UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
`Address: COMMISSIONER FOR PATENTS
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`WVINVJJSPID.gov
`
`APPLICATION
`NUMBER
`
`FILING or
`371(c) DATE
`
`GRP ART
`UNIT
`
`
`
`
`
`F
`
`61/040,281
`
`03/28/2008
`
`FEE REC'D
`
`105
`
`ATTY.DOCKET.NO
`
`PSOOO8USL
`
`TOT CLAIIVIS IND CLAIMS
`
`26259
`LICATA & TYRRELL RC.
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`
`CONFIRMATION NO. 2024
`
`FILING RECEIPT
`
`IIIIIllllIllIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`
`Date Mailed: 04/07/2008
`
`It will not be examined for patentability and will
`Receipt is acknowledged of this provisional patent application.
`become abandoned not later than twelve months after its filing date. Any correspondence concerning the application
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`
`Applicant(s)
`
`Garry Thomas Gwozdz, Nazareth, PA;
`Andrew Loxley, Philadelphia, PA;
`Mark Mitchnick, East Hampton, NY;
`
`Power of Attorney:
`Kathleen Tyrrell--38350
`
`If Required, Foreign Filing License Granted: 04/02/2008
`The country code and number of your priority application, to be used for filing abroad under the Paris Convention,
`is US 61/040,281
`Projected Publication Date: None, application is not eligible for pre-grant publication
`Non-Publication Request: No
`Early Publication Request: No
`** SMALL ENTITY **
`Title
`
`Pharmaceutical Solutions and Method for Solubilizing Therapeutics Agents
`
`PROTECTING YOUR INVENTION OUTSIDE THE UNITED STATES
`
`Since the rights granted by a US. patent extend only throughout the territory of the United States and have no
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`in a specific country or in regional patent offices. Applicants may wish to consider the filing of an international
`application under the Patent Cooperation Treaty (PCT). An international (PCT) application generally has the same
`effect as a regular national patent application in each PCT-member country. The PCT process simplifies the filing
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`AQUESTIVE EXHIBIT 1046
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`

`of patent applications on the same invention in member countries, but does not result in a grant of "an international
`patent" and does not eliminate the need of applicants to file additional documents and fees in countries where patent
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`
`Almost every country has its own patent law, and a person desiring a patent in a particular country must make an
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`
`Applicants also are advised that in the case of inventions made in the United States, the Director of the USPTO must
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`State (with respect to Arms, Munitions and Implements of War (22 CFR 121-128)); the Bureau of Industry and
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`AQUESTIVE EXHIBIT 1046
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`Doc Code:
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`PROVISIONAL APPLICATION FOR PATENT COVER SHEET - Page ‘I of 2
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT under 37 CFR 1.53(c).
`Express Mail Label No.
`
`Family Name or Surname
`Gwozdz
`
`(City and either State or Foreign Country)
`Nazareth, Pennsylvania
`
`Residence
`
`Loxley
`
`Mitchnick
`
`Philadelphia, Pennsylvania
`
`East Hampton, New York
`
`Given Name (first and middle [if any])
`Garry Thomas
`
`Andrew
`
`Mark
`
`
`
`E Additional inventors are being named on
`
`separately numbered sheets attached hereto
`
`TITLE OF THE INVENTION (500 characters max)
`Pharmaceutical Solutions and Method for Solubilizing Therapeutic Agents
`
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`AQUESTIVE EXHIBIT IOWFMALWIgé 0004
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`AQUESTIVE EXHIBIT 1046 page 0004
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`

`
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`Doc Code:
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`
`SIGNATURE
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` The invention was made by an agency of the United States Government or under a contract with an agency of the United States
`
`
`D Yes, the name of the US. Government agency and the Government contract number are:
`
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`after publication of the application (unless a non-publication request in compliance with 37 CFR 1.213(3) is made in the
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`card authorization forms PTO—2038 submitted for payment purposes are not retained in the application file and therefore are
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`/
`/
`t
`////>’«~"~.
`fl /;
`{f/
`
`
`fly/Vt 3/;
`flggyjflfgf“, /
`/
`
`Z
`/ / If
`h
`TYPED or PRINTED NAMEi
`Kathlee’ln A. Tynj’ell
`\
`
`Date
`
`March 28, 2008
`
`REGISTRATION NO-
`(if appropriate)
`
`38,350
`_——‘—‘—
`
`TELEPHONE
`
`
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`(856)810-1515 PSOOOBUS.L Docket Number:
`
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`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0005
`
`page 0005
`
`

`

`PSOOOBUS.L
`
`PATENT
`
`PHARMACEUTICAL SOLUTIONS AND METHOD FOR SOLUBILIZING
`THERAPEUTIC AGENTS
`
`Background of the Invention
`
`A vast
`
`number of potential
`
`therapeutic agents
`
`are
`
`discovered each year, many of which are water
`
`insoluble or
`
`poorly water soluble. For such hydrophobic compounds, direct
`
`injection_ may be
`
`impossible or highly dangerous,
`
`and can
`
`result
`
`in
`
`hemolysis,
`
`phlebitis,
`
`hypersensitivity,
`
`organ
`
`10
`
`failure
`
`and/or
`
`death.
`
`Such
`
`compounds
`
`are
`
`termed
`
`by
`
`pharmacists as “lipophilic”, “hydrophobic”, or in their most
`
`
`
`insoluble form, “amphiphobic”.
`
`A.
`
`few
`
`examples
`
`of
`
`therapeutic
`
`agents
`
`in
`
`these
`
`categories
`
`are
`
`ibuprofen,
`
`diazepam,
`
`
`griseofulvin,
`
`15
`
`cyclosporin, cortisone, proleukin, etoposide and paclitaxel.
`
`(Kagkadis et al.
`
`PDA J. Pharm. Sci. Tech.
`
`1996 50(5):3l7—
`
`and
`
`
`
`323; Dardel Anaesth. Scand.
`
`1976 20:221-24; Sweetana
`
`Akers PDA J} Pharm. Sci. Tech. 1996 50(5):330—342).
`
`Administration
`
`of
`
`chemotherapeutic
`
`agents
`
`is
`
`particularly problematic. Most of
`
`these agents are poorly
`
`soluble
`
`and
`
`thus
`
`are difficult
`
`to deliver
`
`in aqueous
`
`solvents and to supply at
`
`therapeutically effective levels.
`
`Further,
`
`water—soluble,
`
`chemotherapeutic
`
`agents
`
`are
`
`generally taken up by both cancer
`
`and non—cancer cells,
`
`making such agents non-specific and oftentimes unacceptably
`toxic.
`
`For
`
`therapeutic agents that cannot be formulated as an
`
`aqueous solution, emulsions have oftentimes provided a cost—
`
`effective
`
`and
`
`therapeutically
`
`
`
`However, it is di "icult
`
`acceptable
`
`alternative.
`
`to render emulsions sterile and/or
`
`
`endotoxin free for
`
`intravenous
`
`injection. Oils
`
`typically
`
`used for pharmaceutical emulsions include saponifiable oils
`
`from the family of
`
`for example,
`
`soybean oil,
`
`triglycerides,
`
`sesame seed oil, cottonseed oil, safflower oil and the like
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0006
`
`page 0006
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`20
`
`25
`
`30
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`

`

`P80008U8.L
`
`2
`
`PATENT
`
`(Hansrani, et al.
`
`J} Parenter: Sci. Technol.
`
`1983 37:145—
`
`150). One or more
`
`surfactants are used to stabilize the
`
`emulsion,
`
`and excipients are added to render
`
`the emulsion
`
`more biocompatible, stable and less toxic. Lecithin from egg
`
`yolks or
`
`soybeans
`
`is a
`
`commonly used surfactant. Sterile
`
`manufacturing can. be accomplished. by sterilization. of all
`
`the
`
`components
`
`before manufacture,
`
`stages
`
`of‘ manufacture.
`
`
`followed
`
`Improved ease of
`
`by
`
`aseptic
`
`technique in all
`
`manufacture
`
`and
`
`10
`
`terminal
`
`sterilization
`
`assurance
`
`following
`
`of
`
`sterility is
`
`obtained by
`
`sanitary manufacture,
`
`either
`
`by
`
`heat
`
`or
`
`by
`
`sterilization by heat
`
`or
`
`suitable for all emulsions.
`
`filtration.
`
`filtration treatments
`
`However,
`
`terminal
`
`is
`
`not
`
`Vitamin E emulsions have been disclosed. For example,
`
`15
`
`injectable vitamin E emulsions are described by Hidiroglou
`
`and Karpinski
`
`(Brit. J. Nutrit. 1988 59:509-518)
`
`for dietary
`
`sheep
`
`and
`
`for
`
`research
`
`on
`
`the
`
`
`
`supplementation
`
`in
`
`pharmacokinetics of vitamin E
`
`and
`
`its derivatives.
`
`An
`
`
`injectable form of vitamin E for mice was prepared by Kato
`
`et al.
`
`(Chem.
`
`Pharm. Bull.
`
`1993 41(3):599—604). Micellar
`
`a co—solvent,
`
`solutions were formulated with TWEEN 80, BRIJ 58 and HCO—60.
`
`Isopropanol was used as
`
`and was
`
`then removed
`
`by vacuum evaporation;
`
`the residual oil glass was
`
`then taken
`
`up
`
`in water with vortexing as
`
`a micellar
`
`suspension. An
`
`emulsion was also prepared by dissolving vitamin E with soy
`
`phosphatidycholine
`
`(lecithin)
`
`and
`
`soybean oil. Water was
`
`added and the emulsion prepared with sonication.
`
`
`Ethanol—
`
`free
`
`emulsions
`
`of
`
`alpha—tocopherol,
`
`stabilized
`
`biocompatible
`
`surfactants,
`
`as
`
`a vehicle
`
`or carrier
`
`by
`
`
`for
`
`therapeutic drugs
`
`is also disclosed in U.S. Patent Nos.
`
`6,667,048 and 6,660,286.
`
`E—Ferol,
`
`a
`
`vitamin
`
`E
`
`emulsion
`
`for
`
`vitamin
`
`E
`
`supplementation and therapy in neonates was also disclosed
`
`AQUESTIVE EXHIBIT 1046
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`AQUESTIVE EXHIBIT 1046 page 0007
`
`page 0007
`
`2O
`
`25
`
`30
`
`

`

`PSOOOSUS.L
`
`3
`
`PATENT
`
`by Alade
`
`et al.
`
`(Pediatrics
`
`(1986)
`
`77(4):593—597).
`
`The
`
`surfactant mixture used to emulsify the 25 mg/mL vitamin E
`
`
`in iE—Ferol was
`composed, of
`
`and 1% TWEEN 20.
`
`9% TWEEN 80
`
`However,
`
`this supplement was not safe.
`
`An alternative means of
`
`solubilizing low solubility
`
`compounds
`
`for example, alcohols
`
`is direct solubilization in a non—aqueous milieu,
`
`(such as ethanol), dimethylsulfoxide,
`
`and/or triacetin. For example, WO 95/11039 describes the use
`
`of vitamin E
`
`(100 mg),
`
`lecithin (20 mg), ethanol
`
`(100 mg)
`
`amd EUTANOL
`
`(500 Imfl
`
`as
`
`an injectable formulation. of
`
`the
`
`immunosuppressant molecule cyclosporine (50 mg). U.S. Patent
`
`No.
`
`5,689,846
`
`discloses
`
`various
`
`alcohol
`
`solutions
`
`of
`
`paclitaxel.
`
`U.S.
`
`dissolution of paclitaxel
`
`Patent
`
`No.
`
`5,573,781
`
`discloses
`
`the
`
`in ethanol, butanol
`
`and hexanol
`
`and an increase in the antitumor activity of paclitaxel when
`
`delivered in butanol and hexanol as compared to ethanol.
`
`
`
`WO 95/31217 discloses that
`
`tocopherols can be used as
`
`solvents and/or emulsifiers of drugs that are substantially
`
`insoluble in water,
`
`for
`
`the preparation of
`
`an
`
`10
`
`15
`
`20
`
`
`
`
`
`topical
`
`formulations.
`
`in particular
`
`or vitamin E—TPGS
`
`use
`
`The
`
`as
`
`emulsifier
`
`in formulations
`
`containing high levels of
`
`d—
`
`
`
`tocophero;
`
`is mentioned
`
`administration composed of a lipid layer
`
`and
`
`formulations
`
`for
`
`topical
`
`(d—tocopherol),
`
`the
`
`drug and Vitamin E—TPGS as
`
`less than 25% w/w of the formulation.
`
`an emulsifier
`
`in quantities of
`
`WO
`
`97/03651 discloses
`
`lipid vehicle
`
`drug delivery
`
`compositions
`
`that
`
`contain at
`
`least
`
`five
`
`ingredients:
`
`a
`
`therapeutic drug, vitamin E,
`
`an oil
`
`in which the drug and
`
`vitamin E are dissolved,
`
`a stabilizer
`
`(either phospholipid,
`
`3O
`
`a
`
`lecithin,
`
`or
`
`a poloxamer which
`
`is
`
`a polyoxyethylene—
`
`polyoxypropylene copolymer) and water.
`
`Similarly, U.S. Patent No.
`
`6,962,691 teaches
`
`topical
`
`compositions
`
`composed
`
`of
`
`at
`
`least
`
`ten
`
`ingredients:
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0008
`
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`
`

`

`PSOOOBUS.L
`
`4
`
`PATENT
`
`alendronate
`
`sodium,
`
`povidone,
`
`povidone
`
`vinyl
`
`acetate,
`
`vitamin E, menthol, dimethyl
`
`isosorbide, acetone, ethanol,
`
`tetrafluroroethane and, dichlorodifluoromethane.
`
`U.S. Patent No. 4,393,073 also suggests vitamin E as an
`
`active ingredient
`
`in pharmaceutical compositions containing
`
`ethanol.
`
`Summary of the Invention
`
`An
`
`aspect
`
`of
`
`the present
`
`invention relates
`
`to
`
`a
`
`pharmaceutical
`
`solution
`
`comprising
`
`a
`
`therapeutic
`
`agent
`
`
`
`dissolved in one or more natural or synthetic tocopherols or
`
`tocotrienols, or any combination thereof
`
`and one or more
`
`alcohols or glycols, or any combinations thereof.
`
`In some
`
`embodiments,
`
`the tocopherol(s)
`
`and/or
`
`tocotrienol(s)
`
`is in
`
`an
`
`amount
`
`from.
`
`about
`
`30% to about
`
`99%
`
`(w/w)
`
`and
`
`the
`
`alcohol(s) and/or glycol(s)
`
`is in an amount
`
`from about
`
`1% to
`
`10
`
`15
`
`
`
`
`
`about 70% (w/w).
`
`Another aspect of
`
`the present
`
`invention relates
`
`to
`
`methods for producing these pharmaceutical solutions.
`
`aspect of
`
`methods of treatment of a patient with these pharmaceutical
`
`the present
`
`invention relates
`
`to
`
`Another
`
`20
`
`25
`
`30
`
`solutions.
`
`Detailed Description of the Invention
`
`The present
`
`invention is directed to the use of one or
`
`more
`
`tocopherols
`
`and/or
`
`tocotrienols
`
`and
`
`one
`
`or more
`
`alcohols
`
`and/or
`
`glycols
`
`as
`
`pharmaceutically
`
`acceptable
`
`solvents for solubilizing therapeutic agents,
`
`in particular
`
`hydrophobic
`
`or
`
`lipophilic
`
`therapeutic
`
`agents.
`
`Advantageously,
`
`the resulting pharmaceutical solution is not
`
`an emulsion or vesicle,
`
`and can. be used directly" in the
`
`production of pharmaceutical
`
`compositions. Moreover,
`
`the
`
`combination of
`
`a
`
`tocopherol and/or
`
`a
`
`tocotrienol
`
`and an
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0009
`
`page 0009
`
`

`

`PSOOOBUS.L
`
`5
`
`PATENT
`
`alcohol and/or glycol
`
`is much less irritating to the skin
`
`and/or mucous membranes
`
`than pure
`
`alcohol
`
`solutions
`
`and
`
`generally provides higher
`
`loading of
`
`a
`
`therapeutic agent
`
`than emulsions,
`
`liposomes, encapsulations, or cyclodextrins.
`
`A solution in the context of the present invention is a
`
`homogeneous mixture composed of three or more substances.
`
`In
`
`such a mixture,
`
`a solute is dissolved in another substance,
`
`known
`
`as
`
`a
`
`solvent.
`
`In
`
`accordance with
`
`the
`
`present
`
`invention,
`
`a pharmaceutical solution is formed by dissolving
`
`a therapeutic agent
`
`in a tocopherol and/or a tocotrienol and
`
`an alcohol and/or glycol as solvents.
`
`
`In one embodiment of
`
`the present
`
`invention,
`
`the therapeutic agent
`
`is dissolved
`
`completely in the tocopherol and/or
`
`In another embodiment of
`
`a
`
`tocotrienol and the
`
`alcohol and/or glycol solvents.
`
`the present
`
`invention,
`
`the therapeutic agent may not be
`
`completely solubilized.
`
`and thus
`
`is jpartially‘ dissolved in
`
`the tocopherol and/or a tocotrienol and the alcohol and/or
`
`this
`
`embodiment, particulates
`
`of
`
`10
`
`15
`
`
`
`glycol
`
`solvents.
`
`In
`
`therapeutic agent may
`
`be present
`
`in the pharmaceutical
`
`20
`
`solution. The
`
`
`resulting pharmaceutical solutions of either
`
`embodiment
`
`can
`
`be
`
`used
`
`
`in a variety of pharmaceutical
`
`compositions with various modes of administration.
`
`The combination of
`
`tocopherol and/or a tocotrienol and
`
`alcohol and/or glycol
`
`is also useful
`
`in solubilizing at
`
`25
`
`least
`
`in part
`
`amphiphobic
`
`therapeutic agents.
`
`In this
`
`embodiment,
`
`the solution acts as
`
`a
`
`transport phase through
`
`partial
`
`solubilization.
`
`to increase the bioavailability of
`
`the
`
`amphiphobic
`
`suspension of the agent.
`
`therapeutic agent
`
`from.
`
`a
`
`finely divided
`
`3O
`
`Tocopherols and/or
`
`
`tocotrienols for use in accordance
`
`with the present
`
`invention include a family of natural and
`
`synthetic compounds, also known by the generic names
`
`tocols
`
`or
`
`'vitamin, E.
`
`Alpha—tocopherol
`
`is the most abundant
`
`and
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0010
`
`page 0010
`
`

`

`
`
`PSOOOBUS.L
`
`6
`
`PATENT
`
`active forn1 of
`
`following chemical structure:
`
`
`this family of
`
`compounds,
`
`and it has
`
`the
`
`\‘1
`
`HO
`
`Other members of this family include beta—, gamma—, and
`
`delta—tocopherol, alpha—, beta—,
`
`gamma—, and delta—
`
`tocotrienols,
`
`tocopsoralen, alpha—tocopherol derivatives
`
`and/or analogs such as tocopherol acetate, phosphate,
`
`succinate, nicotinate and linoleate, as well as isomers
`
`
`
`thereof and esters thereof. Use of the phrase tocopherol(s)
`
`and/or tocotrienol(s) herein is mean: to be inclusive of any
`
`member of this family alone or in combination.
`
`embodiment of the present invention the tocopherol(s) and/or
`
`In one
`
`tocotrienol(s) employed is alpha—tocopherol.
`
`for use in the present
`
`Examples of alcohol(s)
`
`invention
`
`include, but are not
`
`limited.
`
`to ethanol, propyl alcohol,
`
`butyl alcohol, pentanol, benzyl alcohol,
`
`thereo:, and any combinations thereof.
`
`for use
`
`in the present
`
`invention include,
`
`but
`
`are not
`
`and any isomers
`
`Examples of glycols
`
`limited to ethylene
`
`glycol,
`
`propylene
`
`glycol,
`
`butylene
`
`glycol, pentylene glycol,
`
`and any isomers thereof,
`
`and any
`
`combinations
`
`thereof.
`
`In one
`
`embodiment of
`
`the present
`
`invention the alcohol is ethanol
`
`(ethyl alcohol).
`
`Preferred
`
`is use of an ethanol that is biocompatible in the sense that
`
`it
`
`is not
`
`toxic and does not cause any physiological or
`
`pharmacological effects.
`
`In this
`
`regard,
`
`the
`
`ethanol
`
`is
`
`desirably 180 to 200 proof ethanol,
`
`i.e.,
`
`in the range of
`
`90—100% ethanol. Advantageously, diluting a
`
`'tocopherol or
`
`tocotrienol with an alcohol or glycol dramatically reduces
`
`the
`
`inherent viscosity of
`
`the
`
`tocopherol or
`
`tocotrienol
`
`thereby allowing for generation of sprayable formulations.
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0011
`
`page 0011
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`

`

`PSOOOBUS.L
`
`7
`
`PATENT
`
`In accordance with the present
`
`
`invention, solutions of
`
`one or more tocopherols and/or tocotrienols and one or more
`
`alcohols and/or glycols are used in the solubilization of
`
`hydrophobic
`
`providing
`
`In
`
`agent.
`
`or
`
`lipophilic
`
`therapeutic
`
`increased bioavailability of
`
`agents
`
`thereby
`
`the
`
`therapeutic
`
`some
`
`embodiments,
`
`the
`
`tocopherol(s)
`
`and/or
`
`10
`
`15
`
`tocotrienol(s)
`
`is in an amount
`
`from about
`
`30% to about
`
`99%
`
`(w/W)
`
`and the alcohol(s) and/or glycol(s)
`
`is in an amount
`
`about
`
`1% to about 70% (w/w).
`
`As
`
`a non—limiting example,
`
`
`the solubility of Diazepam
`
`at
`
`room temperature is less than or equal
`
`proof ethanol. However, combining tocopherol and ethanol has
`
`to 6.67% in 190
`
`been found to provide solubility of the Diazepam approaching
`
`the 10% level. By way of illustration, at 70% tocopherol:30%
`
`ethanol
`
`(200 proof), Diazepam is soluble to greater than or
`
`equal
`
`to 8% and at
`
`95% tocopherol:5% ethanol
`
`(200 proof),
`
`Diazepam is soluble at greater than or equal to 9%.
`
`Accordingly, preferred for
`
`some
`
`embodiments
`
`is
`
`that
`
`
`
`
`
`
`
`
`
`iliI§Iis E iIE ili:
`
`20
`
`25
`
`30
`
`alpha—tocopherol and ethanol constitute 60% to 99% and 1% to
`
`40%,
`
`respectively, of
`
`the pharmaceutical solution.
`
`
`In Other
`
`
`
`embodiments,
`
`the
`
`alpha—tocopherol
`
`and
`
`ethanol
`
`constitute
`
`approximately 70% to 90% and 10% to 30%,
`
`respectively, of
`
`the pharmaceutical solution.
`
`In still other embodiments,
`
`tocopherol and ethanol are used at ratios of approximately
`
`the
`
`95:5, 90:10, 85:15,
`
`80—20, 75:25, 70:30, 65:35, or 60:40,
`
`respectively.
`
`Pharmaceutical solutions of
`
`the present
`
`by dissolving any difficult
`
`be
`
`produced
`
`invention can
`
`to
`
`solubilize
`
`therapeutic
`
`agent
`
`(i.e.,
`
`hydrophobic
`
`or
`
`lipophilic
`
`therapeutic
`
`agents)
`
`in one
`
`or more
`
`tocopherols
`
`and/or
`
`tocotrienols
`
`and one or more alcohols and/or glycols
`
`as
`
`pharmaceutically acceptable solvents. By therapeutic agents
`
`it is meant to be inclusive of, but is not limited to, small
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0012
`
`page 0012
`
`

`

`PSOOO8US.L
`
`8
`
`PATENT
`
`organic molecules,
`
`therapeutic peptides,
`
`non—peptides
`
`and
`
`nucleotides.
`
`Hydrophobic
`
`derivatives
`
`of
`
`water—soluble
`
`molecules such as lipid conjugates/prodrugs are also within
`
`the scope of therapeutic agents.
`
`Exemplary hydrophobic or
`
`lipophilic therapeutic agents
`
`which can be
`
`solubilized in accordance with the present
`
`invention include, but are in no way limited to,
`
`steroids
`
`such
`
`as Dexamethasone,
`
`l7-beta—Estradiol;
`
`benzodiazepenes
`
`such as Diazepam, alpraxolam, bromazepam, chlordiazepoxidem,
`
`10
`
`clonazepam, estazolam,
`
`flunitrazepam,
`
`flurazepam,
`
`lorazepam,
`
`lormetazepam, mexazolam,
`
`nitrazepam,
`
`oxazepam,
`
`temazepam,
`
`and triazolam; Rapamycin and analogues; Taxol
`
`(paclitaxel)
`
`
`
`and analogues; Actinomycin D; Prostaglandins (PGEl); Vitamin
`
`Batimastat;
`
`A;
`
`Probucol;
`
`Statins
`
`(HMG—CoA
`
`Reductase
`
`15
`
`Inhibitors; Trapidil
`
`
`(and other anti—proliferative Growth
`
`Factor Inhibitors); Cytochalasin B; and Hdcrotubule binding
`
`agents such as epothilones, elutherobin and discodermolide.
`
`Pharmaceutical
`
`solutions
`
`and compositions
`
`formulated from
`
`the solutions may comprise one or more therapeutic agents in
`
`20
`
`Further, pharmaceutical compositions
`
`formulated
`
` si5i i izIgtJll l1i1 i
`
`solution.
`
`from the pharmaceutical solutions of
`
`the present
`
`invention
`
`may
`
`further
`
`comprise
`
`one or more additional
`
`agents in encapsulated or micronized (not dissolved)
`
`The present
`
`invention also provides
`
`
`for use
`
`of
`
`a
`
`combination of
`
`tocopherol and/or a
`
`tocotrienol and alcohol
`
`and/or glycol
`
`to solubilize at
`
`least
`
`in part amphiphobic
`
`therapeutic agents.
`
`In this embodiment,
`
`the solution acts
`
`as
`
`a
`
`transport
`
`phase
`
`through partial
`
`solubilization to
`
`therapeutic
`
`forms.
`
`increase the bioavailability of
`
`the amphiphobic therapeutic
`
`agent from a finely divided suspension of the agent.
`
`of
`
`Pharmaceutical
`
`solutions
`
`the
`
`invention
`
`can
`
`be
`
`25
`
`30
`
`formulated
`
`into
`
`pharmaceutical
`
`compositions
`
`administration
`
`to
`
`animals,
`
`preferably
`
`humans,
`
`for
`
`via
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0013
`
`page 0013
`
`

`

`
`
`! Ei El
`
`PSOOOBUS.L
`
`9
`
`PATENT
`
`intravascular,
`
`oral,
`
`intramuscular,
`
`cutaneous
`
`and
`
`subcutaneous
`
`routes.
`
`Specifically,
`
`pharmaceutical
`
`compositions of the present
`
`
`of
`following
`
`any
`
`the
`
`invention can be administered by
`
`nonlimiting
`
`exemplary
`
`routes,
`
`intraabdominal,
`
`intraarterial,
`
`intraarticular,
`
`intracapsular,
`
`intracervical,
`
`intracranial,
`
`intraductal,
`
`intradural,
`
`intralesional,
`
`intralocular,
`
`intramural,
`
`intranasal,
`
`intraocular,
`
`intraparietal,
`
`intraperitoneal,
`
`intralumbar,
`
`intraoperative,
`
`intrapleural,
`
`
`
`intrapulmonary,
`
`intraspinal,
`
`intrathoracic,
`
`intratracheal,
`
`intratympanic,
`
`intrauterine,
`
`and
`
`intraventricular.
`
`The
`
`pharmaceutical compositions of
`
`the present
`
`invention can be
`
`nebulized using mechanical nebulizers or suitable aerosol
`
`propellants which
`
`are
`
`known
`
`in the
`
`art
`
`for
`
`pulmonary
`
`
`
`delivery of lipophilic compounds. The most suitable route in
`
`any given case will depend on the nature and severity of the
`
`condition being treated and on the nature of the particular
`
`10
`
`15
`
`therapeutic agent which is being used.
`
`Pharmaceutical solutions of the instant invention are
`
`20
`
`
`particularly useful in formulations to be administered to
`
`mucosal membranes, i.e.
`
`the nasal mucosa or lungs of a
`
`subject by any suitable means. For many therapeutic agents,
`
`administration via the nasal route provides for faster
`
`attainment of therapeutic levels of the therapeutic agent
`
`systemically. However, many therapeutic agents are so
`
`slightly soluble in water that a therapeutically effective
`
`amount cannot be dissolved in a volume of aqueous solvent
`
`that is amenable to application to a mucosal membrane. Use
`
`of a pharmaceutical solution of the present invention,
`
`however, provides for improved ability to dissolve
`
`hydrophilic and lipophilic therapeutic agents,
`
`thus
`
`providing a useful delivery system for administration of
`
`such agents to one or more mucosal membranes,
`
`including the
`
`25
`
`3O
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0014
`
`page 0014
`
`

`

`PSOOOBUS.L
`
`10
`
`PATENT
`
`nasal mucosal membranes.
`
`Such solutions can be administered
`
`via,
`
`
`for example,
`
`a mist sprayer.
`
`a metered dose inhaler or nebulizer, or in
`
`The
`
`instant
`
`pharmaceutical
`
`solutions
`
`comprising
`
`a
`
`therapeutic
`
`agent,
`
`one
`
`or
`
`more
`
`tocopherols
`
`and/or
`
`tocotrienols
`
`and one or more alcohols and/or glycols
`
`can
`
`also be
`
`
`formulated into a pharmaceutical composition for
`
`injection by combining the instant pharmaceutical solution
`
`with,
`
`e.g.,
`
`saline
`
`solution or water
`
`and
`
`a Vitamin E
`
`solubilizing agent
`
`such as Cremophor.
`
`Such pharmaceutical
`
`compositions may
`
`
`further
`
`contain other pharmaceutically
`
`acceptable
`
`additives
`
`such
`
`as,
`
`but
`
`not
`
`limited
`
`to,
`
`acidifying, alkalizing, buffering, chelating, complexing and
`
`solubilizing
`
`agents,
`
`antioxidants
`
`and
`
`antimicrobial
`
`humectants,
`
`suspending
`
`and/or
`
`viscosity
`
`preservatives,
`
`modifying
`
`agents,
`
`tonicity
`
`and
`
`wetting
`
`or
`
`other
`
`biocompatible materials.
`
`instant
`
`10
`
`15
`
`
`
`
`For
`
`oral
`
`therapeutic
`
`administration,
`
`the
`
`pharmaceutical solutions can be combined with one or Hmre
`
`20
`
`
`carriers and used in the form of ingestible tablets, buccal
`
`tablets,
`
`wafers,
`
`troches,
`
`capsules, elixirs,
`
`suspensions,
`
`syrups,
`
`chewing gums,
`
`foods and the like. Such compositions
`
`and preparations
`
`should contain at
`
`least
`
`0.1% of active
`
`compound. Tablets,
`
`troches, pills,
`
`capsules,
`
`and.
`
`the like
`
`can also contain one or more of the following: binders such
`
`as
`
`gum.
`
`tragacanth,
`
`acacia,
`
`corn
`
`starch
`
`or
`
`gelatin;
`
`excipients
`
`such as dicalcium. phosphate;
`
`a disintegrating
`
`agent such as corn starch, potato starch, alginic acid and
`
`the like;
`
`a
`
`lubricant
`
`such as magnesiunl stearate;
`
`and a
`
`sweetening agent
`
`such
`
`as
`
`sucrose,
`
`fructose,
`
`lactose
`
`or
`
`25
`
`30
`
`aspartame or
`
`a
`
`flavoring agent
`
`such as peppermint, oil of
`
`Wintergreen,
`
`or
`
`cherry flavoring.
`
`The
`
`above
`
`listing is
`
`merely representative and
`
`one
`
`skilled in the art
`
`could
`
`AQUESTIVE EXHIBIT 1046
`
`AQUESTIVE EXHIBIT 1046 page 0015
`
`page 0015
`
`

`

`PSOOO8US.L
`
`11
`
`PATENT
`
`envision other binders, excipients,
`
`sweetening agents
`
`and
`
`the like. When the unit dosage fonn is a capsule,
`
`it can
`
`contain,
`
`in addition to materials of
`
`the
`
`above
`
`type,
`
`a
`
`liquid carrier,
`
`such as
`
`a vegetable oil or
`
`a polyethylene
`
`glycol. Various other Haterials can be present as coatin