(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`27 September 2001 (27.09.2001)
`
`• I lllll llllllll II llllll lllll llll I II Ill lllll lllll lllll lllll llll lllllll llll llll llll
`
`(10) lnternational P ublication Number
`WO 01/70194 Al
`
`PCT
`
`(51) International Patent C lassification7: A61K 9/00, 9/20
`
`(74) Agents: FEDERMAN, Evan, J.; Warner-Lambert Com(cid:173)
`pany, 201 Tabor Road, Morris Plains, NJ 07950 e1 al. (US).
`
`(21) International Application Number: PCT/USOl/02192
`
`(22) International F iling Date: 23 January 2001 (23.01.2001)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`09/535.005
`
`23 March 2000 (23.03.2000) US
`
`(71) Applicant:
`WARNER-LAMBERT COMPANY
`[US/US]; 201 Tabor Road, Morris Plains, NJ 07950
`(US).
`
`(81) Designated States (national) : AE, AG. AL, AU. BA, BB,
`BG, BR. BZ, CA. CN. CR, CU, CZ, OM, DZ, EE. GD, GE,
`HR, HU, fD, lL, IN, IS, JP, KP, KR, LC, LK, LR, LT. LY,
`MA, MG, MK. MN, MX. MZ, NO, NZ. PL, RO, SG, SI,
`SK. SL, TR. TI, UA. UZ. VN, YU, ZA.
`
`(84) Designated States (regional) : ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY,KG, KZ, MD. RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, Fl, FR, GB, GR, IE,
`IT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR. NE. SN, TD, TG).
`
`(72) Inventors: BESS, William, S.; 31 Greenwish Road, Edi(cid:173)
`son, NJ 08820 (US). KULKARNI, Neema; 16 Wilkeshire
`Boulevard, Randolph, NJ 07869 (US). AMBIKE, S uhas,
`H.; 73 Charcoal Drive, West Hill, Ontario MIC 3T9 (CA).
`RAMSAY, Michael, Paul; 45 Sayor Drive, Ajax, Ontario
`LIT 3K4 (CA).
`
`-~ ---
`
`Published:
`with imernational search report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations'' appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`--
`
`---------~
`
`,..-j~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~-
`
`,..-j <
`~
`= (54) Title: FAST DISSOLVING ORALLY CONSUMABLE FILMS CONTAINING AN ION EXCHANGE RESIN AS A TASTE
`0\.
`t:: MASKING AGENT
`,..-j
`C
`0 ing polymer, such as pullulan, and a taste masked pharmaceutically active agent, such as dextrometborphan. The taste masking agent
`> is preferably a sulfonated polymer ion exchange resin comprising polystyrene cross-linked with divinylbenzene. such as AMBER(cid:173)
`
`(57) Abstract: Physiologically acceptable films, including edible films, are disclosed. The films include a water soluble film-form-
`
`,_.. LITE. Methods for producing the films are also disclosed.
`
`DRL - EXHIBIT 1033
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`WO 01/70194
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`PCT/USOl/02192
`
`FAST DISSOL YING ORALLY CONSUMABLE FILMS CONTAINING
`AN ION EXCHANGE RESIN AS A TASTE MASKING AGENT
`
`5
`
`10
`
`SPECIFICATION
`
`FIELD OF THE INVENTION
`
`This invention relates to fast dissolving orally consumable films
`
`containing an agent to mask the taste of a pharmaceutically active agent
`
`therein, and more specifically to such fi lms containing an ion exchange resin as
`
`the taste masking agent.
`
`BACKGROUND OF THE INVENTION
`
`It has been known to administer pharmaceutically active agents in an
`
`edible film vehicle.
`
`For example. WO 99/ 17753 discloses rapidly dissolving films for
`
`delivery of drugs to be adsorbed in the digestive tract.
`
`15
`
`WO 98/26780 discloses a flat, foil, paper or wafer type presentation for
`
`the application and release of active substances in the buccal cavity. The
`
`specific active ingredient disclosed in WO 98/26780 is buprenorphine.
`
`WO 98/20862 discloses a fi lm for use in the oral cavity that can contain
`
`a cosmetic or pharmaceutical active substance.
`
`20
`
`WO 98/26763 discloses a flat, foil, paper or wafer like presentation for
`
`release of active substances into the buccal cavity. The particular active
`
`disclosed is apomorphine.
`
`U.S. Patent Application No. 09/395. l 04 also discloses the delivery of
`
`pharmaceutical agents in a edible film vehicle.
`
`25
`
`U.S. Patent No. 5,411,945 to Ozaki et al. discloses a pullulan binder and
`
`products produced therewith, including edible films (Example 8-2). The
`
`products can include a variety of ingredients in addition to pullulan, such as
`
`other polysaccharides. antibacterial agents, flavor-imparting agents and
`
`pharmaceutically active substances (column 4, lines 5-15).
`
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`U.S. Patent No. 3, 784,390 Hijiya et al. discloses pullulan films and their
`
`use in coating and packing materials for foods, pharmaceuticals and other
`
`oxygen sensitive materials. All of the examples in this patent teach mixing
`
`pullulan in hot water.
`
`5
`
`It has also been known to combine ion exchange resins with
`
`pharmaceutically active agents to provide sustained release formulations.
`
`For example, U.S. Patent No. 6,001,392 to Wen et al. discloses a
`
`controlled-release syrup suspension for oral administration containing
`
`dextromethorphan adsorbed to a polystyrene sulfonate ion exchange resin.
`
`10
`
`Pharmaceutical films are not disclosed.
`
`U.S. Patent No. 5,980,882 to Eichman discloses a method for improving
`
`the stability of a pharmaceutical composition that contains a drug-resin
`
`complex, comprising adding a chelating agent in an amount effective to reduce
`
`the rate of degradation of the drug in the drug-resin complex. Although
`
`15
`
`Eichman teaches that complexing a drug with an ion exchange resin can mask
`
`the taste of the drug. Pharmaceutical films are not disclosed.
`
`The inventors are not aware of any suggestion in the published art that
`
`ion exchange resins can act as taste masking agents in a fast dissolving orally
`
`consumable film. Accordingly, an object of this invention is to provide fast
`
`20
`
`dissolving orally consumable films containing an ion exchange resin to mask
`
`the taste of a pharmaceutically active agent therein.
`
`All references cited herein are incorporated herein by reference in their
`
`entireties.
`
`SUMMARY OF THE INVENTION
`
`25
`
`The invention provides a consumable film adapted to adhere to and
`
`dissolve in a mouth of a consumer. wherein the film comprises at least one
`
`water soluble polymer, at least one pharmaceutically active agent and at least
`
`one taste masking agent.
`
`2
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`Also provided is a method for preparing the consumable film of the
`
`invention, comprising:
`
`dissolving water-soluble ingredients in water to provide an
`
`aqueous solution;
`
`5
`
`mixing at least one water soluble film former and at least one
`
`stabilizing agent to provide a film-forming mixture;
`
`combining the film-forming mixture and the aqueous solution to
`
`provide a hydrated polymer gel;
`
`mixing oils to form an oil mixture;
`
`10
`
`adding the oil mixture to the hydrated polymer gel and mixing to
`
`provide a uniform gel;
`
`casting the uniform gel on a substrate; and
`
`drying the cast gel to provide the film.
`
`DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
`
`15
`
`The invention provides a physiologically acceptable film that is
`
`particularly well adapted to adhere to and dissolve in a mouth of a consumer to
`
`deliver a pharmaceutically active agent. Preferred films according to the
`
`invention comprise a pharmaceutically active agent, an ion exchange resin, a
`
`film-forming agent. and at least one of the following additional ingredients:
`
`20
`
`water, antimicrobial agents, plasticizing agents, flavoring agents, saliva
`
`stimulating agents, cooling agents, surfactants, stabilizing agents, emulsifying
`
`agents, thickening agents, binding agents, coloring agents, sweeteners,
`
`fragrances, triglycerides, preservatives, polyethylene oxides. propylene glycol,
`
`and the like.
`
`25
`
`The expression ''physiologically acceptable'' as used herein is intended
`
`to encompass compounds, which upon administration to a patient, are
`
`adequately tolerated without causing undue negative side effects. The
`
`expression encompasses edible compounds.
`
`3
`
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`
`The expression "pharmaceutically active agents" as used herein is
`
`intended to encompass agents other than foods, which promote a structural
`
`and/or functional change in and/or on bodies to which they have been
`
`administered. These agents are not particularly limited; however, they should
`
`s
`
`be physiologically acceptable and compatible with the film. Suitable
`
`pharmaceutically active agents include, but are not limited to:
`
`A.
`
`antimicrobial agents, such as triclosan, cetyl pyridium
`
`chloride. domiphen bromide, quaternary ammonium salts, zinc compounds,
`
`sanguinarine, fluorides, alexidine, octonidine, EDTA, and the like;
`
`10
`
`B.
`
`non-steroidal anti-inflammatory drugs, such as aspirin,
`
`acetaminophen, ibuprofen, ketoprofen, diflunisal, fenoprofen calcium,
`
`naproxen, tolmetin sodium, indomethacin, and the like;
`
`C.
`
`anti-tussives, such as benzonatate, caramiphen edisylate,
`
`menthol, dextromethorphan hydrobromide, chlophedianol hydrochloride, and
`
`1 s
`
`the like;
`
`D.
`
`decongestants, such as pseudoephedrine hydrochloride,
`
`phenylepherine, phenylpropanolamine, pseudoephedrine sulfate, and the like;
`
`E.
`
`anti-histamines, such as brompheniramine maleate,
`
`chlorpheniramine maleate, carbinoxamine maleate, clemastine fumarate,
`
`20
`
`dexchlorpheniramine maleate, diphenhydramine hydrochloride,
`
`diphenylpyraline hydrochloride, azatadine meleate, diphenhydramine citrate,
`
`doxylamine succinate, promethazine hydrochloride, pyrilamine maleate,
`
`tripelennamine citrate, triprolidine hydrochloride, acrivastine, loratadine,
`
`brompheniramine, dexbrompheniramine, and the like;
`
`25
`
`F.
`
`expectorants, such as guaifenesin, ipecac, potassium
`
`iodide, terpin hydrate, and the like;
`
`G.
`
`H.
`
`anti-diarrheals, such a loperamide, and the like;
`
`Hrantagonists, such as famotidine. ranitidine, and the like;
`
`4
`
`DRL - EXHIBIT 1033
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`
`WO 01/70194
`
`and the like;
`
`I.
`
`proton pump inhibitors, such as omeprazole, lansoprazole,
`
`PCT/USOl /02192
`
`J.
`
`general nonselective CNS depressants, such as aliphatic
`
`alcohols, barbiturates and the like;
`
`5
`
`K.
`
`general nonselective CNS stimulants such as caffeine,
`
`nicotine, strychnine, picrotoxin. pentylenetetrazol and the like;
`
`L.
`
`drugs that selectively modify CNS function, such as
`
`phenyhydantoin, phenobarbital, primidone, carbamazepine, ethosuximide,
`
`methsuximide, phensuximide, trimethadione, diazepam, benzodiazepines,
`
`10
`
`phenacemide, pheneturide, acetazolamide. sulthiame, bromide, and the like;
`
`M.
`
`antiparkinsonism drugs such as levodopa. amantadine and
`
`the like;
`
`N.
`
`narcotic-analgesics such as morphine, heroin,
`
`hydromorphone, metopon, oxymorphone, levorphanol, codeine, hydrocodone,
`
`J 5
`
`xycodone, nalorphine, naloxone, naltrexone and the like;
`
`0.
`
`analgesic-antipyretics such as salycilates, phenylbutazone,
`
`indomethacin, phenacetin and the like; and
`
`P.
`
`psychophannacological drugs such as chlorpromazine,
`
`methotrimeprazine, haloperidol. clozapine. reserpine. imipramine,
`
`20
`
`tranylcypromine, phenelzine, lithium and the like.
`
`The amount of pharmaceutically active agent that can be used in the
`
`rapidly dissolving films, according to the present invention, is dependent upon
`
`the dose needed to provide an effective amount of the pharmaceutically active
`
`agent. Examples of doses for specific pharmaceutically active agents that can
`
`25
`
`be delivered per one strip of rapidly dissolving oral film are reviewed in
`
`Table A.
`
`5
`
`DRL - EXHIBIT 1033
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`WO 01/70194
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`PCT/USOl/02192
`
`TABLE A
`
`PHARMACEUTICALLY ACTIVE AGENT
`Chlorpheniramine Maleate
`Brompheniramine Maleate
`Dexchlorpheniramine
`Dexbrompheniramine
`Triprolidine Hydrochloride
`Acrivastine
`Azatadine Maleate
`Loratidine
`Phenylephrine Hydrochloride
`Dextromethorphan Hydrobromide
`Ketoprofen
`Sumatriptan Succinate
`Zolmitriptan
`Loperamide
`Famotidine
`Nicotine
`Diphenhydramine Hydrochloride
`Pseudoephedrine Hydrochloride
`
`5
`
`10
`
`15
`
`20
`
`PREFERRED DOSE
`4mg.
`4mg.
`2mg.
`2mg.
`2.5 mg.
`8mg.
`I mg.
`10 mg.
`IOmg.
`10-30 mg.
`12.5-25 mg.
`35 - 70 mg.
`2.5 mg.
`2mg.
`10 mg.
`2mg.
`12.5-25 mg.
`30mg.
`
`Ion exchange resins preferred for use: in the: films of the invention are
`
`water-insoluble and consist of a pharmacologically inert organic or inorganic
`
`25
`
`matrix containing covalently bound functional groups that are ionic or capable
`
`of being ionized under the appropriate conditions of pH. The organic matrix
`
`may be synthetic (e.g., polymers or copolymers of acrylic acid, methacrylic
`
`acid, sulfonated styrene, sulfonated divinylbenzenc), or partially synthetic (e.g.,
`
`modified cellulose and dextrans). The inorganic matrix can also be, e.g., silica
`
`30
`
`gel modified by the addition of ionic groups. The covalently bound ionic
`
`groups may be strongly acidic (e.g., sulfonic acid), weakly acidic (e.g.,
`
`carboxylic acid), strongly basic (e.g., quaternary ammonium), weakly basic
`
`(e.g., primary amine), or a combination of acidic and basic groups. In general,
`
`those types of ion exchangers suitable for use in ion exchange chromatography
`
`35
`
`and for such applications as deionization of water are suitable for use in these
`
`6
`
`DRL - EXHIBIT 1033
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`WO 01/70194
`
`PCT /USOl/02192
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`controlled release drug preparations. Such ion exchangers are described by H.
`
`F. Walton in "Principles of Ion Exchange" (pp. 312-343). The ion exchange
`
`resins useful in the present invention have exchange capacities below about 6
`
`milliequivalents per gram (meq/g) and preferably below about 5.5 meq/g.
`
`5
`
`The resin is crosslinked with a crosslinking agent selected from
`
`difunctional compounds capable of crosslinking polystyrenes; these are
`
`commonly known in the art. Preferably, the crosslinking agent is a divinyl or
`
`polyvinyl compound. Most preferably the crosslinking agent is divinylbenzene.
`
`The resin is crosslinked to an extent of about 3 to about 20%, preferably about
`
`1 o
`
`4 to about 16%, more preferably about 6 to about 10%, and most preferably
`
`about 8% by weight based on the total resin. The resin is crosslinked with the
`
`crosslinking agent by means well known in the art.
`
`The size of the ion exchange resins should preferably fall within the
`
`range of about 20 to about 200 micrometers. Particle sizes substantially below
`
`15
`
`the lower limit are difficult to handle in all steps of the processing. Particle
`
`sizes substantially above the upper limit, e.g., commercially available ion
`
`exchange resins having a spherical shape and diameters up to about l 000
`
`micrometers, are gritty in liquid dosage forms and have a greater tendency to
`
`fracture when subjected to drying-hydrating cycles.
`
`20
`
`Representative resins useful in this invention include AMBERLITE
`
`IRP-69 (obtained from Rohm and Haas) and Dow XYS-40010.00 (obtained
`
`from The Dow Chemical Company). Both are sulfonated polymers composed
`
`of polystyrene cross-linked with 8% of divinylbenzene, with an ion exchange
`
`capacity of about 4.5 to 5.5 meq/g of dry resin (H+-form). Their essential
`
`25
`
`difference is in physical fonn. AMBERLITE IRP-69 comprises
`
`irregularly-shaped particles with a size range of 47 to 149 micrometers,
`
`produced by milling the parent, large-sized spheres of AMBERLITE IRP-120.
`
`The Dow XYS-40010.00 product comprises spherical particles with a size
`
`7
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`DRL - EXHIBIT 1033
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`
`WO 01170194
`
`PCT/USOl/02192
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`range of 45 to 150 micrometers. Another useful exchange resin, Dow
`
`XYS-40013.00, is a polymer composed of polystyrene cross-linked with 8% of
`
`divinylbenzene and functionalized with a quaternary ammonium group; its
`
`exchange capacity is normally within the range of approximately 3 to 4 meq/g
`
`5
`
`of dry resin.
`
`The most preferred resin is AMBERLITE IRP-69. However, in less
`
`preferred embodiments, the taste masking agent need not be an ion exchange
`
`resin. In these embodiments, the taste masking agent can be, e.g., magnesium
`
`trisilicate. See, e.g., U.S. Patents Nos. 4,650,663 and 4,581,232 to Peters et al.
`
`10
`
`Taste can also be masked by polymers, such as EUDRAGIT E (Rohm and
`
`Haas), and/or cellulosics, such as ethylcellulose, and the like.
`
`The film-forming agent used in the films according to the present
`
`invention can be selected from the group consisting of pullulan,
`
`hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl
`
`15
`
`cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol,
`
`sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum,
`
`acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer,
`
`carboxyvinyl polymer, amylase, high amylase starch, hydroxypropylated high
`
`amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen,
`
`20
`
`gelatin. zein, gluten, soy protein isolate, whey protein isolate, casein and
`
`mixtures thereof. A preferred film former is pullulan, in amounts ranging from
`
`about 0.01 to about 99 wt%, preferably about 30 to about 80 wt%, more
`
`preferably from about 45 to about 70 wt% of the film and even more preferably
`
`from about 60 to about 65 wt% of the film.
`
`25
`
`Unless specified otherwise, the term "wt%'. as used herein with
`
`reference to the final product (i.e., the film, as opposed to the formulation used
`
`to create it), denotes the percentage of the total dry weight contributed by the
`
`subject ingredient. This theoretical value can differ from the experimental
`
`8
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`value, because in practice, the film typically retains some of the water and/or
`
`ethanol used in preparation.
`
`In embodiments containing relatively high oil content, it is preferable to
`
`avoid substantial amounts ofhumectant in the film (and more preferable to
`
`5
`
`have no humectant in the film), so as to avoid producing an overly moist, self(cid:173)
`
`adhering film. In particular, it is preferred to formulate high oil content films
`
`with a plasticizing agent other than glycerin, which is also a humectant, and
`
`with a sweetener other than sorbitol, which is a mild humectant.
`
`Saliva stimulating agents can also be added to the films according to the
`
`10
`
`present invention. Useful saliva stimulating agents are those disclosed in U.S.
`
`Patent No. 4,820,506. Saliva stimulating agents include food acids such as
`
`citri c, lactic, malic, succinic, ascorbic, adipic, fumaric and tartaric acids.
`
`Preferred food acids are citric, malic and ascorbic acids. The amount of saliva
`
`stimulating agents in the film is from about 0.01 to about 12 wt%, preferably
`
`J 5
`
`about l wt% to about 10 wt%, even more preferably about 2.5 wt% to about 6
`
`wt%.
`
`Preferred plasticizing agents include triacetin in amounts ranging from
`
`about 0 to about 20 wt%, preferably about 0 to about 2 wt%. Other suitable
`
`plasticizing agents include monoacetin and diacetin.
`
`20
`
`Preferred cooling agents include monomenthyl succinate. in amounts
`
`ranging from about 0.00 1 to about 2.0 wt%, preferably about 0.2 to about 0.4
`
`wt%. A monomenthyl succinate containing cooling agent is available from
`
`Mane, Inc. Other suitable cooling agents include WS3, WS23, Ultracool II and
`
`the like.
`
`25
`
`Preferred surfactants include mono and diglycerides of fatty acids and
`
`polyoxyethylene sorbitol esters. such as, Atmos 300 and Polysorbate 80. The
`
`surfactant can be added in amounts ranging from about 0.5 to about 15 wt%,
`
`preferably about 1 to about 5 wt% of the film . Other suitable surfactants
`
`9
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`
`WO 01170194
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`include pluronic acid, sodium lauryl sulfate, and the like.
`
`Preferred stabilizing agents include xanthan gum, locust bean gum and
`
`carrageenan, in amounts ranging from about 0 to about I 0 wt%, preferably
`
`about 0.1 to about 2 wt% of the film. Other suitable stabilizing agents include
`
`5
`
`guar gum and the like.
`
`Preferred emulsifying agents include triethanolamine stearate,
`
`quaternary ammonium compounds, acacia, gelatin, lecithin. bentonite,
`
`veegum, and the like, in amounts ranging from about 0 to about 5 wt%,
`
`preferably about 0.0 I to about 0.7 wt% of the film.
`
`10
`
`Preferred th ickening agents include methylcellulose, carboxyl
`
`methylcellulose. and the like, in amounts ranging from about 0 to about 20
`
`wt%, preferably about 0.0 1 to about 5 wt%.
`
`Preferred binding agents include starch, in amounts ranging from about
`
`0 to about I 0 wt%, preferably about 0.01 to about 2 wt% of the film.
`
`15
`
`Suitable sweeteners that can be included are those well known in the art,
`
`including both natural and artificial sweeteners. Suitable sweeteners
`
`include, e.g.:
`
`A. water-soluble sweetening agents such as monosaccharides,
`
`disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose),
`
`20
`
`mannose, galactose, fructose (levulose), sucrose (sugar). maltose, invert sugar
`
`(a mixture of fructose and glucose derived from sucrose), partially hydrolyzed
`
`starch, com syrup solids, dihydrochalcones, monellin, steviosides, and
`
`glycyrrhizin;
`
`B.
`
`water-soluble artificial sweeteners such as the soluble
`
`25
`
`saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the
`
`sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-1 ,2,3-oxathiazine-
`
`4-one-2, 2-dioxide. the potassium salt of 3,4-dihydro-6-methyl-1 ,2.3-
`
`oxathiazine-4-one-2,2-dioxide (acesulfame-K). the free acid form of saccharin,
`
`10
`
`DRL - EXHIBIT 1033
`DRL011
`
`

`
`WO 01170194
`
`and the like;
`
`PCT/USOl/02192
`
`C.
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`dipeptide based sweeteners, such as L-aspartic acid
`
`derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester
`
`(aspartame) and materials described in U.S. Pat. No. 3,492,131, L- alpha-
`
`s
`
`aspartyl-N-(2,2,4,4--tetramethyl-3-thietanyl)-D-alaninamide hydrate, methyl
`
`esters of L-aspartyl-L-phenylglycerin and L-aspartyl-L-2,5,dihydrophenyl(cid:173)
`
`glycine, L-aspartyl-2,5-dihydro- L-phenylalanine, L-aspartyl-L-( 1-
`
`cyclohexyen)-alanine, and the like;
`
`D.
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`water-soluble sweeteners derived from naturally occurring
`
`10
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`water-soluble sweeteners, such as a chlorinated derivative of ordinary sugar
`
`(sucrose), known, for example, under the product description of sucralose; and
`
`E.
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`protein based sweeteners such as thaumatoccous danielli
`
`(Thaumatin I and II).
`
`In general, an effective amount of auxiliary sweetener is utilized to
`
`15
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`provide the level of sweetness desired for a particular composition, and this
`
`amount will vary with the sweetener selected. This amount will normally be
`
`0.01 % to about JO % by weight of the composition when using an easily
`
`extractable sweetener. The water-soluble sweeteners described in category A
`
`above, are usually used in amounts of about 0.01 to about 10 wt%, and
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`20
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`preferably in amounts of about 2 to about 5 wt%. Some of the sweeteners in
`
`category A (e.g., glycyrrhizin) can be used in amounts set forth for categories
`
`B-E below due to the sweeteners' known sweetening ability. In contrast, the
`
`sweeteners described in categories B-E are generally used in amounts of about
`
`0.01 to about 10 wt%, with about 2 to about 8 wt% being preferred and about 3
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`25
`
`to about 6 wt% being most preferred. These amounts may be used to achieve a
`
`desired level of sweetness independent from the flavor level achieved from any
`
`optional flavor oils used. Of course, sweeteners need not be added to films
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`intended for non-oral administration.
`
`I l
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`DRL - EXHIBIT 1033
`DRL012
`
`

`
`WO 01/70194
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`PCT/USOl/02192
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`The flavorings that can be used include those known to the skilled
`
`artisan, such as natural and artificial flavors. These flavorings may be chosen
`
`from synthetic flavor oils and flavoring aromatics, and/or oils, oleo resins and
`
`extracts derived from plants, leaves, flowers, fruits and so forth, and
`
`s
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`combinations thereof. Representative flavor oils include: spearmint oil,
`
`cinnamon oil, peppermint oil, clove oil, bay oil, thyme oil, cedar leaf oil, oil of
`
`nutmeg, oil of sage, and oil of bitter almonds. Also useful are artificial, natural
`
`or synthetic fruit flavors such as vanilla, chocolate, coffee, cocoa and citrus oil,
`
`including lemon, orange, grape, lime and grapefruit and fruit essences
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`10
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`including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple,
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`apricot and so forth. These flavorings can be used individually or in admixture.
`
`Commonl y used flavors include mints such as peppermint, artificial vanilla,
`
`cinnamon derivatives, and various fruit flavors, whether employed individually
`
`or in admixture. Flavorings such as aldehydes and esters including cinnamyl
`
`t 5
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`acetate, cinnamaldehyde, citral, diethylacetal, dihydrocarvyl acetate, eugenyl
`
`formate, p-methylanisole, and so forth may also be used. Generally, any
`
`flavoring or food additive, such as those described in Chemicals Used in Food
`
`Processing, publication 1274 by the National Academy of Sciences, pages 63-
`
`258, may be used. Further examples of aldehyde flavorings include, but are not
`
`20
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`limited to acetaldehyde (apple); benzaldehyde (cherry, almond); cinnamic
`
`aldehyde (cinnamon); citral, i.e., alpha citral (lemon, lime); neral, i.e. beta citral
`
`(lemon, lime); decanal (orange, lemon); ethyl vanillin (vanilla, cream);
`
`heliotropine, i.e., piperonal (vanilla, cream); vanillin (vanilla, cream); alpha(cid:173)
`
`amyl cinnamaldehyde (spicy fruity flavors); butyraldehyde (butter. cheese);
`
`25
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`valeraldehyde (butter, cheese); citronella! (modifies. many types); decanal
`
`(citrus fruits); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits);
`
`aldehyde C-12 (citrus fruits); 2-ethyl butyraldehyde (berry fruits); hexenal, i.e.
`
`trans-2 (berry fruits); tolyl aldehyde (cherry, almond); veratraldehyde (vanilla);
`
`12
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`DRL - EXHIBIT 1033
`DRL013
`
`

`
`WO 01170194
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`PCT /USO 1 /02192
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`2,6-dimethyl- 5-heptenal, i.e. melonal (melon); 2-6-dimethyloctanal (green
`
`fruit); and 2-dodecenal (citrus, mandarin); cherry; grape; mixtures thereof; and
`
`the like.
`
`The amount of flavoring employed is normally a matter of preference
`
`5
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`subject to such factors as flavor type, individual flavor, and strength desired.
`
`Thus, the amount may be varied in order to obtain the result desired in the final
`
`product. Such variations are within the capabilities of those skilled in the art
`
`without the need for undue experimentation. In general, amounts of about 0.1
`
`to about 30 wt% are useable with amounts of about 2 to about 25 wt% being
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`10
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`preferred and amounts from about 8 to about 10 wt% are more preferred.
`
`The compositions of this invention can also contain coloring agents or
`
`colorants. The coloring agents are used in amounts effective to produce the
`
`desired color. The coloring agents useful in the present invention, include
`
`pigments such as titanium dioxide, which may be incorporated in amounts of
`
`t 5
`
`up to about 5 wt%, and preferably less than about I wt%. Colorants can also
`
`include natural food colors and dyes suitable for food, drug and cosmetic
`
`applications. These colorants are known as FD&C dyes and lakes. The
`
`materials acceptable for the foregoing spectrum of use are preferably water(cid:173)
`
`soluble, and include FD&C Blue No. 2, which is the disodium salt of 5,5-
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`20
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`indigotindisulfonic acid. Similarly, the dye known as Green No. 3 comprises a
`
`triphenylmethane dye and is the monosodium salt of 4-[4-N-ethyl-p(cid:173)
`
`sulfobenzylamino) di phenyl-methylene]-[ 1-N-ethyl-N-p-sulfonium benzyl)-
`
`2,5-cyclo-hexadienimine]. A full recitation of all FD&C and D&C dyes and
`
`their corresponding chemical structures may be found in the Kirk-Othmer
`
`25
`
`Encyclopedia of Chemical Technology, Volume 5, Pages 857-884, which text
`
`is accordingly incorporated herein by reference.
`
`The films can also include a triglyceride. Examples of triglycerides
`
`include vegetable oils such as corn oil, sunflower oil, peanut oil, olive oil,
`
`13
`
`DRL - EXHIBIT 1033
`DRL014
`
`

`
`WO 01/70194
`
`PCT/USOl/02192
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`canola oil, soybean oil and mixtures thereof. A preferred triglyceride is olive
`
`oil. The triglyceride is added to the film in amounts from about 0.1 wt% to
`
`about 12 wt%, preferably in a range from about 0.5 wt% to about 9 wt%, of the
`
`film.
`
`5
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`The films can include a preservative in amounts from about 0.001 wt%
`
`to about 5 wt%, preferably from about 0.01 wt% to about 1 wt% of the film.
`
`Preferred preservatives include sodium benzoate and potassium sorbate. Other
`
`suitable preservatives include, but are not limited to, salts of edetate (also
`
`known as salts of ethylenediaminetetraacetic acid, or EDT A, such as disodium
`
`10
`
`EDTA) and parabens (e.g., methyl, ethyl, propyl or butyl-hydroxybcnzoates,
`
`etc.) or sorbic acid. The preservatives listed above are exemplary, but each
`
`preservative must be evaluated on an empirical basis, in each formulation, to
`
`assure the compatibility and efficacy of the preservative. Methods for
`
`evaluating the efficacy of preservatives in pharmaceutical formulations are
`
`15
`
`known to those skilled in the art.
`
`The films can also include a polyethylene oxide compound. The
`
`molecular weight of the polyethylene oxide compound ranges from about
`
`50,000 to about 6,000,000. A preferred polyethylene oxide compound is N-10
`
`available from Union Carbide Corporation. The polyethylene oxide compound
`
`20
`
`is added in amounts from about 0.1 wt% to about 5 wt%, preferably from about
`
`0.2 wt% to about 4.0 wt% of the film.
`
`The films can also include propylene glycol. The propylene glycol is
`
`added in amounts from about 1 wt% to about 20 wt%, preferably from about 5
`
`wt% to about 15 wt% of the film.
`
`25
`
`Methods for preparing films according to the invention are capable of
`
`encapsulating the oil ingredients within the film-forming matrix and
`
`maintaining the integrity of the film, even when the film contains oils in
`
`amounts of I 0 wt% or more.
`
`14
`
`DRL - EXHIBIT 1033
`DRL015
`
`

`
`WO 01170194
`
`PCT/USOl/02192
`
`In certain methods for preparing films according to the invention, the
`
`film-forming ingredients are mixed and hydrated with water separately from
`
`the water-soluble ingredients, which are mixed in aqueous solution separately
`
`from the organic ingredients and surfactants. In these methods, the final
`
`5
`
`formulation is preferably produced by mixing the film-forming phase with the
`
`aqueous phase, then mixing in the organic phase, which includes surfactants,
`
`such as Polysorbate 80 and Atmos 300. This mass is mixed until emulsified.
`
`In other embodiments, the aqueous and film forming phases are combined into
`
`a single phase by dissolving the water soluble ingredients in the water and then
`
`10
`
`adding the gums to hydrate. The organic phase is then added to this single
`
`aqueous phase.
`
`The resulting formulation is cast on a suitable substrate and dried to
`
`form a film. The film is preferably air-dried or dried under warm air and cut to
`
`a desired dimension, packaged and stored. The film can contain from about
`
`15
`
`0.1 % to about 10 wt% moisture, preferably from about 3 % to about 8 wt%
`
`moisture, even more preferably from about 4 to about 7 wt% moisture.
`
`The film-forming phase can include pullulan and stabilizing agents such
`
`as xanthan gum, locust bean gum and carrageenan. These ingredients are
`
`mixed and then hydrated in water for about 30 to about 48 hours to form a gel.
`
`20
`
`The water is preferably heated to a temperature of about 25 to about 45°C to
`
`promote hydration. The amount of water is about 40 to 80% of the gel. The
`
`resulting hydrated gel is then chilled to a temperature of about 20 to about 30°C
`
`for about I to about 48 hours. The water is preferably deionized.
`
`In preferred embodiments, the aqueous phase includes water heated to a
`
`25
`
`temperature of about 60 to 90°C, preferably 70 to 80°C, and ingredients such as
`
`the pharmaceutically active agent, ion exchange resin (or other masking agent),
`
`coloring agent, preservative and sweetener. The water is preferably deionized
`
`and the amount of water used is about 5 to about 80 wt% of the final gel
`
`15
`
`DRL - EXHIBIT 1033
`DRL016
`
`

`
`WO 01170194
`
`mixture.
`
`PCT/USOl/02192
`
`The pharmaceutically active agent is sorbed to the ion exchange resin
`
`(or other masking agent) without separating ion exchanged pharmaceutically
`
`active agent from unexchanged agent and counter ion salts.
`
`5
`
`Adsorption of the phannaceutically active agent onto the ion exchange
`
`resin particJes to fo