HK1171986B - Machine for the manufacture of dosage forms utilizing radiofrequency energy - Google Patents

Description

Machine for manufacturing dosage forms using radiofrequency energy

Cross reference to related patent applications

Priority is claimed in this application for U.S. provisional patent application serial No. 61/245,315 filed on 24/9/2009, U.S. provisional patent application serial No. 61/255,582 filed on 28/10/2009, U.S. provisional patent application serial No. 61/314,629 filed on 17/3/2010, and U.S. provisional patent application serial No. 61/358,167 filed on 24/6/2010. The entire disclosure of the above-identified related U.S. patent application is hereby incorporated by reference herein in its entirety for all purposes.

Background

Pharmaceutical formulations intended for oral use are typically provided in the form of tablets. Tablets may be swallowed whole, chewed in the mouth, or disintegrated in the oral cavity. Where it is not feasible to provide a tablet for swallowing whole, soft tablets that chew or dissolve in the mouth are often employed at the time of administration of the medicament. For chewable tablets, the chewing action helps to break up the tablet particles as the tablet disintegrates and can increase the rate of absorption by the digestive tract. Soft tablets may also be advantageous where it is desired to make the pharmaceutically active agent available locally in the mouth or throat for local effect and/or systemic absorption. Soft tablets are also used to improve drug administration in pediatric and geriatric patients. Soft tablets designed to disintegrate in the mouth prior to swallowing are particularly useful for improving compliance of pediatric patients.

Generally, soft tablets are prepared by compacting a blend of powdered ingredients and typically contain a pharmaceutically active agent, a flavoring agent, and/or a binder. The powder blend is typically fed into the die cavity of a tablet press and tablets are formed by applying pressure. The hardness of the resulting tablets is directly related to the compaction pressure used and the compatibility of the ingredients in the formulation. Softer tablets that are more easily snapped off can be prepared by using reduced compaction pressure. The resulting tablets are softer, but also more brittle, brittle and prone to brittle fracture, and disadvantageously may involve complex and uneconomical processing steps. Examples of soft tablets designed to disintegrate in the mouth without chewing are disclosed in U.S. Pat. nos. 5,464,632, 5,223,264, 5,178,878, 6,589,554 and 6,224,905.

There is a need for an aesthetically pleasing chewable and orally disintegrating tablet that utilizes a compression-type tableting machine commonly used to produce high density swallowable hard tablets. When used at low compression forces, these machines typically produce highly friable tablets that are not sufficiently stable during packaging, shipping, and storage. The present invention relates to the discovery of a machine and method for making tablets, such as chewable or orally disintegrating tablets, using radio frequency energy ("RF energy").

Disclosure of Invention

In one aspect, the present invention describes a machine for preparing solid dosage forms (such as tablets) comprising: (a) a die platen having one or more forming cavities, each forming cavity having an inner wall, a first opening on one side surface of the die platen, and a second opening on an opposite side surface of the die platen; (b) one or more first forming tools, each adapted to move into one of the forming cavities through the first opening of the forming cavity; (c) one or more second forming tools, each adapted to move adjacent to or into one of the second openings through the second opening of the forming cavity; (d) at least one first RF electrode operatively associated with the one or more first forming tools, the one or more second forming tools, or the inner wall of the one or more forming cavities; and (e) at least one second RF electrode operatively associated with the one or more first forming tools, the one or more second forming tools, or the inner wall of the one or more forming cavities; wherein the machine is adapted to form a dosage form between a first forming tool and a second forming tool within a forming cavity, and wherein the first RF electrode and the second RF electrode are disposed within the machine such that when RF energy is conducted between the first RF electrode and the second RF electrode, the RF energy passes through a portion of the forming cavity adapted to form a dosage form. Examples of solid dosage forms include tablets (e.g., swallowable tablets, chewable tablets, and orally disintegrating tablets), gums, and lozenges.

The invention also describes a method for preparing a dosage form using such a machine by: (a) adding the powder blend to a forming cavity; (b) moving a first forming tool through a first opening of a forming cavity into the forming cavity such that the powder blend is formed into a agent parison within the forming cavity between the first forming tool and a second forming tool; (c) conducting RF energy between the first electrode and the second electrode such that the energy heats the powder blend within the forming cavity to form the dosage form; and (d) removing the dosage form from within the forming cavity.

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

Drawings

Fig. 1A-F are cross-sectional side views of one embodiment of the present invention showing the manufacture of a tablet 4a from a powder blend 4 in a die platen 2.

Fig. 2A-H are cross-sectional side views of one embodiment of the present invention showing the manufacture of a bilayer tablet 12 from powder blends 10 and 11 within die platen 2.

Fig. 3A-G are cross-sectional side views of an embodiment of the present invention showing the manufacture of a tablet 40 containing preformed inserts 30 and 31 from powder blend 20 in die platen 2.

Fig. 4A and 4B are perspective views of a rotary indexing machine (screw indexing machine) 195.

Fig. 5A and 5B are top views of a rotary indexing machine 195 in a rest position.

Fig. 6A and 6B are cross-sectional views of lower forming tool assembly 110 in a starting position of a manufacturing cycle.

Fig. 7 is a cross-sectional view through the RF station rotary indexing machine 195 prior to compaction of the powder blend 101.

Fig. 8 is a cross-sectional view through the RF station rotary indexing machine 195 illustrating the manufacture of tablets 101 a.

Fig. 9 is a cross-sectional view through the tablet ejection station 160 prior to ejecting the tablet 101 a.

Fig. 10 is a cross-sectional view through tablet ejection station 160 after tablet 101a has been ejected into blister 190.

Fig. 11A-D are cross-sections of alternative embodiments of forming tools and die platens.

Fig. 12A-D are cross-sections of alternative embodiments of forming tools and die platens.

Fig. 13A is a cross section of a forming tool having a contoured surface.

Fig. 13B is a perspective view of a forming tool having a contoured surface.

Fig. 14 is a cross-section of a forming tool having protrusions on the surface.

Detailed Description

It is believed that one skilled in the art can, using the description herein, utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference. All percentages used herein are by weight unless otherwise indicated.

As discussed above, in one aspect, the present invention describes a method of making a dosage form using such a machine by: (a) adding the powder blend to a forming cavity; (b) moving a first forming tool through a first opening of a forming cavity into the forming cavity such that the powder blend is formed into a agent parison within the forming cavity between the first forming tool and a second forming tool; (c) conducting RF energy between the first electrode and the second electrode such that the energy heats the powder blend within the forming cavity to form the dosage form; and (d) removing the dosage form from the forming cavity. Although the specific examples herein focus on tablets, other dosage forms such as lozenges and chewing gum may be made by such machines and methods.

Powder blends

As discussed above, tablets are made by compacting a powder blend containing a pharmaceutically active agent (as discussed herein), a meltable binder (as discussed herein), and optionally a pharmaceutically acceptable carrier. The carrier contains one or more excipients suitable for the formulation of tablets. Examples of suitable excipients include, but are not limited to: fillers, adsorbents, disintegrants, lubricants, glidants, sweeteners, super-disintegrants, flavors and fragrances, 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 deformable materials (e.g., microcrystalline cellulose or other cellulose 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., as distributed under the prosoll trademark (PenWest Pharmaceuticals, Patterson, NY)), magnesium aluminum metasilicate (e.g., as distributed under the NEUSILIN trademark (Fuji Chemical Industries (USA) inc., robblin, NJ)), clays, silicas, bentonites, zeolites, magnesium silicates, hydrotalcites, colloidal magnesium aluminum silicates, and mixtures thereof.

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

Suitable lubricants include, but are not limited to: long chain fatty acids and their salts (e.g., magnesium stearate and stearic acid), talc, glycerides, waxes, and mixtures thereof.

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

Examples of sweeteners include, but are not limited to: synthetic or natural sugars; artificial sweeteners such as saccharin, sodium saccharin, aspartame, acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcones, alitame, thaumatin, monellin, and stevia; sugar alcohols such as sorbitol, mannitol, glycerol, lactitol, maltitol and xylitol; sugar (sucrose), dextrose (also known as glucose), fructose (also known as levulose), and lactose extracted from sugar cane and sugar beets; isomalt, salts thereof, and mixtures thereof.

Examples of superdisintegrants include, but are not limited to: croscarmellose sodium, sodium starch glycolate, and crospovidone (crospovidone). In one embodiment, the tablet contains up to about 5% by weight of such super disintegrant.

Examples of flavors and fragrances include, but are not limited to: essential oils, including distillates, solvent extracts or cold pressed extracts of cut flowers, leaves, bark or mashed whole fruits, containing mixtures of alcohols, esters, aldehydes and lactones; essences, including dilute solutions of essential oils or mixtures of synthetic chemicals blended to match the natural aroma of fruits (e.g., strawberries, raspberries, and black currants); artificial and natural flavors for brew and alcoholic beverages (e.g., cognac brandy, whiskey, rum, gin, sherry, boer grape and wine); tobacco, coffee, tea, cocoa and mint; juices, including squeezed juices from washed and scrubbed fruits such as lemons, oranges and limes; spearmint, peppermint, wintergreen, cinnamon, cocoa, vanilla, licorice, menthol, eucalyptus, fennel seed; nuts (such as peanuts, coconut, hazelnuts, chestnuts, walnuts and kola), almonds, raisins; and powders, flours or plant material parts including tobacco plant parts (e.g., nicotiana plant parts in amounts that do not contribute significantly to nicotine levels), and ginger.

Examples of antioxidants include, but are not limited to: tocopherol, ascorbic acid, sodium metabisulfite, butylated hydroxytoluene, butylated hydroxyanisole, edetic acid and edetate 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 invention, the powder blend has an average particle size of less than 500 microns, such as from about 50 microns to about 500 microns, such as from about 50 microns to 300 microns. Particles in this size range are particularly useful in direct compaction processes.

In one embodiment of the invention, the tablet may be prepared from a powder blend that is substantially free of hydrated polymer. As used herein, by "substantially free" is meant less than 5%, such as less than 1%, such as less than 0.1%, (e.g., 0%). Such compositions are advantageous for maintaining immediate release dissolution characteristics, minimizing processing and materials such as total freedom from ingredients, and optimizing the physical and chemical stability of the tablet.

In one embodiment, the 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, water insoluble cellulose, starch, corn starch, and modified starch. As described in this example, substantially free is less than 2%, e.g., less than 1% or none.

Fusible adhesive

The powder blend/tablet of the present invention comprises at least one meltable binder. In one embodiment, the meltable binder has a melting point of about 40 ℃ to about 140 ℃, such as about 55 ℃ to about 100 ℃. Softening or melting of the one or more meltable binders results in sintering of the tablet shape by binding of the softened or melted binder with the pharmaceutically active agent and/or other ingredients within the compacted powder blend.

In one embodiment, the meltable adhesive is an RF-meltable adhesive. By RF-meltable adhesive is meant a solid adhesive that softens or melts upon exposure to RF energy. RF-meltable adhesives are generally polar and have the ability to re-harden or re-solidify upon cooling.

In one embodiment, the meltable adhesive is not an RF-meltable adhesive. In this embodiment, the powder blend contains an excipient (e.g., a polar excipient) that heats up upon exposure to RF energy, such that the resulting heat is able to soften or melt the meltable binder. Examples of such excipients include, but are not limited to: polar liquids such as water and glycerol; powdered metals and metal salts such as powdered iron, sodium chloride, aluminum hydroxide and magnesium hydroxide; stearic acid; and sodium stearate.

Examples of suitable meltable adhesives include: fats such as cocoa butter, hydrogenated vegetable oils such as palm kernel oil, cottonseed oil, sunflower oil and soybean oil; mono-, di-and triglycerides; a phospholipid; 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 polyethylene glycol-32 glyceride, and stearoyl polyethylene glycol-32 glyceride; polyethylene oxide; and sucrose esters.

In one embodiment, the meltable binder is an RF-meltable binder and the RF-meltable binder is polyethylene glycol (PEG), such as PEG-4000. Particularly preferred RF-meltable binders are PEG particles having at least 95 wt% 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 one or more meltable binders may be present at a level of from about 0.01% to about 70%, such as from about 1% to about 50%, of the powder blend/tablet, such as from about 10% to about 30% of the powder blend/tablet.

Carbohydrate compound

In one embodiment, the powder blend contains at least one carbohydrate. Carbohydrates can aid in the solubility and mouthfeel of the tablet, help distribute the meltable binder over a wider surface area, and dilute and buffer the pharmaceutically active agent. Examples of carbohydrates include, but are not limited to: water-soluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, isomalt, and lactose), starches (e.g., corn starch), sugar alcohols (e.g., mannitol, sorbitol, maltitol, erythritol, lactitol, and xylitol), and starch hydrolysates (e.g., dextrins and maltodextrins).

The carbohydrate may be present at a level of about 5% to about 95% of the powder blend/tablet, such as about 20% to about 90% or about 40% to about 80% of the powder blend/tablet. The particle size of the carbohydrate may affect the level of meltable binder used, with higher particle size carbohydrates providing lower surface area and therefore requiring lower levels of binder. In one embodiment, if the carbohydrate is greater than 50% by weight of the powder blend and the carbohydrate has an average particle size greater than 100 microns, the meltable binder is from about 10 to about 30% by weight of the powder blend/tablet.

Pharmaceutically active agents

The powder blend/tablet of the present invention comprises at least one pharmaceutically active agent. By "pharmaceutically active agent" it is meant a formulation (e.g., a compound) that is approved or approved by the U.S. food and Drug Administration, the European Medicines Agency, or any inherited entity thereof for 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, spasmolytics, appetite suppressants, bronchodilators, cardiovascular therapeutic agents (e.g., statins), central nervous system therapeutic agents, antitussives, decongestants, diuretics, expectorants, gastrointestinal therapeutic agents, anesthetics, mucolytics, muscle relaxants, osteoporosis therapeutic agents, stimulants, nicotine, and sedatives.

Examples of suitable gastrointestinal therapeutic 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., magnesium aluminate hydrate, magnesium aluminum silicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, and magnesium trisilicate), phosphate-containing pharmaceutically active agents (e.g., aluminum phosphate and calcium phosphate), potassium-containing pharmaceutically active agents (e.g., potassium bicarbonate), sodium-containing pharmaceutically active agents (e.g., sodium bicarbonate), and silicates; laxatives, such as laxatives (e.g., docusate) and stimulant laxatives (e.g., bisacodyl); h2 receptor antagonists such as famotidine, ranitidine, cimetidine, and nizatidine; proton pump inhibitors such as omeprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and lansoprazole; gastrointestinal cytoprotective agents such as sucralfate and misoprostol; gastrointestinal stimulants such as prucalopride; antibiotics against helicobacter pylori (h.pylori), such as clarithromycin, amoxicillin, tetracycline, and metronidazole; antidiarrheals, such as bismuth subsalicylate, kaolin, diphenoxylate, and loperamide; glycopyrrolate; analgesics, such as methamine; antiemetics such as ondansetron, cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, and hydroxyzine; probiotics, including but not limited to lactobacillus (lactobacilli); lactase; racecadotril; and air expulsion agents such as polydimethylsiloxanes (e.g., dimethicones and simethicones, including those disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260); their isomers; and pharmaceutically acceptable salts and prodrugs (e.g., esters) thereof.

Examples of suitable analgesics, anti-inflammatories, and antipyretics include, but are not limited to: non-steroidal anti-inflammatory drugs (NSAIDs), such as propionic acid derivatives (e.g., ibuprofen, naproxen, ketoprofen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, biprofen, carprofen, oxaprozin, pranoprofen, and suprofen) and COX inhibitors, such as celecoxib; acetaminophen; acetylsalicylic acid; acetic acid derivatives such as indomethacin, diclofenac, sulindac, and tolmetin; fenamic acid derivatives, such as mefenamic acid, meclofenamic acid, and flufenamic acid; biphenyl carboxylic acid derivatives such as diflunisal and flufenisal; and oxicams, such as piroxicam, sudoxicam, isoxicam and meloxicam; their isomers; and pharmaceutically acceptable salts and prodrugs thereof.

Examples of antihistamines and decongestants include, but are not limited to, brompheniramine, clorazine, dexbrompheniramine, bromhexine, phenindamine, pheniramine, mepyramine, pinazilamine, pripolidine, ephedrine, phenylephrine, pseudoephedrine, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, doxylamine, astemizole, terfenadine, fexofenadine, naphazoline, oxymetazoline, montelukast, propylhexedrine, phenylpropylenepyridine, clinoptidine, acrivastine, promethazine, oxolamine, mequitazine, buclizine, bromhexine, ketotifen, terfenadine, ebastine, phenizine, xylometazoline, loratadine, desloratadine, and cetirizine; their isomers; and their pharmaceutically acceptable salts and esters.

Examples of antitussives and expectorants include, but are not limited to: diphenhydramine, dextromethorphan, noscapine, chlophedianol, menthol, benzonatate, ethyl morphine, codeine, acetylcysteine, carboxycysteine, ambroxol, belladonna alkaloid, sobutyrol, guaiacol, and guaifenesin; their isomers; and pharmaceutically acceptable salts and prodrugs thereof.

Examples of muscle relaxants include, but are not limited to: cyclobenzaprine and chlorzoxazone, metaxalone, oxfenadrin and methocarbamol; their isomers; and pharmaceutically acceptable salts and prodrugs thereof.

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

Examples of sedatives include, but are not limited to: sleep aids such as antihistamines (e.g., diphenhydramine), eszopiclone, and zolpidem, and their pharmaceutically acceptable salts and prodrugs.

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

Examples of anesthetics (e.g., for treating sore throat) include, but are not limited to: dyclonine, benzocaine and pectin, and their pharmaceutically acceptable salts and prodrugs.

Examples of suitable statins include, but are not limited to: atorvastatin, rosuvastatin, fluvastatin, lovastatin, simvastatin, atorvastatin, pravastatin and their pharmaceutically acceptable salts and prodrugs.

In one embodiment, the pharmaceutically active agent included in the tablet is selected from: phenylephrine, dextromethorphan, pseudoephedrine, acetaminophen, cetirizine, aspirin, nicotine, ranitidine, ibuprofen, ketoprofen, loperamide, famotidine, calcium carbonate, simethicone, chlorpheniramine, methocarbamol, chlobendan, ascorbic acid, pectin, dyclonine, benzocaine, and menthol, as well as pharmaceutically acceptable salts and prodrugs thereof.

As discussed above, the pharmaceutically active agents of the present invention may also be present in the form of pharmaceutically acceptable salts such as acid/anion salts or base/cation salts. Pharmaceutically acceptable acid/anion salts include, but are not limited to: acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, dedonol propionate (estolate), ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, alpha-hydroxyacetaminobenzenearsenate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, naphthalenesulfonate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, camphorate, xanthate, etc, Basic acetate, succinate, sulphate, tannate, tartrate, tea chlorate, tosylate and triiodonium. Pharmaceutically acceptable basic/cationic salts include, but are not limited to: aluminum, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, meglumine, potassium, procaine, sodium and zinc.

As mentioned above, the pharmaceutically active agents of the present invention may also be present in the form of prodrugs of the pharmaceutically active agent. Typically, such prodrugs will be functional derivatives of the pharmaceutically active agent which can be readily converted in vivo to the desired pharmaceutically active agent. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of produgs", h. In addition to salts, the invention also provides esters, amides, and other protected or derivatized forms of the compounds.

If the pharmaceutically active agents according to the invention have at least one chiral center, they may be present as enantiomers. If the pharmaceutically active agents have two or more chiral centers, they may also 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, certain crystalline forms of the pharmaceutically active agent may exist as polymorphs and as such are intended to be included within the scope of the present invention. In addition, certain pharmaceutically active agents may form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also intended to be included within the scope of the present invention.

In one embodiment, the pharmaceutically active agent is 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 this amount, the particular pharmaceutically active agent being administered, the bioavailability characteristics of the pharmaceutically active agent, the dosing regimen, the age and weight of the patient, and other factors must be considered, as is known in the art.

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

The pharmaceutically active agent may be present in pure crystalline form or in particulate form prior to addition of the taste-masking coating. Granulation techniques may be used to improve the flow characteristics or particle size of the pharmaceutically active agent to make it more suitable for compaction or subsequent coating. Binders suitable for granulation include, but are not limited to: starch, polyvinylpyrrolidone, polymethacrylate, hydroxypropylmethylcellulose, and hydroxypropylcellulose. The particles comprising the pharmaceutically active agent may be formed by co-granulating the pharmaceutically active agent with suitable matrix particles using any granulation method known in the art. Examples of such granulation methods include, but are not limited to, high shear wet granulation and fluid bed granulation, such as rotary fluid bed granulation.

As is known in the art, if the pharmaceutically active agent is not palatable, the pharmaceutically active agent may be coated with a taste-masking coating. Examples of suitable taste-masking coatings are described in U.S. Pat. No.4,851,226, U.S. Pat. No.5,075,114, and U.S. Pat. No.5,489,436. Commercially available taste masked pharmaceutically active agents may also be used. For example, acetaminophen particles encapsulated with ethylcellulose or other polymers by a coacervation process can be used in the present invention. Coacervated encapsulated acetaminophen is commercially available from Eurand America, inc. (Vandalia, Ohio) or from Circa Inc.

In one embodiment, the tablet incorporates modified release coated particles (e.g., particles containing at least one pharmaceutically active agent that impart the modified release characteristics of such pharmaceutically active agent). As used herein, "modified release" shall apply to modified 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. Typically, modified release tablets are formulated such that the active agent is available for a prolonged period of time after ingestion, which thus results in a reduction in the frequency of administration compared to administration of the same active agent in conventional tablets. Modified release tablets also allow the use of active agent combinations where the duration of one pharmaceutically active agent may be different from the duration of another pharmaceutically active agent. In one embodiment, the tablet contains one pharmaceutically active agent that is released in an immediate release manner and another active agent or a second portion of the same active agent as the first active agent that is released in a modified release manner.

Examples of swellable erodible hydrophilic materials useful as release-modifying excipients for use in the modified release coating include: water-swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays and gelling starches. Examples of the water-swellable cellulose derivative include: sodium carboxymethylcellulose, cross-linked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyisopropyl cellulose, hydroxybutyl cellulose, hydroxyphenyl 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 polyethylene oxide. Examples of acrylic polymers include potassium methacrylate-divinylbenzene copolymers, polymethyl methacrylate, 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 phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as polyvinyl acetate phthalate, cellulose acetate phthalate and acetaldehyde dimethyl cellulose acetate; and enteric acrylate derivatives, such as polymethacrylate-based polymers, such as poly (methacrylic acid, methyl methacrylate) 1: 2 (available under the trade name EUDRAGIT S from Rohm Pharma GmbH) and poly (methacrylic acid, methyl methacrylate) 1: 1 (available under the trade name EUDRAGIT L from Rohm Pharma GmbH).

In one embodiment, the pharmaceutically active agent is coated with a combination of a water insoluble film forming polymer such as, but not limited to, cellulose acetate or ethyl cellulose and a water soluble polymer such as, but not limited to, povidone, polymethacrylic acid copolymers such as those sold by Rohm America under the trade name Eudragit E-100, and hydroxypropylcellulose. In this embodiment, the ratio of water insoluble film forming polymer to water soluble polymer is from about 50% to about 95% water insoluble polymer and from about 5% to about 50% water soluble polymer, and the weight percent of the coating is from about 5% to about 40% by weight of the taste-masked coated particles. In one embodiment, the coating in the coated particles for the pharmaceutically active agent is substantially free of materials that melt below 85 ℃ (such as polyethylene glycol) in order to prevent damage to the integrity of the coating during the RF heating step.

In one embodiment, one or more pharmaceutically active agents or a portion of the pharmaceutically active agent may be bound to an ion exchange resin to mask the taste of the pharmaceutically active agent or deliver the pharmaceutically active agent in a modified release manner.

In one embodiment, the pharmaceutically active agent is capable of dissolving upon contact with a fluid such as water, gastric acid, intestinal fluid, and the like. In one embodiment, the dissolution profile of the pharmaceutically active agent within the tablet conforms to the USP specifications for immediate release tablets containing the pharmaceutically active agent. For example, for acetaminophen tablets, USP 24 specifies that at least 80% of the acetaminophen contained in the tablet is released from the tablet within 30 minutes after administration using USP apparatus 2 (paddle) at 50rpm in pH 5.8 phosphate buffer, and for ibuprofen tablets, USP 24 specifies that at least 80% of the ibuprofen contained in the tablet is released from the tablet within 60 minutes after administration using USP apparatus 2 (paddle) at 50rpm in pH 7.2 phosphate buffer. See USP 24, 2000 edition, pages 19-20 and 856 (1999). In another embodiment, the dissolution profile of the pharmaceutically active agent is modulated: such as controlled release, sustained release, delayed release, retarded release, long acting, delayed release, and the like.

In one embodiment, the particle size of the pharmaceutically active agent results in more void space in the tablet, where a larger particle size of the pharmaceutically active agent then requires a lower level of meltable binder. In one embodiment, if the pharmaceutically active agent or coated pharmaceutically active agent is greater than 50% of the blend and the carbohydrate has an average particle size greater than 100 microns, based on the weight of the powder blend/tablet, the meltable binder is from about 10 to about 30 weight% of the powder blend/tablet. In one embodiment, if the average particle size of the powder blend is between about 100 microns to about 300 microns, the meltable binder is about 10 to about 20 weight percent of the powder blend/tablet.

The melting point of the pharmaceutically active agent may affect the temperature used during the heating step and the type of meltable binder used. In one embodiment, the meltable binder has a melting point lower than the melting point of the pharmaceutically active agent. In another embodiment, the melting point of the pharmaceutically active agent is the same as or lower than the melting point of the meltable binder, in which case during the melting or heating step both the pharmaceutically active agent and the meltable binder may melt and upon cooling create a eutectic or multiple bridges between the pharmaceutically active agent and the meltable binder and the other substance in the tablet form. In one embodiment, the heating temperature is above the melting point of the meltable binder and below the melting point of the pharmaceutically active agent. In one embodiment where ibuprofen is the pharmaceutically active agent, the meltable binder is heated to about 30 ℃ to about 60 ℃. In one embodiment, the pharmaceutically active agent is a meltable binder.

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

The susceptibility (e.g., melting or degradation) of the pharmaceutically active agent to RF energy may have an effect on the type of energy and/or temperature used during the heating step and the type of meltable binder used.

In one embodiment, the processing of the tablet is free of wet granulation or hot melt granulation steps. In this example, the materials were blended directly prior to heating. In one embodiment, the materials are blended and pressed directly prior to heating.

Production of tablet blanks

In one embodiment, the powder blend is fed into a tablet die of an apparatus that applies pressure to form a tablet shape (e.g., by light compaction such as tamping). Any suitable compaction equipment may be used, including but not limited to conventional single punch or rotary tablet presses. In one embodiment, the tablet shape may be formed by compaction with a rotary tablet press (e.g., such as those commercially available from Fette America Inc. (Rockaway, n.j.) or Manesty Machines LTD (Liverpool, UK)). In one embodiment, the tablet shape is heated after it is removed from the tablet press. In another embodiment, the tablet shape is heated in a tablet press.

In one embodiment, to achieve the desired attributes of an orally disintegrating tablet, the configuration of the tablet can be highly porous, use a minimal amount of binder, and/or have a low density. Thus, such tablets are somewhat brittle and soft. In a preferred embodiment, it is desirable to achieve oral disintegration properties (low density) with minimal packing/compaction force. Experiments have determined that a low force compaction without the application of RF energy produces very brittle tablets that cannot withstand the material handling forces required during the manufacturing process. It was also determined that the above compacted tablets would "slump" and deform under their own weight as the binder became molten when carefully handled and sent to a heating source (RF or conventional convection/conduction).

In most thermodynamic processes or machines, the heat source and heat sink are two distinct machines or steps, requiring the transfer of material from one device to another. In the manufacture of the tablets of the present invention, energy must be added to the tablet to achieve the binding effect, and then energy must be removed from the product to solidify and strengthen the product for its final handling packaging and use. One of the unique and unexpected attributes of one embodiment of the fabrication method of the present invention is that the heat source and heat sink are components of the same apparatus. In fact in earlier experiments the metal forming tool (e.g. the die punch) removed so much heat from the treated tablet shape at room temperature (due to its high thermal conductivity) that the surface of the resulting tablet was unacceptable due to the fact that no uniform melting occurred within the powder blend. The resulting tablet had a well-formed core, but the surface was loose, unbonded and poorly formed powder, which did not adhere to the rest of the tablet. To correct for this heat loss, in one embodiment, heat is added to the forming tool to achieve normal sintering at the surface as well as the center of the tablet.

To take advantage of this unique thermal effect, the powder blend can also be selected for its thermal properties and thermal conductivity and specific heat so that the powder blend particles themselves become a heat sink. In a typical orally disintegrating tablet ("ODT") formulation, the polar binder that heats up in the RF field may constitute less than 10% of the mixture. The remaining 90% of the material acts as a heat sink, which quickly removes heat from the adhesive after the RF field is removed. The desired result of this is that the total processing time can be only a few seconds and there is no need to transfer the tablet from the die platen during the critical tamping and heating process. The die platen may serve as a material handling device as well as a thermoforming tool. This is particularly advantageous for the successful manufacture of brittle orally disintegrating tablets.

In one embodiment, the compaction step (e.g., tamp) that occurs prior to the addition of RF energy utilizes a compaction force that is lower than the force required to compress the chewable or swallowable tablet. In one embodiment, the compaction force is less than about 6.9MPa (1000 psi) (e.g., less than about 3.4MPa (500 psi), such as less than 1.4MPa (200 psi), such as less than 0.3MPa (50 psi)). In one embodiment, energy is applied while the powder blend is under such force.

In one embodiment, the compaction step is performed in an indexing (extended) manner, wherein a group of tablets is compacted simultaneously and then rotated to another indexing (extending) station. In one embodiment, the compaction step is performed at a single indexing station and the application of RF energy is performed at another indexing station. In another embodiment, there is a third indexing station where ejection of the tablet or tablets occurs, wherein the lower forming tool is raised and brought up to the surface of the die. In another embodiment, the compacting step is performed by adding pneumatic or hydraulic cylinders to the top of the upper forming tool. In one embodiment, multiple tablets are simultaneously ejected by a pull-off bar (take-off bar) and separated from the surface of the indexing station and removed.

In another embodiment, tablet shapes can be prepared by the compaction method and apparatus described in U.S. patent application publication No. 20040156902. In particular, a tablet shape may be prepared with a rotary compression module comprising a fill zone, an insertion zone, a compression zone, an ejection zone, and a purge zone in a single apparatus having a dual row die configuration. The dies of the compression module may then be filled by vacuum, with a filter disposed in or near each die. The purge zone of the press module includes an optional powder blend recovery system to recover excess powder blend from the filter and return the powder blend to the die. In one embodiment, RF energy is projected through the die table of a rotary tablet press into a suitable electrode within a forming tool or forming chamber. In one embodiment, the die table is constructed of a non-conductive material.

In another embodiment, a portion of the tablet shape can be prepared by a wet granulation process in which a solution or dispersion of excipients and a wet binder (e.g., a water-cooked starch paste or a polyvinylpyrrolidone solution) is mixed and granulated. Suitable equipment for wet granulation include low shear mixers (e.g., planetary mixers), high shear mixers, and fluidized beds (including rotating fluidized beds). The resulting granular material is then dried and optionally dry blended with additional ingredients (e.g., excipients, such as meltable binders as described herein, lubricants, colorants, and the like). The final dry blend is then suitable for compaction by the methods described herein. Methods for the direct compaction process and the wet granulation process are known in the art.

In one embodiment, the tablet shape is prepared by the compaction method and apparatus described in published U.S. Pat. No.6,767,200. In particular, tablets may be prepared with a rotary compression module comprising a fill zone, a compression zone, and an ejection zone in a single apparatus having a dual row die configuration as shown in fig. 6 herein. The moulds of the press module are filled, preferably by means of vacuum, with a filter in or near each mould.

The tablet shape may have one of a number of different shapes. For example, the tablet shape may be shaped into a polyhedron, such as a cube, pyramid, prism, or the like; or may have a geometry with a spatial profile of some non-flat surface, such as a cone, a truncated cone, a triangle, a cylinder, a sphere, a torus, etc. In certain embodiments, the tablet shape has one or more major surfaces. For example, tablet shape surfaces typically have opposing upper and lower surfaces formed by contact with upper and lower forming tool surfaces (e.g., die punches) in a compaction machine. In such embodiments, the tablet shape surface typically also includes a "belly band" between the upper and lower surfaces, which is formed by contact with the die wall in the compaction machine. The tablet shape/tablet may also be a multilayer tablet shape/tablet. Applicants have found that sharp edges in the die used to make the tablet can cause arcs and thus may require more rounded edges.

In one embodiment, the process for producing the tablet shape is substantially free of solvent. In this example, the powder blend is substantially free of solvent, and the manufacturing process (e.g., the process of filling into a die) is also substantially free of solvent. The solvent may include, but is not limited to, water, an organic solvent (such as, but not limited to, an alcohol, a chlorine-containing solvent, hexane, or acetone), or a gaseous solvent (such as, but not limited to, nitrogen, carbon dioxide, or a supercritical fluid).

A vibration step is employed in one embodiment (e.g., added after filling the powder blend but before the heating or melting step to remove air from the powder blend). In one embodiment, vibrations having a frequency of about 1Hz to about 50KHz are added with a peak-to-peak amplitude of 1 micron to 5mm to allow the flowable powder blend to be deposited into the cavity of the die platen ("forming cavity").

In one embodiment, quantitative volumes of powder blend 4 are filled into Teflon @, as shown in FIGS. 1A-1F(or similar electrically and RF energy insulating material such as ceramic or UHMW plastic) die platen 2. The die platen 2 has a forming cavity 5 with an inner wall 6, an upper opening 7 on the upper surface of the die platen 2 (which allows movement of the powder blend 4 and upper forming tool 1 into the forming cavity 5) and a lower opening 8 on the opposite surface of the die platen 2 (which allows movement of the blend 4 and lower forming die 3 into the forming cavity 5). The powder blend 4 may be gravity fed or mechanically fed from a feeder (not shown). A metal conductive lower forming tool 3 is inserted into the die platen to retain the powder blend 4 within the die platen 2. A similar metallic 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.

The heating station is constituted by an RF generator 7 which generates the necessary high voltage, high frequency energy. The generator 7 is electrically connected to the moveable upper RF electrode plate 8 and the moveable lower RF electrode plate 6. As shown in fig. 1C, in this position, the powder blend 4 is compacted between the upper forming tool 1 and the lower forming tool 3 by the pressure applied by the upper RF electrode plate 8 and the lower electrode plate 6 to form a tablet shape 4 a. Tablet shape 4a 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 turned off, tablet shape 4a cools to form tablet 4 b. In one embodiment, as shown in fig. 1D, the upper forming tool 1 advances the tablet 4b from the die platen 2 into a blister 8 for packaging the tablet 4 b. In an alternative embodiment, as shown in fig. 1E, the lower forming tool 3 pushes the tablet 4b out of the die platen 2 and is guided to an ejection chute by a stationary "lead-off bar (not shown). Fig. 1F shows a three-dimensional view of the forming tools 1 and 4, the die platen 2 and the tablet 4 b.

In fig. 2A-2H, an alternative embodiment of the invention is shown in which a multilayer tablet is made. First, the powder blend 10 is filled into the die platen 2 as shown in fig. 2A. The powder blend 10 is either packed by the upper forming tool 1 as shown in fig. 2B or moved down into the die platen 2 to form a tablet shape 10 a. The tablet shape 10a is then filled with the powder blend 11. The forming tools 1 and 3, die platen 2, tablet shape 10a and powder blend 11 are then moved to a 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 fig. 2F and 2G. Although a bilayer tablet is shown in this figure, additional layers may be created by adding additional powder blend to the die platen 2.

Fig. 3A-3G illustrate another embodiment of the present invention wherein preformed inserts 30 and 31 are inserted into tablet shape 20a as shown in fig. 3A-3D. The forming tools 1 and 3, die platen 2, tablet shape 20 and preformed inserts 30 and 31 are then moved to a compaction and RF heating station as shown in fig. 3E. RF heating is accomplished as described above for fig. 1C to produce the multicomponent tablet 40 shown in fig. 2F and 2G.

Fig. 4A and 4B show two views of a rotary indexing machine 195 designed to produce a large number of tablets. In particular, the configuration of the illustrated apparatus is designed to produce a tablet that is brittle while minimizing the risk of damaging the tablet as it is moved through the various manufacturing steps. This embodiment of the invention consists of an indexing table 170 with four sets of die platens 175 each having sixteen cavities, a powder feeder 100, an RF generator 150, a machine frame 140, moving RF electrode assemblies 120 and 130, a lower forming tool assembly 110, an upper forming tool assembly 210, a tablet ejection station 160, an indexer drive system 180, a blister package web 190, and a roll of blister cover material 191.

Fig. 5A is a top view of the apparatus in the rest position. Fig. 5B is a top view of the apparatus as the indexing table 170 rotates in the direction "a" between stations. Fig. 6A shows a cross-sectional view through the lower forming tool assembly 110 at the start of the manufacturing cycle. The lower forming tool 111 (which is made of a conductive metal material such as brass or stainless steel) is held in a holder plate 112 (made of aluminum or steel, for example). Heating block 117 is attached to holder plate 112 and contains fluid channel 117 b. The heating (or optionally cooling) fluid is circulated through the heating block 117 by connection to flexible hoses 119a and 119b forming supply and return lines. Heating may also be accomplished by a cartridge electric heater or other suitable device (not shown). Attached to the retainer plate are a cam follower 114 and a linear bearing 113. The guide shaft 116 is fixed to the indexing table 170. The retainer plate and the forming tool 111 are movable up and down according to the profile of the barrel cam 115 on which the cam follower 114 rolls. Also shown is a die platen 171 made of an electrically and RF energy insulating material such as teflon, UHMW or ceramic. This is necessary to prevent short circuits when the conductive forming tool is positioned in the RF electric field in a subsequent step. The forming chamber 171a is shown empty at this stage of the process.

Figure 6B depicts a cross section through the powder feeder station 100 of the apparatus. At which point the powdered powder blend 101 is gravity fed into the die platen 171. The movable cam section 118 is adjusted up and down in the direction "B" to change the volume of the cavity 171a by changing the amount of penetration of the lower forming tool 111 into the die platen 171. This adjustable volume feature allows the selection of precise doses of powdered powder blend for a desired tablet weight. As the machine rotates out of the powder feed station, the edge of the feeder 102 wipes across the die platen 171 to create a horizontal powder surface relative to the surface of the die platen 171.

Fig. 7 is a cross-sectional view through the RF station of the apparatus. An RF generator 150 is symbolically depicted here. In one embodiment, RF generator 150 is configured as a free-running oscillator system. It is typically comprised of a power vacuum tube (e.g., a triode), a DC voltage source between 1000 volts and 8000 volts connecting the cathode and plate (anode). The resonant circuit is used to apply a sine wave signal to the control gate and electrodes to generate the necessary frequency (typically 13.56MHZ or 27.12MHZ) and high voltage field. An example of such an RF generator 150 is a COSMOS Model C10X16G4(Cosmos Electronic Machine Corporation, Farmingdale, NY). In another embodiment, the RF energy may be provided by a 50 ohm system consisting of a waveform generator that feeds a radio frequency signal to a power amplifier that is connected to the electrode and the load through an impedance matching network.

In FIG. 7, lower movable RF electrode 121 is shown as being movable in direction "D". It appears to be in its lower position. The linear movement is generated by a linear actuator, which is usually of a design such as a pneumatic cylinder or a servomotor. Two cylinders are depicted in fig. 7. The cylinder blocks 141 and 142 apply pressure to the guide rods 144 and 143. Moving platens 132 and 122 are coupled to the guide rods and provide an electrically insulating pedestal for electrode plates 131 and 121. RF generator 150 is connected to electrode plates 131 and 121 via metal wires 185 and 184. The movable upper RF electrode assembly 130, which can move in the direction "C", is shown in its upper position. The upper shaping tool 133, the holder plate 134, and the heating block 135 are all attached to the movable RF electrode plate 131, and thus move up and down together therewith. The powder blend 101 is in the die platen 171.

Fig. 8 is a cross-section through the same RF station, but showing RF electrodes 131 and 121 pressing against respective forming tool assemblies 133 and 111 to both compact powder blend 101 and apply RF energy to powder blend 101 to produce tablet 101 a. After the application of RF energy is stopped, the movable RF electrode plate is retracted, indexing the indexing plate 170, die platen 171, and lower forming tool assembly 110 to the next station.

Fig. 9 is a cross-sectional view through the tablet ejection station 160. Ejector pins 161 are attached to a movable plate 162 (which may be movable in the "E" direction) that is actuated by an actuator assembly 163 (which may be, for example, a linear servo motor or an air cylinder or other suitable actuator). The actuator rod 166 is connected to the movable plate 162. The linear bearings 164 and guide rods 165 provide rigidity and support to the actuator plate 162 and prevent damaging side loads (side loads) generated by the ejection forces from acting on the actuator 163. Blister pack 190 is shown below die platen 171.

Fig. 10 is a cross-section of the same assembly after ejector pins 161 have pushed finished tablet 101a through die platen 171. This direct placement of the tablets in the blisters helps prevent breakage that can occur when using typical devices such as feeders or by dumping the tablets into a transport drum.

In one embodiment, the lubricant is added to the forming cavity prior to adding the flowable powder blend. The lubricant may be a liquid or a solid. Suitable lubricants include, but are not limited to: solid lubricants, such as magnesium stearate, starch, calcium stearate, aluminum stearate, and stearic acid; or a liquid lubricant such as, but not limited to, simethicone, lecithin, vegetable oil, olive oil, or mineral oil. In certain embodiments, the lubricant is added at a percentage of less than 5%, such as less than 2%, for example less than 0.5%, by weight of the tablet. In certain embodiments, the presence of a hydrophobic lubricant can adversely impair the disintegration or dissolution characteristics of the tablet. In one embodiment, the tablet is substantially free of hydrophobic lubricant. Hydrophobic lubricants include magnesium stearate, calcium stearate, and aluminum stearate.

Radio frequency heating of tablet shape to form tablets

Radio frequency heating generally refers to heating with an electromagnetic field having a frequency of about 1MHz to about 100 MHz. In one embodiment of the invention, the RF energy is in the range of about 1MHz to about 100MHz (e.g., about 5MHz to 50MHz, such as about 10MHz to about 30MHz) in frequency. RF energy is used to heat the binder (e.g., direct heating when the meltable binder is an RF-meltable binder, or indirect heating when the meltable binder is not an RF-meltable binder but is heated by RF-heatable ingredients within the powder blend). Whether an orally disintegrating tablet or a soft chewable tablet is manufactured, the degree of compaction, the type and amount of meltable binder, and the amount of RF energy used may determine the hardness and/or type of tablet.

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 upper and lower forming tools function as electrodes (e.g., they are operably associated with a source of RF energy) through which RF energy can be delivered to the tablet. In one embodiment, there is direct contact between at least one RF electrode (e.g., a forming tool) and the tablet shape. In another embodiment, there is no contact between any RF electrode (e.g., forming tool) and the tablet shape. In one embodiment, the RF electrode is in direct contact with the surface of the tablet shape when RF energy is added. In another embodiment, the RF electrode does not contact (e.g., 1mm to about 1cm from the tablet shape surface) during the addition of RF energy.

In one embodiment, the RF energy is delivered simultaneously with the formation of the tablet shape. In one embodiment, the RF energy is delivered once the tablet shape is formed. In one embodiment, the RF energy is delivered after the tablet shape has been removed from the die.

In one embodiment, the RF energy is applied for a sufficient time to 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 to a portion of the tablet shape, such as the exterior of the tablet shape.

In an alternative embodiment of the invention, the shaping tool may be configured for achieving a local heating effect and may also be configured for shaping the electric field generated on said mould. One such configuration is shown in fig. 11A. The RF generator 200 is connected to RF electrode plates 201 and 202. The forming tools 205 and 204 are constructed of electrically conductive material and they have insulating material such as ceramic, Teflon, from electrical and RF energyAnd attachments 207 and 208 made of polyethylene or high density polyethylene. The die platen 203 is also constructed of an electrically and RF energy insulative material. This configuration creates a larger distance between the conductive forming tools to weaken the electric field, which is beneficial for creating thin tablets without the risk of arcing, which would damage the product and tools. FIG. 11B depicts a similar configuration, but with forming tools 210 and 211 each having a recess that receives inserts 213 and 212, which are made of an electrically and RF energy insulative material. This geometry will produce tablets that will generate less heat in the areas where inserts 213 and 212 are located because the electric field is weaker due to the larger distance between the conductive portions of 211 and 210. Fig. 11C is similar to fig. 11B, only the geometry is reversed so that the tablet formed by this configuration will have a greater thermal effect in the center because the inserts 216 and 217 are at the periphery of the respective forming tools 214 and 215. Fig. 11D depicts another embodiment in which the die platen is constructed of an electrically conductive assembly 221 and an electrically insulating assembly 222, the electrically insulating assembly 222 being made of an electrically and RF energy insulating material. The forming tools 219 and 218 are electrically conductive, but the forming tool 218 also contains a second electrically insulating component 220 around the surface of the upper forming tool 218 that contacts the tablet shape 206. This configuration creates an electric field and associated preferential heating zone of the conductive portion of the die platen.

Fig. 12A is similar to fig. 11D, except that in this embodiment the die platen 233 is constructed entirely of an electrically conductive material. Fig. 12B and 12C depict two embodiments in which the die platens include respective central portions 245 and 254 that are electrically conductive and respective outer portions 244/246 and 252/253 are made of an electrically and RF energy insulative material. Fig. 12B also includes an insulation assembly 220 around the surface of the lower forming tool 219. Fig. 12D is another embodiment in which the forming tools 263 and 262 are made of an electrically and RF energy insulative material. The die platen portions 264 and 265 are made of an electrically and RF energy insulative material, but have two respective conductive portions 267 and 266 that are connected to the RF generator circuit 200. In this configuration, the electric field is applied in a horizontal direction across tablet shape 206.

As mentioned above, the distance between the electrically conductive parts of the forming tool has a strong influence on the field strength and the heating effect. In order to produce tablets with uniform heating and texture, forming tools of an equally spaced configuration are desirable. Fig. 13A and 13B depict such a configuration. In this embodiment, wave shaping tools 270 and 273 are shown to produce tablets 272 with a uniform appearance within the die platen 271. The profile of the forming tool surface is equidistant as indicated by dimension "X".

Fig. 14A is an example in which non-uniform heating is used to make tablet 282. In this example, a tablet having hard and soft regions was produced. The shaping tools 280 and 281 are prepared with protrusions on the surface, producing high field strength (resulting in higher heating) where they are closest (shown by dimension "Z") and weaker field strength (resulting in less heating) where they are further away (shown by dimension "Y").

In one embodiment, to help reduce stickiness, the tablet is cooled within the forming cavity to cool and/or solidify the binder. The cooling may be passive cooling (e.g., at room temperature) or active cooling (e.g., coolant recirculation cooling). When using coolant recirculation, coolant may optionally be circulated through channels internal to the forming tool (e.g., punch or punch platen) and/or channels internal to the die or die platen (e.g., as discussed in fig. 6A and 6B above). In one embodiment, the method uses a die platen having a plurality of die cavities and upper and lower punch platens having a plurality of upper and lower punches for simultaneously forming a plurality of tablets, wherein the platens are actively cooled.

In one embodiment, there is a single powder blend formed into a tablet shape that is then heated with RF energy. In another embodiment, the tablet is formed from at least two different powder blends, at least one powder blend is RF-curable and at least one formulation is not RF-curable. Such tablet shapes produce two or more distinct solidified regions when solidified with RF energy. In one embodiment, the outer regions of the tablet shape are solidified while the middle of the tablet shape is not solidified. By adjusting the focus of the RF heating and the shape of the RF electrode, the heat delivered to the tablet shape can be focused to create custom softer or harder regions on the finished tablet.

In one embodiment, the RF energy is combined with a second heat source, including but not limited to infrared heating, induction heating, or convection heating. In one embodiment, the addition of a second heat source is particularly useful for the second non-RF-meltable binder present in the powder blend.

Microwave heating of tablet shape to form tablets

In one embodiment, microwave energy is used instead of radiofrequency energy to manufacture dosage forms (e.g., tablets). Microwave energy generally refers to heating with an electromagnetic field having a frequency of about 100MHz to about 300 GHz. In one embodiment of the invention, the microwave energy is in a frequency range of about 500MHz to about 100GHz (e.g., about 1GHz to 50GHz, such as about 1GHz to about 10 GHz). Microwave energy is used to heat the adhesive (e.g., directly when the meltable adhesive is sensitive to microwave energy ("microwave meltable adhesive") or time-wise by heating the microwave meltable components in the powder blend instead of the microwave meltable adhesive). In such an embodiment, a microwave energy source and microwave electrodes are used in the machine used to manufacture the dosage form.

Insert in tablet shape

In one embodiment, the insert is incorporated into the tablet shape prior to delivering the RF energy. Examples include solid compressed forms or beads filled with liquid compositions. The incorporation of such an insert is depicted in FIGS. 3A-3G.

In one embodiment, the pharmaceutically active agent is in the form of gel beads, which are liquid filled or semi-solid filled. The gel beads are added as part of the powder blend. In one embodiment, the tablet of the present invention has the added advantage of not using a strong compaction step, thereby allowing the use of liquid or semi-solid filled particles or beads that are deformable, as they will not break after a low 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 starch. The wall of the bead may also contain plasticizers 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, sugar, glycerin, polyethylene glycol, propylene glycol or an oil such as, but not limited to, vegetable oil, olive oil or mineral oil.

In one embodiment, the insert is substantially free of RF absorbing components, in which case the application of RF energy results in no significant heating of the insert itself. In other embodiments, the insert contains multiple components and is heated after exposure to RF energy, and thus such an insert may be used to soften or melt the meltable adhesive.

Multilayer tablet

In certain embodiments, the tablet comprises at least two layers, for example at least two layers 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 fig. 2A-2D. In one embodiment, the tablet comprises two layers, one layer having orally disintegrating properties and the other layer being chewable or swallowable. In one embodiment, one layer has a meltable adhesive and the other layer does not have a meltable adhesive. In one embodiment, one layer is densified relative to another layer at a higher compaction force. In one embodiment, both layers contain the same amount of meltable binder, but different amounts of pharmaceutically active agent and/or other excipients. In one embodiment, all 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 contains one or more effervescent couples. In one embodiment, the effervescent couple comprises a member selected from the group consisting of sodium bicarbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, and sodium carbonate, and a member selected from the group consisting of citric acid, malic acid, fumaric acid, tartaric acid, phosphoric acid, and alginic acid.

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

Orally disintegrating tablet

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

In one embodiment, the tablet meets the standards for Orally Disintegrating Tablets (ODT) as defined in draft Food and Drug Administration regulations published in month 4 of 2007. In one embodiment, the tablet meets the dual definition for orally disintegrating tablets that includes the following criteria: 1) the solid tablets are tablets which contain the pharmaceutical substance and disintegrate rapidly, usually within a few seconds, when placed on the tongue, and 2) solid oral formulations which are considered to disintegrate rapidly in the oral cavity, with an in vitro disintegration time of about 30 seconds or less when tested according to the disintegration test method of the United States Pharmacopoeia (USP) for one or more specific pharmaceutical substances.

Additional edible parts

In one embodiment, the tablet is included immediately adjacent to another edible form. In one embodiment, the edible form is a hard candy or pressed ring that holds the powder blend during the compaction and/or RF heating step.

In one embodiment, the external hard candy form may be made by stamp rolling, twisting into a rope and then cutting and stamping and depositing into a mold. The hard sugar portion comprises one or more sugars selected from isomalt, sucrose, dextrose, corn syrup, lactitol and maltitol (lycasin). In one embodiment, the hard candy portion contains at least 50 wt% (e.g., at least 75 wt%, such as at least 90 wt%) of one or more such sugars.

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 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 that is different from the pharmaceutically active agent in the outer edible form. In one embodiment, the outer edible form disintegrates at a rate that is at least 10 times, such as at least 20 times, the rate of the inner tablet. The first and second portions may be the same or different.

In one embodiment, the tablets having an outer edible form and an inner tablet are coated with an immediate release sugar coat or film coat. In one embodiment, to produce such tablets, the step after melting (heating) and subsequently cooling the tablet will involve additional sugar or film coating in a coating pan.

hardness/Density of tablet shape/tablet

In one embodiment, the tablet is prepared such that the tablet is relatively soft (e.g., capable of disintegrating in the mouth or capable of being chewed). In one embodiment, the tablet hardness is preferably less than about 133.4MPa (3 kilopounds per square centimeter (kp/c)m²) (e.g., less than about 89.0MPa (2 kp/cm)²) E.g., less than about 44.5MPa (1 kp/cm)²))。

Hardness is a term used in the art to describe the radial rupture strength as measured by conventional pharmaceutical hardness testing equipment, such as the Schleuniger hardness tester. In order to compare the values for all different sized tablets, the breaking strength must be normalized for the area of the break. This normalized value (in MPa (kp/cm)²) Expressed) is sometimes referred to in the art as tablet tensile strength. A review of the tablet hardness test can be found in Leiberman et al, Pharmaceutical Dosage Forms- -tables, Vol.2, 2 nd edition, Marcel Dekker Inc., 1990, pp.213-217, 327-329.

A more preferred hardness test for the tablets of the invention relies on a texture analyser TA-XT2i fitted with a flat probe 7 mm in diameter and set to measure and record the compression force in grams. The probe was moved at 0.05 mm/sec to a penetration depth of 2 mm. The maximum compression force was recorded. In one embodiment, tablets prepared according to the present invention have a force measurement of less than 10,000 grams (e.g., less than about 1000 grams, such as less than about 700 grams). In one embodiment, tablets prepared according to the present invention have force measurements ranging 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 tablet has a force measurement of less than 700 grams.

In one embodiment, the tablet has a density of less than about 2g/cc (e.g., less than about 0.9g/cc, such as less than about 0.8g/cc, such as less than about 0.7 g/cc). In one embodiment, the difference in density of the powdered material after the compacting step is less than about 40% (e.g., less than about 25%, such as less than about 15%).

Tablet coating

In one embodiment, the tablet includes an additional outer coating (e.g., a translucent coating such as a clear coating) to help limit the friability of the tablet. Suitable materials for the translucent coating include, but are not limited to: hypromellose, hydroxypropyl cellulose, starch, polyvinyl alcohol, polyethylene glycol, polyvinyl alcohol and polyethylene glycol mixtures and copolymers, and mixtures thereof. The tablets of the invention may comprise a coating in an amount of about 0.05 to about 10 weight%, or about 0.1 to about 3 weight%, of the total tablet.

Surface treatment of dosage forms

In one embodiment, the surface of the agent parison and/or dosage form (e.g., tablet shape and/or tablet) is further treated with energy (e.g., convection, infrared, or RF energy) to soften or melt the material on the surface of the dosage form, which is then cooled or allowed to cool to further smooth the texture, enhance the gloss of the surface of the dosage form, limit the friability of the dosage form, and/or provide indicia for identification. In one embodiment, the surface of the dosage form is further exposed to infrared energy, wherein a majority (at least 50%, such as at least 90%, such as at least 99%) of the wavelength of such infrared energy is from about 0.5 to about 5 microns, such as from about 0.8 to about 3.5 microns (e.g., by using a filter). In one embodiment, the infrared energy source is a quartz lamp with a parabolic reflector (e.g., to intensify the energy) and a filter to remove unwanted frequencies. Examples of such infrared energy sources include SPOT IR 4150 (commercially available from Research, Inc.

Use of tablets

The tablets may be administered as swallowable, chewable, orally disintegrating tablets.

In one embodiment, the invention relates to a method of treating a disease comprising orally administering the above tablet, wherein the tablet comprises an amount of a pharmaceutically active agent effective to treat the disease. Examples of such diseases include, but are not limited to: pain (e.g., headache, migraine, sore throat, angina, back pain and myalgia), fever, inflammation, upper respiratory tract disorders (e.g., cough and congestion), infections (e.g., bacterial and viral infections), depression, diabetes, obesity, cardiovascular disorders (e.g., high cholesterol, hypertriglyceridemia and hypertension), gastrointestinal disorders (e.g., nausea, dysentery, irritable bowel syndrome and bloating), sleep disorders, osteoporosis and nicotine dependence.

In one embodiment, the method is for treating an upper respiratory disorder, wherein the pharmaceutically active agent is selected from the group consisting of: phenylephrine, cetirizine, loratadine, fexofenadine, diphenhydramine, dextromethorphan, chlorpheniramine, clofedanol, and pseudoephedrine.

In this embodiment, a "unit dose" is typically accompanied by instructions for administration which instruct the patient to take an amount of the pharmaceutically active agent, which may be a plurality of such unit doses, depending on, for example, the age or weight of the patient. Generally, the unit dose volume will contain a therapeutically effective amount of the pharmaceutically active agent for the smallest patient. For example, a suitable unit dose volume may comprise one tablet.

Examples of the invention

Specific embodiments of the present invention are shown by the following examples. The invention is not limited to the specific limitations shown in these examples.

Example 1: manufacture of powder blends containing loratadine

A loratadine powder blend for orally disintegrating tablets containing the ingredients of table 1 was prepared as follows:

table 1: loratadine powder blend formulations

Composition (I)	Gram/batch	Milligram/tablet
			Dextrose monohydrate	45.18	120.0

Loratadine	3.765	10.0
			Polyethylene glycol 40001	24.475	65.0
Maltodextrin2	15.062	40.0
			Red colorant	0.028	0.075
Dimethicone DC1003	5.648	15.0
			Sucralose USP	1.13	3.0
Polyethylene oxide	1.883	5.0
			Mint flavoring agent	2.824	7.5
Total of	100	265.575

1: commercially available from Clariant PF (Rothausstr, Switzerland)

2: commercially available from National Starch (Bridgewater, NJ)

3: commercially available from SPI Pharma (Wilmington, DE)

First, sucralose, colorant, and flavor were placed together in a 500cc sealable plastic bottle. The mixture was then blended by hand upside down for about 2 minutes. The resulting mixture, dextrose monohydrate, loratadine, and polyethylene oxide were then added to another 500cc sealable plastic bottle and mixed by hand inversion for approximately 5 minutes. The resulting mixture was then added to a planetary bowl mixer, simethicone DC100 was added and mixed for approximately 3 minutes. Finally, polyethylene glycol 4000 and maltodextrin were added to the mixture and mixed for approximately 3 minutes.

Example 2: manufacture of orally disintegrating tablets containing loratadine

A portion of the powder blend from example 1 was placed in an 1/2 inch diameter forming cavity of an electrically insulated teflon die platen. The powder blend is then packed between upper and lower planar metal forming tools into a blank that conforms to the surface of the forming tools. The packing pressure is typically between 0.07 to about 0.3Mpa (10 to about 50 psi). The forming tool, die platen and tablet blank were then placed between an upper and lower RF electrode, powered by an RF heating unit using a COSMOS Model C10X16G4(COSMOS Electronic Machine Corporation, Farmingdale, NY) RF generator with an output power of 4KW, a frequency of 27MHz, and a vacuum capacitor set at 140. The forming tool was heated with circulating water at a temperature of 57 ℃. The upper RF electrode is brought into contact with the upper forming tool and the lower RF electrode is brought into contact with the lower forming tool. The RF heating unit was energized for 2 to 5 seconds. The resulting tablet is then ejected from the die platen with a lower forming tool.

Example 3: production of orally disintegrating tablet containing diphenhydramine

Diphenhydramine powder blends for orally disintegrating tablets containing the ingredients of table 2 were prepared as follows. Sucralose, yellow colorant, flavor, polyethylene glycol, and maltodextrin from the formulations in table 2 were passed through a 20 mesh screen. The sieved material was placed in a 500cc plastic bottle and blended upside down with the rest of the materials in table 2. The powder blend was placed in a forming cavity, tamped, and activated with RF energy for about 2 to 5 seconds as described in example 2 to form an orally disintegrating tablet, which was subsequently removed from the die platen.

Table 2: powder blend formulations containing Diphenhydramine (DPH)

Composition (I)	Gram/batch	Milligram/tablet
			Dextrose monohydrate	304.11	219.0
Diphenhydramine (with coating)3	49.57	35.70
			Polyethylene glycol 80001	44.16	31.80
Maltodextrin2	88.46	63.70
			Yellow colorant	0.78	0.56
Orange flavoring agent	1.65	1.19
			Vanilla flavoring agent	2.21	1.59
Sucralose USP	1.11	0.80
			Anhydrous citric acid USP	7.96	5.73
Total of	500.00	360.07

1: commercially available from Clariant PF (Rothausstr, Switzerland)

2: commercially available from National Starch (Bridgewater, NJ)

3: encapsulated diphenhydramine coated with cellulose acetate and polymethacrylate using the method shown in US 5,997,905, which is incorporated herein by reference

Example 4: manufacture of orally disintegrating tablet placebo containing dextrose monohydrate

Placebo powder blends for orally disintegrating tablets containing the ingredients of table 3 were prepared as follows. Sucralose, yellow colorant, flavor, polyethylene glycol, and maltodextrin from the formulations in table 3 were passed through a 20 mesh screen. The sieved material was placed in a 500cc plastic bottle and blended upside down with the rest of the materials in table 3. The powder blend was placed in a forming cavity, tamped, and activated with RF energy for about 2 to 5 seconds as described in example 2 to form an orally disintegrating tablet, which was subsequently removed from the die platen.

Table 3: powder blend formulations

Composition (I)	Gram/batch	Milligram/tablet
			Dextrose monohydrate	283.04	255.0
Polyethylene glycol 80001	35.30	31.80
			Maltodextrin2	70.71	63.70
Yellow colorant	0.62	0.56
			Orange flavoring agent	1.32	1.19
Vanilla flavoring agent	1.76	1.59
			Sucralose USP	0.89	0.80
Anhydrous citric acid USP	6.36	5.73
			Total of	400.00	360.37

1: commercially available from Clariant PF (Rothausstr, Switzerland)

3: commercially available from National Starch (Bridgewater, NJ)

Example 5: manufacture of orally disintegrating tablet placebo containing erythritol

Placebo powder blends for orally disintegrating tablets containing the ingredients of table 4 were prepared as follows. Sucralose, yellow colorant, flavor, polyethylene glycol, and maltodextrin from the formulations in table 4 were passed through a 20 mesh screen. The sieved material was placed in a 500cc plastic bottle and blended upside down with the rest of the materials in table 4. The powder blend was placed in a forming cavity, tamped, and activated with RF energy for about 2 to 5 seconds as described in example 2 to form an orally disintegrating tablet, which was subsequently removed from the die platen.

Table 4: placebo powder blend formulation containing erythritol

Composition (I)	Gram/batch	Milligram/tablet
			Directly compressible erythritol3	212.28	255.0
Polyethylene glycol 80001	26.47	31.80
			Maltodextrin2	53.03	63.70
Yellow colorant	0.47	0.56
			Orange flavoring agent	0.99	1.19
Vanilla flavoring agent	1.32	1.59
			Sucralose USP	0.67	0.80
Anhydrous citric acid USP	4.77	5.73
			Total of	300.00	360.37

1: commercially available from Clariant PF (Rothausstr, Switzerland)

3: commercially available from National Starch (Bridgewater, NJ)

4: commercially available from Corn Products (Westchester, IL)

Example 6: manufacture of comparative compressed chewable placebo tablets

Placebo powder blends for comparative chewable placebo tablets containing the ingredients of table 5 were prepared as follows. Sucralose, yellow colorant, and flavor were passed through a 20 mesh screen prior to blending. The sieved material was blended with the rest of the materials in the formulation in table 5 and added to a 500cc plastic bottle, blended upside down for about 3 minutes and poured out. Tablets were compressed with two different compression forces as follows: (a) the tablets were compressed at 6.86 kilonewtons (0.7 metric tons) and (b) at 2.45 kilonewtons (0.25 metric tons) in a single station manual Carver Press (commercially available from Carver Press Corporation (Wabash, Indiana). With a small amount of pressure applied to the formulation, tablet (b) is extremely friable and friable.

Table 5: placebo powder blend formulation for compressed tablets

Composition (I)	Gram/batch	Milligram/tablet
			Dextrose monohydrate	114.773	138.00
Polyethylene glycol 40001	41.584	50.00
			Maltodextrin2	35.763	43.00
Blue colorant	0.075	0.0907
			Yellow colorant	0.153	0.1842
Vanilla flavoring agent	1.830	2.20
			Sucralose USP	1.248	1.50
Mint flavoring agent1	4.574	5.50
			Total of	200	240.47

1: commercially available from Clariant PF (Rothausstr, Switzerland)

3: commercially available from National Starch (Bridgewater, NJ)

Example 7: manufacture of comparative compressed chewable tablets containing acetaminophen

Placebo powder blends for chewable tablets containing the ingredients of table 6 were prepared as follows. Sucralose, yellow colorant, flavor, and citric acid were passed through a 20 mesh screen prior to blending. The sieved material was blended with the rest of the materials in the formulation in table 6 and added to a 500cc plastic bottle, mixed by inversion for about 3 minutes and poured out. Tablets were compressed with two different compression forces as follows: (a) lightly compress the tablet at 6.86 kilonewtons (0.7 metric tons) and (b) compress the tablet at 2.45 kilonewtons (0.25 metric tons) on a single station manual Carver press. With a small amount of pressure applied to the formulation, tablet (b) is extremely friable and friable.

Table 6: powder blend formulations containing acetaminophen

Composition (I)	Gram/batch	Milligram/tablet
			Dextrose monohydrate	32.284	94.00
Acetaminophen (coated)3	29.989	87.32
			Polyethylene glycol 40001	5.152	15.00
Maltodextrin2	20.607	60.00
			Yellow colorant	0.120	0.35
Orange flavoring agent	0.343	1.00
			Vanilla flavoring agent	0.515	1.50
Sucralose USP	0.343	1.00
			Crosslinked polyvinylpyrrolidone5	2.061	6.00
Polyethylene oxide (WSR 303 grade)4	6.869	20.00
			Anhydrous citric acid USP	1.717	5.00
Total of	100	291.17

1: commercially available from Clariant PF (Rothausstr, Switzerland)

2: commercially available from National Starch (Bridgewater, NJ)

3: encapsulated acetaminophen coated with cellulose acetate and polyvinylpyrrolidone using the method shown in U.S. Pat. No.4,851,226, which is incorporated herein by reference

4: commercially available from DOW Corporation (Midland, MI)

5: commercially available from BASF Corporation (Florham Park, NJ) as Kollidon CL-M

Example 8: ODT and Density measurement of compressed tablets

Three tablets from each of examples 3, 4, 5, 6 and 7 were measured to determine the density of the compressed tablets and the tablets produced using the method of the invention. The density was calculated using the volume of the cylinder, calculated by dividing the width and thickness of the tablets by the weight of each tablet.

Table 8: tablet density measurement

Examples of the invention

Weight (mg)

Diameter (mm)

Height (mm)

Volume (mm)3)

Density (mg/mm)3)

Example 3(1)	379	13.13	5.00	677.0	0.560
						Example 3(2)	403	13.10	4.97	669.9	0.602
Example 3(3)	409	13.03	4.87	649.4	0.630
						Example 4(1)	347	12.90	4.85	633.9	0.547
Example 4(2)	416	12.97	4.96	655.3	0.635
						Example 4(3)	398	13.06	4.95	663.1	0.600
Example 5(1)	419	12.90	5.38	703.2	0.596
						Example 5(2)	397	13.15	5.32	722.5	0.549
Example 5(3)	352	12.87	5.00	650.5	0.541
						Example 6a (1)	399	11.18	3.32	325.9	1.220
Example 6a (2)	372	11.16	3.06	299.3	1.240
						Example 6a (3)	391	11.18	3.25	319.0	1.230
Example 6b (1)	433	11.20	4.27	420.7	1.030
						Example 6b (2)	442	11.22	4.35	430.1	1.030
Example 6b (3)	404	11.18	3.93	385.8	1.050
						Example 7a (1)	364	11.20	3.26	321.2	1.130
Example 7a (2)	328	11.18	2.94	288.6	1.140
						Example 7a (3)	404	11.17	3.65	357.7	1.130
Example 7b (1)	413	11.25	4.66	463.2	0.890
						Example 7b (2)	451	11.21	5.00	493.5	0.910
Example 7b (3)	437	11.22	4.82	476.6	0.920

As shown in Table 8, the ODT tablets of the present invention (examples 3, 4, and 5) have a range of 0.541-0.635mg/mm³While the comparative chewable tablets of examples 6 and 7 had a density in the range of 0.890 to 1.240mg/mm³The density of (c). Thus, the ODT tablet of the present invention has a density that is about half that of the comparative example.

Example 9: disintegration test with texture Analyzer TA XT Plus

The following tests were performed using a Texture analyzer TA XT Plus commercially available from Texture Technologies (Scarsdale, NY). The texture analyser was equipped with a TA-55 probe and the probe speed was set at 0.1 mm/sec.

The individual tablets were placed in a 5mm graduated cylinder and placed on the short axis. A 20 gram force was applied to the tablets by a 5mm probe. The force was applied and approximately 10mL of 25 ℃ deionized water was added to cover the tablets. Analyzing the force over time, the following tablets were analyzed: the tablet of example 6a and the tablet of example 3. The tablet of the invention (example 3) disintegrated immediately upon addition of water, the disintegration being indicated by the probe distance, which increased from 0mm to more than 1mm between 10 and 20 seconds. The tablet from example 6a (which represents a chewable tablet) disintegrated within 84.30 seconds from the addition of water, as measured by the change in slope in the texture analyser, wherein the tablet of example 3 disintegrated within 6.99 seconds from the addition of water.

It should be understood that while the invention has been described in conjunction with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the following claims. Other aspects, advantages, and modifications are within the claims.

Claims (21)

1. A machine for preparing solid dosage forms, the machine comprising:

(a) a die platen having one or more forming cavities, each forming cavity having an inner wall, a first opening on one side surface of the die platen, and a second opening on an opposite side surface of the die platen;

(b) one or more first forming tools, each adapted to move into one of the forming cavities through the first opening of the forming cavity;

(c) one or more second forming tools, each adapted to move adjacent to or into one of the second openings through the second opening of the forming cavity;

(d) at least one first RF electrode operatively associated with the one or more first forming tools, the one or more second forming tools, or the inner wall of the one or more forming cavities; and

(e) at least one second RF electrode operatively associated with the one or more first forming tools, the one or more second forming tools, or the inner wall of the one or more forming cavities;

wherein the machine is adapted to form a dosage form between a first forming tool and a second forming tool within a forming cavity, and wherein the first RF electrode and the second RF electrode are disposed within the machine such that when RF energy is conducted between the first RF electrode and the second RF electrode, the RF energy passes through a portion of the forming cavity adapted to form the dosage form.

2. The machine of claim 1, wherein the machine further comprises an RF energy source in communication with the first RF electrode and the second RF electrode.

3. The machine of claim 1, wherein said first RF electrode is operatively associated with said one or more first forming tools, said second RF electrode is operatively associated with said one or more second forming tools, and the portion of said interior wall of said forming cavity adapted to form said dosage form is insulated from said RF energy.

4. The machine of claim 3, wherein only the portion of the surface of the forming tool adapted to contact the dosage form is operatively associated with the first RF electrode.

5. The machine of claim 1, wherein said first RF electrode is operatively associated with said one or more first forming tools and said second RF electrode is operatively associated with a portion of said interior wall of said one or more forming cavities adapted to form said dosage form.

6. The machine of claim 1 wherein said first RF electrode is operatively associated with a first portion of said interior walls of said one or more forming cavities adapted to form said dosage form and said second RF electrode is operatively associated with a second portion of said interior walls of said one or more forming cavities adapted to form said dosage form.

7. The machine of claim 1, wherein the one or more first forming tools and the one or more second forming tools are heated and/or the die platen is heated.

8. The machine of claim 1, wherein the machine further comprises a feeder adapted to feed a powder blend into the one or more forming cavities.

9. The machine of claim 1, wherein the machine further comprises a feeder adapted to add a powder blend into the one or more forming cavities.

10. The machine of claim 1, wherein the die platen includes at least six of the forming cavities.

11. A method of making a solid dosage form using the machine of claim 1, the method comprising:

(a) adding the powder blend into a forming chamber;

(b) moving a first forming tool into said forming cavity through said first opening of said forming cavity such that said powder blend is formed into a shape of said dosage form within said forming cavity between said first forming tool and said second forming tool;

(c) conducting RF energy between said first electrode and said second electrode such that said energy heats said powder blend within said forming cavity to form said dosage form; and

(d) removing the dosage form from the forming cavity.

12. The method of claim 11, wherein the RF energy is conducted at a frequency of 1MHz to 50 MHz.

13. The method of claim 11, wherein said first forming tool and said second forming tool are not in contact with said shaped blank of said dosage form while conducting said RF energy.

14. The method of claim 11, wherein said first RF electrode is operatively associated with said first forming tool, said second RF electrode is operatively associated with said second forming tool, and the portion of said interior wall of said forming cavity suitable for forming said dosage form is insulated from said RF energy.

15. The method of claim 11, wherein said first RF electrode is operatively associated with said first forming tool and said second RF electrode is operatively associated with a portion of said interior wall of said forming cavity adapted to form said dosage form.

16. The method of claim 11, wherein the powder blend is added from a feeder to the at least one of the one or more forming cavities.

17. The method of claim 11 wherein one of the forming tools removes the dosage form from the forming cavity.

18. The method of claim 17, wherein said dosage form is placed in a blister card after said removing from said forming cavity.

19. The method of claim 11, wherein the second forming tool moves within the forming cavity to adjust the amount of powder blend added to the forming cavity.

20. The method of claim 11, wherein the method further comprises adding a second powder blend to the forming cavity, wherein the second powder blend is different from the powder blend.

21. The method of claim 11, wherein the surface of the tablet is further exposed to infrared energy at a wavelength of 0.5 to 5 microns.