Title:  Quickly disintegratable compression-molded materials and process for producing the same

United States Patent:  6,287,596

Assignee:  Daiichi Pharmaceutical Co., Ltd. (Tokyo, JP)

Filed:  January 11, 1999

PCT NO:  PCT/JP97/02386

102(e) Date:  January 11, 1999

PCT PUB. Date:  January 22, 1998

Foreign Application Priority Data:  Jul 12, 1996[JP] (8-183278)

Quickly disintegratable compression-molded materials containing (a) fillers and (b) erythritol. These materials are highly disintegratable and soluble in the oral cavity or water and, therefore, can be easily taken. Also, they are highly hard and thus excellent in storage stability in the production and distribution stages. Owing to these characteristics, they can be appropriately blended with efficacious ingredients and used in the treatment or prevention of diseases in patients, in particular, the aged, infants or those having difficulty in swallowing.

DISCLOSURE OF THE INVENTION

The present inventors have conducted careful studies in an attempt to solve the above-described problems, and have found that when a mixture of erythritol and an ingredient selected from among organic and inorganic excipients is tableted, quite surprisingly there can be obtained a quickly disintegratable compression-molded material which exhibits rapid disintegration and dissolution when placed in the oral cavity or water and which is endowed with high strength that does not permit collapse thereof throughout the processes of manufacture process, thus leading to completion of the invention.

Accordingly, the present invention provides a quickly disintegratable compression-molded material characterized by comprising (a) an excipient, and (b) erythritol.

MODES FOR CARRYING OUT THE INVENTION

As used herein, the expression "a quickly disintegratable compression-molded material" refers to a compression-molded material having practically sufficient strength throughout the processes of manufacture and distribution of the formulation.

Examples of excipients which are used in the present invention include inorganic excipients, and organic excipients selected from among starches, celluloses, and sugar alcohols.

Examples of starches include corn starch, potato starch, wheat starch, rice starch, partly pregelatinized starch, pregelatinized starch, hydroxypropyl starch, and sodium carboxymethyl starch. Of these, cornstarch, partly pregelatinized starch, and pregelatinized starch are preferred. No limitation is imposed on the grain diameter of the starches which are usable in the present invention. However, the grain diameter of the starches is preferably not more than 500 .mu.m, from the viewpoint that larger granules tend to cause rough sensation to the oral cavity.

Examples of celluloses include microcrystalline cellulose, powdered cellulose, low substituted hydroxypropyl cellulose, carmellose, carmellose-Ca, and cross carmellose-Na. Of these, microcrystalline cellulose, powdered cellulose, low substituted hydroxypropyl cellulose, and carmellose are preferred. There is no limitation on the grain diameter of the cellulose used in the present invention. Preferably, the grain diameter of cellulose is 500 .mu.m or less, from the viewpoint that larger granules tend to cause rough sensation to the oral cavity.

Examples of sugar alcohols include sugar alcohols other than erythritol; for example, D-mannitol, D-sorbitol, xylitol, maltitol, anhydrous maltose, hydrous maltose, anhydrous lactitol, hydrous lactitol, and reducing malt sugar syrup. Of these, D-mannitol, xylitol, and multitol are preferred. No particular limitation is imposed on the grain diameter of the sugar alcohol used in the present invention. Preferably, the grain diameter is 500 .mu.m or less, from the viewpoint that larger granules tend to cause rough sensation to the oral cavity.

Examples of the inorganic excipients which may be used in the present invention include synthetic hydrotalcite, precipitated calcium carbonate, anhydrous dibasic calcium phosphate, hydrated silicon dioxide, light anhydrous silicic acid, calcium silicate, magnesium alminosilicate, magnesium oxide, and magnesium hydroxide. Of these, synthetic hydrotalcite, precipitated calcium carbonate, and anhydrous dibasic calcium phosphate are preferred. No particular limitation is imposed on the grain diameter of the excipients used in the present invention. Preferably, the grain diameter is 500 .mu.m or less, from the viewpoint that larger granules tend to cause rough sensation to the oral cavity.

These excipients may be used singly or in combination.

Erythritol in the present invention is a sweetener obtained through fermentation of glucose and is a tetrahydric sugar alcohol.

Erythritol is a white crystalline powder having a melting point of 119^oC., and is freely soluble in water. The heat of dissolution of erythritol is -42.9 cal/g. It is a sweetener which provides a cool sensation, exhibits no moisture-absorbing properties, and has a sweetness degree which is equivalent to 70-80% that of sugar. No particular limitation is imposed on the grain diameter of the erythritol used in the present invention. However, in view that larger granules tend to cause rough sensation to the oral cavity, erythritol having a grain diameter of 500 .mu.m or less is preferred.

The total amount of excipient (a) and erythritol (b) preferably falls within the range of 30-99% by weight, more preferably 50-99% by weight, most preferably 70-99% by weight, of the total weight of the quickly disintegratable compression-molded material. Amounts less than 30% by weight lead to insignificant contribution of these ingredients, resulting in poor disintegration and dissolution.

The ratio of excipient (a) to erythritol (b) is preferably 5-100% by weight, more preferably 10-70% by weight, most preferably 20-50% by weight. If no excipient (a) is incorporated, tableting troubles (capping phenomenon; in which the top portion of the tablet cracks laterally to assume the appearance of a hat) tends to occur, which can be prevented by incorporation of excipient (a) to erythritol (b). On the other hand, when the ratio of excipient (a) to erythritol (b) is in excess of 100% by weight, contribution of erythritol is insignificant, resulting in a prolonged time in terms of disintegration and dissolution. Particularly in the case of celluloses, they are preferably incorporated in an amount of 5-70% by weight, more preferably 5-50% by weight, with respect to the amount of erythritol.

No particular limitation is imposed on the pharmaceutically active ingredients which may be used in the present invention, and they may be added in accordance with intended uses in the form of powder, crystals, oil, solutions, or in any other forms. Instead of the active ingredients, other optional ingredients may be added. Examples of such optional ingredients are described below.

Examples of vitamins include vitamin A, vitamin D, vitamin E (such as d-.alpha.-tocopherol acetate), vitamin B₁ (such as thiamin hydrochloride), vitamin B₂ (such as riboflavin), vitamin B₆ (such as pyridoxine hydrochloride), vitamin C (such as ascorbic acid and sodium ascorbate), vitamin B₁₂ (such as hydroxocobalamin acetate), nicotinamide, calcium pantothenate, and pantethine.

Examples of antipyretic analgesic antiinflammatory agents include aspirin, acetaminophen, ethenzamide, ibuprofen, ketoprofen, indomethacin, and aminopyrine.

Examples of antihistaminic agents include alimemazine tartrate, chlorpheniramine maleate, diphenhydramine hydrochloride, clemastine fumarate, carbinoxamine maleate, dimenhydrinate, and meclizine hydrochloride.

Examples of antitussives include codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, noscapine, and noscapine hydrochloride.

Examples of bactericides include cetylpyridinium chloride, dequalinium chloride, chlorhexidine chloride, iodine, and potassium iodide.

Examples of antacids include magnesium alminosilicate, magnesium alminometasillicate, synthetic hydrotalcite, synthetic aluminum silicate, magnesium oxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, anhydrous dibasic calcium phosphate, and scopolia extract.

Examples of crude drugs include aloe, fennel, phellodendron bark, captis rhizome, glycyrrhiza, cinnamon bark, amomum seed, swertia herb, rhubarb, ginseng, mallotus bark, Corydalis Tuber, and ephedra harb.

Examples of gastric mucosal protective agents include cetraxate hydrochloride, sodium azulene sulfonate, aldioxa, L-glutamine, sodium copper chlorophyllin, and methylmethionine sulfonium chloride.

Examples of analgetic antispasmodic agents include N-methylscopolamine methylsulfate, scopolamine hydrobromide, atropine methyl bromide, methylscopolamine bromide, belladonna extract, scopolia extract, ethyl aminobenzoate, scopolamine butyl bromide, and timepidium bromide.

Examples of anticonstipation agents include aloe, rhubarb, bisacodyl, and sodium picosulfate.

Examples of psychotropic agents include timiperone, oxypertine, diazepam, nitrazepam, flunitrazepam, lorazepam, haloperidol, and bromperidol.

Examples of H2 receptor antagonists include cimetidine, famotidine, ranitidine hydrochloride, nizatidine, and roxatidine acetate hydrochloride.

Examples of antiulcer agents include cetraxate hydrochloride, teprenone, sulpiride, sucralfate, plaunotol, and gefarnate.

Examples of antibiotics include tetracycline, oxytetracycline, metacycline, doxycycline, minocycline, chloramphenicols, and erythromycins.

Examples of antihypertensives include budralazine and hydralazine hydrochloride.

Examples of antiarrhythmic agents include pilsicainide hydrochloride and procainamide hydrochloride.

Examples of central nervous system stimulants include caffeine, anhydrous caffeine, and caffeine and sodium benzoate.

The pharmaceutically active ingredients in the present invention may be used singly or in combination. Examples of preferable effective ingredients include antipsychotic agents, antihistaminic agents, H2 receptor antagonists, antiulcer agents, vitamins, gastrointestinal agents, antitussive and expectorant drugs, anticonstipation agents, antivertigos (anti-motion-sickness drugs), and central nervous system stimulants. Further, not only to pharmaceuticals for humans, these ingredients may be applied to veterinary pharmaceuticals, agricultural chemicals, and diagnostic drugs. The present invention may also be applied to many uses which may obtain benefits from the features of the present invention; for example, health foods, nutritional supplement foods, ozostomia removers, plaque stain, bath-additive agents, and detergents.

The amounts of the pharmaceutically active ingredients vary depending on their properties. The amounts are 1-70% by weight, preferably 1-50% by weight, more preferably 1-30% by weight, of the solid contents.

The present invention may contain a variety of additives which are usually used for production of tablets, so long as the effects of the invention are not impeded.

Examples of such additives include lubricants, disintegrants, diluents, binding agents, coloring agents, flavoring agents, sweeteners, corrigent, effervescent agents, and surfactants.

Examples of lubricants include magnesium stearate, calcium stearate, stearic acid, talc, sucrose fatty acid esters, polyethylene glycol, and hydrogenated oils.

Examples of disintegrants include alginic acid, calcium alginate, powdered traganth, crospovidone, powdered agar, and bentonite.

Examples of diluents include lactose, sucrose, glucose, fructose, light anhydrous silicic acid, calcium silicate, and calcium lactate.

Examples of binding agents include acacia, sodium alginate, carboxyvinyl polymers, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, and macrogol.

Examples of coloring agents include food coloring agents such as food yellow No.5, food red No.2, and food blue No.2, food lakes, yellow ferric oxide, red ferric oxide, titanium oxide, .beta.-carotene, and riboflavin.

Examples of flavoring agents include oranges, lemons, peppermint, and menthol. Examples of the sweeteners include saccharin sodium, aspartame, dipotassium glycyrrhizinate, stevia, and thaumatin.

Examples of taste improvers include sodium chloride, magnesium chloride, disodium inosinate, sodium L-glutamate, and honey.

Examples of the effervescent agents include combinations of an acid such as citric acid, tartaric acid, or malic acid and a base such as sodium bicarbonate or sodium carbonate.

Examples of the surfacants include polyoxyl 40 stearate, sorbitan esters of fatty acid, polyoxyethylene hydrogenated castor oil, polysorbate, glyceryl monostearate, and sodium monododecyl sulfate.

The above-listed additives may be added singly or in combination at any stage of the process for producing a rapidly disintegratable compression-molded material. For example, these additives may be added as desired in suitable amounts during mixing of the pharmaceutically active ingredient, excipient (a), and erythritol (b), or when water is added, or during granulation; or before or after any one of these processes.

The rapidly disintegratable compression-molded material of the present invention is manufactured, for example, through compression-molding of a substantially dry composition which contains an excipient (a) and erythritol (b). More specifically, the rapidly disintegratable compression-molded material of the present invention is manufactured by directly, or after granulation, bringing to substantial dryness the excipient (a), erythritol (b), and if needed, a pharmaceutically active ingredient and the aforementioned additives, followed by tableting. Details of the process are as follows.

Method 1

Excipient (a), erythritol (b), and as necessary, a pharmaceutically active ingredient and the aforementioned additives are mixed and compression-molded (direct compression method).

Method 2

Excipient (a), erythritol (b), and as necessary, pharmaceutically active ingredients and the aforementioned additives are mixed, formed into flakes, compression-molded to form tablets or slug tablets (large tablets) by compression, then crushed into granules, and if desired, combined with the aforementioned additives, dried to a substantially dry state, followed by compression-molding (dry granulation-tableting method).

Method 3

Excipient (a), erythritol (b), and as necessary, pharmaceutically active ingredients and the aforementioned additives are mixed. The mixture is granulated by adding water or an aqueous solution or suspension of starch and/or sugaralcohol, followed by granulation. The granules are substantially dried. Thereafter, the aforementioned additives are added as desired. The resultant mixture is substantially dried and compression-molded (wet granulation-compression method).

Method 4

The pharmaceutically active ingredients are divided into groups A and B, and through the wet granulation-tableting method referred to as Method 3, their respective granules are prepared. If necessary, the aforementioned additives are further added. The resultant mixture is brought to substantial dryness, followed by compression-molding (multi-type-granule-compression method).

The quickly disintegratable compression-molded material of the present invention is produced by use of an apparatus which is generally used in the manufacture of formulations. Specifically, mixing is performed by use of a twin-shell blender, a fluidized bed granulator, an agitated glanulating machine, a nauta mixer, or a cross rotary mixer.

For obtaining flakes compression molded product through dry granulation, a dry granulator is used, and for compression-molding of slug tablet, a rotary tabelting machine is used.

Wet granulation is performed by use of a fluidized bed granulator, a rotating fluid bed granulation and coating machine, an agitated granulating machine, a cylindrical extruting granulator, or a wet-type extruting granulator.

Compression-molding is performed by use of an apparatus which is generally used for molding tablets. For example, there is used a single-punch tablet machine, rotary tableting machine, or a multilayer rotary tablet machine.

The molding pressure during tableting can be arbitrarily determined based on the hardness of the molded material, and disintegration and dissolution properties of the molded material when put into the oral cavity or water. A characteristic feature of the present invention is that the disintegration and dissolution properties of the molded material when put into the oral cavity or water are not significantly marred even when the material has undergone an increased molding pressure. Thus, the molding pressure may be as high as that applied to common tablets; i.e., 400-2000 kg/cm², preferably 600-1800 Kg/cm², more preferably 800-1600 kg/cm². The density of the molded material is 800-1600 mg/cm³, preferably 1000-1400 mg/cm³. The hardness is regulated to not less than 2 kg, preferably 2-15 kg, more preferably 3-10 kg, for the case in which the diameter or the major length of the quickly disintegratable compression-molded material is 10 mm.

The thus-obtained quickly disintegratable compression-molded material is endowed with excellent disintegration and dissolution properties when put in the oral cavity or water, has improved hardness, and exhibits excellent falling impact strength.

The disintegration and dissolution properties of the quickly disintegratable compression-molded product of the present invention differ depending on the size of the product. Preferably, the disintegration time as measured according to the Japanese Pharmacopoeia (see the disintegration test method (without use of an auxiliary disk) described in the Japanese Pharmacopoeia 12th Revision, under the heading "Tablets") is within 60 seconds for the case in which the diameter or the major length of the quickly disintegratable compression-molded material is less than 8 mm; within 90 seconds for the case of the size being not less than 8 mm and less than 10 mm; within 120 seconds for the case of the size being not less than between 10 mm and less than 15 mm; within 180 seconds for the case of the size being not less than between 15 mm and less than 20 mm; and within 240 seconds for the case of the size being not less than 20 mm. Also, the disintegration and dissolution properties in the oral cavity as measured in terms of time required for disintegration or dissolution is within 40 seconds in the case in which the diameter or the major length of the quickly disintegratable compression-molded material is less than 8 mm; within 60 seconds for the case of the size being not less than 8 mm and less than 10 mm; within 90 seconds for the case of the size being not less than between 10 mm and less than 15 mm; within 120 seconds for the case of the size being not less than between 15 mm and less than 20 mm; and within 180 seconds for the case of the size being not less than 20 mm, all determined when the material is put in the oral cavity. Specifically, preferable disintegration time is generally 5-120 seconds, preferably 5-60 seconds, more preferably 5-30 seconds, in the case in which the diameter or the major length of the quickly disintegratable compression-molded material is less than 10 mm, and the time required for disintegration and dissolution in the oral cavity (i.e., the time required for a tablet to be dissolved completely in the oral cavity of a healthy adult man, without use of water but only use of saliva) is typically 5-90 seconds, preferably 5-60 seconds, most preferably 5-30 seconds.

When placed in the oral cavity, the rapidly disintegratable compression-molded material of the present invention disintegrates or dissolves in the presence of saliva. Application of pressure in the oral cavity, namely pressure applied by the upper jaw and the tongue, or through friction produced against the tongue, namely "licking" movement, etc., causes the tablet to be disintegrated or dissolved in a shorter time. When the tablet is taken by a subject having a dry mouth, or by a subject who secretes less saliva, cold water or warm water may be used for disintegration and dissolution of the tablet in the oral cavity. Alternatively, the tablet of the present invention may be taken exactly in the same manner together with water, as in the case of conventional tablets.

The rapidly disintegratable compression-molded material of the present invention does not disintegrate or dissolve instantaneously (e.g., within 1 sec), allowing the user to enjoy the intraoral organolestic sensation or spit the tablet if desired.

The hardness (as measured by use of a tablet hardness tester) of the rapidly disintegratable compression-molded material of the present invention is typically not less than 2 kg, preferably 2-15 kg, more preferably 3-10 kg, in the case in which the diameter or the major length of the quickly disintegratable compression-molded material is 10 mm. The falling impact strength (which is a breakage ratio obtained when a tablet is allowed to fall from the height of 50 cm onto a stainless steel plate, and defined by: {(broken tablets)/(tested tablets)}.times.100(%)) is typically about 0-50%, preferably 0-20%, more preferably 0%.

Thus, the rapidly disintegratable compression-molded material of the present invention exhibits enhanced hardness that does not permit breakage of the process of manufacture and distribution. Also, the tablet satisfactorily endures through the operation of removal thereof from a PTP package. Moreover, the tablet has a harness that allows packaging in bottles (i.e., packaging using a container made of, for example, glass or plastics). When tablets are taken out of aluminum sheet of a PTP package, in the case in which tablets having a diameter of 8 mm are concerned, it is preferred that they exhibit a hardness of 1 kg or more, and in the case in which tablets having a diameter of 10 mm are concerned, it is preferred that they exhibit a hardness of 2 kg or more, although the size and shape of the tablets may shift the range. In the case of packaging in a bottle, preferably, the tablets, if they are 10 mm in diameter, have a hardness of 3 kg or more so as to endure impact which may be applied during the process of ditribution.

The quickly disintegratable compression-molded material of the present invention contains a sweetener erythritol as a base material. Erythritol provides cool sensation and sweetness to the tablet. Also, since erythritol is a sugaralcohol, Mailard reaction (browning of an amino acid and a saccharide, also called an amino-carbonyl reaction) does not occur. This is advantageous in that the presence of a pharmaceutical ingredient having an amino group prevents the browning phenomenon, which means improved stability over time.

The quickly disintegratable compression-molded material of the present invention is used as a formulation that can be easily taken by the aged or infants, or as a formulation which is safely taken by normal adults, for the treatment or prevention of a variety of diseases, in the same manner as in the case of conventional formulations. Also, the material exhibits excellent long-term storageability and stability.

The shape of the quickly disintegratable compression-molded material of the present invention is not particularly limited. Examples of the shape of tablets include triangle, square, round, animal-shape, irregular shape (Caplet-type), ring (donut shape), multi-layer tablet, dry coated tablet, etc. In addition, letters or characters may be marked or applied for discernment. Tablets may be coated by a coating method which is customarily employed for the manufacture of coated formulations.

Claim 1 of 65 Claims

What is claimed is:

1. A quickly disintegratable compression-molded material, comprising:

an excipient (a); and

erythritol (b);

wherein said compression-molded material has a density of 800-1600 mg/cm³.

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