111111111111111111111111111!1011911811111)1111111111111111111111111
`
`(12) United States Patent (cid:9)
`Cartt et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 9,763,876 B2
`*Sep. 19, 2017
`
`(54) ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
` 514/221
`USPC (cid:9)
`See application file for complete search history.
`
`(71) Applicant: Hale Biopharma Ventures, LLC,
`Encinitas, CA (US)
`
`(72)
`
`Inventors: Steve Cartt, Union City, CA (US);
`David Medeiros, South San Francisco,
`CA (US); Garry Thomas Gwozdz, Jim
`Thorpe, PA (US); Andrew Loxley,
`Philadelphia, PA (US); Mark
`Mitchnick, East Hampton, NY (US);
`David Hale, San Diego, CA (US);
`Edward T. Maggio, San Diego, CA
`(US)
`
`(73) Assignee: Hale Biopharma Ventures, LLC,
`Encinitas, CA (US)
`
`( * ) Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 17 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/527,613
`
`(22) Filed: (cid:9)
`
`Oct. 29, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2015/0065491 Al (cid:9)
`
`Mar. 5, 2015
`
`Related U.S. Application Data
`
`(56)
`
`References Cited
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`U.S. PATENT DOCUMENTS
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`OTHER PUBLICATIONS
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`(63) Continuation of application No. 13/495,942, filed on
`Jun. 13, 2012, now Pat. No. 8,895,546, which is a
`continuation-in-part of application No. 12/413,439,
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`
`CN
`EP
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2017.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A61K 9/00 (cid:9)
`A61K 45/06 (cid:9)
`A61K 31/355 (cid:9)
`A61K 31/5513 (cid:9)
`A61K 9/08 (cid:9)
`A61K 47/10 (cid:9)
`A61K 47/22 (cid:9)
`A61K 47/26 (cid:9)
`(52) U.S. Cl.
` A61K 9/0043 (2013.01); A61K 9/008
`CPC (cid:9)
`(2013.01); A61K 9/08 (2013.01); A61K 31/355
`(2013.01); A61K 31/5513 (2013.01); A61K
`45/06 (2013.01); A61K 47/10 (2013.01); A61K
`47/22 (2013.01); A61K 47/26 (2013.01)
`(58) Field of Classification Search
`CPC (cid:9)
` A61K 9/0043; A61K 45/06; A61K 9/008;
`A61K 31/355; A61K 31/5513; A61K
`9/08; A61K 47/10; A61K 47/22; A61K
`47/26
`
`CA 2,723,470 Office Action dated Feb. 19, 2015.
`(Continued)
`
`Primary Examiner — Adam C Milligan
`(74) Attorney, Agent, or Firm — Wilson Sonsini Goodrich
`& Rosati
`
`(57) (cid:9)
`
`ABSTRACT
`
`The invention relates to pharmaceutical compositions com-
`prising one or more benzodiazepine drugs for nasal admin-
`istration, methods for producing and for using such compo-
`sitions.
`
`36 Claims, 5 Drawing Sheets
`
`AQUESTIVE EXHIBIT 1001 page 0001
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`

`(56) (cid:9)
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`

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`
`AQUESTIVE EXHIBIT 1001 page 0004
`
`

`

`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 1 of 5 (cid:9)
`
`US 9,763,876 B2
`
`Linear Scale
`
`p 'Moat Swerision 10 mg
`SoIotion 10 tag
`— IV 5 mg
`
`1 l 1 192 2! 240
`
`AQUESTIVE EXHIBIT 1001 page 0005
`
`(cid:9)
`

`

`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 2 of 5 (cid:9)
`
`US 9,763,876 B2
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`Figure 2
`
`Semi4c.varithmic Scale
`
`Nasal fic.spemioo tO
`$(>1):giint 10 In t?.
` IV 5 Trig
`
`U
`
`AQUESTIVE EXHIBIT 1001 page 0006
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`(cid:9)
`(cid:9)
`

`

`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 3 of 5 (cid:9)
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`US 9,763,876 B2
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`Figure 3
`
`Li nee r .Sca ie
`
`—G-- Nat).11 Suwension Wing
`Solistiou nig,
`IV 5 mg
`
`0
`
`12
`
`16
`
`20
`
`24
`
`AQUESTIVE EXHIBIT 1001 page 0007
`
`(cid:9)
`

`

`U.S. Patent (cid:9)
`
`Sep. 19, 2017
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`Sheet 4 of 5 (cid:9)
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`US 9,763,876 B2
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`Figure 4: Flow Diagram for the Manufacture of Diazepam Solution
`
`Combine:
`• Vitamin E, USP
`• Benzyl Alcohol, NF
`• Dehydrated Alcohol, USP
`
`1+
`Heat to 45 ± 2°C
`
`1+
`Add Intravail and mix until
`dissolved and homogeneous
`
`1+
`Maintaining temperature at 45°C,
`add Diazepam, USP and mix until
`dissolved and homogenous
`
`17
`Cool to 25 ± 2°C
`
`1+
`
`Q.S. to final target weight with
`Dehydrated Alcohol, USP.
`
`AQUESTIVE EXHIBIT 1001 page 0008
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`(cid:9)
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`

`U.S. Patent (cid:9)
`
`Sep. 19, 2017
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`Sheet 5 of 5 (cid:9)
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`US 9,763,876 B2
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`Figure 5: Flow Diagram for Preparation of Diazepam Suspension
`
`Flow Diagram for the Manufacture of NRL-1A
`
`Sieve Diazepam, USP
`
`•
`
`Micronize Diazepam, USP
`
`Combine Propylene Glycol, USP
`Purified Water, USP, and
`Vitamin E Polyethylene Glycol
`Succinate, NF
`
`Add Povidone, USP and mix
`until dissolved.
`
`Heat to 45 ± 2°C and mix until
`Vitamin E Polyethylene Glycol
`Succinate, NF is dissolved.
`
`Q.S. to final target weight with
`Purified Water, USP. Mix well to
`assure homogeneity
`
`•
`
`•
`
`High pressure/
`small size
`(Diazepam)
`
`Low pressure/
`larger size
`(Diazepam B)
`
`Add Methylparaben, NF,
`Propylparaben, NF and Intravail
`and mix until dissolved.
`
`Fill 3 mL finished product into
`5 inL Amber glass vial with
`PTFE lined phenolic closure.
`
`Sample Diazepam A and Diazepam
`B for in-process testing
`
`Cool to 25 t 2°C.
`
`Add Micronized Diazepam ALB
`and mix vigorously to disperse.
`
`(cid:9)►
`
`AQUESTIVE EXHIBIT 1001 page 0009
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`(cid:9)
`

`

`1
`ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation of U.S. patent appli-
`cation Ser. No. 13/495,942, filed Jun. 13, 2012, which is a
`Continuation-in-Part of U.S. patent application Ser. No.
`12/413,439, filed Mar. 27, 2009, published as US 2009/
`0258865 on Oct. 15, 2009, which is incorporated herein by
`reference in its entirety, and which claims priority to U.S.
`provisional application 61/040,558, filed Mar. 28, 2008,
`which is incorporated herein by reference; U.S. patent
`application Ser. No. 13/495,942, filed Jun. 13, 2012, also
`claims priority to U.S. provisional application 61/497,017,
`filed Jun. 14, 2011 and U.S. provisional application 61/570,
`110, filed Dec. 13, 2011, each of which is incorporated
`herein by reference in its entirety.
`
`US 9,763,876 B2
`
`2
`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
`5 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
`0 patients suffering from a phobia of needles. In addition,
`intravenous administration of benzodiazepines is associated
`with respiratory depression. Thus, use of intravenous ben-
`zodiazepines is limited to professional health care environ-
`ments.
`Rectal suppository compositions of benzodiazepine drugs
`can have a rapid onset of action. However, the inconve-
`nience of rectally administered drug is an obvious impedi-
`ment to their being administered by anyone outside a very
`small group of the patient's intimate acquaintances and the
`20 patient's professional medical care-givers.
`
`15 (cid:9)
`
`FIELD OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`This application relates to the nasal administration of
`benzodiazepine drugs and combinations thereof.
`
`BACKGROUND OF THE INVENTION
`
`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 prop-
`erties. They are frequently classified as anxiolytic and skel-
`etal 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-
`aminobutyric 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 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 par-
`ticularly 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
`significantly limited due, in many cases, to solubility chal-
`lenges.
`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 benzo-
`diazepine drug to reach therapeutically relevant concentra-
`tions 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
`
`In some embodiments, there are provided (non-aqueous)
`25 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
`30 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 benzo-
`diazepine drug is dissolved in the one or more natural or
`35 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
`40 from the group consisting of: alprazolam, brotizolam,
`chlordiazepoxide, clobazam, clonazepam, clorazepam,
`demoxazepam, diazepam, flumazenil, flurazepam, halaze-
`pam, midazolam, nordazepam, medazepam, nitrazepam,
`oxazepam, lorazepam, prazepam, quazepam, triazolam,
`45 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 embodi-
`ments, the solution contains about 1 to about 20% (w/v) of
`so benzodiazepine, e.g. about 1 to about 20% (w/v) of diaz-
`epam. In some embodiments, the one or more natural or
`synthetic tocopherols or tocotrienols are selected from the
`group consisting of: a-tocopherol, 13-tocopherol, y-tocoph-
`erol, 8-tocopherol, a-tocotrienol, p-tocotrienol, y-tocotrie-
`55 nol, 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
`60 alcohol, a