IE980519A1 - Quick disintegrating tablets - Google Patents

Abstract

Comestible units which disintegrate readily in the mouth or in aqueous solutions, having porosities of about 20% to about 50%, can be made using a wide range of compaction pressures.

Description

Background of the Invention 10 The use of effervescent agents (e.g., acid/carbonate systems) and disintegrating agents (e.g., crosslinked polyvinylpyrrolidone, croscarmellose sodium and the like) in formulations from which comestible units are made is known. Also, comestible units that disintegrate quickly in 15 aqueous environments, e.g., in aqueous solutions or in the mouth, can be molded at unconventionally low pressures, so that they are highly porous. Using generally accepted engineering principles, it is possible to compress a comestible unit at very low pressures, i.e., less than 5,000 20 psi, so that the finished unit will be very porous, thereby permitting water or other moisture to penetrate it readily. However, it is difficult to process compositions containing only non-disintegrating comestible ingredients, e.g., conventional carriers and active agents, so that they can be 25 molded at higher pressures, i.e., greater than 5,000 psi, while still yielding products that are readily disintegrating .

Shearform compositions which are useful in making comestible units have been described in various patents and applications which are owned by Fuisz Technologies, Ltd. . -2Shearform matrices and devices and processes useful in making them are described in U. S. Patents 5,458,823; 5,429,836; 5,587,172; PCT applications PCT/US95/07144 and PCT/US95/07194, both filed June 6, 1995; Italian application B096A 000453, entitled “ Meto Do E Macchina Per La Produzione Di Pasti Glie Di Polvere Medicinale” (“Method and Machine for Tablet Production of Medicine Powder”) , filed September 11, 1996; U. S. Patent Application SN. 08/859,344, filed May 12, 1997, and U. S. Patent Applications SN. 08/914,972; SN. 08/915,067; and SN. 08/915,068; all filed on August 20, 1997. Such compositions are easily handled before shaping and may be shaped arid compressed, at low to moderate pressures, to yield comestible units.

Before the discovery of these shearform technologies, the art was unaware of methods for making quick disintegrating comestible units, such as pharmaceutical tablets, which can be compressed at conventional pressures and do not contain added effervescent or disintegrating agents .

Summary of the Invention Applicant has discovered that shearform compositions can be compression molded at conventional tableting pressures to yield comestible units, e.g., tablets, having porosities of about 20% to about 50% and disintegration times of about 25 seconds or less.

Description of the Invention The invention deals with comestible units and methods of making same, which units have a porosity value of about -320% to about 50%, preferably about 35% to about 45%, a disintegration time of about 5 seconds (sec.) to about 25 sec. and which are made, using pressures of about 300 psi to about 10,000 psi, preferably about 5,000 to about 10,000 psi, from shearform compositions containing no added effervescent agents or disintegrants.

The terms “matrix” and floss” will be used interchangeably to refer to the shearform products made using flash flow technologies. “Shearform compositions contain one or more of these products along with one or more other ingredients.

Matrices useful herein include those described in U.S. 5,587,172.

The matrices used herein include a carrier, or feedstock, material which carrier material comprises at least one selected from materials which are capable of undergoing the physical and/or chemical changes associated with flash flow processing. Useful carriers include carbohydrates that become free-form particulates when flash heat processed. Saccharide-based carriers, including saccharides (i.e., sugars), polysaccharides and mixtures thereof can be used.

The feedstocks used in the invention can include carriers chosen from various classes of “sugars”. “Sugars are those substances that are based on simple crystalline mono- and di - saccharide structures, i.e., based on C5 and C6 sugar structures. They may include glucose, sucrose, fructose, lactose, maltose, pentose, arbinose, xylose, ribose, mannose, galactose, sorbose, dextrose and sugar alcohols, such as sorbitol, mannitol, xylitol, maltitol, isomalt, sucralose and the like and mixtures thereof.

Sucrose is the preferred sugar.

Useful mixtures of carriers include the sugars listed above along with additional mono- di-, tri- and polysaccharides. Additional saccharides can be used in amounts of up to 50% by weight of the total sugar, preferably up to 30%, most preferably up to 20%.

Optionally, the polysaccharides can be used alone as carriers. Polysaccharide carriers include polydextrose and the like. Polydextrose is a non-sucrose, essentially nonnutritive, carbohydrate substitute. It can be prepared through polymerization of glucose in the presence of polycarboxylic acid catalysts and polyols. Generally, polydextrose is commercially available in three forms: polydextrose A and polydextrose K, which are powdered solids; and polydextrose N supplied as a 70% solution. U.S. Patent No. 5,501,858 discusses polydextrose-containing carriers .

If other carrier materials, such as maltodextrins, are used, they are usually employed in combination with sugar and not as total replacement therefor. Maltodextrins include mixtures of carbohydrates resulting from the hydrolysis of a saccharide. They are solids having a dextrose equivalent (DE) of 65 or less.

The carrier can also include maltooligo-saccharides produced by selective hydrolysis of corn starch. A general description of maltooligo-saccharides useful herein is set forth in co-owned U.S. Patent Nos. 5,347,431 and 5,429,836.

The matrix portions of the shearform compositions are typically formed via flash-heat processing into a floss. -5The strands of the floss are macerated or chopped into rods for further processing. The rods of chopped floss have lengths of about 50 to about 500 microns.

Often, flosses are used along with bio-affecting, or active, particulates, which may be in the form of microspheres, in the tableting process. One floss may be added to one or more active agents and an optional second floss may be added later. Typically, the ratio of total floss to active material is about 1:1 or greater.

By “excipients and pharmaceutical excipients”, Applicants mean ingredients, other than bio-affecting (active) agents, effervescent agents and disintegrating agents .

The compositions to be processed into comestible units can contain various conventional excipients. However, they need not contain effervescent agents or disintegrating agents that serve to fracture or open the surface of the tablet when it is contacted with water, saliva or other sources of moisture. Such agents are referred to as “effervescent” or “disintegrating” agents. It is believed that the nature of Applicant's shearform matrices renders the compressed comestible units readily disintegratable.

Applicants exclude from the invention the use of effervescent agents such as those that evolve a gas, e.g., carbon dioxide. Typical effervescent agents are discussed in U.S. patent 5,622,719.

Conventional quantities of excipient(s) may be incorporated into one or more of the matrices or may be mixed therewith prior to tableting. Useful amounts of excipient(s) range from about 0.01% to about 80% by weight, -6based on the weight of the matrices or formulations in which they are used. Quantities used may vary from these amounts, depending on the functions of the excipient(s) and the characteristics desired in the matrices and/or the final tablet compositions.

Conventional tableting aids may be selected from a wide variety of materials such as lubricants, glidants, anticaking agents and flow agents. For example, one or more lubricants such as sodium chloride, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, glyceryl monostearate, talc, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, adipic acid, light mineral oil and others may be employed. Sodium stearyl fumarate is very effective. Waxy fatty esters, such as glyceryl behenate, sold as Compritol” products, are useful.

Lubricants are used in amounts ranging from about 0% to about 10%, with about 0.5% to about 5.0% typically used.

One useful lubricant additive is adipic acid, used in an amount of about 0.01% to about 5%, typically about 2%.

Glidants such as starch, talc, lactose, stearates, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, Cabosil, Syloid, and silicon dioxide aerogels may be employed. Glidants are present in amounts ranging from about 0% to about 20%, with amounts of about 0.1% to about 5.0% being typical.

Lactose, which may be a filler or glidant, can be used at about 2% concentration to prevent clumping of chopped matrix particles.

It is desirable that the shearform compositions be at -7least partially crystalline. The degree of crystallinity of the compositions enhances their flowability while preserving cohesiveness and improves the structural integrity of comestible units, e.g., tablets, made therefrom.

The shearform matrices may be rendered more crystalline by one or more of the. following crystallizing techniques.

The terms “crystallization and recrystallization” are used interchangeably in the following discussion. When noncrystalline feedstocks are used, the matrices are said to “crystallize”. When feedstock materials start out as crystalline, the matrices made are “re crystallized during processing.

One technique for recrystallizing involves the use of crystallization enhancers. These are used after the floss has been formed, but before the floss-containing composition is tableted. Suitable crystallization enhancers include ethanol, uncrosslinked polyvinylpyrrolidone, water (e.g. moisture), glycerine, radiant energy (e.g., microwaves, heat, etc.) and the like. Combinations can be used. When they are physical materials, typical amounts of these enhancers range from about 0.01% to about 10.0% by weight of the tablet composition.

Another technique calls for crystallization modifiers. These crystallization modifiers are floss ingredients, used at levels of about 0.01% to about 20.0% by weight of the floss .

Surfactants are preferred crystallization modifiers. Other materials that are non-saccharide hydrophilic organic materials may also be used. Crystallization modifiers generally have a hydrophilic to lipid balance (HLB) of about -86 or more. Such materials include, without limitation, anionic, cationic, and zwitterionic surfactants as well as neutral materials with suitable HLB values. Hydrophilic materials having polyethylene oxide linkages are effective. Those with molecular weights of at least about 200, and especially at least about 400, are useful.

Crystallization modifiers useful herein include: lecithin, polyethylene glycol (PEG), propylene glycol (PPG), dextrose, the SPANS and TWEENS which are commercially available from ICI America, and the surface active agents known as “Carbowax”. Generally, the polyoxy-ethylene sorbitan fatty acid esters or combinations of such modifiers are used.

Crystallization modifiers are usually incorporated into matrices in amounts of between about 0% and 10%.

Optionally, the matrices are allowed to recrystallize, with or without added crystallization modifiers, either before or after they are combined with the non-matrix component (s) , e.g., the bio-affecting additive(s). When recrystallization occurs before tableting, the recrystallization level of the matrix generally reaches at least about 10%. The use of such partially recrystallized matrices leads to compositions that are free flowing and tabletable using conventional machines. U.S. Patent 5,597,416 describes a process for recrystallizing in the presence of additives.

Methods for effecting the recrystallization of the matrices include: use of Tween 80 or other crystallization modifier(s) in the matrix premix; aging of the matrix for ud to several weeks, contacting the matrix with sufficient moisture and heat to induce crystallization, and treating -9the floss or the floss-containing composition with ethanol or another crystallization enhancer. Combinations of these may be used.

When a surfactant, such as a Tween is used, about 5 0.001% to about 1.00% is included in the floss as a crystallization modifier. Following preblending, the formulations are processed into flosses, then chopped and used, with or without additives, to make tablets. Mixtures of surfactants can be used.

Aging may be used to recrystallize the matrix or floss.

The aging process involves a two-step process. First the matrix, which typically contains at least one crystallization modifier, is formed, chopped and allowed to stand in closed or sealed containers without fluidization or 15 other agitation under ambient conditions, e.g., at room temperature and atmospheric pressure, for up to several days, preferably for about 1 to about 3 days. Later, the matrix is mixed, and optionally further chopped, with one or more other ingredients, e.g., fillers and the like.

Allowing it to stand for an additional period of about 1 to about 3 days then ages the mix. Generally, the two-step aging process takes a total of about one week, with periods of about 4 to about 5 days being typical.

The flosses may also be recrystallized by subjecting them to increased heat and moisture. This process is similar to aging, but involves shorter periods of time.

Using a fluidized bed apparatus or other suitable device, chopped floss is fluidized while heating, at ambient humidity and pressure, to a temperature of about 25°C to 30 about 50cC. Generally, the temperature must be monitored to »r> -10minimize the floss particles clumping during this operation. If any clumping occurs, the floss particles must be sieved before being further processed into tablets. Heating times of about 5 to about 30 minutes are typical.

When ethanol is used as a crystallization enhancer it is used in amounts, based upon the weight of the matrix, of about 0.1% to about 10%, with amounts of about 0.5% to about 8.0% being very effective. The preformed matrix is contacted with ethanol. Excess ethanol is evaporated by drying for about an hour at about 85°F to about 120°F, with 105°F being highly useful. The drying step is carried out using tray drying, a jacketed mixer or other suitable method. Following ethanol treatment, the matrix becomes partially recrystallized on standing for a period ranging from about a few hours up to several weeks. When the floss is believed to be about 5% to about 30% recrystallized, it is tableted after blending with other ingredients. The tableting compositions flow readily and are cohesive.

Recrystallization of the matrix may take place in the presence of one or more bio-affecting agents or other additives .

Recrystallization of the matrix can be monitored by measuring the transmittance of polarized light therethrough or by the use of a scanning electron microscope. Amorphous floss or shearform matrix does not transmit polarized light and appears black in the light microscope when viewed with polarized light. Using bright field microscopy or the scanning electron microscope, the surface of the floss appears very smooth. In this condition, it is 0% recrystallized. That is, the floss is 100% amorphous. -11Recrystallization of amorphous matrix starts at the surface of the mass and can be modified, e.g., accelerated, by the presence of crystallization modifiers, as well as moisture. When TWEENS assist the recrystallization, initiation of recrystallization is evidenced by a birefringence observed on the surface of the shearform matrix (floss) as viewed with polarized light. There are faint points of light riddled throughout the matrix’ surface. When birefringence appears, recrystallization has begun. At this stage, recrystallization is between about 1% and 5%.

As recrystallization proceeds, the birefringence on the surface of the matrix grows continually stronger and appears brighter. The points of light grow in size, number and intensity, seeming to almost connect. Using bright field or scanning electron microscopy, the surface of the matrix appears wrinkled. At this point, about 5 to 10% recrystallization has occurred.

Surfactant (e.g., TWEEN 80) droplets added to the matrix particles become entrapped within the particles as the particles re-crystallize. These droplets are obscured as recrystallization proceeds. As long as they are visible, the floss is generally not more than about 10% to 20% recrystallized. When they are no longer observable, the extent of recrystallization is no more than about 50%.

The recrystallization of the matrix results in reduction of the total volume of material. Ordered arrays of molecules take up less space than disordered arrays.

Since recrystallization begins at the surface of the floss, a crust is formed which maintains the size and shape of the -12floss. There is an increase in the total free volume space within the floss as recrystallization nears completion, which manifests itself as a void inside the floss. This is evidenced by a darkened central cavity in light microscopy and a hollow interior in -scanning electron microscopy. At this stage, the floss.is believed to be about 50% to about 75% recrystallized.

The intensity of transmitted polarized light increases as the floss becomes more crystalline. The polarized light can be measured by a photon detector and assigned a value against calculated standards on a gray-scale.

The final observable event in the recrystallization of floss is the appearance of fine, cat whisker-like” needles and tiny blades which grow and project from the surface of the floss. These fine crystals, believed to be sorbitol (cat whiskers) and xylitol (blades), literally cover the floss like a blanket of fuzz. These features can be easily recognized by both light and electron microscopes. Their appearance indicates the final stage of recrystallization. The floss is now 100% recrystallized, i.e., substantially non-amorphous.

When active agents, such as bio-affecting agents, are added, they are often added in the form of particulates. Preferably the particulates are spheroidal particles, generally uniform microspheres. Suitable microspheres and other spheroidal particles can be made by “liquiflash” processes .

“Liquiflash processing involves the use of heat and pressure to reduce the feedstock to a condition in which resistance to flow, e.g., viscosity, which impedes the -13propensity to form liquid droplets, is eliminated. In this condition, the mass has become liquid or “liquiform. Once all resistance to flow is gone, shear force is applied to the feedstock until discrete particles separate from the mass. The particles, called “shearlite” particles, have a size and shape influenced only by natural mass separation of the flowing feedstock. U.S. Patent 5,458,823 and U.S. application SN. 08/330,412, filed October 28, 1994, both incorporated herein by reference, show processes and devices for such processing.

The bio-affecting agent used may be prescription or over the counter medications. They may be selected from a broad range of drug, therapeutic or prophylactic materials. Representative classes of drugs include those in the following therapeutic categories: ace - inhibitors; antianginal drugs; anti - arrhythmia agents; antiasthmatics; anticholesterolemics; anticonvulsants; antidepressants; antidiarrheal preparations; antihistamines; antihypertensives; anti - infectives; anti-inflammatories; antilipid agents; antimaniacs; antinauseants; antistroke agents; antithyroid preparations; anabolic drugs; antiparasitics; antipsychotics; antipyretics; antispasmodics; antithrombotics; anxiolytic agents; appetite stimulants; appetite suppressants; beta-blocking agents; bronchodilators; cardiovascular agents; cerebral dilators; chelating agents; cholecystekinin antagonists; chemotherapeutic agents; cognition activators; contraceptives; coronary dilators; cough suppressants' decongestants; deodorants; dermatological agents; diabetes agents; diuretics; emollients; enzymes; erythropoietic -14drugs; expectorants; fertility agents; fungicides; gastrointestinal agents; growth regulators; hormone replacement agents; hyperglycemic agents; laxatives; migraine treatments; mineral supplements; mucolytics, narcotics; neuroleptics; neuromuscular drugs; non-steroidal anti-inflammatories (NSAIDs); nutritional additives; peripheral vasodilators; polypeptides; prostaglandins; psychotropics; renin inhibitors; respiratory stimulants; steroids; stimulants; sympatholytics; thyroid preparations; tranquilizers; uterine relaxants; vaginal preparations; vasoconstrictors; vertigo agents; vitamins; wound healing agents; and others.

Bio-affecting agents which may be used in the invention include: acetaminophen; acetic acid; acetylsalicylic acid, including its buffered forms; albuterol and its sulfate; alcohol; alkaline phosphatase; allantoin; aloe; aluminum acetate, carbonate, chlorohydrate and hydroxide; alprozolam; amino acids; aminobenzoic acid; amoxicillin; ampicillin; amsacrine; amsalog; anethole; ascorbic acid; aspartame; atenolol; bacitracin; balsam peru; BCNU (carmustine); beclomethasone diproprionate; benzocaine; benzoic acid; benzophenones; benzoyl peroxide; bethanechol; biotin; bisacodyl; bornyl acetate; bromopheniramine maleate; buspirone; caffeine; calamine; calcium carbonate, casinate and hydroxide; camphor; captopril; cascara sagrada; castor oil; cefaclor; cefadroxil; cephalexin; cetyl alcohol; cetylpyridinium chloride; chelated minerals; chloramphenicol; chlorcyclizine hydrochloride; chlorhexidine -15gluconate; chloroxylenol; chloropentostatin; chlorpheniramine maleate; cholestyramine resin; choline bitartrate; chondrogenic stimulating protein; cimetidine and its hydrochloride; cinnamedrine hydrochloride; citalopram; citric acid; clarithromycin; clonidine and its hydrochloride salt; clorfibrate; cocoa butter; cod liver oil; codeine and codeine phosphate; cortisone acetate; ciprofloxacin HCl; cyanocobalamin; cyclizine hydrochloride; danthron; dexbromopheniramine maleate; dextromethorphan hydrobromide; diazepam; dibucaine; diclofenac sodium; digoxin; diltiazem; dimethicone; dioxybenzone; diphenhydramine and its citrate; diphenhydramine hydrochloride; docusate calcium, potassium, and sodium; doxycycline hydrate; doxylamine succinate; efaroxan; enalapril; enoxacin; erythromycin; estropipate; ethinyl estradiol; ephedrine; epinephrine bitartrate; erythropoietin; eucalyptol; famotidine; ferrous fumarate, gluconate and sulfate; flluoxetine; folic acid; fosphenytoin; 5 - fluorouracil (5-FU); fluoxetine and its hydrochloride;flurbiprofen, flurosemide; gabapentan; gentamicin; gemfibrozil; glipizide; glycerine; glyceryl stearate; griseofulvin; growth hormone; guafenesin; hexylresorcinol; hydrochlorothiazide; hydrocodone bitartrate; hydrocortisone and its acetate; 8hydroxyquinoline sulfate; ibuprofen; indomethacin; inositol; insulin; iodine; ipecac; iron; isosorbide and its mono- and dinitrates; isoxicam; ketamine; kaolin; lactic acid; lanolin; lecithin; leuprolide acetate; lidocaine and its hydrochloride salt; lifinopril; liotrix; loratadine; lovastatin; luteinizing hormore; LHRH (lutenizing hormone replacement hormone); magnesium carbonate, hydroxide, -16salicylate, and trisilicate; mefenamic acid; meclofenamic acid; meclofenamate sodium; medroxyprogesterone acetate; methenamine mandelate; menthol; meperidine hydrochloride; metaproterenol sulfate; methyl nicotinate; methyl salicylate; methyl cellulose; methsuximide; metronidazole and its hydrochloride.; metoprotol tartrate; miconazole nitrate; mineral oil; minoxidil; morphine; naproxen and its sodium salt; nifedipine; neomycin sulfate; niacin; niacinamide; nicotine; nicotinamide; nimesulide; nitroglycerine; nonoxynol-9; norethindrone and its acetate; nystatin; octoxynol; octoxynol-9; octyl dimethyl PABA; octyl methoxycinnamate; omega-3 polyunsaturated fatty acids; omeprazole; ondansetron; oxolinic acid; oxybenzone; oxtriphylline; para-aminobenzoic acid (PABA); padimate-O; paramethadione; pentastatin; peppermint oil; pentaerythritol tetranitrate; pentobarbital sodium; pheniramine maleate; phenobarbital; phenol; phenolphthalein; phenylephrine hydrochloride; phenylpropanolamine and its hydrochloride salt; phenytoin; phenelzine sulfate; pirmenol; piroxicam; polymicin B sulfate; potassium chloride and nitrate; prazepam; procainamide hydrochloride; procaterol; proxephene and its HCI salt; propoxyphene napsylate; pramiraoetin; pramoxine and its hydrochloride salt; propanolol HCI; pseudoephedrine hydrochoride and sulfate; pyridoxine; quinapril; quinidine gluconate and sulfate; quinestrol; ralitoline; ranitadine; resorcinol; riboflavin; salicylic acid; sesame oil; shark liver oil; simethicone; sodium bicarbonate, citrate, and fluoride; sodium monofluorophosphate; sucralfate; sulfanethoxazole; sulfasalazine; sulfur; tacrine and its HCI salt; -17theophylline; terfinidine; thioperidone; trimetrexate; triazolam; timolol maleate; tretinoin; tetracycline hydrochloride; tolmetin; tolnaftate; tramadol; triclcsan; tripolidine hydrochloride; undecylenic acid; vancomycin; verapamil HCl; vidaribine phosphate; vitamins A, B, C, D, B., B2, B6, B12, E, and K; witch hazel; xylometazoline hydrochloride; zinc; zinc sulfate; zinc undecylenate. Mixtures and pharmaceutically acceptable esters and salts of these and other actives can be used.

One group of preferred active ingredients are antacids, K2-antagonists and analgesics.

Antacids dosages can be prepared using ingredients such as: aluminum hydroxide, dihydroxyaluminum aminoacetate, aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodium carbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate, calcium carbonate, calcium phosphate, citrate ion (acid or salt), amino acetic acid, hydrate of magnesium aluminum sulfate, magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesium glycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, milk solids, aluminum mono- or di-basic calcium phosphate, tricalcium phosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate, magnesium aluminosilicates, tartaric acids and salts, and the like. Mixtures are operable. Moreover, antacids can be used in combination with H;-antagonists.

Chewable antacid compositions which dissolve quickly can be made using the compositions of the invention.

Preferred analgesics include aspirin, acetaminophen, -18acetaminophen plus caffeine and ibuprofen.

Other ingredients which may be included are fillers, fragrances, dyes, flavors, sweeteners (both artificial and natural), and other conventional tablet additives.

For example, fillers may be used to increase the bulk of the tablet. Some of the commonly used fillers are calcium sulfate, both di- and tri-basic; starch; calcium carbonate; microcrystalline cellulose; modified starches, lactose, sucrose; mannitol and sorbitol.

Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A non-limiting representative list of these includes citric oils, such a lemon, orange, grape, lime and grapefruit an fruit essences, including apple, pear, peach grape strawberry raspberry, cherry, plum, pineapple, apricot, or other fruit flavors.

Other useful flavorings include aldehydes and esters, such as benzaldehyde (cherry, almond); citral, i.e., alphacitral (lemon, lime); neral, i.e., beta-citral (lemon, lime); decanal (orange, lemon); aldehyde C-8 (citrus fruits); aldehyde C-9 (citrus fruits); aldehyde C-12 (citrus fruits); tolyl aldehyde (cherry, almond); 2,6dimethyloctanal (green fruit); 2-dodedenal (citrus, mandarin); mixtures thereof and the like.

The sweeteners may be chosen from the following nonlimiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); -19saccharin and its various salts, such as the sodium salt; dipeptide sweeteners such as aspartame; dihydro-chalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives or sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, xylitol, and the like.

Also contemplated are hydrogenated starch hydrolysates and the synthetic sweeteners such as 3,6-dihydro-6-methyl-1-11,2,3-oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof. Other sweeteners may be used.

Other ingredients include binders which contribute to the ease of formation and general quality of the tablet. Binders include starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, methyl cellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone and polyvinylalcohols.

Color additives can be used in preparing tablets. Such color additives include food, drug and cosmetic colors (FDScC) , drug and cosmetic colors (D&C) or external drug and cosmetic colors (Ext. D&C). These colors are dyes, lakes, and certain natural and derived colorants. Useful lakes include dyes absorbed on aluminum hydroxide or other suitable carriers.

An optional feature involves microspheres which are components of substrate/coating systems. The substrate can be a non-active ingredient, such as a saccharide-based material, or it can be an active or a combination of actives. In one embodiment, the substrates are sugar shearlite particles having active agents coated thereon.

The coating may include other types of coating materials, -20e.g., coloring agents. Additional coatings can be used.

Other useful substrate/coating systems employ substrates which are shearlite particles of one or more actives. Coatings thereon can contain saccharides and other ingredients .

Controlled release coatings, e.g., sustained release coatings, are among the preferred types of coatings for use in dosage forms which include bio-affecting agents.

Using the invention, strong, highly attractive dosage units, e.g, tablets, can be produced having textures and internal structures which are relatively open to solubilization. Applicants’ compositions are intended generally formed into tablets at pressures of from about 500 up to about 10,000 psi. These tablets have initial hardness values of about 0.5 to about 5.0 lbs.

Disintegration Test This section describes the disintegration test that was used in testing the tablets herein.

The test employs upright jacketed polycarbonate columns (6 ft. X 1.5 ft. and 0.25 inch wall thickness) and a stainless steel tank. A bayonet style pail immersion heater, a Rotronic-Hygroskop DT equivalent (temperature reading) and a pump are used for heating and water recirculation .

The test method involved filling up the steel tank with tap water, turning on the pump and filling up the jacket of the disintegration column. When the jacket is full, water is added to the tank to leave a head space of 3 inches. The heater is turned on until the temperature equilibrates at -2137°C -0.5°C. The column is filled with distilled water, leaving a 1 cm head space at the top. After 30 minutes, the temperature inside the column equilibrates to 37°C =0.5°C.

With an individually weighed tablet in one hand and a stopwatch in the other, the tablet is released gently into the column, while simultaneously activating the stopwatch. The tablet descends down the column and when it disintegrates, the disintegration time of the tablet is recorded. Complete disintegration is defined when the tablet has broken into pieces no larger than 2 to 3 mm in size. The results of a series of tablets are recorded.

Tablets which go to the bottom without disintegrating in 25 seconds or less are noted as “Did Not Disintegrate” or “DND”. Some tablets break into two or more pieces. These are termed “DND” and “Broke in two pieces at X time(s)”.

Examples The following non-limiting examples illustrate the invention .

Example I Ibuprofen Microspheres Ibuprofen was processed into spheres as follows: An ibuprofen powder feedstock was fed to the 5-inch spinning head disclosed in a U.S. Application S.N. 08/847,215, filed on June 13, 1997. The head was rotated at about 3600 rpm while the heating elements were raised to a temperature which produced the flash flow conditions. The feedstock also contained 10% Compritol 888 ATO and 2% Gelucire 50/13. (Compritol 888 ATO is glycerol behenate NF, a lipophilic additive from Gattefosse S.A., a French -22company. Gelucire, a polyethylene glycol 32 glyceryl ester solubility enhancer, is also available from Gattefosse.) The spinning head forced the material through the screen and the product was permitted to free fall a distance of from 6 to 8 feet below the head. The product consists of spheres having a highly consistent particle size, with diameters ranging from about 50 to about 200 microns.

Example II Shearform Composition Using a procedure similar to that of Example I, ibuprofen microspheres were made from a formulation containing 88% ibuprofen, 10% Compritol and 2% Gelucire.

A floss was made from the composition shown below.

This material was spun into a floss in a device described in U. S. Patent Application Serial No. 08/854,344, filed on May 12, 1997, and entitled “Apparatus for Melt Spinning Feedstock Material Having a Flow Restricting Ring.” The spun floss was collected and chopped in a mixer and granulated after the addition of sufficient ethanol to recrystallize the floss about 5% to about 30%.

The microspheres and floss were then admixed according to the following composition: Microspheres 34.4% Floss 62.7%* Citric acid 0.7% Lemon flavor 0.4% Whipped cream flavor 0.3% Syloid 244 FP 0.5% Sodium stearyl fumarate -23*The floss ingredients were: 48.1% sucrose, 0.45% Tween 80, 6.8% sorbitol, 6.1% xylitol and 1.25% lactose.

Using a Kilian T-200 press at 5,000 psi, 750 mg. tablets were pressed to a 2 lb. initial hardness. The tablets had 38-41% porosity values. They disintegrated, when tested as described above, in about 18 seconds.

Example III Non-Shearform Composition Using the same ingredients as those in Example II, a tablet was made without producing a shearform floss.

A preblend was made containing 48.1% sucrose and 0.45% Tween 80. The preblend was processed on a Hobart mixer for 3 minutes. To the preblend was added 6.80% sorbitol and 6.1% xylitol the mix was blended for 3 minutes. 1.25% lactose and 34.4% ibuprofen microspheres (from Example I) were then mixed for 2 minutes, with the preblend followed by 0.7% citric acid, 0.4% lemon flavor, and 0.3% whipped creme flavor which were also mixed for 2 minutes and, finally, 0.5% Syloid 244FP and sodium stearyl fumarate, also mixed for 2 minutes.

From this mix, 750 mg tablets were pressed at 7,000 psi using a Kilian T-200 to a 2 lb. initial hardness. These tablets had very poor structural integrity, and did not disintegrate, in the disintegration test above, in 25 seconds or less.

Examples II and III show that the use of shearform matrices, made via flash flow technology, in the production of tablets and other comestible units gives products which disintegrate faster than ones made by molding the same -24ingredients at high pressures without intermediate flow operations.

Example IV Low Compression Tableting Using the procedure described in Example II, was produced from the following composition: flash a floss Sorbitol 11.00 Xylitol 10.00 Sucrose 78.75 TWEEN 80 0.25 The floss was then combined with ibuprofen microspheres made in accordance with Example I and with other tablet ingredients as follows: Floss 64.1% Ibuprofen Microspheres 34.4% Citric Acid 0.7% Lemon Flavor 0.4% Whipped Cream Flavor 0.3% CAB-O-SIL 0.1% The mixture was tableted, at a rate of about 15,000 to 20,000 tablets per hour, using the low compression tableting apparatus described in Italian Patent Application No. B096A 000453 (Attorney Docket No. 0004.ITAL), filed September 11, 1996, and entitled “Meto Do E Macchina Per La Produzione Di Pasti Glie Di Polvere Medicinale (“Method and Machine for Tablet Production of Medicine Power) .

The resultant tablets had good structural integrity, weighed 750 mg., and had an initial hardness of 1 lb. When -25tested using the disintegration test above, they disintegrated in about 7 seconds. Tablets having 1 lb hardness are found to have porosity values of about 41% to about 43%.

Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.

Claims (10)

1. A comestible unit having a porosity of about 20% to about 50% and a disintegration time of about 25 seconds or less, which unit is made from a shearform composition.

2. The unit of claim 1 which contains no added effervescent or disintegrating agents.

3. The unit of claim 1 containing a shearform matrix and one or more ingredients selected from the group consisting of: active agents and pharmaceutical excipients.

4. The unit of claim 1 which is a tablet.

5. The unit of claim 4 which contains an analgesic.

6. A method of making a comestible unit which unit disintegrates in less than 25 seconds comprising the steps of : (1) making a shearform matrix; 2. (2) compressing the matrix, in the presence of added active agent(s) and excipient(s), to a pressure of about 5,000 psi to about 10,000 psi to produce a comestible unit having a porosity of from about 20% to about 50%.

7. The method of claim 6 wherein the unit is a tablet.

8. The method of claim 7 wherein the tablet contains an analgesic .

-279. A comestible unit substantially as herein described and exemplified.

10. A method of making a comestible unit substantially as herein described and exemplified.