WO2004019885A2 - Delivrance sous forme de film a dissolution rapide de nucleotides inhibant le gout desagreable de medicaments au gout amer - Google Patents

Delivrance sous forme de film a dissolution rapide de nucleotides inhibant le gout desagreable de medicaments au gout amer Download PDF

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Publication number
WO2004019885A2
WO2004019885A2 PCT/US2003/027111 US0327111W WO2004019885A2 WO 2004019885 A2 WO2004019885 A2 WO 2004019885A2 US 0327111 W US0327111 W US 0327111W WO 2004019885 A2 WO2004019885 A2 WO 2004019885A2
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WO
WIPO (PCT)
Prior art keywords
monophosphate
film
consumable film
nucleotide
consumable
Prior art date
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PCT/US2003/027111
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English (en)
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WO2004019885A3 (fr
Inventor
Richard Alexander Mcgregor
Harvey Donald Homan
Stephen Anthony Gravina
Original Assignee
Linguagen Corp.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Linguagen Corp. filed Critical Linguagen Corp.
Priority to AU2003268262A priority Critical patent/AU2003268262A1/en
Publication of WO2004019885A2 publication Critical patent/WO2004019885A2/fr
Publication of WO2004019885A3 publication Critical patent/WO2004019885A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015—Devices specially adapted for taking medicines
    • A61J7/0046—Cups, bottles or bags
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/70—Fixation, conservation, or encapsulation of flavouring agents
    • A23L27/79—Fixation, conservation, or encapsulation of flavouring agents in the form of films
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/86—Addition of bitterness inhibitors
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/13—Nucleic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015—Devices specially adapted for taking medicines
    • A61J7/0061—Swallow helping devices, e.g. tongue shields
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0092—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine for holding medicines in, or fixing medicines on, a tooth, e.g. holder containing medicines fixed on a tooth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • 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.
  • 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. 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.
  • 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.
  • bitter 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
  • 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.
  • 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.
  • 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".
  • 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.
  • medicament includes orally administrable pharmacologically active materials which are used in an amount which delivers a conventional oral dose of the medicament.
  • 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.
  • FIG. 1 is data for the bitter taste inhibitor adenosine 5'-mono ⁇ hosphate 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.
  • 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.
  • 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.
  • 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 %.
  • 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.
  • 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.
  • 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.
  • a nonstick agent e.g., a plastic film, paper or other support
  • 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.:
  • 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;
  • 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;
  • soluble saccharin salts i.e., sodium or calcium saccharin salts, cyclamate salts
  • 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.
  • 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).
  • 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
  • sweeteners need not be added to films intended for non-oral adnjinistration.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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].
  • 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,
  • 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.
  • 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-cWoroguar ⁇ ine, 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
  • 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.
  • 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.
  • 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 ⁇ -subunit of heterolximeric G proteins. Thus, transducin activation by bitter stimulated taste membranes may be measured by uptake of GTP.
  • G proteins have an intrinsic GTPase activity, which terminates the activation cycle
  • a radioactive nonhydrolyzable analogue of GTR such as [ 35 S] GTP ⁇ S or [ 3 H] GppNHp must be used.
  • nucleotide compounds To test for the inhibitory activity of nucleotide compounds, several modifications of the standard [ 35 S] GTP ⁇ S 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:GTP ⁇ S ratios, buffer composition, and specific activity of the [ 35 S] GTP ⁇ S were adjusted. Ruiz-Avila et al.
  • 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 [ 35 S] GTP ⁇ S binding assay mix are 10 mM HEPES pH 7.5, 5 mM MgCl 2 , 50 mM NaCl, 1 mM dithiolthreitol, 10 ⁇ M GDP, 1 ⁇ M [ 35 S] GTP ⁇ S (O.l ⁇ Ci/sample), 0.5 ⁇ g/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 5 ⁇ g/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).
  • 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.
  • 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.
  • nucleotide 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.
  • 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.
  • 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.
  • 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.
  • sodium saccharin and copper gluconate are both ingredients in the formulation, it is preferable to dissolve them separately in solution to avoid precipitation.
  • 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.
  • local heating effects, generated in the shear regions provide energy for hydration without substantially raising the temperature of the mass.
  • 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.
  • 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.
  • 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:
  • antimicrobial agents such as triclosan, cetyl pyridium chloride, domiphen bromide, quaternary ammonium salts, zinc compounds, sanguinarine, fluorides, alexidine, octonidine, EDTA, and the like,
  • 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
  • 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.
  • the ingredients used to make the pharmaceutical containing films are similar to those used to make nucleotide bitter taste inhibitor compound films.
  • 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.
  • 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.
  • 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
  • the film-forming ingredients e.g., xanthan gum, locust bean gum, carrageenan and pullulan
  • 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.
  • preparation B The coloring agent(s), copper gluconate and sweetener are added to and dissolved in purified water to form preparation B.
  • Preparation B is added to preparation A and mixed well to form preparation C.
  • the nucleotide bitter taste inhibitor compound e.g., adenosine 5 '-monophosphate
  • the nucleotide bitter taste inhibitor compound is mixed to form preparation D.
  • preparation E The polysorbate 80 and Atmos 300 are added to preparation D and mixed well to form preparation E.
  • 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.
  • step 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;
  • step 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;
  • step G add the oil mixture from step F to the hydrated polymer gel from step D and mix until uniform;
  • 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 are 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 has no glycerin and sorbitol. The films do not stick together during processing and packaging and are moisture stable over a long time frame.
  • 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.

Abstract

La présente invention a trait à des films physiologiquement acceptables, y compris des films comestibles. Ces films comprennent un polymère filmogène hydrosoluble tel que le pullulane. L'invention a trait à des films comestibles comprenant du pullulane et une quantité efficace d'un ou de plusieurs composés nucléotidiques qui contient un groupe purique ou pyrimidique ou un dérivé de ceux-ci qui inhibent l'activation de la perception sensorielle de la protéine G du goût amer de médicaments au goût amer.
PCT/US2003/027111 2002-08-29 2003-08-28 Delivrance sous forme de film a dissolution rapide de nucleotides inhibant le gout desagreable de medicaments au gout amer WO2004019885A2 (fr)

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US40671602P 2002-08-29 2002-08-29
US60/406,716 2002-08-29

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Cited By (14)

* Cited by examiner, † Cited by third party
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WO2007033064A1 (fr) * 2005-09-13 2007-03-22 Mcneil Nutritionals, Llc Procedes et compositions permettant d'ameliorer la sapidite d'aliments
WO2008108940A1 (fr) * 2007-03-05 2008-09-12 Mcneil-Ppc, Inc. Préparation de film se dissolvant/désintégrant rapidement, qui présente une proportion élevée d'agent actif
EP2701534A1 (fr) * 2011-04-28 2014-03-05 ACME Specialty Products, LLC Compositions de masquage du goût et leurs formes comestibles
EP2793858A4 (fr) * 2011-12-19 2015-09-02 Kimberly Clark Co Compositions naturelles, à libération multiple et réutilisables
CN105193769A (zh) * 2015-09-06 2015-12-30 合肥华方医药科技有限公司 一种盐酸苯海拉明口腔速溶膜剂的制备方法
US9648874B2 (en) 2010-12-07 2017-05-16 Kimberly-Clark Worldwide, Inc. Natural, multiple use and re-use, user saturated wipes
US9789112B2 (en) 2010-10-28 2017-10-17 Hexal Ag Oral pharmaceutical film formulation for bitter tasting drugs
WO2018175261A1 (fr) 2017-03-20 2018-09-27 Bayer Healthcare Llc Produits de gel à mâcher pour principes actifs pharmaceutiques
US10098376B2 (en) 2003-11-07 2018-10-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
WO2019033149A1 (fr) * 2017-08-16 2019-02-21 Sci-Chem International Pty Ltd Compositions de traitement d'infections de membranes de la peau et des muqueuses
RU2729028C2 (ru) * 2014-08-27 2020-08-03 Нитто Денко Корпорейшн Пероральные основа и препарат в форме пленки
WO2020226889A1 (fr) * 2019-05-07 2020-11-12 Wellstat Therapeutics Corporation Formulations d'uridine triacétate dans de la triacétine
US10945454B2 (en) 2003-11-07 2021-03-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
WO2022106923A1 (fr) 2020-11-18 2022-05-27 BioPharma Synergies, S. L. Composition de poudre orodispersible comprenant un composé antihistaminique

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US5518902A (en) * 1992-08-20 1996-05-21 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo High pullulan content product, and its preparation and uses

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US5518902A (en) * 1992-08-20 1996-05-21 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo High pullulan content product, and its preparation and uses

Cited By (21)

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US10765140B2 (en) 2003-11-07 2020-09-08 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10945454B2 (en) 2003-11-07 2021-03-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
US10098376B2 (en) 2003-11-07 2018-10-16 U.S. Smokeless Tobacco Company Llc Tobacco compositions
WO2007033064A1 (fr) * 2005-09-13 2007-03-22 Mcneil Nutritionals, Llc Procedes et compositions permettant d'ameliorer la sapidite d'aliments
WO2008108940A1 (fr) * 2007-03-05 2008-09-12 Mcneil-Ppc, Inc. Préparation de film se dissolvant/désintégrant rapidement, qui présente une proportion élevée d'agent actif
EP2444076A1 (fr) * 2007-03-05 2012-04-25 McNeil-PPC, Inc. Préparation de film se dissolvant/désintégrant rapidement, qui présente une proportion élevée d'agent actif
AU2008223583B2 (en) * 2007-03-05 2013-08-15 Mcneil-Ppc, Inc. Fast-dissolving/disintegrating film preparation having high proportion of active
US9789112B2 (en) 2010-10-28 2017-10-17 Hexal Ag Oral pharmaceutical film formulation for bitter tasting drugs
US9648874B2 (en) 2010-12-07 2017-05-16 Kimberly-Clark Worldwide, Inc. Natural, multiple use and re-use, user saturated wipes
US9764168B2 (en) 2011-04-28 2017-09-19 Acme Specialty Products, Llc Taste masking compositions and edible forms thereof
EP2701534A1 (fr) * 2011-04-28 2014-03-05 ACME Specialty Products, LLC Compositions de masquage du goût et leurs formes comestibles
EP2793858A4 (fr) * 2011-12-19 2015-09-02 Kimberly Clark Co Compositions naturelles, à libération multiple et réutilisables
RU2729028C2 (ru) * 2014-08-27 2020-08-03 Нитто Денко Корпорейшн Пероральные основа и препарат в форме пленки
CN105193769A (zh) * 2015-09-06 2015-12-30 合肥华方医药科技有限公司 一种盐酸苯海拉明口腔速溶膜剂的制备方法
WO2018175261A1 (fr) 2017-03-20 2018-09-27 Bayer Healthcare Llc Produits de gel à mâcher pour principes actifs pharmaceutiques
EP3599892A4 (fr) * 2017-03-20 2020-09-02 Bayer Healthcare LLC Produits de gel à mâcher pour principes actifs pharmaceutiques
US10537519B2 (en) 2017-08-16 2020-01-21 Sci-Chem International Pty Ltd Compositions for treating infections
WO2019033149A1 (fr) * 2017-08-16 2019-02-21 Sci-Chem International Pty Ltd Compositions de traitement d'infections de membranes de la peau et des muqueuses
US11510866B2 (en) 2017-08-16 2022-11-29 Sci-Chem International Pty Ltd Compositions for treating infections
WO2020226889A1 (fr) * 2019-05-07 2020-11-12 Wellstat Therapeutics Corporation Formulations d'uridine triacétate dans de la triacétine
WO2022106923A1 (fr) 2020-11-18 2022-05-27 BioPharma Synergies, S. L. Composition de poudre orodispersible comprenant un composé antihistaminique

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