Classifications

• • 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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent
• • 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
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

• the present invention relates to a good tasting, nonrupturable, fast dissolving, taste masking compositions that provide immediate release of pharmaceutically acceptable active ingredients.
• Taste masking of pharmaceutically active ingredients is easily effected by creating structural matrices with or covering such products with various types of "taste masking" agents.
• Prior art examples include Polymeric polycarboxylates (U.S. Patent 4.971.7911 clay silicates (U.S. Patent 3.140.978) and natural or polysaccharide gums (TJ.S. Patent 5.288.500V
• the effervescent system will usually comprise an acidifying agent and a carbonate containing material which upon addition of an aqueous liquid bursts into a vigorous effervescence.
• Effervescent technology is further described in chapter 6 of Phar ⁇ maceutical Dosage Forms: Tablets. Vol. I, 2 n ⁇ - ed., A Lieberman ed., 1989, Marcel Dekker, Inc. which is herein incorporated by reference.
• Examples of such effervescent compositions include U.S. Patent 3.882.228 to Boncey et al., which discloses preparing wettable aspirin particles.
• the aspirin particles are coated in a spray drying process with a mixture of a water soluble coating material, a wetting agent, and/or a water soluble film forming agent.
• the coated aspirin particles are then incorporated into effervescent tablets. See also U.S. Patent 4.687.662 to Schobel, which discloses a therapeutic fast dissolving effervescent composition.
• the composition is prepared by admixing a granulated therapeutic agent having a predetermined particle size to an effervescent system having roughly the same particle size.
• Effervescent compositions providing a controlled release include U.S. Patent 4.940.588 to Sparks et al., which discloses a controlled release powder which comprises discreet microparticles ("pharmasomes") composed of an pharmacologic active and at least one nontoxic polymer in the form of a micromatrix, and also U.S. Patent 5.055.306 to Barry et al., which discloses a sustained release effervescent composition.
• the composition of Barry et al. is prepared by compressing granules coated with a water insoluble, yet water swellable acrylic polymer and a water soluble hydroxylated cellulose derivative together with an effervescent system to form effervescent tablets.
• Both Sparks et al. and Barry et al. describe their compositions as resisting breakage (i.e., nonrupturable).
• U.S. Patent 5.178.878. to Wehling et al. discloses effervescent dosage forms comprising microparticles.
• the composition is composed of microparticles substan ⁇ tially encompassed and, or in the alternative, formed into a matrix with a protective polymer.
• the polymeric substances of the invention added to enhance the taste- masking properties of the effervescent system.
• the microparticles are described as "rupturable” as opposed to the “nonrupturable” particles of Sparks et al. and Barry et al.
• a nonrupturable drug matrix comprising: i) a taste masking agent; and ii) a safe and effective amount of a pharmaceutically active in ⁇ gredient; and (b) an orally acceptable pharmaceutical carrier wherein said pharmaceutically acceptable carrier is rapidly disintegrated in aqueous solution without the need for mastication and wherein said composition provides an immediate release of the pharmaceutically active ingredient.
• the present invention further relates to methods of treating symptoms of respiratory illnesses such as those associated with the cough, cold, cold-like, allergy and/or flu symptoms as well as gastrointestinal disorders, comprising the administra ⁇ tion of a safe and effective amount of the compositions of the present invention.
• safety and effective amount is an amount that is effective to mitigate and/or treat the symptoms for which the active ingredient is indicated in a human without undue adverse side effects commensurate with a reasonable risk/'benefit ratio.
• nonrupturable means an ability to withstand those forces commonly associated with the chewing process (i.e. direct compression forces ranging from about above 4 Kilograms to about 5.6 Kilograms).
• immediate release is meant that at least about 75 % of said pharmaceutical ingredient is released within 45 minutes after administration.
• rapidly disintegrating is meant that the shaped particles are disintegrated in water within 30 seconds. Preferably the shaped particle disintegrates (dissolves or disperses) within 10 seconds or less. Procedures for measuring disintegration time are described in U.S. Patent 4.371.516 to Gregory et al. which is herein incorporated by reference.
• compositions of the present invention contain essential components as well as various nonessential components as indicated below.
• ESSENTIAL COMPONENTS ' Taste Masking Agent The first essential component of the present invention is a safe and effective amount of a taste masking agent.
• Taste masking agents suitable for the present invention include those substances effective at masking the untoward taste(s) of comestible compounds and which will form a nonrupturable matrix when combined with a pharmaceutical active.
• the taste masking agent may be incorporated to substantially encompass the pharmaceutically active ingredient.
• substantially encompassing as used herein means that the taste masking agent substantially shields the pharmaceutically active ingredient from contact with the environment outside the active. Alternatively and/or additionally, the pharmaceutically active ingredient may be dispersed or dissolved within the taste masking agent to form the drug matrix compositions. Suitable taste masking agents are described below.
• Silicate clays are useful taste masking agents. Examples of such clays which include using magnesium trisilicate are describe in U.S. Patent 3.085.942 to Clifton et al., April 16, 1963; and U.S. Patents 4.581.232. April 8, 1966; 4.632.821. December 30, 1986; 4.632.822. December 30, 1986; 4.623.823. December 30, 1986; 4.462.231. February 10, 1987; 4.643.898. February 17, 1987; 4.643.892. February 17, 1987; 4.647.449. March 3, 1987; 4.647.450. March 3, 1987; 4.647.459. March 3, 1987; 4.649.041. March 19, 1987; 4.650.663. March 17, 1987 to Peters et al. all of which are herein incorporated by reference.
• acrylic polymer resins are useful taste masking agents and suitable for use in the present invention.
• the use acrylic polymer resins in this capacity has been disclosed in, for example, U.S. Patent 4.940.588. U.S. Patent 4.971.791. U.S. Patent 5.055.306 and U.S. Patent 5.178.878 and are herein incorpo- rated by reference.
• Natural gums such as gum karaya, gum arabic, and gum tragacanth and polysaccharide gums such as xanthan gum may also be used as the taste masking agent of the present invention.
• Gums useful to the present invention are further described in U.S. Patent 5.288.500 herein incorporated by reference.
• Waxes suitable for use as taste masking agents in the present invention include mono- or di-glycerrides, carnauba wax and paraffin wax. A particularly useful example of such taste masking waxes appears in the encapsulated, "micro- sponge” technology marketed by Particle Dynamics under the tradename Descote®.
• Pharmaceutically acceptable actives useful in the present invention may be selected from among the various groups of chemical compounds or materials suitable for oral administration and having a pharmacological action. These pharmaceutically acceptable active compounds or materials should be compatible with the other essential ingredients and compatible in combination with other included active materials or compounds.
• the pharmaceuti ⁇ cally acceptable active compounds or materials are present at a level from about 0.01% to about 90%, preferably from about 0.1% to about 75%, more preferably from about 1.0% to about 50% and most preferably from about 1.0% to about 25%.
• Useful pharmaceutically acceptable active materials or compounds may include, but are not limited to: bronchodilators, anorexiants, antihistamines, nutritional supple ⁇ ments (such as vitamins, minerals, fatty acids, amino acids, and the like), laxatives, analgesics, antacids, H2-receptor antagonists, antidiarrheals, decongestants, anti- tussives, antinauseants, antimicrobials, antifungals, antivirals, expectorants, anti- inflammatory agents, antipyretics, their pharmaceutically acceptable salts and mixtures thereof.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including, but not limited to: inorganic bases and organic bases. Salts derived from inorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganic salts and the like.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, tertiary and quaternary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, polyamine resins and the like.
• basic ion exchange resins such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine
• decongestants useful in the compositions of the present inven ⁇ tion include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof.
• antitussives useful in the compositions of the present invention include dextromethorphan, chlopedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, their pharmaceutically ac ⁇ ceptable salts, and mixtures thereof.
• expectorants also known as mucolytic agents
• examples of expectorants useful in the pre ⁇ sent invention include: guaifenesin, terpin hydrate, ammonium chloride, N- acetylcysteine, and ambroxol, their pharmaceutically acceptable salts, and mixtures thereof.
• analgesics useful in the present invention include; morphine, co ⁇ characteristic, meperidine, pentazocine, propoxyphene, acetaminophen, allopurinol, acetyl- salicylic acid, choline salicylate, ketoprofen, magnesium silicate, fenoprofen, ibupro- fen, indomethacin, naproxen, and many others and their pharmaceutically acceptable salts and mixtures thereof.
• antihistamines useful in the present invention include; brom- pheniramine, chlorpheniramine, clemastine, dexchlorpheniramine, diphenhydramine, doxylamine, promethazine, terfenadine, triprolidine and many others and their phar ⁇ maceutically acceptable salts and mixtures thereof.
• gastrointestinal agents suitable for use in the present invention include anticholinergics, including atropine, clidinium and dicyclomine; antacids, in- eluding aluminum hydroxide, bismuth subsalicylate, calcium carbonate and magaldrate; H2-receptor antagonists including: cimetidine, famotidine, nizatidine and ranitidine; laxatives, including: phenolphthalein and casanthrol; and antidiarrheals including: diphenoxylate and loperamide.
• anticholinergics including atropine, clidinium and dicyclomine
• antacids in- eluding aluminum hydroxide, bismuth subsalicylate, calcium carbonate and magaldrate
• H2-receptor antagonists including: cimetidine, famotidine, nizatidine and ranitidine
• laxatives including: phenolphthalein and casanthrol
• antidiarrheals including: di
• analgesics decongestants, antitussives, expecto- rants and antihistamines as well as bronchodilators, anorexiants, laxatives, antiemet- ics, antimicrobials, antibacterials, antifungals, anti-inflammatory agents, antivirals, antipyretics, nutritional supplements, anticholinergics, antacids, H2-receptor antago ⁇ nists, antidiarrheals and other miscellaneous gastrointestinal compounds and their ac ⁇ ceptable dosage ranges are described in Remington's Pharmaceutical Sciences, pp.
• Nonessential components include, but are not limited to: coloring agents; flavoring agents, including: vanilla, cherry, grape, orange, peppermint, spearmint, anise, blueberry raspberry, banana, chocolate, caramel, strawberry, lemon, lime, menthol and ProsweetTM MM50 (a combination of natural and artificial flavors and propylene glycol, available from Virginia Dare Extract Co., Inc., Brooklyn, NY); sweeteners, including saccharin, dextrose, levulose, sucrose, cyclamate, mannitol and aspartate, along with many others; suspending agents, including xanthum gum, acacia gum, carboxymethylcellulose, starch and methylcellulose; preservatives; releasing agents, including polysorbate 80, sodium lauryl sulfate, vegetable oils and magnesium stearate; and water.
• coloring agents including: vanilla, cherry, grape, orange, peppermint, spearmint, anise, blueberry raspberry, banana, chocolate, caramel, strawberry, lemon, lime, menthol and Prosweet
• Another preferred nonessential component of the present invention is a cool ⁇ ing agent or a combination of cooling agents.
• Suitable cooling agents are those des- cribed in U.S. Patent 4.136.163. January 23, 1979, to Watson et al., U.S. Patent 4.230.688. October 28, 1980, to Rowsell et al. and U.S. Patent 4.032.661. to Rowsell et al., all of which are herein incorporated by reference.
• Particularly pre ⁇ ferred cooling agents include N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by Sterling Organics) taught by the above incorporated U.S.
• Patent 4.136.163 and N,2,3-trimethyl-2-isopropylbutanamide which is commercially available as WS-23 from Wilkinson Sword Limited and taught by the above incorporated U.S. Patent 4.230.688.
• Another particularly preferred cooling agent is 3-1-menthoxypropane 1,2-diol (TK-10 supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan). This material is described in detail in U.S. Patent 4.459.425. July 10, 1984 to Amano et al. and incorporated herein by reference.
• Good tasting pharmaceutical adsorbate compositions of the present invention are prepared using art-recognized principles and methodologies in mixing the ingre ⁇ washers together and in choosing the type of mixing equipment to be used.
• multiply charged cationic drugs means compounds containing more than one posi ⁇ tively charged substituent.
• the crucial steps involve maintaining the pH in a range equal to that of the pKa of the multiply charged cationic drug(s) and, additionally, reserving the addition of said multiply charged cationic drug(s) until after the addition of at least one other cationic compound.
• compositions incorporating alternative taste masking agents are similarly prepared using art-recognized principles and method- ologies. A more detailed description of these preparation processes are disclosed in the examples listed below.
• the matrix of the present invention is formed, it is incorporated into an orally acceptable pharmaceutical carrier which rapidly disintegrates in aqueous solutions.
• Suitable carriers can incorporate effervescent or other water-dispersible substances and dried into dosage forms that rapidly disintegrate upon coming into contact with an aqueous liquid.
• Suitable effervescent technology is described in Chapter 6 of Pharmaceutical Dosage Forms: Tablets. Vol. I, 2 n - ed., A Lieberman ed., 1989, Marcel Dekker, Inc. herein incorporated by reference.
• the above men- tioned compositions may be formed by using any of a multitude of solid dosage forming techniques and equipment. Methods of solid dosage formulation are well known in the art and any appropriate method may be utilized.
• compositions of the present invention may be achieved by incorporating the matrix into a freeze dried form. Freeze-drying or lyophilization facilitates disintegration of the composition by forming the dried composition into an open matrix network. In most cases, this results in rapid permeation by the aqueous media, promoting timely delivery of the product's active ingredients.
• Suitable meth- ods of freeze drying are well known in the art and commonly employed. Any suitable conventional method of freeze-drying may be utilized.
• a preferable method of freezing and drying is to fast freeze the composition and then dry the composition to a final moisture content of about 2% to about 5%.
• Suitable methods of freeze-drying and production are taught by U.S. Patent 4.642.903. February 17, 1987, to Davies, U.S. Patent 4.946.684. August 7, 1990, to Blank et al., U.S. Patents 4.305.502 and 4.371.516 . issued December 15, 1981 and February 1, 1983 respectively, to Gregory et al., and U.S. Patent 5.188.825. February 23,1993, to lies et al.; which are all in ⁇ corporated herein by reference.
• compositions of the present invention may be vacuum dried.
• Vacuum drying involves at least the partial drying of compositions at temperatures above compositions' collapse temperature.
• Freeze drying involves the drying of compositions at temperatures below the compositions; collapse temperature. Any suitable method of vacuum drying may be used. Suitable vacuum drying processes are described in U.S. Patent 5.298.261. to Pebley et al., issued March 29, 1994, herein incorporated by reference.
• fast dissolving technology is a liquid/liquid extract developed by Janssen Pharmaceutica Inc. and is identified by the trade name QuicksolvTM. This technology is fully described in U.S. Patent 5.215.756 herein incorporated by reference.
• LightninTM mixer (model #TS2010 (or a high shear homogenizer set at 30 to 50 RPM)) mixing at approximately 250 to 1000 RPM, add the following agents allowing each to dissolve before adding the next: water (add a sufficient amount of water to thoroughly wet chlorpheniramine maleate and xanthum gum for mixing; water will be driven off via drying), chlorpheniramine maleate, xanthum gum. Mix vigorously (250 to 1000 RPM) for 45 minutes. Dry mixture in 45 °C oven for 12 hours or until mixture is dry and water is driven off. Grind dry mixture to a particle size suitable for compressing.
• LightninTM mixer (model #TS2010 (or a high shear homogenizer set at 30 to 50 RPM)) mixing at approximately 250 to 1000 RPM, add the following agents allowing each to dissolve before adding the next: water (add a sufficient amount of water to thoroughly wet dextromethorphan HBr and methyl methacrylic copolymer for mixing; water will be driven off via drying), dextromethorphan HBr, methyl methacrylic copolymer. Mix vigorously (250 to 1000 RPM) for 45 minutes. Dry mixture in 45 °C oven for 12 hours or until mixture is dry and water is driven off. Grind dry mixture to a particle size suitable for compressing.
• Dry blend via conventional blending methods (e.g., V- blender) the dextrome ⁇ thorphan HBr and methyl methacrylic copolymer pre-complex with magnesium stearate, compressible sorbitol, silicone dioxide, citric acid anhydrous, pretreated sodium bicarbonate and lemon/lime flavor.
• V- blender conventional blending methods
• EXAMPLE III Ingredients W ⁇ V% citric acid, anhydrous, fine 6.25000 sodium bicarbonate, pretreated 1 18.75000 magnesium aluminum silicate 2 42.00000 pseudoephedrine HCl 6.00000 chlorpheniramine maleate 0.40000 methyl salicylate 0.20000 magnesium stearate 0.50000 menthol 0.50000
• N-ethyl-p-menthane-3-carboxamide ⁇ 0.08000 monoammonium glycyrrhizate ⁇ 0.06000 sodium saccharin 0.05000 silicone dioxide 5 0.50000 vanilla creme 0.03000 mannitol 23.18000 Pretreating is performed by heating overnight in a forced air oven (Despatch, Model # LDB-l-23) at 66 °C.
• Magnasweet® 185 supplied by McAndrews & Forbes, Camden, NJ.
• Examples IV -VI are further examples of combinations used in treating the symptoms of gastrointestinal illnesses in humans and are manufactured in a manner substantially similar to Example III. Administration of two tablets is the normal and customary dosage.

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  • 1995-05-31 JP JP8501157A patent/JPH10501235A/ja not_active Ceased
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  • 1995-05-31 BR BR9507909A patent/BR9507909A/pt not_active Application Discontinuation
  • 1995-05-31 EP EP95921526A patent/EP0762869A1/de not_active Ceased
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