(12) INTERNATIONAL APPLICATION PUBLISHED
`UNDER THE PATENT COOPERATION TREATY (PCT)
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`(19) World Intellectual Property Organization
`International Bureau
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`11111111111111 1111111111111111111111111111 11111111111111111111111111111111111111111111111111111
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`(43) International Publication Date
`1 October 2009 (01.10.2009)
`
`PCT
`
`(10) International Publication Number
`
`WO 2009/120933 A2
`
`(81) Designated States (unless otherwise indicated,
`(51) International
`for every
`Patent Classification:
`A61K 9/08 (2006.01)
`AE, AG, AL, AM,
`
`kind of national protection available):
`
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`(21) International
`
`Application Number:
`
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`PCT/US2009/038518
`EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`(22) International
`
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`Filing Date:
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`27 March 2009 (27.03.2009)
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO,
`
`NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`
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`SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`English
`
`English
`
`(25) Filing Language:
`(26) Publication
`Language:
`(30) Priority Data:
`61/040,281 28 March 2008 (28.03.2008) us
`(71) Applicant (for all designated
`
`States except US): PARTI­
`CLE SCIENCES, INC. [US/US]; 3894 Courtney Street,
`
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`Suite 180, Bethlehem, PA 18017 (US).
`
`(84) Designated States (unless otherwise indicated, for every
`
`ARIPO (BW, GH,
`
`
`kind of regional protection available):
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR),
`
`
`OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`MR, NE, SN, TD, TG).
`
`(72)
`(75)
`
`Inventors; and
`
`(for US only):
`Inventors/Applicants
`GWOZDZ, Garry,
`Thomas [US/US]; 329 South Main Street, Nazareth, PA
`
`18064 (US). LOXLEY, Andrew [GB/US]; 126 Market
`
`
`Street, #5, Philadelphia, PA 19106 (US). MITCHNICK,
`Published:
`Mark [US/US]; 80 Three Mile Harbor Drive, East Hamp­
`without international search report and to be republished
`
`
`
`ton, NY 11937 (US).
`
`
`upon receipt of that report (Rule 48.2(g))
`(74) Agent: LICATA, Jane, Massey; Licata & Tyrrell P.C.,
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`66 E. Main Street, Marlton, NJ 08053 (US).
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`(54) Title: PHARMACEUTICAL SOLUTIONS AND METHOD FOR SOLUBILIZING THERAPEUTIC AGENTS
`(57) Abstract: Pharmaceutical solutions
`containing hydrophobic or lipophilic therapeutic agents and methods for producing the
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`same are provided. Pharmaceutical solutions of the invention are produced by dissolving the therapeutic agent in one or more to­
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`copherols or tocotrienols and one or more alcohols or glycols. These solutions are used to produce pharmaceutical compositions.
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`AQUESTIVE EXHIBIT 1014 page 0000
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`PHARMACEUTICAL SOLUTIONS AND METHOD FOR SOLUBILIZING
`THERAPEUTIC AGENTS
`
`This patent application claims the benefit of priority
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`5
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`from U. S. Application Serial No. 61/040, 28 1, filed March 28,
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`2008, teachings of which are herein incorporated by
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`reference in their entirety.
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`Background of the Invention
`
`10
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`A vast number of potential therapeutic agents are
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`discovered each year, many of which are water insoluble or
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`poorly water soluble. For such hydrophobic compounds, direct
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`injection may be impossible or highly dangerous, and can
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`result in hemolysis, phlebitis, hypersensitivity, organ
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`15
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`failure and/or death. Such compounds are termed by
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`pharmacists as "lipophilicn, "hydrophobicn, or in their most
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`insoluble form, "amphiphobicn.
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`A few examples of therapeutic agents in these
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`categories are ibuprofen, diazepam, griseofulvin,
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`20
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`cyclosporin, cortisone, proleukin, etoposide and paclitaxel.
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`(Kagkadis et al. FDA J. Fharm. Sci. Tech. 1996 50 (5) :317-
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`323; Dardel Anaesth. Scand. 1976 20:2 21-24; Sweetana and
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`Akers FDA J. Fharm. Sci. Tech. 1996 50 (5) :330-342).
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`Administration of chemotherapeutic agents is
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`25
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`particularly problematic. Most of these agents are poorly
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`soluble and thus are difficult to deliver in aqueous
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`solvents and to supply at therapeutically effective levels.
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`Further, water-soluble, chemotherapeutic agents are
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`generally taken up by both cancer and non-cancer cells,
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`30
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`making such agents non-specific and oftentimes unacceptably
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`toxic.
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`For therapeutic agents that cannot be formulated as an
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`aqueous solution, emulsions have oftentimes provided a cost­
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`effective and therapeutically acceptable alternative.
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`35
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`However, it is difficult to render emulsions sterile and/or
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`AQUESTIVE EXHIBIT 1014 page 0001
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`endotoxin free for intravenous injection. Oils typically
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`used for pharmaceutical emulsions include saponifiable oils
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`from the family of triglycerides, for example, soybean oil,
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`sesame seed oil, cottonseed oil, safflower oil and the like
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`5
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`(Hansrani, et al. J. Parenter. Sci. Technol. 1983 37:145-
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`150). One or more surfactants are used to stabilize the
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`emulsion, and excipients are added to render the emulsion
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`more biocompatible, stable and less toxic. Lecithin from egg
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`yolks or soybeans is a commonly used surfactant. Sterile
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`10
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`manufacturing can be accomplished by sterilization of all
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`the components before manufacture, followed by aseptic
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`technique in all stages of manufacture. Improved ease of
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`manufacture and assurance of sterility is obtained by
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`terminal sterilization following sanitary manufacture,
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`15
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`either by heat or by filtration. However, terminal
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`sterilization by heat or filtration treatments is not
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`suitable for all emulsions.
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`Vitamin E emulsions have been disclosed. For example,
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`injectable vitamin E emulsions are described by Hidiroglou
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`20
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`and Karpinski (Brit. J. Nutrit. 1988 59 :509-518) for dietary
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`supplementation in sheep and for research on the
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`pharmacokinetics of vitamin E and its derivatives.
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`An
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`injectable form of vitamin E for mice was prepared by Kato
`
`et al.
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`(Chem. Pharm. Bull. 1993 41 (3) :599-604). Micellar
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`25
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`solutions were formulated with TWEEN 80, BRIJ 58 and HC0-60.
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`Isopropanol was used as a co-solvent, and was then removed
`
`by vacuum evaporation; the residual oil glass was then taken
`
`up in water with vortexing as a micellar suspension. An
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`emulsion was also prepared by dissolving vitamin E with soy
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`30
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`phosphatidycholine
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`(lecithin) and soybean oil. Water was
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`added and the emulsion prepared with sonication. Ethanol­
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`free emulsions of alpha-tocopherol, stabilized by
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`biocompatible surfactants, as a vehicle or carrier for
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`AQUESTIVE EXHIBIT 1014 page 0002
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`therapeutic drugs is also disclosed in U. S. Patent Nos.
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`6, 667, 048 and 6, 660, 286.
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`E-Ferol, a vitamin E emulsion for vitamin E
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`supplementation and therapy in neonates was also disclosed
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`5
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`by Alade et al.
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`( Pediatrics ( 1986) 77 (4) : 593-597). The
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`surfactant mixture used to emulsify the 25 mg/mL vitamin E
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`in E-Ferol was composed of 9% TWEEN 80 and 1% TWEEN 20.
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`However, this supplement was not safe.
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`An alternative means of solubilizing low solubility
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`10
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`compounds is direct solubilization in a non-aqueous milieu,
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`for example, alcohols
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`(such as ethanol), dimethylsulfoxide,
`
`and/or triacetin. For example, WO 95/11039 describes the use
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`of vitamin E
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`(100 mg), lecithin
`
`( 20 mg), ethanol (100 mg)
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`and EUTANOL
`
`(500 mg) as an injectable formulation of the
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`15
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`immunosuppressant molecule cyclosporine
`
`(50 mg). U. S. Patent
`
`No. 5, 689, 846 discloses various alcohol solutions of
`
`paclitaxel. U. S. Patent No. 5, 5 73, 781 discloses the
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`dissolution of paclitaxel in ethanol, butanol and hexanol
`
`and an increase in the antitumor activity of paclitaxel when
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`20
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`delivered in butanol and hexanol as compared to ethanol.
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`WO 95/312 1 7 discloses that tocopherols can be used as
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`solvents and/or emulsifiers of drugs that are substantially
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`insoluble in water, in particular for the preparation of
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`topical formulations. The use of vitamin E-TPGS as an
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`25
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`emulsifier in formulations containing high levels of a­
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`tocopherol is mentioned and formulations for topical
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`administration composed of a lipid layer
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`(a-tocopherol), the
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`drug and vitamin E-TPGS as an emulsifier in quantities of
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`less than 25% w/w of the formulation.
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`30
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`WO 9 7/03651 discloses lipid vehicle drug delivery
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`compositions that contain at least five ingredients : a
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`therapeutic drug, vitamin E, an oil in which the drug and
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`vitamin E are dissolved, a stabilizer
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`(either phospholipid,
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`AQUESTIVE EXHIBIT 1014 page 0003
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`a lecithin, or a poloxamer which is a polyoxyethylene­
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`polyoxypropylene copolymer) and water.
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`Similarly, U. S. Patent No. 6, 962, 691 teaches topical
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`compositions composed of at least ten ingredients :
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`5
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`alendronate sodium, povidone, povidone vinyl acetate,
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`vitamin E, menthol, dimethyl isosorbide, acetone, ethanol,
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`tetrafluroroethane and, dichlorodifluoromethane.
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`U.S. Patent No. 4, 393, 073 also suggests vitamin E as an
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`active ingredient in pharmaceutical compositions containing
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`10
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`ethanol.
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`Summary of the Invention
`
`An aspect of the present invention relates to a
`
`pharmaceutical solution comprising a therapeutic agent
`
`15
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`dissolved in one or more natural or synthetic tocopherols or
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`tocotrienols, or any combination thereof and one or more
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`alcohols or glycols, or any combinations thereof. In some
`
`embodiments, the tocopherol (s) and/or tocotrienol (s) is in
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`an amount from about 30% to about 99%
`
`(w/w) and the
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`20
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`alcohol (s) and/or glycol (s) is in an amount from about 1% to
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`about 70%
`
`(w/w).
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`Another aspect of the present invention relates to
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`methods for producing these pharmaceutical solutions.
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`Another aspect of the present invention relates to
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`25
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`methods of treatment of a patient with these pharmaceutical
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`solutions.
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`Detailed Description of the Invention
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`The present invention is directed to the use of one or
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`30
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`more tocopherols and/or tocotrienols and one or more
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`alcohols and/or glycols as pharmaceutically acceptable
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`solvents for solubilizing therapeutic agents, in particular
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`hydrophobic or lipophilic therapeutic agents.
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`Advantageously, the resulting pharmaceutical solution is not
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`AQUESTIVE EXHIBIT 1014 page 0004
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`an emulsion or vesicle, and can be used directly in the
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`production of pharmaceutical compositions. Moreover, the
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`combination of a tocopherol and/or a tocotrienol and an
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`alcohol and/or glycol is much less irritating to the skin
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`5
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`and/or mucous membranes than pure alcohol solutions and
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`generally provides higher loading of a therapeutic agent
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`than emulsions, liposomes, encapsulations, or cyclodextrins.
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`A solution in the context of the present invention is a
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`homogeneous mixture composed of three or more substances. In
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`10
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`such a mixture, a solute is dissolved in another substance,
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`known as a solvent. In accordance with the present
`
`invention, a pharmaceutical solution is formed by dissolving
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`a therapeutic agent in a tocopherol and/or a tocotrienol and
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`an alcohol and/or glycol as solvents. In one embodiment of
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`15
`
`the present invention, the therapeutic agent is dissolved
`
`completely in the tocopherol and/or a tocotrienol and the
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`alcohol and/or glycol solvents.
`
`In another embodiment of
`
`the present invention, the therapeutic agent may not be
`
`completely solubilized and thus is partially dissolved in
`
`20
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`the tocopherol and/or a tocotrienol and the alcohol and/or
`
`glycol solvents.
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`In this embodiment, particulates of
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`therapeutic agent may be present in the pharmaceutical
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`solution. The resulting pharmaceutical solutions of either
`
`embodiment can be used in a variety of pharmaceutical
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`25
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`compositions with various modes of administration.
`
`The combination of tocopherol and/or a tocotrienol and
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`alcohol and/or glycol is also useful in solubilizing at
`
`least in part amphiphobic therapeutic agents.
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`In this
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`embodiment, the solution acts as a transport phase through
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`30
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`partial solubilization to increase the bioavailability of
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`the amphiphobic therapeutic agent from a finely divided
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`suspension of the agent.
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`Tocopherols and/or tocotrienols for use in accordance
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`with the present invention include a family of natural and
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`AQUESTIVE EXHIBIT 1014 page 0005
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`synthetic compounds, also known by the generic names tocols
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`or vitamin E.
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`Alpha-tocopherol is the most abundant and
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`active form of this family of compounds, and it has the
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`following chemical structure :
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`5
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`Other members of this family include beta-, gamma-, and
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`delta-tocopherol, alpha-, beta-, gamma-, and delta­
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`tocotrienols, tocopsoralen, alpha-tocopherol derivatives
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`and/or analogs such as tocopherol acetate, phosphate,
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`10
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`succinate, nicotinate and linoleate, as well as isomers
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`thereof and esters thereof.
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`Use of the phrase tocopherol (s)
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`and/or tocotrienol{s) herein is meant to be inclusive of any
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`member of this family alone or in combination. In one
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`embodiment of the present invention the tocopherol (s) and/or
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`15
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`tocotrienol (s) employed is alpha-tocopherol.
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`Examples of alcohol (s) for use in the present invention
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`include, but are not limited to ethanol, propyl alcohol,
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`butyl alcohol, pentanol, benzyl alcohol, and any isomers
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`thereof, and any combinations thereof.
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`Examples of glycols
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`20
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`for use in the present invention include, but are not
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`limited to ethylene glycol, propylene glycol, butylene
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`glycol, pentylene glycol, and any isomers thereof, and any
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`combinations thereof. In one embodiment of the present
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`invention the alcohol is ethanol
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`(ethyl alcohol).
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`Preferred
`
`25
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`is use of an ethanol that is biocompatible in the sense that
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`it is not toxic and does not cause any physiological or
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`pharmacological effects. In this regard, the ethanol is
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`desirably 180 to 200 proof ethanol, i. e. , in the range of
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`90-100% ethanol. Advantageously, diluting a tocopherol or
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`30
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`tocotrienol with an alcohol or glycol dramatically reduces
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`AQUESTIVE EXHIBIT 1014 page 0006
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`the inherent viscosity of the tocopherol or tocotrienol
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`thereby allowing for generation of sprayable formulations.
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`In accordance with the present invention, solutions of
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`one or more tocopherols and/or tocotrienols and one or more
`
`5
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`alcohols and/or glycols are used in the solubilization of
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`hydrophobic or lipophilic therapeutic agents thereby
`
`providing increased bioavailability of the therapeutic
`
`agent. In some embodiments, the tocopherol (s) and/or
`
`tocotrienol (s) is in an amount from about 30% to about 99%
`
`10
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`(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 to 6. 67% in 190
`
`proof ethanol. However, combining tocopherol and ethanol has
`
`15
`
`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%.
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`20
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`Accordingly, preferred for some embodiments is that
`
`alpha-tocopherol and ethanol constitute 60% to 99% and 1% to
`
`40%, respectively, of the pharmaceutical solution. In other
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`embodiments, the alpha-tocopherol and ethanol constitute
`
`approximately 70% to 90% and 10% to 30%, respectively, of
`
`25
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`the pharmaceutical solution. In still other embodiments, the
`
`tocopherol and ethanol are used at ratios of approximately
`
`95 :5, 90 : 10, 85 :15, 80-20, 75 :25, 70 :30, 65 :35, or 60 :40,
`
`respectively.
`
`Pharmaceutical solutions of the present invention can
`
`30
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`be produced by dissolving any difficult 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
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`AQUESTIVE EXHIBIT 1014 page 0007
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`it is meant to be inclusive of, but is not limited to, small
`
`organic molecules, therapeutic peptides, non-peptides and
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`nucleotides. Hydrophobic derivatives of water-soluble
`
`molecules such as lipid conjugates/prodrugs are also within
`
`5
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`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, 17-beta-Estradiol; benzodiazepenes
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`10
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`such as Diazepam, alpraxolam, bromazepam, chlordiazepoxidem,
`
`clonazepam, estazolam, flunitrazepam, flurazepam, lorazepam,
`
`lormetazepam, mexazolam, nitrazepam, oxazepam, temazepam,
`
`and triazolam; Rapamycin and analogues; Taxol
`
`(paclitaxel)
`
`and analogues; Actinomycin D; Prostaglandins (PGEl); Vitamin
`
`15
`
`A; Probucol; Batimastat; Statins
`
`(HMG-CoA Reductase
`
`Inhibitors; Trapidil
`
`(and other anti-proliferative Growth
`
`Factor Inhibitors); Cytochalasin B; and microtubule binding
`
`agents such as epothilones, elutherobin and discodermolide.
`
`Pharmaceutical solutions and compositions formulated from
`
`20
`
`the solutions may comprise one or more therapeutic agents in
`
`solution.
`
`Further, pharmaceutical compositions formulated
`
`from the pharmaceutical solutions of the present invention
`
`may further comprise one or more additional therapeutic
`
`agents in encapsulated or micronized
`
`(not dissolved) forms.
`
`25
`
`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
`
`30
`
`increase the bioavailability of the amphiphobic therapeutic
`
`agent from a finely divided suspension of the agent.
`
`Pharmaceutical solutions of the invention can be
`
`formulated into pharmaceutical compositions for
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`administration to animals, preferably humans, via
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`AQUESTIVE EXHIBIT 1014 page 0008
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`intravascular, oral, intramuscular, cutaneous and
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`subcutaneous routes. Specifically, pharmaceutical
`
`compositions of the present invention can be administered by
`
`any of the following nonlimiting exemplary routes,
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`5
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`intraabdominal, intraarterial, intraarticular,
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`intracapsular, intracervical, intracranial, intraductal,
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`intradural, intralesional, intralocular, intralumbar,
`
`intramural, intranasal, intraocular, intraoperative,
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`intraparietal, intraperitoneal, intrapleural,
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`10
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`intrapulmonary, intraspinal, intrathoracic, intratracheal,
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`intratympanic, intrauterine, and intraventricular. The
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`pharmaceutical compositions of the present invention can be
`
`nebulized using mechanical nebulizers or suitable aerosol
`
`propellants which are known in the art for pulmonary
`
`15
`
`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
`
`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
`
`25
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`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,
`
`30
`
`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
`
`nasal mucosal membranes.
`
`Such solutions can be administered
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`AQUESTIVE EXHIBIT 1014 page 0009
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`10
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`via, for example, a metered dose inhaler or nebulizer, or in
`
`a mist sprayer.
`
`The instant pharmaceutical solutions comprising a
`
`therapeutic agent, one or more tocopherols and/or
`
`5
`
`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
`
`10
`
`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
`
`preservatives, penetration enhancers, humectants, suspending
`
`15
`
`and/or viscosity modifying agents, tonicity and wetting or
`
`other biocompatible materials.
`
`For oral therapeutic administration, the instant
`
`pharmaceutical solutions can be combined with one or more
`
`carriers and used in the form of ingestible tablets, buccal
`
`20
`
`tablets, troches, capsules, elixirs, suspensions, syrups,
`
`wafers, 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
`
`25
`
`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 magnesium stearate; and a
`
`sweetening agent such as sucrose, fructose, lactose or
`
`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
`
`envision other binders, excipients, sweetening agents and
`
`the like. When the unit dosage form is a capsule, it can
`
`AQUESTIVE EXHIBIT 1014 page 0010
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`contain, in addition to materials of the above type, a
`
`liquid carrier, such as a vegetable oil or a polyethylene
`
`glycol. Various other materials can be present as coatings
`
`or to otherwise modify the physical form of the solid unit
`
`5
`
`dosage form. For instance, tablets, pills, or capsules can
`
`be coated with gelatin, wax, shellac or sugar and the like.
`
`A syrup or elixir can contain the instant
`
`pharmaceutical solution, sucrose or fructose as a sweetening
`
`agent, methyl and propylparabens as preservatives, a dye and
`
`10
`
`flavoring such as cherry or orange flavor. Of course, any
`
`material used in preparing any unit dosage form should be
`
`substantially non-toxic in the amounts employed.
`
`In addition, the instant pharmaceutical solution can be
`
`formulated into sustained-release preparations and devices
`
`15
`
`including, but not limited to, those relying on osmotic
`
`pressures to obtain a desired release profile.
`
`Formulations suitable for parenteral administration can
`
`be aqueous or non-aqueous injection solutions, which are
`
`generally isotonic with the blood of the intended recipient.
`
`20
`
`These preparations can contain anti-oxidants, buffers,
`
`bacteriostats and solutes which render the formulation
`
`isotonic with the blood of the intended recipient. Aqueous
`
`and non-aqueous sterile suspensions can include suspending
`
`agents and thickening agents. The formulations can be
`
`25
`
`presented in unit\dose or multi-dose containers, for example
`
`sealed ampoules and vials.
`
`Formulations suitable for topical application to the
`
`skin can take the form of an ointment, cream, lotion, paste,
`
`gel, spray, aerosol, oil or other pharmaceutical formulation
`
`30
`
`which accomplishes direct contact between the therapeutic
`
`agent and the skin. Topical formulations can also be
`
`prepared which are suitable for occlusive therapy.
`
`Formulations in the forms of ointments, creams, lotions
`
`and pastes can generally have carriers in the forms of
`
`AQUESTIVE EXHIBIT 1014 page 0011
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`oleaginous bases (e. g. , White Petrolatum and White
`
`Ointment); absorption bases formed by adding a water-in-oil
`
`emulsifying agent to an oleaginous base (e. g. , Hydrophilic
`
`Petrolatum, AQUABASE, and AQUAPHOR); water-in-oil emulsion
`
`5
`
`bases, prepared by adding water to an absorption base (e. g. ,
`
`HYDROCREAM, EUCERIN, NIVEA, and Cold Cream); oil-in-water
`
`emulsion bases (e. g. , DERMABASE, UNIBASE, VELVACHOL, and
`
`hydrophilic ointment); and water soluble bases (e. g. ,
`
`polyethylene glycol ointment such as PEG 400-600 G or PEG
`
`10
`
`3350-400 G) . Suitable carriers to produce a spray, gel, or
`
`aerosol are well-known in the art.
`
`A carrier for topical application can also contain
`
`additional ingredients such as other carriers, moisturizers,
`
`penetration enhancers, humectants, emollients, dispersants,
`
`15
`
`radiation blocking compounds, cleansing agents, anti­
`
`infective agents (e. g. , antibiotics, fungicides, scabicides,
`
`or pediculicides), anti-inflammatory agents (e. g. ,
`
`corticosteroids), keratolytics
`
`(agents that soften, loosen,
`
`and facilitate exfoliation of the squamous cells of the
`
`20
`
`epidermis), as well as other suitable materials that do not
`
`have a significant adverse effect on the activity of the
`
`topical composition. Additional ingredients can include, for
`
`example a sodium acid phosphate moisturizer, witch hazel
`
`extract, glycerine humectant, apricot kernal oil emollient,
`
`25
`
`or corn oil dispersant. Other materials which can optionally
`
`be included in a topical composition include inositol or B­
`
`complex vitamins.
`
`Formulations suitable for transdermal administration
`
`can be presented as discrete patches adapted to remain in
`
`30
`
`intimate contact with the epidermis of the recipient for a
`
`prolonged period of time. Formulations suitable for
`
`transdermal administration can also be delivered by
`
`iontophoresis (see, for example, Pharmaceutical Research 3
`
`(6) :318
`
`( 1986)) and typically take the form of an optionally
`
`AQUESTIVE EXHIBIT 1014 page 0012
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`buffered aqueous solution.
`
`Formulations of the present
`
`invention are also suitable for delivery via microneedle
`
`delivery technology for cutaneous administration.
`
`AQUESTIVE EXHIBIT 1014 page 0013
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`
`What is claimed is:
`
`1.
`
`A pharmaceutical solution comprising one or more
`
`therapeutic agents dissolved in one or more tocopherols or
`
`tocotrienols and one or more alcohols or glycols.
`
`5
`
`10
`
`2.
`
`The pharmaceutical solution of claim 1 wherein the
`
`one or more tocopherol or tocotrienol is 30% to 99% and the
`
`one or more alcohol or glycol is 1% to 70% of the volume of
`
`the pharmaceutical solution.
`
`3.
`
`The pharmaceutical solution of claim 1 wherein the
`
`one or more tocopherols or tocotrienols is alpha-tocopherol.
`
`4.
`
`The pharmaceutical solution of claim 1 wherein the
`
`15
`
`one or more alcohols or glycols is ethanol.
`
`5. A pharmaceutical solution consisting of a
`
`therapeutic agent dissolved in alpha-tocopherol and ethanol.
`
`20
`
`6.
`
`A pharmaceutical composition comprising the
`
`pharmaceutical solution of any of claims 1 through 5.
`
`7.
`
`The pharmaceutical composition of claim 6 further
`
`comprising one or more additional therapeutic agents in
`
`25
`
`encapsulated or micronized forms.
`
`8.
`
`The pharmaceutical solution of any of claims 1
`
`through 5 wherein the one or more therapeutic agents is
`
`partially dissolved in one or more tocopherols or
`
`30
`
`tocotrienols and one or more alcohols or glycols.
`
`9. A method for solubilizing a therapeutic agent
`
`comprising dissolving a therapeutic agent in one or more
`
`AQUESTIVE EXHIBIT 1014 page 0014
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`15
`
`tocopherols or tocotrienols and one or more alcohols or
`
`glycols to form a pharmaceutical solution.
`
`10. The method of claim 9, wherein the one or more
`
`5
`
`tocopherol or tocotrienol is 30% to 99% and the one or more
`
`alcohol or glycol is 1% to 70% of the volume of the
`
`pharmaceutical solution.
`
`11.
`
`The method of claim 9 wherein the one or more
`
`10
`
`tocopherols or tocotrienols is alpha-tocopherol.
`
`12.
`
`The method of claim 9 wherein the one or more
`
`alcohols or glycols is ethanol.
`
`15
`
`13. The method of any of claims 9 through 12 wherein
`
`the therapeutic agent is partially dissolved in one or more
`
`tocopherols or tocotrienols and one or more alcohols or
`
`glycols.
`
`AQUESTIVE EXHIBIT 1014 page 0015
`
`