(19) World Intellectual Property Organization
`
`
`
`International Bureau
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`(43) International Publication
`Date
`WO 2009/121039 A2
`1 October 2009 (01.10.2009)
`PCT
`
`(10) International Publication Number
`
`(51)
`
`International Patent Classification:
`A61K 3115513 (2006.01) A61K 47110 (2006.01)
`A61K 311355 (2006.01) A61P 25122 (2006.01)
`A61K 9/16 (2006.01)
`(21) International
`
`
`(81)
`
`Designated States (unless otherwise indicated, for every
`
`
`
`AE, AG, AL, AM,
`
`kind of national protection available):
`
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`Application Number:
`
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`PCT/US2009/038696
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA , MD, ME,
`MG, MK, MN, MW , MX, MY, MZ , NA, NG, NI,
`(22) International
`NO,
`Filing Date:
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`NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`27 March 2009 (27.03.2009)
`
`SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`English
`English (84)
`
`
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`as to applicant's entitlement to apply for and be granted
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`as to the applicant's entitlement to claim the priority of
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`
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`
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`the earlier application (Rule 4.17 (iii))
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`without international search report and to be republished
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`
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`upon receipt of that report (Rule 48.2(g))
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`(25) Filing Language:
`(26) Publication
`Language:
`Designated States (unless otherwise indicated, for every
`
`(30) Priority Data:
`ARIPO (BW, GH,
`
`kind of regional protection available):
`March 2008 (28.03.2008) us
`GM, KE, LS, MW , MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`61/040,558
`28
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`(71) Applicant (for all
`designated States except US): HALE
`
`
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`BIOPHARMA VENTURES, LLC [US/US]; 1042-B N.
`
`
`El Camino Real, Suite 430, Encinitas, CA 92024 (US).
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR),
`
`
`OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`(72) Inventors;
`and
`MR, NE, SN, TD, TG).
`(75)
`CARTT, Steve [US/
`(for US only):
`Inventors/Applicants
`under Rule 4.17:
`
`US]; 3260 Whipple Road, Union City, CA 94587 (US).
`Declarations
`;;;;;;;;;;;;;;;
`MEDEIROS, David [US/US]; 212 Crown Circle, South
`
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`San Francisco, CA 94080 (US). GWOZDZ, Garry,
`a patent (Rule 4.17 (ii))
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`Thomas [US/US]; 329 South Main Street, Nazareth, PA
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`18064 (US). LOXLEY, Andrew [GB/US]; 126 Market
`;;;;;;;;;;;;;
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`Street, #5, Philadephia, PA 18064 (US). MITCHNICK,
`;;;;;;;;;;;;;;;
`Mark [US/US]; 80 Three Mile Harbor Drive, East Hamp­
`;;;;;;;;;;;;;;;
`Published:
`ton, NY 11937 (US). HALE, David [US/US]; 1042-b N.
`
`El Camino Real, Suite 430, Encinitas, CA 92024 (US).
`;;;;;;;;;;;;;
`(74) Agents: AKHAVAN, Ramin et al.; Wilson Sonsini
`Goodrich & Rosati, 650 Page Mill Road, Palo Alto, CA
`94304 (US).
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`(54) Title: ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`(57) Abstract: The invention
`
`
`
`
`
`
`ministration, methods for producing and for using such compositions.
`
`
`
`relates to pharmaceutical compositions comprising one or more benzodiazepine drugs for nasal ad­
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`AQUESTIVE EXHIBIT 1009 page 0000
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`wo 2009/121039
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`PCT/US2009/038696
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`ADMINISTRATION OF BENZODIAZEPINE COMPOSITIONS
`
`[001] This application claims priority under 35 U.S.C. § 119(e) from United States provisional
`patent application number 611040,558, which was filed on March 28, 2008, and which is incorporated
`
`5
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`herein in its entirety.
`
`FIELD OF THE INVENTION
`[002] This application relates to the nasal administration of benzodiazepine drugs and combinations
`thereof.
`
`I 0
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`15
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`20
`
`BACKGROUND OF THE INVENTION
`[003] 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 aoxiolytic
`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.
`[004] Benzodiazepines are thought to act by binding to the GABAA receptor of a neuron, possibly
`causing the receptor to change shape and making it more accessible to gama-aminobutyric acid
`(GABA).
`[OOS] GABA is an inhibitory neurotransmitter that, when bound to the GABAA receptor, facilitates
`cr ions flooding into the neuron to which the receptor is bound. The increase in cr 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
`
`25 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 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.
`
`30
`
`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
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`-I-
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`of seizures and muscle spasms, it can be extremely difficult for either a patient or a care-giver to
`administer the benzodiazepine drug orally.
`Intravenous administration perhaps provides a faster route of administration. However
`(008]
`intravenous administration is generally limited to trained health care professionals in tightly controlled
`clinical settings. Additionally, sterility must be maintained. Furthermore, administering any drug
`
`5
`
`intravenously can be painful and is likely impractical for patients suffering from a phobia of needles.
`(009] 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
`
`10
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`professional medical caretakers.
`
`SUMMARY OF THE INVENTION
`
`(010] In some embodiments, the phannaceutical 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
`
`15
`
`glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably
`
`about 10% to about 700/o (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 700/o (w/w), preferably about 10%
`to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system.
`
`In some embodiments, at least part of the benzodiazepine drug is in a form comprising
`
`benzodiazepine rnicroparticles, nanoparticles or combinations thereof. In some embodiments, the
`composition is substantially free of benzodiazepine rnicroparticles, nanoparticles or combinations
`thereof.
`
`[011) In some embodiments, the benzodiazepine drug is selected from the group consisting of:
`
`alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam,
`
`diazepam, flumazenil, flurazepam, halazepam, rnidazolam, nordazeparn, medazepam, nitrazeparn,
`oxazepam, medazepam, lorazepam, prazeparn, quazeparn, triazolam, temazeparn, loprazolarn, 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 rnicroparticles, nanoparticles, or
`combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective
`average particle size of less than about 5000 nm. In some embodiments, the benzodiazepine drug is
`substantially free of benzodiazepine rnicroparticles, nanoparticles or combinations thereof.
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`20
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`25
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`30
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`5
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`10
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`[012] In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`selected from the group consisting of: a-tocopherol, fl-tocopherol, y-tocopherol, li-tocopherol, a­
`tocotrienol, � tocotrienol, y- tocotrienol, 0- 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
`or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol).
`Thus, in some embodiments, the compositions described herein exclude Vitamin E lPGS.
`[013] In. some embodiments, one or more alcohols are selected from the group consisting of:
`ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any
`combinations thereof. In. some embodiments, the one or more glycols are selected from the group
`consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers
`thereof, and any combinations thereof. In. some preferred embodiments, the glycols exclude glycol
`polymers. In some preferred embodiments, the glycols exclude glycol polymers having an average
`15 molecular weight of greater than 200. In. some embodiments, the glycols exclude polyethylene glycol
`having an average molecular weight of greater than about 200.
`[014] In some embodiments, the benzodiazepine drug is present in the carrier system in a
`concentration from about 1 mg/mL to about 600 mglmL. 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
`mglmL to about SO mg/mL.
`[015] 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%
`
`20
`
`25
`
`(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).
`[016) In some embodiments, the carrier system comprises one or more alcohols or glycols, or any
`combinations thereof, in an amount from about 10% to about 70% (w/w). In. some embodiments, the
`carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount
`
`from about 15% to about 55% (w/w). In some embodiments, the carrier system comprises one or
`
`more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40%
`(w/w). In. some embodiments, the carrier system comprises one or more alcohols or glycols, or any
`combinations thereof, in an amount of about 30% (w/w).
`[017) In some embodiments, the composition comprises at least one additional ingredient selected
`from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents
`
`30
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`35
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`used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or
`
`taste.
`[018] In some embodiments, the composition comprises one or more additional excipients, such as
`one or more parabens, one or more povidones, and/or one or more alkyl glycosides.
`[019] The invention also discloses a method of treating a patient with a disorder that may be
`treatable with a benzodiazepine drug. In some embodiments, the patient is a human. In some
`embodiments, the method comprises: administering to one or more nasal mucosal membranes of a
`
`5
`
`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
`10 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 100/o to about 70% (w/w). In
`
`1 5
`
`20
`
`25
`
`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% t o 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.
`[020] 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, nordazeparn, medazepam, nitrazeparn,
`
`oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, ternazeparn, loprazolarn, 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 more natural or synthetic tocopherols or tocotrienols and one or more alcohols or glycols. In
`some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles,
`or combinations thereof. In some such embodiments, the composition further comprises water. In
`
`30
`
`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.
`[021] In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`selected from the group consisting of: a.-tocopherol, �-tocopherol, y-tocopherol, li-tocopherol, a-
`tocotrienol, �- tocotrienol, y- tocotrienol, li- tocotrienol, tocophersolan, any isomers thereof, any esters
`thereof, any analogs or derivatives thereof, and any combinations thereof.
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`-4-
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`AQUESTIVE EXHIBIT 1009 page 0004
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`WO 2009/121039
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`PCT/US2009/038696
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`(022] 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
`5 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).
`(023] In some embodiments, the benzodiazepine drug is present in the carrier system in a
`concentration from about I mglmL to about 600 mglmL. In some embodiments, the benzodiazepine
`drug is present in the carrier system in a concentration of from about 10 mg/mL to about 250 mglmL.
`10 In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of
`
`from about 20 mglmL to about 50 mglmL.
`(024] 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).
`(025) 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).
`(026] 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
`
`15
`
`20
`
`25
`
`taste.
`(027) In some embodiments, the composition is in a pharmaceutically-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 I mg to about 20
`30 mg of the benzodiazepine. In some embodiments, the pharmaceutical composition is in a
`pharmaceutically-acceptable spray formulation having volume from about 10 J.LL to 200 J.LL.
`(028) 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
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`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.
`(029] In some embodiments, the administration of the composition begins at any time before or
`after onset of symptoms of a disorder which may be treatable with the composition.
`(030] 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
`(031] 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.
`
`5
`
`10
`
`DETAILED DESCRIPTION OF THE INVENTION
`(032] Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and
`15 methods of using such pharmaceutical compositions. Such pharmaceutical compositions are
`
`administered nasally.
`(033) 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 I 0% to about 70% (w/w) in a
`pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes
`
`20
`
`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
`25 from about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in
`a carrier system. In some embodiments, at least part of the benzodiazepine drug is in a form of
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is
`
`substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`(034] In some embodiments, the pharmaceutical composition for nasal administration comprises: a
`
`30
`
`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
`
`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
`
`35
`
`or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to
`
`-6-
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`AQUESTIVE EXHIBIT 1009 page 0006
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`5
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`10
`
`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 beozodiazepine drug is dissolved in a
`carrier system. In some embodiments, at least part of the benzodiazepine drug is in a form of
`microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is
`substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`
`[035] 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. In some embodiments, the composition is
`
`15
`
`substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
`
`20
`
`25
`
`[036] In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are
`
`selected from the group consisting of: a-tocopherol, (3-tocopherol, y-tocopherol, 6-tocopherol, a­
`tocotrienol, (3- tocotrienol, y- tocotrienol, 6- tocotrienol, tocophersolan, any isomers thereof, any esters
`thereof, any analogs or derivatives thereof, and any combinations thereof. In some embodiments, the
`carrier system includes one or more synthetic tocopherols having a polymer glycol covalently bonded
`
`or linked to a tocopherol core, such as Vitamin E TPGS, which is described in United States Patent
`No. 6,193,985, which is incorporated herein by reference in its entirety. In particular, it has been
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`found that in some particulate suspensions of benzodiazepines, wherein the benzodiazepine is not
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`dissolved in a tocopherol phase, Vitamin E TPGS can be a desirable excipient for stabilizing the
`particulate (microparticle, nanoparticle or combination) suspension. In some embodiments, on the
`other hand, the carrier system specifically excludes synthetic tocopherols having a polymer glycol
`covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in
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`United States Patent No. 6,193,985, which is incorporated herein by reference in its entirety.
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`[037] In some embodiments, one or more alcohols are selected from the group consisting of:
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`ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any
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`combinations thereof. In some embodiments, the alcohol is ethanol (dehydrated, USP). 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 glycol is propylene glycol USP. 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
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`or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol).
`Thus, in some embodiments, the compositions described herein exclude Vitamin E TPGS.
`[038) In some embodiments, the benzodiazepine drug is present in the carrier system in a
`concentration from about l mg'mL to about 600 mg'mL. In some embodiments, the benzodiazepine
`drug is present in a carrier system in a concentration from about I 0 mg'mL to about 250 mg'mL. In
`some embodiments, the benzodiazepine is present in a carrier system in a concentration from about 20
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`mg'mL to about 50 mg'mL.
`[039] 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). 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 or linked (e.g. through a diacid linking group) to a glycol polymer, such as
`polyethylene glycol). Thus, in some embodiments, the compositions described herein exclude
`Vitamin E TPGS.
`[040] In some embodiments, the carrier system comprises one or more alcohols or glycols, or any
`combinations thereof, in an amount from about l 0% to about 55%, about I 00/o to about 40%, about
`10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%,
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`about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about
`12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%,
`about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about
`50%, about 52.5% or 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 400/o
`(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). In some embodiments, the alcohol is
`ethanol or contains ethanol. In some preferred embodiments, the glycols exclude glycol polymers. In
`some preferred embodiments, the glycols exclude glycol polymers having an average molecular
`weight of greater than 200. In some embodiments, the glycols exclude polyethylene glycol having an
`average molecular weight of greater than about 200.
`[041] 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
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`from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or
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`more alcohols or glycols, or any combinations thereof: in an amount of about 30% (w/w).
`[042) In some embodiments, the composition comprises at least one additional ingredient selected
`from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents
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`used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or
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`taste.
`[043) In some embodiments, the compositions comprise at least one alkyl glycoside. In some
`embodiments, the at least one alkyl glycoside is one described in United States Patent No. 5,661 ,130,
`which is incorporated by reference herein.
`[044) In some embodiments, the composition comprises a benzodiazepine drug that is fully
`dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and an alcohol or
`glycol. In some embodiments, the composition comprises a benzodiazepine drug that is fully
`dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol and an alcohol or
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`glycol, wherein the solution is at least substantially free of water. (In some embodiments,
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`"substantially free of water" indicates that the solution contains less than about 1%, Jess than about
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`0.5%,less than about 0.25% or less than about 0.1% water.) In some embodiments, the composition
`
`consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or
`
`more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally
`
`one or more alkyl glycosides. In some embodiments, the composition consists essentially of a
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`benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic
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`tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl
`glycosides wherein the solution is at least substantially free of water. (In some embodiments,
`"substantially free of water" indicates that the solution contains less than about 1%, less than about
`0.5%, less than about 0.25% or less than about 0.1% water.) In some embodiments, the composition
`consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic
`
`tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl
`glycosides. In some embodiments, the composition consists of a benzodiazepine diss