WSGRDocket No. 32103-716.101
`
`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.
`
`WR
`Wilson Sonsini Goodrich & Rosati
`PROFESSIONAL CORPORATION
`
`650 Page Mill Road
`Palo Alto, CA 94304
`(650) 493-9300
`(650) 493-6811
`
`Electronically Filed on March 28, 2008
`
`AQUESTIVE EXHIBIT 1008
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`AQUESTIVE EXHIBIT 1008 page 0001
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`page 0001
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`FIELD OF THE INVENTION
`[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 drugsin this family have been observed as possessing sedative, tranquilizing
`and musclerelaxing properties. They are frequently classified as an anxiolytic and skeletal muscle relaxants.
`They are thought to be useful in preventing,treating, or ameliorating the symptomsof anxiety, insomnia,
`agitation, seizures (such as those caused by epilepsy), muscle spasmsand rigidity (which can be caused by
`tetanus), the symptomsof drug withdrawal associated with the continuous abuse of central nervous system
`
`depressants, and exposure to nerve agents.
`[003] Benzodiazepines are thoughtto act by binding to the GABA,receptor of a neuron, possibly causing the
`receptor to change shape and makingit more accessible to gama-aminobutyric acid (GABA).
`[004}
`GABAisan inhibitory neurotransmitter that, when bound to the GABA,receptor, facilitates Cl 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 reducesthe 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 administeredorally, rectally, or parenterally. The
`ability to utilize these and other types of formulations has been significantly limited due, in manycases, to
`
`solubility challenges.
`
`Theoral route of administration may be considered sub-optimal due to several disadvantages. For
`[006]
`example, the amountoftime required for an orally administered benzodiazepine drug to reach therapeutically
`relevant concentrations in blood plasma maybe 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.
`
`[907]
`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.
`
`-I-
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`WSGR Docket No. 32103-716.101
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`AQUESTIVE EXHIBIT 1008 page 0002
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`Suppository compositions of benzodiazepine drugs can have a rapid onset of action. However, the
`{008]
`inconvenience of suppositories is an obvious impedimentto their being administered by anyoneoutside a very
`small group ofthe patient’s intimate acquaintances and the patient’s professional medical caretakers.
`
`SUMMARYOF THE INVENTION
`
`In some embodiments, the pharmaceutical composition for nasal administration comprises: a
`[009]
`benzodiazepine drug; one or morenatural or synthetic tocopherols or tocotrienols, or any combinations thereof, in
`an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations
`thereof, in an amount from about 5% to about 70% (w/w) in a pharmaceutically-acceptable formulation for
`administration to one or more nasal mucosal membranes ofthe patient. In some embodiments the benzodiazepine
`drugis dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinationsthereof,
`in an amount from about 30% to about 95% (w/w); and the one or more alcchols or glycols, or any combinations
`thereof, in an amount from about 5% to about 70% (w/w). In some embodiments, the benzodiazepine drugis
`
`dissolved in a carrier system.
`[010]
`in some embodiments, the benzodiazepine drugis selected from the group consisting of: alprazolam,
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil,
`flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam,lorazepam,
`prazepam, quazepam,triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any
`combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-
`acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine,
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles
`
`have an effective average particle size of less than about 5000 nm.
`[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, 6-tocopherol, a-tocotrienol, B- tocotrienol, y-
`tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinationsthereof.
`{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 combinationsthereof.
`{013]
`In some embodiments, the benzodiazepine drugis present in the carrier system in a concentration from
`
`about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drugis present in 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-
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`In some embodiments,the carrier system comprises one or more natural or synthetic tocopherols or
`[014]
`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
`combinationsthereof, 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 combinationsthereof, 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 carrier system comprises
`one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w).
`In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinationsthereof,
`
`in an amount of about 30% (w/w).
`[016]
`In some embodiments, the composition comprisesat 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, ortaste.
`[017] The invention also discloses a method oftreating 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 membranesof a patient a pharmaceutical composition for
`nasal administration comprising a benzodiazepine drug; one or more natural or synthetic tocopherols or
`
`tocotrienols, or any combinationsthereof, 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 combinationsthereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or
`
`glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w). In some embodiments,
`
`the benzodiazepine drug is dissolved in a carrier system.
`
`[018]
`
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil,
`
`flurazepam, halazepam, midazolam, nordazepam, medazepam,nitrazepam, oxazepam, medazepam, lorazepam,
`
`prazepam, quazepam,triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and
`
`any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-
`
`acceptable salt thereof. In some embodiments, the benzodiazepine drug 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.
`
`[019]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienolsare selected from
`
`the group consisting of: a-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol, a-tocotrienol, B- tocotrienol, y-
`
`-3-
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`tocotrienol, 5- 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 combinationsthereof. 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 benzodiazepinedrug is presentin the carrier system in a concentration from
`about | mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is presentin 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.
`In some embodiments,the carrier system comprises one or more natural or synthetic tocopherols or
`[022]
`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
`combinationsthereof, 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% (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).
`
`[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 pharmaceutically-acceptable spray formulation, and further
`
`comprising administering the composition to one or more nasal mucosal membranesof the patient. In some
`
`embodiments, the therapeutically effective amountis from about 1 mg to about 20 mg of the benzodiazepine. In
`
`some embodiments, the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having
`
`volume from about 10 pL to 200 nL.
`
`[626]
`
`In some embodiments, the administration of the composition comprises spraying at least a portion ofthe
`
`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 thefirst nostril, spraying a second quantity of the composition
`
`~4-
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`into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition
`into the first nostril. Some embodiments further comprise, optionally after a pre-selected timedelay,
`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 ofa disorder which may betreatable with the composition.
`[028] Additional embodiments, uses, and advantagesofthe invention will become apparentto the person skilled
`in the art upon consideration of the disclosure set forth herein.
`
`INCORPORATION BY REFERENCE
`
`[029] All publications, patents, and patent applications mentionedin this specification are herein incorporated
`by reference to the same extent as if each individual publication, patent, or patent application was specifically and
`individually indicated to be incorporated by reference.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and methodsof
`[030]
`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 amountfrom about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations
`
`thereof, in an amount from about 5% to about 70% (w/w)in a pharmaceutically-acceptable formulation for
`
`administration to one or more nasal mucosal membranesofthe patient. In some embodiments the benzodiazepine
`
`drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinationsthereof,
`in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations
`
`thereof, in an amount from about 5% to about 70% (w/w). In some embodiments, the benzodiazepine drugis
`
`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,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.
`
`[033]
`
`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, 6-tocopherol, a-tocotrienol, B- tocotrienol, y-
`
`-5-
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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 morealcohols 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 combinationsthereof.
`[035]
`In some embodiments, the benzodiazepine drugis presentin 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% (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).
`[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 combinationsthereof,
`
`in an amount of about 30% (w/w).
`
`In some embodiments, the composition comprises at least one additional ingredient selected from the
`[038]
`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.
`[039]
`‘The invention also discloses a method oftreating 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 membranesof 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 combinationsthereof, 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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`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`[040]
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,diazepam, flumazenil,
`flurazepam,halazepam, midazolam, nordazepam, medazepam,nitrazepam, oxazepam, medazepam, lorazepam,
`prazepam, quazepam,triazolam, temazepam, loprazolam,or any pharmaceutically-acceptable salts thereof, and
`any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam,or a pharmaceutically-
`acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine,
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles
`have an effective averageparticle 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: a-tocopherol, B-tocopherol, y-tocopherol, §-tocopherol, a-tocotrienol, B- tocotrienol, y-
`tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives
`
`thereof, and any combinationsthereof.
`[042}
`In some embodiments, the one or morealcohols 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 combinationsthereof.
`[043]
`In some embodiments,the benzodiazepine drugis present in the carrier system in a concentration from
`about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is presentin 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.
`In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or
`[044]
`tocotrienols, or any combinationsthereof, 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
`combinationsthereof, 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).
`[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 alcoholsor glycols, or any combinations thereof,
`
`in an amountfrom 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-
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`AQUESTIVE EXHIBIT 1008
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`AQUESTIVE EXHIBIT 1008 page 0008
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`In some embodiments, the composition is in a pharmaceutically-acceptable spray formulation, and further
`[047]
`comprising administering the composition to one or more nasal mucosal membranesofthe patient. In some
`embodiments, the therapeutically effective amountis from about 1 mg to about 20 mg of the benzodiazepine. In
`some embodiments, the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having
`
`volume from about 10 pL to 200 wL.
`[048]
`In some embodiments,the administration of the composition comprises spraying at least a portion of the
`therapeutically effective amountof the composition into at least one nostril. In some embodiments, the
`administration ofthe 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
`sprayinga first quantity of the compositioninto thefirst nostril, spraying a second quantity of the composition
`into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition
`into the first nostril. Some embodiments further comprise, optionally after a pre-selected timedelay,
`
`administering at least a fourth quantity of the composition to the second nostril.
`[049]
`In some embodiments, the administration of the composition begins at any time before or after onset of
`
`symptomsof a disorder which maybetreatable with the composition.
`
`Definitions
`
`[050] As used herein the phrase “therapeutically effective amount” (or more simply “effective amount”)
`includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a
`patient in need ofparticular treatment. The skilled clinician will recognize that the therapeutically effective
`amount of drug will depend upon the patient, the indication and the particular drug administered.
`
`[051] As used herein, the modifier “about” is intended to have its regularly recognized meaning of
`approximately. In some embodiments, the term may be moreprecisely interpreted as meaning within a particular
`
`percentage of the modified value, e.g. “about” may in some embodiments mean + 20%, + 10%, + 5%, + 2%, or +
`
`1% or less.
`
`[052] As used herein, the phrase “analogs or derivatives” includes moleculesthat differ from one another
`
`molecule due to one or more atomsor functional groups having been replaced with a different atom or functional
`
`group. This may result in molecules with similar chemical formulas but different chemical and/or biological
`
`properties.
`
`[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
`
`identical chemical formulas but different chemical properties. By way of non-limiting example, propanol has the
`
`chemical formula C;H;OH. It may be found as propan-1-ol, wherein the -OH is found attached to an end carbon.
`
`Alternatively, it may be found as propan-2-ol, wherein the --OHis found attached to the second carbon.
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`propan-1-ol
`
`propa-2-ol
`[054] As used herein, the term “seizure” includes commonly recognized typesof seizures, including absence
`seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. Often
`seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or moreaura that will be
`familiar to the patient or those familiar with the patient. Each patient will generally experience a different type of
`aura, which is unique to the patient; however auras may be classified as audible, visual, olfactory or tactile
`sensations that usually, or at least often, precedes a patient’s experiencing a seizure.
`(Notall patients whosuffer
`seizures experience aura; however aura are not uncommon amongst those whosuffer the worst type of seizures,
`
`especially tonic-clonic seizures.)
`[055]
`Asused herein, the term “prevention”refers to a forestalling, including temporary forestalling, of the
`onset of a disorder. In the case of seizures, this can occur either with or without the benefit of a warning aura.
`[056] As used herein, the term “treatment”refers to a reduction in the intensity and/or duration ofa disorder, or
`similar effects. The term also encompassesthe side-effects of such a “treatment.”
`
`Benzodiazepine Drugs
`[087]
`In the context of the present invention, the term “benzodiazepine drug” includes any therapeutically
`effective benzodiazepine compound, or pharmaceutically acceptable salt, or combinations thereof. In some
`embodiments, benzodiazepine comprises a memberofthe group consisting of alprazolam, diazepam, flurazepam,
`lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and
`
`combinationsthereof.
`
`It should be recognized by thoseofskill in the art that additional benzodiazepine compoundsthat have
`[058]
`heretofore been considered to have marginalorlittle therapeutic benefit, either because of low bioavailability,
`poor pharmacokinetic properties or poor pharmacodynamic properties, may find use through the present
`invention, which can provide for improved bioavailability of benzodiazepine drugs, delivery of higher
`concentrations of benzodiazepine drugsvia the nasal route, faster attainment of therapeutic levels of
`benzodiazepinein the blood plasma, avoidance ofthe liver portal vein and concomitant avoidanceoffirst pass
`effects and/or faster presentation of benzodiazepine drug to the brain.
`[059]
`For example, most benzodiazepinesare so slightly soluble in water that a therapeutically effective amount
`cannot be dissolved in a volume of aqueoussolventthat is amenable to application to a mucosal membrane. By
`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
`mucosal membranes, including to nasal mucosal membranes. This can allow one to administer the drug without
`
`hospitalization or unnecessary discomfort. Additionally, in some embodiments ofthe 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 ofthe
`liver portal vein, and/or concomitant avoidance offirst pass effects.
`[060] Nasal administration of the composition can result in faster presentation ofthe one or more
`benzodiazepine drugsto the brain due to the close proximity of the membranes and the brain. A seizing patient,
`for example, suffers from rigid muscles and uncontrollable movement. This can make oral and/or intravenous
`administration difficult or inconvenient. However, the nasal passageways remain open and easily accessible, and
`
`therefore is a useful route of administration for of the present invention.
`{061]
`In some embodiments, the pharmaceutical compositionis used to treat a patient suffering from a disorder
`that is amenable to treatment or prevention with an effective amount ofthe one or more benzodiazepine drugs.
`By way ofnon-limiting example such disorders can include: insomnia, anxiety, seizures, muscle spasms and
`rigidity, and the symptomsof drug withdrawal.
`[062}
`In some embodiments, the one or more benzodiazepine drugs, are used aloneor in combination with
`another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure,
`reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
`[063] Alprazolam (8-chloro-6-pheny]-1-methyl-4H-1,2,4-triazolo[4,3-a]{1,4]benzodiazepine).
`
`ao\~ ’,
`
`Ci
`
`aN
`
`[064] Alprazolam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is
`classified as an anxiolytic. Alprazolam has also been shown to be useful in the treatment of panic disorder. The
`dosage ofalprazolam varies by indication, howeverit is expected that a therapeutic dose will be in the range of
`about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some
`preferred embodiments about 4 to about6 times per day. Alprazolam may be manufacturedusing the process
`disc