIBIT 1008 page 0007
`
`page 0007
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`
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`[040]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil,
`
`flurazepam, halazepam, midazolarn, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam,
`
`prazepam, quazepam, triazolam, temazepam, loprazolam, or any phannaceutically—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.
`
`[041]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from
`
`the group consisting of: u—tocopherol, [l-tocopherol, y—tocopherol, B-tocopherol, ct-tocotrienol, B— tocotrienol, y-
`
`tocotrienol, 6- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinations thereof.
`
`[042]
`
`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.
`
`[043]
`
`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.
`
`[044]
`
`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% (WM).
`
`[045]
`
`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).
`
`[046]
`
`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.
`
`-7-
`
`WSGR Docket No. 32103-716101
`
`AQUESTIVE EXHIBIT 1008
`
`AQUESTIVE EXHIBIT 1008 page 0008
`
`page 0008
`
`
`
`[047]
`
`In some embodiments, the composition is in a phannaceutically-acceptable spray formulation, and finther
`
`comprising administering the composition to one or more nasal mucosal membranes of the patient. In some
`
`embodiments, the therapeutically effective amount is fiom about 1 mg to about 20 mg of the benzodiazepine. In
`
`some embodiments, the pharmaceutical composition is in a phannaceutically—acceptable spray formulation having
`
`volume from about 10 [LL to 200 uL.
`
`[048]
`
`In some embodiments, the administration of the composition comprises spraying at least a portion of the
`
`therapeutically effective amount of the composition into at least one nostril. In some embodiments, the
`
`administration of the composition comprises spraying at least a portion of the therapeutically effective amount of
`
`the composition into each nostril. In some embodiments, the administration of the composition comprises
`
`spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition
`
`into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition
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`into the first nostril. Some embodiments fithher comprise, optionally afier a pre—selected time delay,
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`administering at least a fourth quantity of the composition to the second nostril.
`
`[049]
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`In some embodiments, the administration of the composition begins at any time before or after onset of
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`symptoms of a disorder which may be treatable with the composition.
`
`Definitions
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`[050] As used herein the phrase ‘therapeutically effective amount” (or more simply “effective amount”)
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`includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a
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`patient in need of particular treatment. The skilled clinician will recognize that the therapeutically effective
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`amount of drug will depend upon the patient, the indication and the particular drug administered.
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`[051] As used herein, the modifier “about” is intended to have its regularly recognized meaning of
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`approximately. In some embodiments, the term may be more precisely interpreted as meaning within a particular
`
`percentage of the modified value, e.g. “about” may in some embodiments mean i 20%, 2t 10%, d: 5%, :l: 2%, or i
`
`1% or less.
`
`[052] As used herein, the phrase “analogs or derivatives” includes molecules that differ from one another
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`molecule due to one or more atoms or functional groups having been replaced with a different atom or functional
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`group. This may result in molecules with similar chemical formulas but different chemical and/or biological
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`properties.
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`[053] As used herein, the term, “isomer” includes molecules with identical chemical formulas, but between
`
`which the arrangement of the molecules may vary. These varying arrangements may result in molecules with
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`identical chemical formulas but different chemical properties. By way of non-limiting example, propanol has the
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`chemical formula C3H70H. It may be found as propan-l-o], wherein the —OH is found attached to an end carbon.
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`Alternatively, it may be found as propan-Z-ol, wherein the -—OH is found attached to the second carbon.
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`propan— 1-01
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`pmpm-Z o]
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`[054] As used herein, the term “seizure” includes commonly recognized types of seizures, including absence
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`seizures, myoclonic seizures, cionic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. Ofien
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`seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura that will be
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`familiar to the patient or those familiar with the patient. Each patient will generally experience a different type of
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`aura, which is unique to the patient; however auras may be classified as audible, visual, olfactory or tactile
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`sensations that usually, or at least often, precedes a patient’s experiencing a seizure. (Not all patients who suffer
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`seizures experience aura; however aura are not uncommon amongst those who suffer the worst type of seizures,
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`especially tonic-clonic seizures.)
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`[055] As used herein, the term “prevention” refers to a forestalling, including temporary forestalling, of the
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`onset of a disorder. In the case of seizures, this can occur either with or without the benefit of a warning aura.
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`[056] As used herein, the term “treatment” refers to a reduction in the intensity and/or duration of a disorder, or
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`similar effects. The term also encompasses the side-effects of such a “treatment.”
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`Benzodiazepine Drugs
`
`[057]
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`In the context of the present invention, the term “benzodiazepine drug” includes any therapeutically
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`effective benzodiazepine compound, or pharmaceutically acceptable salt, or combinations thereof. In some
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`embodiments, benzodiazepine comprises a member of the group consisting of aiprazolam, diazepam, flurazepam,
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`lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceuticaliy acceptable salts and
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`combinations thereof.
`
`[058]
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`It should be recognized by those of skill in the art that additional benzodiazepine compounds that have
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`heretofore been considered to have marginal or little therapeutic benefit, either because of low bioavailability,
`
`poor pharmacokinetic properties or poor pharmacodynamic properties, may find use through the present
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`invention, which can provide for improved bioavailability of benzodiazepine drugs, delivery of higher
`
`concentrations of benzodiazepine drugs via the nasal route, faster attainment of therapeutic levels of
`
`benzodiazepine in the blood plasma, avoidance of the liver portal vein and concomitant avoidance of first pass
`
`effects and/or faster presentation of benzodiazepine drug to the brain.
`
`[059]
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`For example, most benzodiazepines are so slightly soluble in water that a therapeutically effective amount
`
`cannot be dissolved in a volume of aqueous solvent that is amenable to application to a mucosa] membrane. By
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`use of the present carrier system, which in some embodiments, provides an improved ability to dissolve
`
`benzodiazepine drugs, the present invention allows benzodiazepine drugs to be administered to one or more
`
`mucosa] membranes, including to nasal mucosal membranes. This can allow one to administer the drug without
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`hospitalization or unnecessary discomfort. Additionally, in some embodiments of the present invention, such as
`
`nasal administration, the digestive system largely may be bypassed. This latter improvement can yield improved
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`bioavailability, faster attainment of therapeutic levels of benzodiazepine in the blood plasma, avoidance of the
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`liver portal vein, and/or concomitant avoidance of first pass effects.
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`[060] Nasal administration of the composition can result in faster presentation ofthe one or more
`
`benzodiazepine drugs to the brain due to the close proximity of the membranes and the brain. A seizing patient,
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`for example, suffers from rigid muscles and uncontrollable movement. This can make oral and/or intravenous
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`administration difficult or inconvenient. However, the nasal passageways remain open and easily accessible, and
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`therefore is a useful route of administration for of the present invention.
`
`[061]
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`In some embodiments, the pharmaceutical composition is used to treat a patient suffering from a disorder
`
`that is amenable to treatment or prevention with an effective amount of the one or more benzodiazepine drugs.
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`By way of non-limiting example such disorders can include: insomnia, anxiety, seizures, muscle spasms and
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`rigidity, and the symptoms of drug withdrawal.
`
`[062]
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`In some embodiments, the one or more benzodiazepine drugs, are used alone or in combination with
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`another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure,
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`reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
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`[063] Alprazolam (3-chloro-6-phenyl-1-methyl-4H—1,2,4-triazolo[4,3-a][1,4]benzodiazepine).
`
`CI
`
`/N
`
`[064] Alprazolam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is
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`classified as an anxiolytic. Alprazolam has also been