Organization
`
`International Bureau
`
`=z
`Soe=\
`
`AMAIA TAMUATARAAA
`
`(10) International Publication Number
`WO 2012/174158 A2
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`(19) World Intellectual Property
`=
`
`(43) International Publication Date
`20 December 2012 (20.12.2012) WIPO! PCT
`
`(51) International Patent Classification:
`A61K 31/5513 (2006.01)
`
`(21) International Application Number:
`
`PCT/US2012/042311
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`13 June 2012 (13.06.2012)
`
`English
`
`English
`
`(30) Priority Data:
`61/497,017
`61/570,110
`
`14 June 2011 (14.06.2011)
`13 December 2011 (13.12.2011)
`
`US
`US
`
`(71) Applicant (for all designated States except US): HALE
`BIOPHARMA VENTURES, LLC [US/US];
`1042-B
`North El Camino Real, Suite 430, Encinitas, CA 92024
`(US).
`
`(72)
`(75)
`
`Inventors; and
`(for US only): CARTT, Steve
`Inventors/Applicants
`[US/US]; 3260 Whipple Road, Union City, CA 94587
`(US). MEDEIROS, David [US/US]; 212 Crown Circle,
`
`(74)
`
`(81)
`
`South San Francisco, CA 94080 (US). GWOZDZ, Garry,
`Thomas [US/US]; 432 Pine Street, Jim Thorpe, PA 18229
`(US). LOXLEY, Andrew [US/US]; 126 Market Street,
`#5, Philadelphia, PA 19106 (US). MITCHNICK, Mark
`[US/US]; 80 Three Mile Harbor Drive, East Hampton, NY
`11937 (US). HALE, David [US/US]; 9232 Bernardo
`Lakes Drive, San Diego, CA 92127 (US). MAGGIO, Ed-
`ward, T. [US/US]; 16870 W. Bernardo Drive, Suite 390,
`San Diego, CA 92127 (US).
`
`Agent: GRUMBLING, Matthew, V.; Wilson Sonsini
`Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA
`94304 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW,MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM,PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`
`(54) Title: ADMINISTRATION OF BENZODIAZEPINE
`
`FIG. 1
`
`[Continued on next page]
`
`(57) Abstract: The invention relates to
`pharmaceutical compositions compris-
`ing one or more benzodiazepine drugs
`for nasal administration, methods for
`producing and for using such composi-
`tions.
`
`Linger Scale
`
`
`
`
`
`“Cire Uh)
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`page 0001
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`WO 2012/174158 A2 IIfNMOTTNIUT AAT TNA TAT TAT AMAA AACT
`
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, Declarations under Rule 4.17:
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`as to applicant's entitlement to apply for and be granted
`a patent (Rule 4.17(ii))
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, LR, LS, MW, MZ, NA, RW,SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FL FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO,PL, PT, RO, RS, SE, SI, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW,ML, MR, NE,SN, TD, TG).
`
`as to the applicant's entitlement to claim the priority of
`the earlier application (Rule 4.17/(iii))
`Published:
`
`without international search report and to be republished
`upon receipt of that report (Rule 48.2(g))
`
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`WO 2012/174158
`
`PCT/US2012/042311
`
`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`This application claimspriority to United States provisional application 61/497,017, filed June 14,
`[001]
`_ 2011 and United States provisional application 61/570,110, filed December 13, 2011, each of which is
`incorporated herein by reference inits entirety.
`
`[002]
`
`This application relates to the nasal administration of benzodiazepine drugs and combinationsthereof.
`
`FIELD OF THE INVENTION
`
`BACKGROUNDOFTHE INVENTION
`{003] By way of non-limiting example,
`the benzodiazepine family consists of drugs such as diazepam,
`lorazepam, and midazolam. The drugs in this family have been observed as possessing sedative, tranquilizing
`and muscle relaxing properties. They are frequently classified as anxiolytic and skeletal muscle relaxants.
`
`They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety,
`insomnia,
`agitation, seizures (such as those caused by epilepsy), muscle spasms andrigidity, the symptoms of drug
`withdrawalassociated with the continuousabuseof central nervous system depressants, and exposure to nerve
`
`agents.
`
`{004] Benzodiazepines are thought to act by binding to the GABA, receptor of a neuron, possibly causing
`
`the receptor to change shape and making it more accessible to gama-aminobutyric acid (GABA).
`
`[005]
`
`GABAis an inhibitory neurotransmitter that, when bound to the GABAgreceptor, facilitates Cl’ ions
`
`flooding into the neuron to which the receptor is bound. The increase in Cl’ 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
`
`mayresult from too manyaction potentials proceeding through the nervous system.
`
`[006] Current formulations of benzodiazepine drugs can be administered orally, rectally, or parenterally.
`
`The ability to utilize these and other types of formulations has been significantly limited due, in many cases,
`
`to solubility challenges.
`[007] The oral route of administration may be considered sub-optimal due to several disadvantages. For
`example, the amountof 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 throughtheliver a significant amount of the drug may be metabolized. Thus, large
`
`doses may be required to achieve therapeutic plasma levels. Furthermore, due to the nature of seizures and
`
`to administer the
`for either a patient or a care-giver
`it can be extremely difficult
`muscle spasms,
`benzodiazepine drug orally and care-givers may be reluctant to place their hands in patients’ mouths.
`[008]
`Intravenous administration perhaps provides a faster route of administration. However intravenous
`
`administration is generally limited to trained health care professionals in tightly controlled clinical settings.
`
`Additionally, sterility must be maintained. Furthermore, administering any drug intravenously can be painful
`
`-|-
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`intravenous
`In addition,
`for patients suffering from a phobia of needles.
`likely impractical
`and is
`administration of benzodiazepines is associated with respiratory depression. Thus, use of intravenous
`benzodiazepinesis limited to professional health care environments.
`[009] Rectal suppository compositions of benzodiazepine drugs can havea rapid onset of action. However,
`the inconvenience of rectally administered drug is an obvious impediment to their being administered by
`
`anyone outside a very small group of the patient’s intimate acquaintances and the patient’s professional
`
`medical care-givers.
`
`SUMMARYOF THE INVENTION
`for nasal
`solutions
`there are provided (non-aqueous) pharmaceutical
`In some embodiments,
`[010]
`administration consisting of: (a) a benzodiazepine drug; (b) one or more natural or synthetic tocopherols or
`tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); (c) one or more
`alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w); and (d)
`
`an alkyl glycoside, in a pharmaceutically-acceptable solution for administration to one or more nasal mucosal
`
`membranes of a patient.
`
`In some embodiments, the benzodiazepine drug is dissolved in the one or more
`
`natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to
`about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from
`about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is selected from the group
`
`consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,
`
`diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam,
`
`lorazepam, prazepam, quazepam,triazolam, temazepam, loprazolam, any pharmaccutically-acceptable salts
`
`thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a
`
`pharmaceutically-acceptable salt thereof..In some embodiments, the solution contains about | to about 20 %
`
`(w/v) of benzodiazepine, e.g. about 1
`
`to about 20 % (w/v) of diazepam. In some embodiments, the one or
`
`more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: a-tocopherol,
`B-tocopherol, y-tocopherol, 6-tocopherol, a-tocotrienol, B-
`tocotrienol, y-
`tocotrienol, 8-
`tocotrienol,
`
`tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any
`
`combinations thereof. In some embodiments, the one or more alcohols are selected from the group consisting
`
`of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl] alcohol, any isomers thereof, or any combinations
`
`thercof. In some embodiments, the solution contains two or more alcohols, such as ethanol (1-25 % (w/v)) and
`benzyl alcohol (1-25 % (w/v)), or ethanol (10-22.5 % (w/v)) and benzyl alcohol (7.5-12.5 % (w/v)). In some
`embodiments, the benzodiazepineis present in the pharmaceutical composition in a concentration from about
`
`20 mg/mL to about 200 mg/mL. In some embodiments, the one or more natural or synthetic tocopherols or
`
`tocotrienols, or any combinations thereof, is in an amount from about 45% to about 85% (w/w). In some
`
`embodiments, the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, is
`
`in an amount from about 50% to about 75% (w/w). In some embodiments, the one or more alcohols or
`
`glycols, or any combinations thereof, is in an amount from about 15% to about 55% (w/w), e.g. about 25% to
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`about 40% (w/w). In some embodiments, the solution consists of diazepam (5-15 % (w/v)), alky! glycoside
`(0.01-1 % (w/v)), vitamin E (45-65 % (w/v)), ethanol (10-25 % (w/v)) and benzyl alcohol (5-15 % (w/v)). In
`some embodiments, the solution comprises at least about 0.01% (w/w)of an alkyl glycoside, e.g. about 0.01%
`to 1% (w/w) ofan alkyl glycoside, such as dodecy! maltoside. In some embodiments, the solution consists of
`diazepam (5-15 % (w/v)), dodecyl maltoside (0.01-1 % (w/v)), vitamin E (45-65 % (w/v)), ethanol (10-25 %
`(w/v)) and benzyl alcohol (5-15 % (w/v)); more particularly the solution may consist of diazepam (9-11 %
`(w/v)), dodecyl maltoside (0.1-0.5 % (w/v)), vitamin E (50-60 % (w/v)), ethanol (15-22.5 % (w/v)) and benzyl
`alcohol (7.5-12.5 % (w/v)); and even moreparticularly, 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)).
`
`[011]
`
`- Some embodiments described herein provide a methodof treating a patient with a disorder which may
`
`be treatable with a benzodiazepine drug, comprising: administering to one or more nasal mucosal membranes
`
`of a patient a pharmaceutical solution for nasal administration consisting of a benzodiazepine drug, one or
`
`more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about
`
`30% to about 95% (w/w); one or more alcohols or glycols, or any combinations thereof, in an amount from
`
`about 10% to about 70% (w/w); and an alkyl glycoside. In some embodiments, the benzodiazepine drugis
`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),andthe one or more alcohols or glycols, or any combinations
`thereof, in an amount from about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is
`selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam,
`clorazepam, demoxazepam, diazepam,
`flumazenil,
`flurazepam, halazepam, midazolam, nordazepam,
`medazepam,nitrazepam, oxazepam,lorazepam, prazepam, quazepam,triazolam, temazepam,loprazolam, any
`pharmaceutically-acceptable salts
`thereof, and any combinations thereof.
`In some embodiments,
`the
`benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the
`solution contains about
`|
`to about 20 % (w/v) of benzodiazepine, e.g. about
`1
`to about 20 % (w/v) of
`diazepam. In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected
`from the group consisting of: a-tocopherol, B-tocopherol, y-tocopherol, 8-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. In some embodiments, the one or more alcohols are
`selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any
`isomers thereof, or any combinations thereof.
`In some embodiments,
`the solution contains two or more
`alcohols, such as ethanol (1-25 % (w/v)) and benzyl alcohol (1-25 % (w/v)), or ethanol (10-22.5 % (w/v)) and
`benzy! alcohol (7.5-12.5 % (w/v)). In some embodiments, the benzodiazepine is present in the pharmaceutical
`composition in a concentration from about 20 mg/mL to about 200 mg/mL. In some embodiments, the oneor
`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
`
`-3-
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`embodiments, the one or more alcohols or glycols, or any combinations thereof, is in an amount from about
`
`15% to about 55% (w/w), e.g. about 25% to about 40% (w/w). In some embodiments,the solution consists of
`
`diazepam (5-15 % (w/v)), alkyl glycoside (0.01-1 % (w/v)), vitamin E (45-65 % (w/v)), ethanol (10-25 %
`
`(w/v)) and benzyl alcohol (5-15 % (w/v)). In some embodiments, the solution comprises at least about 0.01%
`
`(w/w) of an alkyl glycoside, e.g. about 0.01% to 1% (w/w) of an alky! glycoside, such as dodecy! maltoside.
`
`In some embodiments, the solution consists of diazepam (5-15 % (w/v)), dodecyl maltoside (0.01-1 % (w/v)),
`
`vitamin E (45-65 % (w/v)), ethanol (10-25 % (w/v)) and benzy! alcohol (5-15 % (w/v)); more particularly the
`solution may consist of diazepam (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 alcohol (7.5-12.5 % (w/v)); and even moreparticularly, 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 therapeutically effective amount from
`
`about 1 mg to about 20 mg. In some embodiments, the benzodiazepine is administered as in a dosage volume
`
`from about 10 pL to about 200 pL.
`
`In some embodiments,
`
`the administration of the pharmaceutical
`
`composition comprises spraying. at
`
`least a portion of the therapeutically effective amount of the
`
`benzodiazepine into at least one nostril. In some embodiments, the administration of the pharmaceutical
`
`least a portion of the therapeutically effective amount of the
`composition comprises spraying at
`benzodiazepine into each nostril. In some embodiments, administration of the pharmaceutical composition
`comprises spraying a first quantity of the pharmaceutical composition into the first nostril, spraying a second
`
`quantity of the pharmaceutical composition into a second nostril, and optionally after a pre-selected time
`
`delay, spraying a third quantity of the pharmaceutical composition into the first nostril. In some embodiments,
`the method further comprises, optionally after a pre-selected time delay, administering at
`least a fourth
`quantity of the pharmaceutical composition to the second nostril. In some embodiments, nasal administration
`
`of the pharmaceutical composition begins at any time before or after onset of symptoms ofa disorder which
`
`may be treatable with the pharmaceutical composition.
`
`In some embodiments,
`
`the treatment achieves
`
`bioavailability that is from about 80-125% (e.g. about 90-110%, or more particularly about 92.5-107.5%) of
`
`that achieved with the same benzodiazepine administered intravenously, e.g. In this context, it is intended that
`
`bioavailability be determined by a suitable pharmacodynamic method, such as comparison of area under the
`
`blood plasma concentration curve (AUC) for the nasally and intravenously administered drug. It is further
`
`understood that the percent bioavailability of the nasally administered benzodiazepine may be determined by
`
`comparing the area under the blood plasma concentration curve obtained with one dose of the benzodiazepine
`(e.g. 10 mg of nasal diazepam) with another dose of the same benzodiazepine administered intravenously (c.g.
`5 mg of i.v. diazepam), taking into consideration the difference in dose. Thus, for the sake of illustration, a 10
`
`mg nasal diazepam dose that achieves an AUCthatis precisely half of the AUC obtained with 5 mg ofiv.
`
`diazepam would havea bioavailability of 100%. In some embodiments,the disorder to be treated is a seizure,
`
`such as an epileptic seizure, a breakthrough seizure, or other seizure. In some embodiments, the solution and
`treatment with the solution are substantially non-irritating and well-tolerated.
`
`-4-
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`a
`the pharmaceutical composition for nasal administration comprises:
`In some embodiments,
`[012]
`benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations
`
`thereof,
`
`in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any
`
`combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70%
`
`(w/w)
`
`in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal
`
`membranes of the patient. In some embodiments the benzodiazepine drug is dissolved in the one or more.
`
`natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to
`about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from
`
`the
`about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w). In some embodiments,
`benzodiazepine drug is dissolved in a carrier system.
`In some embodiments, at
`least part of the
`benzodiazepine drug is in a form comprising benzodiazepine microparticles, nanoparticles or combinations
`thereof.
`In some embodiments,
`the composition is substantially free of benzodiazepine microparticles,
`nanoparticles or combinations thereof.
`,
`[013]
`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam,
`flumazenil,
`flurazepam, halazepam, midazolam, nordazepam, medazepam,nitrazepam, oxazepam, lorazepam, prazepam,
`
`triazolam,
`quazepam,
`combinations thercof.
`
`loprazolam, any pharmaceutically-acceptable salts thereof, and any
`temazepam,
`In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-
`
`the benzodiazepine drug comprises benzodiazepine
`In some embodiments,
`thereof.
`acceptable salt
`thereof.
`In
`some
`embodiments,
`the benzodiazepine
`microparticles, nanoparticles, or
`combinations
`nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the
`benzodiazepine drug is substantially free of benzodiazepine microparticles, nanoparticles or combinations
`thereof.
`,
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected
`[014]
`from the group consisting of: a-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol, a-tocotrienol, p-
`tocotrienol, y- tocotrienol, 5- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs
`or derivatives thereof, and any combinations thereof.
`In some embodiments, a synthetic tocopherol can
`include Vitamin E TPGS (Vitamin E polyethylene glycol succinate). In some embodiments,on the other hand,
`synthetic tocopherols exclude tocopherols covalently bonded orlinked (e.g. through a diacid linking group) to
`a glycol polymer, such as polyethylene glycol). Thus,
`in some embodiments, the compositions described
`herein exclude Vitamin E TPGS.
`
`In some embodiments, one or more alcohols are selected from the group consisting of: ethanol, propyl
`[015]
`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, propylenc
`glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof.
`In some
`preferred embodiments, the glycols exclude glycol polymers.
`In some preferred embodiments, the glycols
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`exclude glycol polymers having an average molecular weight of greater than 200. In some embodiments,the
`glycols exclude polyethylene glycol having an average molecular weightof greater than about 200.
`[016]
`In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration
`from about 1 mg/ml, to about 600 mg/mL.In some embodiments, the benzodiazepine drug is present in a
`carrier system in a concentration from about 10 mg/mL to about 250 mg/mL.
`In some embodiments, the
`
`benzodiazepine is present in a carrier system in a concentration from about 20 mg/mLto about 50 mg/mL,
`{017|
`In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or .
`tocotriencls, or any combinations thereof,
`in an amount from about 45% to about 85% (w/w).
`In some
`embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or
`
`any combinations thereof,
`
`in an amount from about 60% to about 75% (w/w). In some embodiments, the
`
`carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations
`
`thereof, in an amount of about 70% (w/w).
`[018]
`In some embodiments,
`the carrier system comprises one or more alcohols or glycols, ‘or any
`combinations thereof, in an amount from about 10% to about 70% (w/w). In some embodiments, the carrier
`system comprises one or morealcohols 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
`
`in an amount from about 25% to about 40% (w/w). In some embodiments, the
`_ any combinations thereof,
`carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about
`
`30% (w/w).
`
`[019]
`
`In some embodiments, the composition comprises at least one additional ingredient selected from the
`
`group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the
`
`pH,buffer the composition, prevent degradation, and improve appearance, odor, or taste.
`
`[020]
`
`In some embodiments, the composition comprises one or more additional excipients, such as one or
`
`more parabens, one or more povidones, and/or one or morealkyl glycosides.
`[021] 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 membranes ofa patient a pharmaceutical composition
`for nasal administration comprising a benzodiazepine drug; one or more natural or synthetic tocopherols or
`
`tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more
`
`alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%,preferably about
`
`10% to about 70% (w/w). In some embodiments, the benzodiazepine is dissolved in the one or more natural or
`
`synthetic tocopherols or tocotrienols, or any combinations thereof,
`
`in an amount from about 30% to about
`
`95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about
`
`5% to about 70%, preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug
`
`is dissolved in a carrier system. In some embodiments, the benzodiazepine drug includes benzodiazepine
`
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially
`
`free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`
`-6-
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`In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam,
`[022]
`brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam,
`flumazenil,
`
`flurazepam, halazepam, midazolam, nordazepam, medazepam,nitrazepam, oxazepam, lorazepam, prazepam,
`
`quazepam,
`
`triazolam,
`
`temazepam,
`
`loprazolam, or any pharmaceutically-acceptable salts thereof, and any
`
`combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-
`
`acceptable salt thereof. In some embodiments, the benzodiazepine drug is fully dissolved in a single phase
`
`comprising one or more one or morenatural or synthetic tocopherols or tocotrienols and one or more alcohols
`
`or glycols.
`
`In some embodiments,
`
`the benzodiazepine drug comprises benzodiazepine microparticles,
`
`nanoparticles, or combinations thereof. In some such embodiments, the composition further comprises water.
`
`In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than
`
`about 5000 nm. In some embodiments, the composition is substantially free of benzodiazepine microparticles,
`
`nanoparticles or combinations thereof.
`
`[023]
`
`In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected
`
`from the group consisting of: a-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol, a-tocotrienol, B-
`tocotrienol, y- tocotrienol, 6- tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs
`
`or derivatives thereof, and any combinations thereof.
`[024]
`In some embodiments, the one or more alcohols are selected from the group consisting of: ethanol,
`propy! alcohol, butyl alcohol, pentanol, benzyl! alcohol, any isomers thereof, and any combinations thereof. In
`
`some embodiments,
`
`the one or more glycols are selected from the group consisting of: ethylene glycol,
`
`propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. In
`
`some embodiments, the alcohol or glycol
`
`is free of water (dehydrated, USP). In some embodiments, the
`
`alcohol is ethanol (dehydrated, USP).
`
`[025]
`
`In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration
`
`from about 1 mg/mL to about 600 mg/mL.In some embodiments, the benzodiazepine drug is present in the
`
`carrier system in a concentration of from about 10 mg/mL to about 250 mg/mL. In some embodiments, the
`
`benzodiazepine drug is present in the carrier system in a concentration of from about 20 mg/mL to about 50
`_mg/mL.
`
`In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or
`[026]
`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).
`
`the carrier system comprises one or more alcohols or glycols, or any
`In some embodiments,
`[027]
`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%
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`to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or
`
`any combinations thereof, in an amount from about 30% (w/w).
`[028]
`In some embodiments, the composition comprises at least one additional ingredient selected from the
`group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the
`pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
`{029]
`In some embodiments, the composition is in a pharmaccutically-acceptable spray formulation, and
`
`further comprising administering the composition to one or more nasal mucosal membranesofthe 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 pharmaceutically-acceptable
`
`spray formulation having volume from about 10 wL to 200 pL.
`
`{030]
`
`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 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.
`
`{031]
`
`In some embodiments, the administration of the composition begins at any time before or after onset
`
`of symptomsof a disorder which maybe treatable with the composition.
`
`[032] Additional embodiments, uses, and advantages of the invention will become apparent to the person
`
`skilled in the art upon consideration of the disclosure set forth herein.
`
`INCORPORATION BY REFERENCE
`
`[033] 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
`
`wasspecifically and individually indicated to be incorporated by reference.
`
`{034]
`
`Some embodiments of the invention may be further appreciated upon consideration of the appended
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`drawings, of which:
`
`[035]
`
`Figure 1 depicts a 240 hour linear plot of the arithmetic mean plasma concentration of diazepam after
`
`intranasal administration of 10 mg of diazepam as a suspension of Table 11-2, intranasal administration 10 mg
`
`of diazepam as a solution of Table 11-1, and 5 mg of diazepam asan intravenousinjection.
`
`[036]
`
`Figure 2 depicts a 240 hour semi-logarithmic plot of the arithmetic mean plasma concentration of
`
`diazepam after intranasal administration of 10 mg of diazepam as a suspension of Table 11-2,
`
`intranasal
`
`administration 10 mg of diazepam as a solution of Table 11-1, and 5 mg of diazepam as an intravenous
`
`injection.
`
`-8-
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