(12) Unlted States Patent
`(10) Patent No.:
`US 8,895,546 B2
`
`Cartt et al.
`(45) Date of Patent:
`Nov. 25, 2014
`
`USOO8895546B2
`
`(54) ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`(75)
`
`Inventors: Steve Cartt, San Carlos, CA (US);
`David Medeiros, South San Francisco,
`CA (US); Garry Thomas Gwozdz, Jim
`~
`-
`-
`.
`Thorpe, PA (US), Andrew Loxley,
`.
`Ph}ladel,phla’ PA wS)’ Mark
`Mltfthks Ea“ Hampton: NY (Us):
`DaVId Hale, San Dlego, CA (US);
`Edward T. Maggio, San Diego, CA
`(US)
`
`.
`.
`(73) Ass1gnee: Hale Blopharma Ventures, LLC,
`Enc1n1tas, CA (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U S C 154(1)) 1‘) 0 da S
`'
`'
`'
`y
`y '
`
`(21) APP1~ N0: 13/495,942
`
`3,722,371 A
`3,849,341 A
`3,987,052 A
`133332: 2
`4,608,278 A
`4,748,158 A
`4,826,689 A
`,
`,
`4 868 289 A
`4,921,838 A
`4,973,465 A
`4,997,454 A
`5,091,188 A
`5,100,591 A
`5,118,528 A
`5,145,684 A
`5,182,258 A
`5,188,837 A
`5,192,528 A
`5,236,707 A
`5,268,461 A
`5,308,531 A
`5,317,010 A
`5,369,095 A
`5,457,100 A
`5,550,220 A
`5,560,932 A
`5,639,733 A
`5,661,130 A
`5,662,883 A
`5,665,331 A
`5,716,642 A
`5,738,845 A
`5,780,062 A
`5’789’375 A
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`(65)
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`Filed;
`
`Jun. 13, 2012
`-
`-
`-
`Pm" Pubhcat‘on Data
`US 2013/0065886 A1
`Mar. 14, 2013
`.
`.
`Related U.S. Appllcatlon Data
`(63) Continuation-in-part of application No. 12/413,439,
`filed on Mar. 27, 2009.
`
`(60) Provisional application NO. 61/497,017, filed on Jun.
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`'
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`'
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`CPC """"(2013431§216€I§§3325§3080143601§92060:]:
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`
`Primary Examiner 7 Adam C Milligan
`(74) Attorney, Agent, or Firm 7 Wilson Sonsini Goodrich &
`Rosati
`
`(57)
`
`ABSTRACT
`
`The invention relates to pharmaceutical compositions com-
`prising one or more benzodiazepine drugs for nasal adminis-
`tration, methods for producing and for using such composi-
`110115-
`
`22 Claims, 5 Drawing Sheets
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0001
`
`page 0001
`
`

`

`US 8,895,546 B2
`
`Page 2
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`(56)
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`30(3):331-334 (1986).
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`US 8,895,546 B2
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`(56)
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`the Albino Rabbit”, The Journal of Pharmacology and Experimental
`Therapeutics, Apr. 1989, pp. 249-255, vol. 249; No. 1.
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`
`AQUESTIVE EXHIBIT 1003
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`US. Patent
`
`Nov. 25, 2014
`
`Sheet 1 of5
`
`US 8,895,546 B2
`
`Figure 1
`
`: r;
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`
`AQUESTIVE EXHIBIT 1003
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`US. Patent
`
`Nov. 25, 2014
`
`Sheet 2 of5
`
`US 8,895,546 B2
`
`Figure 2
`
`Samfivimgarithmic Seam
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`AQUESTIVE EXHIBIT 1003
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`page 0006
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`US. Patent
`
`Nov. 25, 2014
`
`Sheet 3 0f5
`
`US 8,895,546 B2
`
`Figure 3
`
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`
`Linear Scam
`
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`
`AQUESTIVE EXHIBIT 1003
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`US. Patent
`
`Nov. 25, 2014
`
`Sheet 4 of5
`
`US 8,895,546 B2
`
`Figure 4: Flow Diagram for the Manufacture of Diazepam Solution
`
`Combine:
`
`0 Vitamin E, USP
`
`0 Benzyl Alcohol, NF
`
`0 Dehydrated Alcohol, USP
`
`
`Heat to 45 :: 2°C
`
`Add lntravail and mix until
`
`dissolved and homogeneous
`
`
`
`Maintaining temperature at 45°C,
`add Diazepam, USP and mix until
`dissolved and homo genous
`
`Cool to 25 :
`
`Q.S. to final target weight with
`Dehydrated Alcohol, USP.
`
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`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 5 of5
`
`US 8,895,546 B2
`
`Figure 5: Flow Diagram for Preparation of Diazepam Suspension
`
`Flow Diagram for the Manufacture of NRL-lA
`
`Sieve Diaz
`
`a USP
`ep m
`
`Micronize Diazepam USP
`
`Combine Propylene Glycol, USP
`Purified \Vater, USP, and
`Vitamin E Polyethylene Glycol
`Succinate, NF
`
`
`Heat to 45 I 2°C and mix until
`Vitamin E Polyethylene GIYCOI
`Succmate, NF is dissolved.
`
`'d
`Add P
`9VI 0116,
`.
`untll ‘hSSOIVC‘L
`
`USP . d
`(111
`
`.
`[DIX
`
`(2.8. to final target weight with
`Purified Water, USP. Mix well to
`assure homogeneity
`
`and mix vigorously to disperse.
`
`High pressure/
`small size
`(Diazepam)
`
`Low pressure/
`larger size
`(Diazepam B)
`
`‘
`Add Mcthylparabcn, NF,
`Propylparabcn, NF and Intravail
`and mix until dissolved.
`
`Fill 3 mL finished product into
`5 mL Amber glass Vlal w1th
`PTFE lillcd phenolic closure.
`
`Sample Diazepam A and Diazepam
`B for in-process testing
`
`Cool to 25 :
`
`
`
`Add Micronized Diazepam A/B
`
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`US 8,895,546 B2
`
`1
`ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation-in-Part of US. patent
`application Ser. No. 12/413,439, filed Mar. 27, 2009, pub-
`lished as US 2009/0258865 on Oct. 15, 2009, which is incor-
`porated herein by reference in its entirety; this application
`also claims priority to US. provisional application 61/040,
`558, filed Mar. 28, 2008, US. provisional application 61/497,
`017, filed Jun. 14, 2011 and US. provisional application
`61/570,110, filed Dec. 13, 2011, each of which is incorpo-
`rated herein by reference in its entirety.
`
`10
`
`15
`
`FIELD OF THE INVENTION
`
`This application relates to the nasal administration of ben-
`zodiazepine drugs and combinations thereof.
`
`20
`
`BACKGROUND OF THE INVENTION
`
`By way of non-limiting example, the benzodiazepine fam-
`ily consists of drugs such as diazepam, lorazepam, and mida-
`zolam. The drugs in this family have been observed as pos-
`sessing
`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 anxi-
`ety, insomnia, agitation, seizures (such as those caused by
`epilepsy), muscle spasms and rigidity, the symptoms of drug
`withdrawal associated with the continuous abuse of central
`
`nervous system depressants, and exposure to nerve agents.
`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 gamma-ami-
`nobutyric acid (GABA).
`GABA is an inhibitory neurotransmitter that, when bound
`to the GABAA receptor, facilitates Cl' ions flooding into the
`neuron to which the receptor is bound. The increase in C1"
`ions hyperpolarizes the membrane of the neuron. This com-
`pletely or substantially reduces the ability of the neuron to
`carry an action potential. Targeting this receptor is particu-
`larly useful in treating many disorders, such as tetanus and
`epilepsy, which may result from too many action potentials
`proceeding through the nervous system.
`Current formulations of benzodiazepine drugs can be
`administered orally, rectally, or parenterally. The ability to
`utilize these and other types of formulations has been signifi-
`cantly limited due, in many cases, to solubility challenges.
`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 benzodi-
`azepine drug to reach therapeutically relevant concentrations
`in blood plasma may be rather long, such as an hour or more.
`Moreover, as benzodiazepine drugs pass through the liver a
`significant amount 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 muscle
`spasms, it can be extremely difficult for either a patient or a
`care-giver to administer the benzodiazepine drug orally and
`care-givers may be reluctant to place their hands in patients’
`mouths.
`
`Intravenous administration perhaps provides a faster route
`of administration. However intravenous administration is
`
`generally limited to trained health care professionals in
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`tightly controlled clinical settings. Additionally, sterility must
`be maintained. Furthermore, administering any drug intrave-
`nously can be painful and is likely impractical for patients
`suffering from a phobia of needles. In addition, intravenous
`administration of benzodiazepines is associated with respira-
`tory depression. Thus, use of intravenous benzodiazepines is
`limited to professional health care environments.
`Rectal suppository compositions of benzodiazepine drugs
`can have a 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.
`
`SUMMARY OF THE INVENTION
`
`In some embodiments, there are provided (non-aqueous)
`pharmaceutical solutions for nasal 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 benzodi-
`azepine drug is dissolved in the one or more natural or syn-
`thetic 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, chlordiaz-
`epoxide,
`clobazam,
`clonazepam,
`clorazepam,
`demox-
`azepam, 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 embodi-
`ments, the benzodiazepine drug is diazepam, or a pharmaceu-
`tically-acceptable salt thereof. In some embodiments, the
`solution contains about 1 to about 20% (w/v) of benzodiaz-
`epine, e.g. about 1 to about 20% (w/v) of diazepam. In some
`embodiments, the one or more natural or synthetic toco-
`pherols or tocotrienols are selected from the group consisting
`of ot-tocopherol, B-tocopherol, y-tocopherol, 5-tocopherol,
`ot-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 benzyl alcohol
`(7.5-12.5% (w/v)).
`In some
`embodiments, the benzodiazepine is present in the pharma-
`ceutical 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 com-
`binations thereof, is in an amount from about 50% to about
`75% (w/w). In some embodiments, the one or more alcohols
`or glycols, or any combinations thereof, is in an amount from
`about 15% to about 55% (w/w), e.g. about 25% to about 40%
`
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`US 8,895,546 B2
`
`3
`(w/w). In some embodiments, the solution consists of diaz-
`epam (5-15% (w/v)), alkyl glycoside (0.01-1% (w/v)), vita-
`min 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
`dodecyl maltoside. In some embodiments, the solution con-
`sists ofdiazepam (5-1 5% (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 solu-
`tion may consist of diazepam (9-11% (w/v)), dodecyl malto-
`side (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 more particularly, the solution may consist of diazepam
`(10% (w/v)), dodecyl maltoside (0.15-0.3% (w/v)), vitaminE
`(50-60% (w/v)), ethanol (17-20% (w/v)) and benzyl alcohol
`(10-12% (w/v)).
`Some embodiments described herein provide a method of
`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 benzodiaz-
`epine 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 drug is dissolved in
`the one or more natural or synthetic tocopherols or tocot-
`rienols, 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, clon-
`azepam, clorazepam, demoxazepam, diazepam, flumazenil,
`flurazepam,
`halazepam,
`midazolam,
`nordazepam,
`medazepam, nitrazepam, oxazepam, lorazepam, prazepam,
`quazepam, triazolam, temazepam, loprazolam, any pharma-
`ceutically-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 1 to about
`20% (w/v) ofbenzodiazepine, 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 ot-tocopherol, B-tocopherol, y-toco-
`pherol, 5-tocopherol, ot-tocotrienol, [3-tocotrienol, y-tocot-
`rienol, 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