WO2002092058A1

WO2002092058A1 - Rapidly disintegratable solid preparation

Info

Publication number: WO2002092058A1
Application number: PCT/JP2002/004641
Authority: WO
Inventors: Kazuhiro Ohkouchi; Hiroyoshi Koyama
Original assignee: Takeda Chemical Industries, Ltd.
Priority date: 2001-05-15
Filing date: 2002-05-14
Publication date: 2002-11-21

Abstract

A rapidly disintegratable solid preparation which comprises group (1) containing (a) an active ingredient, (b-1) a sugar and/or a sugar alcohol and (c-1) a cellulose and group (2) containing (b-2) a sugar and/or a sugar alcohol and (c-2) a cellulose, group (1) and/or group (2) containing (d) a dissolution aid. The solid preparation can be prepared by a dry method even under a low compression pressure and has a practically acceptable hardness and excellent properties necessary to drug, e.g., rapid disintegration, excellent dissolution control, and less trouble in preparation.

Description

Technical field of fast-disintegrating solid preparation

The present invention provides a rapid disintegration which is rapidly disintegrated in the presence of bodily fluids, especially saliva or a small amount of water in the oral cavity, and in which the elution of the active ingredient is properly adjusted, and particularly useful as a disintegrable solid preparation in the oral cavity. A solid solid preparation. Background art

Conventionally, solid preparations that disintegrate and dissolve rapidly in the oral cavity have been developed as a dosage form that is easy to take for patients, the elderly, and children who have difficulty swallowing the drug.

For example, JP-A-6-218028 and JP-A-8-19589 disclose that a kneaded wet powder is filled into a hole for tablet molding, wet-molded, and then dried to form a tablet. A method for producing is described. Since the obtained tablets are porous and have an appropriate porosity, rapid crushing properties are obtained. However, this production method is inferior in industrial productivity because it requires filling and compressing a wet material with poor fluidity, and in addition to a large filling variation, a special dryer is required.

For this reason, production of orally disintegrating tablets by dry tableting, which is excellent in industrial productivity, has also been reported.

For example, International Publication No. WO95 / 230380 describes a method for producing an orally disintegrating tablet by dry tableting in which a saccharide having high moldability and a saccharide having low moldability are combined.

In addition, International Publication No. WO988Z0185 includes an oral disintegrating tablet prepared by dry tableting using dry or wet granulated granules in which an excipient and a sugar alcohol, erythritol, are combined. Is described.

In addition, International Publication No. WO 97/472 787 states that a sugar or a sugar alcohol having an average particle size of 30 μππ or less is combined with an active ingredient and a disintegrant, and is rapidly administered in the oral cavity. Methods for making disintegrating tablets are described. According to the production method described therein, a crushed product obtained by finely pulverizing sugar such as D-mannitol or lactose or a sugar alcohol and then adding a disintegrant or the like has rapid disintegration. However, in the case of molded products using coarse sugar before milling (lactose, average particle diameter 80 / zm) or sugar alcohol (D-mannitol, average particle diameter 60 μm), molding at low tableting pressure However, sufficient mechanical hardness is not obtained even when molded at high tableting pressure.

When a commercially available product containing the same active ingredient as the existing active ingredient is developed as an orally disintegrating tablet, the elution behavior of the active ingredient between the commercially available product and the orally disintegrating tablet is required to maintain the efficacy and safety of the active ingredient Are preferably equal. JP-A-9-171523, International Publication No.WO0 / 072922 evaluates the disintegration property in the oral cavity, but describes the control of dissolution of active components. Absent. Purpose of the invention

After oral administration of the tablet, the tablet component comes into contact with various ionic components and the like by contact with meal components and gastrointestinal fluid in the gastrointestinal tract such as the stomach and small intestine. As a result of these actions, if the components of the excipients in the tablet are not properly designed, the elution of the active ingredient may be affected, which may affect the absorption behavior of the drug and, consequently, the onset of the drug effect. In general, poorly water-soluble active ingredients do not elute sufficiently because of slow elution, and water-soluble active ingredients are too fast to elute because of rapid elution.

The present invention is a commercial product containing the same active substance that can be industrially produced with general equipment without the need for special formulation technology (a formulation that is not a fast-disintegrating solid formulation). A rapidly disintegrating solid preparation, particularly an orally disintegrating tablet, which exhibits the same dissolution behavior and absorption behavior as tablets. Summary of the Invention

After various studies, the present inventors include a group containing an active ingredient and a sugar or sugar alcohol and celluloses, and a group containing a sugar and a sugar or sugar alcohol and celluloses. And elute to one or both groups Incorporation of the agent makes it hard to cause practical problems even at low dry compression pressures, and has excellent properties as a pharmaceutical such as rapid disintegration, dissolution control, and excellent manufacturability. It has been found that solid preparations, particularly orally disintegrating tablets, can be obtained, and the present invention has been completed based on these. That is, the present invention

(1) a) active ingredient, b-1) sugar and / or sugar alcohol and c-1) group 1 and b-2) containing celluloses and sugar and / or sugar alcohol and c-1) cellulose D) a fast-disintegrating solid preparation comprising a dissolution aid in Group 1 and Z or Group 2;

(2) a) Active ingredient, b-1) Sugar and / or sugar alcohol, c-1) Cellose d) d) Group containing dissolution aid and b-2) Sugar and / or Or a rapidly disintegrating solid preparation comprising sugar alcohol and c-1) a group comprising celluloses;

(3) a) Active ingredient, b-1) sugar and / or sugar alcohol and c-1) group containing cellulose and b-2) sugar sugar Z or sugar alcohol, c-1) A rapidly disintegrating solid preparation comprising celluloses and d) a group comprising a dissolution aid;

(4) a) Active ingredient, b— 1) Sugar sugar Z or sugar alcohol and c-1) Group 1 and b_2) containing sugars and b_2) Sugar and Z or sugar alcohol and c-2) Cellulose A) a rapidly disintegrating solid preparation comprising Group 1 and Group 2 d) a dissolution aid;

(5) The preparation according to the above (1), which is a rapidly disintegrating solid preparation in the oral cavity;

(6) the preparation according to (1), which is a tablet;

(7) The preparation according to (1), which contains 40 to 95 parts by weight of sugar Z or sugar alcohol based on 100 parts by weight of the solid preparation;

(8) The preparation according to the above (1), which contains 0.5 to 40 parts by weight of a cellulose based on 100 parts by weight of the solid preparation;

(9) The preparation according to the above (1), wherein the dissolution aid is contained in an amount of 0.01 to 5 parts by weight per 100 parts by weight of the solid preparation;

(10) One kind of sugar selected from glucose, fructose, lactose, sucrose and trehalose Or two or more preparations according to (1) above;

(11) The preparation according to the above (1), wherein the sugar is lactose;

(12) The preparation according to (1), wherein the sugar alcohol is one or more selected from D-mannitol, erythritol, xylitol, maltitol, and sorbitol;

(13) The preparation according to the above (1), wherein the sugar alcohol is D-mannitol;

(14) The average particle size of sugar or sugar alcohol is 3 μμπ! The preparation according to the above (1), which is from 300 to 300 / in;

(1 5) D-mannitol has an average particle size of 30! The formulation according to the above (13), which has a viscosity of ~ 300 / zm;

(16) The preparation according to the above (1), wherein the cellulose is one or more selected from crystalline cellulose, powdered cellulose, 'low-substituted hydroxypropylcellulose and carmellose;

(17) The preparation according to the above (1), wherein the cellulose is a low-substituted hydroxypropylcellulose;

(18) The dissolution aid is one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic powder, gelatin, methylcellulose, polyvinyl alcohol and pullulan A certain preparation according to the above (1);

(19) The process according to (1), wherein the dissolution aid is hydroxypropylcellulose.

20) The preparation according to the above (1), wherein the active ingredient is manidipine hydrochloride;

21) The preparation according to the above (1), wherein the active ingredient is voglibose;

22) the preparation according to (1), wherein the active ingredient is candesartan cilexetil; (23) the preparation according to (1), wherein the active ingredient is pioglitazone hydrochloride;

24) The formulation according to (1), wherein Group 2 further contains an active ingredient;

25) The preparation according to the above 24), wherein the active ingredient contained in Group 1 and the active ingredient contained in Group 2 are not the same;

26) The preparation according to (1), wherein component b-1) and component b-2) are not the same; (27) The preparation according to (1), wherein component c-1) is not the same as component c-1).

(28) The preparation according to (1), which does not contain a disintegrant selected from crospovidone;

(29) The preparation according to the above (1), wherein the preparation contains low-substituted hydroxypropylcellulose in Groups 1 and Z or Group 2;

(30) The preparation according to the above (1), which is a preventive or therapeutic agent for hypertension or diabetes;

(3 1) a) Active ingredient, b-1) sugar and / or sugar alcohol, c-1) cellulose d) d) group containing dissolution aid and b-2) 'sugar and / or Or a mixture comprising a sugar alcohol and _c- 1) a group comprising celluloses, and compression-molding the mixture.

(3 2) a) Active ingredient, b— 1) sugar and / or sugar alcohol and c— 1) group containing celluloses and b— 2) sugar sugar Z or sugar alcohol, c— 2) Compression-molding a mixture containing celluloses and d) a group containing a dissolution aid, the method for producing the preparation according to (3) above,

(3 3) a) Active ingredient, b-1) sugar and / or sugar alcohol, c-1) celluloses d) dissolution aid for the preparation of the preparation according to (2) above Use of the group comprising and b-2) sugars and / or sugar alcohols and c_2) celluloses;

(34) A group comprising a) an active ingredient, b-1) sugar and ぴ Z or sugar alcohol and c_1) cellulose for the production of the preparation according to (3), and b-2. 2) Use of a group comprising sugar Z or sugar alcohol, c-1) celluloses and d) dissolution aids;

(35) A method for preventing or treating hypertension or diabetes, which comprises administering an effective amount of an active ingredient to a mammal using the preparation according to (1). The active ingredient used in the present invention may be any of solid, crystalline, oily, solution, and the like. For example, nourishing tonic health drug, antipyretic analgesic and anti-inflammatory drug, psychotropic drug, anxiolytic drug, antidepressant drug , Sedative-hypnotics, antispasmodics, central nervous system drugs, cerebral metabolism improvers, cerebral circulation improvers, antiepileptics, sympathetic stimulants, gastrointestinal drugs, antacids, antiulcers, antiseptic, antiemetic Agents, respiratory stimulants, bronchodilators, allergy agents, dental oral agents, anti-hista Mining, cardiotonic, arrhythmic, diuretics, antihypertensives, vasoconstrictors, coronary vasodilators, peripheral vasodilators, hyperlipidemia, cholerics, antibiotics, chemotherapeutics, diabetes Drugs, osteoporosis drugs, antirheumatic drugs, skeletal muscle relaxants, antispasmodics, hormonal drugs, alkyloid drugs, sulfa drugs, gout drugs, anticoagulants, anticancer drugs, etc. One or more components may be used.

Nutrition and tonic health medications include, for example, Vitamin A, Vitamin D, Vitamin E (such as d- _α -tocopherol acetate), Vitamin B 1 (such as dibenzoylthiamine, fursultiamine hydrochloride), and vitamin Β2 (such as riboflavin butyrate) Vitamins such as vitamin Β6 (such as pyridoxine hydrochloride), vitamin C (ascorbic acid, sodium L-ascorbate), and vitamin Β12 (such as hydroxocobalamin acetate and cyanocobalamin), calcium, magnesium, Contains minerals such as iron, proteins, amino acids, oligosaccharides, and crude drugs.

Antipyretic analgesics and anti-inflammatory drugs include, for example, aspirin, acetaminophen, etenzamide, ibuprofen, diphenhydramine hydrochloride, dl-chronorefueuramine maleate, dihydrocodine phosphate, nospin, methylephedrine hydrochloride, fenilpropanol hydrochloride Examples include min, caffeine, anhydrous caffeine, serapeptase, chloridized lysozyme, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminobiline, ketoprofen, indomethacin, pcolome, and pentazocine.

Psychotropic drugs include, for example, chlorpromazine, reserpine and the like. Examples of anxiolytics include alprazolam, chlordazepoxide, diazepam and the like.

Examples of antidepressants include imibramine, maprotiline hydrochloride, amphetamine and the like.

Hypnotic sedatives include, for example, estazolam, nitrazepam, diazepam, perlapine, phenobarbital sodium and the like.

Antispasmodics include, for example, scoboramine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride, and the like.

Examples of central nervous system drugs include citicoline. Examples of the brain metabolism improving agent include meclofenixate hydrochloride and the like. Examples of the cerebral circulation improving agent include vinpocetine.

Examples of antiepileptic agents include phenytoin, carbamazepine and the like.

Examples of the sympathetic stimulant include isoproterenol hydrochloride. Gastrointestinal drugs include, for example, stomach digestives such as diastase, sugar-containing pepsin, funnel extract, cellulase AP3, lipase AP, Keiich oil, intestinal preparations such as berberine chloride, resistant lactic acid bacteria, and bifidobacteria.

Examples of the antacid include magnesium carbonate, sodium hydrogen carbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide, and the like. .

Examples of the anti-ulcer agent include lansoprazole, omebrazole, labebrazole, famotidine, cimetidine, ranitidine hydrochloride and the like.

Antitussive expectorants include, for example, cloperastine hydrochloride, dextromethonolephan hydrobromide, theophylline, guaiacol sulfonic acid potassium, guaifenesin, codine phosphate and the like.

Examples of the antiemetic include difenidole hydrochloride, methoxide pramide and the like.

Examples of the respiratory enhancer include levallorphan tartrate.

Examples of the bronchodilator include theophylline, sulphamol sulfate and the like.

Allergic drugs include amlexanox and seratrodast.

Examples of the oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.

Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isottipendyl hydrochloride, dl-chlorpheniramine maleate, and the like.

Examples of cardiotonic agents include caffeine and digoxin.

Examples of antiarrhythmic agents include proforce inamide hydrochloride, propranolol hydrochloride, Pindolol and the like are included.

Diuretics include, for example, isosorbide, furosemide, hydroclothiazide and the like. .

Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors such as delapril hydrochloride, captopril and perindopril elpmin; vasodilators such as hydralazine hydrochloride; α, / 3 blockers such as labetalol hydrochloride; dicardipine hydrochloride; Ca antagonists such as lupadipine, -fedipine, vedipine hydrochloride, diltiazem hydrochloride, disordipine hydrochloride, nitrendipine, barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besilate, ferodipine, cilnidipine, aranidipine, manidipine hydrochloride, oral sultane Angiotensin II receptor antagonists, such as candesartan, norsartan, telmisartan, irbesartan, olmesartan, tasosanoletan, forcedesenorentan cilexetinole, and sympathetic central depression such as methyldopa Antibiotics and the like.

As the vasoconstrictor, for example, fenirephrine hydrochloride and the like can be mentioned.

Examples of coronary vasodilators include carbochromene hydrochloride, molsidomine, verapamil hydrochloride and the like.

Peripheral vasodilators include, for example, cinnarizine and the like.

Examples of the agent for hyperlipidemia include cerivastatin sodium, simpastatin, pravastatin sodium, atorvastatin calcium hydrate, and the like.

Bile agents include, for example, dehydrocholic acid, trepiptone and the like. Antibiotics include cephalexins, cefaclor, amoxicillin, pipmecillinam hydrochloride, cefotiam hexetil, cephadroxyl, cefixime, cefditoren pivoxil, cefteram pivoxil, cefpodoximiproxetil, etc. Synthetic antibacterial agents such as nalidixic acid and enoxacin; monobatamates such as carmonam sodium; penems; and carbapenem antibiotics.

Examples of the chemotherapeutic agent include sulfamethizole.

Examples of antidiabetic agents include sulfonamides such as tolptamide and glibenclamide. _Α- Darcosidase inhibitors such as urea drugs, acarbose, voglipose, miglitol, and emidalitate; and insulin-sensitizing drugs such as pioglitazone hydrochloride, troglidazone, and rosiglitazone.

Examples of the agent for osteoporosis include ipriflavone and the like.

Examples of the skeletal muscle relaxant include metcarpamol.

Examples of antispasmodic agents include methalizine hydrochloride and dimenhydrinate. Examples of anti-rheumatic drugs include methotrexate and bucillamine. Hormonal agents include, for example, liothyronine sodium, dexamethasone sodium phosphate, prednisolone, oxendrone, leuprorelin acetate, and the like.

Alkyloid-type narcotic drugs include aphen, morphine hydrochloride, tocon, oxycodone hydrochloride, aphen alkaloid hydrochloride, cocaine hydrochloride and the like.

Examples of the sulfa drug include sulfisomidine and sulfamethizole.

Gout remedies include, for example, aloprinol, colchicine and the like. Examples of the anticoagulant include dicoumarol.

Antineoplastic agents include, for example, 5-fluoroperacil, peracil, mitomycin and the like.

Among them, as the active ingredient, mardipine hydrochloride, voglibose, candesartan cilexetil, pioglitazone hydrochloride and the like, particularly, manidipine salt are preferably used.

The active ingredient may be diluted with a diluent or the like generally used in the medical and food fields. Moreover, you may process for the purpose of masking the bitterness of an active ingredient. The amount of the active ingredient used varies depending on the type and dosage of the active ingredient. For example, 0.01 to 40 parts by weight per 100 parts by weight of the solid pharmaceutical preparation of the present invention is preferable. Is from 0.01 to 20 parts by weight.

Examples of the sugar used in the present invention include glucose, fructose, lactose, sucrose, trehalose and the like, and lactose is preferably used.

Examples of the sugar alcohol used in the present invention include D-mannitol and Elis Litol, xylitol, maltitol, sorbitol and the like can be mentioned, and D-mannitol and the like are preferably used.

In addition, sugars and sugar alcohols may be used alone or in combination of two or more, and sugars and sugar alcohols may be used in combination.

The average particle size of the sugar or sugar alcohol (preferably, sugar alcohol, more preferably, D-mannitol) used in the present invention is 1 to 300 / πι (for example, a laser-diffraction particle size distribution analyzer, SYMPATEC Company: measured by HELQS & RODOS, etc.), preferably sugars or sugar alcohols having an average particle size of more than 30 μm, more preferably sugars or sugar alcohols having an average particle size of 31 m or more. Sugar or sugar alcohol having an average particle size of 35 to 200 m is preferably used. Sugars or sugar alcohols having such a particle size are commercially available products (Lactose Granulated Powder Dilactose Scale, Dilactose, Megreja Pan Tablets, Florac 100, Manufactured by Towa Kasei Kogyo Co., Ltd.). and marine Christa Norre, Merck & Co., Inc. of 1.05980, CEL-STAR Japan of Mannidex, trehalose of Asahi chemical industry Co., Ltd.?, sorbitol DP- ⁵ 0M of Towa chemical industry Co., Ltd., Amaruti MR- 50, such as pure fructose S of Kato chemical) Can be obtained as In addition, sugars or sugar alcohols having an average particle size of 5 to 30 im are commercially available products (Dalanulak 230, Solpolak 400, Megrejapan, Mannit P, Xyli Tonore P, Amalti MR-100, Towa Kasei Kogyo Co., Ltd., Japan) It is available as erythritol (fine powder) from Ken Kagaku Co., Ltd., and sugars or sugar alcohols with an average particle size of 200 to 50 ◦μm are commercially available (Sachelac 80 of Megre Japan, Asahi Kasei It can be obtained as trehalose 0, xylitol XC from Kogyo Co., Ltd., erythritol from Niken Kagaku Co., Ltd., anhydrous crystalline glucose TD A-S from Sanei Gyosaido, and hydrous crystalline glucose TDH. .

Commercially available sugars or sugar alcohols with an average particle size of 500 m or more (such as Prismalac 40 of Megre Japan, pure fructose of Kato Chemical, Amalti MR-20 of Towa Kasei Kogyo Co., Ltd., and Sorbitol DP-10M) It can be obtained as To obtain sugar or sugar alcohol with the required average particle size, Can also be prepared. Powdering can be performed using a cutter mill, a jet mill, a hammer mill, or the like.

In addition, a sugar or sugar alcohol having an average particle diameter of 30 to less than 90 Aim for increasing the strength of the molded product and an average particle diameter of 90 m to 50 for improving the fluidity during production. 0 zm (preferably 90 zm to 300 μπι) of sugar or sugar alcohol may be used in combination. Further, a fine sugar or sugar alcohol having an average particle diameter of 30 to less than 90 to 90 μm (preferably an average particle diameter of 35 to 80 xm) and an average particle diameter of 90 μm to 500 μm (preferably When used in combination with a coarse sugar or sugar alcohol having an average particle size of 90 μm to 300 μm, more preferably 90 to 200 μm), 1 part by weight of fine sugar or sugar alcohol is used. Usually, 0.1 to 10 parts by weight of coarse sugar or sugar alcohol is used, preferably 0.2 to 5 parts by weight. In particular, when the active ingredient is manidipine hydrochloride, usually 0.2 to 3.5 parts by weight, preferably 0.3 parts by weight of coarse sugar or sugar alcohol is added to 1 part by weight of fine sugar or sugar alcohol. It is better to use 2.5 parts by weight.

When a combination of fine sugar or sugar alcohol and coarse sugar or sugar alcohol is used, one or more of them may be used in combination, and fine sugar or sugar alcohol may be used in combination with coarse sugar or sugar alcohol. May be the same or different. Further, the mixture of fine sugar or sugar alcohol and coarse sugar or sugar alcohol in the form of powder may be used as a raw material to form the rapidly disintegrating solid preparation of the present invention. Alternatively, the sugar alcohol and the coarse sugar or sugar alcohol may be divided into two or more groups to produce granules or the like, which may then be molded as the rapidly disintegrating solid preparation of the present invention. Fine, sugar or sugar alcohol and coarse! / When a mixture obtained by mixing a sugar or a sugar alcohol in a powder state is used as a raw material, it is desirable that the particle size distribution of the mixture shows two or more peaks, and the average particle diameter of the mixture is , 30 / zm to 300 μπι.

Preferred combinations of fine sugars or sugar alcohols with coarse sugars or sugar alcohols have an average particle size of 30! 990; D-mannitol less than zm D-mannitol having an average particle size of 90 μπι to 300 μπι and the like. The amount of sugar or sugar alcohol to be used is 40 to 95 parts by weight, preferably 50 to 90 parts by weight, per 100 parts by weight of the solid pharmaceutical preparation.

The “sugar and / or sugar alcohol” as the component b—1) in one group and the “sugar and / or sugar alcohol” as the component b_2) in the other group are the same. May also be different.

As the celluloses, for example, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, carmellose, and the like (preferably low-substituted hydroxypropylcellulose, etc.) are used, and the amount used is 100 parts by weight of the solid pharmaceutical preparation. The amount is 0.5 to 40 parts by weight, preferably 1 to 20 parts by weight.

Specific examples of the crystalline cellulose include, for example, CEOLUS KG801, CEOLUS KG802, Avicel PH101, PH102, PH301, PH302, PH-F20, Avicel RC-A591NF (all manufactured by Asahi Kasei Corporation). However, what is called microcrystalline cellulose is also included.

Specific examples of low-substituted hydroxypropylcellulose include, for example, low-substituted hydroxypropylcellulose LH11, LH21, LH31, LH22, LH32, LH20, LH30, LH32, LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.) And low-substituted hydroxypropylcellulose having a hydroxypropoxyl group content of 5 to 16% by weight. These are commercially available. Alternatively, it can be produced by a known method, for example, the method described in JP-B-57-53100 or a method analogous thereto.

The active ingredient and celluloses may be used alone or in combination of two or more.

Group 2 may further contain an active ingredient, and the active ingredient contained in one group and the active ingredient contained in the other group may be the same or different. — "Cellulose" as component c-1) in one group and "Cellulose" as component c-1) in the other group may be the same or different .

The elution aid may be any as long as it can adjust or regulate the elution of the active ingredient.For example, even if it promotes the elution of an active ingredient with a slow elution, It may be one that suppresses rapid elution of the active ingredient. Examples of the dissolution aid include, for example, hydroxypine pinoresenorelose, hydroxypropinolemethinolecellulose, polyvinylpyrrolidone, gum arabic powder, gelatin, methylcellulose, polyvinyl alcohol, pullulan and the like (preferably hydroxy Propylcellulose) is used in an amount of 0.01 to 5 parts by weight, preferably 0.1 to 2 parts by weight, more preferably 0.2 to 100 parts by weight of the solid pharmaceutical preparation. ~ 1 part by weight.

Generally, when the dissolution aid has a binding force and is uniformly distributed inside the tablet, the tablet hardness increases and the disintegration property in the oral cavity deteriorates. Therefore, by preparing the group containing the dissolution aid and the group not containing the elution aid, it is possible to have rapid oral disintegration properties. Further, when both Group 1 and Group 2 contain an active ingredient, both Group 1 and Group 2 may contain an elution aid. Here, when both Group 1 and Group 2 contain the dissolution aid, the dissolution aid contained in one group and the dissolution aid contained in the other group are different even if they are the same. You may. When the dissolution aid contained in one group is the same as the dissolution aid contained in the other group, the content of the dissolution aid in one group is the same as the content of the dissolution aid in the other group. Or different.

When developing a commercially available product containing the same active ingredient as the existing active ingredient (a formulation that is not an orally disintegrating tablet; for example, a tablet) as an orally disintegrating tablet, it is necessary to maintain the efficacy and safety of the active ingredient. For this reason, it is preferable to make the dissolution behavior of the active ingredient of the commercially available product and the orally disintegrating tablet the same.

The formulation of the present invention is preferably a formulation that does not contain a disintegrant that gels in saliva, for example, a formulation that does not contain a disintegrant selected from carmellose calcium, sodium carboxymethyl starch, cross force, crospovidone, and the like. Among them, a preparation containing no crospovidone as a disintegrant is preferable.As the preparation of the present invention, a preparation containing low-substituted hydroxypropyl cellulose in Group 1 and / or Group 2 is preferable. More preferred are formulations containing low-substituted hydroxypropyl cellulose in Groups 1 and 2. Here, the low-substituted hydroxypropyl celluloses in Groups 1 and 2 may be the same or different. Good.

When low-substituted hydroxypropylcellulose is used as the cellulose, In this case, in the preparation of the present invention, low-substituted hydroxypropylcellulose can also act as an elution aid. Therefore, as long as the object of the present invention is achieved, the use of the other leaching aids described above can be omitted.

In addition, as long as the effects of the invention are not hindered, the formulation of the present invention may be used as a corn starch, potato starch, wheat starch, rice starch, partially-alpha-starched starch, alpha-mono-starch, perforated starch, etc. Starches and various additives used in the production of general preparations. Examples of such additives include excipients, acidulants, foaming agents, artificial sweeteners, flavors, lubricants, coloring agents, stabilizers, pH adjusters, surfactants, and the like.

Examples of the excipient include inorganic excipients such as anhydrous calcium phosphate, precipitated calcium carbonate, canolecidium silicate, and light silicic anhydride.

Examples of the sour agent include citric acid, tartaric acid, malic acid, and ascorbic acid.

Examples of the foaming agent include sodium bicarbonate, sodium carbonate, and the like.

Examples of the sweetener include saccharin sodium, glycyrrhizinni potassium, aspartame, stevia, thaumatin, and acesulfame potassium.

Examples of the flavor include lemon oil, orange oil, and menthol. Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, polyethylene dalicol, talc, stearic acid, and stearyl sodium fumarate.

Examples of the coloring agent include food colors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, etc., food lake colors, iron sesquioxide and the like.

Examples of the stabilizing agent include sodium edetate, tocopherol, cyclodextrin and the like.

Examples of the pH adjuster include citrate, phosphate, carbonate, tartrate, fumarate, acetate, and amino acid salt.

As surfactants, for example, sodium radium sulfate, polysorbate 80, hard Oil, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like.

There is no particular limitation on the particle size of these excipients, but it is preferable that the particle size be less than 500 μηη, which is less likely to give a rough feeling in the oral cavity. Any one of these excipients may be used, or two or more excipients may be used in combination. When the solid preparation of the present invention is produced, fine-grained nuclei may be used, and after such nuclei are coated with an active ingredient, an additive or the like, masking of taste and odor, entericizing or It may be coated by a known method for the purpose of sustained release.

As a method for producing the solid preparation of the present invention, for example,

① a) active ingredient, b-1) sugar and Z or sugar alcohol, c-1) celluloses d) group 1 and b- 2) sugar and / or sugar alcohol and c containing dissolution aid — 2) Mix Group 2 containing celluloses, mix celluloses, fluidizers, lubricants, sweeteners, fragrances, etc. in an appropriate amount, if necessary, and press-mold; ② a) Active ingredient , B— 1) sugar cane Z or sugar alcohol and c-1) group 1 and b—2) sugar cane containing Z or sugar alcohol, c—2) cellulose and d) Mix Group 2 containing dissolution aids, mix appropriate amounts of celluloses, superplasticizers, lubricants, sweeteners, flavorings, etc., if necessary, and press-mold. Can be

Here, any of Group 1 and Group 2 (preferably, Group 1 containing the active ingredient) is preferably granules, and more preferably both are granules.

Further, the solid preparation of the present invention may be a mononuclear preparation in which group 1 forms an internal phase and group 2 forms an external phase.

As a specific production method, tablet granules are prepared by wet granulation of the active ingredient and the drug substance using water, acetone, ethyl alcohol, propyl alcohol or a mixture thereof in which a binder is dispersed or dissolved. A method for preparing tablet granules in two or more separate groups, or dispersing the Group 2 ingredients in water, acetone, ethyl alcohol, propyl alcohol or a mixture thereof, and then coating the Group 1 tablet granules. To produce mononuclear tablet granules consisting of an internal phase and an external phase And the like.

When manufacturing a preparation from granules for tablets, celluloses, disintegrants, fluidizers, lubricants, flavors, sweeteners and the like may be mixed as necessary.

Tablets are formed by using, for example, a single-shot tableting machine or a rotary tableting machine. The pressure during tableting is usually 2.5 to 30 kN m. Although the shape of the solid preparation of the present invention is not particularly limited, it may be in the form of a round, caplet, donut, oblong or the like, and may be a laminated tablet, a dry coated tablet, or the like. You can also. Marks and characters for discrimination, and dividing lines for division may also be added.

The rapidly disintegrating solid preparation of the present invention, preferably an intraorally fast disintegrating solid preparation, obtained by force shows rapid disintegration in the oral cavity and dissolves in the same manner as a commercial product containing the same active substance Show behavior. The effect of various ionic components on the elution of the active ingredient is small. In addition, it shows moderate formulation strength. In addition, it shows excellent manufacturability.

That is, the dissolution time in the mouth of the orally disintegrating tablet of the present invention (the time until the tablet completely breaks down with the saliva in the mouth of healthy adult males and females) differs depending on the size and thickness of the tablet. Usually, it is about 5 to 90 seconds, preferably about 5 to 60 seconds. The hardness (measured by a tablet hardness tester) is usually about 10 to 200, preferably about 10 to 15 ON.

Therefore, the orally disintegrating tablet of the present invention contains a drug component as a tablet that is easy to take for patients, elderly people, and children who have difficulty swallowing the drug, and as a safe preparation for emergency of general adults. It can be used for the treatment and prevention of various diseases as well as conventional pharmaceutical preparations, and has excellent long-term storage and stability.

This formulation can be taken without disintegration in the oral cavity or taken with water. The preparation can be taken after dispersing in water or the like in a cup or the like. Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but these do not limit the present invention.

The tablets obtained in Examples, Reference Examples and Comparative Examples were tested for tablet hardness and hardness by the following test methods. And oral disintegration time were measured.

(1) Hardness test

It was measured using a tablet hardness tester (manufactured by Toyama Sangyo Co., Ltd.). The test is performed with 3 or 5 tablets, and the average value is shown.

(2) Oral disintegration time

The time required for the tablet to disintegrate with only oral saliva was measured by three healthy adult males.

(3) Dissolution test

Each tablet is placed in a 90 OmL test solution adjusted to pH 4 using 0.4 mol / L sodium monohydrogen phosphate and 0.2 mol / L citric acid, and the rotation speed is 50 rpm, 37 ° C. After sampling at, the sample was filtered, the absorbance at 350 nm was measured with a spectrophotometer, and the amount of eluted manidipine hydrochloride was calculated (n = 3). Example 1

4480 g of manidipine hydrochloride, lactose granulated powder (Freund Corporation) 131 56 g, corn starch 660 g, low-substituted hydroxypropylcellulose (Shin-Etsu Chemical: LH-31) FD-S type 2), sprayed with 9284 g of purified water containing 44 Og of hydroxypropylcellulose (Nippon Soda) and 44 g of yellow iron sesquioxide, and granulated and dried. I got Next, the granulated product A was sized using a power mill (Showa Chemical Machinery Works, P-3S) with a screen size (1.2πιηιφ) to obtain a sized product. On the other hand, D-mannitol (Towa Kasei: Mannit S) 86 14 g, D-mannitol tonore (Menorek: 1.005980) 4514 g, low-substituted hydroxypropyl cellulose (Shin-Etsu Chemical: LH-11) 1438 g Into a fluidized-granulation dryer (Powrex, FD-S2 type), and spray 521 5 g of purified water containing 460 g of D-mannitol, 144 g of anhydrous citrate and 11.5 g of yellow iron sesquioxide. Then, a granulated product B was obtained through a granulating and drying process. Next, the granulated product B was sized using a power mill at a screen size (1.2πιπιφ) to obtain a sized product.

1800 g of sized product A, 2376 g of sized product B, 248 g of crystalline cellulose, 9.0 g of Aspartame, and 67.5 g of magnesium stearate were mixed. The mixed powder was tableted at 250 mg per tablet (Kikusui Seisakusho, Collect 19K AWC, tablet size 9.5 mm, compression pressure 5.4 kN / cm ² ).

Example 2

A fluidized granulating dryer (PAREX,? 0-32) was prepared by mixing 2660 g of manidipine hydrochloride, 131 g of lactose granulated powder, 131 g of corn starch, 559 g of corn starch and 1995 g of low-substituted hydroxypropylcellulose (LH-31) ), And sprayed with 7727 g of purified water containing 266 g of hydroxypropylcellulose and 13 g of yellow iron sesquioxide, followed by granulation and drying steps to obtain granules C. Next, the granulated product C was sized using a power mill with a screen size (1.2 mm <|)) to obtain a sized product C.

On the other hand, 9585 g of D-mannitol (Mannit S), 5053 g of D-mannitol (Merck: 1.005980), and 1418 g of low-substituted hydroxypropylcellulose (Shin-Etsu Chemical: LH-11) Granulation dryer (PAREC, FD-S2 type) is charged and sprayed with 6089 g of purified water containing 540 g of D-mannitol, 142 g of citric anhydride and 6.8 g of yellow iron sesquioxide, and granulated. After a drying step, a granulated product D was obtained. Next, the granulated product D was sized using a power mill at a screen size (1.2πιπιφ) to obtain a sized product D.

1259 g of the sized product C, 2233 g of the sized product D, 224 g of crystalline cellulose, 7.6 g of aspartame, and 56.7 g of magnesium stearate were mixed.

The mixed powder was tableted at 21 Omg per tablet (Kikusui Seisakusho, collect 19K AWC, tablet size (J size 9. Οπιπιφ, compression pressure 6.5 kN / cm ² ) _Q

Example 3

Fluidized granulation dryer (Fuji Sangyo, FD-5S) 600 g of merdipine hydrochloride, 1644 g of lactose granulated powder, 90 g of corn starch, and 600 g of low-substituted hydroxypropylcellulose (LH-31) Then, 1266 g of purified water containing 60 g of hydroxypropylcellulose and 6 g of yellow iron sesquioxide was atomized and subjected to granulation and drying steps to obtain granules E. Next, the granulated product E was sized using a power mill with a screen size (0.8πιπιφ) to obtain a sized product E.

On the other hand, D-mannitol (mannit S) 21 21 g, D-mannitol (Merck: 1.005980) 111 g, carboxymethyl cellulose (Gotoku Pharmaceutical: NS-300) 563 g was charged into a fluidized-granulation dryer (Fuji Sangyo, FD-5S type), and purified water 1356 containing D-mannitol (120 g), anhydrous citrate (30 g) and yellow iron sesquioxide (6 g) was added. g was sprayed, and a granulated product E was obtained through a granulating and drying process. Next, the granulated material F was sized using a power mill with a screen size (0.8πιπιφ) to obtain a sized granulated material F.

Granulated product 物 10 g, Granulated product F1 3.2 g, crystalline cellulose 1.38 g, aspartame 0.055 g, and magnesium stearate 0.38 g were mixed.

The mixed powder was tableted at 250 mg per tablet (universal testing machine, tablet size 9.5πιιηφ, compression pressure 5.3 kN / cm ² ).

Reference example 1

Dissolution tests were performed using commercially available Calslot tablets (2 Omg) (Lot No. 581).

Reference example 2

Dissolution tests were performed using commercially available Calslot tablets (1 Omg) (Lot No. 559).

Comparative Example 1

100 g of manidipine hydrochloride, 21 1 g of lactose granulated powder, and 23.5 g of corn starch are charged into a fluidized granulation dryer (Bowlec, LAB—! Type), and purified water containing 1.1 g of yellow iron sesquioxide 201 g were sprayed, and a granulated product G was obtained through a granulating and drying process. D-Mannitole (Mannit S) 10234 g, D-Mannitole (Merk: 1 · 05980) 591 3 g, Crospovidone 892 g, fluidized granulation dryer (Parek, FD-S2) ), And sprayed with 6074 g of purified water containing 538 g of D-man-tol, 134 g of anhydrous citrate and 26.9 g of yellow iron sesquioxide. I got Next, the granulated material H was sized using a power mill with a screen size (1.2 lηιηφ) to obtain a sized particle Η.

Granulated product G 3.4 g., Sized product H 8.25 g, crystalline cellulose 0.69 g, aspartame 0.025 g, and magnesium stearate 0.19 g were mixed.

The mixed powder was tableted at 250 mg per tablet (universal testing machine, tablet size: 9.5ηιπιφ, compression pressure: 5.4 kN / cm ² ). Comparative Example 2

952 g of manidipine hydrochloride, 1369 g of lactose granulated powder, 212 g of corn starch, and 302 g of crospovidone were charged into a fluidized granulation dryer (PAREC, FD-5S type), and 204 g of hydroxypropylcellulose and yellow powder were added. 4290 g of purified water containing 2 g of iron dioxide was sprayed, and a granulation G was obtained through a granulation and drying steps. Next, the granulated product I was sized using a power mill (Showa Chemical Machinery Works, P-3S) with a screen size (1.2ηιπιφ) to obtain a sized product I.

On the other hand, 2856 g of D-mannitol (Towa Kasei: Mannit S), 1650 g of D-mannitol (Menorek: 1.005980), and 249 g of crospovidone were flowed and granulated (Palek, Model 0-53). ), Spray 150 g of purified water containing 150 g of D-mantol, 37.5 g of citric anhydride and 7.5 g of yellow iron sesquioxide, granulate through granulation and drying processes I got the thing J. Next, the granulated product J was sized using a power mill with a screen size (1.2 lηιηφ) to obtain a sized product Η. The sized product I (804 g), the sized product J (1980 g), crystalline cellulose (165 g), aspartame (6.0 g), and magnesium stearate (45 g) were mixed.

The mixed powder was tableted at 250 mg per tablet (Kikusui Seisakusho, Collect 19K, tablet size 9.5πιπιφ, compression pressure 5.2 kN / cm ² ).

Tables 1 and 2 show the results showing the dissolution rate of manidipine hydrochloride eluted by each time after the start of the dissolution test of the tablets obtained in Examples, Reference Examples and Comparative Examples by the above-mentioned test method. The dissolution from the tablets produced in Examples 1 and 3 was similar to that of Reference Example 1, whereas the dissolution from the tablets produced in Comparative Examples 1 and 2 was lower than that of Reference Example 1. Showed a trend.

The dissolution from the tablet produced in Example 2 was similar to that of Reference Example 2. table 1 Ginseng fruit

Time (minutes)

β ^ 0 10 15 30 45 60

Example 23 211 1 0 22.3 32.7 46.8 54.9 62.4

Example 3 0 24.2 37.6 48.7 56.4 60.2

Reference example 1 0 18.5 31.2 47.8 56.5 61.6

Comparative Example 1 0 8 1 1.4 19.8 27.9 36.4

Comparative Example 2 0 14 19.7 32 39.6 45.5

Table 2 Time (minutes)

0 10 20 30 45 60

Example 2 0 35.8 52.7 62.9 73.1 83.1

Reference example 2 0 20.1 48 64.1 75.8 81

Table 3 shows the results obtained by measuring the hardness and the oral disintegration time of the tablets obtained in Examples and Comparative Examples by the above-mentioned test methods. The hardness of the tablets produced in Examples 1 to 3 was 29 to 33 (N), which showed rapid disintegration in the oral cavity, whereas the tablets of Reference Examples 1 and 2 exhibited disintegration in the oral cavity. Did not exfoliate. Table 3

Hardness (N) Oral disintegration time (sec)

31.2 32.3

33.3 30

29.4 25

59 Does not collapse

81.8 Does not collapse Industrial availability

The rapidly disintegrating solid preparation of the present invention obtained by forcing, and preferably the rapidly disintegrating solid preparation in the oral cavity, exhibits rapid disintegration in the oral cavity and dissolves in the same manner as a commercial product containing the same active substance Show behavior. The effect of various ionic components on the elution of the active ingredient is small. In addition, it shows moderate formulation strength. In addition, it shows excellent manufacturability.

Claims

The scope of the claims

1. a) Active ingredients, b-1) Sugar and / or sugar alcohol and c-1) Cellulose containing groups 1 and b-2) Sugar and Z or sugar alcohol and c-1) Cellulose And d) a rapidly disintegrating solid preparation comprising a dissolution aid in Group 1 and / or Group 2.

2. a) Active ingredients, b-1) sugar and / or sugar alcohol, c-1) cellulose and d) group containing elution aid and b-2) bran and / or sugar alcohol and c-1 2) A rapidly disintegrating 'solid preparation comprising a group comprising celluloses.

3. a) Active ingredient, b-1) sugar and / or sugar alcohol c-1) group containing celluloses and b-2) sugar Z or sugar alcohol, c-1 ) Cellulose and d) a group containing a dissolution aid.

4. a) Active ingredients, b-1) sugar and / or sugar alcohols c_1) groups 1 and b-2) containing celluloses and sugars and / or sugar alcohols and c-2) A rapidly disintegrating solid preparation comprising Group 2 comprising celluloses and Group 1 and Group 2 containing d) an elution aid.

5. The preparation according to claim 1, which is a solid preparation rapidly disintegrating in the oral cavity.

6. The preparation according to claim 1, which is a tablet.

7. The preparation according to claim 1, wherein the preparation contains 40 to 95 parts by weight of sugar and / or sugar alcohol based on 100 parts by weight of the solid preparation.

8. The preparation according to claim 1, comprising 0.5 to 40 parts by weight of a cellulose based on 100 parts by weight of the solid preparation.

9. The preparation according to claim 1, wherein the dissolution aid is contained in an amount of 0.01 to 5 parts by weight based on 100 parts by weight of the solid preparation.

10. The preparation according to claim 1, wherein the sugar is one or more selected from pudose, fructose, lactose, sucrose and trehalose.

1 1. The preparation according to claim 1, wherein the sugar is lactose.

12. The preparation according to claim 1, wherein the sugar anocol is one or more selected from D-mannitol, erythritol, xylitolone, manoletitol and sorbitol.

13. The preparation according to claim 1, wherein the sugar alcohol is D-mannitol.

14. The preparation according to claim 1, wherein the average particle size of the sugar or sugar alcohol is 30 µm to 300 µm.

1 5. The average particle size of D-mannitol is 30 μπ! The formulation according to claim 13, wherein the formulation is from 300 to 300 Atm.

16. The preparation according to claim 1, wherein the cellulose is one or more selected from crystalline cellulose, powdered cellulose, low-substituted hydroxypropyl cellulose, and carmellose.

1 7. The preparation according to claim 1, wherein the cellulose is low-substituted hydroxypropylcellulose.

18. The dissolution aid is one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gum arabic, gelatin, methylcellulose, polyvinyl alcohol and pullulan. The preparation according to claim 1, wherein

19. The preparation according to claim 1, wherein the dissolution aid is hydroxypropylcellulose.

20. The preparation according to claim 1, wherein the active ingredient is manidipine hydrochloride.

21. The formulation according to claim 1, wherein the active ingredient is voglipose.

22. The formulation according to claim 1, wherein the active ingredient is force desartan cilexetil.

23. The preparation according to claim 1, wherein the active ingredient is pioglitazone hydrochloride.

24. The formulation of claim 1, wherein Group 2 further comprises an active ingredient.

25. The formulation according to claim 24, wherein the active ingredient contained in Group 1 and the active ingredient contained in Group 2 are not the same.

26. The formulation of claim 1, wherein component b-1) and component b-2) are not the same.

27. The formulation of claim 1, wherein component c-1) and component c-1) are not the same.

28. The formulation according to claim 1, which does not contain crospovidone.

29. Group 1 and Z or Group 2 contain low substituted hydroxypropylcellulose The preparation of claim 1, wherein

30. The preparation according to claim 1, which is a preventive or therapeutic agent for hypertension or diabetes.

3 1. a) Active ingredient, b-1) sugar and / or sugar alcohol, c_1) celloses and d) group containing elution aid and b-2) sugar and no or sugar 3. The method for producing a pharmaceutical preparation according to claim 2, wherein a mixture containing alcohol and c-1) is formed by compression molding.

3 2. a) Active ingredient, b-1) Sugar and / or sugar alcohol and c-1) 1) Cellulose-containing group and b_2) Sugar salt Z or sugar alcohol, c-1 4. The method for producing a pharmaceutical preparation according to claim 3, wherein a mixture containing the cellulose containing d) and a group containing a dissolution aid is subjected to compression molding.

3 3. Contains no a) active ingredient, b-1) sugar and / or sugar alcohol, c-1) celluloses d) dissolution aid for the manufacture of the preparation of claim 2. And b_2) sugars or sugar alcohols and c_2) a group comprising celluloses.

34. A group comprising a) an active ingredient, b_l) sugar and Z or sugar alcohol and c-1) cellulose and b-2) sugar and (2) Cellulose, d) Use of a group containing a dissolution aid.

3 5. A method for preventing or treating hypertension or diabetes, comprising administering an effective amount of an active ingredient to a mammal using the preparation according to claim 1.