KR20130106399A - Manufacture of tablets from energy-applied powder blend - Google Patents

Abstract

The present invention provides a method for preparing a tablet containing one or more pharmaceutically active agent (s) and one or more binder (s), comprising (i) in a powder blend comprising the pharmaceutically active agent (s) and binder (s), Applying energy for a period sufficient to activate the binder (s) in the powder blend, and (ii) forming a predetermined amount of the energized powder blend into the tablet. It is done.

Description

Preparation of Tablets from Energy-Applied Powder Blends {MANUFACTURE OF TABLETS FROM ENERGY-APPLIED POWDER BLEND}

Cross reference to related application

This application is directed to US Provisional Application No. 61 / 245,315, filed Sep. 24, 2009, US Provisional Application No. 61 / 255,582, filed Oct. 28, 2009, US Provisional Application No. 61, filed March 17, 2010. / 314,629, US Provisional Application No. 61 / 358,167, filed Jun. 24, 2010, US Patent Application No. 12 / 887,544, filed September 22, 2010, and US, filed September 22, 2010. Claims benefit from the priority of the application of patent application 12 / 887,552. As such, the entire disclosure of the aforementioned related U.S. patent applications is incorporated herein by reference for all purposes.

Agents intended for oral administration are typically provided in tablet form. Tablets are swallowed whole, chewed in the mouth, or disintegrated in the mouth. Soft tablets that are chewed or dissolved in the mouth are often used in the administration of pharmaceutical products to provide tablets for whole swallowing. With chewable tablets, chewing action can help break up the tablet particles as the tablet disintegrates and increase the rate of absorption by the digestive tract. Soft tablets are also advantageous when it is desirable to make the pharmaceutical active topically available in the mouth or throat for both local effect and / or systemic absorption. Soft tablets are also used to improve drug administration in pediatrics and the elderly and patients. Soft tablets designed to disintegrate in the mouth before swallowing are particularly useful for improving compliance in pediatric patients.

Generally, soft tablets are prepared by compacting a blend of powdered ingredients and typically comprise a pharmaceutically active agent, a flavoring agent, and / or a binder. Powder blends are typically supplied into the cavity of the die of the tablet press, and the tablets are formed by applying pressure. The hardness of the resulting tablet is a direct function of the compaction pressure employed and the compatibility of the components in the formulation. Softer tablets that can be bitten more easily can be made by employing a reduced consolidation pressure. The resulting tablets are softer, but may also be more brittle, brittle, easily broken, and disadvantageously involved in complex and expensive processing steps. Examples of soft tablets designed to disintegrate in the mouth without chewing are disclosed in US Pat. Nos. 5,464,632, 5,223,264, 5,178,878, 6,589,554, and 6,224,905.

Swallowable tablets have been prepared using a melt extrusion process in which the active ingredient is mixed with excipients, heated as agglomerates and extruded into a preformed die. Such tablets are intended to be swallowed immediately and in some cases have altered or sustained release properties. Examples of melt extruded tablets are disclosed in US Pat. Nos. 6,387,401 and 7,022,344.

There is a need for aesthetically beautiful chewable tablets and intraorally disintegrating tablets using compression-based tableting machines typically used to produce high density hard swallowable tablets. When used at low compression forces, these machines typically produce very brittle tablets, which are not sufficiently stable during packaging, transportation, and storage. The present invention relates to the discovery of a method for preparing tablets, such as chewable tablets or orally disintegrating tablets, by applying energy (eg, high frequency energy) to the powder blend to activate the binder in the powder blend.

In one aspect, the present invention is a method of making a tablet containing one or more pharmaceutically active agent (s) and one or more binder (s), comprising: (i) a powder comprising the pharmaceutically active agent (s) and binder (s) Applying the energy to the blend for a period sufficient to activate the binder (s) in the powder blend, and (ii) forming a predetermined amount of the energized powder blend into the tablet. It is characterized by. In a further embodiment, the tablet has a density of less than 0.8 g / cc and the tablet disintegrates in the mouth in less than about 30 seconds when placed on the tongue.

In another aspect, the present invention relates to a powder blend containing a pharmaceutically active agent and an RF-melt binder, by applying high frequency energy for a time period sufficient to soften or melt the RF-binder, and in advance of the energized powder blend. Characterized by the step of forming the determined amount into a tablet.

In another aspect, the invention features a tablet made according to the method.

Other features and advantages of the invention will be apparent from the description and the claims.

It is believed that one of ordinary skill in the art, based on the description herein, may utilize the present invention to its fullest extent. The following specific embodiments may be construed as illustrative only, and in no way limit the rest of the invention.

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 this invention belongs. In addition, 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 provides a method of preparing a tablet containing one or more pharmaceutically active agent (s) and one or more binder (s), comprising: (i) a pharmaceutically active agent (s) and a binder ( To the powder blend comprising a) sufficient time to activate the binder (s) in the powder blend, and (ii) forming a predetermined amount of the energized powder blend into a tablet. do.

powder Blend

As discussed above, tablets may provide energy to a powder blend containing a pharmaceutically active agent (as discussed herein), a binder (as discussed herein), and optionally a pharmaceutically acceptable carrier. It is manufactured by. Examples of binders include, but are not limited to, melt binders and water-activated binder materials. The carrier contains one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include fillers, adsorbents, disintegrants, lubricants, glidants, sweeteners, superdisintegrants, flavoring and fragrances, antioxidants, preservatives, texture enheancers, and mixtures thereof. Included, but not limited to. One or more of the above components 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 modified materials (eg, microcrystalline cellulose or other cellulose derivatives), and mixtures thereof.

Suitable adsorbents include those sold as water insoluble adsorbents such as dicalcium phosphate, tricalcium phosphate, such as those sold under the tradename PROSOLV (PenWest Pharmaceuticals, Paterson, NY). Silicified microcrystalline cellulose, such as those sold under the tradename NEUSILIN (Fuji Chemical Industries (USA) Inc., Robbinsville, NJ). Such as) magnesium aluminomethilicate, clay, silica, bentonite, zeolite, magnesium silicate, hydrotalcite, bum, and mixtures thereof.

Suitable disintegrants include, but are not limited to, sodium starch glycolate, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose, starch, microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fatty acids and salts thereof, such as magnesium stearate and stearic acid, talc, glyceride waxes, and mixtures thereof.

Suitable glidants include, but are not limited to, colloidal silicon dioxide.

Examples of sweetening agents include synthetic or natural sugars; Artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, taumartin, glycyrizine, sucralose, dihydrochalcone, alitam, miraculin, monelin, and stevesides; Sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol, and xylitol; Sugars (sucrose), dextrose (also called glucose), fructose (also called fructose), and lactose (also called lactose) extracted from sugar cane and sugar beet; Isomalts, 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 fragrances include distillates, solvent extracts, or cold presses of chopped flowers, leaves, shells or pulped whole fruits containing mixtures of alcohols, esters, aldehydes and lactones. Essential oils including water; Essences comprising dilute solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavors of fruits (eg, strawberries, raspberry and black currant); Artificial and natural flavors of brews and spirits such as cognac, whisky, rum, gin, sherry, port, and wine; Tobacco, coffee, tea, cocoa, and mint; Fruit juice including juice extruded from washed, rubbed fruit, such as lemons, oranges, and limes; Spearmint, peppermint, wintergreen, cinnamon, cacoe / cocoa, vanilla, liquorice, menthol, eucalyptus, anise fruit, nuts (e.g. peanuts, coconut, hazelnuts, chestnuts, walnuts, Coke berries), almonds, raisins; And parts of tobacco plants, such as powder, flour, or vegetable material portions, including ginger, and ginger, in parts that do not significantly contribute to the level of nicotine, such as the genus Nicotiana.

Examples of antioxidants include, but are not limited to, tocopherol, 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, the texture enhancer is used at a level of about 0.1% to about 10% by weight.

In one embodiment of the present invention, the powder blend has an average particle size of less than 500 micrometers, for example from about 50 micrometers to about 500 micrometers, for example from about 50 micrometers to 300 micrometers. Particles in this size range are particularly useful for direct compaction processes.

In one embodiment of the invention, tablets may be made from a powder blend that is substantially free of hydrated polymer. As used herein, “substantially free” means less than 5%, for example less than 1%, for example less than 0.1%, for example completely absent (eg 0%). Such compositions are beneficial for maintaining an immediate release dissolution profile, minimizing treatment and material costs, and providing optimal physical and chemical stability of the tablet.

In one embodiment, the powder blend / tablet is substantially free of directly compressible water insoluble filler. Water insoluble fillers include, but are not limited to, microcrystalline cellulose, directly compressible microcrystalline cellulose, cellulose, water insoluble cellulose, starch, corn starch, and modified starch. As described in this embodiment, substantially free is less than 2%, for example less than 1% or completely absent.

Melt Binder

In one embodiment, the powder blends / tablets of the present invention comprise at least one meltable binder. In one embodiment, the melt binder has a melting point of about 40 ° C. to about 140 ° C., such as about 55 ° C. to about 100 ° C. Softening or melting of the meltable binder (s) sinters the powder blend through the combination of the softened or melted binder with the pharmaceutical active agent and / or other ingredients in the powder blend.

In one embodiment, the meltable binder is an RF-melt binder. By RF-melt binder is meant a solid binder that can soften or melt upon exposure to RF energy. RF-melt binders are typically polar and have the ability to re-harden or re-stock upon cooling.

In one embodiment, the meltable binder is not an RF-melt binder. In such embodiments, the powder blend contains excipients that generate heat upon exposure to RF energy (eg, polar excipients) such that the heat generated therein can soften or melt the meltable binder. Examples of such excipients include 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 maltodextrin and sodium stearate are included, but are not limited to these.

Other examples of meltable binders include amorphous carbohydrate polymers. "Amorphous carbohydrate polymer" means a molecule having a plurality of carbohydrate monomers and having a crystallinity of less than 20%, such as less than 10%, such as less than 5%. Examples of amorphous carbohydrate polymers include, but are not limited to, hydrogenated starch hydrosolates, polydextrose, and oligosaccharides. Examples of oligosaccharides include, but are not limited to, fructo-oligosaccharides, galacto-oligosaccharides, malto-oligosaccharides, inulin, and isomalto-oligosaccharides.

Examples of suitable meltable binders include fats such as cocoa butter, hydrogenated vegetable oils such as palm kernel oil, cottonseed oil, sunflower oil, and soybean oil; Monoglycerides, diglycerides, and triglycerides; Phospholipids; Cetyl alcohol; Waxes such as carnauba wax, spermatozoon, beeswax, candelilla wax, shellac wax, microcrystalline wax, glyceryl behenate, glycerol distearate, copolymers of polyethylene glycol and propylene glycol, polyethylene glycol behenate and paraffin wax ; Water soluble polymers such as polyethylene glycol, polycaprolactone, GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl macrogol-32 glycerides; Polyethylene oxide; And sucrose esters.

In one embodiment, the meltable binder is an RF-melt binder and the RF-melt binder is polyethylene glycol (PEG), for example PEG-4000. Particularly preferred RF-melt binders are PEG-wherein PEG is at least 95% by weight of the PEG particles (when measured by conventional means such as light or laser scattering or sieve analysis) and has a molecular weight of less than 100 micrometers. 3000 to 8000 Daltons.

The meltable binder (s) are present at a level of about 0.01% to about 70% of the powder blend / tablet, for example about 1% to about 50%, for example about 10% to about 30% of the powder blend / tablet. Can be.

In one embodiment, the average particle size of the binder is less than 250 micrometers, eg, less than 100 micrometers.

Water-containing materials

In one embodiment, the powder blends / tablets of the present invention comprise at least one water-containing material. Examples of water-containing materials include materials in which water is chemically bonded to the material (eg, hydrate salts), materials in which water is adsorbed or absorbed by the material (eg, porous materials such as silica and microsponges), and Materials include, but are not limited to, materials in which water is encapsulated therein (eg, liquid filled capsules). Examples of such materials include dry silica; Colloidal silica such as colloidal silicon dioxide; Silicates such as calcium silicate, aluminum silicate, magnesium aluminum metasilicate (e.g., NUSILIN, US-2 from Fuji Chemical Ltd), and magnesium silicate; clay; Zeolite; And daggers, but are not limited to these.

In one embodiment, the powder blend / tablet comprises 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 a molecular weight of about 150 to about 400 Daltons, for example about 200 to about 350 Daltons.

In one embodiment, the powder blend / tablet comprises at least one liquid filled capsule. In a further embodiment, water is released from the capsule upon rupture, where such rupture is caused by the addition of energy.

The water-containing material (s) may comprise from about 0.01% to about 70% of the powder blend / tablet, for example from about 1% to about 50% of the powder blend / tablet, for example from about 1% to about 30%, for example For example, at levels of about 2% to about 10%.

Water-activated bonding material

In one embodiment, the powder blends / tablets of the present invention comprise at least one water-activated binding material. By water-activated binding material is meant a material that is activated or hydrated upon contact with water (eg, released from the water-containing material upon addition of energy) and which will assist in binding / fusion of the powder blend into the tablet. Examples of such materials include, but are not limited to, hydrolyzed proteins, hydrated polymers, and hydrocolloids. Suitable hydrolyzed proteins include, but are not limited to, hydrolyzed collagen. Suitable hydrated 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.

carbohydrate

In one embodiment, the powder blend contains at least one carbohydrate. Carbohydrates can contribute to the solubility and mouth feel of the tablets and can help distribute the meltable binder over a larger surface area and dilute and cushion the pharmaceutical active. Examples of carbohydrates include water-soluble, compressible carbohydrates such as sugars (eg dextrose, sucrose, maltose, isomalt, and lactose), starch (eg corn starch), sugar-alcohol (eg Mannitol, sorbitol, maltitol, erythritol, lactitol, and xylitol), and starch hydrolysates (eg, dextrins, and maltodextrins).

The carbohydrate (s) may be present at a level of about 5% to about 95% of the powder blend / tablet, for example about 20% to about 90%, or about 40% to about 80% of the powder blend / tablet. The particle size of the carbohydrate can affect the level of the meltable binder used, where larger particle sizes of the carbohydrate provide a smaller surface area and consequently require lower levels of the meltable binder. In one embodiment where the carbohydrate (s) is greater than 50% by weight of the powder blend and the average particle size of the carbohydrate (s) is greater than 100 micrometers, the binder is about 10 to about 30% by weight of the powder blend / tablet.

Pharmaceutically active agents

The powder blends / tablets of the invention comprise at least one pharmaceutically active agent. "Pharmaceutically active agent" means that is licensed or approved by the US Food and Drug Administration, the European Medicines Agency, or any successor thereof for oral treatment of a disease or condition. Means an agent (eg, a compound). Suitable pharmaceutically active agents include analgesics, anti-inflammatory agents, antipyretics, antihistamines, antibiotics (e.g. antibacterial agents, antiviral agents, and antifungal agents), antidepressants, antidiabetics, antispasmodic, appetite suppressants, bronchodilators, cardiovascular agents (e.g. Statins), central nervous system therapies, cough suppressants, decongestants, diuretics, expectorants, gastrointestinal therapies, anesthetics, mucolytic agents, muscle relaxants, osteoporosis agents, stimulants, nicotine, and sedatives.

Examples of suitable gastrointestinal therapeutic agents include, but are not limited to, aluminum-containing pharmaceutical actives (eg, aluminum carbonate, aluminum hydroxide, dihydroxyaluminum sodium carbonate, and aluminum phosphate), bicarbonate-containing pharmaceuticals Active agents, bismuth-containing pharmaceutical actives (eg, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, and bismuth subnitrate), calcium-containing pharmaceutical actives ( For example, calcium carbonate), glycine, magnesium-containing pharmaceutical actives (eg magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium Oxides, and magnesium trisilicates), phosphate-containing pharmaceutical actives (eg Antacids such as, for example, aluminum phosphate and calcium phosphate), potassium-containing pharmaceutical actives (eg potassium bicarbonate), sodium-containing pharmaceutical actives (eg sodium bicarbonate), and silicates ; Laxatives, such as stool softeners (eg docusate) and irritant laxatives (eg bisaccodyl); H2 receptor antagonists such as famotidine, ranitidine, cimetadine, and nizatidine; Proton pump inhibitors such as omeprazole, dextansoprazole, esomeprazole, pantoprazole, rabeprazole, and lansoprazole; Gastrointestinal cytoprotective agents such as sucrraflate and misoprostol; Gastrointestinal motility promoters such as prucalopride; Antibiotics for H. pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole; Antimicrobial agents such as bismuth subsalicylate, kaolin, diphenoxylate, and loperamide; Glycopyrrolate; Analgesics such as mesalamine; Anti-emetics such as ondansetron, cyclizine, diphenyhydroamine, dimenhydrinate, meclizine, promethazine, and hydroxyazine antiemetic); Probiotic bacteria, including but not limited to, Lactobacillus; Lactase; Racecadotril; And antiflatulents such as polydimethylsiloxanes (eg, dimethicone and simethicone, including those disclosed in US Pat. Nos. 4,906,478, 5,275,822, and 6,103,260); Isomers thereof; And their pharmaceutically acceptable salts and prodrugs (eg, esters).

Examples of suitable analgesics, anti-inflammatory agents, and antipyretic agents include non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (eg ibuprofen, naproxen, ketoprofen, flu) Flurbiprofen, fenbufen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carpropene (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; Phenamic acid derivatives such as mefanamic acid, meclofenamic acid, and flufenamic acid; Biphenylcarbodiic acid derivatives such as diflunisal and flufenisal; And oxycams such as piroxicam, sudoxicam, isoxicam, and meloxicam; Isomers thereof; And their pharmaceutically acceptable salts and prodrugs.

Examples of antihistamines and decongestants include bromopheniramine, chlorcyclizine, dexbrompheniramine, bromhexane, phenindamine, pheniramine and pyrilamine ), Tonzylamine, prepolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan , Diphenhydramine, doxylamine, asemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, montelukast, Propylhexadrine, triprolidine, clemastine, acrivastine, promethazine, oxomemazi ne), mequitazine, buclizine, bromexine, bromhexine, ketotifen, terfenadine, ebastin, oxatamide, xylomezoline ), Loratadine, desloratadine, and cetirizine; Isomers thereof; And pharmaceutically acceptable salts and esters thereof.

Examples of cough suppressants and expectorants include diphenhydramine, dextromethorphan, noscapine, clophedianol, menthol, benzonatate, ethylmorphone, codeine ), Acetylcysteine, carbocisteine, ambroxol, belladona alkaloid, sobrerenol, guaiacol, and guapenesin; Isomers thereof; And pharmaceutically acceptable salts and prodrugs thereof. Isomers thereof; And their pharmaceutically acceptable salts and prodrugs.

Examples of muscle relaxants include cyclobenzaprine and chlorzoxazone metaxalone, orphenadrine, and metocarbamol; Isomers thereof; And their pharmaceutically acceptable salts and prodrugs.

Examples of stimulants include, but are not limited to, caffeine.

Examples of sedatives include, but are not limited to, sleep aids such as antihistamines (eg, diphenhydramine), eszopiclone, and zolpidem, and pharmaceutically acceptable salts and prodrugs thereof. It is not limited.

Examples of appetite suppressants include, but are not limited to, phenylpropanolamine, phentermine, and diethylcathinone, and pharmaceutically acceptable salts and prodrugs thereof.

Examples of anesthetics (eg, for treating a sore throat) include, but are not limited to, diclonine, benzocaine, and pectin and their pharmaceutically acceptable salts and prodrugs.

Examples of suitable statins include atorvastin, rosuvastatin, fluvastatin, lovastatin, simvustatin, atorvastatin, pravastatin and their Pharmaceutically acceptable salts and prodrugs are included, but are not limited to these.

In one embodiment, the pharmaceutically active agents included in the tablets are phenylephrine, dextromethorphan, pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine, ranitidine, ibuprofen, ketoprofen, loperamide, pamotidine , Calcium carbonate, simethicone, chlorpheniramine, metocarbomal, chlophedianol, ascorbic acid, pectin, diclonin, benzocaine and mannitol, and pharmaceutically acceptable salts thereof Selected from prodrugs.

As discussed above, the pharmaceutically active agents of the present invention may also be present in the form of pharmaceutically acceptable salts, for example acidic / anionic or basic / cationic salts. Pharmaceutically acceptable acidic / anionic salts include acetates, benzenesulfonates, benzoates, bicarbonates, bitartrates, bromide, calcium edetates, chamlates, carbonates, chlorides, citrates, dihydrochlorides , Edetate, edylate, estoleate, acrylate, fumarate, glyceptate, gluconate, glutamate, glycolyl anilate, hexyl sorbinate, hydravamin, hydrobromide, hydrochloride, hydride Loxynaphthoate, iodide, isethionate, lactate, lactobionate, maleate, maleate, mandelate, mesylate, methyl bromide, methylnitrate, methylsulfate, mucate, lead silicate, nitrate , Pamoate, pantothenate, phosphate / diphosphate, polygalacturone Agent, salicylate, stearate, sub-acetate, succinate, sulfate, titanate, tartrate, Theo clay agent, and tosylate, but the tri-thio die Degas include, but are not limited to. Pharmaceutically acceptable basic / cationic salts include aluminum, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, meglumine, potassium , Procaine, sodium and zinc, but are not limited to these.

As discussed above, the pharmaceutically active agents of the present invention may also exist in the form of prodrugs of pharmaceutically active agents. In general, such prodrugs will be functional derivatives of the pharmaceutical active, which can be readily converted to the required pharmaceutical active in vivo. 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 present invention provides esters, amides, and other protected or derivatized forms of the described compounds.

If the pharmaceutical active according to the invention has at least one chiral center, the pharmaceutical active may accordingly be present as enantiomer. If the pharmaceutically active agent has two or more chiral centers, the pharmaceutically active agent may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are included within the scope of the present invention. In addition, some of the crystalline forms of the pharmaceutical active may exist as polymorphs and are intended to be included in the invention in such forms. In addition, some of the pharmaceutically active agents may form solvates (eg, hydrates) or conventional organic solvates with water, which solvates are also intended to be included within the scope of the present invention.

In one embodiment, the pharmaceutically active agent or active agents are present in the tablet in a therapeutically effective amount, which amounts to a desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, as is known in the art, the particular pharmaceutical active administered, the bioavailability characteristics of the pharmaceutical active, the dosage plan, the age and weight of the patient, and other factors should be considered. .

Pharmaceutically active agents can exist in various forms. For example, the pharmaceutically active agent can be dispersed, for example melted, at the molecular level in a tablet, or it can be in the form of particles, which may or may not be coated, then. When the pharmaceutically active agent is in the form of particles, the particles (whether coated or uncoated) typically have an average particle size of about 1 to about 2000 micrometers. In one embodiment, such particles are crystals having an average particle size of about 1 to about 300 micrometers. In another embodiment, the particles are granules or pellets having an average particle size of about 50 to about 2000 micrometers, such as about 50 to about 1000 micrometers, such as about 100 to about 800 micrometers.

Pharmaceutically active agents may be present in pure crystalline form or in granulated form prior to the addition of a taste masking coating. Granulation techniques can be used to improve the flow properties or particle size of the pharmaceutical actives, making them more suitable for compaction or subsequent coating. Suitable binders for granulation include, but are not limited to, starch, polyvinylpyrrolidone, polymethacrylate, hydroxypropylmethylcellulose, and hydroxypropylcellulose. Particles comprising the pharmaceutical active agent (s) may be prepared by cogranulating the pharmaceutical active agent (s) and suitable substrate particles together via any granulation method known in the art. Examples of such granulation methods 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 unpleasant taste, the pharmaceutically active agent may be coated with a taste masking coating as is known in the art. Examples of suitable taste masking coatings are described in US Pat. No. 4,851,226, US Pat. No. 5,075,114, and US Pat. No. 5,489,436. Commercially available taste masked pharmaceutical actives may also be used. For example, acetaminophen particles encapsulated with ethylcellulose or other polymers by a coacervation process can be used in the present invention. Coacervation-encapsulated acetaminophen is commercially available from Eurand America, Inc. (Vandalia, OH) or commercially from Circa Inc. (Dayton, Ohio). You can buy it.

In one embodiment, the tablet comprises modified release coded particles (eg, particles containing at least one pharmaceutically active agent, which delivers the modified release properties of such formulations). As used herein, "modified release" will apply to altered release or dissolution of the active agent in a dissolution medium, such as gastrointestinal fluid. Types of modified release include, but are not limited to, sustained release or delayed release. In general, modified release tablets are formulated such that the active agent (s) are available over a long period of time after digestion, thereby allowing a reduction in the frequency of administration compared to administration of the same active agent (s) in conventional tablets. do. Modified release tablets also allow the use of active agent combinations in which the duration of one pharmaceutical active may differ from the duration of the other pharmaceutical active. In one embodiment, the tablet contains one pharmaceutical active that is released in an immediate release mode, and a second portion of the same active agent as the additional active agent or first portion that is modified release.

Examples of expandable, erosive hydrophilic materials that can be used as release modifying excipients for use in modified release coatings include water expandable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, and gelled starches. Included. Examples of water swellable cellulose derivatives include sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyisopropyl cellulose, hydroxybutyl cellulose, hydroxy Phenyl cellulose, hydroxyethyl cellulose (HEC), hydroxypentyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose, and hydroxypropyl ethyl cellulose. Examples of polyalkylene glycols include polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include poly (ethylene oxide). Examples of acrylic polymers include potassium methacrylate divinylbenzene copolymers, polymethylmethacrylates, and high molecular weight crosslinked acrylic acid homopolymers and copolymers.

Suitable pH-dependent polymers for use as release-modifying excipients for use in modified release coatings include enteric cellulose derivatives such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, and cellulose acetate. Phthalates; 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 polymethacrylate based polymers such as poly (methacrylic acid, methyl methacrylate) 1: 2 (trade name EUDRAGIT from Rohm Pharma GmbH) ) And poly (methacrylic acid, methyl methacrylate) 1: 1 (available under the tradename Eudragit L from Rohm Pharma GmbH).

In one embodiment the pharmaceutically active agent is 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, from Rohm America). Polymethacrylic co-polymers such as those marketed as Eudragit E-100, and hydroxypropylcellulose). In such embodiments, the ratio of water insoluble film forming polymer to water soluble polymer is about 50 to about 95% water insoluble polymer and about 5 to about 50% water soluble polymer, based on the weight of the coated taste masking particles. Weight percent of the coating is from about 5% to about 40%. In one embodiment, the coating used for the coated particles of the pharmaceutically active agent is substantially free of material (eg, polyethylene glycol) that is melted below 85 ° C. to prevent damage to the integrity of the coating during the RF heating step. There is no.

In one embodiment, one or more pharmaceutical actives or portions of pharmaceutical actives may be bound to the ion exchange resin for the purpose of concealing the taste of the pharmaceutical active or delivering the active in a modified release manner.

In one embodiment, the pharmaceutically active agent may dissolve upon contact with a fluid such as water, gastric acid, intestinal fluid, and the like. In one embodiment, the dissolution properties of the pharmaceutical active in the tablet meet the USP specification for immediate release tablets comprising the pharmaceutical active. For example, for acetaminophen tablets, USP 24 is released from within 30 minutes after taking at least 80% of acetaminophen contained in the tablet, using USP Apparatus 2 (paddles) at 50 rpm in pH 5.8 phosphate buffer. For ibuprofen tablets, USP 24 uses 50 rpm USP Apparatus 2 (paddles) in pH 7.2 phosphate buffer to release more than 80% of the ibuprofen contained in the tablet within 60 minutes after dosing. It is specified. See USP 24, 2000 Version, 19-20 and 856 (1999). In another embodiment, the dissolution characteristics of the pharmaceutical active are altered; For example, controlled, sustained, extended, delayed, extended, delayed, and the like.

In one embodiment, the particle size of the pharmaceutical active results in more empty space present in the tablet, where larger particle sizes of the pharmaceutical active require a lower level of binder as a result. In one embodiment, when 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 average particle size of the carbohydrate is greater than 100 micrometers, the binder is powder blend / From about 10 to about 30% by weight of the tablet. In one embodiment, when the average particle size of the powder blend is about 100 micrometers to about 300 micrometers, the binder is about 10 to about 20% by weight of the powder blend / tablet.

The melting point of the pharmaceutical active may affect the temperature used during the heating step and the type of binder used. In one embodiment, the melting point of the binder is lower than the melting point of the pharmaceutical active. In another embodiment, the melting point of the pharmaceutical active is equal to or lower than the melting point of the binder, in which case, during the fusing or heating step, both the pharmaceutical active and the binder melt to form a eutectic mixture or upon cooling Various bridges of pharmaceutically active agents and binders can be created between different materials in tablet form. In one embodiment, the heating temperature is above the melting point of the binder and below the melting point of the pharmaceutical active. In one embodiment where the ibuprofen is a pharmaceutically active agent, the binder is heated to about 30 ° C to about 60 ° C. In one embodiment, the pharmaceutically active agent is a binder.

In one embodiment, the pharmaceutically active agent is in the form of particles coated with a binder.

The sensitivity of the pharmaceutical active agent (eg, to melt or decompose) to the RF energy can affect the type and / or temperature of the energy used during the heating step as well as the type of binder used.

In one embodiment, the treatment of the tablets does not have a wet or hot melt granulation step. In this embodiment, the materials are blended directly before the addition of heat. In one embodiment, the materials are blended and compressed directly before the addition of heat.

Applying energy to the powder blend

The method includes applying energy to the powder blend for a period of time sufficient to activate the binder (s) in the powder blend. Various forms of energy can be used in the process to activate the binder. Suitable energy sources include, but are not limited to, convection, high frequency, microwave, UV light, infrared light, induction, laser light, and ultrasound.

In one embodiment, the binder is a meltable material (eg, RF-melt binder) having a melting point of about 40 ° C. to about 140 ° C. and the powder blend is applied to energy for a period of time sufficient to melt or soften the melt material. Exposed.

In one embodiment, high frequency energy (“RF-energy”) is used. High frequency heating generally refers to heating by an electromagnetic field at a frequency of about 1 MHz to about 100 MHz. In one embodiment of the invention, the RF-energy is within a frequency range of about 1 MHz to about 100 MHz (eg about 5 MHz to 50 MHz, eg about 10 MHz to about 30 MHz). In one embodiment, the RF-energy is heated directly to the binder (e.g., if the binder is an RF-melt binder, or by the RF-heatable component in the powder blend, although the binder is not an RF melt binder. If used indirectly). The type and amount of binder and the amount of RF energy used may determine the hardness and / or type of the tablet, whether orally disintegrating tablets or soft chewable tablets are prepared. 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, NY). In one embodiment, the RF energy is combined with a second heat source, including but not limited to infrared, induction, or convective heating. In one embodiment, the addition of the second heat source is particularly useful when secondary non-RF-melt binders are present in the powder blend.

In one embodiment, microwave heating generally refers to heating by an electromagnetic field at a frequency of about 100 MHz to about 300 GHz. In one embodiment of the invention, the RF-energy is in the frequency range of about 500 MHz to about 100 GHz (eg about 1 GHz to 50 GHz, eg about 1 GHz to about 10 GHz). Microwave energy can be heated directly by the binder (e.g., when the binder is sensitive to microwave energy ("microwave melt binder") or by the microwave heatable component in the powder blend although the melt binder is not a microwave melt binder. If used indirectly).

In one embodiment, the binder is a water-activated binding material and the powder blend further comprises a water-containing material. In a further embodiment, the powder blend is exposed to energy for a period of time sufficient to heat the water-containing material above its dehydration temperature and such released water activates the water-activated binding material.

In one embodiment, the powder blend is heated as a unitary mass of material, which mass is at least two times the size of a single dosage form, for example ten times the mass of a single dosage form, for example 100 times or more. In one embodiment, the powder blend is heated as a lump in a cylinder, tube, sheet or other chamber.

In one embodiment, the energy (eg, RF energy) is sufficient to activate substantially all (eg, at least 90%, eg, at least 95%, eg, all) of the binder in the powder blend. Applied for a sufficient time (eg to soften and melt).

In embodiments in which the powder blend is heated using RF-energy, electrodes are included into a chamber (eg, a cylinder, walled-sheet, or other chamber) containing the powder blend. In one embodiment, the chamber is made of a conductive metal. In one embodiment, the chamber has a portion composed of a non-conductive, insulating material. In embodiments in which the powder blend is heated using conductive heating, the chamber may be comprised of a thermally conductive metal. In one embodiment, the chamber has an insert that is non-conductive when the body of the chamber is conductive. In one embodiment, the insert includes less surface area than the surface area of the chamber. The conductive material may be composed of any material that conducts RF-energy, including but not limited to aluminum, copper, iron, zinc, nickel, and mixtures and alloys thereof. The non-conductive material may be composed of a non-conductive solid material, including but not limited to plastic and Teflon®. In one embodiment, the chamber has at least one electrode embedded in the wall of the cylinder or walled sheet. The electrode can be surrounded by a non-conductive material, where the electrode is the only conductive wall portion exposed to the powder blend. In one embodiment, the powder blend is tamped prior to the addition of RF-energy.

In one embodiment, one chamber contains the powder blend, which is put into a separate chamber (eg oven) for the addition of energy. In another embodiment, the chamber containing the powder blend has additional heating elements included in the chamber.

Formation of tablets

After applying the energy, the powder blend can optionally be cooled (eg, actively cooled or left to cool) before the predetermined amount of energized powder blend is formed into a tablet.

Tablets may be formed by various means.

In one embodiment, the shape of the tablet (eg, tablet shape) is preformed by weak consolidation of the energized powder blend. In one embodiment, the powder blend is fed into a tablet die of an apparatus under pressure to form tablet features by, for example, by weak consolidation such as tamping. Any suitable compaction apparatus may be used, including but not limited to conventional one-piece or rotary tablet presses. In one embodiment, the tablet features are, for example, such as those available from Fette America Inc., Rockaway, NJ, or Manesty Machines LTD, Liverpool, UK. ) By consolidation using a rotary tablet press.

In one embodiment, tablets are extruded from the cylinder after forming the agglomerates by RF-energy, and the agglomerates are cut into individual tablets using a cutting device such as a reciprocating blade or a rotary blade when extruded from the cylinder. In another embodiment, the mass of powder is sintered into a single sheet using RF-energy and cut into the dimensions of the tablet using a punch or die. In another embodiment, the tablets are cut from the sintered powder mass using a laser or water cutting tool.

In one embodiment, to obtain the desired properties of the oral deformable tablet, the composition of the tablet is highly porous (eg, causes the tablet to collapse in the oral cavity) and / or uses a minimum amount of binder and / or Can have a low density. Thus such tablets are rather brittle and soft. In a preferred embodiment, minimal tamping force / consolidation force is desired to achieve intraoral deformable properties (low density). Experiments determined that small force consolidation without energizing the powder blend produced a very brittle tablet that could not withstand the material handling forces required in manufacturing.

In one embodiment, the consolidation step (eg, tamping) that occurs prior to the addition of energy uses a compaction force that is less than the force required to compress the chewable or swallowable tablets. In one embodiment, the consolidation force is less than about 6894.8 kPa (1000 pounds per square inch) (eg, less than about 3447.4 kPa (500 pounds per square inch), for example, less than 1379.0 kPa (200 pounds per square inch), For example, less than 344.7 kPa (50 pounds per square inch). In one embodiment, energy is applied while the powder blend is under such force.

In one embodiment, the consolidation step takes place in an indexing manner in which a set of tablets are simultaneously consolidated before rotating to another indexing station. In one embodiment, the consolidation step occurs in a single indexing station and the energy of occurs in a separate indexing station. In another embodiment, there is a third indexing station where the ejection of tablets or multiple tablets occurs and the bottom forming tool is raised through the die to the surface of the die. In another embodiment, the consolidation step is performed by adding a pneumatic cylinder or a hydraulic cylinder on top of the top forming tool. In one embodiment, multiple tablets are simultaneously discharged from the surface of the indexing station, separated and removed through a take-off bar.

In another embodiment, tablet features may be prepared by the consolidation methods and apparatus described in US Patent Application Publication No. 20040156902. Specifically, tablet features may be made using a rotary compression module that includes a fill zone, insertion zone, compression zone, discharge zone, and purge zone in a single device having a double row die configuration. The die of the compression module can then be filled with the aid of a vacuum, with the filter located in or near each die. The purge zone of the compression module includes an optional powder blend recovery system that recovers excess powder blend from the filter and returns the powder blend to the die.

In one embodiment, tablet features are prepared by the consolidation method and apparatus described in registered US Pat. No. 6,767,200. Specifically, the tablet feature is manufactured using a rotary compression module that includes a filling zone, a compression zone, and a discharge zone in a single device having a dual row die configuration as shown in FIG. 6 therein. The die of the compression module is preferably filled with the aid of a vacuum with the filter located in or near each die.

The tablet feature may have one of a variety of different shapes. For example, the tablet form may be formed as a polyhedron, for example a cube, a pyramid, a prism, or the like; Or a spatial figure with several non-flat faces, for example cones, truncated cones, triangles, cylinders, spheres, toruses and the like. In certain embodiments, the tablet feature has one or more major faces. For example, tablet feature surfaces typically have opposing top and bottom surfaces formed by contact with a top forming tool face and a bottom forming tool face (eg, die punches) in a compaction machine. In such embodiments, the tablet feature surface typically further includes a "belly-band" located between the top and bottom surfaces and formed by contact with the die wall in the compaction machine. Tablet form / tablets may also be multilayer. Applicants have found that the sharp edges of the tools used to make the tablets can cause arcing, thus requiring more rounded edges.

In one embodiment, the method of making the tablet form is substantially free of the use of a solvent. In this embodiment, the powder blend is substantially free of solvent and substantially free of solvent in the manufacturing process (eg, filling into the die). Solvents include, but are not limited to, water, organic solvents such as alcohols, chlorinated solvents, hexanes, or acetone; Or a gaseous solvent such as, but not limited to, nitrogen, carbon dioxide or a supercritical fluid.

In one embodiment, a vibrating step is used (eg, added after the filling of the powder blend but before the heating or fusing step, for example to remove air from the powder blend). In one embodiment, a vibration with a frequency of about 1 Hz to about 50 KHz is added at an amplitude of 1 micrometer to 5 mm peak-to-peak such that the flowable powder blend is added to the cavity of the die platen. Settle into ("forming cavity").

In one embodiment, agglomerates of the energized powder blend are cut to form tablets. In one embodiment, the mass is then removed (eg, pushed or extruded) from the chamber, or cut in the chamber prior to removal. In one embodiment, the shape is cut in a sequential manner (eg, when the mass is extruded from the cylinder). In other embodiments, multiple shapes are simultaneously cut from the mass. The cutting device and method may be in the form of a physical cutting device such as a blade, a reciprocating blade, or a circular or rotary blade. Cutting devices and methods can be performed using chemical or laser cutting devices.

Insert in tablet

In one embodiment, the insert is included into a tablet. Examples include solid compressed forms or beads filled with liquid compositions.

In one embodiment, the pharmaceutically active agent is in the form of liquid filled or semi-solid filled gel beads. Gel bead (s) is added as part of the powder blend. In one embodiment, the tablets of the present invention have the added advantage of not using a strong consolidation step, which allows the use of deformable, liquid or semisolid filled particles or beads, since they are after the tablet forming step Because it will not rupture. These bead walls can include gelling materials 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 starch. The bead wall may further comprise plasticizers such as glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate and tributyl citrate. Pharmaceutically active agents include, but are not limited to, filler materials, such as, but not limited to, high fructose corn syrup, sugars, glycerin, polyethylene glycols, propylene glycols, or oils, such as vegetable oils, olive oils, or mineral oils. It can be dissolved, suspended or dispersed in.

Multilayer tablets

In certain embodiments, the tablet comprises, for example, at least two layers having different types and / or concentrations of binders and / or other components, or different concentrations of pharmaceutically active agents. In one embodiment, the tablet comprises two layers, one layer having intraoral disintegration properties and the other layer being chewable or swallowing. In one embodiment, one layer has a binder and the other layer does not have a binder. In one embodiment, one layer is consolidated at a higher compaction force than the other layer. In one embodiment, both layers contain the same amount of binder, but have different amounts of pharmaceutically active agents and / or other excipients. In one embodiment, all the properties of the two layers are the same, but the colors of the two layers are different.

Effervescent couple

In one embodiment, the powder blend further comprises one or more effervescent couples. In one embodiment, the expandable couple is one member from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, and sodium carbonate, and citric acid, malic acid, fumaric acid And one member selected from the group consisting of tartaric acid, phosphoric acid, and alginic acid.

In one embodiment, the combined amount of foamable couple (s) in the powder blend / tablet is about 2 to about 20 weight percent, such as about 2 to about 10 weight percent of the total weight of the powder blend / tablet.

Oral Disintegration Tablets

In one embodiment, the tablet is designed to disintegrate in the mouth within less than about 60 seconds, such as less than about 45 seconds, such as less than about 30 seconds, such as less than about 15 seconds when placed on the tongue.

In one embodiment, the tablet meets the criteria for an Orally Disintegrating Tablet (ODT) as defined by the draft Food and Drug Administration Handbook, issued April 2007. . In one embodiment, the tablet meets a twofold definition for an orally disintegrating tablet comprising the following criteria: 1) Solid tablets contain a medicinal substance and disintegrate rapidly within seconds, usually when placed on the tongue. And 2) solid oral preparations that disintegrate rapidly in the oral cavity, with an in vitro disintegration time of approximately 30 seconds or less, based on the United States Pharmacopeia (USP) disintegration test method for a particular pharmaceutical substance or substances. do.

Additional edible parts

In one embodiment, the tablet is included directly in another edible form. In one embodiment, this edible form is a hard candy or compressed ring that contains a powder blend.

In one embodiment, the outer hard candy form can be made using not only rolling into the mold, but also using ununilast rolling or roping and subsequent cutting and stamping. 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 comprises at least 50% by weight (eg at least 75% by weight, 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 as is in the outer edible form. In one embodiment, the outer edible form contains a pharmaceutically active agent and the inner tablet contains a pharmaceutically active agent different from that in the outer edible form. In one embodiment, the outer edible form disintegrates at a rate of at least 10 times the rate of the inner tablet, for example at least 20 times. The first portion and the second portion may be the same or different.

In one embodiment, the tablet with the outer edible form and the inner tablet is coated with a immediate release release coating or a film coating. In one embodiment, to produce such tablets, the steps after fusing (heating) and subsequent cooling of the tablets will further include sugar or film coating in the coating pan.

Hardness / density of tablets

In one embodiment, the tablets are prepared so that the tablets are relatively soft (eg, may disintegrate or chew in the mouth). In one embodiment, the hardness of the tablets is preferably less than about 133.4 MPa (3 kilopond / square centimeter (kp / cm 2)) (eg, less than about 89.0 MPa (2 kp / cm 2), for example about 44.5 MPa (less than 1 kp / cm 2).

Hardness is the term used in the art to describe the diameter fracture strength as measured by conventional pharmaceutical hardness testing equipment, such as the Schleuniger Hardness Tester. In order to compare values over tablets of various sizes, the fracture strength must be normalized to the fracture area. This normalized value, expressed in kp / cm 2, is sometimes referred to in the art as tablet tensile strength. A general discussion of tablet hardness testing can be 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 of the hardness of the tablets of the present invention relies on a Texture Analyzer TA-XT2i equipped with a 7 millimeter diameter flat faced probe and set to measure and record the compressive force in grams. The probe moves at 0.05 millimeters per second to a penetration depth of 2 millimeters. Record the maximum compressive force. In one embodiment, the measured force recorded for a tablet made in accordance with the present invention is less than 10,000 grams (eg less than about 1000 grams, eg less than about 700 grams). In one embodiment, the measured force recorded for a tablet made in accordance with the present invention is 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. Range and deviation is ± 50 grams. In another embodiment, the measured force recorded for the tablet is less than 700 grams.

In one embodiment, the tablet has a density of less than about 2 g / cc (eg less than about 0.9 g / cc, for example less than about 0.8 g / cc, for example less than about 0.7 g / cc).

Tablet coating

In one embodiment, the tablet comprises an additional outer coating (eg translucent coating, eg transparent coating) that helps limit the friability of the tablet. Suitable materials for the translucent coating include, but are not limited to, hypromellose, hydroxypropylcellulose, starch, polyvinyl alcohol, polyethylene glycol, polyvinyl alcohol and polyethylene glycol mixtures and copolymers, and mixtures thereof. Tablets of the invention may comprise from about 0.05 to about 10 weight percent, or from about 0.1 to about 3 weight percent of the total tablets.

Surface treatment of tablets

In one embodiment, the surface of the tablet is further treated with energy (eg, convection, infrared, or RF energy) to soften or melt the material on the surface of the tablet and then cooled or cooled to further smoothen the texture. / Or improve the gloss of the surface of the tablet, and / or limit the brittleness of the tablet, and / or provide a mark for identification. In one embodiment, the surface of the tablet is further exposed to infrared energy, where a wavelength of most (such as at least 50%, for example at least 90%, for example at least 99%) of such infrared energy is (eg, By the use of a wavelength filter) from about 0.5 to about 5 micrometers, for example from about 0.8 to about 3.5 micrometers. In one embodiment, the infrared energy source is a quartz mercury lamp having a parabolic reflector (eg, energy enhancing) and a filter to remove unwanted frequencies. Examples of such infrared energy sources include SPOT IR 4150 (commercially available from Research, Inc., Edin Prairie, MN).

Use of tablets

Tablets can be used as swallowing, chewable, or orally disintegrating tablets for administering a pharmaceutical active.

In one embodiment, the invention features a method of treating a disease, the method comprising orally administering a tablet as described above, wherein the tablet comprises an amount of a pharmaceutically active agent effective to treat the disease. Examples of such diseases include pain (such as headaches, migraines, sore throat, cramps, back pain and myalgia), fever, inflammation, upper airway diseases (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 upper airway disease, wherein the pharmaceutically active agent is phenylephrine, cetirizine, loratadine, fexofenadine, diphenhydramine, dextromethorphan, chlorpeniramin, chlor Pedianol, and pseudoephedrine.

In such embodiments, a “unit dose” typically involves a dosing manual that instructs the patient to take an amount of a pharmaceutically active agent, which may be, for example, multiple unit doses, depending on the age or weight of the patient. do. Typically the unit dose will comprise the amount of pharmaceutically active agent that is therapeutically effective for the smallest patient. For example, a suitable unit dose may comprise one tablet.

Example

Particular embodiments of the invention are illustrated by the following examples. The invention is not limited to the specific limitations described in these examples.

Example 1 Blends for Sintered ODTs Using Polymer Coated Active Ingredients

The powder blend of Table 1 was prepared as follows.

First, sucralose, colorant, and flavoring agent are placed together in a 500 cc sealed plastic bottle. The resulting mixture is then blended end-over-end by hand for approximately 2 minutes. The resulting mixture and coated acetaminophen, dextrose monohydrate, and polyethylene oxide are added to another 500 cc sealed plastic bottle and mixed by hand spinning for approximately 5 minutes. Finally, polyethylene glycol 4000 and tapioca maltodextrin are added to the blend and mixed for approximately 3 minutes.

Example  2: Cylinder  Containing the polymer coated active ingredient within ODT Sintering

A portion of the powder blend from Example 1 is placed in a plastic cylinder approximately 2.8 cm (1.1 ") in diameter, 0.44 cm (0.175") in length, and 50 cm in length. A cylinder containing the blend is placed between the electrodes of the RF heating unit, including the electrodes within the wall of the cylinder at approximately 1 cm spacing. The cylinder is energized for 5 seconds. The sintered tablet blend is extruded from the cylinder and simultaneously cut into 1091.14 mg of disc per tablet using a metal blade. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 3: Sintering of ODTs Containing Polymer-Coated Active Ingredients in Sheet Shapes

A portion of the powder blend from Example 1 is placed in a plastic sheet with sidewalls. The sheet is approximately 30 cm x 30 cm and the side wall height is approximately 2.5 cm. The powder blend is layered on the sheet to a height of approximately 0.75 cm. The sheet containing the powder blend is then placed between the electrodes of the RF heating unit, including the electrodes within the wall of the metal sheet at intervals of approximately 1 cm. The sheet is energized for 5 seconds. The sintered, formed blend is cut into individual dosage forms with a metal cutting die at 1091.14 mg of disc per tablet. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 4 Sintering of ODT in Chamber and Formation in Die

A portion of the powder blend from Example 1 is placed in a stainless steel cylinder (with screw mixing blade and portal at the bottom of the cylinder). The cylinder is about 5 cm in diameter and about 10 cm in height. The metal cylinder containing the powder blend is placed in a 120 ° C. oven for 15 minutes to heat using convection.

The cylinder is then removed from the oven and the mixer is started. While the powder blend is still warm, open the portal while rotating the screw mixer to 10 RPM and feed the warm powder blend into the die precooled to 20 ° C. Form tablets in the die using upper and lower punches with a force less than 4448.2 Newtons (1 KP). The resulting tablet is provided at 1091.14 mg per tablet and the tablet is removed and left to cool at room temperature for at least 5 minutes. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 5 Blends for Sintered ODTs Containing Hot Melt Coated Active Ingredients

Part A: Preparation of Hot Melt Coated Ibuprofen

2000 g of ibuprofen crystals (particle size grade 110 μm) are charged into a Glass fluid bed GPCG 5/9 coater with Worster Insert. Glyceryl palmitostearate, available as Precirol® ATO from Gattefosse Corporation (St-Priest, France), is placed in a suitable stainless steel container and 70 degrees Celsius until it is fully melted. Melt at. The molten material is sprayed onto ibuprofen at a spray rate of approximately 20 g / min while fluidizing at a product temperature of approximately 30 degrees Celsius. The coated ibuprofen is then discharged from the unit.

Part B: Powder Blend Formulation

The powder blend of Table 2 is prepared as follows:

First, sucralose, colorant, and flavoring agent are placed together in a 500 cc sealed plastic bottle. The resulting mixture is then blended by hand spinning around for about 2 minutes. The resulting mixture and coated ibuprofen, dextrose monohydrate, and polyethylene oxide are added to another 500 cc sealed plastic bottle and mixed by hand spinning for approximately 5 minutes. Finally, polyethylene glycol 4000 and tapioca maltodextrin are added to the blend and mixed for approximately 3 minutes.

Example 6 Sintering of an ODT Containing a Hot Melt Coated Active Component in a Cylinder

A portion of the powder blend from Example 5 is placed in a plastic cylinder approximately 2.8 cm (1.1 ") in diameter, 0.44 cm (0.175") in length, and 50 cm in length. A cylinder containing the blend is placed between the electrodes of the RF heating unit, including the electrodes within the wall of the cylinder at approximately 1 cm spacing. The cylinder is energized for 5 seconds. The sintered tablet blend is extruded from the cylinder and simultaneously cut into 1091.14 mg of disc per tablet using a metal blade. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 7 Sintering of ODTs Containing Hot Melt Coated Active Ingredients in the Shape of Sheets

A portion of the powder blend from Example 5 is placed in a plastic sheet with sidewalls. The sheet is approximately 30 cm x 30 cm and the side wall height is approximately 2.5 cm. The powder blend is layered on the sheet to a height of approximately 0.75 cm. The sheet containing the powder blend is then placed between the electrodes of the RF heating unit, including the electrodes within the wall of the metal sheet at intervals of approximately 1 cm. The sheet is energized for 5 seconds. The sintered, formed blend is cut into individual dosage forms with a metal cutting die at 1091.14 mg of disc per tablet. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 8 Sintering of ODT in Chamber and Formation in Die

A portion of the powder blend from Example 5 is placed in stainless steel cylinder 5 (with screw mixing blade and portal at the bottom of the cylinder). The cylinder is about 5 cm in diameter and about 10 cm in height. The metal cylinder containing the powder blend is placed in a 120 ° C. oven for 15 minutes to heat using convection.

The cylinder is then removed from the oven and the mixer is started. While the powder blend is still warm, open the portal while rotating the screw mixer to 10 RPM and feed the warm powder blend into the die precooled to 20 ° C. Form tablets in the die using upper and lower punches with a force less than 4448.2 Newtons (1 KP). The resulting tablet is provided at 1091.14 mg per tablet and the tablet is removed and left to cool at room temperature for at least 5 minutes. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example  9: with water activated binder Acetaminophen  powder Blend  Produce

Acetaminophen powder blends for intraoral disintegration tablets containing the ingredients of Table 3 were prepared as follows.

Each component is sieved through a 30 mesh screen, put together in a 500 cc plastic bottle and mixed by spinning for 5 minutes.

Example 10 Sintering of an ODT Containing a Hot Melt Coated Active Component in a Cylinder

A portion of the powder blend from Example 9 is placed in a plastic cylinder approximately 2.8 cm (1.1 ") in diameter, 0.44 cm (0.175") in length and 50 cm in length. A cylinder containing the blend is placed between the electrodes of the RF heating unit, including the electrodes within the wall of the cylinder at approximately 1 cm spacing. The cylinder is energized for 5 seconds. The sintered tablet blend is extruded from the cylinder and simultaneously cut into 1091.14 mg of disc per tablet using a metal blade. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 11 Sintering of ODTs Containing Hot Melt Coated Active Ingredients in the Shape of Sheets

A portion of the powder blend from Example 9 is placed in a plastic sheet with sidewalls. The sheet is approximately 30 cm x 30 cm and the side wall height is approximately 2.5 cm. The powder blend is layered on the sheet to a height of approximately 0.75 cm. The sheet containing the powder blend is then placed between the electrodes of the RF heating unit, including the electrodes within the wall of the metal sheet at intervals of approximately 1 cm. The sheet is energized for 5 seconds. The sintered, formed blend is cut into individual dosage forms with a metal cutting die at 1091.14 mg of disc per tablet. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

Example 12 Sintering of ODT in Chamber and Forming in Die

A portion of the powder blend from Example 9 is placed in a stainless steel cylinder 9 (with a screw mixing blade and portal at the bottom of the cylinder). The cylinder is about 5 cm in diameter and about 10 cm in height. The metal cylinder containing the powder blend is placed in a 120 ° C. oven for 15 minutes to heat using convection.

The cylinder is then removed from the oven and the mixer is started. While the powder blend is still warm, open the portal while rotating the screw mixer to 10 RPM and feed the warm powder blend into the die precooled to 20 ° C. Form tablets in the die using upper and lower punches with a force less than 4448.2 Newtons (1 KP). The resulting tablet is provided at 1091.14 mg per tablet and the tablet is removed and left to cool at room temperature for at least 5 minutes. Subsequently, the identification marks "AP" and "500" are printed on the tablet.

While the invention has been described in conjunction with the detailed description for carrying out the invention, the specific description for carrying out the invention is intended to be illustrative, and it is not intended to limit the scope of the invention defined by the scope of the appended claims. I understand. Other aspects, advantages, and modifications are within the scope of the claims.

Claims (20)

A method of making a tablet comprising at least one pharmaceutically active agent (s) and at least one binder (s), comprising: (i) in a powder blend comprising the pharmaceutically active agent (s) and the binder (s), the powder Applying energy for a period sufficient to activate the binder (s) in the blend, and (ii) forming a predetermined amount of the energized powder blend into the tablet, the tablet having a density of 0.8 less than g / cc, and wherein the tablet disintegrates in the mouth in less than about 30 seconds when placed on the tongue. The tablet of claim 1, wherein the binder is a meltable material having a melting point of about 40 ° C. to about 140 ° C. and the powder blend is exposed to the energy for a period of time sufficient to melt or soften the meltable material. How to manufacture. The method of claim 2, wherein the binder is an RF-melt binder and the powder blend is exposed to RF energy for a period of time sufficient to melt or soften the meltable material. The method of claim 3, wherein the high frequency energy has a frequency of about 1 MHz to 100 MHz. The method of claim 1, wherein the binder is a water-activated binding material, the powder blend further comprises a water-containing material, wherein the powder blend heats the water-containing material above its dehydration temperature. A method of making a tablet, said method being exposed to said energy for a period sufficient to The method of claim 1, wherein the powder blend comprises about 0.01 to about 30 weight percent of the pharmaceutically active agent and about 1 to about 30 weight percent of the meltable binder. The method of claim 1, wherein the binder is polyethylene glycol. The method of claim 1, wherein the powder blend further comprises one or more carbohydrates selected from the group consisting of dextrose monohydrate, mannitol, erythritol, dextrose, lactose, sorbitol, isomalt, sucrose, dexrate, and maltodextrin. The method of manufacturing a tablet. The method of claim 8, wherein the powder blend comprises about 30 to about 95 weight percent of the one or more carbohydrates. The method of claim 1, wherein the powder blend has an average particle size of less than 500 micrometers. The method of claim 1, wherein the energized powder blend is cooled before forming the tablet. The method of claim 1, wherein the tablet is formed in a tablet die. The method of claim 1, wherein the energized powder blend is cut to form the tablet. The tablet of claim 1, wherein the tablet meets the criteria for orally disintegrating tablets as defined by the draft Food & Drug Administration guidance issued in April 2007. How to. The method of claim 1, wherein the tablet has a hardness of less than 700 grams as measured using a Texture Analyzer TA-XT2i equipped with a 7 millimeter diameter flat faced probe. The method of claim 1, wherein the surface of the tablet is further exposed to infrared energy, and most of the wavelength of the infrared energy is about 0.5 to about 5 micrometers. A method of making a tablet, comprising: applying a high frequency energy to a powder blend comprising a pharmaceutically active agent and an RF-melt binder, for a period sufficient to soften or melt the RF-binder, and the energized powder blend Forming a predetermined amount of the tablet into a tablet. The method of claim 17, wherein the tablet has a density of less than 0.8 g / cc. The method of claim 15, wherein the tablet disintegrates in the mouth in less than about 30 seconds when placed on the tongue. Tablets prepared according to the method of claim 1.