US20120022170A1 - Manufacture of tablet in a die utilizing powder blend containing water-containing material - Google Patents
Manufacture of tablet in a die utilizing powder blend containing water-containing material Download PDFInfo
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- US20120022170A1 US20120022170A1 US13/246,884 US201113246884A US2012022170A1 US 20120022170 A1 US20120022170 A1 US 20120022170A1 US 201113246884 A US201113246884 A US 201113246884A US 2012022170 A1 US2012022170 A1 US 2012022170A1
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- powder blend
- water
- pharmaceutically active
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- 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
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61J3/10—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of compressed tablets
-
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61K9/0058—Chewing gums
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- A—HUMAN NECESSITIES
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- 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
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- A—HUMAN NECESSITIES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/288—Compounds of unknown constitution, e.g. material from plants or animals
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P11/02—Nasal agents, e.g. decongestants
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- A61P23/00—Anaesthetics
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C43/00—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor
- B29C43/02—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor of articles of definite length, i.e. discrete articles
- B29C43/04—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor of articles of definite length, i.e. discrete articles using movable moulds
- B29C43/06—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor of articles of definite length, i.e. discrete articles using movable moulds continuously movable in one direction, e.g. mounted on chains, belts
- B29C43/08—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor of articles of definite length, i.e. discrete articles using movable moulds continuously movable in one direction, e.g. mounted on chains, belts with circular movement, e.g. mounted on rolls, turntables
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
- B30B11/022—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space whereby the material is subjected to vibrations
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
- B30B11/027—Particular press methods or systems
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
- B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
- B30B11/08—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable
- B30B11/10—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with moulds carried by a turntable intermittently rotated
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
- B30B15/02—Dies; Inserts therefor; Mounting thereof; Moulds
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B30—PRESSES
- B30B—PRESSES IN GENERAL
- B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
- B30B15/34—Heating or cooling presses or parts thereof
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C35/00—Heating, cooling or curing, e.g. crosslinking or vulcanising; Apparatus therefor
- B29C35/02—Heating or curing, e.g. crosslinking or vulcanizing during moulding, e.g. in a mould
- B29C35/08—Heating or curing, e.g. crosslinking or vulcanizing during moulding, e.g. in a mould by wave energy or particle radiation
- B29C35/0805—Heating or curing, e.g. crosslinking or vulcanizing during moulding, e.g. in a mould by wave energy or particle radiation using electromagnetic radiation
- B29C2035/0861—Heating or curing, e.g. crosslinking or vulcanizing during moulding, e.g. in a mould by wave energy or particle radiation using electromagnetic radiation using radio frequency
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Abstract
The present invention features the present invention features a process for making a tablet by compacting a powder blend in a die platen to form a tablet shape, wherein the powder blend includes a pharmaceutically active agent and a water-containing material, and applying energy to the tablet shape for a sufficient period of time to heat the water-containing material within the tablet shape above its dehydration temperature to form the tablet.
Description
- This application is a continuation of prior U.S. patent application Ser. No. 12/887,552, filed Sep. 22, 2010, which claims the benefits of the filing of U.S. Provisional Application Ser. No. 61/245,315, filed Sep. 24, 2009, U.S. Provisional Application Ser. No. 61/255,582, filed Oct. 28, 2009, U.S. Provisional Application Ser. No. 61/314,629, filed Mar. 17, 2010, and U.S. Provisional Application Ser. No. 61/358,167, filed Jun. 24, 2010. The complete disclosures of the aforementioned related U.S. patent applications are hereby incorporated herein by reference for all purposes.
- Pharmaceuticals intended for oral administration are typically provided in tablet form. Tablets are swallowed whole, chewed in the mouth, or disintegrated in the oral cavity. Soft tablets that either are chewed or dissolve in the mouth are often employed in the administration of pharmaceuticals where it is impractical to provide a tablet for swallowing whole. With chewable tablets, the act of chewing helps to break up the tablet particles as the tablet disintegrates and may increase the rate of absorption by the digestive tract. Soft tablets are also advantageous where it is desirable to make a pharmaceutically active agent available topically in the mouth or throat for both local effects and/or systemic absorption. Soft tablets are also utilized to improve drug administration in pediatric and geriatric patients. Soft tablets designed to disintegrate in the mouth prior to swallowing are particularly useful for improving compliance of pediatric patients.
- Generally, soft tablets are made by compaction of a blend of powdered ingredients and typically include a pharmaceutically active agent, flavoring, and/or binders. The powder blend is typically fed into the cavity of a die of a tablet press and a tablet is formed by applying pressure. Hardness of the resulting tablet is a direct function of the compaction pressure employed and the compatibility of the ingredients in the formulation. A softer tablet, having an easier bite-through, may be prepared by employing reduced compaction pressures. The resulting tablet is softer, but also more fragile, brittle, and easily chipped and disadvantageously can involve complex and costly processing steps. Examples of soft tablets designed to disintegrate in the mouth without chewing are disclosed in U.S. Pat. Nos. 5,464,632, 5,223,264, 5,178,878, 6,589,554, and 6,224,905.
- There is a need for aesthetically pleasing chewable and orally disintegrating tablets that utilizes compression-based tableting machines typically used to produce high density, hard swallowable tablets. When used at low compression forces, these machines typically produce highly friable tablets, which are not sufficiently stable during packaging, shipping, and storage. The present invention relates to the discovery of a process for making tablets, such as chewable or orally disintegrating tablets, by heating (e.g., radiofrequency heating) a water-containing material that can utilize high speed tableting machines.
- In one aspect, the present invention features a process for making a tablet by compacting a powder blend in a die platen to form a tablet shape, wherein the powder blend includes a pharmaceutically active agent and a water-containing material, and applying energy to the tablet shape for a sufficient period of time to heat the water-containing material within the tablet shape above its dehydration temperature to form the tablet. In one embodiment, the energy is radiofrequency (“RF”) energy.
- Other features and advantages of the present invention will be apparent from the detailed description of the invention and from the claims.
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FIGS. 1A-F are cross-section, side views of an embodiment of the invention showing the manufacture oftablet 4 a from powder blend 4 within dieplaten 2. -
FIGS. 2A-H are cross-section, side views of an embodiment of the invention showing the manufacture of abilayer tablet 12 frompowder blends platen 2. -
FIGS. 3A-G are cross-section, side views of an embodiment of the invention showing the manufacture oftablet 40 containingpreformed inserts powder blend 20 within dieplaten 2. -
FIGS. 4A and 4B are a perspective view of arotary indexing machine 195. -
FIGS. 5A and 5B are top views of therotary indexing machine 195 in the dwell position. -
FIGS. 6A and 6B are section views of the lower formingtool assembly 110 in the start position of the manufacturing cycle. -
FIG. 7 is a section view through the RF stationrotary indexing machine 195 prior to compactingpowder blend 101. -
FIG. 8 is a section view through the RF stationrotary indexing machine 195 prior showing the manufacture oftablets 101 a. -
FIG. 9 is a section view throughtablet ejection station 160 beforetablets 101 a have been ejected. -
FIG. 10 is a section view throughtablet ejection station 160 aftertablets 101 a have been ejected intoblister 190. -
FIGS. 11A-D are cross sections of alternate embodiments of forming tools and the die platen. -
FIGS. 12A-D are cross sections of alternate embodiments of forming tools and the die platen. -
FIG. 13A is a cross section of forming tools having a wave-shaped surface. -
FIG. 13B is a perspective view of forming tools having a wave-shaped surface. -
FIG. 14 is a cross section of forming tools having protrusions at the surface. - It is believed that one skilled in the art can, based upon the description herein, utilize the present invention to its fullest extent. The following specific embodiments can be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
- Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. As used herein, all percentages are by weight unless otherwise specified.
- As discussed above, in one aspect, the present invention features a process for making a tablet by compacting a powder blend in a die platen to form a tablet shape, wherein the powder blend includes a pharmaceutically active agent and a water-containing material, and applying energy to the tablet shape for a sufficient period of time to heat the water-containing material within the tablet shape above its dehydration temperature to form the tablet.
- As discussed above, the tablet is manufactured by compacting a powder blend containing a pharmaceutically active agent (as discussed herein), a water-containing material (as discussed herein), and optionally a pharmaceutically-acceptable carrier. The carrier contains one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, disintegrants, lubricants, glidants, sweeteners, superdisintegrants, flavor and aroma agents, antioxidants, preservatives, texture enhancers, and mixtures thereof. One or more of the above ingredients may be present on the same particle of the powder blend.
- Suitable fillers include, but are not limited to, carbohydrates (as discussed herein) and water insoluble plastically deforming materials (e.g., microcrystalline cellulose or other cellulosic derivatives), and mixtures thereof.
- Suitable adsorbents include, but are not limited to, water-insoluble adsorbents such as dicalcium phosphate, tricalcium phosphate, silicified microcrystalline cellulose (e.g., such as distributed under the PROSOLV brand (PenWest Pharmaceuticals, Patterson, N.Y.)), magnesium aluminometasilicate (e.g., such as distributed under the NEUSILIN brand (Fuji Chemical Industries (USA) Inc., Robbinsville, N.J.)), clays, silicas, bentonite, zeolites, magnesium silicates, hydrotalcite, veegum, and mixtures thereof.
- Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
- Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
- Suitable glidants include, but are not limited to, colloidal silicon dioxide.
- Examples of sweeteners include, but are not limited to, synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, and stevside; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called laevulose), and lactose (also called milk sugar); isomalt, salts thereof, and mixtures thereof.
- Examples of superdisintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross-linked povidone (crospovidone). In one embodiment the tablet contains up to about 5% by weight of such superdisintegrant.
- Examples of flavors and aromatics include, but are not limited to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry and black currant); artificial and natural flavors of brews and liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e.g., genus Nicotiana, in amounts not contributing significantly to the level of nicotine, and ginger.
- Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.
- Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.
- Examples of texture enhancers include, but are not limited to, pectin, polyethylene oxide, and carrageenan, and mixtures thereof. In one embodiment, texture enhancers are used at levels of from about 0.1% to about 10% percent by weight.
- In one embodiment of the invention, the powder blend has an average particle size of less than 500 microns, such as from about 50 microns to about 500 microns, such as from about 50 microns and 300 microns. Particles in this size range are particularly useful for direct compacting processes.
- In one embodiment of the invention, the tablet may be a made from a powder blend that is substantially free of hydrated polymers. As used herein, what is meant by “substantially free” is less than 5%, such as less than 1%, such as less than 0.1%, such as completely free (e.g., 0%). Such a composition is advantageous for maintaining an immediate release dissolution profile, minimizing processing and material costs, and providing for optimal physical and chemical stability of the tablet.
- In one embodiment, powder blend/tablet is substantially free of directly compressible water insoluble fillers. Water insoluble fillers include but are not limited to microcrystalline cellulose, directly compressible microcrystalline cellulose, celluloses, water insoluble celluloses, starch, cornstarch and modified starches. As described in this embodiment, substantially free is less than 2 percent, e.g. less than 1 percent or none.
- The powder blend/tablet of the present invention includes at least one water-containing material. Examples of water-containing materials include, but are not limited to, materials wherein the water is chemically bound to the material (e.g., a hydrate salt or hydrated sugar), materials wherein the water is adsorbed or absorbed to the material (e.g., porous material such a silicas and microsponges), and materials that have water encapsulated therein (e.g., liquid filled capsules).
- In one embodiment, the powder blend/tablet contains at least one hydrated salt. Examples of hydrated salts include, but are not limited to, sodium sulfate hydrate, sodium carbonate hydrate, calcium chloride hydrate, sodium hydrogen phosphate hydrate, and mixtures thereof. In one embodiment, the hydrated salt has molecular weight from about 150 to about 400 Daltons, such as from about 200 to about 350 Daltons.
- In one embodiment, the powder blend/tablet contains at least one hydrated sugar. Examples of hydrated sugars include, but are not limited to, dextrose monohydrate.
- In one embodiment, the powder blend/tablet contains at least one material wherein the water is adsorbed or absorbed to the material. Examples of such materials include, but are not limited to, fumed silicas; colloidal silicas such as colloidal silicon dioxide; silicates such as calcium silicate, aluminum silicate, magnesium aluminum metasilicate (such as NEUSILIN, US-2 from Fuji Chemical Ltd), and magnesium silicate; clays; zeolites; and veegum.
- In one embodiment, the powder blend/tablet contains at least one liquid filled capsule. In a further embodiment, the water is released from the capsule upon rupture, wherein such rupture is caused by the addition of energy.
- The water-containing material(s) may be present at level of about 0.01 percent to about 70 percent of the powder blend/tablet, such as from about 1 percent to about 50 percent, such as from about 1 percent to about 30 percent, such as from about 2 percent to about 10 percent of the powder blend/tablet.
- In one embodiment, the powder blend/tablet contains at least one carbohydrate. The carbohydrate can (i) upon contact with the water released from the water-containing material, contribute to binding the powder blend into a tablet, (ii) enhance the dissolvability and mouth feel of the tablet, (iii) aid in distributing the water-containing material across a broader surface area, and (iv) diluting and cushioning the pharmaceutically active agent. Examples of carbohydrates include, but are not limited to, water-soluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, isomalt, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, lactitol, and xylitol), and starch hydrolysates (e.g., dextrins, and maltodextrins).
- The carbohydrate(s) may be present at level of about 5 percent to about 95 percent of the powder blend/tablet, such as from about 20 percent to about 90 percent or from about 40 percent to about 80 percent of the powder blend/tablet. In one embodiment, the powder blend/tablet is substantially free (e.g., completely free) of a water-reacting binding material or meltable binder, such that the carbohydrate acts to fuse the dosage form upon the addition of the energy (e.g., RF energy). In this embodiment substantially free is defined as less than 0.1 percent, such as 0%.
- In one embodiment, the powder blend/tablet of the present invention includes at least one water-reacting binding material. What is meant by a water-reacting binding material is a material that will react or hydrate upon contact with water (e.g. released from the water containing material upon the addition of the energy) and assist in binding the powder blend into a tablet. Examples of such materials include, but are not limited to, hydrating polymers and hydrocolloids. Suitable hydrating polymers include, but are not limited to starch, modified starch, methylcellulose, hydroxypropylcellulose, and hydroxypropylcellulose. Suitable hydrocolloids include, but are not limited to, gelatin, gellan gum, carrageenan, and pectin.
- In one embodiment, the powder blend/tablet of the present invention includes at least one meltable binder. In one embodiment, the meltable binder has a melting point of from about 40° C. to about 140° C., such as from about 55° C. to about 100° C. The softening or melting of the meltable binder(s) results in the sintering of the tablet shape through the binding of the softened or melted binder with the pharmaceutically active agent and/or other ingredients within the compacted powder blend.
- In one embodiment, the meltable binder is a RF-meltable binder. What is meant by an RF-meltable binder is a solid binder that can be softened or melted upon exposure to RF energy. The RF-meltable binder typically is polar and has the capability to re-harden or resolidify upon cooling.
- In one embodiment, the meltable binder is not a RF-meltable binder. In such embodiment, the powder blend contains an excipient that heats upon exposure to RF energy (e.g., a polar excipient), such that the resulting heat from is able to soften or melt the meltable binder. Examples of such excipients include, but are not limited to, polar liquids such as water and glycerin; powdered metals and metal salts such as powdered iron, sodium chloride, aluminum hydroxide, and magnesium hydroxide; stearic acid; and sodium stearate.
- Examples of suitable meltable binders include: fats such as cocoa butter, hydrogenated vegetable oil such as palm kernel oil, cottonseed oil, sunflower oil, and soybean oil; mono, di, and triglycerides; phospholipids; cetyl alcohol; waxes such as Carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; water soluble polymers such as polyethylene glycol, polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides; polyethylene oxides; and sucrose esters.
- In one embodiment, the meltable binder is a RF-meltable binder, and the RF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000. A particularly preferred RF-meltable binder is PEG having at least 95% by weight of the PEG particles less than 100 microns (as measured by conventional means such as light or laser scattering or sieve analysis) and a molecular weight between 3000 and 8000 Daltons.
- In one embodiment, the meltable binder is hydrated. In a further embodiment, upon addition of the energy the meltable binder releases the water into the powder blend. In one embodiment, the hydrated meltable binder includes up to 60 percent, such as up to about 50 percent, by weight of water.
- The meltable binder(s) may be present at level of about 0.01 percent to about 70 percent of the powder blend/tablet, such as from about 1 percent to about 50 percent, such as from about 10 percent to about 30 percent of the powder blend/tablet.
- The powder blend/tablet of the present invention includes at least one pharmaceutically active agent. What is meant by a “pharmaceutically active agent” is an agent (e.g., a compound) that is permitted or approved by the U.S. Food and Drug Administration, European Medicines Agency, or any successor entity thereof, for the oral treatment of a condition or disease. Suitable pharmaceutically active agents include, but are not limited to, analgesics, anti-inflammatory agents, antipyretics, antihistamines, antibiotics (e.g., antibacterial, antiviral, and antifungal agents), antidepressants, antidiabetic agents, antispasmodics, appetite suppressants, bronchodilators, cardiovascular treating agents (e.g., statins), central nervous system treating agents, cough suppressants, decongestants, diuretics, expectorants, gastrointestinal treating agents, anesthetics, mucolytics, muscle relaxants, osteoporosis treating agents, stimulants, nicotine, and sedatives.
- Examples of suitable gastrointestinal treating agents include, but are not limited to: antacids such as aluminum-containing pharmaceutically active agents (e.g., aluminum carbonate, aluminum hydroxide, dihydroxyaluminum sodium carbonate, and aluminum phosphate), bicarbonate-containing pharmaceutically active agents, bismuth-containing pharmaceutically active agents (e.g., bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, and bismuth subnitrate), calcium-containing pharmaceutically active agents (e.g., calcium carbonate), glycine, magnesium-containing pharmaceutically active agents (e.g., magaldrate, magnesium aluminosilicates, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, and magnesium trisilicate), phosphate-containing pharmaceutically active agents (e.g., aluminum phosphate and calcium phosphate), potassium-containing pharmaceutically active agents (e.g., potassium bicarbonate), sodium-containing pharmaceutically active agents (e.g., sodium bicarbonate), and silicates; laxatives such as stool softeners (e.g., docusate) and stimulant laxatives (e.g., bisacodyl); H2 receptor antagonists, such as famotidine, ranitidine, cimetadine, and nizatidine; proton pump inhibitors such as omeprazole, dextansoprazole, esomeprazole, pantoprazole, rabeprazole, and lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics such as prucalopride; antibiotics for H. pylori, such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate, and loperamide; glycopyrrolate; analgesics, such as mesalamine; antiemetics such as ondansetron, cyclizine, diphenyhydroamine, dimenhydrinate, meclizine, promethazine, and hydroxyzine; probiotic bacteria including but not limited to lactobacilli; lactase; racecadotril; and antiflatulents such as polydimethylsiloxanes (e.g., dimethicone and simethicone, including those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260); isomers thereof; and pharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.
- Examples of suitable analgesics, anti-inflammatories, and antipyretics include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (e.g., ibuprofen, naproxen, ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, and suprofen) and COX inhibitors such as celecoxib; acetaminophen; acetyl salicylic acid; acetic acid derivatives such as indomethacin, diclofenac, sulindac, and tolmetin; fenamic acid derivatives such as mefanamic acid, meclofenamic acid, and flufenamic acid; biphenylcarbodylic acid derivatives such as diflunisal and flufenisal; and oxicams such as piroxicam, sudoxicam, isoxicam, and meloxicam; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof.
- Examples of antihistamines and decongestants, include, but are not limited to, bromopheniramine, chlorcyclizine, dexbrompheniramine, bromhexane, phenindamine, pheniramine, pyrilamine, thonzylamine, pripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, propylhexadrine, triprolidine, clemastine, acrivastine, promethazine, oxomemazine, mequitazine, buclizine, bromhexine, ketotifen, terfenadine, ebastine, oxatamide, xylomeazoline, loratadine, desloratadine, and cetirizine; isomers thereof; and pharmaceutically acceptable salts and esters thereof.
- Examples of cough suppressants and expectorants include, but are not limited to, diphenhydramine, dextromethorphan, noscapine, clophedianol, menthol, benzonatate, ethylmorphone, codeine, acetylcysteine, carbocisteine, ambroxol, belladona alkaloids, sobrenol, guaiacol, and guaifenesin; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof.
- Examples of muscle relaxants include, but are not limited to, cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, and methocarbamol; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof.
- Examples of stimulants include, but are not limited to, caffeine.
- Examples of sedatives include, but are not limited to sleep aids such as antihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, and pharmaceutically acceptable salts and prodrugs thereof.
- Examples of appetite suppressants include, but are not limited to, phenylpropanolamine, phentermine, and diethylcathinone, and pharmaceutically acceptable salts and prodrugs thereof.
- Examples of anesthetics (e.g., for the treatment of sore throat) include, but are not limited to dyclonine, benzocaine, and pectin and pharmaceutically acceptable salts and prodrugs thereof.
- Examples of suitable statins include but are not limited to atorvastin, rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin, pravastatin and pharmaceutically acceptable salts and prodrugs thereof.
- In one embodiment, the pharmaceutically active agent included within the tablet is selected from phenylephrine, dextromethorphan, pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine, ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calcium carbonate, simethicone, chlorpheniramine, methocarbomal, chlophedianol, ascorbic acid, pectin, dyclonine, benzocaine and menthol, and pharmaceutically acceptable salts and prodrugs thereof.
- As discussed above, the pharmaceutically active agents of the present invention may also be present in the form of pharmaceutically acceptable salts, such as acidic/anionic or basic/cationic salts. Pharmaceutically acceptable acidic/anionic salts include, and are not limited to acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate and triethiodide. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, meglumine, potassium, procaine, sodium and zinc.
- As discussed above, the pharmaceutically active agents of the present invention may also be present in the form of prodrugs of the pharmaceutically active agents. In general, such prodrugs will be functional derivatives of the pharmaceutically active agent, which are readily convertible in vivo into the required pharmaceutically active agent. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985. In addition to salts, the invention provides the esters, amides, and other protected or derivatized forms of the described compounds.
- Where the pharmaceutically active agents according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the pharmaceutically active agents possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the pharmaceutically active agents may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the pharmaceutically active agents may form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- In one embodiment, the pharmaceutically active agent or agents are present in the tablet in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular pharmaceutically active agent being administered, the bioavailability characteristics of the pharmaceutically active agent, the dose regime, the age and weight of the patient, and other factors must be considered, as known in the art.
- The pharmaceutically active agent may be present in various forms. For example, the pharmaceutically active agent may be dispersed at the molecular level, e.g. melted, within the tablet, or may be in the form of particles, which in turn may be coated or uncoated. If the pharmaceutically active agent is in form of particles, the particles (whether coated or uncoated) typically have an average particle size of from about 1 to about 2000 microns. In one embodiment, such particles are crystals having an average particle size of from about 1 to about 300 microns. In another embodiment, the particles are granules or pellets having an average particle size of from about 50 to about 2000 microns, such as from about 50 to about 1000 microns, such as from about 100 to about 800 microns.
- The pharmaceutically active agent may be present in pure crystal form or in a granulated form prior to the addition of the taste masking coating. Granulation techniques may be used to improve the flow characteristics or particle size of the pharmaceutically active agents to make it more suitable for compaction or subsequent coating. Suitable binders for making the granulation include but are not limited to starch, polyvinylpyrrolidone, polymethacrylates, hydroxypropylmethylcellulose, and hydroxypropylcellulose. The particles including pharmaceutically active agent(s) may be made by cogranulating the pharmaceutically active agent(s) with suitable substrate particles via any of the granulation methods known in the art. Examples of such granulation method include, but are not limited to, high sheer wet granulation and fluid bed granulation such as rotary fluid bed granulation.
- If the pharmaceutically active agent has an objectionable taste, the pharmaceutically active agent may be coated with a taste masking coating, as known in the art. Examples of suitable taste masking coatings are described in U.S. Pat. No. 4,851,226, U.S. Pat. No. 5,075,114, and U.S. Pat. No. 5,489,436. Commercially available taste masked pharmaceutically active agents may also be employed. For example, acetaminophen particles, which are encapsulated with ethylcellulose or other polymers by a coacervation process, may be used in the present invention. Coacervation-encapsulated acetaminophen may be purchased commercially from Eurand America, Inc. (Vandalia, Ohio) or from Circa Inc. (Dayton, Ohio).
- In one embodiment, the tablet incorporates modified release coated particles (e.g., particles containing at least one pharmaceutically active agent that convey modified release properties of such agent). As used herein, “modified release” shall apply to the altered release or dissolution of the active agent in a dissolution medium, such as gastrointestinal fluids. Types of modified release include, but are not limited to, sustained release or delayed release. In general, modified release tablets are formulated to make the active agents(s) available over an extended period of time after ingestion, which thereby allows for a reduction in dosing frequency compared to the dosing of the same active agent(s) in a conventional tablet. Modified release tablets also permit the use of active agent combinations wherein the duration of one pharmaceutically active agent may differ from the duration of another pharmaceutically active agent. In one embodiment the tablet contains one pharmaceutically active agent that is released in an immediate release manner and an additional active agent or a second portion of the same active agent as the first that is modified release.
- Examples of swellable, erodible hydrophilic materials for use as a release modifying excipient for use in the modified release coating include water swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, and gelling starches. Examples of water swellable cellulose derivatives include sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose. Examples of polyalkylene glycols include polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include poly (ethylene oxide). Examples of acrylic polymers include potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, and high-molecular weight cross-linked acrylic acid homopolymers and copolymers.
- Suitable pH-dependent polymers for use as release-modifying excipients for use in the modified release coating include: enteric cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinylacetate phthalate, cellulose acetate phthalate, and acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2 (available from Rohm Pharma GmbH under the tradename EUDRAGIT S) and poly(methacrylic acid, methyl methacrylate) 1:1 (available from Rohm Pharma GmbH under the tradename EUDRAGIT L).
- In one embodiment the pharmaceutically active agent is coated with a combination of a water insoluble film forming polymer (such as but not limited to cellulose acetate or ethylcellulose) and a water soluble polymer (such as but not limited to povidone, polymethacrylic co-polymers such as those sold under the tradename Eudragit E-100 from Rohm America, and hydroxypropylcellulose). In this embodiment, the ratio of water insoluble film forming polymer to water soluble polymer is from about 50 to about 95 percent of water insoluble polymer and from about 5 to about 50 percent of water soluble polymer, and the weight percent of the coating by weight of the coated taste-masked particle is from about 5 percent to about 40 percent. In one embodiment, the coating which is used in the coated particle of the pharmaceutically active agent is substantially free of a material (such as polyethylene glycol) which melts below 85° C., in order to prevent damage to the integrity of the coating during the RF heating step.
- In one embodiment, one or more pharmaceutically active agents or a portion of the pharmaceutically active agent may be bound to an ion exchange resin for the purposes of taste-masking the pharmaceutically active agent or delivering the active in a modified release manner.
- In one embodiment, the pharmaceutically active agent is capable of dissolution upon contact with a fluid such as water, stomach acid, intestinal fluid or the like. In one embodiment, the dissolution characteristics of the pharmaceutically active agent within the tablet meets USP specifications for immediate release tablets including the pharmaceutically active agent. For example, for acetaminophen tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the acetaminophen contained in the tablet is released there from within 30 minutes after dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least 80% of the ibuprofen contained in the tablet is released there from within 60 minutes after dosing. See USP 24, 2000 Version, 19-20 and 856 (1999). In another embodiment, the dissolution characteristics of the pharmaceutically active agent are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like.
- In one embodiment, the particle size of the pharmaceutically active agent causes more void spaces to be present in the tablet, wherein a higher particle size of the pharmaceutically active agent subsequently requires a lower level of the water-containing material. In one embodiment, the mean particle size of the carbohydrate is greater than 100 microns, the pharmaceutically active agent or coated pharmaceutically active agent(s) is greater than 50% by weight of the powder blend/tablet and the water-containing material is from about 2% to about 30% by weight of the powder blend/tablet. In one embodiment, wherein the mean particle size of the powder blend is from about 100 microns and about 300 microns, then the water-containing material is from about 2% to about 15% percent by weight of the powder blend/tablet.
- The melting point of the pharmaceutically active agent can have an impact on the temperature used during the heating step and the type of the water-containing material used. In one embodiment, the dehydration temperature of the water-containing material is less than the melting point of the pharmaceutically active agent. In another embodiment, the melting point of the pharmaceutically active agent is the same or lower than the dehydration temperature of the water-containing material. In one embodiment, the heating temperature is above the melting dehydration temperature of the water-containing material and below the melting point of the pharmaceutically active agent. In one embodiment wherein ibuprofen is the pharmaceutically active agent, the water-containing material is heated from about 30° C. to about 60° C. In one embodiment, the pharmaceutically active agent is the water-reacting binding material.
- In one embodiment, the pharmaceutically active agent is in the form of a particle that is coated with the water-reacting binding material.
- The susceptibility to RF energy of the pharmaceutically active agent (e.g., to melt or degrade) can have an impact on the type of energy and/or temperature used during the heating step as well as the type of the water-containing compound used.
- In one embodiment, the processing of the tablet is free of a wet or hot melt granulation step. In this embodiment, the materials are directly blended prior to the addition of heat. In one embodiment, the materials are directly blended and compressed prior to the addition of heat.
- In one embodiment, the powder blend is fed into the tablet die of an apparatus that applies pressure to form the tablet shape (e.g., by light compaction such as tamping). Any suitable compacting apparatus may be used, including, but not limited to, a conventional unitary or rotary tablet press. In one embodiment, the tablet shape may be formed by compaction using a rotary tablet press (e.g., such as those commercially available from Fette America Inc., Rockaway, N.J. or Manesty Machines LTD, Liverpool, UK). In one embodiment, the tablet shape is heated after it is removed from the tablet press. In another embodiment, the tablet shape is heated within the tablet press.
- In one embodiment, to obtain desired attribute of an orally disintegrating tablet, the tablet's construction may be highly porous, use a minimal amount of binder, and/or have a low density. Such tablets, therefore, are somewhat fragile and soft. In a preferred embodiment, a minimum of tamping/compaction force is desired to achieve the orally disintegrating property (low density). Experiments have determined that low force compaction without application of RF energy produced very fragile tablets that could not withstand the forces of material handling required in manufacturing.
- In most thermodynamic processes or machines, the heat source and the heat sink are two distinct machines or steps requiring material to be transferred from one apparatus to the other. In the manufacture of the tablets of the present invention, the energy must be added to the tablet to achieve the binding effect and then must be removed from the product to solidify and strengthen it for its final handling packaging and use. One of the unique and unanticipated attributes of one embodiment of the manufacturing process of the present invention is that heat source and heat sink are part of the same apparatus. In fact in early experiments the metallic forming tool (e.g., a die punch) which was at room temperature removed so much heat from the treated tablet shape (due to its high thermal conductivity) that the surface of the resulting tablet was unacceptable due to the fact that uniform melting within the powder blend had not taken place. The resulting tablet had a well formed core, but the surface was loose unbound and poorly formed powder that did not adhere to the rest of the tablet. To correct for this thermal loss, in one embodiment, heat is added to the forming tools to achieve proper sintering at the surface as well as at the center of the tablet.
- To exploit this unique thermal effect, powder blends can also be chosen for their thermal properties and thermal conductivity and specific heat such that the powder blend particles themselves become heat sinks In a typical ODT formulation the binders may compose less than 10% of the mixture. The remaining 90% of the materials act as a heat sink that quickly removes heat once the energy (e.g., RF energy) is removed. The desirable result of this is that the total process time can be just a few seconds and that the tablet does not need to be transferred from the die platen during the critical tamping and heating process. The die platen can function then as a material handling apparatus as well as a thermal forming tool. This is particularly advantageous for successful manufacture of fragile orally disintegrating tablets.
- In one embodiment, the compaction step (e.g., tamping) which occurs prior to the addition of the energy (e.g., RF energy) utilizes a compaction force which is less than the force required to compress a chewable or swallowable tablet. In one embodiment, the compaction force is less than about 1000 pounds per square inch (e.g., less than about 500 pounds per square inch, such as less than 200 pounds per square inch, such as less than 50 pounds per square inch). In one embodiment, the energy is applied while the powder blend is under such force.
- In one embodiment, the compaction step occurs in an indexed manner, where one set of tablets are compacted simultaneously, before rotating to another indexing station. In one embodiment, the compaction step occurs at a single indexing station and the application of energy (e.g., RF energy) occurs at a separate indexing station. In another embodiment, a third indexing station is present wherein the ejection of the tablet or multiple tablets occurs, wherein the lower forming tool is raised up through and up to the surface of the die. In another embodiment the compaction step is performed through the addition of air pressure or hydraulic cylinder to the top of the upper forming tools. In one embodiment multiple tablets are ejected simultaneously and separated from the surface of the indexing station and removed via a take-off bar.
- In another embodiment, the tablet shape may be prepared by the compaction methods and apparatus described in United States Patent Application Publication No. 20040156902. Specifically, the tablet shape may be made using a rotary compression module including a fill zone, insertion zone, compression zone, ejection zone, and purge zone in a single apparatus having a double row die construction. The dies of the compression module may then be filled using the assistance of a vacuum, with filters located in or near each die. The purge zone of the compression module includes an optional powder blend recovery system to recover excess powder blend from the filters and return the powder blend to the dies. In one embodiment the energy source (e.g., RF energy source) is projected through the die table of a rotary press into the appropriate electrode within the forming tool or the forming cavity. In one embodiment the die table is constructed of non-conductive material.
- In another embodiment, a portion of the tablet shape may be prepared by a wet-granulation method, in which the excipients and a solution or dispersion of a wet binder (e.g., an aqueous cooked starch paste or solution of polyvinyl pyrrolidone) are mixed and granulated. Suitable apparatus for wet granulation include low shear mixers (e.g., planetary mixers), high shear mixers, and fluid beds (including rotary fluid beds). The resulting granulated material may then be dried, and optionally dry-blended with further ingredients (e.g., excipients such as, for example, the water-containing compound described in the invention herein, lubricants, colorants, and the like). The final dry blend is then suitable for compaction by the methods described herein. Methods for direct compaction and wet granulation processes are known in the art.
- In one embodiment, the tablet shape is prepared by the compaction methods and apparatus described in issued U.S. Pat. No. 6,767,200. Specifically, the tablet shape is made using a rotary compression module including a fill zone, compression zone, and ejection zone in a single apparatus having a double row die construction as shown in
FIG. 6 therein. The dies of the compression module are preferably filled using the assistance of a vacuum, with filters located in or near each die. - The tablet shape may have one of a variety of different shapes. For example, the tablet shape may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, triangle, cylinder, sphere, torus, or the like. In certain embodiments, a tablet shape has one or more major faces. For example, the tablet shape surface typically has opposing upper and lower faces formed by contact with the upper and lower forming tool faces (e.g., die punches) in the compaction machine. In such embodiments, the tablet shape surface typically further includes a “belly-band” located between the upper and lower faces, and formed by contact with the die walls in the compaction machine. A tablet shape/tablet may also be a multilayer. Applicants have found that sharp edges in the tooling used to make the tablets can cause arcing, and thus more rounded edges may be needed.
- In one embodiment, the method of producing the tablet shape is substantially free of the use of solvents. In this embodiment, the powder blend is substantially free of solvents, and the manufacturing process (e.g., filling process into the die) is also substantially free of solvents. Solvents may include, but are not limited to, water, organic solvents such as but not limited to alcohols, chlorinated solvents, hexanes, or acetone; or gaseous solvents such as but not limited to nitrogen, carbon dioxide or supercritical fluids.
- In one embodiment a vibratory step is utilized (e.g., added after filling of the powder blend but prior to the heating or fusing step, in order to remove air from the powder blend). In one embodiment a vibration with the frequency from about 1 Hz to about 50 KHz is added with amplitude from 1 micron to 5 mm peak-to-peak to allow for the flowable powder blend to settle into the cavity of a the die platen (“forming cavity”).
- In one embodiment, as shown in
FIGS. 1A-1F , a metered volume of powder blend 4 is filled into a Teflon® (or similar electrical and RF energy insulative material such as ceramic or UHMW plastic) dieplaten 2. Dieplaten 2 has formingcavity 5 withinner wall 6,upper opening 7 on the upper surface of die platen 2 (which allows powder blend 4 and upper formingtool 1 to move into the forming cavity 5), andlower opening 8 on the opposite surface of die platen 2 (which allows powder blend 4 and lower formingtool 3 to move into the forming cavity 5). Powder blend 4 may be either gravity fed or mechanically fed from a feeder (not shown). A metallic, electrically conductive lower formingtool 3 is inserted into the die platen to retain the powder blend 4, withindie platen 2. A similar metallic, electrically conductive upper formingtool 1 is positioned above thedie platen 2 as shown inFIG. 1B . The formingtools platen 2, and powder blend 4 are then moved to a compaction and RF heating station as shown inFIG. 1C to formtablet shape 4 a. - This heating station is comprised of an
RF generator 7 which produces the necessary high voltage, high frequency energy. Thegenerator 7 is electrically connected to movable upperRF electrode plate 8 and movable lowerRF electrode plate 6. As shown inFIG. 1C , at this position, the powder blend 4 is compacted between an upper formingtool 1 and a lower formingtool 3 by pressure exerted by upperRF electrode plate 8 andlower electrode plate 6 to formtablet shape 4 a.Tablet shape 4 a is then exposed to RF energy fromRF generator 7, which heats the water-containing compound withintablet shape 4 a. After the RF energy is switched off,tablet shape 4 a cools to form thetablet 4 b. In one embodiment, as shown inFIG. 1D ,tablet 4 b is pushed by upper formingtool 1 from thedie platen 2 intoblister 8, which is used to packagetablet 4 b. In an alternative embodiment, as shown inFIG. 1E ,tablet 4 b is pushed from thedie platen 2 by the lower formingtool 3 and guided to an ejection chute by a stationary “take-off” bar (not shown).FIG. 1F shows a 3 dimensional representation of the formingtools 1 and 4, dieplaten 2, andtablet 4 b. - In
FIGS. 2A-2H , an alternate embodiment of the invention is shown where a multilayer tablet is produced. First,powder blend 10 is filled intodie platen 2 as shown inFIG. 2A .Powder blend 10 is tamped or moved down intodie platen 2 by upper formingtool 1 as shown inFIG. 2B to formtablet shape 10 a. Then,powder blend 11 is then filled on top oftablet shape 10 a. The formingtools platen 2,tablet shape 10 a andpowder blend 11 are then moved to the compaction and RF heating station as shown inFIG. 2E . RF heating is accomplished as described above inFIG. 1C to producemultilayer tablet 12 as shown inFIGS. 2F and 2G . While a bi-layer tablet is shown in the drawing, additional multiple layers can be produced by adding additional powder blends to dieplaten 2. -
FIGS. 3A-3G show another embodiment of the invention where preformed inserts 30 and 31 are inserted intotablet shape 20 a as shown inFIGS. 3A-3D . Formingtools platen 2,tablet shape 20, and preformedinserts FIG. 3E . RF heating is accomplished as described above inFIG. 1C to produce amulti-component tablet 40 shown inFIGS. 2F and 2G . -
FIGS. 4A and 4B show two views of arotary indexing machine 195 which is designed to create large quantities of tablets. In particular, the configuration of the apparatus shown is designed to manufacture fragile tablets with minimized risk of damaging them as they are moved through the various manufacturing steps. This embodiment of the invention is comprised of an indexing table 170 having four sets ofdie platens 175 each having sixteen cavities,powder feeder 100,RF generator 150, amachine frame 140, movingRF electrode assemblies tool assembly 110, upper formingtool assembly 210,tablet ejection station 160,indexer drive system 180,blister package web 190, and blisterlid material roll 191. -
FIG. 5A is a top view of the apparatus in the dwell position.FIG. 5B is a top view of the apparatus as the indexing table 170 rotates between stations in direction “A”.FIG. 6A depicts a section view through the lower formingtool assembly 110 in a start position of the manufacturing cycle. The lower formingtools 111, which are made of an electrically conductive metallic material such as brass or stainless steel, are retained in retainer plate 112 (e.g., made of aluminum or steel).Heated block 117 is attached to theretainer plate 112 and containsfluid passages 117 b. Heated (or optionally cooling) fluid is circulated through theheated block 117 by connections toflexible hoses follower 114 andlinear bearing 113. Aguide shaft 116 is fixed to indexing table 170. The retainer plate and formingtools 111 and are moveable up or down according to the profile ofbarrel cam 115 whichcam follower 114 rolls upon. Also shown isdie platen 171, which is made of electrical and RF energy insulative material such as Teflon, UHMW, or ceramic. This is necessary to prevent a short circuit when the electrically conductive forming tools are positioned in the RF electric field in subsequent steps. The formingcavity 171 a is shown empty at this stage of the process. -
FIG. 6B depicts a section through thepowder feeder station 100 of the apparatus. In this station powderedpowder blend 101 is gravity fed intodie platen 171.Movable cam segment 118 is adjusted up or down in direction “B” to vary the volume of the formingcavity 171 a by changing the amount that the lower formingtools 111 penetrate into thedie platen 171. This adjustable volume feature enables the precise dose of powdered powder blend to be selected for a desired tablet weight. When the machine indexes out of the powder feeder station, the rim offeeder 102 scrapes against thedie platen 171 to create a level powder surface relative to the surface of thedie platen 171. -
FIG. 7 is a section view through the RF station of the apparatus. TheRF generator 150 is depicted symbolically here. In one embodiment, the configuration of theRF generator 150 is a free running oscillator system. It is typically composed of a power vacuum tube (such as a triode), a DC voltage source between 1000 and 8000 volts connected across the cathode and plate (anode). A tank circuit is used to impose a sinusoidal signal upon the control grid and electrodes thereby producing the necessary frequency (typically 13.56 MHZ or 27.12 MHZ) and high voltage field. An example ofsuch RF generator 150 is the COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.). In another embodiment, RF energy can be provided by a 50 Ohm system composed of a waveform generator which feeds a radio frequency signal to power amplifiers which are coupled to the electrodes and the load by an impedance matching network. - In
FIG. 7 , a lowermovable RF electrode 121 is shown, movable in direction “D”. It is represented in its down position. The linear movement is generated by linear actuators which are typically devises such as air cylinders or servo motors. Two air cylinders are depicted inFIG. 7 .Air cylinder bodies rods platens electrode plates RF generator 150 connects to theelectrode plates wires RF electrode assembly 130, movable in direction “C”, is shown in its up position. Upper formingtools 133,retainer plate 134, andheated block 135 are all attached to the movableRF electrode plate 131 and, consequently, move up and down with it.Powder blend 101 is withindie platen 171. -
FIG. 8 is a section through the same RF station but shows theRF electrodes tool assemblies powder blend 101 creatingtablet 101 a. After application of the RF energy is stopped, the moveable RF electrode plates refract, and theindexing plate 170, dieplaten 171, and lower formingtool assembly 110 are indexed to the next station. -
FIG. 9 is a section view through thetablet ejection station 160. Ejector pins 161 are attached to movable plate 162 (movable in the “E” direction), which is actuated by actuator assembly 163 (for example, this can be a linear servo motor or air cylinder or other suitable actuator).Actuator rod 166 connects to themovable plate 162. Linear bearing 164 and guiderod 165 provide rigidity and support for theactuator plate 162 and prevent destructive side loads created by the ejection force from acting uponactuator 163. Ablister package 190 is shown belowdie platen 171. -
FIG. 10 is a section through the same assembly after the ejector pins 161 have pushedfinished tablets 101 a through thedie platen 171. This direct placement of tablet into blister helps prevent breakage that could occur while using typical means such as feeders or by dumping tablets into transport drums. - In one embodiment, a lubricant is added to forming cavity prior to the addition of the flowable powder blend. This lubricant may be a liquid or solid. Suitable lubricants include but are not limited to solid lubricants such as magnesium stearate, starch, calcium stearate, aluminum stearate and stearic acid; or liquid lubricants such as but not limited to simethicone, lecithin, vegetable oil, olive oil, or mineral oil. In certain embodiments, the lubricant is added at a percentage by weight of the tablet of less than 5 percent, e.g. less than 2 percent, e.g. less than 0.5 percent. In certain embodiments, the presence of a hydrophobic lubricant can disadvantageously compromise the disintegration or dissolution properties of a tablet. In one embodiment the tablet is substantially free of a hydrophobic lubricant. Hydrophobic lubricants include magnesium stearate, calcium stearate and aluminum stearate.
- Various forms of energy may be used in the process to heat the water-containing compound. Suitable sources of energy include but are not limited to convection, radio frequency, microwave, UV light, infrared, induction, laser light, and ultrasonic sound. In one embodiment, radiofrequency energy is used. Radiofrequency heating generally refers to heating with electromagnetic field at frequencies from about 1 MHz to about 100 MHz. In one embodiment of the present invention, the RF-energy is within the range of frequencies from about 1 MHz to about 100 MHz (e.g., from about 5 MHz to 50 MHz, such as from about 10 MHz to about 30 MHz). RF energy generators are well known in the art. Examples of suitable RF generators include, but are not limited to, COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.).
- The energy (e.g., RF energy) is used to heat the water-containing compound. The degree of compaction, the type and amount of water-containing compound, and the amount of energy used can determine the hardness and/or type of tablet whether an oral disintegrating tablet or a soft chewable tablet is manufactured.
- In one embodiment when RF energy is used, the upper and lower forming tools serve as the electrodes (e.g., they are operably associated with the RF energy source) through which the RF energy is delivered to the tablet shape. In one embodiment, there is direct contact between at least one RF electrode (e.g., forming tool) and the tablet shape. In another embodiment, there is no contact between any of the RF electrode (e.g., forming tools) and the tablet shape. In one embodiment, the RF electrodes are in direct contact with the surface of the tablet shape when the RF energy is added. In another embodiment, the RF electrodes are not in contact (e.g., from about 1 mm to about 1 cm from the surface of the tablet shape) during the addition of the RF energy.
- In one embodiment, the RF energy is delivered while the tablet shape is being formed. In one embodiment, the RF energy is delivered once the tablet shape is formed. In one embodiment, the RF energy is delivered after the tablet shape has been removed from the die.
- In one embodiment, the RF energy is applied for a sufficient time to heat substantially all (e.g., at least 90%, such as at least 95%, such as all) of the water-containing material within said tablet shape above its dehydration temperature. In one embodiment, the RF energy is applied for a sufficient time to heat only a portion (e.g., less than 75%, such as less than 50%, such as less than 25%) of the water-containing material within the tablet shape, for example only on a portion of the tablet shape, such as the outside of the tablet shape.
- In alternate embodiments of the invention, the forming tools can be constructed to achieve localized heating effects and can also be configured to shape the electric field that is developed across the tools.
FIG. 11A shows one such configuration. AnRF generator 200 is connected toRF electrode plates tools attachment platen 203 is also constructed of electrical and RF energy insulative material. This configuration creates greater distance between the conductive forming tools to weaken the electric field which is beneficial for producing thin tablets without the risk of an electric arc forming which would damage the product and tooling.FIG. 11B depicts a similar configuration but with formingtools recess containing insert inserts FIG. 11C is similar toFIG. 11B only the geometry is reversed so the tablet formed by this configuration will have a greater heating effect at the center since theinserts tools FIG. 11D depicts another embodiment whereby the die platen is constructed of an electricallyconductive component 221 and electrically insulatingcomponent 222, which is made of electrical and RF energy insulative material. Formingtools tool 218 further contains second electrically insulatingcomponent 220 around the surface of upper formingtool 218 whichcontact tablet shape 206. This configuration creates an electric field and associated zones of heating that is preferential to the conductive portions of the die platen. -
FIG. 12A is similar toFIG. 11D except thedie platen 233 in this embodiment is constructed entirely of electrically conductive material.FIGS. 12B and 12C depict two embodiments where the die platen comprises arespective center portion outer portions 244/246 and 252/253 is are made of electrical and RF energy insulative material.FIG. 12B further includes insulatingcomponent 220 around the surface of lower formingtool 219.FIG. 12D is a further embodiment where the formingtools die platen portions conductive portions RF generator circuit 200. In this configuration, the electric field is applied in the horizontal direction across thetablet shape 206. - As described above, the distance between conductive portions of the forming tool has a strong effect on field strength and heating effect. To create a tablet with uniform heating and texture, a forming tool that is constructed with equidistant spacing is desirable.
FIGS. 13A and 13B depict such a configuration. In this embodiment, a wave-shaped formingtools tablet 272 withindie platen 271 with a unique appearance. The profiles of the forming tool surfaces are equidistant as shown by dimension “X”. -
FIG. 14 is an embodiment wherein a non-uniform heating is used to manufacturetablet 282. In this embodiment, a tablet with hard and soft zones is created. The formingtools - In one embodiment, to help reduce sticking, the tablet is cooled within the forming cavity to cool and/or solidify the binder. The cooling can be passive cooling (e.g., at room temperature) or active cooling (e.g., coolant recirculation cooling). When coolant recirculation cooling is used, the coolant can optionally circulate through channels inside the forming tools (e.g., punches or punch platen) and/or die or die platen (e.g., as discussed above in
FIGS. 6A and 6B ). In one embodiment, the process uses a die platen having multiple die cavities and upper and lower punch platens having multiple upper and lower punched for simultaneous forming of a plurality of tablets wherein the platens are actively cooled. - In one embodiment, there is a single powder blend forming the tablet shape which is then heated with the RF energy. In another embodiment, the tablet is formed of at least two different powder blends, at least one powder blend being RF-curable and at least one formulation being not RF-curable. When cured with RF energy, such tablet shape develops two or more dissimilarly cured zones. In one embodiment, the outside area of the tablet shape is cured, while the middle of the tablet shape is not cured. By adjusting the focus of the RF heating and shape of the RF electrodes, the heat delivered to the tablet shape can be focused to create customized softer or harder areas on the finished tablet.
- In one embodiment the RF energy is combined with a second source of heat including but not limited to infrared, induction, or convection heating. In one embodiment, the addition of the second source of heat is particularly useful with a secondary non-RF-meltable binder present in the powder blend.
- In one embodiment, the powder blend is sealed within a chamber during the step with which the energy is applied, so that the water is contained and can be distributed throughout the powder blend. In one version of this embodiment, the sealed chamber consists of a die, and at least one heat source (e.g., RF applying electrode). In one embodiment, upon opening of the sealed chamber, the fused tablet is further dried in order to allow for the water to escape. This drying step may be achieved using the energy source or another source of heat.
- In one embodiment, microwave energy is used (e.g., in place of radiofrequency energy) to manufacture the tablet. Microwave heating generally refers to heating with electromagnetic field at frequencies from about 100 MHz to about 300 GHz. In one embodiment of the present invention, the RF-energy is within the range of frequencies from about 500 MHz to about 100 GHz (e.g., from about 1 GHz to 50 GHz, such as from about 1 GHz to about 10 GHz). The microwave energy is used to heat the water-containing material. In such an embodiment, a microwave energy source and microwave electrodes are used in the machine used to manufacture the tablet.
- Inserts within Tablet Shape
- In one embodiment, an insert is incorporated into the tablet shape before the energy is delivered. Examples include solid compressed forms or beads filled with a liquid composition. Such incorporation of an insert is depicted in
FIGS. 3A-3G . - In one embodiment the pharmaceutically active agent is in the form of a gel bead, which is liquid filled or semi-solid filled. The gel bead(s) are added as a portion of the powder blend. In one embodiment, the tablet of this invention has the added advantage of not using a strong compaction step, allowing for the use of liquid or semisolid filled particles or beads which are deformable since they will not rupture following the reduced pressure compaction step. These bead walls may contain gelling substances such as: gelatin; gellan gum; xanthan gum; agar; locust bean gum; carrageenan; polymers or polysaccharides such as but not limited to sodium alginate, calcium alginate, hypromellose, hydroxypropyl cellulose and pullulan; polyethylene oxide; and starches. The bead walls may further contain a plasticizer such as glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate and tributyl citrate. The pharmaceutically active agent may be dissolved, suspended or dispersed in a filler material such as but not limited to high fructose corn syrup, sugars, glycerin, polyethylene glycol, propylene glycol, or oils such as but not limited to vegetable oil, olive oil, or mineral oil.
- In one embodiment when RF energy is used, the insert is substantially free of RF-absorbing ingredients, in which case application of the RF energy results in no significant heating of the insert itself. In other embodiments, the insert contains ingredients and are heated upon exposure to RF energy and, thus, such inserts can be used to soften or melt the water-containing material and/or meltable binder.
- In certain embodiments, the tablet includes at least two layers, e.g., with different types and/or concentrations of water-containing material and/or other ingredients or different concentrations of pharmaceutically active agents. Such an embodiment is shown in
FIGS. 2A-2D . In one embodiment, the tablet includes two layers, one layer having orally disintegrating properties and another layer being chewable or swallowable. In one embodiment, one layer has a water-containing material and another layer does not have a water-containing material. In one embodiment one layer is compacted at higher compaction force versus the other layer. In one embodiment, both layers contain same amount of the water-containing material, but have different amount of pharmaceutically active agents and/or other excipients. In one embodiment, all properties of the two layers are identical but the colors of the two layers are different. - In one embodiment, the powder blend further contains one or more effervescent couples. In one embodiment, effervescent couple contains one member from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, and sodium carbonate, and one member selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, phosphoric acid, and alginic acid.
- In one embodiment, the combined amount of the effervescent couple(s) in the powder blend/tablet is from about 2 to about 20 percent by weight, such as from about 2 to about 10 percent by weight of the total weight of the powder blend/tablet.
- In one embodiment, the tablet is designed to disintegrate in the mouth when placed on the tongue in less than about 60 seconds, e.g. less than about 45 seconds, e.g. less than about 30 seconds, e.g. less than about 15 seconds.
- In one embodiment, the tablet meets the criteria for Orally Disintegrating Tablets (ODTs) as defined by the draft Food and Drug Administration guidance, as published in April, 2007. In one embodiment, the tablet meets a two-fold definition for orally disintegrating tablets including the following criteria: 1) that the solid tablet is one which contains medicinal substances and which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue and 2) be considered a solid oral preparation that disintegrates rapidly in the oral cavity, with an in vitro disintegration time of approximately 30 seconds or less, when based on the United States Pharmacopeia (USP) disintegration test method for the specific medicinal substance or substances.
- In one embodiment, the tablet is contained next to another edible form. In one embodiment, this edible form is a hard candy or compressed ring that holds the powder blend during compaction and/or the heating step.
- In one embodiment, the outer hard candy form may be made using uniplast rolling or roping and subsequent cutting and stamping, as well as depositing into molds. The hard candy portion contains one or more sugars selected from the group consisting of isomalt, sucrose, dextrose, corn syrup, lactitol, and lycasin. In one embodiment, the hard candy portion contains at least 50% (such as at least 75%, such as at least 90%) by weight of such sugar(s).
- In one embodiment, the outer edible form contains a pharmaceutically active agent and the inner tablet contains a second portion of the same pharmaceutically active agent that is in the outer edible form. In one embodiment, the outer edible form contains a pharmaceutically active agent and the inner tablet contains a different pharmaceutically active agent than that in the outer edible form. In one embodiment, the outer edible form disintegrates at a rate of at least 10 times, such as at least 20 times, the rate of the inner tablet. The first and second portions can be the same or different.
- In one embodiment, the tablet having an outer edible form and an inner tablet is coated with an immediate release sugar coating or film coating. In one embodiment, to produce such a tablet, the step following the fusing (heating) and subsequent cooling of the tablet would involve further sugar or film coating in a coating pan.
- In one embodiment, the tablet is prepared such that the tablet is relatively soft (e.g., capable of disintegrating in the mouth or being chewed). In one embodiment, the hardness of the tablet is preferably less than about 3 kiloponds per square centimeter (kp/cm2) (e.g., less than about 2 kp/cm2, such as less than about 1 kp/cm2).
- Hardness is a term used in the art to describe the diametral breaking strength as measured by conventional pharmaceutical hardness testing equipment, such as a Schleuniger Hardness Tester. In order to compare values across different size tablets, the breaking strength must be normalized for the area of the break. This normalized value, expressed in kp/cm2, is sometimes referred in the art as tablet tensile strength. A general discussion of tablet hardness testing is found in Leiberman et al., Pharmaceutical Dosage Forms—Tablets,
Volume 2, 2.sup.nd ed., Marcel Dekker Inc., 1990, pp. 213-217, 327-329. - A more preferred test for hardness of the tablet of the present invention relies upon a Texture Analyzer TA-XT2i that is fitted with a 7 millimeter diameter flat faced probe and setup to measure and report compression force in grams. The probe moves at 0.05 millimeters per second to a depth of penetration of 2 millimeters. The maximum compression force is recorded. In one embodiment, the measured forces recorded for tablets made in accordance with the present invention are less than 10,000 grams (e.g., less than about 1000 grams, such as less than about 700 grams. In one embodiment, the measured forces recorded for tablets made in accordance with the present invention ranges from about 100 grams to about 6000 grams, such as from about 100 grams to about 1000 grams, such as from about 75 grams to about 700 grams) with a deviation of ±50 grams. In another embodiment the measured forces recorded for tablets is less than 700 grams.
- In one embodiment, the density of the tablet is less than about 2 g/cc (e.g., less than about 0.9 g/cc, such as less than about 0.8 g/cc, such as less than about 0.7 g/cc). In one embodiment, the difference in the density of the powdered material following the compaction step is less than about 40 percent (e.g., less than about 25 percent, such as less than about 15 percent).
- In one embodiment, the tablet includes an additional outer coating (e.g., a translucent coating such as a clear coating) to help limit the friability of the tablet. Suitable materials for translucent coatings include, but are not limited to, hypromellose, hydroxypropylcellulose, starch, polyvinyl alcohol, polyethylene glycol, polyvinylalcohol and polyethylene glycol mixtures and copolymers, and mixtures thereof. Tablets of the present invention may include a coating from about 0.05 to about 10 percent, or about 0.1 to about 3 percent by weight of the total tablet.
- In one embodiment, the surface of the tablet shape and/or the tablet is further treated with energy (e.g., convection, infrared, or RF energy) to soften or melt the material on the surface of the tablet and then cooled or allowed to cool to further smooth the texture, enhance the gloss of surface of the tablet, limit the friability of the tablet, and/or provide a mark for identification. In one embodiment, the surface of the tablet is further exposed to infrared energy wherein the majority (at least 50 percent, such as least 90 percent, such as at least 99 percent) of the wavelength of such infrared energy is from about 0.5 to about 5 micrometers such as from about 0.8 to about 3.5 micrometers (e.g., by use of a wavelength filter). In one embodiment, the infrared energy source is a quartz lamp with a parabolic reflector (e.g., to intensify the energy) and a filter to remove unwanted frequencies. Examples of such infrared energy sources include the SPOT IR 4150 (commercially available from Research, Inc., Eden Prairie, Minn.).
- The tablets may be used as swallowable, chewable, or orally disintegrating tablets to administer the pharmaceutically active agent.
- In one embodiment, the present invention features a method of treating an ailment, the method including orally administering the above-described tablet wherein the tablet includes an amount of the pharmaceutically active agent effective to treat the ailment. Examples of such ailments include, but are not limited to, pain (such as headaches, migraines, sore throat, cramps, back aches and muscle aches), fever, inflammation, upper respiratory disorders (such as cough and congestion), infections (such as bacterial and viral infections), depression, diabetes, obesity, cardiovascular disorders (such as high cholesterol, triglycerides, and blood pressure), gastrointestinal disorders (such as nausea, diarrhea, irritable bowel syndrome and gas), sleep disorders, osteoporosis, and nicotine dependence.
- In one embodiment, the method is for the treatment of an upper respiratory disorder, wherein the pharmaceutically active agent is selected from the group of phenylephrine, cetirizine, loratadine, fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine, chlophedianol, and pseudoephedrine.
- In this embodiment, the “unit dose” is typically accompanied by dosing directions, which instruct the patient to take an amount of the pharmaceutically active agent that may be a multiple of the unit dose depending on, e.g., the age or weight of the patient. Typically the unit dose volume will contain an amount of pharmaceutically active agent that is therapeutically effective for the smallest patient. For example, suitable unit dose volumes may include one tablet.
- Specific embodiments of the present invention are illustrated by way of the following examples. This invention is not confined to the specific limitations set forth in these examples.
- The acetaminophen powder blend for an orally disintegrating tablet, containing the ingredients of Table 1, is manufactured as follows:
-
TABLE 1 Coated Acetaminophen Powder Blend Formulation Ingredient G/Batch Mg/Tablet Dextrose Monohydrate 6.14 552.78 Maltodextrin 0.6 54 Sucralose NF 0.06 5.4 D&C Yellow # 10 Al Lake0.01 0.54 Coated Acetaminophen (91%)* 1.94 174.78 Peppermint 0.1 9 Disodium H Phosphate 0.75 67.5 Dodecahydrate USP** Polyethylene Oxide NF 0.4 36 Total 10 900 *Commercially Available from Eurand in Vidalia, OH **Na2HPO4•7H2O -Commercially available from the Dow Corporation in Midland, MI
Each ingredient is screened through a 30 mesh screen, placed together into a 500 cc plastic bottle, and mixed end-over-end for 5 minutes. - A portion of the powder blend from Example 1 is placed into a ½ inch diameter forming cavity of an electrically insulative Teflon die platen. The powder blend is then tamped between an upper and lower flat-faced metal forming tools into a shape conformal to the surface of the forming tools. The tamping pressure is typically between 10 and approximately 50 psi of pressure. The forming tools, die platen and tablet shape are then placed between the upper RF electrode and lower RF electrode powered by an RF heating unit using a COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.) RF generator having an output of 4 KW of power, frequency of 27 MHz, and the vacuum capacitor is set at 140. The forming tools are heated with recirculating water at a temperature of 57° C. The upper RF electrode is brought into contact with the upper forming tool and the lower RF electrode is brought into contact with lower forming tool. The RF heating unit is energized for 2 to 5 seconds. The resulting tablet is then ejected from the die platen using the lower forming tool.
- All materials set forth in Table 2 below are manually passed through a 30 mesh screen. One and a half (1.5) kg of the resulting blend are then placed in a 4 quart V-Blender and mixed for 5 minutes.
-
TABLE 2 Weight Percent Ingredients (w/w) Weight (mg) Sorbitol 5 50 Compressible Sucrose* 92.75 927.5 Menthol 1 10 Peppermint Flavor 0.5 5 Magnesium Stearate 0.75 7.5 TOTAL 100 1000 *Commercially available from Domino Specialty Ingredients, Baltimore, MD
Four hundred grams (400 g) of the resulting blend is then removed from the blender and compressed on a rotary tablet press at 60 rpm using ¾″ ringed tablet tooling in order to yield flat faced rings having ½″ empty centers having a weight of 1000 mg, a hardness range of not less than 15 kp/cm2, and a thickness of about 0.20 inches. - An orally disintegrating immediate release loratadine powder blend formulation including the ingredients of Table 3 is manufactured as follows:
-
TABLE 3 Granulation Blend G/Batch Mg/Tablet Dextrose 86.67 433.3 Monohydrate Sodium Hydrogen 9.62 48.1 Phosphate Hydrate Sucralose USP 0.6 3 Flavor 1.12 5.6 Loratadine 2 10 Total 100 500 - Dextrose Monohydrate, sucralose and flavor are screened through a 30 mesh screen and placed into a 500 cc plastic bottle and mixed end-over-end for 5 minutes. The loratadine and sodium hydrogen phosphate hydrate are added and blended end over end for an additional 3 minutes.
- (c): Preparation of Outer Edible Ring with Fused Orally Disintegrating Tablet Inner Portion
- The resulting powder blend from part (b) is then removed from the blender. The edible outer ring portions from part (a) are individually placed into the forming cavity of a die platen as set forth in Example 2. The powder blend from part (b) is then placed in the center portion of the ring portions and gently tamped at 100 pounds in order to yield a dosage form and having a total weight of 1500 mg. The upper forming tool is then positioned at a distance of approximately 1 cm above the surface of the dosage form, and the RF electrodes are then energized for 2 to 5 seconds as set forth in Example 2. The resulting tablet is then ejected from the die platen using the lower forming tool.
- It is understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the claims.
Claims (21)
1-22. (canceled)
23. A process for making a tablet comprising introducing a powder blend into a die platen to form a tablet shape, wherein said powder blend comprises a pharmaceutically active agent, a carbohydrate, and a water-containing material, and applying energy to said tablet shape for a sufficient period of time to form said tablet.
24. A process of claim 23 , wherein said energy is radiofrequency energy.
25. The process of claim 23 , wherein said radiofrequency energy is applied to said tablet shape within said die platen.
26. The process of claim 23 , wherein said carbohydrate is selected from the group consisting of dextrose monohydrate, mannitol, erythritol, dextrose, lactose, sorbitol, isomalt, sucrose, and dextrates.
27. The process of claim 23 , wherein said carbohydrate is erythritol.
28. The process of claim 23 , wherein water is chemically bound to said water-containing material.
29. The process of claim 23 , wherein said powder blend is compacted with a force less than 0.3 kiloNewtons.
30. The process of claim 23 , wherein said radiofrequency energy has a frequency of from about 1 MHz to 100 MHz.
31. The process of claim 23 , wherein said tablet disintegrates in the mouth when placed on the tongue in less than about 30 seconds.
32. The process of claim 23 , wherein said tablet meets the criteria for orally disintegrating tablets as defined by the draft Food & Drug Administration guidance, as published April, 2007.
33. The process of claim 23 , wherein said tablet has a hardness of less than 700 grams as measure using Texture Analyzer TA-XT2i that is fitted with a 7 millimeter diameter flat faced probe.
34. The process of claim 23 , wherein said tablet has a density less than 0.7 g/cc.
35. The process of claim 23 wherein said process comprises the steps of:
(i) introducing said powder blend into a forming cavity within said die platen;
(ii) by introducing at least one forming tool into said die platen such that a tablet shape is formed;
(iii) applying said energy to said tablet shape, within said forming cavity to form said tablet; and
(iv) removing said tablet from said forming cavity.
36. The process of claim 35 , wherein said process further comprises the step of cooling said tablet in said die prior to removing said tablet from said die platen.
37. The process of claim 35 , wherein said energy is radiofrequency energy and at least one said forming tool emits said radiofrequency energy to said tablet shape.
38. The process of claim 35 , wherein said energy is radiofrequency energy and the die platen emits said radiofrequency energy to said tablet shape.
39. The process of claim 35 , wherein said energy is radiofrequency energy and said powder blend is compacted using an upper forming tool and a lower forming tool, and at least one of said upper forming tool or lower forming tool emits said radiofrequency energy to said tablet shape.
40. The process of claim 23 , wherein the surface of said tablet is further exposed to infrared energy wherein the majority of the wavelength of said infrared energy from about 0.5 to about 5 micrometers.
41. A tablet manufactured according to the process of claim 23 .
42. A tablet of claim 1, wherein said carbohydrate is erythritol.
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US12/887,582 Active 2032-03-20 US8784781B2 (en) | 2009-09-24 | 2010-09-22 | Manufacture of chewing gum product with radiofrequency |
US12/887,575 Active US8343533B2 (en) | 2009-09-24 | 2010-09-22 | Manufacture of lozenge product with radiofrequency |
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US14/693,112 Abandoned US20150224057A1 (en) | 2009-09-24 | 2015-04-22 | Orally transformable tablets |
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- 2010-09-23 WO PCT/US2010/049909 patent/WO2011038058A1/en active Application Filing
- 2010-09-23 AU AU2010298289A patent/AU2010298289B2/en not_active Ceased
- 2010-09-23 ES ES10760863.0T patent/ES2667845T3/en active Active
- 2010-09-23 EP EP10759791.6A patent/EP2480214B1/en not_active Not-in-force
- 2010-09-23 CN CN201510464891.0A patent/CN105055349A/en active Pending
- 2010-09-23 WO PCT/US2010/049931 patent/WO2011049706A1/en active Application Filing
- 2010-09-23 CN CN2010800539125A patent/CN102639119A/en active Pending
- 2010-09-23 EP EP10761099.0A patent/EP2480404B1/en active Active
- 2010-09-23 AU AU2010298272A patent/AU2010298272B2/en not_active Ceased
- 2010-09-23 KR KR1020127010101A patent/KR101746487B1/en active IP Right Grant
-
2011
- 2011-03-21 ES ES11710979T patent/ES2699195T3/en active Active
- 2011-09-28 US US13/246,884 patent/US20120022170A1/en not_active Abandoned
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2012
- 2012-12-12 HK HK12112865.3A patent/HK1171986A1/en not_active IP Right Cessation
- 2012-12-12 HK HK12112863.5A patent/HK1171955A1/en not_active IP Right Cessation
- 2012-12-14 HK HK12112962.5A patent/HK1171965A1/en not_active IP Right Cessation
- 2012-12-14 HK HK12112961.6A patent/HK1171964A1/en not_active IP Right Cessation
- 2012-12-18 US US13/718,357 patent/US8865204B2/en active Active
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2013
- 2013-01-30 HK HK13101320.4A patent/HK1174262A1/en not_active IP Right Cessation
- 2013-03-25 HK HK13103737.7A patent/HK1176862A1/en not_active IP Right Cessation
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2014
- 2014-08-08 US US14/455,126 patent/US9107807B2/en active Active
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2015
- 2015-04-22 US US14/693,112 patent/US20150224057A1/en not_active Abandoned
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8739251B2 (en) | 2008-07-14 | 2014-05-27 | International Business Machines Corporation | Apparatus and method for managing access among devices |
US8865204B2 (en) | 2009-09-24 | 2014-10-21 | Mcneil-Ppc, Inc. | Manufacture of lozenge product with radiofrequency |
US9107807B2 (en) | 2009-09-24 | 2015-08-18 | Mcneil-Ppc, Inc. | Machine for the manufacture of dosage forms utilizing radiofrequency energy |
US9233491B2 (en) | 2012-05-01 | 2016-01-12 | Johnson & Johnson Consumer Inc. | Machine for production of solid dosage forms |
US9445971B2 (en) | 2012-05-01 | 2016-09-20 | Johnson & Johnson Consumer Inc. | Method of manufacturing solid dosage form |
US9511028B2 (en) | 2012-05-01 | 2016-12-06 | Johnson & Johnson Consumer Inc. | Orally disintegrating tablet |
US20150196493A1 (en) * | 2014-01-10 | 2015-07-16 | Mcneil-Ppc, Inc. | Process for making tablet using radiofrequency and lossy coated particles |
US9789066B2 (en) * | 2014-01-10 | 2017-10-17 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
US10493026B2 (en) | 2017-03-20 | 2019-12-03 | Johnson & Johnson Consumer Inc. | Process for making tablet using radiofrequency and lossy coated particles |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: JOHNSON & JOHNSON CONSUMER INC., NEW JERSEY Free format text: MERGER AND CHANGE OF NAME;ASSIGNORS:MCNEIL-PPC, INC.;JOHNSON & JOHNSON CONSUMER INC.;REEL/FRAME:036042/0443 Effective date: 20150623 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |