RU2359671C2 - Method of obtaining of preparation with covering - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutical chemistry, namely to the method of obtaining of a medical product with a covering from a Pioglitazone hydrochloride which can be used as a therapeutic agent for treatment of diabetes, lipidemias, and also can be an antihypertensive agent, an antiobesity agent, diuretic or an antithrombotic agent.

EFFECT: medical product covered with a hydrochloride pioglitazon, possesses larger stability of an agent at storage, and also improved properties, such as solubility of a Pioglitazone hydrochloride.

11 cl, 30 ex, 3 tbl

Description

FIELD OF THE INVENTION

The present invention relates to a method for producing a drug coated with pioglitazone hydrochloride, which can be used as a therapeutic agent for diabetes and the like.

State of the art

The following pharmaceutical compositions have been reported including an insulin sensitizer, such as a thiazolidinedione compound and the like, and biguanide:

1. A pharmaceutical agent comprising an insulin sensitizer in combination with at least one of the group comprising an α-glucosidase inhibitor, an aldose reductase inhibitor, biguanide, a statin compound, a squalene synthesis inhibitor, a fibrate compound, an LDL (low density lipoprotein) catabolism enhancer, and an angiotensin inhibitor a converting enzyme (see EP-749751 A).

2. A pharmaceutical composition comprising an insulin sensitizer, a biguanide antihyperglycemic agent, and a pharmaceutically acceptable carrier (see WO 98/57634).

3. A pharmaceutical composition comprising thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein thiazolidinedione is on the surface of metformin hydrochloride (see WO 01/35940).

4. A pharmaceutical composition comprising thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein the thiazolidinedione and metformin hydrochloride are dispersed in their own pharmaceutically acceptable carriers (see WO 01/35941).

5. A core composition comprising (a) a first layer consisting of pioglitazone hydrochloride or a pharmaceutically acceptable salt thereof as an active component, and (b) a core containing biguanide as an active component in which at least a portion of the core is coated with the aforementioned first layer (see WO 01/82875).

6. The composition of the core, including the first layer containing pioglitazone hydrochloride, which covers at least a portion of the core containing biguanide, in which the core and the first layer or only one of them are dispersed in a controlled release agent such as polysaccharides and the like (see USP 6403121).

Description of the invention

The present invention relates to a method for producing a preparation coated with pioglitazone hydrochloride, which can be used as a therapeutic agent for diabetes and the like and would have greater storage stability, improved properties, such as the solubility of pioglitazone hydrochloride.

The inventors of the present invention have found that by preparing a preparation coated with pioglitazone hydrochloride, it is possible to achieve improved dissolution ability of pioglitazone hydrochloride (especially the ability to dissolve during the first 15 minutes of the solubility test) by applying an aqueous dispersion of pioglitazone hydrochloride containing a coating material with a low viscosity. The authors carried out further studies based on this discovery, which led to the implementation of the present invention.

Thus, the present invention relates to:

1) to a method for producing a coated preparation, which consists in applying an aqueous dispersion of pioglitazone hydrochloride containing a coating material with a low viscosity;

2) to a coated preparation obtained in accordance with the above production method 1);

3) to the above production method 1), where the coating material with a low viscosity in a 5% aqueous solution exhibits a viscosity of not more than 35 MPa · s at 20 ° C;

4) to the above production method 1), where the coating material with a low viscosity is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or a graft copolymer of polyvinyl alcohol and polyethylene glycol;

5) to the above production method 1), where the core containing the active substance is coated with an aqueous dispersion of pioglitazone hydrochloride containing a coating material with a low viscosity;

6) to the above production method 5), where the active substance is a therapeutic agent for diabetes;

7) to the above production method 6), wherein the therapeutic agent for diabetes is biguanide;

8) to the above production method 7), where the biguanide is metformin hydrochloride;

9) to the above production method 5), where the active substance is a therapeutic agent for hyperlipidemia;

10) to the above production method 9), where the therapeutic agent for the treatment of hyperlipidemia is an HMG-CoA reductase inhibitor;

11) a method for improving the solubility of pioglitazone hydrochloride from a preparation coated with pioglitazone hydrochloride, wherein said preparation process comprises coating with an aqueous dispersion of pioglitazone hydrochloride containing a coating material with a low viscosity;

12) to a coated preparation obtained in accordance with the above production method 1) from which at least 50% of pioglitazone hydrochloride is released during the first 15 minutes of the solubility test by the rotational grid method using a buffer solution of hydrochloric acid and potassium chloride (pH 2 , 0) as a control solution at 37 ° C and 100 rpm;

13) to a coated preparation obtained in accordance with the above production method 1), from which at least 50% of pioglitazone hydrochloride is released during the first 15 minutes of the solubility test by the paddle mixer method using a buffer solution of hydrochloric acid and potassium chloride (pH 2 , 0) as a control solution at 37 ° C, 50 rpm; etc.

The average particle size of pioglitazone hydrochloride used in the present invention is preferably 0.5-500 microns, more preferably 1-150 microns.

The aqueous dispersion used in the present invention is an aqueous solution or an aqueous suspension.

The concentration of pioglitazone hydrochloride in the aqueous dispersion is, for example, 1-25% (w / w), preferably 1-15% (w / w). A concentration within these limits is preferred in order to improve coating, standardize the content of pioglitazone hydrochloride in the resulting coated preparation, and the like.

An “aqueous dispersion of pioglitazone hydrochloride” (hereinafter sometimes abbreviated to “dispersion of the present invention”) includes a coating material with a low viscosity.

In the present description, a coating material with a low viscosity means, for example, a coating material whose viscosity of a 5% (w / v) aqueous solution is not more than 35 MPa · s (preferably not more than 30 MPa · s, more preferably not more than 25 MPa · s) at 20 ° С. The value of the viscosity of the coating material can change with changing concentration of the coating material in an aqueous solution, measurement conditions, for example, temperature measurement and the like. Coating materials whose viscosity index under modified measurement conditions does not go beyond the above limits set for a 5% (w / v) aqueous solution at 20 ° C are considered as “low viscosity coating materials” of the present invention.

As a “low viscosity coating material”, for example, hydroxypropyl cellulose (class: SL, SSL (trademark); Nippon Soda Co., Ltd.); hydroxypropyl methylcellulose (class: MW, E, EW (trademark); Shin-Etsu Chemical Co., Ltd.) (class: E-3 (trademark); Nippon Soda Co., Ltd.); premix (class: SSM (trademark), Nippon Soda Co., Ltd.) of hydroxypropyl cellulose (class: SSL, Nippon Soda Co., Ltd.) and hydroxypropyl methylcellulose (class: E-3); graft copolymer of polyvinyl alcohol and polyethylene glycol [Kollicoat IR (trademark), BASF, Germany] and the like.

The above coating material may be a mixture of two or more of the above listed in appropriate proportions. If the mixture for the coating material obtained by mixing in the appropriate proportions of one or more of the above coating materials and one or more of the coating materials with high viscosity is a “coating material whose viscosity is 5% (w / v) of an aqueous solution of not more than 35 MPa · s at 20 ° C ", such a mixture can be used as the" coating material with low viscosity "according to the present invention. Here, by “coating material with a high viscosity” is meant, for example, a coating material whose viscosity is 5% (w / v) of an aqueous solution of more than 35 MPa · s at 20 ° C. Specific examples thereof include hydroxypropylcellulose (class: L (trademark); Nippon Soda Co., Ltd.) (class: Klucel LF (trademark); Aqualon (USA)); hydroxypropyl methylcellulose (class: R (trademark); Shin-Etsu Chemical Co., Ltd.); etc.

A coating material with a low viscosity preferably comprises hydroxypropyl cellulose SL (viscosity of 5% aqueous solution at 20 ° C: approximately 24 mPa · s; and / or viscosity of 2% aqueous solution at 20 ° C: 3.0-5.9 mPa · c) SSL hydroxypropyl cellulose (viscosity of 5% aqueous solution at 20 ° C: approximately 8 mPa · s; and / or viscosity of 2% aqueous solution at 20 ° C: 2.0-2.9 MPa · s), graft copolymer polyvinyl alcohol and polyethylene glycol [Kollicoat IR (trademark), BASF, Germany] (viscosity of a 5% aqueous solution at 20 ° C: approximately 18 mPa · s) and the like.

The coating material with low viscosity can be obtained in the form of a solution or suspension in the dispersed system of the present invention. For greater efficiency, to obtain a coated preparation that would be better for the uniformity of the pioglitazone hydrochloride contained therein and for the hardness of the preparation, it is preferable to dissolve the coating material in the dispersion system of the present invention.

The dispersion system of the present invention, in addition, may include additional coating means. Such additional coating agents include light-shielding and / or coloring agents, such as, for example, titanium oxide, talc, iron oxide and the like; plasticizers, such as polyethylene glycol, triethyl citrate, castor oil, polysorbates and the like; organic acids, such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; lactose, D-mannitol, low substituted hydroxypropyl cellulose, calcium carmellose, crospovidone and the like.

For cases where the additional coating agent is insoluble in water, it is preferable that the average particle size thereof be not more than 500 microns, more preferably not more than 150 microns, particularly preferably not more than 75 microns. Thanks to the use of an additional coating agent having the indicated average particle sizes, it is possible to achieve high results in preparing a coated preparation that would be characterized by a high degree of uniformity of the pioglitazone hydrochloride contained therein and the hardness of the preparation itself.

The concentration of the low viscosity coating material in the dispersion system of the present invention is, for example, 1-30% (w / w), preferably 1-25% (w / w), more preferably 2-25% ( wt./wt.). Concentrations within these ranges are preferred in order to increase the effectiveness of the coating, the uniformity of the pioglitazone hydrochloride coated in the resulting preparation, and the like.

The concentration of the additional coating agent in the dispersion system of the present invention is, for example, 0.2-35% (w / w), preferably 0.2-30% (w / w), more preferably 0.5 -15% (w / w). Concentrations within these ranges are preferred in order to increase the effectiveness of the coating, the uniformity of the pioglitazone hydrochloride coated in the resulting preparation, and the like.

As the core, the base for coating with an aqueous dispersion of pioglitazone hydrochloride containing a coating material with a low viscosity (hereinafter sometimes referred to as the core of the present invention), solid preparations such as tablets, capsules, granules, powder, lozenges, etc. like that. The solid form may be a controlled release preparation, for example, an immediate release preparation or a sustained release preparation and the like. The solid preparation may include additives customary in pharmaceutical practice and may be prepared by any well-known method. As additives, mention may be made, for example, of an excipient, a disintegrating agent, a binding agent, a lubricant, a dye, a pH adjuster, a surfactant, a release agent, a stabilizer, an acidifier, a flavoring agent, an swallowing agent, and the like like that. These additives are used in amounts generally accepted in pharmaceutical fields.

As examples of the excipient, starch, such as corn, potato, wheat, rice, partially pre-gelatinized starch, pre-gelatinized starch, porous starch and the like; sugars and sugar alcohols such as lactose, fructose, glucose, D-mannitol, sorbitol and the like; anhydrous calcium phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like.

As an example of a disintegrating agent, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl starch and the like can be mentioned. The amount of disintegrant used is preferably 0.5-25 parts by weight, more preferably 1-15 parts by weight per 100 parts by weight of the preparation in solid form.

As an example of a binder, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, gum arabic powder and the like can be mentioned. The amount of binder used is preferably 0.1-50 parts by weight, more preferably 0.5-40 parts by weight per 100 parts by weight of the preparation in solid form.

Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate and the like.

As an example of a dye, food coloring such as food yellow No. 5, food red No. 2, food blue No. 2 and the like, food grafts, iron oxide and the like can be mentioned.

As an example of a pH regulator, citrates, phosphates, carbonates, tartrates, fumarates, acetates, amino acid salts and the like can be mentioned.

As an example of a surfactant, sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) -polyoxypropylene (30) -glycol and the like can be mentioned.

Examples of a release agent include cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, (preferably hydroxypropyl methyl cellulose 2910, hydroxypropyl methyl cellulose 2208 and the like), cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40% ), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, ethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose in the form of crystalline cellulose and volume u like that; sodium alginate, carboxyvinyl polymer; acrylic acid polymers such as copolymer of aminoalkyl methacrylate RS [Eudragit RS (trademark), Rohm Pharma], a suspension of a copolymer of methyl methacrylate and ethyl acrylate [Eudragit NE (trademark), Rohm Pharma] and the like. The release inhibitor may, for example, include a flux diluent (for example, sodium chloride, potassium chloride, sucrose, sorbitol, D-mannitol, polyethylene glycol (preferably polyethylene glycol 400 and the like), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl hydroxypropyl cellulose cellulose, polyvinyl alcohol, methacrylic acid polymer), plasticizers (e.g. triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerol, sorbitol, diethyl oxalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacetate, triethyl citrate, tributyl citrate triterite, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate, tri tributyl citrate or tributyl citrate Preferred examples of release retarding agents include (1) a semi-permeable film coating containing cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400 and the like) and triacetin ; (2) a slow release composition comprising sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose 2910, hydroxypropyl methyl cellulose 2208 and microcrystalline cellulose; etc.

As the stabilizer, for example, tocopherol, tetrasodium salt of ethylenediaminetetraacetic acid, nicotinamide, cyclodextrins and the like.

As the acidifying agent, for example, ascorbic acid, citric acid, tartaric acid, malic acid and the like can be mentioned.

As flavoring agents, mention may be made, for example, of menthol, peppermint oil, lemon oil, vanillin and the like.

As swallowing agents, mention may be made, for example, of partially dehydrated silicic acid, hydrated silicon dioxide and the like.

The above additives can be used as a mixture of two or more of them, taken in appropriate proportions.

The core of the present invention preferably contains an active substance. Among the active substances of the present invention, therapeutic agents for diabetes, for complications caused by diabetes, therapeutic agents for hyperlipidemia, blood pressure lowering agents, obesity drugs, diuretics, antithrombotic agents and the like can be mentioned. These active substances may be a low molecular weight compound, a high molecular weight protein, a polypeptide or antibody, a vaccine or the like. The active substance may be a mixture of two or more components, taken in appropriate proportions.

Such use of a core containing the active substance of the present invention gives the best results, namely: 1) an increase in the action of pioglitazone hydrochloride or the active substance (synergistic effect of the action of the pharmaceutical agent), 2) a decrease in the dose of pioglitazone hydrochloride or the active substance (effect of reducing the dose of the pharmaceutical agent regarding the introduction of only one drug), 3) a decrease in side effects (for example, weight gain, ketosis, acidosis) of pioglitazone hydrochloride or active substance and the like.

Examples of therapeutic agents for diabetes include insulin preparations (e.g., animal insulin preparations obtained from the pancreas of cattle, pigs; human insulin preparations synthesized by genetic engineering using the Escherichia coil or yeast; zinc-insulin, protamine-zinc -insulin; insulin fragments or derivatives (e.g., INS-1 and so on) and the like), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably hydrochloride ), rosiglitazone or its salt (preferably maleate), GI-262570, reglixan (JTT-501), netoglitazone (MCC-555), YM-440, KRP-297, CS-011, FK-614, the compounds described in W099 / 58510 (e.g. (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid), ragaglitazar (NN-622), tezaglitazar (AZ-242) , BMS-298585, ONO-5816, LM-4156, BM-13-1258, MBX-102, GW-1536, LY-519818 and so on), α-glucosidase inhibitors (e.g., voglibose, acarbose, miglitol, emiglate and so on), biguanides (e.g., phenformin, metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate) and so on), stimulant secretion of insulin [sulfonylureas (for example, tolbutamide, glibenclamide, glyclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glibuzol and so on), repaglinide, nateglinide, calcium hydrate-salt, etc. or dipeptidyl peptidase IV inhibitors (e.g., NVP-DPP-278, PT-100, NVP-DDP-728, LAF237, etc.), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307 , SB-226552, AJ-9677, BMS-196085, AZ-40140 and so on), amylin agonists (e.g. pramlintide and so on), phosphothyrosine phosphatase inhibitors (e.g. sodium vanadate and so on alley), gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase, glucagon antagonists, etc.) and inhibitors SGLUT (sodium-glucose cotransporter) (e.g., T-1095 etc.).

Examples of therapeutic agents for diabetes complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), CT-112 and so on), neurotrophic factors (e.g. NGF, NT-3 , BDNF and so on), neurotrophin production-secretion promoters [for example, neurotrophin production-secretion promoters described in WO 01/14372 (eg 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) - 5- (3- (2-methylphenoxy) propyl) oxazole and the like)], PKC inhibitors (eg, LY-333531 and so on), AGE inhibitors (n for example, ALT946, pimagedin, piratoxanthin, N-phenacylthiazolium bromide (ALT766), EXO-226 and so on), absorbers of active oxygen (for example, lipoic acid and so on) and cerebral vasodilators (for example, tiapride, mexiletine and so on).

Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, cerivastatin, itavastatin, rosuvastatin (ZD-4522) or their salts (e.g., sodium salts and so on) and so on), fibrate compounds (for example, bezafibrate, beclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pyrifibrate, ronifibrate, inifibrate, simfibrate, simfibrate, squalene synthase inhibitors (e.g., compounds described in WO 97/10224 (e.g., 1 - [[(3R, 53) -1- (3-acetoxy-2,2-dimethylpropyl) -7-chloro-5- (2,3 -dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidin-4-acetic acid and so on), ACAT inhibitors (e.g. Avasimibe, Eflucimibe and etc.), anion exchange resins (e.g., colestyramine, etc.), probucol, nicotinic acid medicines (e.g., nicomol, niceritrol, etc.), ethyl acosapentate, plant sterols (e.g., soy sterol, γ-oryzanol, etc.). d Leia) and the like.

Examples of drugs used in the treatment of hypertension include angiotensin-converting enzyme inhibitors (e.g. captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g. candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, irbesartan so on), calcium antagonists (e.g., manidipine, nifedipine, nicardipine, amlodipine, efonidipine and so on), potassium channel activators (e.g., levcromacalim, L-27152, AL 0671, NIP-121 and so on), clonidine and the like .

Examples of anti-obesity drugs include agents that affect the central nervous system (e.g., dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibitors (e.g., orlistat and β3 agonists (e.g. CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140 and so on), peptic drugs that reduce appetite (e.g. leptin, CNTF (ciliary neurotrophic factor) and so on), cholecystokinin agonists (e.g. lint trypt, FPL-15849 etc.) and the like.

Examples of diuretics include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine and so on), thiazide preparations (e.g., etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, pentazlithide, pithazlithide, pithazlithide, pentazlithide, pentazlithide anti-aldosterone preparations (e.g., spironolactone, triamteren, etc.), carbonate dehydratase inhibitors (e.g., acetazolamide, etc.), chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruzide, inda amide, etc.), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of antithrombotic agents include heparin (e.g., sodium-heparin, calcium-heparin, sodium-dalteparin, and so on), warfarin (e.g., potassium-warfarin, and so on), antithrombin drugs (e.g., aragatroban, etc.), thrombolytic agents ( for example, urokinase, tizokinase, alteplase, nateplase, monteplase, pamiteplase and so on), platelet aggregation inhibitors (e.g. ticlopidine hydrochloride, cilostazol, ethyl acosapentate, beraprost sodium, sarpogrelate hydrochloride, etc. and so on).

The active substance is preferably a therapeutic agent for diabetes, more preferably biguanide, particularly preferably metformin or a salt thereof (preferably metformin hydrochloride).

In addition, the therapeutic agent used for hyperlipidemia is also preferred as the active substance. HMG-CoA reductase inhibitor is more preferred as a therapeutic agent for hyperlipidemia. Especially preferred is simvastatin and the like.

The amount of active substance in the core of the present invention is, for example, 0.1-100 parts by weight, preferably 1-99 parts by weight per 100 parts by weight of the core of the present invention.

The core of the present invention, preferably, is a tablet containing the active substance (preferably a therapeutic agent for diabetes, more preferably biguanide, particularly preferably metformin hydrochloride). The shape of the tablet can be any, from round to droplet-like, oblong and the like. These tablets can be obtained, for example, by mixing or granulating the active substance together with the above additives, followed by compression molding of the mixture or granules obtained after mixing according to one of the methods conventional in pharmaceutical production.

Here, the mixing is carried out using, for example, a mixer such as a V-type mixer, a drum mixer and the like; and granulation is carried out using, for example, a high-speed mixer-granulator, fluidized bed granulator and the like. In compression molding, stamping is usually carried out under a pressure of 5-35 kN / cm ² on a tablet machine with one punch, a rotary tablet machine and the like.

In the case where the active substance contained in the core of the present invention is not a pharmaceutical agent intended for single administration during the day (and, for example, a pharmaceutical agent for administration twice or thrice a day), a core containing said active substance is preferably is a sustained release drug.

In the case where pioglitazone hydrochloride is poorly compatible with the active substance contained in the core of the present invention, the core containing the active substance can be coated with the above coating material and the like.

The core of the present invention, more preferably, is a sustained release preparation (preferably in tablet form) comprising a biguanide (preferably metformin hydrochloride). An example of such a preparation is a tablet with a controlled-release pharmaceutical agent described in WO 99/47125, a two-layer controlled-release delivery system described in WO 99/47128, an oral controlled-release pharmaceutical agent described in USP 6340475 and the like.

As a sustained release preparation containing biguanide, preferred is

(1) a biguanide-containing tablet coated with a semipermeable membrane coating that contains cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400 and the like) and triacetin (said semipermeable membrane the coating may have a hole or pore);

(2) a tablet obtained by mixing a sustained release composition containing sodium carboxymethyl cellulose, 2910 hydroxypropyl methyl cellulose, 2208 hydroxypropyl methyl cellulose and crystalline cellulose, with biguanide, followed by compression molding of the mixture, and the like.

In accordance with the production method of the present invention, the coating is performed according to one of the conventional methods. For example, coating is performed using a film coating device.

In addition, the coating is carried out in such a way that the core of the present invention is usually 50-99 parts by weight, preferably 70-99 parts by weight, more preferably 70-98 parts by weight per 100 parts by weight of the resulting coated preparation.

Moreover, a “preparation coated with pioglitazone hydrochloride” obtained in accordance with the preparation method of the present invention (sometimes abbreviated here to be coated with the invention) can be coated in order to increase the hardness of the preparation, correct the bitter taste, enhance light fastness, for coloring etc. Such a coating can be applied by any well-known method, using, for example, the aforementioned coating materials and the like.

As an example of a coated dosage form, a tablet, capsule, granule, powder, lozenge and the like can be mentioned. A preferred coated dosage form is a tablet. It can be of any shape, from round and drop-shaped to oblong and the like. In addition, an icon or letter may be extruded onto the tablet for better identification and a dividing line may be drawn for ease of separation.

The amount of active substance in a coated preparation of the present invention is usually, for example, 0.01-99 parts by weight, preferably 0.1-99 parts by weight per 100 parts by weight of the coated preparation. In particular, in cases where the active substance is a biguanide (preferably metformin hydrochloride), the amount of this biguanide in a coated preparation, for example, is usually 5-98 parts by weight, preferably 15-96 parts by weight per 100 parts by weight coated drug.

The amount of pioglitazone hydrochloride in a coated preparation of the present invention, for example, is usually 0.01-30 parts by weight, preferably 0.5-25 parts by weight, more preferably 0.5-10 parts by weight per 100 parts by weight weight of the drug coated.

The coated preparation of the present invention can be administered orally, which is safe, to various mammals (e.g., mouse, rat, rabbit, cat, dog, cattle, horse, monkey, human, and the like).

The coated preparation of the present invention is best for its properties such as the solubility of pioglitazone hydrochloride (in particular, the ability to dissolve after administration into the body or within 15 minutes of the solubility test) and the like, and can be used as a prophylactic or therapeutic agent for treating, for example, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), used for hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia) hypo-HDL -emia that occurs after eating hyperlipidemia and so on), with impaired glucose tolerance (IGT), with complications caused by diabetes (e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, for infectious diseases (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, soft tissue infections of the skin, infectious disease of the lower extremities, and so on), for diabetic gangrene, xerostomia, incidents, cerebrovascular disorders, peripheral circulation disorders, and so on], with obesity, osteoporosis, cachexia (eg, cancer cachexia, tuberculous cachexia, diabetic cachexia, cachexia for blood diseases, cachexia for endocrine diseases, cachexia, cachexia, due to acquired immunodeficiency syndrome), with fatty liver, hypertension, polycystic ovary syndrome, kidney disease (e.g., diabetic nephropathy, lomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, the final stage of kidney disease and so on), with muscular dystrophy, myocardial infarction, angina pectoris, acute cerebrovascular accident (for example, cerebral infarction, cerebral apoplexy), with X syndrome of resistance to , hyperinsulinemia, loss of sensitivity caused by hyperinsulinemia in neoplasms (e.g., leukemia, breast cancer, prostate cancer, skin cancer, etc.), irritable bowel syndrome, acute sludge and chronic diarrhea, inflammatory diseases [for example, Alzheimer's disease, chronic rheumatoid arthritis, deforming spondylosis, deforming osteoarthritis, lumbago, gout, inflammatory processes of postoperative or traumatic origin, tumor remission, neuralgia, pharyngolaryngitis, cystitis, non-hepatopathy (including hepatitis) with pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis and so on], with visceral obesity syndrome, arteriosclerosis (for example , Atherosclerosis, etc.) and the like.

The coated preparation of the present invention can also be used for secondary prophylaxis (e.g., secondary prophylaxis of an attack of a disease of the cardiovascular system such as myocardial infarction, etc.) and to prevent the progression of the disease in the above cases (e.g., preventing the development of impaired glucose tolerance in diabetes, preventing the progression of arteriosclerosis in diabetic patients).

The daily dose of the coated preparation of the present invention is 7.5-60 mg / day, preferably 15-60 mg / day, more preferably 15-45 mg / day, based on the amount of pioglitazone hydrochloride per adult (body weight 60 kg).

When a coated preparation of the present invention is prepared using a core containing an active substance, this coated preparation preferably contains an effective amount of the active substance. For example, the effective amount in cases where the active substance is biguanide (preferably metformin hydrochloride) is 125-2550 mg / day, preferably 250-2550 mg / day per adult (weighing 60 kg). Further, the effective amount in cases where the active substance is an inhibitor of HMG-CoA reductase (preferably simvastatin, atorvastatin calcium, fluvastatin sodium) is 1-100 mg / day, preferably 5-80 mg / day per adult (body weight 60 kg).

The coated preparation of the present invention can be used in combination with one or more pharmaceuticals selected from the therapeutic agents for diabetes, therapeutic agents for complications of diabetes, therapeutic agents for hyperlipidemia, antihypertensive drugs, anti-obesity drugs, diuretics, anti-thrombotic agents and the like. (hereinafter abbreviated as concomitant medications). The active substances listed above as examples can be used as such concomitant medications. The time of administration of the coated drug of the present invention, as well as the time of administration of the concomitant medication, is not limited; they can be administered to the patient simultaneously or with a time shift. The dosage of concomitant medication is determined appropriately based on clinically tested doses. In addition, the ratio of the components in the mixture, the coated preparation of the present invention and the concomitant medication is determined depending on the patient to be administered, the route of administration, the disease to be treated, the condition, combination and the like. For example, if the patient is a woman, then the concomitant medication can be used in an amount of 0.01-100 parts by weight per 1 part by weight of the coated drug.

The use of a concomitant medication in this way can provide the best results, namely: 1) enhancing the effect of a coated drug of the present invention or the effect of a concomitant drug (synergistic effect on the effects of pharmaceutical agents), 2) reducing the dose of a coated drug of the present invention or concomitant drugs (the effect of reducing the dose of pharmaceutical agents compared with the introduction of one drug), 3) reducing the side effects of the coated drug of the present invention s or concomitant medication (for example, weight gain, ketosis, acidosis) and the like.

The present invention also relates to a “method for increasing the dissolution of pioglitazone hydrochloride from a preparation coated with pioglitazone hydrochloride, which comprises, for preparing said preparation, coating with an aqueous dispersion of pioglitazone hydrochloride containing a coating substance with a low viscosity."

Due to the application of the preparation method in accordance with the present invention, upon the preparation of a preparation coated with pioglitazone hydrochloride, a high degree of solubility (in particular, the ability to dissolve immediately after administration to the body or within 15 minutes from the start of the solubility test) of pioglitazone hydrochloride in a coated preparation can be achieved .

In addition, the present invention relates to a “coated preparation prepared in accordance with the production method of the present invention, which releases at least 50% of pioglitazone hydrochloride within a 15 minute solubility test using a rotational grid method using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as a control solution at 37 ° C and 100 rpm. " As is customary here, the solubility test is carried out according to the method described in the 14th edition of the Japanese Pharmacopoeia. A "buffer solution of hydrochloric acid and potassium chloride (pH 2.0)" used as a control solution can be obtained by any of the known methods. The amount of buffer solution of hydrochloric acid and potassium chloride used as a control solution is usually 900 ml.

"A coated preparation obtained by the production method in accordance with the present invention, which releases at least 50% of pioglitazone hydrochloride within 15 minutes of the solubility test by the rotational grid method using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as a control solution at 37 ° C and 100 rpm, "can be administered orally and completely safely to mammals (eg, mouse, cat, rat, rabbit, dog, bull, horse, monkey, human and the like) for sure same as the aforementioned coated preparation of the present invention, when the disease to be treated, the dose and the like are the same as the aforementioned coated preparation of the present invention.

In addition, the present invention relates to a “coated preparation obtained in accordance with the production method of the present invention, which releases at least 50% of pioglitazone hydrochloride within a 15 minute solubility test using a paddle mixer using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as a control solution at 37 ° C and 50 rpm. " As is customary here, the solubility test is carried out according to the method described in the 14th edition of the Japanese Pharmacopoeia. A "buffer solution of hydrochloric acid and potassium chloride (pH 2.0)" used as a control solution can be obtained by any of the known methods. The amount of buffer solution of hydrochloric acid and potassium chloride used as a control solution is usually 900 ml.

"A coated preparation obtained by the production method in accordance with the present invention, which releases at least 50% of pioglitazone hydrochloride within a 15 minute solubility test using a paddle mixer using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as control solution at 37 ° C and 50 rpm, "can be administered orally and completely safely to mammals (eg, mouse, cat, rat, rabbit, dog, bull, horse, monkey, human and the like) for sure ak same as the above-mentioned preparation of coated according to the present invention, where the disease being treated, the dose, and the like are the same as in the above preparation coated with the present invention.

The present invention is explained in detail in the following examples, reference examples, comparative examples and experimental examples, which should not be construed as limiting.

As preparative additives (e.g., D-mannitol, corn starch, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, lactose, hydroxypropyl methyl cellulose, polyethylene glycol 6000, titanium oxide, low-substituted hydroxypropyl cellulose, talc, carboxymethyl examples, reference examples, calcium examples, reference examples, examples, apply those that meet the standards of the 14th edition of the Japanese Pharmacopoeia. As for triethyl citrate, yellow iron oxide, iron oxide and an aqueous dispersion of ethyl cellulose, those that meet the standards of Japanese pharmaceutical excipients (1998) are used.

Example 1

Hydroxypropyl cellulose (26.4 g, class: SSL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 8 mPa s), polyethylene glycol 6000 (1.32 g), titanium oxide (2, 64 g) and pioglitazone hydrochloride (16.5 g) are dispersed in water (297 g) to obtain a coating solution.

The tablets (300 g) obtained in Reference Example 1 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. to obtain a coated preparation with a tablet weight of 260.9 mg.

Example 2

Hydroxypropyl cellulose (24 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 24 mPa · s), polyethylene glycol 6000 (1.2 g), titanium oxide (2.4 g ) and pioglitazone hydrochloride (15 g) are dispersed in water (344.7 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 75 ° C. to obtain a coated preparation with a tablet weight of 381 mg.

Example 3

Hydroxypropyl cellulose (24 g, class: SSL, Nippon Soda Co., Ltd.) (viscosity of 5% aqueous solution at 20 ° C: 8 mPa · s), polyethylene glycol 6000 (1.2 g), titanium oxide (2.4 g ) and pioglitazone hydrochloride (15 g) are dispersed in water (344.7 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 75 ° C. to obtain a coated preparation with a tablet weight of 382 mg.

Example 4

Hydroxypropyl methylcellulose (24 g, class: MW, Shin-Etsu Chemical Co. Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 21 mPa · s), polyethylene glycol 6000 (1.2 g), titanium oxide (2.4 g) and pioglitazone hydrochloride (15 g) are dispersed in water (310 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. to obtain a coated preparation with a tablet weight of 382 mg.

Example 5

Hydroxypropyl methylcellulose (24 g, class: EW, Shin-Etsu Chemical Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 12 mPa s), polyethylene glycol 6000 (1.2 g), titanium oxide (2, 4 g) and pioglitazone hydrochloride (15 g) are dispersed in water (344.7 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. to obtain a coated preparation with a tablet weight of 382 mg.

Example 6

Graft copolymer of polyvinyl alcohol and polyethylene glycol (24 g, brand: Kollicoat IR, BASF, Germany) (viscosity of a 5% aqueous solution at 20 ° C: 18 mPa · s), titanium oxide (2.4 g) and pioglitazone hydrochloride ( 15 g) are dispersed in water (200 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 75 ° C. to obtain a coated preparation with a tablet weight of 380.5 mg.

Example 7

Hydroxypropyl cellulose (48.0 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 24 mPa s), polyethylene glycol 6000 (2.4 g), titanium oxide (4, 8 g) and pioglitazone hydrochloride (30.0 g) are dispersed in water (540 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 4 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 90 ° C. to obtain a coated preparation with a tablet mass of 459 mg.

Example 8

Graft copolymer of polyvinyl alcohol and polyethylene glycol (48.0 g, brand: Kollicoat IR, BASF, Germany) (viscosity of a 5% aqueous solution at 20 ° C: 18 mPa · s), polyethylene glycol 6000 (2.4 g) in oxide titanium (4.8 g) and pioglitazone hydrochloride (30.0 g) are dispersed in water (540 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 4 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 90 ° C. to obtain a coated preparation with a tablet weight of 461 mg.

Example 9

Graft copolymer of polyvinyl alcohol and polyethylene glycol (18.0 g, trademark: Kollicoat IR, BASF, Germany) (viscosity of a 5% aqueous solution at 20 ° C: 18 mPa · s), titanium oxide (1.8 g), low-substituted hydroxypropyl cellulose (3.6 g, brand:

L-HPC 31, Shin-Etsu Chemical Co. Ltd.) and pioglitazone hydrochloride (11.3 g) are dispersed in water (207 g) to obtain a coating solution.

The tablets (30 tablets) obtained in Reference Example 5 and the tablets (240 g, approximately 800 tablets) obtained in Reference Example 3 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 95 ° C. Based on the appearance of the obtained tablets, a coated preparation (479 mg per tablet) containing the tablet obtained in Reference Example 5 as a core is selected.

Example 10

Hydroxypropyl cellulose (24.0 g, class: SSL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 8 mPa s), polyethylene glycol 6000 (1.2 g), titanium oxide (2, 4 g) and pioglitazone hydrochloride (15.0 g) are dispersed in water (350 g) to obtain a coating solution.

Glucophage XR tablets (brand name, 30 tablets, sustained release tablet containing 500 mg of metformin hydrochloride) (Bristol-Myers Squibb Company) and tablets (250 g) obtained in Reference Example 3 are loaded into a film coating device (Hicoater- Mini, Freund Industrial Co. Ltd.) and are coated using the above coating solution at an inlet temperature of 70 ° C. Based on the appearance of the obtained tablets, coated preparations are selected (weight per tablet: 1.086 g) containing Glucophage XR tablets as a core and containing metformin hydrochloride 500 mg / pioglitazone hydrochloride 16.53 mg per tablet.

Example 11

Graft copolymer of polyvinyl alcohol and polyethylene glycol (36.0 g, brand: Kollicoat IR, BASF, Germany) (viscosity of a 5% aqueous solution at 20 ° C: 18 mPa · s), titanium oxide (3.6 g) and hydrochloride pioglitazone (22.5 g) is dispersed in water (300 g) to obtain a coating solution.

Glucophage XR tablets (brand name, 30 tablets, sustained release tablet containing 500 mg of metformin hydrochloride) (manufactured by Bristol-Myers Squibb Company) and tablets (250 g) obtained in Reference Example 3 are loaded into a film coating device (Hicoater -Mini, Freund Industrial Co. Ltd.) and are coated using the above coating solution at an inlet temperature of 70 ° C. Based on the appearance of the obtained tablets, coated preparations are obtained (weight per tablet: 1.082 g) containing Glucophage XR tablets as a core and containing metformin hydrochloride 500 mg / pioglitazone hydrochloride 16.53 mg per tablet.

Example 12

Hydroxypropyl cellulose (24.0 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 24 mPa s), polyethylene glycol 6000 (1.2 g), titanium oxide (2, 4 g) and pioglitazone hydrochloride (15.0 g) are dispersed in water (350 g) to obtain a coating solution.

Lipovas 20 tablets (brand name, 30 tablets, Banyu Pharmaceutical Co., Ltd., major axis 14.0 mm, minor axis 7.5 mm, weight 400 mg) containing simvastatin as an active substance, and tablets (250 g) obtained in Reference Example 9 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. Based on the appearance of the obtained tablets, coated preparations are obtained (mass per tablet: 449 mg) containing simvastatin 20 mg / pioglitazone hydrochloride 17.78 mg per tablet.

Example 13

Hydroxypropyl cellulose (72 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 24 mPa · s), polyethylene glycol 6000 (3.6 g), titanium oxide (7.2 g ) and pioglitazone hydrochloride (45 g) are dispersed in water (1050 g) to obtain a coating solution.

The tablets (30 tablets) obtained in Reference Example 10 and the tablets (250 g) obtained in Reference Example 9 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above solution coatings at an inlet temperature of 80 ° C. Based on the appearance of the obtained tablets, coated preparations are obtained (mass per tablet: 349 mg) containing simvastatin 15 mg / pioglitazone hydrochloride 16.25 mg per tablet.

Example 14

Hydroxypropyl cellulose (72 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 24 mPa · s), polyethylene glycol 6000 (3.6 g), titanium oxide (7.2 g ) and pioglitazone hydrochloride (45 g) are dispersed in water (1050 g) to obtain a coating solution.

The tablets (30 tablets) obtained in Reference Example 11 and the tablets (250 g) obtained in Reference Example 9 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above solution coatings at an inlet temperature of 80 ° C. Based on the appearance of the obtained tablets, coated preparations (mass per tablet: 349 mg) containing atorvastatin calcium 21 mg / pioglitazone hydrochloride 16.93 mg per tablet are obtained.

Reference Example 1

D-mannitol (2176 g) and corn starch (918 g) are loaded into a fluidized bed granulator (FD-3S, manufactured by POWREX CORPORATION) and granulated while spraying an aqueous solution (1700 g) containing hydroxypropyl cellulose (102 g), s the subsequent stage of drying to obtain granules. Microcrystalline cellulose (160.2 g) and magnesium stearate (32 g) are added to the obtained granular powder (3012 g) and mixed. The resulting granular powder mixture was tabletted on a tabletting machine (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) (tablet size: 8.5 mm diameter, compression pressure 9 kN / stroke) to obtain tablets weighing 244 mg each.

Reference Example 2

Lactose (2470 g), corn starch (315 g) and calcium carmellose (157.5 g) are loaded into a fluidized bed granulator (FD-3S, manufactured by POWREX CORPORATION) and granulated while spraying an aqueous solution (1575 g) containing hydroxypropyl cellulose (94.5 g), followed by a drying step to obtain granules. Calcium carmellose (89.3 g) and magnesium stearate (17.9 g) are added to the obtained granular powder (2868 g) and mixed. The resulting granular powder mixture was tabletted on a tabletting machine (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) (tablet size: major axis 12 mm, minor axis 7 mm, compression pressure 15 kN / impact) to obtain tablets weighing 350 mg each.

Reference Example 3

Lactose (1976 g), corn starch (252 g) and calcium carboxymethyl cellulose (126 g) are loaded into a fluidized bed granulator (FD-3S, manufactured by POWREX CORPORATION) and granulated while spraying an aqueous solution (1260 g) containing hydroxypropyl cellulose ( 75.6 g), followed by a drying step to obtain granules. Calcium carboxymethyl cellulose (71.4 g) and magnesium stearate (14.3 g) are added to the obtained granular powder (2294 g) and mixed. The resulting granular powder mixture was tabletted on a tablet machine (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) (tablet size: 9 mm diameter, compression pressure 7 kN / stroke) to give tablets with a weight of 300 mg each.

Reference Example 4

The tablets (400 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using a coating solution containing an aqueous dispersion of ethyl cellulose (trademark: Aquacoat, Asahi Kasei Corporation, 148.2 g), talc (2.2 g), triethyl citrate (13.3 g), yellow iron oxide (0.36 g) and water (231.1 g), at an inlet temperature of 90 ° C, this produces tablets weighing 391 mg each. The tablets are then coated with a solution of hydroxypropyl methylcellulose (47.3 g), polyethylene glycol 6000 (9.5 g), titanium oxide (6.3 g) and iron oxide (0.09 g) in water (473 g) under conditions similar to above, receiving tablets with a mass of 416 mg each.

Reference Example 5

The tablets (400 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using a coating solution containing an aqueous dispersion of ethyl cellulose (trademark: Aquacoat, Asahi Kasei Corporation, 74.1 g), talc (1.1 g), triethyl citrate (6.7 g), yellow iron oxide (0.18 g) and water (115.6 g), at an inlet temperature of 58 ° C, this gives tablets with a mass of 381 mg each. The tablets are then coated with a solution of hydroxypropyl methylcellulose (47.3 g), polyethylene glycol 6000 (9.5 g), titanium oxide (6.3 g) and iron oxide (0.09 g) in water (473 g) under conditions similar to above, receiving tablets with a mass of 429 mg each.

Reference Example 6

Hydroxypropyl cellulose (26.4 g, class: L, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 42 mPa s), polyethylene glycol 6000 (1.32 g), titanium oxide (2, 64 g) and pioglitazone hydrochloride (16.5 g) are dispersed in water (297 g) to obtain a coating solution.

The tablets (300 g) obtained in Reference Example 1 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. to obtain a coated preparation with a tablet weight of 262.1 mg.

Reference Example 7

Hydroxypropyl cellulose (24 g, class: L, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 42 MPa · s), polyethylene glycol 6000 (1.2 g), titanium oxide (2.4 g ) and pioglitazone hydrochloride (15 g) are dispersed in water (344.7 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 75 ° C. to obtain a coated preparation with a tablet weight of 382 mg.

Reference Example 8

Hydroxypropyl methylcellulose (24 g, class: R, Shin-Etsu Chemical Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 40 mPa s), polyethylene glycol 6000 (1.2 g), titanium oxide (2, 4 g) and pioglitazone hydrochloride (15 g) are dispersed in water (270 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 2 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. to obtain a coated preparation with a tablet weight of 381.2 mg.

Reference Example 9

Lactose (41160 g), corn starch (5250 g) and calcium carmellose (2625 g) are loaded into a fluidized bed granulator (FD-WSG-60, manufactured by POWREX CORPORATION) and granulated while spraying an aqueous solution (31510 g) containing hydroxypropyl cellulose (1575 g), followed by a drying step to obtain granules. Calcium carmellose (1491 g) and magnesium stearate (298.2 g) are added to the obtained granular powder (47910 g) and mixed. The resulting granular powder mixture was tabletted on a tabletting machine (Correct 19K, Kikusui Seisakusho Ltd.) (tablet size: diameter 7 mm, compression pressure 5.7 kN / stroke) to give tablets weighing 105 mg each.

Reference Example 10

Lipovas 5 mg tablets (brand name, Banyu Pharmaceutical Co., Ltd., 100 mg), containing simvastatin as the active substance, are ground into powder in a mortar, and 300 mg of ground powder, corresponding to 15 mg of simvastatin, are tabletted using a universal test devices (Shimadzu Corporation, UH-10A) (compression pressure 9.5 kN / impact) using a stamping punch with R, diameter 9.0 mm, and a stamping die to produce 30 tablets.

Reference Example 11

5 mg Lipitor tablets (trademark, Yamanouchi Pharmaceutical Co., Ltd., weight approximately 72 mg) containing atorvastatin calcium as an active substance were ground into a powder in a mortar and 300 mg of powdered powder corresponding to 21 mg of atorvastatin calcium were tabletted with using a universal testing device (Shimadzu Corporation, UH-10A) (compression pressure 9.5 kN / impact), using a stamping punch with R, diameter 9.0 mm, and a stamping matrix, to obtain 30 tablets.

Comparative Example 1

Hydroxypropyl cellulose (48.0 g, class: L, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 42 mPa s), polyethylene glycol 6000 (2.4 g), titanium oxide (4, 8 g) and pioglitazone hydrochloride (30.0 g) are dispersed in water (540 g) to obtain a coating solution.

The tablets (250 g) obtained in Reference Example 4 are loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 90 ° C. to obtain a coated preparation with a tablet mass of 459 mg.

Reference Example 2

Hydroxypropyl cellulose (48.0 g, class: L, Nippon Soda Co., Ltd.) (viscosity of a 5% aqueous solution at 20 ° C: 42 mPa s), polyethylene glycol 6000 (2.4 g), titanium oxide (4, 8 g) and pioglitazone hydrochloride (30.0 g) are dispersed in water (700 g) to obtain a coating solution.

Lipovas-20 tablets (brand name, 30 tablets, Banyu Pharmaceutical Co., Ltd., major axis 14.0 mm, minor axis 7.5 mm, weight 400 mg) containing simvastatin as an active substance, and tablets (250 g ) obtained in Reference Example 9 is loaded into a film coating device (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated using the above coating solution at an inlet temperature of 70 ° C. Based on the appearance of the obtained tablets, coated preparations are obtained (weight per tablet: 445 mg) containing simvastatin 20 mg / pioglitazone hydrochloride 16.23 mg per tablet.

Experimental Example 1

The coated preparations obtained in the above examples are evaluated for the solubility of pioglitazone hydrochloride using a rotational grid method (100 rpm) using a 0.3 M buffer solution of hydrochloric acid and potassium chloride (900 ml, 37 ° C, pH 2.0) . The results are shown in table 1.

Table 1 Solubility (%) of pioglitazone hydrochloride Time 15 minutes 30 minutes 45 minutes 60 minutes Example 10 60.6 77.4 84.3 88.3 Example 11 71.2 78.1 84.7 86.9

As follows from table 1, the coated preparation obtained in accordance with the production method of the present invention is superior to others in the ability to dissolve pioglitazone hydrochloride.

Experimental Example 2

The coated preparations obtained in the above examples and comparative examples are evaluated for the solubility of pioglitazone hydrochloride according to the method with a paddle mixer (50 rpm) using 0.3 M buffer solution of hydrochloric acid and potassium chloride (900 ml, 37 ° C, pH 2.0). The results are shown in table 2.

table 2 Solubility (%) of pioglitazone hydrochloride Time 15 minutes 30 minutes 45 minutes 60 minutes Example 7 62.0 76.5 83.5 86.2 Example 8 80.6 89.4 91.5 91.5 Comparative Example 1 29.9 44,2 55.8 65.3

As follows from table 2, the coated drug of the present invention is superior to others in the ability to dissolve pioglitazone hydrochloride.

Experimental Example 3

The coated preparations obtained in the above examples and comparative examples are evaluated for the solubility of pioglitazone hydrochloride in a manner analogous to experimental example 2. The results are shown in table 3.

Table 3 Solubility (%) of pioglitazone hydrochloride Time 15 minutes 30 minutes 45 minutes 60 minutes Example 12 66,2 92.5 97.9 98.8 Reference Example 2 33.8 68.6 83,2 90.6

As follows from table 3, the coated drug of the present invention is superior to others in the ability to dissolve pioglitazone hydrochloride.

Industrial application

The coated preparation obtained by the method in accordance with the present invention can be used as a therapeutic agent for diabetes and the like, by its characteristics, such as the ability to dissolve pioglitazone hydrochloride (in particular, the ability to dissolve immediately after administration to the body or within 15 minutes of solubility test), and in its ability to maintain its hardness and the like, it is superior to others (drugs).

In addition, in accordance with the production method of the present invention, preparations coated with pioglitazone hydrochloride can be easily obtained. In addition, the production method of the present invention is convenient as an industrial production method for mass production of the aforementioned coated preparations.

Claims (14)

1. A method for producing a coated drug, comprising coating a core with an aqueous dispersion of pioglitazone hydrochloride containing a coating material selected from the group consisting of
(a) hydroxypropyl cellulose, whose 5% (w / v) aqueous solution has a viscosity of not more than 35 MPa · s at 20 ° C., and
(b) a grafted copolymer and polyvinyl alcohol polyethylene glycol, whose 5% (w / v) aqueous solution has a viscosity of not more than 35 MPa · s at 20 ° C,
moreover, the core includes an active substance, which is a therapeutic agent for diabetes, a therapeutic agent for complications of diabetes, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic or antithrombotic agent. 2. The coated drug obtained in accordance with the production method according to claim 1. 3. The production method according to claim 1, where the hydroxypropyl cellulose is a hydroxypropyl cellulose SL or hydroxypropyl cellulose SSL. 4. The production method according to claim 1, where the active substance is a therapeutic agent for the treatment of diabetes. 5. The production method according to claim 4, where the therapeutic agent for diabetes is biguanide. 6. The production method according to claim 5, where the biguanide is metformin hydrochloride. 7. The production method according to claim 1, where the active substance is a therapeutic agent used for hyperlipidemia. 8. The production method according to claim 7, wherein the therapeutic agent used for hyperlipidemia is an HMG-CoA reductase inhibitor. 9. A method of increasing the solubility of pioglitazone hydrochloride from a drug comprising a core coated with pyglitazone hydrochloride, which comprises, upon receipt of said drug, a step of coating with an aqueous dispersion of pioglitazone hydrochloride containing a coating material selected from the group consisting of
(a) hydroxypropyl cellulose, whose 5% (w / v) aqueous solution has a viscosity of not more than 35 MPa · s at 20 ° C., and
(b) a grafted copolymer and polyvinyl alcohol polyethylene glycol, whose 5% (w / v) aqueous solution has a viscosity of not more than 35 MPa · s at 20 ° C,
moreover, the core includes an active substance, which is a therapeutic agent for diabetes, a therapeutic agent for complications of diabetes, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic or antithrombotic agent. 10. The coated drug obtained in accordance with the production method according to claim 1, which releases at least 50% of pioglitazone hydrochloride during the first 15 minutes of the solubility test by the rotational grid method using a buffer solution of hydrochloric acid and potassium chloride (pH 2 , 0) as a control solution at 37 ° C and 100 rpm. 11. The coated drug obtained in accordance with the production method according to claim 1, which releases at least 50% of pioglitazone hydrochloride during the first 15 minutes of the solubility test according to the method of a paddle mixer using a buffer solution of hydrochloric acid and potassium chloride (pH 2 , 0) as a control solution at 37 ° C and 50 rpm.
Priority on points: 01/29/2003 - according to claims 1, 2, 4-11; 07/18/2003 - according to claims 1-11; 01/06/2004 - according to claims 1-11.