WO1995033446A1 - Fast dissolving dosage forms - Google Patents

Fast dissolving dosage forms Download PDF

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Publication number
WO1995033446A1
WO1995033446A1 PCT/US1995/006855 US9506855W WO9533446A1 WO 1995033446 A1 WO1995033446 A1 WO 1995033446A1 US 9506855 W US9506855 W US 9506855W WO 9533446 A1 WO9533446 A1 WO 9533446A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
agent
mixtures
pharmaceutical
Prior art date
Application number
PCT/US1995/006855
Other languages
French (fr)
Inventor
Michelle Elizabeth Brideau
Original Assignee
The Procter & Gamble Company
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 The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to BR9507909A priority Critical patent/BR9507909A/en
Priority to EP95921526A priority patent/EP0762869A1/en
Priority to JP8501157A priority patent/JPH10501235A/en
Priority to MX9606041A priority patent/MX9606041A/en
Publication of WO1995033446A1 publication Critical patent/WO1995033446A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007Effervescent
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0053Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056Mouth 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2095Tabletting 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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Abstract

A nonrupturable, fast dissolving, taste masking composition providing immediate release of pharmaceutically acceptable active ingredients.

Description

FAST DISSOLVING DOSAGE FORMS
TECHNICAL FIELD The present invention relates to a good tasting, nonrupturable, fast dissolving, taste masking compositions that provide immediate release of pharmaceutically acceptable active ingredients.
BACKGROUND OF THE INVENTION A topic of which many physicians and pharmacists are keenly aware concerns the notion of patient compliance. The concern focuses on how to maintain or increase compliance with prescribed regimens. A major obstacle with regard to medication compliance relates to the patient's unwillingness or inability to swallow traditional solid dosage forms. Recognizing the problem, manufacturers strive to introduce novel formulations geared at revolutionizing solid dosage form technology and meeting this common need.
One approach has focused on taste masking technology. 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
One other approach pursued by a number of pharmaceutical manufacturers to improve patient compliance concerns the use of "quick dissolving" technology. Several methods of accomplishing this form of technology have been disclosed in, for example, U.S. Patent 4.642.903. U.S. Patent 4.946.684. U.S. Patent 4.305.502. U.S. Patent 4.371.516. U.S. Patent 5.188.825. U.S. Patent 5.215.756 and U.S. Patent 5.298.261. The use of effervescent compositions is a particularly well known means of accomplishing rapid carrier dissolution. Effervescent compositions are prepared by admixing active ingredients together with an appropriate effervescent system. 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, 2n<- 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.
While the prior art discloses various compositions useful in masking taste and facilitating the dissolution of carriers containing pharmacologically active com¬ pounds, there is still a need for improved, rapidly dissolving, immediate release, taste masked pharmaceutical compositions. Prior art disclosures in this field which relate to immediate release compositions have not directed their attention to forming a nonrupturable matrix between the taste masking agent and the pharmaceutically active compounds. Incorporating such a matrix provides reliable taste masking since it is not easily ruptured (e.g. by chewing) so as to free the bitter tasting actives from the matrix. Moreover, the pharmaceutical compositions maintain their immediate release profile. It is therefore an object of the present invention to provide a good- tasting, immediate release composition. It is a further object of the present invention to provide a nonrupturable, rapidly dissolving composition, incorporating pharma¬ ceutical actives. Still a further object is to provide a method of making a good tasting, rapidly dissolving medicament containing pharmaceutical actives. These objectives and additional objectives will become readily apparent from the detailed description which follows.
SUMMARY OF THE INVENTION The present invention relates to an oral pharmaceutical composition comprising:
(a) 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.
All percentages and ratios herein are by weight unless otherwise specified. Additionally, all measurements are made at 25°C unless otherwise specified. By "safe and effective amount," as used herein, 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.
By "nonrupturable," as used herein, 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).
By "immediate release" as used herein, is meant that at least about 75 % of said pharmaceutical ingredient is released within 45 minutes after administration.
By "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.
DETAILED DESCRIPTION OF THE INVENTION The 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. The term "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. Further examples using magnesium aluminum silicates are described in U.S. Patent 4.761.274. August 2, 1988, to Denick, Jr. et al.; U.S. Patent 4.753.800. June 28, 1988, to Mozda, and U.S. Patent 3.140.978. July 14, 1964 to Zentner; all of which are herein incorporated by reference.
Additionally, 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. 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.
The term "pharmaceutically acceptable 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.
Examples of decongestants useful in the compositions of the present inven¬ tion include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof.
Examples of 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. Examples of expectorants (also known as mucolytic agents) useful in the pre¬ sent invention include: guaifenesin, terpin hydrate, ammonium chloride, N- acetylcysteine, and ambroxol, their pharmaceutically acceptable salts, and mixtures thereof. Examples of analgesics useful in the present invention include; morphine, co¬ deine, 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. Examples of 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.
Analgesics, decongestants, antihistamines, expectorants and antitussives, as well as their acceptable dosage ranges are described in U.S. Patent 4.783.465 to Sun¬ shine et al., issued November 8, 1988, and U.S. Patent 4.619.934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein.
Examples of 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.
Further examples of suitable 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. 734-789, 791-799, 861-868, 907-945, 875-888, 1002-1034, 1098-1121, 1124-1131, 1173-1224, 1232-1241, (Alfonso R.Gennaro, editor) (18th ed. 1990), herein incor¬ porated by reference.
NONESSENTIAL COMPONENTS Persons skilled in the art will quickly realize many other ingredients will be suitable for inclusion into the present invention. 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 Prosweet™ 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.
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¬ dients together and in choosing the type of mixing equipment to be used.
When using certain taste masking agents such as magnesium aluminum silicate, there is a potential for adverse interactions between the agent and various multiply charged cationic drugs (e.g. chlorpheniramine) - resulting in poor drug dis¬ solution, it is critical that certain measures be followed to insure effective drug dissolution. Such a situation is described in McGinty, J.W. and Lach, J.L., In Vitro Adsorption of Various Pharmaceuticals to Montmorillonite. Jour, of Pharm. Sci., 65, 896-902 (1976) and is herein incorporated by reference. By "multiply charged cationic drugs" as used herein, 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.
Good tasting, pharmaceutical 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.
After 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, 2n- 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. Further information regarding solid dosage formulation can be found in Remington's Pharmaceutical Sci¬ ences, pp. 1633-1664, (Alfonso R. Gennaro, editor) (18th ed. 1990). Alternatively, the 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.
Similarly, the 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, on the other hand, 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.
One other form of fast dissolving technology that may be applicable to the present invention is a liquid/liquid extract developed by Janssen Pharmaceutica Inc. and is identified by the trade name Quicksolv™. This technology is fully described in U.S. Patent 5.215.756 herein incorporated by reference.
EXAMPLES The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the pur¬ pose of illustration and are not to be construed as limitations of the present invention, as many variations are possible without departing from the spirit and scope of the in¬ vention.
EXAMPLE I Ingredients WΛV% magnesium stearate 0.50000 sorbitol, compressible 44.17000 silicone dioxide1 0.10000 citric acid, anhydrous 6.25000 sodium bicarbonate, pretreated^ 18.75000 chlorpheniramine maleate 0.80000 phenylpropanolamine HC1 5.00000 xanthum gum 24.00000 orange flavor 0.40000 cream flavor 0.30000
1 Available as Cab-o-sil from Cabot Corporation, Tuscola, Illinois 2pretreating is performed by heating overnight in a forced air oven (Despatch, Model # LDB-1-23) at 66 °C.
In an appropriately sized container, with Lightnin™ 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.
In a separate, appropriately sized container, following the same procedure, combine phenylpropanolamine HC1 with xanthum gum.
Next, dry blend via conventional blending methods (e.g., V- blender) the above xanthum gum pre-complexes with magnesium stearate, compressible sorbitol, Silicone dioxide, citric acid anhydrous, pretreated sodium bicarbonate and orange and cream flavors. Using a conventional tablet press in a humidity controlled room (< 25 % RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in glass jars or in foil pouches or blisters. Administration of two tablets is the normal and customary dosage. EXAMPLE II
Ingredients W/W% magnesium stearate 0.50000 sorbitol, compressible 56.76000 silicone dioxide1 0.10000 citric acid anhydrous 6.25000 sodium bicarbonate, pretreated^ 18.75000 dextromethorphan HBr 4.00000 methyl methacrylic copolymer^ 13.34000 lemon/lime flavor 0.30000 available as Cab-o-sil from Cabot Corporation, Tuscola, Illinois.
2pretreating is performed by heating overnight in a forced air oven (Despatch, Model
# LDB-l-23) at 66 °C.
3 Available as Eudragit®L3()D from Rohm and Haas.
In an appropriately sized container, with Lightnin™ 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.
Using a conventional tablet press in a humidity controlled room (< 25 % RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in glass jars or in foil pouches or blisters. Administration of two tablets is the normal and customary dosage. EXAMPLE III Ingredients WΛV% citric acid, anhydrous, fine 6.25000 sodium bicarbonate, pretreated1 18.75000 magnesium aluminum silicate2 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 dioxide5 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.
2 Available as Veegum® HS from R.T. Vanderbilt, Norwalk, CT. 3 Available as WS-3 supplied by Sterling Organics.
4 Available as Magnasweet® 185 supplied by McAndrews & Forbes, Camden, NJ.
In an appropriately sized container, with Lightnin™ mixer (model #TS2010
(or a high shear homogenizer set at 30 to 50 RPM)) mixing at approximately 250 to
1000 RPM, heat 800 ml purified water to 54°C. Add 43.75 g Veegum® HS while mixing. Continue mixing and heat solution to 71°C, reduce heat to approximately 38
°C and mix for 2 hours. Add pseudoephedrine HCl slowly and heat to 66°C and add additional water if necessary. Mix an additional 2 hours. Pour the mixture into teflon or stainless steel pans and dry for 12 hours at 45°C or until mixture is dry.
Grind dry mixture to a particle size suitable for compressing. Dry blend via conventional blending methods (e.g., V- blender) the Veegum®
HS Pseudoephedrine HCl pre-complex with chlorpheniramine maleate, citric acid
(anhydrous), pretreated sodium bicarbonate, aspartame, methyl salicylate, magnesium stearate, mannitol, monoammonium glycyrrhizate, sodium saccharin, Silicone dioxide, N-ethyl-p-menthane-3-carboxamide, menthol and vanilla cream flavors. Using a conventional tablet press in a humidity controlled room (< 25 % RH), press tablets to a tablet weight of 500 mg. Protect tablets from moisture by sealing in glass jars or in foil pouches or blisters. Administration of two tab and customary dosage.
EXAMPLE IV
Ingredients W /% magnesium aluminum silicate 8.48900 loperamide 2.44000 polysorbate 80 0.04000 sodium saccharin 0.05200 aspartame 0.05200 sucrose 14.00000 mannitol 12.25500 novagel RCN-151 1.60000 lemon flavor 0.47200 vanilla creme 0.15000 citric acid 0.45000 purified water q.s. to 100
EXAMPLE V
Ingredients w/v% magnesium aluminum silicate 4.00000 bismuth subsalicylate 21.69930 polysorbate 80 0.03500 sodium saccharin 0.04550 aspartame 1.00000 sucrose 2.00000 mannitol 4.15000 novagel RCN-151 1.40000 strawberry flavor 0.54600 vanilla creme 0.54990 citric acid 0.06690 klucel EF NF2 0.25200 antifoam AF^ 0.21000 purified water q.s. to 100
EXAMPLE VI
Ingredients w/v% magnesium aluminum silicate 4.00000 simethicone 3.50000 polysorbate 80 0.03500 sodium saccharin 0.04550 aspartame 0.04550 sorbitol 0.70000 sucrose 8.25000 mannitol 16.29800 novagel RCN-151 1.40000 cherry flavor 0.19460 vanilla creme 0.24780 citric acid 0.28320 antifoam AF3 0.21000 purified water q.s. to 100
1 Supplied by FMC Corporation, Philadelphia, Pa.
2Supplied by AQUALON, Hopewell, Va.
3 Supplied by Dow Corning, Midland, Mich.
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.

Claims

What is claimed is:
1. An oral pharmaceutical composition comprising:
(a) a nonrupturable drug matrix comprising: i) a taste masking agent; and ii) a safe and effective amount of a pharmaceutically active ingredient; 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.
2. A pharmaceutical composition according to Claim 1 wherein said carrier is a freeze- dried matrix, an effervescent system, or a liquid/liquid extract system.
3. " A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more flavoring agents wherein the flavoring agent is preferably selected from the group consisting of menthol, peppermint, spearmint, raspberry, cherry, orange, vanilla, anise, blueberry, banana, chocolate, caramel, strawberry, lemon, lime, grape and mixtures thereof.
4. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more sweetening agents wherein the sweetening agent is preferably selected from the group consisting of sodium saccharin, aspartame, monoammonium glycyrrhizate, sucrose, mannitol and mixtures thereof.
5. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more releasing agents wherein the releasing agent is preferably selected from the group consisting of: polysorbate 80, sodium lauryl sulfate, magnesium stearate and mixtures thereof.
6. A pharmaceutical composition according to any one of the preceding Claims wherein the composition additionally contains one or more cooling agents wherein the cooling agent is preferably selected from the group consisting of 3-1- methoxypropane 1,2-diol, N-ethyl-p-methane-3-carboxamide, N,2,3-trimethyl-2- isopropylbutanamide and mixtures thereof.
7. A pharmaceutical composition according to any one of the preceding Claims wherein the pharmaceutically active ingredient is a gastrointestinal agent.
8. A pharmaceutical composition according to any one of the preceding Claims wherein the pharmaceutical actives are selected from the group of pharmaceutical actives consisting of acetaminophen, ibuprofen, dextromethorphan, HBr, doxylamine succinate, pseudoephedrine HCl, phenylpropanolamine HCl, chlor¬ pheniramine maleate, guaifenesin, triprolidine HCl, diphenhydramine HCl, and mixtures thereof, preferably pseudoephedrine HCl and chlorpheniramine maleate.
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US8980229B2 (en) 2009-04-01 2015-03-17 Colgate-Palmolive Company Dentifrice compositions and methods for treating and preventing damage to tooth surfaces
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US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
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JP6907486B2 (en) * 2015-09-10 2021-07-21 大正製薬株式会社 Solid formulation
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US9492443B2 (en) 2003-11-26 2016-11-15 Acura Pharmaceuticals, Inc. Abuse deterrent compositions and methods of making same
US9034373B2 (en) 2006-03-16 2015-05-19 Euro-Celtique S.A. Pharmaceutical spheroids
US9884019B2 (en) * 2008-08-05 2018-02-06 Wyeth Llc Lyophilization above collapse
US20100041870A1 (en) * 2008-08-05 2010-02-18 Wyeth Lyophilization above collapse
US8980229B2 (en) 2009-04-01 2015-03-17 Colgate-Palmolive Company Dentifrice compositions and methods for treating and preventing damage to tooth surfaces
US8901113B2 (en) 2009-09-30 2014-12-02 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US10155044B2 (en) 2009-09-30 2018-12-18 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US9101636B2 (en) 2012-11-30 2015-08-11 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
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CN112972439A (en) * 2019-12-16 2021-06-18 南京亿华药业有限公司 Yumei effervescent tablet and preparation method thereof

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EP0762869A1 (en) 1997-03-19
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BR9507909A (en) 1997-08-12

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