US20110070301A1 - Orally transformable tablets - Google Patents

Orally transformable tablets Download PDF

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Publication number
US20110070301A1
US20110070301A1 US12/887,564 US88756410A US2011070301A1 US 20110070301 A1 US20110070301 A1 US 20110070301A1 US 88756410 A US88756410 A US 88756410A US 2011070301 A1 US2011070301 A1 US 2011070301A1
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US
United States
Prior art keywords
tablet
pharmaceutically active
binder
active agent
energy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/887,564
Other languages
English (en)
Inventor
Joseph R. Luber
Harry S. Sowden
Frank J. Bunick
Leo B. Kriksunov
David W. Wynn
Christopher E. Szymczak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Johnson and Johnson Consumer Inc
Original Assignee
McNeil PPC Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by McNeil PPC Inc filed Critical McNeil PPC Inc
Priority to US12/887,564 priority Critical patent/US20110070301A1/en
Priority to PCT/US2010/049931 priority patent/WO2011049706A1/en
Priority to MX2012003551A priority patent/MX2012003551A/es
Priority to CA2775110A priority patent/CA2775110A1/en
Priority to RU2012116335/15A priority patent/RU2012116335A/ru
Priority to CN201510464891.0A priority patent/CN105055349A/zh
Priority to AU2010308458A priority patent/AU2010308458B2/en
Priority to CN201080053917.8A priority patent/CN102639121B/zh
Priority to EP10759791.6A priority patent/EP2480214B1/en
Priority to KR1020127010289A priority patent/KR20120104187A/ko
Priority to BR112012007412A priority patent/BR112012007412A2/pt
Assigned to MCNEIL-PPC, INC. reassignment MCNEIL-PPC, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SOWDEN, HARRY S., WYNN, DAVID W., LUBER, JOSEPH R., SZYMCZAK, CHRISTOPHER E., KRIKSUNOV, LEO B., BUNICK, FRANK J.
Publication of US20110070301A1 publication Critical patent/US20110070301A1/en
Priority to HK12112863.5A priority patent/HK1171955A1/zh
Priority to US14/693,112 priority patent/US20150224057A1/en
Priority to AU2015203155A priority patent/AU2015203155B2/en
Abandoned legal-status Critical Current

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    • 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
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    • 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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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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    • B29C43/00—Compression moulding, i.e. applying external pressure to flow the moulding material; Apparatus therefor
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    • 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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    • 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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Definitions

  • Tablets typically 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 often because of the amount of pharmaceutically active agent to be delivered or for improving compliance of pediatric patients. Many patients, however, do not like chewable tablets. 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. However, these technologies are often impractical for use with tablets containing a large amount of pharmaceutically active agents, such as acetaminophen which can be dosed at 325 mg or greater per tablet.
  • the present invention relates to the discovery of such a tablet, including the use of such tablets and the process for making such tablets.
  • the present invention features a tablet including one or more pharmaceutically active agent(s), one or more thickeners, and one or more binder(s), wherein the tablet includes at least 200 mg of the pharmaceutically active agent(s) and the tablet has been fused with the binder(s) such that the tablet (i) has a water permeation time of less than 60 seconds and (ii) has an in vitro disintegration time of greater than 60 seconds.
  • the present invention features a method of administering one or more pharmaceutically active agent(s) by placing a solid tablet including the pharmaceutically active agent(s) into the mouth followed by swallowing a liquid, wherein the tablet includes at least 200 mg of the pharmaceutically active agent(s) and the tablet (i) has a water permeation time of less than 60 seconds and (ii) has an in vitro disintegration time of greater than 60 seconds.
  • the present invention features a process for making a tablet including at one or more pharmaceutically active agent(s) by the steps of: (a) forming a tablet shape including a powder blend including the pharmaceutically active agent(s) and a binder; and (b) applying energy to the tablet shape for a sufficient period of activate the binder within the tablet shape to fuse the tablet shape into the tablet, such that the tablet (i) has a water permeation time of less than 60 seconds and (ii) has an in vitro disintegration time of greater than 60 seconds.
  • FIGS. 1A-F are cross-section, side views of an embodiment of the invention showing the manufacture of tablet 4 a from powder blend 4 within die platen 2 .
  • FIGS. 2A-H are cross-section, side views of an embodiment of the invention showing the manufacture of a bilayer tablet 12 from powder blends 10 and 11 within die platen 2 .
  • FIGS. 3A-F are cross-section, side views of an embodiment of the invention showing the manufacture of tablet 40 containing preformed inserts 30 and 31 from powder blend 20 within die platen 2 .
  • FIGS. 4A and 4B are a perspective view of a rotary indexing machine 195 .
  • FIGS. 5A and 5B are top views of the rotary indexing machine 195 in the dwell position.
  • FIGS. 6A and 6B are section views of the lower forming tool assembly 110 in the start position of the manufacturing cycle.
  • FIG. 7 is a section view through the radiofrequency (“RF”) station rotary indexing machine 195 prior to compacting powder blend 101 .
  • RF radiofrequency
  • FIG. 8 is a section view through the RF station rotary indexing machine 195 prior showing the manufacture of tablets 101 a.
  • FIG. 9 is a section view through tablet ejection station 160 before tablets 101 a have been ejected.
  • FIG. 10 is a section view through tablet ejection station 160 after tablets 101 a have been ejected into blister 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.
  • FIG. 15 is a graph depicting the results of a water permeation test.
  • the present invention features a tablet including one or more pharmaceutically active agent(s), one or more thickeners, and one or more binder(s), wherein the tablet includes at least 200 mg of the pharmaceutically active agent(s) and the tablet has been fused with the binder(s) such that the tablet (i) has a water permeation time of less than 60 seconds and (ii) has an in vitro disintegration time of greater than 60 seconds.
  • the benefit of such a tablet is that it allows for the ease of swallowing of a tablet with a large amount of pharmaceutically active agent(s).
  • the tablet transforms from a solid tablet to a formless mass once placed in the mouth, which formless mass is then more easily swallowed (e.g., with a liquid, such as water).
  • the tablet is manufactured by compacting a powder blend containing pharmaceutically active agent(s), binder(s), thickener(s), and optionally a pharmaceutically-acceptable carrier.
  • binders include but are not limited to meltable binders and water-activating binding materials.
  • the carrier contains one or more suitable excipients for the formulation of tablets.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • superdisintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross-linked povidone (crospovidone).
  • the tablet contains up to about 5% by weight of such superdisintegrant.
  • 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
  • antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.
  • 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.
  • 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.
  • 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.
  • powder blend/tablet contains less than about 20 percent, by weight, of carbohydrates, such as less than about 10 percent, by weight, of carbohydrates, such as being substantially free of a carbohydrate.
  • 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).
  • sugars e.g., dextrose, sucrose, maltose, isomalt, and lactose
  • starches e.g., corn starch
  • sugar-alcohols e.g., mannitol,
  • 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 meltable binder.
  • 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.
  • the meltable binder is a RF-meltable binder.
  • an RF-meltable binder is a solid binder that can be softened or melted upon exposure to radiofrequency (“RF”) energy.
  • the RF-meltable binder typically is polar and has the capability to re-harden or resolidify upon cooling.
  • the meltable binder is not a RF-meltable binder.
  • 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.
  • 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.
  • 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.
  • the meltable binder is a RF-meltable binder
  • the RF-meltable binder is a polyethylene glycol (PEG), such as PEG-4000.
  • PEG polyethylene glycol
  • 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.
  • the meltable binder(s) may be present at level of about 0.01 percent to about 50 percent by weight of the powder blend/tablet, such as from about 1 percent to about 40 percent, such as from about 5 percent to about 30 percent of the powder blend/tablet, such as from about 10 percent to about 20 percent of the powder blend/tablet.
  • the powder blend/tablet contains at least 1 percent by weight, such as at least 5 percent by weight, such as at least 10 percent by weight of the powder blend/tablet.
  • the powder blend/tablet of the present invention includes at least one water-containing material.
  • water-containing materials include, but are not limited to, materials wherein the water is chemically bound to the material (e.g., a hydrate salt), 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).
  • 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.
  • the powder blend/tablet contains at least one hydrated salt.
  • hydrated salts include, but are not limited to, sodium sulfate hydrate, sodium carbonate hydrate, calcium chloride hydrate, sodium hydrogen phosphate hydrate, and mixtures thereof.
  • the hydrated salt has molecular weight from about 150 to about 400 Daltons, such as from about 200 to about 350 Daltons.
  • the powder blend/tablet contains at least one liquid filled capsule.
  • 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.
  • the powder blend/tablet of the present invention includes at least one water-activating binding material.
  • a water-activating binding material is a material that will activate or hydrate upon contact with water (e.g. released from the water containing material upon the addition of the energy) and assist in binding/fusing the powder blend into a tablet.
  • examples of such materials include, but are not limited to, hydrolyzed proteins, hydrating polymers and hydrocolloids.
  • Suitable hydrolyzed proteins include, but are not limited to, hydrolyzed collagen.
  • Suitable hydrating polymers include, but are not limited to starches, modified starches, methylcellulose, hydroxypropylcellulose, and hydroxypropylcellulose.
  • Suitable hydrocolloids include, but are not limited to, gelatin, gellan gum, carrageenan, and pectin.
  • the powder blend contains at least one thickener, which allows the tablet to be transformed into a formless mass upon contact with an aqueous liquid, and which facilitates swallowing.
  • thickeners include but are not limited to hydrocolloids (also referred to herein as gelling polymers), gelling starches, crystallizable carbohydrates, and polyethylene oxides.
  • hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, and chitosan.
  • Suitable clays include but are not limited to smectites such as bentonite, kaolin, and laponite, magnesium trisilicate, and magnesium aluminum silicate.
  • suitable gelling starches include but are not limited to acid hydrolyzed starches.
  • crystallizable carbohydrates include but are not limited to monosaccharides such as aldohexoses (e.g., the D and L isomers of allose, altrose, glucose, mannose, gulose, idose, galactose, and talose) and the ketohexoses (e.g., the D and L isomers of fructose and sorbose) along with their hydrogenated analogs (e.g., sorbitol and mannitol).
  • aldohexoses e.g., the D and L isomers of allose, altrose, glucose, mannose, gulose, idose, galactose, and talose
  • ketohexoses e.g., the D and L isomers of fructose and sorbose
  • their hydrogenated analogs e.g., sorbitol and mannitol
  • the thickener may be present at level of about 0.1 percent to about 25 percent of the powder blend/tablet, such as from about 2 percent to about 15 percent or from about 4 percent to about 10 percent of the powder blend/tablet.
  • the powder blend/tablet of the present invention includes at least one pharmaceutically active agent.
  • 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.
  • analgesics e.g., 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., statin
  • 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., aluminum
  • 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.
  • 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
  • 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,
  • 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.
  • muscle relaxants include, but are not limited to, cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, and methocarbamol; isomers thereof; and pharmaceutically acceptable salts and prodrugs thereof.
  • stimulants include, but are not limited to, caffeine.
  • 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.
  • sleep aids such as antihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, and pharmaceutically acceptable salts and prodrugs thereof.
  • appetite suppressants include, but are not limited to, phenylpropanolamine, phentermine, and diethylcathinone, and pharmaceutically acceptable salts and prodrugs thereof
  • anesthetics include, but are not limited to dyclonine, benzocaine, and pectin and pharmaceutically acceptable salts and prodrugs thereof.
  • statins include but are not limited to atorvastin, rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin, pravastatin and pharmaceutically acceptable salts and prodrugs thereof.
  • the pharmaceutically active agent included within the tablet is selected from acetaminophen, antacids, a vitamin, metformin, and pharmaceutically acceptable salts thereof.
  • 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
  • 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.
  • the pharmaceutically active agents of the present invention may also be present in the form of prodrugs of the pharmaceutically active agents.
  • 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.
  • the invention provides the esters, amides, and other protected or derivatized forms of the described compounds.
  • the pharmaceutically active agents according to this invention 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.
  • 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.
  • 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.
  • the particles typically have an average particle size of from about 1 to about 2000 microns.
  • such particles are crystals having an average particle size of from about 1 to about 300 microns.
  • 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.
  • he pharmaceutically active agent may be present in the form of an uncoated particle (e.g., in crystal form).
  • an uncoated particle has the benefit of reducing cost associated with the pharmaceutically active agent and size of the particle (e.g., grittiness).
  • the pharmaceutically active agent may be coated with a taste masking coating, as known in the art.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • polyalkylene glycols include polyethylene glycol.
  • suitable thermoplastic polyalkylene oxides include poly (ethylene oxide).
  • 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).
  • enteric cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose
  • 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).
  • a water insoluble film forming polymer such as but not limited to cellulose acetate or ethylcellulose
  • 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.
  • 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
  • the weight percent of the coating by weight of the coated taste-masked particle is from about 5 percent
  • 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.
  • the susceptibility to energy of the pharmaceutically active agent can have an impact on the type of energy and/or temperature used during the heating step as well as the type of the binder used.
  • the processing of the tablet is free of a wet or hot melt granulation step.
  • the materials are directly blended prior to the addition of heat.
  • the materials are directly blended and compressed prior to the addition of heat.
  • the tablet contains at least 200 mg of one or more pharmaceutically active agent(s) (i.e., the combined weight of the pharmaceutically active agent(s) in the tablet), such as at least 300 mg of one or more pharmaceutically active agent(s), such as at least 500 mg of one or more pharmaceutically active agent(s), such as at least 1000 mg of one or more pharmaceutically active agent(s).
  • the pharmaceutically active agent(s) is present at level of at least about 25 percent by weight of the powder blend/tablet, such as at least about 50 percent by weight of the powder blend/tablet, such as at least about 75 percent by weight of the powder blend/tablet.
  • 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.
  • 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).
  • the dissolution characteristics of the pharmaceutically active agent are modified: e.g. controlled, sustained, extended, retarded, prolonged, delayed and the like.
  • 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 meltable binder.
  • the pharmaceutically active agent or coated pharmaceutically active agent(s) is greater than 50% of the blend by weight of the powder blend/tablet and the mean particle size of the carbohydrate is greater than 100 microns
  • the meltable binder is from about 10 to about 30 percent by weight of the powder blend/tablet.
  • meltable binder is from about 10 to about 20 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 meltable binder used.
  • the melting point of the meltable binder is less than the melting point of the pharmaceutically active agent.
  • the melting point of the pharmaceutically active agent is the same or lower than the melting point of the meltable binder, in which case during the fusing or heating step, both the pharmaceutically active agent and the meltable binder may melt and create a eutectic or various bridges of the pharmaceutically active agent and meltable binder between the other materials in the tablet form upon cooling.
  • the heating temperature is above the melting point of the meltable binder and below the melting point of the pharmaceutically active agent.
  • the meltable binder is heated from about 30° C. to about 60° C.
  • the pharmaceutically active agent is the meltable binder.
  • the pharmaceutically active agent is in the form of a particle that is coated with the binder.
  • binder coated particles include, but are not limited to, meltable materials such as glyceryl palmitostearate.
  • the tablet shape is pre-formed by light compaction.
  • 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.
  • 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).
  • the tablet shape is heated after it is removed from the tablet press.
  • the tablet shape is heated within the tablet press.
  • the tablet's construction may be highly porous, use a minimal amount of binder, and/or have a low density (e.g., to allow the tablet to collapse in the oral cavity).
  • a minimum of tamping/compaction force is desired to achieve the orally transformable property (low density).
  • the heat source and the heat sink are two distinct machines or steps requiring material to be transferred from one apparatus to the other.
  • 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.
  • the metallic forming tool e.g., a die punch
  • the metallic forming tool 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.
  • heat was added to the forming tools to achieve proper sintering at the surface as well as at the center of the tablet.
  • 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.
  • 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 transformable tablets.
  • the compaction step (e.g., tamping) which occurs prior to the addition of the energy utilizes a compaction force which is less than the force required to compress a chewable or swallowable tablet.
  • 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).
  • the energy is applied while the powder blend is under such force.
  • the compaction step occurs in an indexed manner, where one set of tablets are compacted simultaneously, before rotating to another indexing station.
  • the compaction step occurs at a single indexing station and the application of energy occurs at a separate indexing station.
  • 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.
  • the compaction step is performed through the addition of air pressure or hydraulic cylinder to the top of the upper forming tools.
  • multiple tablets are ejected simultaneously and separated from the surface of the indexing station and removed via a take-off bar.
  • the tablet shape may be prepared by the compaction methods and apparatus described in United States Patent Application Publication No. 20040156902.
  • 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.
  • the energy source e.g., RF energy source
  • the die table is constructed of non-conductive material.
  • 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.
  • a wet binder e.g., an aqueous cooked starch paste or solution of polyvinyl pyrrolidone
  • 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 binders 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 gran
  • 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.
  • 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.
  • a tablet shape has one or more major faces.
  • 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.
  • 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.
  • the method of producing the tablet shape is substantially free of the use of solvents.
  • 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.
  • 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).
  • 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”).
  • 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) die platen 2 .
  • Die platen 2 has forming cavity 5 with inner wall 6 , upper opening 7 on the upper surface of die platen 2 (which allows powder blend 4 and upper forming tool 1 to move into the forming cavity 5 ), and lower opening 8 on the opposite surface of die platen 2 (which allows powder blend 4 and lower forming tool 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 forming tool 3 is inserted into the die platen to retain the powder blend 4 , within die platen 2 .
  • a similar metallic, electrically conductive upper forming tool 1 is positioned above the die platen 2 as shown in FIG. 1B .
  • the forming tools 1 and 3 , die platen 2 , and powder blend 4 are then moved to a compaction and RF heating station as shown in FIG. 1C to form tablet shape 4 a.
  • This heating station is comprised of an RF generator 7 which produces the necessary high voltage, high frequency energy.
  • the generator 7 is electrically connected to movable upper RF electrode plate 8 and movable lower RF electrode plate 6 .
  • the powder blend 4 is compacted between an upper forming tool 1 and a lower forming tool 3 by pressure exerted by upper RF electrode plate 8 and lower electrode plate 6 to form tablet shape 4 a.
  • Tablet shape 4 a is then exposed to RF energy from RF generator 7 , which heats the meltable binder within tablet shape 4 a. After the RF energy is switched off, tablet shape 4 a cools to form the tablet 4 b .
  • FIG. 1 C the powder blend 4 is compacted between an upper forming tool 1 and a lower forming tool 3 by pressure exerted by upper RF electrode plate 8 and lower electrode plate 6 to form tablet shape 4 a.
  • Tablet shape 4 a is then exposed to RF energy from RF generator 7 , which heats the meltable binder within tablet shape 4 a
  • tablet 4 b is pushed by upper forming tool 1 from the die platen 2 into blister 8 , which is used to package tablet 4 b.
  • tablet 4 b is pushed from the die platen 2 by the lower forming tool 3 and guided to an ejection chute by a stationary “take-off” bar (not shown).
  • FIG. 1F shows a 3 dimensional representation of the forming tools 1 and 4 , die platen 2 , and tablet 4 b.
  • FIGS. 2A-2H an alternate embodiment of the invention is shown where a multilayer tablet is produced.
  • powder blend 10 is filled into die platen 2 as shown in FIG. 2A .
  • Powder blend 10 is tamped or moved down into die platen 2 by upper forming tool 1 as shown in FIG. 2B to form tablet shape 10 a.
  • powder blend 11 is then filled on top of tablet shape 10 a.
  • the forming tools 1 and 3 , die platen 2 , tablet shape 10 a and powder blend 11 are then moved to the compaction and RF heating station as shown in FIG. 2E .
  • RF heating is accomplished as described above in FIG. 1C to produce multilayer tablet 12 as shown in FIGS. 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 die platen 2 .
  • FIGS. 3A-3G show another embodiment of the invention where preformed inserts 30 and 31 are inserted into tablet shape 20 a as shown in FIGS. 3A-3D .
  • Forming tools 1 and 3 , die platen 2 , tablet shape 20 , and preformed inserts 30 and 31 are then moved to the compaction and RF heating station as shown in FIG. 3E .
  • RF heating is accomplished as described above in FIG. 1C to produce a multi-component tablet 40 shown in FIGS. 2F and 2G .
  • FIGS. 4A and 4B show two views of a rotary indexing machine 195 which is designed to create large quantities of tablets.
  • 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 of die platens 175 each having sixteen cavities, powder feeder 100 , RF generator 150 , a machine frame 140 , moving RF electrode assemblies 120 and 130 , lower forming tool assembly 110 , upper forming tool assembly 210 , tablet ejection station 160 , indexer drive system 180 , blister package web 190 , and blister lid 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 forming tool assembly 110 in a start position of the manufacturing cycle.
  • the lower forming tools 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 the retainer plate 112 and contains fluid passages 117 b. Heated (or optionally cooling) fluid is circulated through the heated block 117 by connections to flexible hoses 119 a and 119 b which form a supply and return circuit.
  • Heating can also be accomplished by electric cartridge heaters or other suitable means (not shown).
  • Attached to the retainer plate are cam-follower 114 and linear bearing 113 .
  • a guide shaft 116 is fixed to indexing table 170 .
  • the retainer plate and forming tools 111 and are moveable up or down according to the profile of barrel cam 115 which cam follower 114 rolls upon.
  • die 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 forming cavity 171 a is shown empty at this stage of the process.
  • FIG. 6B depicts a section through the powder feeder station 100 of the apparatus.
  • powdered powder blend 101 is gravity fed into die platen 171 .
  • Movable cam segment 118 is adjusted up or down in direction “B” to vary the volume of the forming cavity 171 a by changing the amount that the lower forming tools 111 penetrate into the die platen 171 .
  • This adjustable volume feature enables the precise dose of powdered powder blend to be selected for a desired tablet weight.
  • the rim of feeder 102 scrapes against the die platen 171 to create a level powder surface relative to the surface of the die platen 171 .
  • FIG. 7 is a section view through the RF station of the apparatus.
  • the RF generator 150 is depicted symbolically here.
  • the configuration of the RF 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 of such RF generator 150 is the COSMOS Model C10X16G4 (Cosmos Electronic Machine Corporation, Farmingdale, N.Y.).
  • 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.
  • a lower movable 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 in FIG. 7 .
  • Air cylinder bodies 141 and 142 apply pressure to guide rods 144 and 143 .
  • Moving platens 132 and 122 are connected to the guide rods and provide an electrically isolated mounting for electrode plates 131 and 121 .
  • RF generator 150 connects to the electrode plates 131 and 121 through wires 185 and 184 .
  • a movable upper RF electrode assembly 130 movable in direction “C”, is shown in its up position.
  • Upper forming tools 133 , retainer plate 134 , and heated block 135 are all attached to the movable RF electrode plate 131 and, consequently, move up and down with it.
  • Powder blend 101 is within die platen 171 .
  • FIG. 8 is a section through the same RF station but shows the RF electrodes 131 and 121 pressing against the respective forming tool assemblies 133 and 111 to both compact and apply RF energy to powder blend 101 creating tablet 101 a. After application of the RF energy is stopped, the moveable RF electrode plates retract, and the indexing plate 170 , die platen 171 , and lower forming tool assembly 110 are indexed to the next station.
  • FIG. 9 is a section view through the tablet 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 the movable plate 162 .
  • Linear bearing 164 and guide rod 165 provide rigidity and support for the actuator plate 162 and prevent destructive side loads created by the ejection force from acting upon actuator 163 .
  • a blister package 190 is shown below die platen 171 .
  • FIG. 10 is a section through the same assembly after the ejector pins 161 have pushed finished tablets 101 a through the die 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.
  • 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.
  • 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.
  • the presence of a hydrophobic lubricant can disadvantageously compromise the disintegration or dissolution properties of a tablet.
  • the tablet is substantially free of a hydrophobic lubricant.
  • Hydrophobic lubricants include magnesium stearate, calcium stearate and aluminum stearate.
  • Suitable sources of energy include but are not limited to convection, radio frequency, microwave, UV light, infrared, induction, laser light, and ultrasonic sound.
  • radiofrequency energy is used.
  • Radiofrequency heating generally refers to heating with electromagnetic field at frequencies from about 1 MHz to about 100 MHz.
  • 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 activate the binder.
  • the degree of compaction, the type and amount of binder, and the amount of energy used can determine the hardness and/or type of tablet.
  • 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.
  • the RF electrodes are in direct contact with the surface of the tablet shape when the RF energy is added.
  • the RF electrodes are not in contact (e.g., from about 1mm to about 1 cm from the surface of the tablet shape) during the addition of the RF energy.
  • 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.
  • the RF energy is applied for a sufficient time to soften and melt substantially all (e.g., at least 90%, such as at least 95%, such as all) of the binder within the tablet shape. In one embodiment, the RF energy is applied for a sufficient time to soften and melt only a portion (e.g., less than 75%, such as less than 50%, such as less than 25%) of the binder within the tablet shape, for example only on a portion of the tablet shape, such as the outside of the tablet shape.
  • 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.
  • An RF generator 200 is connected to RF electrode plates 201 and 202 .
  • Forming tools 205 and 204 are constructed of an electrically conductive material and they have an attachment 207 and 208 which are made of electrical and RF energy insulative material such as ceramic, Teflon®, polyethylene, or high density polyethylene.
  • Die 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. 11A shows one such configuration.
  • An RF generator 200 is connected to RF electrode plates 201 and 202 .
  • Forming tools 205 and 204 are constructed of an electrically conductive material and they have an attachment 207 and 208 which are made of
  • FIG. 11B depicts a similar configuration but with forming tools 210 and 211 that, respectively, have a recess containing insert 213 and 212 which are made of electrical and RF energy insulative material.
  • This geometry will produce a tablet with lesser heating in the area where the inserts 213 and 212 are located since the electric field is weaker due to the greater distance between the conductive portions of 211 and 210 .
  • FIG. 11C is similar to FIG. 11B only the geometry is reversed so the tablet formed by this configuration will have a greater heating effect at the center since the inserts 216 and 217 are at the periphery of respective forming tools 214 and 215 .
  • 11D depicts another embodiment whereby the die platen is constructed of an electrically conductive component 221 and electrically insulating component 222 , which is made of electrical and RF energy insulative material.
  • Forming tools 219 and 218 are electrically conductive, but forming tool 218 further contains second electrically insulating component 220 around the surface of upper forming tool 218 which contact 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 to FIG. 11D except the die platen 233 in this embodiment is constructed entirely of electrically conductive material.
  • FIG. 12B further includes insulating component 220 around the surface of lower forming tool 219 .
  • FIG. 12D is a further embodiment where the forming tools 263 and 262 are made of electrical and RF energy insulative material.
  • the die platen portions 264 and 265 are made of electrical and RF energy insulative material, but there are two respective electrically conductive portions 267 and 266 which are attached to the RF generator circuit 200 . In this configuration, the electric field is applied in the horizontal direction across the tablet shape 206 .
  • FIG. 13A and 13B depict such a configuration.
  • a wave-shaped forming tools 270 and 273 are shown to create a tablet 272 within die 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 manufacture tablet 282 .
  • a tablet with hard and soft zones is created.
  • the forming tools 280 and 281 are made with protrusions at the surface that create high field strength (resulting in greater heating) where they are closest together (shown by the dimension “Z”) and weaker field strength (resulting in lesser heating) where they are further apart (shown by the dimension “Y”).
  • 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).
  • 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 ).
  • 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.
  • the tablet shape there is a single powder blend forming the tablet shape which is then heated with the RF energy.
  • 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.
  • the RF energy is combined with a second source of heat including but not limited to infrared, induction, or convection heating.
  • a second source of heat including but not limited to infrared, induction, or convection heating.
  • the addition of the second source of heat is particularly useful with a secondary non-RF-meltable binder present in the powder blend.
  • 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.
  • the sealed chamber consists of a die, and at least one heat source (e.g., RF applying electrode).
  • the fused tablet upon opening of the sealed chamber, 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.
  • 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.
  • 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 binder (e.g., either directly when the meltable binder is susceptible to microwave energy (“microwave meltable binder”) or indirectly when the meltable binder is not a microwave meltable binder but is heated by a microwave heatable ingredient within the powder blend.
  • a microwave energy source and microwave electrodes are used in the machine used to manufacture the dosage form.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • the insert contains ingredients and are heated upon exposure to RF energy and, thus, such inserts can be used to soften or melt the meltable binder.
  • the tablet includes at least two layers, e.g., with different types and/or concentrations of binders and/or other ingredients or different concentrations of pharmaceutically active agents. Such an embodiment is shown in FIGS. 2A-2D .
  • the tablet includes two layers, one layer having orally disintegrating properties and another layer having the disintegration properties upon contact with water as described in the water permeation test.
  • one layer has a binder and another layer does not have a binder.
  • one layer is compacted at higher compaction force versus the other layer.
  • one layer is compacted and the other layer is formed or shaped by a preform step and then fused utilizing the thermal methods described herein.
  • one layer is fused using one level of thermal energy and a second layer is fused using a second level of thermal energy.
  • both layers contain same amount of the binder, but have different amount of pharmaceutically active agents and/or other excipients.
  • all properties of the two layers are identical but the colors of the two layers are different.
  • the powder blend further contains one or more effervescent couples.
  • 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.
  • 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.
  • the tablet is prepared such that the tablet is relatively soft (e.g., capable of disintegrating in the mouth or being chewed).
  • the hardness of the tablet is preferably less than about 3 kiloponds per square centimeter (kp/cm 2 ) (e.g., less than about 2 kp/cm 2 , such as less than about 1 kp/cm 2 ).
  • 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/cm 2 , is sometimes referred in the art as tablet tensile strength.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • a translucent coating such as a clear coating
  • 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.
  • the tablet has a water permeation time of less than 60 seconds, such as less than 30 seconds, such as less than 15 seconds.
  • water permeation time is the amount of time it takes for a 5 millimeter diameter flat faced probe, at 25 grams of force, to penetrate 2 mm through the tablet following immersion of the tablet deionized water at 25° C.
  • a texture analyzer such as Texture Analyzer TA-XT2i, that is fitted with the 5 millimeter diameter flat faced probe is used.
  • the texture analyzer is set to measure and report the distance in mm that the probe penetrates into the submersed tablet.
  • the tablet is placed into a 1 oz. plastic cup and the probe is placed along the longest axis (the circumference).
  • the probe is activated so that it pushes against the tablet. Ten seconds after the probe is activated and pushing against the tablet, deionized water at 25° C. is added to the cup in an amount to cover the tablet. The distance the probe penetrates into the tablet is then recorded over time. The amount of time it takes for the probe to penetrate 1 mm through the tablet is recorded as the water permeation time.
  • the tablet has an in vitro disintegration time of greater than 60 seconds, such as less than 180 seconds, such as less than 300 seconds.
  • in vitro disintegration time is the amount of time it takes for the tablet to fully disintegrate utilizing the disintegration test and apparatus as described in the General Chapter Section 701 of the United States Pharmacopeia (USP), wherein the disintegration apparatus is fitted with a 10 mesh screen and the disintegration of the tablet is observed in water at 37° C.
  • 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.
  • energy e.g., convection, infrared, or RF energy
  • 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).
  • 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.
  • a parabolic reflector e.g., to intensify the energy
  • a filter e.g., to remove unwanted frequencies.
  • examples of such infrared energy sources include the SPOT IR 4150 (commercially available from Research, Inc., Eden Prairie, Minn.).
  • 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.
  • 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.
  • 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.
  • the pharmaceutically active agent is selected from the group of phenylephrine, cetirizine, loratadine, fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine, chlophedianol, and pseudoephedrine.
  • 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.
  • the unit dose volume will contain an amount of pharmaceutically active agent that is therapeutically effective for the smallest patient.
  • suitable unit dose volumes may include one tablet.
  • the solid tablet is designed to collapse to form a semi-solid mass upon administration in the mouth. This mass is then swallowed with the assistance of a aqueous liquid such as water. As being a semisolid, it is much easier to swallow than a hard tablet.
  • the volume of the semisolid mass is not more than 10 times the volume of the tablet prior to placement into an aqueous liquid at 37° C. at 60 seconds.
  • the tablet shapes of Table 1 were prepared as follows. The sucralose, peppermint flavor and tapioca maltodextrin were manually passed through a 50 mesh screen. The acetaminophen (APAP) granular, polyethylene glycol (PEG), and polyethylene oxide (PEO) were added to the above mixture in a plastic bottle, mixed end-over end for approximately three minutes, and then discharged. The blend was then individually dosed into a simulated capsule-like medicament (“caplet”) die utilizing 624 mg of the blend per tablet. The tablet shapes were then heated using convection heat to fuse the granulation into a unified tablet.
  • APAP acetaminophen
  • PEG polyethylene glycol
  • PEO polyethylene oxide
  • ibuprofen crystals (particle size grade 110 ⁇ m) is charged into a Glatt fluid bed GPCG 5/9 coater equipped with a Wurster Insert.
  • Glyceryl palmitostearate commercially available from the Gattefosse Corporation (St-Priest, France) as Precirol ATO is placed into a suitable stainless steel container and melted at 70 degrees Celsius until it is completely melted. The melted material is then sprayed onto the ibuprofen at a spray rate of approximately 20 g/minute while fluidizing at a product temperature of approximately 30 degrees Celsius. The coated ibuprofen is then discharged from the unit.
  • the tablet shapes of Table 3 are prepared as follows.
  • the sucralose, peppermint flavor, and tapioca maltodextrin are manually passed through a 50 mesh screen.
  • the coated ibuprofen, polyethylene glycol, and polyethylene oxide are added to the above mixture in a plastic bottle, mixed end-over end for approximately three minutes, and then discharged.
  • the blend is then individually dosed into a simulated capsule-like medicament (“caplet”) die utilizing 624 mg of the blend per tablet.
  • caplet simulated capsule-like medicament
  • the tablet shapes are then heated using convection heat to fuse the granulation into a unified tablet.
  • the water permeation test was performed utilizing the Texture Analyzer TAXT Plus, commercially available from Texture Technologies in Scarsdale, N.Y., equipped with a TA-55 probe.
  • the following tablets were analyzed: (i) a tablet of Example 1; (ii) a Motrin® 100 mg Chewable tablet, commercially available from McNeil Consumer Healthcare (Fort Washington, Pa.); and (iii) Tylenol® 160 mg Meltaways, commercially available from McNeil Consumer Healthcare. The results are depicted in FIG. 15 .
  • Example 1 disintegrated immediately following the addition of the water as indicated by the probe distance, which increased to almost 2 mm within 10 seconds following immersion in water.
  • the two reference chewable tablets did not disintegrate until after 170 seconds following immersion, when the probe distance increased to more than 1 mm.
  • the tablets of the present invention were analyzed utilizing the disintegration apparatus described in the United States Pharmacopeia (USP 33-NF 28), Section ⁇ 701>, wherein the apparatus was equipped with a 10 mesh screen.
  • the tablet formulations from Example 2 were used, having various levels of the hydrocolloid polyethylene oxide, in order to observe the effect of this hydrocolloid on the disintegration time.
  • Example 2F the presence of the effervescent couple citric acid and sodium bicarbonate were added to the blend in order to evaluate its effect on disintegration.
  • the commercially available fast disintegrating tablets Nurofen Meltlets and Risperdal M-Tabs were also tested. The results are shown in Table 4. The results indicate that while they broke down into a semisolid mass in the water, the samples with higher levels of hydrocolloid were remained as a semi solid mass and did not fully pass through the screen for over well over 60 seconds.
  • Example 2A 0.0 Disintegrated in 12 seconds
  • Example 2B 1.0 Disintegrated in 20 seconds
  • Example 2C 4.8 Disintegrated in 300 seconds
  • Example 2D 7.1 Intact at 300 seconds
  • Example 2E 9.2 Intact at 300 seconds
  • Example 2F 6.2 Disintegrated in 65 seconds Nurofen Meltlets a NA Disintegrated in 75 seconds Risperdal M-Tab b NA Disintegrated in 2 seconds Children's Tylenol Meltaways c NA Disintegrated in 180 seconds a Nurofen Meltlets (Commercially available from Crookes Healthcare, in Nottingham, UK) b Risperdal M-Tab Orally Disintegrating Tablet (Commercially available from Janssen Corporation, in New Brunswick, NJ) c Children's Tylenol Meltaways (Commercially available from McNeil Consumer Healthcare in Fort Washington, PA)
  • the tablet shapes of Table 5 are prepared as follows.
  • the sucralose, peppermint flavor and tapioca maltodextrin are manually passed through a 50 mesh screen.
  • the acetaminophen (APAP) granular, sodium hydrogen phosphate hydrate are added to the above mixture in a plastic bottle, mixed end-over end for approximately three minutes, and then discharged.
  • the blend is then individually dosed into a simulated capsule-like medicament (“caplet”) die utilizing 624 mg of the blend per tablet.
  • the die is constructed of a non-conductive plastic and the forming tools are in operably associated with the electrodes within an Rf unit.
  • the tablet shapes are then heated and activated utilizing Rf energy for 2 to 5 seconds to sinter the powder blend into a unified tablet.
  • the tablet is then ejected from the die platen.
  • Example 6 The tablet shapes and resulting tablets of Table 6 are prepared as above in Example 6.
  • APAP 500 mg Tablet Shape Formulation Material G/Batch mg/tab Weight % Sucralose 0.68 4.0 0.68 Peppermint Flavor 1.71 10.0 1.71 APAP Granular (uncoated granulation) 85.6 500.0 85.6 Tapioca Maltodextrin (N-Zorbit M) 5.14 30.0 5.14 Polyethylene Oxide NF 2 2.57 15.0 2.57 Carnauba wax 1 4.28 25.0 4.28 TOTAL 100.0 584.0 100.0 1 Microcare 350 commercially available from Micro Powders Inc. (Tarrytown, NY) 2 Polyox WSR 303 commercially available from Dow Corporation (Midland, MI)

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US12/887,564 US20110070301A1 (en) 2009-09-24 2010-09-22 Orally transformable tablets
CN201080053917.8A CN102639121B (zh) 2009-09-24 2010-09-23 可口腔转化的片剂
EP10759791.6A EP2480214B1 (en) 2009-09-24 2010-09-23 Orally transformable tablets
CA2775110A CA2775110A1 (en) 2009-09-24 2010-09-23 Orally transformable tablets
RU2012116335/15A RU2012116335A (ru) 2009-09-24 2010-09-23 Таблетки, преобразуемые в ротовой полости
CN201510464891.0A CN105055349A (zh) 2009-09-24 2010-09-23 可口腔转化的片剂
AU2010308458A AU2010308458B2 (en) 2009-09-24 2010-09-23 Orally transformable tablets
PCT/US2010/049931 WO2011049706A1 (en) 2009-09-24 2010-09-23 Orally transformable tablets
MX2012003551A MX2012003551A (es) 2009-09-24 2010-09-23 Tabletas transformables via oral.
KR1020127010289A KR20120104187A (ko) 2009-09-24 2010-09-23 구강내 변형가능 정제
BR112012007412A BR112012007412A2 (pt) 2009-09-24 2010-09-23 tabletes transformáveis de forma oral.
HK12112863.5A HK1171955A1 (zh) 2009-09-24 2012-12-12 可口腔轉化的片劑
US14/693,112 US20150224057A1 (en) 2009-09-24 2015-04-22 Orally transformable tablets
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US12/887,544 Active 2031-04-05 US8871263B2 (en) 2009-09-24 2010-09-22 Manufacture of tablet in a die utilizing radiofrequency energy and meltable binder
US12/887,564 Abandoned US20110070301A1 (en) 2009-09-24 2010-09-22 Orally transformable tablets
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