WO2004019885A2 - Fast dissolving film delivery of nucleotides that inhibit the unpleasant taste of bitter tasting medications - Google Patents

Abstract

Physiologically acceptable films, including edible films, are disclosed. The films include a water soluble film-forming polymer such as pullulan. Edible films are disclosed that include pullulan and an effective amount of one or more nucleotide compound which contains a purine or pyrimidine group or derivative thereof which inhibit activation of bitter taste G protein sensory perception of bitter tasting medicaments.

Description

FAST DISSOLVING FILM DELIVERY OF NUCLEOTIDES THAT INHΪBrT THE UNPLEASANT TASTE OF BITTER TASTING MEDICATIONS

FIELD OF THE INVENTION

This invention relates to fast dissolving orally consumable films that are used to deliver compounds which inhibit the sensory perception of unpleasant taste. The films can also be used to deliver pharmaceutically active agents.

BACKGROUND OF THE INVENTION

The approach to addressing unpleasant taste in the oral cavity has been to overpower it with compounds that have a strong taste such as menthol or mask it through the use of certain coatings. The applicant is not aware of any disclosure or suggestion in the art of using a compound that does not impart a strong taste to abrogate unpleasant taste in the oral cavity. The active ingredient whose use is herein claimed has been disclosed as having the property of decreasing the perception of the bitter taste of various foods and pharmaceuticals when they are mixed with and administered contemporaneously with such foods and pharmaceuticals. (U.S. Serial No. 09/865,346 filed May 25, 2001 which is incorporated by reference.)

It has been proposed to use an edible film as a vehicle for unobtrusively delivering breath-freshening agents. See JP 5-236885. This Japanese patent application does not, however, teach the inclusion of bitter taste inhibitors in the film, using the film to decrease the perception of the bitter taste invoked by other active components of foods and drugs that are placed in the oral cavity. Furthermore, this patent application does not disclose employing its film for purposes other than breath freshening or within cavities other than the mouth. U.S. Pat. No. 5,518,902 to Ozaki et al. (Hayashibara) discloses high pullulan content products, such as edible films, dentifrices and pharmaceuticals (column 3, lines 44- 56 and Example B-8). The products can include a variety of ingredients in addition to pullulan, such as other polysaccharides, polyhydric alcohols, antiseptics and flavor- imparting agents (column 4, line 58 to column 5, line 11). None of the taste inhibitors are mentioned as suitable ingredients. U.S. Pat. No. 5,411,945 to Ozaki et al. (Hayashibara) discloses a pullulan binder and products produced therewith, including edible films (Example B-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). None of the taste inhibitors are mentioned as suitable ingredients. U.S. Pat. No. 4,851,394 to Kubodera discloses glucomannan/polyhydric alcohol edible films, which can comprise pullulan (column 3, line 59 to column 4, line 21). The films are contrasted with existing pullulan-based films, which are said to lack resistance to water (column 1 lines 40-44). None of the taste inhibitors are mentioned as suitable ingredients. U.S. Pat. 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. U.S. Pat. No. 4,623,394 Nakamura et al. discloses a gradually disintegrable molded article that can be a film made with pullulan. The articles contain a particular heteromannan, which can be locust bean gum. U.S. Pat. No. 4,562,020 Hijiya et al. discloses a process for producing a self-supporting film of a glucan, which can be pullulan. Japanese Patent Document JP5- 1198 discloses films made of polyvinyl alcohol and at least one of carrageenan, water- soluble cellulose alpha-starch and water-soluble polysaccharides. WO 99/17753 discloses rapidly dissolving films for delivery of drugs to be adsorbed in the digestive tract. 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 film for use in the oral cavity that can contain a cosmetic or pharmaceutical active substance. 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. Despite the existence of rapidly dissolving orally consumable films in the prior art, there is still room for improvement in such films, and in processes for making them. All references cited herein are incorporated herein by reference in their entireties.

The effect of these taste inhibitors on the bitter taste perception that has previously imparted by bitter taste moieties, has not been reported and could not have been predicted, based on the prior art. As used herein the term "unpleasant taste" means a taste that a majority of a taste test panel of six randomly selected individuals will agree is a taste that lingers for 2 to

3 hours after the ingestion of a food or beverage and is unacceptable.

Accordingly it is an object of the invention to provide a rapidly dissolving orally consumable film formulation comprising a bitter taste ixihibitor that is capable of decreasing the perception of unpleasant taste in the oral cavity, which has been cause by pharmaceuticals or other compositions.

It is also an object of the invention to provide a rapidly dissolving orally consumable film formulation comprising a bitter taste inhibitor to control an unpleasant taste in the oral cavity wherein the active ingredient inherently has no significant taste. These and other objects of the invention will become apparent from a review of the appended specification.

SUMMARY OF THE INVENTION

The invention provides a physiologically acceptable film, which is particularly well adapted to adhere to and rapidly dissolve in the mouth of a human being. In a first embodiment of the invention, the film delivers an effective amount of a composition, comprising a nucleotide compound and related chemical derivatives thereof as described therein in combination with 0 wt % to an effective amount of a medicament. Those medacaments which have bitter taste are prefered. The compounds which contain a purine or pyrimidine group or derivative thereof which are bonded to a ribose or deoxyribose sugar moiety, or a derivative of ribose or deoxyribose and an ionizable phosphate may be used to decrease or abrogate the perception of bitterness of bitter tastants. In this capacity they are referred to as "bitterness inhibitors". The term effective amount is used to describe the amount of the bitterness inhibitor which is effective to reduce unpleasant tastes in the oral cavity. The film former used to make the films according to the present invention entraps the bitterness inhibitor compound in the oral cavity to provide extended efficacy.

The term medicament includes orally administrable pharmacologically active materials which are used in an amount which delivers a conventional oral dose of the medicament.

In a second embodiment of the invention, the rapidly dissolvable film acts as a vehicle for administering a pharmaceutically active agent orally, through a mucous membrane or an open wound of a patient.

The invention is also directed to a method for producing a supple, non-self- adhering film especially suitable for oral delivery. The method comprises mixing a film forming agent and at least one stabilizing agent to provide a film-forming mixture; dissolving water-soluble ingredients in water to provide an aqueous solution; combining the film-forming mixture and the aqueous solution to provide a hydrated polymer gel; mixing nucleotide bitterness inhibitor compounds; adding the nucleotide bitterness inhibitor compounds to the hydrated polymer gel and mixing to provide a uniform emulsified gel; casting the uniform gel on a substrate; and drying the cast gel to provide a film.

The amount of the nucleotide compound employed in the invention may comprise about 2.5% to 51% by weight and preferably between about 2.5% and 25% by weight is used based on the total weight of the particular composition in which it is employed.

BRIEF DESCRJPΉON OF THE DRAWINGS

FIG. 1 is data for the bitter taste inhibitor adenosine 5'-monoρhosphate nucleotide compound and its effectiveness in decreasing aversiveness of dextromethorphan to mice.

FIG. 2 is a graph depicting doxylamine induced taste membrane activation of G protein verses adenosine 5'-monophosphate ability to decrease doxylamine induced taste membrane activation of G protein in vitro.

FIG. 3 graphically represents adenosine 5'-monophosphate, cytidine 5'-monophosphate, 2- deoxyadenosine 5'-monophosphate and guanosine 5'-monophosphate ability to decrease the intensity of bitter taste elicited by quinine in human sensory testing.

DETAILED DESCRIPTION OF THE INVENTION

The first embodiment of the invention is a physiologically acceptable film that is particularly well adapted to adhere to and dissolve in a mouth of a consumer to deliver a bitter taste inhibiting nucleotide compound that operates by blocking unpleasant tastes which may be present in the oral cavity of a human subject. Thus, the film can be an effective tool for inhibiting the bitter sensory perception associated with foods and pharmaceutical compounds. This film preferably comprises pullulan, adenosine 5'-monophosphate or a structural homolog thereof, flavorings such as pepperrnint oil, wintergreen oil and eucalyptus oil, sweeteners such as sucrose, aspartyl phenyl alanine methyl ester and saccharin and preservatives such as benzoate. The invention incorporates concentrations of the bitterness inhibitors into the film that are similar to the concentrations used in mouthwash (see U.S. Patent Application No. 60/362,739 filed March 8, 2002 and incorporated by reference), providing similar taste inhibiting efficacy in the oral cavity.

Although the inventors are presently unaware of any other taste inhibiting consumable film that provides bitter taste inhibiting efficacy, they are aware of a consumable film disclosed in JP 5-236885, which is said to possess breath-freshening activity, but is not described as possessing any ingredients having significant bitter taste inhibiting activity. Moreover, JP 5-236885 teaches that its film should contain flavor masking extracts in amounts of 5 to 7 wt %, with the flavor masking agent being added as an oil (the essential oils are not disclosed), whereas the film of the invention preferably has an flavor masking oil content of at least about 10 wt %, more preferably about 15 wt % to about 30 wt %, most preferably about 15 wt % to about 25 wt %. Except as otherwise noted in the examples, the amounts of oils and other ingredients in the film are wt % after the film formulation has been dried to create the film. The essential oils are used in the film compositions in amounts sufficient to provide flavor masking efficacy. Generally, flavor masking agents such as thymol, methyl salicylate and eucalyptol are used in concentrations that range from about 0.01 to about 4 wt % of the film composition, preferably about 0.50 to about 3.0 wt % and even more preferably from about 0.70 to about 2.0 wt % of the film. Menthol can be added from about 0.01 to about 15 wt % of the composition, preferably about 2.0 to about 10 wt % and even more preferably from about 3 to about 9 wt % of the film. The amounts added can be readily detennined to those skilled in the art and can exceed these amounts as long as the total oil content does not create sticking or other processing problems.

Difficulties in formulating a film having numerous components which may result in a film which is too moist or too dry requires the precise proportions of the many ingredients to result in a film that is easy to handle or process. A non-self-adhering film according to the invention can be stored in contact with another such film (e.g., in a stack), or can be wound about itself (e.g., around a spool), without having to place a nonstick agent (e.g., a plastic film, paper or other support) between adjacent portions of film. 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 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, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, 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. The film of the invention preferably comprises pullulan as a film-forming agent and the nucleotide taste inhibitors compounds, and can further comprise water, additional nucleotide taste inhibitors compounds, additional film-forming agents, plasticizing agents, additional flavoring agents, sulfur precipitating agents, saliva stimulating agents, cooling . agents, surfactants, stabilizing agents, emulsifying agents, thickening agents, binding agents, coloring agents, sweeteners, fragrances, and the like.

Saliva stimulating agents can also be added to the oral care films according to the present invention. Useful saliva stimulating agents are those disclosed in U.S. Pat. No. 4,820,506, which is incorporated by reference herein in its entirety. Saliva stimulating agents include food acids such as citric, 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 about 1 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. Preferred cooling agents include monomenthyl succinate, in amounts ranging from about 0.001 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.

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 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 10 wt %, preferably about 0.1 to about 2 wt % of the film. Other suitable stabilizing agents include 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 0.01 to about 0.7 wt % of the film.

Preferred thickening agents include methylcellulose, carboxyl methylcelTulose, and the like, in amounts ranging from about 0 to about 20 wt %, preferably about 0.01 to about 5 wt %.

Preferred binding agents include starch, in amounts ranging from about 0 to about 10 wt %, preferably about 0.01 to about 2 wt % of the film.

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), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin;

B. water-soluble artificial sweeteners such as the soluble 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-l,2,3-oxathiazine-4-one-2,2-dioxide (acesulfame-K), the free acid form of saccharin, and the like;

C. 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-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-glycine, L-aspartyl-2,5-dihydro-L-phenylal- anine, L-aspartyl-L-(l-cyclohexyen)-alarιine, and the like;

D. water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, such as a chlorinated derivative of ordinary sugar (sucrose), known, for example, under the product description of sucralose; and

E. protein based sweeteners such as thaumatoccous danielli (Thaumatin I and II).

In general, an effective amount of auxiliary sweetener is utilized to 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 10% 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 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 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 intended for non-oral adnjinistration.

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 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 including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavorings can be used individually or in admixture. Commonly 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 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 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-amyl cinnamaldehyde (spicy fruity flavors); butyraldehyde (butter, cheese); valeraldehyde (butter, cheese); citronellal (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); 2,6-dirnethyl-5-heptenal, i.e. melonal (melon); 2-6- , d methyloctanal (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 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 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 up to about 5 wt %, and preferably less than about 1 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-soluble, and include FD&C Blue No. 2, which is the disodium salt of 5,5-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-sulfobenzylamino) diphenyl-methylene]-[l-N-ethyl-N- p-sulfonium benzyl)-2,5-cyclo-hexadienim- ine]. A full recitation of all FD&C and D&C dyes and their corresponding chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical Technology, Volume 5, Pages 857-884, which text is accordingly incorporated herein by reference.

The nucleotide compounds are well known and comprise adenosine, guanine, cytosine and thymidine, inosine and uracyl in chemical combination with a sugar and a phosphate. The preferred nucleotide compounds include, but are not limited to, adenosine 5'-monophosphate, inosine 5 '-monophosphate, adenosine 3':5'-cyclic monophosphate, guanosine 2':3'-cyclic monophosphate, guanosine 3':5'-cyclic monophosphate, cytidine 5 '-monophosphate, guanosine 2'-monophosphate, guanosine 3'-monophosphate, guanosine 5'-monophosphate, uridine 5'- monophosphate, 2'-deoxyadenosine 5 '-monophosphate, 2'-deoxyadenosine 5'-triphosphate, 2'- deoxycytidine 5'-monophosphate, and 2'-deoxyguanosine 5 '-monophosphate. In specific, non-limiting embodiments, where adenosine 5'- monophosphate, inosine

5 'monophosphate, adenosine 3'-5'cyclic-monophosphate, uridine 5 '-monophosphate, 2- deoxycytidine 5'-triphosρhate or 2' deoxyguanosine 5'-monophosphate is used to decrease unpleasant taste in the mouth an oral formulation comprising a concentration of the nucleotide of between about 1% and 50% by weight, preferably between about 2.5% and 18.5% is used. In specific, non-lirniting embodiments, where guanosine 2':3'-cyclic monophosphate, guanosine 3':5'cyclic monophosphate, cytidine 5 '-monophosphate, guanosine 2'- monophosphate, guanosine 5 '-monophosphate, 2'deoxycytidine 5'monophosphate or guanosine 3 '-monophosphate is used to decrease unpleasant taste in the mouth an oral formulation comprising a concentration of the nucleotide of between about 1% and 30% by weight, preferably between about 10% and 18% by weight based on the total weight of composition is used.

The preferred embodiment of the invention is such that the compounds claimed to decrease unpleasant taste are nucleotides in the form of adenosine, inosine, guanosine, cytodine, thymidine uracyl, 5-methylcytosrne, thiouracil, bromothymine, azaadenines, azaguanosine, xanthine, hypoxanthine, 8-bromoguanine, 8-cWoroguarιine, 8-aminoguanine, 8- hydrazinoguanine, 8-hydroxyguanine, 8-methylguanine, 8-thioguanine, 2-aminopurine, 2,6- diaminopurine, 5-ethylcytosine, 5-methylcytosine, 5-bromouracil, 5-iodouracil, 5-ethyluracil, 5- proluracil, 5-vinyluracil, and 5-bromovinyluracil combined with ribose or deoxyribose sugar, or derivative thereof, and contain an ionizable phosphate or similar anionic organic molecule. The compositions as described above are sufficient to block unpleasant tastes present in the mouth of human subjects as determined by subjective determination of the taste intensity.

Bitter Taste Inhibition Efficacy of Consumable Films

The preferred embodiment of the oral film composition according to the present invention contains the nucleotide bitter taste inhibitor compound. The films are shaped and sized to be placed in the oral cavity. The film adheres to a surface in the mouth, usually the roof of the mouth or the tongue, and quickly dissolves. The amount of bitterness inhibitor compound in one individual film that is a preferred size for placing in the mouth in the recommended amount of 1 to 30mg. The inventors believe that the efficacy of the nucleotide bitter taste inhibitor compounds is enhanced by the creation of a layer of pullulan in the oral cavity that holds the nucleotide bitter taste inhibitor compound. This is unexpected because pullulan is water-soluble and the film dissolves very quickly.

The data from studies support the following conclusions: (1) Pullulan polymer- based film containing nucleotide bitter taste inhibitor compound is an effective bitter taste sensory inhibitor and (2) significant in vivo bitter taste inhibition was achieved at 1/2, 5 and 20 minutes post use.

Experimental Procedures Figure 1:

Mice were initially presented with two bottles containing water for 48 hours to avoid novelty artifacts. Next, mice were presented with two bottles containing the various combinations of water, dexrromethorphan and AMP. The volume of liquid consumed at 24 and 48 hours were recorded. Bottle positions are switched at 24 hrs. From these data the preference ratio can be calculated. A value of 0.5 indicates no preference for one bottle verses another. A significant deviation above 0.5 indicates a preference for a particular solution, while a deviation below 0.5 suggests avoidance of a particular solution. The mice employed for these studies were equally mixed male and female C57 strain.

Experimental procedure Figure 2:

Previously, it has been shown that membranes isolated from bovine circumvallate papillae activate transducin in response to bitter compounds (Ruiz-Avila et al. , 1995 Nature 376:80-5). The heterotrimeric guanine nucleotide binding protein (G protein) transducin is an ideal reporter enzyme of bitter taste signal transduction because it can be highly purified (>95%), in large quantities (5-10 mg/200 retina). Furthermore, transducin has a very low level of basal activity, and in conjunction with nonhydrolyzable GTP analogues, can generate activated species that are readily measured by guanine radionucleotide binding.

The G effect was initially defined as the binding of GTP upon stimulation of tissue with a ligand (Rodbell et al, 1971 J. Biol. Chem. 246:1877-82). It is now known that these ligands activate seven-transmembrane-helical G protein coupled receptors, which catalyze the exchange of GTP for bound GDP in the α-subunit of heterolximeric G proteins. Thus, transducin activation by bitter stimulated taste membranes may be measured by uptake of GTP.

Since G proteins have an intrinsic GTPase activity, which terminates the activation cycle, a radioactive nonhydrolyzable analogue of GTR such as [³⁵S] GTPγS or [³H] GppNHp must be used. To test for the inhibitory activity of nucleotide compounds, several modifications of the standard [³⁵S] GTPγS binding assay were made to efficiently measure activation by bitter responsive receptors that couple to gustducin or transducin (Gravina et al, in preparation). To maximize the bitter dependent change in radiolabel uptake GDP:GTPγS ratios, buffer composition, and specific activity of the [³⁵S] GTPγS were adjusted. Ruiz-Avila et al. demonstrated taste membrane dependent activation of exogenously added transducin by bitter tastants in trypsin digest assays (Ruiz-Avila et al, 1995 Nature 376:80-5; Ruiz-Avila et al, 2000 Chem Senses 25:361-8). Radionucleotide bound to transducin can be measured by filter binding followed by washing to remove unbound label (Asano et al, 1984 Biochemistry 23:5460-5467). The final concentrations in the [³⁵S] GTPγS binding assay mix are 10 mM HEPES pH 7.5, 5 mM MgCl₂, 50 mM NaCl, 1 mM dithiolthreitol, 10 μM GDP, 1 μM [³⁵S] GTPγS (O.lμCi/sample), 0.5 μg/0.05 ml transducin heterotrimer. A 2 X stock of the above mixture is added to the bitter compound. Reactions are started by addition of 5μg/0.05ml bovine circumvallate membranes and the sample volume is adjusted to 0.05 ml with water. Samples are incubated at room temperature (25 ± 2°C for 2 hours). Long incubation times are necessary due to the low density of receptors in the membranes. Similar results are obtained with high dilutions of rhodopsin. Samples are then filtered through BA-85 nitrocellulose filters and washed 3 times with 3 ml of 50 mM Tris-HCl pH 7.5, 4 mM MgCl₂, and 0.1 M NaCl. FUters are dried, placed in scintillation fluid and the radioactivity is determined by scintillation counting. Experiments are performed in triplicate with several concentrations of the tastant of interest. Controls include: (i) a rhodopsin positive control, (if) a no tastant negative control and (iii) a no membrane control +/- tastants. This assay can measure activation of transducin by bitter compounds in the presence of taste membrane, and can identify compounds that block this activation

Experimental procedure Figure 3: Assessors were trained to evaluate the taste quality of aqueous solutions (3 mL each) of the following standard taste compounds by using a triangle test: saccharose (50 mmol/L) for sweet taste; lactic acid (20 mmol L) for sour taste; NaCl (12 mmol/L) for salty taste; caffeine (1 mmol L) for bitter taste; monosodium glutamate (MSG, 8 mmol/L, pH 5.7) for umami taste; tannin (gallustannic acid; 0.05%) for astringency. In addition, the panelists were asked to evaluate the taste intensity and the time/response function of aqueous solutions containing increasing amounts of these taste compounds. Sensory analyses were performed in a sensory panel room at 22-25°C on three different sessions.

Increasing amounts of nucleotide were added to constant concentrations of bitter compound. Each compound was tested subsequently without and in the presence of increasing concentrations of nucleotide, respectively, and, finally again without of nucleotide. The tests were performed as triangle test by six experienced panelists. The panelists were asked to score the intensities of the given samples on a scale from 0 (not detectable) to 5 (strong). The values between individuals and two separate sessions differed not more than 1 unit.

Methods for preparing films according to the invention are capable of encapsulating the nucleotide bitter taste inhibitor compound within the film-forming matrix and maintaining the integrity of the film, even when the film contains nucleotide bitter taste inhibitor compound in amounts of 50 wt % or more.

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 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 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 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. The water is preferably heated to a temperature of about 25 to about 45. degree. 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.degree. C. for about 1 to about 48 hours. The water is preferably deionized.

The aqueous phase can include ingredients such as coloring agent(s), copper gluconate and sweetener. The water is preferably deionized and the amount of water used is about 5 to about 80 wt % of the final gel mixture.

If sodium saccharin and copper gluconate are both ingredients in the formulation, it is preferable to dissolve them separately in solution to avoid precipitation.

In a preferred method of producing nucleotide bitter taste inhibitor compound containing films according to the invention, it is possible to hydrate the film-forming ingredients and combine all of the ingredients without heating. The preferred method of producing films comprises dissolving the water-soluble ingredients in water to form an aqueous mixture; mixing the film-forming ingredients in powder form to form a powder mixture; adding the powder mixture to the aqueous mixture to form a hydrated polymer gel; stirring the hydrated polymer at room temperature for about 30 minutes to about 48 hours; mixing adenosine 5' -monophosphate in the flavor oil to form an oil mixture; adding surfactants to the oil mixture; adding the oil mixture to the hydrated polymer gel and mixing until uniform; deaerating the film until air bubbles are removed, casting the uniform mixture on a suitable substrate; and drying the cast mixture to form a film.

The preferred method for making a nucleotide bitter taste inhibitor compound containing film hydrates the film-forming ingredients without heating the water. Heating the ingredients increases energy costs in the manufacturing process. Moreover, heating results in undesirable losses of volatile ingredients to evaporation. Further, mixing the oils in two steps mmimizes the amount of flavor lost. While not wishing to be bound by any theories, it is believed that the fitm-forrning ingredients can be hydrated and mixed without heating due to an ionic effect known as the Donnan equilibrium. Hydrating the f m-forming agents in the presence of electrolytes in solution effectively lowers the viscosity of the polymer gel being formed, thus increasing the efficiency of the hydrating process. The water-soluble ingredients of the formulation provide the electrolytes, which are dissolved in the hydration solution prior to addition of the film-forming ingredients. High-shear mixing also accelerates hydration, which delumps the powders, providing greater surface area for water contact. In addition, local heating effects, generated in the shear regions, provide energy for hydration without substantially raising the temperature of the mass.

It is preferable to avoid adding both copper gluconate and saccharin at the same time to the aqueous solution, as a precipitate will form. Thus, it is preferred to combine sweeteners other than saccharin with copper gluconate.

Description of Film Compositions that Deliver Pharmaceutical Agents

A second embodiment of the invention is a fast dissolving film that includes at least one physiologically acceptable, pharmaceutically active agent and at least one nucleotide bitter taste inhibitor compound. 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.

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 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,

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 the like, D. decongestants, such as pseudoephedrine hydrochloride, phenylepherine, phenylpropanolamine, pseudoephedrine sulfate, and the like,

E. anti-histamines, such as brompheniramine maleate, chlorpheniramine maleate, carbmoxarnine maleate, clemastine fumarate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, diphenylpyraline hydrochloride, azatadine meleate, dipherLhydra ine citrate, doxylamine succinate, promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate, triprolidine hydrochloride, acrivastine, loratadrne, bromphen amine, dexbrompheniramine, and the like,

F. expectorants, such as guaifenesin, ipecac, potassium iodide, terpin hydrate, and the like,

G. anti-diarrheals, such a loperamide, and the like, H. H.sub.2-antagonists, such as famotidrne, ranitidine, and the like; and I. proton pump inhibitors, such as omeprazole, lansoprazole, and the like, J. general nonselective CNS depressants, such as aliphatic alcohols, barbiturates and the like, 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, prirnidone, carbamazepine, ethosukimide, methsuxi ide, phensuximide, trimethadione, diazepam, benzodiazepines, 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, xycodone, nalorphine, naloxone, naltrexone and the like, O. analgesic-antipyretics such as salycilates, phenylbutazone, indomethacin, phenacetin and the like,

P. psychopharmacological drugs such as chlorpromazine, methotrimeprazine, haloperidol, clozapine, reserpine, Mpramine, tranylcypromine, phenelzine, lithium and the like. The amount of medicament 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 medicament. Examples of doses for specific medicaments that can be delivered per one strip of rapidly dissolving oral film are reviewed in Table 1.

TABLE 1 MEDICAMENT DOSE

Dextromethorphan Hydrochloride 5-20 mg.

Desloratidine 5mg Cetirizine 5-1 Omg

Hydrocodone 2.5-15mg

Oxycodone 2.5-1 Omg

Omeprazole 10-20mg

Dicyclomine 25mg Flurazepam 15-30mg

Chloφheniramine Maleate 4 mg.

Brompheniramine Maleate 4 mg.

Dexchlorpheniramine 2 mg.

Dexbrompheniramine 2 mg. Triprolidine Hydrochloride 2.5 mg.

Acrivastine 8 mg. Azatadine Maleate 1 mg. Loratidine 10 mg.

Phenylephrine Hydrochloride 10 mg. Ketoprofen 12.5 mg.

Sumatriptan Succinate 35-70 mg. Zol itriptan 2.5 mg. Loperamide 2 mg. Famotidine 10 mg. Nicotine 2 mg.

Dipherjhydramine Hydrochloride 25 mg. Pseudoephedrine Hydrochloride 30 mg.

The ingredients used to make the pharmaceutical containing films are similar to those used to make nucleotide bitter taste inhibitor compound films. Specifically, the plasticizing agents, cooling agents, surfactants, stabilizing agents, emulsifiers, thickening agents, binding agents, film formers, sweeteners, flavors and colors described above can also be used in all of the films according to the present invention.

The films that deliver a pharmaceutical agent and a nucleotide bitter taste inhibitor compound can also include a triglyceride. Examples of triglycerides include vegetable oils such as corn oil, sunflower oil, peanut oil, olive oil, 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 16 about 12 wt %, preferably in a range from about 0.5 wt % to about 9 wt %, of the film.

The films that contain pharmaceutical agents and a nucleotide bitter taste inhibitor compound also can include a preservative. The preservative is added 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. The pharmaceutical agent and nucleotide bitter taste inhibitor compound containing 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 is added in amounts from about 0.1 wt % to about 5 wt %, preferably from about 0.2 wt 20% to about 4.0 wt % of the film. The pharmaceutical agent and nucleotide bitter taste inhibitor compound containing 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. The active ingredient used in the film also incorporates the nucleotide compound to inhibit the bitter taste of the active ingredient or to prevent the active ingredient from numbing the tongue or other surfaces in the oral cavity. The bitter tastant inhibitors that can be used include nucleotides in the form of adenosine, inosine, guanosine, cytodine, thymidine uracyl, 5-methylcytosine, thiouracil, bromothymine, azaadenines, azaguanosine, xanthine, hypoxanthine, 8-bromoguanine, 8-cWoroguanine, 8-arninoguanine, 8- hydrazinoguanine, 8-hydroxyguanine, 8-methylguanine, 8-thioguanine, 2-aminopurine, 2,6- dianjinopurine, 5-ethylcytosine, 5-methylcytosine, 5-bromouracil, 5-iodouracil, 5-ethyluracil, 5- proluracil, 5-vinyluracil, and 5-bromovinyluracil combined with ribose or deoxyribose sugar, or derivative thereof, and contain an ionizable phosphate or similar anionic organic molecule. EXAMPLES

The invention will be illustrated in more detail with reference to the following Examples, but it should be understood that the present invention is not deemed to be limited thereto.

Preparation Method I

The procedure of Examples 1, 2, 3 4 and 5 is followed by:

A. The film-forming ingredients (e.g., xanthan gum, locust bean gum, carrageenan and pullulan) other than Polysorbate 80 and Atmos 300 are mixed and hydrated in hot purified water to form a gel and stored in a refrigerator overnight at a temperature of approximately 4.degree. C. to form preparation A.

B. The coloring agent(s), copper gluconate and sweetener are added to and dissolved in purified water to form preparation B. C. Preparation B is added to preparation A and mixed well to form preparation C.

D. The nucleotide bitter taste inhibitor compound (e.g., adenosine 5 '-monophosphate) is mixed to form preparation D.

E. The polysorbate 80 and Atmos 300 are added to preparation D and mixed well to form preparation E. F. Preparation E is added to preparation C and mixed well to form preparation F.

Preparation F is poured on a mold and cast to form a film of a desired thickness at room temperature. The film is dried under warm air and cut to a desired dimension, packaged and stored.

A composition in Examples 1-5 will be formed in accordance with the appended claims.

Preparation Method II

The procedure of Examples 6, 7, 8, 9 and 10 is followed by: A. dissolve copper gluconate, acesulfame K, aspartame, glycerin, sorbitol and dye in purified water to form an aqueous mixture;

B. mix pullulan, xanthan gum, locust bean gum and carrageenan together in powder form to form a powder mixture; C. add the powder mixture from step B to the aqueous mixture from step A to form a hydrated polymer gel;

D. stir the hydrated polymer from step C at slow speed (about 50-100 RPM) overnight at room temperature;

E. mix and dissolve the nucleotide bitter taste inhibitor compound in the flavor oil; F. add Polysorbate 80 and Atmos 300 to the oil mixture from step E;

G. add the oil mixture from step F to the hydrated polymer gel from step D and mix until uniform;

H. cast the uniform mixture from step G on a suitable backing; and I. dry the cast mixture to form a film. A composition in Examples 6-10 will be formed in accordance with the appended claims.

Example 1, 2, 3, 4 and 5.

Example 1 is a film according to the invention having a blue-green tint, a mint odor and a refreshing mint taste. Examples 2-4

Examples 2-4 contain sorbitol, glycerin or both. These examples yield products that easily break off pieces, or can be too moist and/or self-adhering. However they do produce films that rapidly dissolved in the oral cavity.

Example 5 Example 5 has no glycerin and sorbitol. The films do not stick together during processing and packaging and are moisture stable over a long time frame.

The formulas for examples 1-5 are summarized in Table 2. The amounts in these examples are presented as the actual weight (grams) or w/w %. These formulas create the solution/gel that is cast and dried into a film. The actual amount of each ingredient in the finished, dried film depends upon the amount of relative moisture removed during drying. TABLE 2

Ex. 1 2 ₃ 4 5 6 7 8 9 10

Ingredient w/w % wt(g) wt (g) wt (g) wt (g) wt (g) wt (g) wt (z) wt (g) wt (g) Adenosine 5'-monophosphatel4.2960 12.153 12.15 12.2 12.0 12.153 12.15 12.15 12.10 12.15

Xanthan Gum, Food grade 0.1070 0.0342 0.0342 0.0342 .004 .004

Xanthan Gum 1% solution 3.85 3.85 3.85 3.85

Locust Bean Gum, Clarified 0.2150 0.0684 0.0684 0.0684 0.07 0.07

Locust Bean Gum (1% solution) 7.70 7.70 7.70 7.70 Polyvinyl Pyrrolidone 16.5

Konjac Gum 5.0

Carrageenan 1.0730 0.342 0.342 0.342 0.34 0.34

Carrageenan (5% solution) 7.70 7.70 7.70 7.70

Pullulan 51.5780 16.43 16.43 16.43 11.0 Pullulan (25% solution) 74 74 74 74

Mint flavor 5.3640 2 3.0 2.664 2.344 2.664 2.664 2.664

Copper gluconate 1.1150 0.275 0.41

Purified water USP/EP 22.32 2 10.22 12.22 8.0 74.81 74.63 74.81 75 75

Sod. saccharin USP granulate2.6910 1.8 1.4 1.4 2.0

Acesulfame-K 0.444 0.444 0.444 0.45 0.45 Aspartame 1.421 1.421 1.421 1.4 1.4

Cooling agent 0.05 0.05 0.089 0.089 0.089 0.089 0.089

Maltitol 2.80

Sorbitol 70% sol. 4 4.0

Glycerin 2 2.0

Polysorbate 80 NF/EP 0.5580 0.3 0.2 0.2 0.2 0.355 0.355 0.355 0.355 0.355

Atmos 300 0.5580 0.355 0.355 0.355 0.355 0.355

Atlas 3000 0.3 0.2 0.2 0.2

FD&C Green #3 0.0084 0.3 0.3 0.3 0.3 0.0026 .0026 .0026 .0026 .0026

The following examples are films according to the second embodiment of the present invention, in which the rapidly dissolving film contains a pharmaceutical agent and a nucleotide bitter taste inhibitor compound. Examples 11-15, listed in Table 3, are medicament containing rapidly dissolvable oral film formulas. The amounts in Table 3 are in milligrams.

TABLE 3

Example Number 11 12 13 14 15

Adenosine 5 '-monophosphate 15.000 7.5000 7.5000 7.5000 7.5000

Dextromethorphan HBr 15.000 15.000 Phenylepherine HCI 10.0000

Chlorpheniramine Maleate 4 .0000

Loperamide HCI 2.0000

Nicotine 2.0000

Xanthan Gum 0.0818 0.0818 0.0818 0.0818 0.0818 Locust Bean Gum 0.0954 0.0954 0.0954 0.0954 0.0954

Carrageenan 0.4088 0.4088 0.4088 0.4088 0.4088

Pullulan 21.8036 21.8036 21.8036 21.8036 21.8036

Sodium Benzoate 0.0954 0.0954 0.0954 0.0954 0.0954

Acesulfame Potassium Salt 0.6814 Aspartame NF 1.9078 1.9078 1.9078 1.9078 1.9078

Purified Water * * * * *

Cooling agent 0.1363 0.1363 0.1363 0.1363 0.1363

Polysorbate 80 NF 0.4770 0.4770 0.4770 0.4770 0.4770

Atmos 300 0.4770 0.4770 0.4770 0.4770 0.4770 Propylene Glycol 4.0882 4.0882 4.0882 4.0882 4.0882

Olive Oil 0.6814 0.6814 0.6814 0.6814 0.6814

Titanium Dioxide 0.3407 0.3407 0.3407 0.3407 0.3407

Total Dose Weight 61.2745 48.7745 67.7745 40.7745 40.7745 *Calculated assuming complete evaporation of water from the films after drying.

While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

WE CLAIM:

1. A consumable film adapted to adhere to and dissolve in a mouth of a patient, wherein said film comprises at least one water soluble polymer and an effective amount of a nucleotide compound which contains a purine or pyrimidine group or derivative thereof which is bonded to a ribose or deoxyribose sugar moiety, or a derivative of ribose or deoxyribose and an ionizable phosphate and from 0 wt % to an effective amount of a medicament.

2. A consumable film as defined in claim 1 which contains adenosine 5'- monophosphate.

3. A consumable film as defined in claim 1 which contains inosine 5'- monophosphate

4. A consumable film as defined in claim 1 which contains adenosine 3',5'-cyclic monophosphate.

5. A consumable film as defined in claim 1 which contains guanosine 2':3'-cyclic monophosphate.

6. A consumable film as defined in claim 1 which contains guanosine 3',5'-cyclic monophosphate.

7. An oral formulation as defined in claim 1 which contains cytidine 5'- monophosphate.

8. A consumable film as defined in claim 1 which contains guanosine 2'- monophosphate.

9. A consumable film as defined in claim 1 which contains guanosine 3'- monophosphate.

10. A consumable film as defined in claim 1 which contains guanosine 5'- monophosphate.

11. A consumable film as defined in claim 1 which contains uridine 5'- monophosphate.

12. A consumable film as defined in claim 1 which contains 2'-deoxyadenosine 5'- monophosphate.

13. A consumable film as defined in claim 1 which contains 2'-deoxycytidrne 5'- monophosphate.

14. A consumable film as defined in claim 1 which contains 2'-deoxyguanosine 5'- monophosphate.

15. A consumable film as defined in claim 1 which contains 2'-deoxyadenosrne 5'- triphosphate.

16. The consumable film according to claim 1, further comprising a salt or gluconic acid.

17. The consumable film according to claim 1, further comprising copper gluconate.

18. The consumable film according to claim 1, wherein said water soluble polymer is selected from the group consisting of pullulan, hydroxyproplymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures thereof.

19. The consumable film according to claim 18, wherein said water soluble polymer is pullulan.

20. The consumable film of claim 19, comprising: about 40 to about 80 wt % pullulan; about 0.01 to about 4 wt % thymol; about 0.01 to about 4 wt % methyl salicylate; about 0.01 to about 4 wt % eucalyptol; and about 0.01 to about 15 wt % menthol.

21. The consumable film according to claim 18, further comprising: about 0.01 to about 5 wt % of at least one stabilizing agent; about 0.001 to about 0.1 wt % of at least one of at least one coloring agent; about 0.1 to about 8 wt % of water; about 0.1 to about 15 wt % of at least one sweetening agent; about 0.1 to about 15wt % of at least one flavoring agent; about 0.1 to about 4 wt % of at least one cooling agent; and about 0.1 to about 5 wt % of at least one surfactant.

22. The consumable film according to according to claim 21, wherein said at least one stabilizing agent is selected from the group consisting of xanthan gum, locust bean gum and carrageenan, and said at least one sweetening agent is selected from the group consisting of saccharin, aspartame and acesulfame K.

23. The consumable film according to claim 1, wherein said film does not substantially adhere to itself.

24. The consumable film according to claim 1, wherein said film is free of glycerin and sorbitol.

25. The consumable film according to claim 1, wherein said film is free of humectants.

26. The consumable film according to claim 1, wherein the nucleotide compound comprises at least about 1.5 to 6.5 wt % of the film.

27. The consumable film according to claim 18, wherein the nucleotide compound comprises at least about 18.5wt % of the film.

28. The consumable film according to claim 1 , further comprising water in an amount from about 3 wt % to about 8 wt %.

29. A method for preparing a physiologically compatible film, said method comprising: mixing at least one water soluble film former and at least one stabilizing agent to provide a film-forming mixture; dissolving water-soluble ingredients in water to provide an aqueous solution; combining said film-forming mixture and said aqueous solution to provide a hydrated polymer gel; mixing oils to form an oil mixture; adding said oil mixture to said hydrated polymer gel and mixing to provide a uniform gel; casting the uniform gel on a substrate; and drying the cast gel to provide said film.

30. The method according to claim 29, wherein at least one surfactant is mixed into said oil mixture.

31. The method according to claim 29, wherein the total amount of said oils in said oil mixture is at least about 5 wt % of the total weight of ingredients in said method.

32. The method according to claim 31, wherein said total amount of oils is at least about 15 wt %.

33. The method according to claim 29, wherein said drying is conducted untD said film has a moisture content of about 3 wt % to about 8 wt %.

34. The method according to claim 29, wherein, prior to being combined with said aqueous solution, said film-forming mixture is hydrated with water at a temperature of about 25 to about 50. degree. C. and subsequently chilled to a temperature of about 4 to about 30.degree. C. for about 2 to 48 hours.

35. The method according to claim 29, wherein said film-forming mixture is a powder, which is directly combined with said aqueous solution.

36. The method according to claim 35, wherein said hydrated polymer gel is formed without heating.

37. The method according to claim 36, wherein said hydrated polymer gel is stirred at room temperature for about 2 to about 48 hours.

38. A non-self-adhering film produced according to the method of claim 29.

39. The method according to claim 29, wherein the water soluble film former is selected from the group consisting of pullulan, hydroxyproplymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsrnan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures thereof.

40. The method according to claim 39, wherein said water soluble polymer is pullulan.

41. A consumable film adapted to dissolve in the mouth of a patient, wherein said film comprises a single layer including pullulan and at least one pharmaceutical agent and at least one nucleotide bitter tastant inhibitor compound.

42. The consumable film according to claim 41, wherein said pharmaceutical agent is selected from the group consisting of antimicrobial agents, non-steroidal anti- inflammatory agents, anti-tussives, decongestants, anti-histamines, expectorants, anti- diaherrals, H.sub.2-antagonists, proton pump inhibitors, central nervous system agents, analgesics, and mixtures thereof.

43. The consumable film according to claim 42, wherein the antimicrobial agent is selected from the group consisting of triclosan, cetyl pyridium chloride, domiphen bromide, quaternary ammonium salts, zinc compounds, sanguinarine, fluorides, alexidine, octonidine, EDTA and mixtures thereof.

44. The consumable film according to claim 42, wherein the non-steroidal anti- inflammatory agent is selected from the group consisting of aspirin, acetaminophen, ibuprofen, diflunisal, fenoprofen calcium, naproxen, tolmetin sodium, indomethacin, and mixtures thereof.

45. The consumable film according to claim 42, wherein the anti-tussive is selected from the group consisting of benzonatate, caramiphen edisylate, dextromethorphan hydrobromide, chlophedianol hydrochloride and mixtures thereof.

46. The consumable film according to claim 42, wherein the decongestant is selected from the group consisting of pseudoephedrine hydrochloride, phenylepherine, phenylpropanolamine and mixtures thereof.

47. The consumable film according to claim 42, wherein the anti-histamine is selected from the group consisting of brompheniramine maleate, c orpheniramine maleate, carbinoxamine maleate, clemastine fumarate, dexchioφheniramine maleate, diphei±ydramine hydrochloride, dipherωydramine citrate, diphenylpyraline hydrochloride, doxylamine succinate, promethazine hydrochloride, pyrilamine maleate, tripelennamine citrate, triprolidine hydrochloride and mixtures thereof.

48. The consumable film according to claim 42, wherein the expectorant is selected from the group consisting of guaifenesin, ipecac, potassium iodide, terpin hydrate and mixtures thereof.

49. The consumable film according to claim 42, wherein the anti-diarrheal is loperamide.

50. The consumable film according to claim 42, wherein the H.sub.2-antagonist is selected from the group consisting of famotidine, ranitidine and mixtures thereof.

51. The consumable film according to claim 42, wherein the proton pump inhibitor is selected from the group consisting of omeprazole, lansoprazole, and mixtures thereof.

52. The consumable film according to claim 42, wherein the nucleotide bitter tastant inhibitor compound is selected from the group consisting of adenosine 5'- monophosphate, inosine 5' -monophosphate, adenosine 3',5'-cyclic monophosphate, guanosine 2':3'-cyclic monophosphate, guanosine 3',5'-cyclic monophosphate, cytidine 5'- monophosphate, guanosine 2'-monophosphate, guanosine 3'-monophosphate, guanosine 5 '-monophosphate, uridine 5 '-monophosphate, 2'-deoxyadenosine 5 '-monophosphate, 2'- deoxycytidine 5'-monophosphate, 2'-deoxyguanosine 5 '-monophosphate, 2'- deoxyadenosine 5'-triphosphate or a structural homolog of adenosine 5'-monophosphate.

53. A method for delivering and enhancing the retention of an effective amount of an nucleotide bitter tastant inhibitor to the oral cavity comprising introducing in the oral cavity a rapidly dissolving film comprising pullulan and adenosine 5 '-monophosphate or a structural homolog thereof, wherein said pullulan enhances the retention of adenosine 5'-monophosphate or a structural homolog thereof in the oral cavity.

54. The method according to claim 53, wherein the nucleotide bitter tastant inhibitor compound is adenosine 5 '-monophosphate or a structural homolog thereof.

55. The method according to claim 53, wherein the amount of pullulan in the film is from about 40 wt % to about 80 wt %.

56. The method according to claim 53, wherein the amount of adenosine 5'- monophosphate or a structural homolog thereof is from about 2.5 wt % to about 47.5 wt %.

57. The method according to claim 53, wherein the amount of adenosine 5'- monophosphate or a structural homolog thereof is from about 2.5 wt % to about 12.5 wt %.

58. A method for delivering and enhancing the retention of an effective amount of a nucleotide bitter tastant compound to the oral cavity comprising introducing in the oral cavity the consumable film according to claim 18.

Data for nucleotides blocking bitter taste of compounds

Water Dex Dex + AMP

Figure 1 : Adenosine 5'-monophosphate decreases aversiveness of dextromethorphan to mice.

Doxylamine Concentration (m )

Figure 2: Adenosine 5'-monophosphate decreases doxylamine induced taste membrane activation of G protein in vitro.

2.5 5 10 100 1000 2500 concentration of nucleotide (μmol/L)

Figure 3: Adenosine 5'-monophosphate, cytidine 5'-monophosphate, 2-deoxyadenosine 5 monophosphate and guanosine 5'-monophosphate all decrease the intensity of bitter tasti elicited by quinine in human sensory testing.

Definitions of nucleotides: the hydrolysis product of a nucleic acid, consisting of a purine or pyrimidine base combined with a ribose or deoxyribose sugar and with a phosphate group; a phosphate ester of a nucleoside. 5

Nucleotides are nitrogen-containing molecules which link together to form strands of DNA and RNA.

A. Nucleotides

1. Definition

a. Nucleoside + phosphate(s)

b. Deoxynucleotide

1. Contains deoxyribose

c. Ribonucleotide

1. Contains ribose

2. Nucleotide monophosphates

a. Nucleoside plus one phosphate

3. Nucleotide diphosphates

a. Nucleoside plus two phosphates

4. Nucleotide triphosphates

a. Nucleoside plus three phosphates

31 b. Ribonucleotide triphosphates often used to drive endergonic reactions

c. Only the nucleoside triphosphates can be used to make nucleic acids

1. Cleavage of phosphates provides energy to drive nucleic acid synthesis

I. NUCLEOTIDES

A. Pentose sugars

1. Types

a. Ribose and Deoxyribose

1. Deoxyribose replaces the 2-hydroxyl group found in RNA with a hydrogen

2. Numbering of carbons

a. Both ribose and deoxyribose are pentose sugars

b. Carbons are numbered 1' - 5'

1. These are primed numbers so as not to confuse them with the ordinary numbers used to label the nitrogenous bases

2. 1' carbon is bound to the base via an n-glycosidic bond

3. 3' carbon is bound to phosphate of adjacent nucleotide

4. 5' carbon is bound to phosphate in its nucleotide

B. Bases

32

1. Guanine, Adenine, Thymine, Uracil, and Cytosine

a. Uracil found in RNA only; thymine is found in DNA only

b. Adenine and guanine are purines

1. Having two ring structures

2. Base pairings

a. Purines always pairs with pyrimidines (equal amounts)

1. Thymine - Adenine

a. 2 hydrogen bonds

b. A - U bonds may form in RNA

2. Cytosine - Guanine

a. 3 hydrogen bonds

b. Denaturation studies estimate the G + C content

3. Bases have hydrophobic ring structures

a. This causes them to stack up on one another, instead of facing out into the aqueous medium

C. Phosphate

1. Nucleotide triphosphates are the building blocks for nucleic acids

a. Two phosphates are cleaved during synthesis, the released energy used to form the phosphodiester bonds between bases

2. Phosphate is negatively charged giving DNA an overall negative charge

33 A nucleotide unit is the repeating unit of a polynucleotide chain; it comprises three distinct parts: the D-ribose or 2-deoxy-D-ribose (2-deoxy-D-eryt/zropentose) sugar ring, the phosphate group, and the purine or pyrimidine base. The sugar ring and the phosphate group form the backbone of the polynucleotide chain; the base ring linked to the sugar residue consitutes the side chain.

A nucleotide unit is defined by the sequence of atoms from the phosphorus atom at the 5'- end to the oxygen atom at the 3'-end of the pentose sugar; it includes all atoms of the sugar and base rings.

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