Method of obtaining of preparation with covering

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

 

The technical field to which the invention relates.

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

The level of technology

It was reported on the following pharmaceutical compositions comprising an insulin sensitizer, such as the connection thiazolidinedione and the like, and biguanid:

1. Pharmaceutical preparation containing an insulin sensitizer in combination with at least one from the group comprising an inhibitor of α-glucosidase, an inhibitor alsoreported, biguanide, the connection statin, an inhibitor of the synthesis of squalene, a compound of fibrate, power catabolism of LDL (low density lipoprotein) and angiotensin-converting enzyme (see EP-749751 A).

2. Pharmaceutical composition comprising an insulin sensitizer, biguanide-protivogipergonichesky agent and pharmaceutically acceptable carrier (see WO 98/57634).

3. Pharmaceutical composition comprising thiazolidinedione, Metformin hydrochloride and a pharmaceutically acceptable carrier, where thiazolidinedione is on the surface of Metformin hydrochloride (see WO 01/35940).

4. Pharmaceutical composition comprising thiazolidinedione, hydrochloride Metformin and pharmaceuticas is acceptable carrier, where thiazolidinedione hydrochloride and Metformin respectively dispersed in a private pharmaceutically acceptable carriers (see WO 01/35941).

5. The structure of the nucleus, including (a) a first layer consisting of hydrochloride pioglitazone or its pharmaceutically acceptable salt as an active ingredient, and (b) a core containing biguanide as the active component, in which at least part of the core is covered with the above-mentioned first layer (see WO 01/82875).

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

Description of the invention

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

The authors of the present invention found that when a drug covered hydrochloride pioglitazone, it is possible to achieve improved ability to dissolve the hydrochloride pioglitazone (especially when osobnosti to dissolve within the first 15 minutes of the test solubility) by applying a water dispersion of pioglitazone hydrochloride, containing the coating material with low viscosity. The authors conducted further research based on this discovery, which led to the implementation of the present invention.

Thus, the present invention relates:

1) the method of production of the drug coating, which consists in applying a water dispersion of pioglitazone hydrochloride-containing coating material with a low viscosity;

2) to the drug coating obtained in accordance with the above method of obtaining 1);

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

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

5) to the above method of obtaining 1), where the core containing the active substance, cover with water dispersion of pioglitazone hydrochloride-containing coating material with a low viscosity;

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

7) to the above method of obtaining 6), where therapeutic agent for diabetes is biguanid

8) to the above method of obtaining 7)where biguanide is a hydrochloride Metformin;

9) to the above method of obtaining 5), where the active substance is a therapeutic drug for hyperlipidemia;

10) to the above method of obtaining 9)where a therapeutic tool for the treatment of hyperlipidemia is an inhibitor of HMG-CoA reductase;

11) the method for improving the solubility of pioglitazone hydrochloride from preparation coated with pioglitazone hydrochloride, where the process of obtaining includes coating the aqueous dispersion of pioglitazone hydrochloride-containing coating material with a low viscosity;

12) to the drug coating obtained in accordance with the above method of obtaining 1), which is released at least 50% of pioglitazone hydrochloride within the first 15 minutes of testing the solubility of the rotational grid using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as a test solution at 37°C and 100 rpm;

13) to the drug coating obtained in accordance with the above method of obtaining 1), which is released at least 50% of pioglitazone hydrochloride for the first 15 minutes of the test solubility by way blade mixer using a buffer solution chloritoid is one acid and potassium chloride (pH 2.0) as a test solution at 37°C, 50 rpm; and the like.

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

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

The concentration of pioglitazone hydrochloride in water dispersion is, for example, 1-25% (wt./wt.), preferably 1-15% (wt./wt.). The concentration in this range is preferred in order to improve the coating process, the standardization of the content of pioglitazone hydrochloride in received the drug coating, and the like.

"Aqueous dispersion of pioglitazone hydrochloride" (herein sometimes abbreviated as "dispersion of the present invention") includes a coating material with a low viscosity.

In the present description, the coating material with a low viscosity is assumed, for example, the coating material, the viscosity of 5% (wt./volume) aqueous solution of which not more than 35 MPa·s (preferably not more than 30 MPa·s, more preferably not more than 25 MPa·s) at 20°C. the viscosity of the coating material may change when the concentration of the coating material in an aqueous solution, the measurement conditions, for example, temperature measurement, and the like. The coating materials, the viscosity of which is ri changed conditions of measurement does not exceed the above limits, set to 5% (wt./volume) aqueous solution at 20°C are referred to as "coating materials with low viscosity" of the present invention.

As a coating material with a low viscosity can be specified, for example, hydroxypropylcellulose (grade: SL, SSL (trade mark); Nippon Soda Co., Ltd.); the hypromellose (class: MW, E, EW (trade mark); Shin-Etsu Chemical Co., Ltd.) (grade: E-3 (trade mark); Nippon Soda Co., Ltd.); premix (class: SSM (trade mark), Nippon Soda Co., Ltd.) from hydroxypropylcellulose (class: SSL, Nippon Soda Co., Ltd.) and hydroxypropylmethylcellulose (grade: E-3); a graft copolymer of polyvinyl alcohol and polyethylene glycol [Kollicoat IR (trade mark), BASF, Germany), and the like.

The above coating material may be a mixture of two or more substances from the numbers above in the appropriate proportions. If mixture for the coating material obtained by mixing appropriate proportions of one or more of the above coating materials and one or more of the coating materials with high viscosity, represents a coating material, the viscosity of 5% (wt./volume) aqueous solution of which not more than 35 MPa·s at 20°C, this mixture can be used as a coating material with a low viscosity" of the present invention. Here, under "material pokr is ment for high viscosity" means, for example, the coating material, the viscosity of 5% (wt./volume) aqueous solution of which more than 35 MPa·s at 20°C. specific examples include hydroxypropylcellulose (class: L (trade mark); Nippon Soda Co., Ltd.) (class: Klucel LF (trade mark); Aqualon (USA)), hypromellose (class: R (trade mark); Shin-Etsu Chemical Co., Ltd.); and the like.

The coating material with low viscosity includes, preferably, hydroxypropylcellulose 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 to 5.9 MPa·s), hydroxypropylcellulose SSL (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), the graft-copolymer of polyvinyl alcohol and polyethylene glycol [Kollicoat IR (trade mark), BASF, Germany] (viscosity of 5% aqueous solution at 20°C: approximately 18 MPa·s) and the like.

The coating material with a low viscosity can be obtained in the form of a solution or suspension in the dispersion system of the present invention. For greater efficiency to obtain drug coverage, which would be the better homogeneity of the contained hydrochloride pioglitazone and the hardness of the drug, it is preferable to dissolve the coating material in the dispersion system of the present invention.

Disperse the system of the present invention, in addition, may include additional coverage tools. These additional funds coverage include lighting and/or coloring agents such as titanium oxide, talc, iron oxide and the like; plasticizers, such as polyethylene glycol, triethylcitrate, castor oil, Polysorbate and the like; organic acids, such as citric acid, tartaric acid, malic acid, ascorbic acid and the like; lactose, D-mannitol, nizkozameshhennoj hydroxypropylcellulose, carmellose calcium, crosspovidone and the like.

For cases where additional means of coating insoluble in water, it is preferable that the average size of the particles was not more than 500 μm, more preferably does not exceed 150 μm, particularly preferably does not exceed 75 microns. Through the use of additional forms of coverage, with the average size of the particles, it is possible to achieve high results in obtaining the drug from the coating, which is characterized by a high degree of homogeneity contained hydrochloride pioglitazone and hardness of the drug.

The concentration of the coating material with a low viscosity in the dispersion system of the present invention is, for example, 1-30% (wt./wt.), preferably 1-25% (wt./wt.), more preferably, 225% (wt./wt.). Concentration within the specified limits are preferred in order to increase the efficiency of coating uniformity contained in the received drug coated with pioglitazone hydrochloride and the like.

The concentration of the additional coverage in the dispersion system of the present invention is, for example, 0.2 to 35% (wt./wt.), preferably, 0.2 to 30% (wt./wt.), more preferably, 0.5 to 15% (wt./wt.). Concentration within the specified limits are preferred in order to increase the efficiency of coating uniformity contained in the received drug coated with pioglitazone hydrochloride and the like.

As the core, the basis for coating aqueous dispersion of pioglitazone hydrochloride-containing coating material with low viscosity (hereinafter abbreviated sometimes to the core of the present invention), you can specify, for example, such solid preparations such as tablets, capsules, granules, powders, lozenges, and the like. The solid form can be a drug controlled release, for example, the drug immediate-release or delayed drug release, and the like. The drug in solid form may include a conventional pharmaceutical practice additives and can be obtained by any well-known manner. As additives can decree the ü such as, for example, excipient, disintegrity agent, binding agent, lubricant, coloring agent, a pH regulator, a surfactant, an agent that slows the release, stabilizer, acidulant, flavouring agent, to facilitate swallowing, and the like. These additives are used in amounts customary in the pharmaceutical fields.

As examples of excipient you can specify the starch, such as corn, potato, wheat, rice, partially pre-gelatinising starch, pre-gelatinising starch, porous starch and the like; sugar 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 dezintegriruetsja agent, you can specify carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboximetilkrahmal, croscarmellose sodium, crosspovidone, nitrosamino hydroxypropylcellulose, hydroxypropylmethyl and the like. The number dezintegriruetsja agent, preferably, 0.5-25 parts by weight, more preferably 1-15 parts by weight per 100 parts by weight of the drug in solid form.

As an example swiatowej the substance you can specify crystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, gum Arabic powder, and the like. The amount of the binder is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight per 100 parts by weight of the drug in solid form.

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

As an example, the dye can be specified food dyes such as food yellow No. 5, food red No. 2, food blue No. 2 and the like, food kreplach, iron oxide, and the like.

As examples of the pH regulator, you can specify the citrates, phosphates, carbonates, tartratami, fumarate, acetates, salts of amino acids, and the like.

As an example, surfactants can specify lauryl sulfate, Polysorbate 80, polyoxyethylene(160)-polyoxypropylene(30)glycol, and the like.

As examples of the agent that slows the release, you can specify such polymers cellulose, as hydroxypropylcellulose, hypromellose, (preferably, hypromellose 2910, hypromellose 2208, and the like), cellulose acetate (preferably, the cellulose acetate is with the content of acetyl, components 39,3-40%), cellulose diacetate, cellulose triacetate, acetotrophic cellulose, ethylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose sodium in the form of crystalline cellulose and the like; sodium alginate, carboxyvinyl polymer; polymers of acrylic acid such as a copolymer of aminoalkylsilane RS [Eudragit RS (trademark), Rohm Pharma], the suspension of a copolymer of methyl methacrylate and ethyl acrylate [Eudragit NE (trademark), Rohm Pharma] and the like. The agent that slows the release, may, for example, to enable the flux thinner (for example, sodium chloride, potassium chloride, sucrose, sorbitol, D-mannitol, polyethylene glycol (preferably, polyethylene glycol 400 and the like), propylene glycol, hydroxypropylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose, acetated cellulose, polyvinyl alcohol, a polymer of methacrylic acid), plasticizers (for example, triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributyl, acetyltributyl, glycerin, sorbitol, diethyloxalate, diethylmaleate, diethylfumarate, dibutylamine, diethylmalonate, dioctylphthalate, dibutylsebacate triethylcitrate, tributyltin, tributyrin glycerol), and the like. Among the preferred examples of agents that slow Svobodnye, includes (1) a semi-permeable film coating containing cellulose acetate (preferably cellulose acetate with an acetyl content of constituting 39,3-40%), polyethylene glycol (preferably, polyethylene glycol 400 and the like) and triacetin; (2) the composition, contributing to the slow release containing carboxymethylcellulose sodium, hypromellose 2910, hypromellose 2208, and microcrystalline cellulose; and the like.

As the stabilizer, you can specify, for example, tocopherol, Terentieva salt of ethylenediaminetetraacetic acid, nicotinamide, cyclodextrins and the like.

As an acidifier, you can specify, for example, ascorbic acid, citric acid, tartaric acid, malic acid and the like.

As flavourings, you can specify, for example, menthol, peppermint oil, lemon oil, vanilla and the like.

As agents facilitating ingestion, you can specify, for example, partially dehydrated silicic acid, hydrated silicon dioxide and the like.

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

The core of the present invention preferably contains the active substance. Used as active substances the tion of the present invention can specify a therapeutic agent for diabetes, complications caused by diabetes, a therapeutic agent for hyperlipidemia, a means of reducing blood pressure, remedies for obesity, diuretics, antithrombotic tools and the like. These active ingredients can be a compound with low molecular weight protein with a high molecular weight, the polypeptide or antibody, a vaccine, or the like. The active substance may be a mixture of two or more components, taken in the appropriate proportions.

This use of a core containing the active substance of the present invention, gives the best results, namely: 1) strengthening actions hydrochloride pioglitazone or active substances (synergistic effect of pharmaceutical agents), 2) dose reduction of pioglitazone hydrochloride or the active substance (the effect of decreasing the dose of the pharmaceutical agents on the introduction of only one drug), 3) reduction of side effects (e.g., increased body weight, ketosis, acidosis) hydrochloride pioglitazone or active substances and the like.

Examples of therapeutic agents for diabetes include insulin preparations (e.g., the insulin of animal origin, obtained from the pancreas of cattle, swine is; the insulin preparations of human origin, synthesized by means of genetic engineering using Escherichia coil or yeast; zinc insulin, Protamine-zinc-insulin; fragments or derivatives of insulin (e.g., INS-1, and so on), and the like), insulin sensitizers (e.g., pioglitazone or its salt (preferably hydrochloride), rosiglitazone or its salt (preferably maleate), GI-262570, regexen (JTT-501), netoglitazone (MCC-555), YM-440, KRP-297, CS-011, FK-614, compounds described in W099/58510 (e.g., (E)-4-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzylamino]-4-fenilalanina acid), ragaglitazar (NN-622), tesaglitazar (AZ-242), BMS-298585, ONO-5816, LM-4156, VM-13-1258, MBX-102, GW-1536, LY-519818, and so on), inhibitors of α-glucosidase (e.g., voglibose, acarbose, miglitol, emiglitate and so on), biguanides (e.g., phenformin, Metformin, buformin or its salt (e.g. hydrochloride, fumarate, succinate), and so on), stimulants of insulin secretion [sulfonylureas (for example, tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole and so on), Repaglinide, nateglinide, mitiglinide or hydrated salts of calcium, GLP-1, and so on], inhibitors dipeptidylpeptidase IV (for example, NVP-DPP-278, RT-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 the Sabbath.), Amylin agonists (for example, pramlintide and so on), inhibitors phosphoribosyltransferase (for example, sodium Vanadate, and so on), inhibitors of gluconeogenesis (e.g., glycogen phosphorylase inhibitors, inhibitors of glucose-6-phosphatase, glucagon antagonists, and so on) and inhibitors SGLUT (sodium-glucose cotransporter) (e.g., T-1095 etc.).

Examples of therapeutic agents used in the complications of diabetes include inhibitors alsoreported (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat (SNK-860), CT-112 etc.), neurotrophic factors (e.g., NGF, NT-3, BDNF, and so on), the promoters of production-secretion of neurotrophin [for example, promoters of production-secretion of neurotrophin described in WO 01/14372 (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-(3-(2-methylphenoxy)propyl)oxazole and the like)], inhibitors of the RCC (e.g., LY-333531 etc.), AGE inhibitors (e.g., ALT946, pimagedine, piratensender, bromide, N-phenacylthiazolium (ALT766), EXO-226, and so on), scavengers of active oxygen (for example, lipoic acid, and so forth) and cerebral vasodilators (e.g., tiaprid, meksiletin and so on).

Examples of therapeutic agents used in hyperlipidemia include inhibitors of HMG-CoA reductase (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, l is pentyl, the tseriwastatina, itavastatin, rosuvastatin (ZD-4522) or their salts (for example, salts of sodium, calcium salts, and so forth), and so on), fibrate connection (for example, bezafibrat, clofibrate, unifibre, ciprofibrate, clinofibrate, clofibrate, katibnikova acid, etofibrate, fenofibrate, gemfibrozil, micofiber, peripheral, ronifibrate, simfibrate, Teofipol and so on), inhibitors stvalentines (for example, compounds described in WO 97/10224 (for example, 1-[[(3R,53)-1-(3-acetoxy-2.2-dimethylpropyl)-7-chloro-5-(2,3-acid)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid, and so forth), ACAT inhibitors (e.g. Avasimibe, Eflucimibe, and so on), anion exchange resins (eg, cholestyramine, and so on), probucol, medicines on the basis of nicotinic acid (for example, nicomol, niceritrol and so on), ethylacetat, sterols of plant origin (for example, soy Sterol, γ-oryzanol) and the like.

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

Examples of anti-obesity include means acting on the Central nervous system (for example, dexfenfluramin, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex and so on), inhibitors of pancreatic lipase (e.g., orlistat, etc.), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140, and so on), peptide drugs that reduce appetite (for example, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (e.g., lintitript, FPL-15849 etc.) and the like.

Examples of the diuretics include xanthine derivatives (e.g., sodium salicylate and theobromine, calcium salicylate and theobromine, and so on), drugs thiazide (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydroxylamine, panflutes, polythiazide, methyclothiazide and so on), drugs antialdosterone (e.g., spironolactone, triamterene etc.), inhibitors carbonatehydroxide (e.g., acetazolamide etc.), drugs chlorobenzenesulfonamide (e.g., chlorthalidone, mefruside, indapamide, and so gave the (e) azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of the antithrombotic funds include heparin (e.g., sodium heparin, calcium heparin, sodium-dalteparin and so on), warfarin (e.g., potassium-warfarin, and so on), antithrombine drugs (for example, argatroban and so on), thrombolytic tools (e.g., urokinase, isocynate, alteplaza, nameplate, monteplase, pamiteplase and so on), platelet aggregation inhibitors (e.g., hydrochloride, ticlopidine, Cilostazol, ethylacetat, beraprost-sodium, hydrochloride of sarpogrelate and so on), and the like.

The active substance, preferably, is a therapeutic tool for the treatment of diabetes, more preferably, biguanide, particularly preferably, Metformin or its salt (preferably, Metformin hydrochloride).

In addition, as the active substances are also preferred is a therapeutic tool used in hyperlipidemia. More preferred as a therapeutic agent for hyperlipidemia is an inhibitor of reductase HMG-COA. Especially preferred is simvastatin, and the like.

The amount of active substance in the nucleus of the present invention is, for example, 0.1 to 100 parts by weight, predpochtite is) 1-99 parts by weight per 100 parts by weight of the engine according to the present invention.

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

Here the mixing is done using, for example, such a mixer as the mixer, V-type, drum-type mixer and the like; and the granulation is performed using, for example, high-speed mixer-granulator, granulator, fluidized bed and the like. In compression molding, stamping is usually carried out under pressure 5-35 kN/cm2on a tablet machine with a single punch, rotary tablet machine, and the like.

In the case when the active substance contained in the core of the present invention, is not a pharmaceutical agent, is intended to odncrt the CSOs introduction during the day (and, for example, a pharmaceutical agent for the introduction of twice or three times a day), the nucleus that contain the specified active ingredient, preferably, is a drug slow release.

When hydrochloride pioglitazone hardly compatible with the active substance contained in the core of the present invention, the core containing the active substance, it is possible to cover the above material coating and the like.

The core of the present invention, more preferably, is a drug sustained-release (preferably in the form of tablets), including biguanide (preferably, Metformin hydrochloride). As an example of such a drug can be called a tablet with the pharmaceutical agent of supervised release, described in WO 99/47125, two-layer delivery system for the controlled release described in WO 99/47128, oral pharmaceutical agent controlled-release described in USP 6340475 and the like.

As drug sustained-release containing biguanide is preferred

(1) containing biguanide tablet covered with a semi-permeable membrane coating, which contains cellulose acetate (preferably cellulose acetate with an acetyl content of equal to 39.3-40%), polyethylene glycol (prefer is Ino, the polyethylene glycol 400 and the like) and triacetin (specified semi-permeable membrane coating may have a hole or pore);

(2) the tablet obtained by mixing the composition sustained release, containing carboxymethylcellulose sodium, hypromellose 2910, hypromellose 2208, and crystalline cellulose, biguanides, with subsequent compression molding the mixture, and the like.

In accordance with the method of receiving according to the present invention, the coating is performed by one of the conventional ways. For example, the coating is performed using a device for film coating.

In addition, the coating is performed in such a way that the core of the present invention is typically 50-99 parts by weight, preferably 70-99 parts by weight, more preferably 70-98 parts by weight to 100 parts by mass of the obtained drug coverage.

Moreover, the drug-coated pioglitazone hydrochloride obtained in accordance with the method of receiving according to the present invention (abbreviated here sometimes to the drug coating of the present invention), can be coated to increase hardness of the drug, correction bitter taste, enhance svetostoyjkostj, for dyeing, and the like. This coating can be applied to any overall the known way, using, for example, the above-mentioned coating materials and the like.

As an example, the dosage form of the drug coated can be called a tablet, capsule, granule, powder, toffee, and the like. The preferred dosage form of the drug coated tablet is. It can be any shape, from round and teardrop-shaped to oblong, and the like. In addition, the tablet in order to better identify can be extruded icon or letter and marked the dividing line for ease of separation.

The amount of active ingredient in the drug coating of the present invention is typically, for example, from 0.01 to 99 parts by weight, preferably 0.1 to 99 parts by weight per 100 parts by weight of drug coating. In particular, when the active substance is biguanide (preferably hydrochloride Metformin), the amount of this biguanide in the product is coated, for example, is usually 5-98 parts by weight, preferably, 15-96 parts by weight per 100 parts by weight of drug coating.

The number of pioglitazone hydrochloride in the drug coating of the present invention, for example, is usually 0.01 to 30 parts by weight, preferably 0.5 to 25 parts by weight, more preferably 0.5 to 10 parts by weight per 100 parts by weight of drug coating.

The drug coating according to the present invention can be administered orally, what is safe to representatives of various mammals (e.g. mouse, rat, rabbit, cat, dog, representative of the cattle, horse, monkey, human and the like).

The drug coating of the present invention is best according to its properties, such as solubility of pioglitazone hydrochloride (in particular, the ability to dissolve after introduction into the body or within 15 minutes of the test solubility) and the like, and can be used as a preventive or therapeutic agent for the treatment of, for example, diabetes (e.g., type 1 diabetes type 2 diabetes type gestational diabetes, and so forth), be used in hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, Hypo-HDL-Accademia arising after eating hyperlipidemia, and so below), in violation glucose tolerance (IGT), when the complications of diabetes (e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (e.g., respiratory infection, urinary tract infection, gastrointestinal infection, soft tissue infection of the skin, an infectious disease of the lower limbs, and so gave the (e) in diabetic gangrene, xerostomia, hypoacusia, cerebrovascular disorders, peripheral circulatory disorders, and so forth], obesity, osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, cachexia when blood diseases, cachexia in endocrine diseases, cachexia caused by infectious disease, or cachexia due to acquired immunodeficiency syndrome), fatty infiltration of the liver, hypertension, syndrome polycystic ovary, kidney disease (such as diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end stage kidney disease and so on), in muscular dystrophy, myocardial infarction, angina, acute violation of cerebral circulation (for example, cerebral infarction, stroke), syndrome of insulin resistance, syndrome X, hyperinsulinemia-induced hyperinsulinemia loss of sensitivity, tumor (e.g., leukemia, breast cancer, prostate cancer, skin cancer and so forth), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases [e.g., Alzheimer's disease, chronic rheumatoid arthritis, spondylosis deformans, deforming osteoarthritis, lumb the th, gout, inflammatory processes posleoperatsionnogo or traumatic origin, the remission of the tumor, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including nonalcoholic steatohepatitis origin), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, and so forth], syndrome of visceral obesity, arteriosclerosis (e.g., atherosclerosis, and so forth), and the like.

The drug coating of the present invention can also be used for secondary prevention (e.g., secondary prevention of attack of diseases of the cardiovascular system such as myocardial infarction and so on) and to prevent progression of the disease in these cases (e.g., prevent the development of disorders of glucose tolerance in the diabetes prevention of progression of arteriosclerosis in diabetic patients).

Daily dose of the drug coating of the present invention is 7.5-60 mg/day, preferably 15-60 mg/day, more preferably 15-45 mg/day based on the number of pioglitazone hydrochloride per adult (body weight 60 kg).

When the drug coating of the present invention is obtained using a kernel, containing the active substance, the drug coating contains, preferably, effectively the active amount of the active substance. For example, the effective amount in cases where the active substance is biguanide (preferably hydrochloride Metformin)is 125-2550 mg/day, preferably 250-2550 mg/day per adult (body weight 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 for an adult (weighing 60 kg).

The drug coating of the present invention can be used in combination with one or more pharmaceuticals, selected from among therapeutic agents against diabetes, therapeutic agents against diabetic complications, therapeutic agents against hyperlipidemia, antihypertensive drugs, anti-obesity drug, diuretics, antithrombotic funds and the like (hereinafter indicated here abbreviated as concomitant drug). Listed above as examples of active substances can be used such as concomitant medications. The introduction of the drug coating of the present invention, as well as the introduction of the concomitant drug is not restricted, they can be administered to the patient simultaneously or with a time shift. Dosage SOP is stuudio drugs is determined appropriately based on the clinically proven doses. In addition, the ratio of components in the mixture, the drug coating of the present invention and the concomitant drug is determined depending on the patient, which is the introduction, route of administration, the disease to be treated, condition, combination and the like. For example, if the patient is a woman, a concomitant drug can be used in an amount of 0.01-100 parts by weight per 1 part by weight of drug coating.

The use, therefore, the concomitant drug may provide better results, namely: 1) enhanced activity of the drug coating of the present invention or the actions of concomitant medications (synergistic effect on the action of pharmaceutical agents), 2) a lower dose of the drug coating of the present invention or the concomitant drug (effect of reducing the dose of the pharmaceutical agents in comparison with the introduction of a single drug), 3) reduction of side effects of the drug coating of the present invention or the concomitant drug (e.g., increased body weight, ketosis, acidosis), and the like.

The present invention also relates to the method of increasing the dissolution of pioglitazone hydrochloride from preparation coated with pioglitazone hydrochloride, which includes, for this drug, covered the e water dispersion of pioglitazone hydrochloride, containing the substance coating with low viscosity".

Through the application of the method of obtaining, in accordance with the present invention when receiving a drug-coated hydrochloride pioglitazone, it is possible to achieve a high degree of solubility (in particular, the ability to dissolve immediately upon introduction into the body or within 15 minutes of starting the test solubility) hydrochloride pioglitazone in drug coated.

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

"Drugs is coated, obtained according to the method of obtaining, in accordance with the present invention, which releases at least 50% of pioglitazone hydrochloride within 15 minutes of testing the solubility of the rotational grid using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as the control solution at 37°C and 100 rpm,can be administered orally and is perfectly safe to representatives of mammals (e.g., mouse, cat, rat, rabbit, dog, ox, horse, monkey, human and the like) is exactly the same as the above-mentioned drug coverage under this the invention, when the disease to be treated, dose and the like are the same as in the above preparation with a coating according to the present invention.

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

"The drug from the coating obtained by the method of obtaining, in accordance with the present invention, which releases at least 50% of pioglitazone hydrochloride within 15 minutes of testing the solubility by way blade mixer using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as the control solution at 37°C and 50 rpm,can be administered orally and is perfectly safe to representatives of mammals (e.g., mouse, cat, rat, rabbit, dog, ox, horse, monkey, human and the like) same as above the drug coating of the present invention, when the disease to be treated, dose and the like are the same as in the above preparation with a coating according to 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 a preparative additives (for example, D-mannitol, corn starch, hydroxy who replicalouis, magnesium stearate, microcrystalline cellulose, lactose, hypromellose, polyethylene glycol 6000, titanium oxide, nizkozameshhennoj hydroxypropylcellulose, talc, carboxymethylcellulose calcium), used in the following examples, reference examples and comparative examples, use those that meet the standards 14th edition of the Japanese Pharmacopoeia. As triethylcitrate, yellow iron oxide, iron oxide and aqueous dispersions of ethyl cellulose, use those that meet the standards of the Japanese pharmaceutical excipients (1998).

Example 1

Hydroxypropylcellulose (26,4 g, class: SSL, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (297 g) to obtain a coating solution.

Tablets (300 g)obtained in reference example 1, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 70°C, receiving the drug coated with a mass of tablets 260,9 mg.

Example 2

Hydroxypropylcellulose (24 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (344,7 g) obtained for the I solution coating.

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 75°C receives the drug is coated with a mass of tablets 381 mg.

Example 3

Hydroxypropylcellulose (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) was dispersed in water (344,7 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 75°C receives the drug is coated with a mass of tablets 382 mg

Example 4

The hypromellose (24 g, class: MW, Shin-Etsu Chemical Co. Ltd.) (viscosity of 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) was dispersed in water (310 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 70°C, receiving the drug coated with a mass of tabla is key 382 mg

Example 5

The hypromellose (24 g, class: EW, Shin-Etsu Chemical Co., Ltd.) (viscosity of 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) was dispersed in water (344,7 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 70°C, receiving the drug coated with a mass of tablets 382 mg

Example 6

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

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 75°C receives the drug is coated with a mass of tablets 380,5 mg.

Example 7

Hydroxypropylcellulose (48,0 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (540 g) to obtain a solution of ocrite.

Tablets (250 g)obtained in reference example 4, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 90°C receives the drug is coated with a mass of tablets 459 mg.

Example 8

The graft-copolymer of polyvinyl alcohol and polyethylene glycol (48,0 g brand: Kollicoat IR, BASF, Germany) (viscosity of 5% aqueous solution at 20°C: 18 MPa·s), polyethylene glycol 6000 (2.4 g) of titanium oxide (4.8 g) and pioglitazone hydrochloride (30.0 g) was dispersed in water (540 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 4, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 90°C receives the drug is coated with a mass of tablets 461 mg

Example 9

The graft-copolymer of polyvinyl alcohol and polyethylene glycol (18.0 g, brand: Kollicoat IR, BASF, Germany) (viscosity of 5% aqueous solution at 20°C: 18 MPa·s), titanium oxide (1.8 g), nitrosamino hydroxypropylcellulose (3.6 g, brand:

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

Tablets (30 tablets)obtained in reference example 5, and tablets (240 g, approximately 800 tablets)obtained is in reference example 3, loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at the inlet temperature of 95°C. from the appearance of the obtained tablets are taken the drug coated (479 mg per tablet)containing the tablet obtained in reference example 5, as a kernel.

Example 10

Hydroxypropylcellulose (24,0 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 (15.0 g) was dispersed in water (350 g) to obtain a coating solution.

Tablets Glucophage XR (brand, 30 tablets, tablet delayed release containing 500 mg of Metformin hydrochloride) Bristol-Myers Squibb Company) and tablets (250 g)obtained in reference example 3, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at the inlet temperature of 70°C. from the appearance of the obtained tablets are taken drugs with coating (weight per tablet: 1,086 g)containing tablets Glucophage XR in the kernel and contains Metformin hydrochloride 500 mg/pioglitazone hydrochloride 16,53 mg per pill.

Example 11

The graft-copolymer of polyvinyl alcohol and polyethylene glycol (36,0 g brand: Kollicoat IR, BASF, Germany) (viscosity of 5% aqueous what about the solution at 20°C: 18 MPa·s), the titanium oxide (3.6 g) and pioglitazone hydrochloride (22,5 g) was dispersed in water (300 g) to obtain a coating solution.

Tablets Glucophage XR (brand, 30 tablets, tablet delayed release containing 500 mg of Metformin hydrochloride) (produced by Bristol-Myers Squibb Company) and tablets (250 g)obtained in reference example 3, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at the inlet temperature of 70°C. from the appearance of the obtained tablets, get the drugs coated (weight per tablet: 1,082 g)containing tablets Glucophage XR in the kernel and contains Metformin hydrochloride 500 mg/pioglitazone hydrochloride 16,53 mg per pill.

Example 12

Hydroxypropylcellulose (24,0 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (350 g) to obtain a coating solution.

Tablets Lipovas 20 (trademark, 30 tablets, Banyu Pharmaceutical Co., Ltd., the major axis of 14.0 mm, the minor axis of 7.5 mm, weight 400 mg)containing simvastatin as the active substance, and tablets (250 g)obtained in reference example 9, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above rest the RA of the coating at the inlet temperature of 70°C. From the appearance of the obtained tablets, get the drugs coated (weight per tablet: 449 mg)containing simvastatin 20 mg/pioglitazone hydrochloride 17,78 mg per pill.

Example 13

Hydroxypropylcellulose (72 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (1050 g) to obtain a coating solution.

Tablets (30 tablets)obtained in reference example 10, and tablets (250 g)obtained in reference example 9, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at the inlet temperature of 80°C. from the appearance of the obtained tablets, get the drugs coated (weight per tablet: 349 mg)containing simvastatin 15 mg/pioglitazone hydrochloride 16,25 mg per pill.

Example 14

Hydroxypropylcellulose (72 g, class: SL, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (1050 g) to obtain a coating solution.

Tablets (30 tablets)obtained in reference example 11, and tablets (250 g)obtained in reference example 9, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) innosat coated with the above coating solution at the inlet temperature of 80°C. From the appearance of the obtained tablets, get the drugs coated (weight per tablet: 349 mg)containing atorvastatin calcium 21 mg/pioglitazone hydrochloride 16,93 mg per pill.

Reference example 1

D-mannitol (2176 g) and corn starch (918 g) is loaded into the granulator, fluidized bed (FD-3S, production POWREX CORPORATION) and subjected to granulation while spraying an aqueous solution (1700 g)containing hydroxypropylcellulose (102 g), followed by a stage of drying to obtain granules. Add microcrystalline cellulose (160,2 g) and magnesium stearate (32 g) to the obtained granular powder (3012 g) and mix. The resulting mixture was granulated powder tabletirujut on teletrauma machine (Correct C, production Kikusui Seisakusho Ltd.) (tablet size: diameter 8.5 mm, compression pressure 9 kN/punch)to give tablets with a weight of 244 mg each.

Reference example 2

Lactose (2470 g), corn starch (315 g) and carmellose calcium (157,5 g) is loaded into the granulator, fluidized bed (FD-3S, production POWREX CORPORATION) and subjected to granulation while spraying an aqueous solution (1575), containing hydroxypropylcellulose (94,5 g), followed by a stage of drying to obtain granules. Add carmellose calcium (89,3 g) and magnesium stearate (17.9 g) to the obtained granular powder (2868 g) and mix. The resulting mixture is granulirovannogo powder tabletirujut on teletrauma machine (Correct 19K, production Kikusui Seisakusho Ltd.) (tablet size: large axle 12 mm, the minor axis of 7 mm, the compression pressure of 15 kN/punch), getting a tablet weight of 350 mg each.

Reference example 3

Lactose (1976), corn starch (252 g) and carboxymethyl cellulose calcium (126 g) is loaded into the granulator, fluidized bed (FD-3S, production POWREX CORPORATION) and subjected to granulation while spraying an aqueous solution (1260 g)containing hydroxypropylcellulose (75,6 g), followed by a stage of drying to obtain granules. Add carboxymethylcellulose calcium (71,4 g) and magnesium stearate (14.3 g) to the obtained granular powder (2294 g) and mix. The resulting mixture was granulated powder tabletirujut on teletrauma machine (Correct 19K, production Kikusui Seisakusho Ltd.) (tablet size: diameter 9 mm, the compression pressure of 7 kN/punch)to give tablets weighing 300 mg each.

Reference example 4

Tablets (400 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated by using a coating solution containing an aqueous dispersion of ethyl cellulose (brand: Aquacoat, Asahi Kasei Corporation, 148,2 g), talc (2.2 g), triethylcitrate (13.3 g), yellow iron oxide (0.36 g) and water (231,1 g), when the inlet temperature 90°C, thus obtained tablets weight 391 mg each. Next on the pill cause coating the solution hydroxypropylmethylcellulose (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 the above, obtaining tablets with a weight of 416 mg each.

Reference example 5

Tablets (400 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated by using a coating solution containing an aqueous dispersion of ethyl cellulose (brand: Aquacoat, Asahi Kasei Corporation, 74,1 g), talc (1.1 g), triethylcitrate (6.7 g), yellow iron oxide (0.18 g) and water (115,6 g), when the inlet temperature of 58°C, thus obtained tablets with a weight of 381 mg each. Next on the tablets are coated with a solution of hydroxypropylmethylcellulose (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 the above, obtaining tablets with a weight of 429 mg each.

Reference example 6

Hydroxypropylcellulose (26,4 g, class: L, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (297 g) to obtain a coating solution.

Tablets (300 g)obtained in reference example 1, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at a temperature of at I is de 70°C, receiving the drug coated with a mass of tablets 262,1 mg.

Reference example 7

Hydroxypropylcellulose (24 g, class: L, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (344,7 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 75°C receives the drug is coated with a mass of tablets 382 mg

Reference example 8

The hypromellose (24 g, class: R, Shin-Etsu Chemical Co., Ltd.) (viscosity of 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) was dispersed in water (270 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 2, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 70°C, receiving the drug coated with a mass of tablets 381,2 mg.

Reference example 9

Lactose (41160 g), corn starch (5250 g) and carmellose calcium (2625 g) is loaded into the granulator, fluidized bed (FD-WSG-60, manufacturing, POWREX CORPORATION) and subjected to pellet the tion while spraying an aqueous solution (31510 g), contains hydroxypropylcellulose (1575), followed by a stage of drying to obtain granules. Add carmellose calcium (1491 g) and magnesium stearate (298,2 g) to the obtained granular powder (47910 g) and mix. The resulting mixture was granulated powder tabletirujut on teletrauma machine (Correct 19K, Kikusui Seisakusho Ltd.) (tablet size: diameter 7 mm, compression pressure of 5.7 kN/punch)to give tablets with a weight of 105 mg each.

Reference example 10

Tablets Lipovas 5 mg (brand, Banyu Pharmaceutical Co., Ltd., weight 100 mg), containing as active substance simvastatin, ground to powder in a mortar, and tabletirujut 300 mg of crushed powder, corresponding to 15 mg of simvastatin, using a universal device for testing (Shimadzu Corporation, UH-10A) (compression pressure of 9.5 kN/punch), using stamping punch with R, with a diameter of 9.0 mm, and forming a matrix with 30 tablets.

Reference example 11

5 mg tablets Lipitor (brand, Yamanouchi Pharmaceutical Co., Ltd., weight approximately 72 mg), containing as active substance is atorvastatin calcium, ground to powder in a mortar, and tabletirujut 300 mg of crushed powder, corresponding to 21 mg of atorvastatin calcium using a universal device for testing (Shimadzu Corporation, UH-10A) (compression pressure of 9.5 kN/punch), using stamping punch with R, d is amerom 9.0 mm, and forming a matrix with 30 tablets.

Comparative example 1

Hydroxypropylcellulose (48,0 g, class: L, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (540 g) to obtain a coating solution.

Tablets (250 g)obtained in reference example 4, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution when the inlet temperature 90°C receives the drug is coated with a mass of tablets 459 mg.

Comparative example 2

Hydroxypropylcellulose (48,0 g, class: L, Nippon Soda Co., Ltd.) (viscosity of 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) was dispersed in water (700 g) to obtain a coating solution.

Tablets Lipovas-20 (trademark, 30 tablets, Banyu Pharmaceutical Co., Ltd., the major axis of 14.0 mm, the minor axis of 7.5 mm, weight 400 mg)containing simvastatin as the active substance, and tablets (250 g)obtained in reference example 9, is loaded into the device for film coating (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above coating solution at the inlet temperature of 70°C. from the appearance of the obtained tablets, get the drugs coated (m the SSA on the tablet: 445 mg), containing simvastatin 20 mg/pioglitazone hydrochloride 16,23 mg per pill.

Experimental example 1

Preparations of coating obtained in the above examples, evaluate the solubility of pioglitazone hydrochloride by the method of rotational grid (100 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 1.

Table 1
The ability to dissolution (%) of the hydrochloride pioglitazone
Time15 minutes30 minutes45 minutes60 minutes
Example 1060,677,484,388,3
Example 1171,278,184,786,9

As follows from table 1, the drug coating obtained in accordance with the method of receiving according to the present invention, is superior to the other on the ability of pioglitazone hydrochloride to dissolve.

The experience is imentally example 2

Preparations of coating obtained in the above examples and comparative examples, evaluate the solubility of pioglitazone hydrochloride by the method with a blade stirrer (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
The ability to dissolution (%) of the hydrochloride pioglitazone
Time15 minutes30 minutes45 minutes60 minutes
Example 762,076,5to 83.586,2
Example 880,689,491,591,5
Comparative example 129,944,255,865,3

As follows from table 2, the drug coating of the present invention is superior to the other on the ability of pioglitazone hydrochloride to the rastvoreniyu.

Experimental example 3

Preparations of coating obtained in the above examples and comparative examples, evaluate the solubility of pioglitazone hydrochloride in a manner analogous to experimental example 2. The results are shown in table 3.

Table 3
The ability to dissolution (%) of the hydrochloride pioglitazone
Time15 minutes30 minutes45 minutes60 minutes
Example 1266,292,597,998,8
Comparative example 2to 33.868,683,290,6

As follows from table 3, the drug coating of the present invention is superior to the other on the ability of pioglitazone hydrochloride to dissolve.

Industrial application

The drug coating obtained by the method in accordance with the present invention, can be used as a therapeutic agent against dia the ETA and the like, its characteristics, such as the ability of pioglitazone hydrochloride to dissolve (in particular, the ability to dissolve immediately upon introduction into the body or within 15 minutes of the test solubility), and the ability to maintain its hardness and the like he is superior to others (drugs).

In addition, in accordance with the method of receiving according to the present invention the drugs covered hydrochloride pioglitazone, can be easily obtained. Furthermore, the method of receiving according to the present invention is useful as an industrial method of producing for the mass production of the above mentioned drugs with the floor.

1. A method of obtaining a medicinal product with a coating, which consists in coating the core water dispersion of pioglitazone hydrochloride-containing coating material selected from the group consisting of
(a) hydroxypropylcellulose, whose 5% (wt./about.) the aqueous solution has a viscosity of not more than 35 MPa·s at 20°C, and
(b) graft copolymer and polyvinyl alcohol-polyethylene glycol whose 5% (wt./about.) the aqueous solution has a viscosity of not more than 35 MPa·s at 20°C,
moreover, the core comprises an active agent which is a therapeutic agent for diabetes, a therapeutic drug for diabetic complications, therapeutic drug for hyperlipidemia, and theperceived means, tool against obesity, diuretic or anti-thrombotic agent.

2. The drug coating is obtained in accordance with the method of receiving according to claim 1.

3. The method of receiving according to claim 1, where hydroxypropylcellulose is hydroxypropylcellulose SL or hydroxypropylcellulose SSL.

4. The method of receiving according to claim 1, where the active substance is a therapeutic agent for the treatment of diabetes.

5. The method of receiving according to claim 4, where therapeutic agent for diabetes is biguanides.

6. The method of receiving according to claim 5, where biguanide is Metformin hydrochloride.

7. The method of receiving according to claim 1, where the active substance is a therapeutic tool used in hyperlipidemia.

8. The method of receiving according to claim 7, where therapeutic agent used in hyperlipidemia, is an inhibitor of HMG-CoA reductase.

9. The method of increasing the solubility of pioglitazone hydrochloride from medicines, which includes a core, covered in a hydrochloride of pioglitazone, which includes upon receipt of the specified medicines the stage of coating the aqueous dispersion of pioglitazone hydrochloride-containing coating material selected from the group consisting of
(a) hydroxypropylcellulose, whose 5% (wt./about.) the aqueous solution has a viscosity of not more than 3 MPa·s at 20°C, and
(b) graft copolymer and polyvinyl alcohol-polyethylene glycol whose 5% (wt./about.) the aqueous solution has a viscosity of not more than 35 MPa·s at 20°C,
moreover, the core comprises an active agent which is a therapeutic agent for diabetes, a therapeutic drug for diabetic complications, therapeutic drug for hyperlipidemia, antihypertensive agent, anti-obesity, diuretic or anti-thrombotic agent.

10. The drug coating is obtained in accordance with the method of receiving according to claim 1, which releases at least 50% of pioglitazone hydrochloride during the first 15 min of testing the solubility of the rotational grid using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as a test solution at 37°C and 100 rpm

11. The drug coating is obtained in accordance with the method of receiving according to claim 1, which releases at least 50% of pioglitazone hydrochloride during the first 15 min of the test solubility by way blade mixer using a buffer solution of hydrochloric acid and potassium chloride (pH 2.0) as a test solution at 37°C and 50 rpm
Priority items:

29.01.2003 - according to claims 1, 2, 4-11;

18.07.2003 - claims 1 to 11;

06.01.2004 - claims 1 to 11.



 

Same patents:
Solid preparation // 2359661

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns pharmaceutics and medicine and concerns a solid medical product for treatment of diabetes containing a layer, including Pioglitazone, and the layer including Glimepiridum and Polysorbate 80. The agent possesses good indicators of solubility.

EFFECT: development of a preparation with good indicators of solubility.

2 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new pyrrolopyrimidinone derivatives with formula (I) and their pharmaceutically used salts, with inhibition properties towards GSK-3, as well as to intermediate compounds with formula (Ic). In compounds with formula (I) and formula (Ic)

A1 is -(CH2)2- or -(CH2)3-; A is a single bond or a group, which links A1 and G1 in form of A1 -C(=O)-G1, A1- (C=O)-O-G1, A1 -(C=O)-NR101-G1, A1-O-(C=O)-G1, A1 -NR104-G1, A1-NR105-(C=O)-G1, A1-NR106-S(=O)2-G1, A1-NR107-(C=O)-O-G1 or A1-NR108-(C=O)-NR109-G1; G1 is a single bond or a bivalent group, which can be obtained through removal of two hydrogen atoms from any alicyclic hydrocarbon with 3-6 carbon atoms, phenylene, monocyclic or cyclic aromatic heterocyclic compound with 2-9 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N, or monocyclic heterocyclic compound 2-6 carbon atoms, with 1-2 heteroatoms in a ring, chosen from O or N; A3 is a single bond or bivalent acyclic aliphatic hydrocarbon group with 1-3 carbon atoms, which links G1 with A4 of the same or different carbon atom; A4 is a single bond or a group, which links A3 with G2 in form of A3-C(=0)-G2, A3-C(=0)-0-G2, A3-C(=0)-NR121-G2, A3-O-G2, A3-NR124-G2, A3-NR125-C(=0)G2 or A3-S-G2. Description of other radical is given in the formula of invention.

EFFECT: compounds can be used in treating such diseases as diabetes, neurodegenerative diseases and others.

43 cl, 3 tbl, 513 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical combination possesses antihyperglycemic action, contains a compound of formula (1) and at least one compound chosen from sulphonyl carbamide, biguanides, glitazones, insulin preparations and insulin derivatives.

EFFECT: combination possesses synergetic action.

19 cl, 5 dwg, 3 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and pharmaceutics and concerns applications of biologically active agent of formula (1) to prepare a medicinal agent for treatment of the condition chosen from the group including insulin unresponsiveness syndrome, diabetes, hyperlipidemia, hypertensia, nephropathy, neuropathy, retinopathy, feet ulceration or diabetes associated cataracts, method of mammal treatment, pharmaceutical composition and biologically active agent containing compound of formula (1).

EFFECT: invention provides improved clinical effectiveness.

22 cl, 4 tbl, 3 ex

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to pyrazole derivatives, which are represented by general formula (I), as well as theirpharmacologically acceptable salts, which have inhibiting activity against human SGLT1, to pharmacological composition, inhibitor of human SGLT1 and based on them medications, to their application for producing pharmacologic composition and to intermediate compounds for their obtaining. where R1 represents H, hydroxy(C2-6)alkyl group, one of Q and T represents group, which is presented by general formula: or group, which is presented by general formula while another presents C1-6alkyl group; R2 represents hydrogen atom, C1-6alkyl group or group of formula: -A-R8, where A represents oxygen atom, and R8 represents C6hetherocycloalkyl group, containing oxygen atom as heteroatom; X represents simple bond or oxygen atom, Y represents C1-6alkylene group or C2-6alkylene group; Z represents carbonyl group or sulphonyl group; R4 and R5 are similar or different, and each represents hydrogen atom or C1-6alkyl group, which can have similar or different 1-3 substituents, selected from substituents (i) Values of sunstituents (i) are iven in invention formula.

EFFECT: obtaining of pyrazole derivatives and based on them medications.

28 cl, 3 tbl, 197 ex

FIELD: medicine.

SUBSTANCE: invention refers to Aloe Vera extract of family Liliaceae to be applied in pharmaceutical and food industry. Aloe Vera extract of family Liliaceae, containing mixed compound cyclolanostane and compound lophenol in certain amount where the extract produced by supercritical fluid extraction, is characterised with certain properties. There is disclosed foodstuff or beverage contains Aloe Vera extract of family Liliaceae in certain amount, method of producing Aloe Vera extract of family Liliaceae, a hyperglycemia-reducing agent containing Aloe Vera extract of family Liliaceae as an active component an extract of the Aloe belief of family Liliaceae, application of Aloe Vera extract of family Liliaceae containing mixed compound cyclolanostane and compound lophenol in certain amount to produce a hyperglycemia-reducing agent, introduction mode of Aloe Vera extract of family Liliaceae containing mixed compound cyclolanostane and compound lophenol in certain amount to reduce hyperglycemia in the medically indigent patient.

EFFECT: extract disclosed above develops sufficient pharmacological activity as applied in food industry and is characterised by maximally low content of anthraquinone compound.

13 cl, 3 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmacy. Alchemilla herb milled to particle size 3 mm is extracted with treated water in ratio raw material-extractant 1:10 by expedited fraction maceration in three-staged heating to 90°-95°C: within 1 hour, 45 minutes and 30 minutes. The combined extracts are settled, filtered, decanted, softened by steam and dried in a flash drier.

EFFECT: invention allows representing the specified object matter.

6 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns novel pyrazole derivatives of the formula (IIIa) , where R1 is T-(ring D), where ring D is naphthyl or phenyl optionally substituted by -R5; Rx, Ry, R2, R2' and R5 are as defined in the claim; and pharmaceutical composition containing claimed compounds. Compounds inhibit protein kinases such as Aurora-2, GSK-3 or Src and can be applied in treatment methods for diseases mediated by the indicated protein kinases, such as cancer, diabetes and Alzheimer's disease.

EFFECT: compounds also applicable in methods of hyperphosphorylated protein Tau products inhibition and β-catenin phosphorylation inhibition.

24 cl, 12 tbl, 292 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel compounds of the formula I and their pharmaceutically acceptable salts. Claimed compounds display PPAR agonistic effect. In the general formula I A is O; X is a link or CH2; R1 is selected out of C1-C3alkyl; each R4 is independently selected out of group including halogen or -OC1-C3alkyl, where -OC1-C3alkyl can be optionally substituted by 1-3 F; each R5 is independently selected out of group including F, CI; R6 is selected out of group including C2-C5alkyl and -CH2cyclopropyl; m is 0; n is integer 1-2; p is integer 0-1.

EFFECT: pharmaceutical composition including claimed compound as active component.

11 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes solid dispersed measured drug including a core with pharmacological agent dispersed in the first matrix for controlled liberation at relatively low speed; and coating covering the core and including the agent dispersed in the second matrix for controlled liberation at relatively high speed. The first matrix can be represented by cross-linked starch with high amylose content, and the second matrix can be represented by polyvinylacetate and polyvinylpyrrolidone mix. Solid measured drug is preferably a pill.

EFFECT: reduced administration frequency, relatively stable medicine concentration in organism for a given time period and reduced undesired side effect frequency and intensity due to reduction of high concentrations in plasma.

19 cl, 5 dwg, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: claimed composition contains core including Rabeprasol or pharmaceutically acceptable salt thereof as acid secretion inhibitor in stomach and basic compound, intermediate coat coating the core, and overcoat applied on intermediate layer and containing water insoluble polymer and enterosoluble polymer. Also described is method for production of composition containing said preparation.

EFFECT: composition of prolonged storage time providing effective concentration of Rabeprasol in blood for long period of time.

16 cl, 5 dwg, 14 ex

FIELD: chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to solid medicinal formulations covered by enterosoluble envelope. Enterosoluble envelope represents a polymeric derivative as conglomerate of hydroxypropylcellulose and acetatephthalatecellulose in the presence of wax and Tween. Envelope has 1-10 layers and its mass is 0.1-10% of the solid pharmaceutical composition mass in the definite ratio of component in envelope. Also, invention represents methods for coating a pharmaceutical composition by such enterosoluble envelope. Invention provides the required disintegration of envelope for capsules as a whole and expanding assortment of active components among medicinal agents useful for applying the claimed cover and with inclusion to this enumeration of thermolabile medicinal immunobiological preparations.

EFFECT: improved and valuable properties of envelope, improved coating method.

9 cl, 7 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a composition comprising as active components pyridoxine hydrochloride and doxylamine succinate and a disintegrating agent that provide the following dissolving pattern: 20-90% of the total amount of each component among pyridoxine hydrochloride and doxylamine succinate are dissolved in 5-120 min. The composition is made preferably as a tablet with an enterosoluble envelope. The tablet has a core comprising pyridoxine hydrochloride and doxylamine succinate, and inactive excipients also. The composition is used in treatment of nausea, vomiting being especially in pregnancy. The composition provides rapid and simultaneous release of synergetic pair of indicated active components.

EFFECT: improved and valuable properties of composition.

24 cl, 2 dwg, 9 tbl, 3 ex

The invention relates to pharmaceutical compositions cefuroxime aksetila in the form of particles
The invention relates to chemical-pharmaceutical industry, namely intersolubility shell of solid dosage forms having two layers, one of which contains a film-forming component, and a second plasticizer, dye and technological additives

The invention relates to the field of pharmacology, and relates to a composition containing diphosphonic acid

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medical products and concerns the method of obtaining of a Solifenacin composition or its salts for use in a solid preparation which includes at least one stage chosen of the group consisting of (i) stage of wet granulation with use of a dissolvent for Solifenacin or its salts, thereat quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent makes less than 0.1 mg, (ii) stage of dicrease of quantity or rate of addition of a dissolvent if the dissolvent moves Solifenacin or its salt in an amorphous condition, and quantity of Solifenacin or its salts which should be dissolved in 1 ml of a dissolvent 10 mg or more and (iii) stage of activisation of process of crystallisation of a composition of the wet granulation received by means of a usual way. Also the pharmaceutical composition for use in the solid preparation, showing selective opposing action against muscarinic M3 receptors is revealed.

EFFECT: rising of stability of the compositions containing Solifenacin or its salt.

12 cl, 3 tbl, 10 ex

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