KR20050017090A - Process for producing coated preparation - Google Patents

Abstract

The present invention provides a method for preparing a formulation coated with pioglitazone hydrochloride, useful as a therapeutic agent for diabetes and the like and excellent in the characteristics of the formulation such as elution of pioglitazone hydrochloride.

Description

Production method of coating agent {PROCESS FOR PRODUCING COATED PREPARATION}

The present invention relates to a process for preparing a formulation coated with pioglitazone hydrochloride, useful as a therapeutic agent for diabetes and the like.

The following reports are reported for pharmaceutical compositions containing insulin sensitizers such as thiazolidinedione compounds and the like and biguanides.

1) EP-A-749751 contains at least one selected from α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statin compounds, squalene synthesis inhibitors, fibrate compounds, LDL catabolism enhancers and angiotensin converting enzyme inhibitors. Pharmaceutical formulations containing insulin sensitizers in combination with members have been reported.

2) WO 98/57634 reports pharmaceutical compositions containing insulin sensitizers, biguanide antihyperglycemic agents and pharmaceutically acceptable carriers.

3) WO01 / 35940 reports pharmaceutical compositions containing thiazolidinedione, metformin hydrochloride and a pharmaceutically acceptable carrier, wherein thiazolidinedione is formulated on the surface of metformin hydrochloride.

4) WO01 / 35941 reports pharmaceutical compositions containing thiazolidinedione, metformin hydrochloride and pharmaceutically acceptable carriers, wherein thiazolidinedione and metformin hydrochloride are each of their own pharmaceutically acceptable Dispersed in a carrier.

5) WO01 / 82875 discloses a core formulation comprising (a) a first layer containing pioglitazone hydrochloride or a pharmaceutically acceptable salt thereof as the active ingredient, and (b) a core containing a biguanide as the active ingredient. Water is reported, wherein at least a portion of the core is sealed with the first layer.

6) USP6403121 reports a core formulation comprising a first layer containing pioglitazone hydrochloride covering at least a portion of the core containing biguanides, wherein one or both of the core and the first layer are release modulators. For example, it is dispersed in polysaccharides and the like.

There is a need for development of a method for producing a coating coated with pioglitazone hydrochloride, which is useful as a therapeutic agent for diabetes and the like, and excellent in the characteristics of the preparation, such as solubility of pioglitazone hydrochloride.

In preparation of a coating coated with pioglitazone hydrochloride, the present inventors have applied a pioglitazone hydrochloride dispersion (organic solvent dispersion of pioglitazone hydrochloride) in an organic solvent, containing a coating substrate soluble in an organic solvent, to provide excellent pioglitazone hydrochloride solubility. It has been found that a coating may be obtained that indicates. The inventors further conducted a study based on this finding to complete the present invention.

Accordingly, the present invention relates to the following:

1) a process for preparing a coating comprising a coating with a dispersion of pioglitazone hydrochloride in an organic solvent, the coating substrate being soluble in an organic solvent;

2) coatings obtained according to the process of 1) mentioned above;

3) the process of 1) mentioned above, which comprises coating the core containing the active ingredient with a dispersion of pioglitazone hydrochloride in an organic solvent, the coating substrate being soluble in an organic solvent;

4) The method of preparation of 3) above, wherein the active ingredient is a diabetes therapeutic agent;

5) The process of 4) mentioned above, wherein the diabetic agent is biguanide;

6) the process of 5) mentioned above, wherein the biguanide is metformin hydrochloride;

7) The process of 1) mentioned above, wherein the organic solvent is an alcohol or a ketone;

8) the process of 1) mentioned above, wherein the organic solvent is ethanol;

9) The process of 1) mentioned above, wherein the coating substrate soluble in the organic solvent is polyvinylpyrrolidone;

10) A method for improving the dissolution of pioglitazone hydrochloride from a formulation coated with pioglitazone hydrochloride, which is coated with a dispersion of pioglitazone hydrochloride in an organic solvent containing a coating substrate soluble in an organic solvent at the time of preparation of the formulation. A method comprising doing so;

11) Coatings obtained according to the above-mentioned production method of 1), in 50 minutes in a dissolution test by a rotating basket method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 ° C., 100 rpm. Coatings exhibiting at least% pioglitazone hydrochloride elution;

12) For the coating obtained according to the above-mentioned production method of 1), 50% in 15 minutes in a dissolution test by the puddle method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 ° C., 50 rpm Coating agents exhibiting the above-described pioglitazone hydrochloride elution.

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

The organic solvent dispersion to be used in the present invention may be an organic solvent solution or an organic solvent suspension.

As the organic solvent, for example, alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, 2-methyl-1-propanol and the like; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; Esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, ethyl formate and the like; Hydrocarbons such as heptane and the like; Halogenated hydrocarbons such as dichloromethane and the like can be mentioned. The organic solvents may be used in a suitable ratio and in a mixture of two or more thereof. The organic solvent may contain water. When the organic solvent contains water, the ratio of water to organic solvent is for example 50% (W / W) or less, preferably 30% (w / w) or less, more preferably 20% (W / W) or less.

The organic solvent is preferably alcohol or ketone, more preferably methanol, ethanol, propyl alcohol, isopropyl alcohol, acetone and the like. Of these, ethanol is preferred.

The concentration of pioglitazone hydrochloride in the organic solvent dispersion is, for example, 1-25% (W / W), preferably 1-15% (W / W). The above concentration range is preferable in view of coating workability, content uniformity of pioglitazone hydrochloride in the obtained coating agent, and the like.

"Dispersions of pioglitazone hydrochloride in organic solvents" (hereinafter sometimes abbreviated as dispersions of the present invention) contain coating substrates that are soluble in organic solvents.

As used herein, a coating substrate soluble in an organic solvent means a coating substrate that can be dissolved in a mixture of the above-mentioned organic solvents (the organic solvent may be a mixture of two or more thereof and may contain water).

As used herein, "soluble in organic solvent" means a property that is dissolved in an organic solvent at a rate of 2% (W / V) or more, for example, at room temperature (preferably 20 ° C).

As "coating substrates soluble in organic solvents", for example, cellulose polymers (eg hydroxypropyl cellulose, hydroxyethyl cellulose, etc.); Synthetic polymers such as polyvinylacetal diethylaminoacetate [AEA (trade name), SANKYO CO., LTD.], Aminoalkylmethacrylate copolymer E [Eudragit E (trade name), Rohm Pharma], polyvinylpyrrolidone Etc.) may be mentioned.

The aforementioned coating substrates may be mixtures of two or more thereof in suitable ratios.

The coating substrate soluble in the organic solvent is preferably polyvinylpyrrolidone, hydroxypropyl cellulose, or the like, more preferably polyvinylpyrrolidone.

Coating substrates soluble in organic solvents may be dissolved or suspended in the dispersions of the present invention. For efficient preparation of coatings with good content uniformity and formulation strength of pioglitazone hydrochloride, the coating substrate is preferably dissolved in the dispersion of the invention.

The dispersions of the present invention may further contain coating additives. As the coating additive, for example, shading and / or coloring agents such as titanium oxide, talc, ferric oxide and the like; Plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbate 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, carmellose calcium, crospovidone and the like can be mentioned.

If the coating additives are not soluble in the organic solvent, their average particle size is preferably 500 μm or less, more preferably 150 μm or less, particularly preferably 75 μm or less. When a coating additive having the above average particle size is used, a coating having excellent content uniformity and formulation strength of pioglitazone hydrochloride can be efficiently obtained.

The concentration of the coating substrate soluble in the organic solvent in the dispersion of the present invention is, for example, 1-25% (W / W), preferably 2-20% (W / W). The concentration range is preferable in view of coating workability, content uniformity of pioglitazone hydrochloride in the coating agent obtained, and the like.

The concentration of the coating additive in the dispersion of the present invention is, for example, 0.2-25% (W / W), preferably 0.5-15% (W / W). The concentration range is preferable in view of coating workability, content uniformity of pioglitazone hydrochloride in the coating agent obtained, and the like.

As a core to be coated with a dispersion of pioglitazone hydrochloride in an organic solvent, sometimes abbreviated to the core of the present invention, which contains a coating substrate soluble in an organic solvent, for example solid preparations such as tablets, capsules, granules, powders, Premises may be mentioned. Solid formulations may be controlled release formulations such as immediate release formulations, delayed release formulations (sustained release formulations) and the like. Solid formulations may contain additives conventional in the pharmaceutical formulation art and may also be prepared according to known methods. As the additive, for example, excipients, disintegrants, binders, lubricants, colorants, pH adjusting agents, surfactants, sustained-release agents, stabilizers, acidulants, flavoring agents, glidants and the like can be mentioned. Such additives are used in amounts commonly used in the pharmaceutical formulation art.

As excipients, for example, starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized 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 carbonates, calcium silicates and the like can be mentioned.

As the disintegrant, for example, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch and the like are used. 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 solid preparation.

As the binder, for example, crystalline cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, gum arabic powder and the like can be mentioned. The amount of the 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 solid preparation.

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

As the colorant, for example, food colorings such as food yellow No. 5, food red No. 2, food blue No. 2 and the like, food crimson pigments, ferric oxide and the like can be mentioned.

As the pH adjusting agent, citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salts and the like can be mentioned.

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

As sustained-release agents, for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose (preferably hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208, etc.), cellulose acetate (preferably acetyl content 39.3) -40% phosphorus cellulose acetate), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, ethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose, sodium carboxymethyl cellulose and the like; Sodium alginate, carboxyvinyl polymer; Acrylic acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma] and the like can be mentioned. . Sustained release agents include, for example, flow enhancers (eg, sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (preferably polyethylene glycol 400, etc.), propylene glycol, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, polyvinyl alcohol, methacrylic acid copolymer), plasticizers (e.g. triacetin, acetylated monoglycerides, grapeseed oil, olive oil, sesame oil, acetyltributyl citrate, acetyltriethyl Citrate, glycerin sorbitol, diethyl oxalate, diethyl maleate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, Glycerol Tributi Site) it may contain the like. Preferred examples of sustained-release agents include (1) semipermeable membrane coatings containing cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400, etc.) and triacetin; (2) sustained release compositions containing sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208 and microcrystalline cellulose and the like can be mentioned.

As stabilizers, for example, tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin and the like can be mentioned.

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

As the fragrance, for example, menthol, peppermint oil, lemon oil, vanillin and the like can be mentioned.

As the glidant, for example, hard silicic anhydride, hydrated silicon dioxide and the like can be mentioned.

The above-mentioned additives may be used in a mixture of two or more thereof at an appropriate ratio.

The core of the present invention preferably contains the active ingredient. As the active ingredient used herein, there may be mentioned antidiabetic agents, antidiabetic agents, antihypertensive agents, anti-obesity agents, diuretics, antithrombotic agents and the like. The active ingredient may be a low molecular weight compound, a high molecular weight protein, a polypeptide or an antibody, a vaccine, or the like. The active ingredient may be a mixture of two or more ingredients in an appropriate ratio.

The use of a core containing the active ingredient in the core of the present invention in this manner is, for example, 1) enhancing the action of pioglitazone hydrochloride or the active ingredient (synergistic effect of the pharmaceutical formulation action), 2) reducing the dose of pioglitazone hydrochloride or the active ingredient. (Lower effect of pharmaceutical formulations compared to single drug administration), and 3) superior effects such as reduced secondary action of pioglitazone hydrochloride or active ingredient.

Examples of antidiabetic agents include insulin preparations (eg, animal insulin preparations extracted from the pancreas of cattle, pigs; human insulin preparations synthesized by genetic engineering techniques using E. coli or yeast; zinc insulin; protamine zinc insulin; fragments of insulin or Insulin sensitizers (e.g., pioglitazone or hydrochloride, rosiglitazone or maleate thereof, GI-262570, legic acid (JTT-501), netoglitazone (MCC-555), such as derivatives (e.g., INS-1, etc.) , YM-440, KRP-297, CS-011, FK-614, compounds described in WO99 / 58510 (e.g. (E) -4- [4- (5-methyl-2-phenyl-4-oxazolylmethoxy ) Benzyloxyimino] -4-phenylbutyric acid), ragaglitazar (NN-622), tesaglitazar (AZ-242), BMS-298585, ONO-5816, LM-4156, BM-13-1258, MBX-102, GW-1536, LY-519818, etc.), α-glucosidase inhibitors (e.g., boliboose, acarbose, miglitol, emiglitate, etc.) , Biguanides (eg phenformin, metformin, buformin, or salts thereof (eg hydrochloride, fumarate, succinate), etc.), insulin secretagogues [sulfonylurea (eg, tolbutamide, Glybenclamide, glyclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glymepiride, glypizide, glybazole, etc.), repaglinide, nateglinide, mitiglinide or these Calcium hydrate, GLP-1, etc.], dipeptidyl peptidase IV inhibitors (eg, NVP-DPP-278, PT-100, NVP-DDP-728, LAF237, etc.), β3 agonists (eg, CL-316243, SR) -58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.), amylin agonists (e.g., frramintide, etc.), phosphotyrosine phosphatase inhibitors ( For example, vanadic acid, etc., Glucose-synthesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6) Phosphatase inhibitors, glucagon antagonists, and the like) and SGLUT (sodium-glucose coatrantpoter) inhibitors (eg, T-1095, etc.).

Examples of agents for treating diabetic complications include aldose reductase inhibitors (e.g., tolesatt, epalestat, genarestad, zopolet, minaret, fidarestat (SNK-860), CT-112, etc.), neurotrophic factors (e.g., NGF, NT-3, BDNF, etc.), neurotrophin production-secretion promoters [eg, neurotropin production-secretion promoters described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl) -1-imidazolyl) -5- (3- (2-methylphenoxy) propyl) oxazole, etc.), PKC inhibitors (eg, LY-333531, etc.), AGE inhibitors (eg, ALT946, pimagedin, Pyratoxanthin, N-phenacylthiazolium bromide (ALT766), EXO-226, etc.), active oxygen trapping agents (eg, thioctic acid, etc.) and cerebral vasodilators (eg, thiaprid, mexyltine, etc.).

Examples of therapeutic agents for hyperlipidemia include HMG-CoA reductase inhibitors (e.g. pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rifantyl, cerivastatin, itavastatin, ZD-4522, or salts thereof (e.g., sodium salts, Fibrate compounds (e.g., bezafibrate, beclofibrate, vinibibrate, cipropibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibate) Brozil, nicofibrate, pyrifibrate, ronifibrate, simfibrate, theofibrate and the like, squalene synthetase inhibitors (e.g., compounds described in WO97 / 10224 (e.g., N-[[(3R, 5S)- 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] piperidine-4-acetic acid), ACAT inhibitor (Eg, Avasimibe, Eflucimibe, etc.), anion exchange resins (eg, cholestyramine, etc.), probucol, nicotinic acid drugs (eg, nicomol, niceritrol, etc.), ethyl Icosapentatate, vegetable sterols (eg, soysterol, γ-orizanol, and the like) and the like.

Examples of antihypertensive agents include angiotensin converting enzyme inhibitors (such as captopril, enalapril, delapril, etc.), angiotensin II antagonists (such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, Irbesartan, tasosartan, etc.), calcium antagonists (eg, manidipine, nifedipine, nicardipine, amlodipine, eponidipine, etc.), potassium channel openers (eg, leprochromalim, L-27152, AL 0671 , NIP-121, etc.), clonidine, and the like.

Examples of anti-obesity agents include, but are not limited to, central anti-obesity agents (e.g., dexfenfluramine, fenfluramine, phentermin, sibutramine, ampfepramone, dexamphetamine, magdol, phenylpropanolamine, clobenzorex, etc.), pancreatic lipase inhibitors (e.g. , Olistat, etc.), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140, etc.), peptide appetite loss Agents (eg, peptin, CNTF (ciliary neurotrophic factor), etc.), cholecystokinin agonists (eg, lintitript, FPL-15849, etc.) and the like.

Examples of diuretics include xanthine derivatives (such as sodium salicylate and theobromine, calcium salicylate and theobromine, etc.), thiazide preparations (such as ethiazide, cyclopentthiazide, trichloromethazide, hydrochlorothiazide, Hydroflumethiazide, benzylhydrochlorothiazide, fenflutizide, polythiazide, methiclothiazide, etc.), anti-aldosterone agents (e.g. spironolactone, triamterene, etc.), carbonate dehydratase inhibitors (E.g., acetazolamide, etc.), chlorobenzenesulfonamide preparations (e.g., chlortalidone, mepruside, indamide, etc.), azosemide, isosorbide, ethacrynic acid, pyretanide, bumetanide, Furosemide and the like.

Examples of antithrombotic agents include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium, etc.), warfarin (eg, warfarin potassium, etc.), antithrombin drugs (eg, aragatavan, etc.), thrombolytics (eg, euro Kinases, tisokinases, alteplases, natateases, monteplases, pamitheplases, etc.), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, cilostazol, ethyl isosaptate, veraprost sodium, sarfogrerel Latex hydrochloride, etc.), and the like.

The active ingredient is preferably an antidiabetic agent, more preferably biguanide, particularly preferably metformin or a salt thereof (preferably metformin hydrochloride).

The amount of active ingredient 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 is preferably a tablet containing the active ingredient (preferably an antidiabetic agent, more preferably biguanide, particularly preferably metformin hydrochloride). The shape of the tablet may be any of pills, caplets, ovals and the like. Tablets may be prepared, for example, by mixing or granulating the active ingredient with the aforementioned additives, according to methods commonly used in the pharmaceutical formulation field, and then compression molding the mixture or granules obtained after mixing.

Here, mixing is performed using, for example, a mixer such as a V-type mixer, a tumbler mixer, and the like, and granulation is performed using, for example, a high speed mixing granulator, a fluidized bed granulator-dryer, and the like. For compression molding, punching is generally performed at a pressure of 5-35 kN / cm ² using a single punch tablet press, rotary tablet press, and the like.

When the active ingredient contained in the core of the present invention is not a pharmaceutical preparation for once-daily administration (eg, for a pharmaceutical preparation for twice- or three-day administration), the core containing the active ingredient is preferably Delayed release formulation.

If the mixing stability of the pioglitazone hydrochloride and the active ingredient contained in the core of the present invention is poor, the core containing the active ingredient may be coated with the above-mentioned coating substrate or the like.

The core of the present invention is more preferably a delayed release formulation (preferably a tablet) containing biguanide (preferably metformin hydrochloride). As such preparations, mention may be made, for example, of controlled release pharmaceutical formulation tablets described in WO99 / 47125, two-layer controlled release delivery systems described in WO99 / 47128, controlled release oral pharmaceutical formulations described in USP6340475 and the like.

As a delayed-release preparation containing biguanides,

(1) Biguanide-containing tablets coated with a semipermeable membrane coating containing cellulose acetate (preferably cellulose acetate with an acetyl content of 39.3-40%), polyethylene glycol (preferably polyethylene glycol 400, etc.) and triacetin (The semipermeable membrane coating can have pores or pores);

(2) tablets obtained by compression-molding the mixture after mixing a sustained release composition containing sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose 2910, hydroxypropylmethyl cellulose 2208 and crystalline cellulose and biguanide desirable.

In the production method of the present invention, the coating is carried out according to known methods. For example, the coating is performed using a film coating apparatus.

The coating is also carried out so that the core of the invention is generally 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 coating agent obtained.

In addition, the "coated formulation coated with pioglitazone hydrochloride" (hereinafter sometimes abbreviated to the coating agent of the present invention) obtained according to the preparation method of the present invention may be coated for the purpose of improving the formulation strength, coloring of the coating agent, and the like. The coating can be applied according to known methods and for example using the above mentioned coating substrates and the like.

As dosage forms of the coatings of the invention, mention may be made, for example, of tablets, capsules, granules, powders, oral tablets and the like. The dosage form of the coating is preferably a tablet. The shape of the tablet may be any of pills, caplets, ovals and the like. In addition, a label or text may be printed on the tablet for identification, and distinct lines may be drawn to facilitate segmentation.

The amount of active ingredient in the coating of the present invention is generally 0.01-99 parts by weight, preferably 0.1-99 parts by weight, for example per 100 parts by weight of the coating. In particular, when the active ingredient is biguanide (preferably metformin hydrochloride), the amount of biguanide in the coating is generally 5-98 parts by weight, preferably 15-96 parts by weight per 100 parts by weight of the coating, for example. It is wealth.

The amount of pioglitazone hydrochloride in the coating of the present invention is, for example, generally 0.01-25 parts by weight, preferably 0.01-15 parts by weight, more preferably 0.5-15 parts by weight per 100 parts by weight of the coating.

Coatings of the present invention can be safely orally administered to mammals (eg, mice, rats, rabbits, cats, dogs, cattle, horses, monkeys, humans, etc.).

The coating agent of the present invention is excellent in the characteristics of the formulation, such as solubility of pioglitazone hydrochloride, and the like, for example, diabetes (eg, type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), hyperlipidemia (eg, hypertriglyceridemia, Hypercholesterolemia, hypo-HDL-emia, postprandial hyperlipidemia, etc.), impaired glucose tolerance [IGT (damaged glucose tolerance)], diabetic complications [eg neuropathy, nephropathy, retinopathy, cataracts, macroangiopathy, osteopenia, hypertension Osmotic diabetic coma, infectious disease (e.g. respiratory infection, urinary tract infection, gastrointestinal tract infection, skin soft tissue infection, lower limb infection, etc.), diabetic necrosis, dry mouth, deafness, cerebrovascular disorders, peripheral blood circulation disorders, etc.], Obesity, osteoporosis, cachexia (e.g. cancer cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia Or cachexia due to acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary syndrome, kidney disease (e.g., diabetic nephropathy, glomerulonephritis, glomerulosclerosis, kidney disease, hypertensive nephropathy, terminal stage kidney disease, etc.), muscular dystrophy , Myocardial infarction, angina pectoris, cerebrovascular accident (eg cerebral infarction, cerebral stroke), insulin resistance syndrome, syndrome X, hyperinsulinemia, hyperinsulinemia-induced sensory disorder, tumor (eg leukemia, breast cancer, prostate cancer, skin cancer Irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g. Alzheimer's disease, chronic rheumatoid arthritis, modified spondylitis, modified osteoarthritis, back pain, gout, postoperative or traumatic inflammation, swelling relief, neuralgia, sore throat, cystitis, hepatitis) (Including nonalcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease, ulcerative colitis, etc., visceral obesity syndrome, arteriosclerosis (e.g., It is useful as a preventive or therapeutic agent for atherosclerosis or the like the like).

The coatings of the present invention can also be used for secondary prevention of various diseases mentioned above (such as secondary prevention of cardiovascular events such as heart infarction) and inhibition of progression (such as inhibiting the progression of impaired glucose tolerance to diabetes, inhibiting the progression of atherosclerosis in diabetic patients). Useful for

The dosage of the 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 amount of pioglitazone hydrochloride for adults (60 kg body weight). to be.

When the coating of the present invention is obtained using a core containing the active ingredient, the coating preferably contains an effective amount of the active ingredient. For example, when the active ingredient is biguanide (preferably metformin hydrochloride), the effective amount is 125-2550 mg / day, preferably 250-2550 mg / day for adults (60 kg body weight).

The coating agent of the present invention may be used in combination with one or more pharmaceutical agents (hereinafter sometimes abbreviated as concomitant drugs) selected from antidiabetic agents, diabetic complications, hyperlipidemia agents, antihypertensive agents, anti-obesity agents, diuretics, antithrombotic agents and the like. As the combination drug, those exemplified above as active ingredients can be used. The administration time of the coating agent and the concomitant drug of the present invention is not limited, and they may be co-administered or staggered to the administered subject. The dose of the concomitant drug may be appropriately determined based on the dose used clinically. In addition, the mixing ratio of the coating agent and the concomitant drug of the present invention may be appropriately determined depending on the subject to be administered, the route of administration, the target disease, the condition, the combination, and the like. For example, when the subject to be administered is a human, the combination drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the coating agent.

The use of the concomitant drug in this manner is, for example, 1) enhancing the action of the coating or concomitant drug of the present invention (synergistic effect of the pharmaceutical agent action), 2) decreasing the dose of the coating or concomitant drug of the present invention (pharmaceutical preparation compared to single drug administration). Dose reducing effect), 3) a secondary effect of the coating or concomitant drug of the present invention.

The invention also relates to "method for improving the dissolution of pioglitazone hydrochloride from a formulation coated with pioglitazone hydrochloride", wherein the pioglitazone hydrochloride dispersion in an organic solvent contains a coating substrate soluble in an organic solvent when the formulation is prepared. To a method comprising the coating of "

The use of the preparation method of the present invention in the preparation of a formulation coated with pioglitazone hydrochloride can provide a coating with good solubility of pioglitazone hydrochloride.

The present invention also shows "at least 50% pioglitazone hydrochloride elution within 15 minutes in a dissolution test by a rotating basket method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at" 37 ° C, 100 rpm. Coating agent obtained according to the production method ". The dissolution test used herein is performed according to the method described in the Japanese Pharmacopoeia 14th Edition. "Hydrochloric acid-potassium chloride buffer (pH 2.0)" used as test solution can be prepared according to known methods. The amount of hydrochloric acid-potassium chloride buffer used as test solution is generally 900 ml.

According to the preparation method of the present invention, in the dissolution test by rotating basket method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 ° C., 100 rpm, at least 50% of pioglitazone hydrochloride elution within 15 minutes Coatings obtained "can be safely orally administered to mammals (eg, mice, rats, rabbits, cats, dogs, cows, horses, monkeys, humans, etc.) as in the coatings of the invention mentioned above, wherein the target disease , Capacity and the like are the same as in the coating of the present invention mentioned above.

The present invention also shows "at least 50% pioglitazone hydrochloride elution within 15 minutes in a dissolution test by the puddle method using hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution at" 37 ° C, 50 rpm. Coatings obtained according to the process ". The dissolution test used herein is performed according to the method described in the Japanese Pharmacopoeia 14th Edition. "Hydrochloric acid-potassium chloride buffer (pH 2.0)" used as the test solution can be prepared according to known methods. The amount of hydrochloric acid-potassium chloride buffer used as test solution is generally 900 ml.

Obtained according to the preparation method of the present invention, which exhibits at least 50% pioglitazone hydrochloride elution within 15 minutes in a dissolution test by the Puddle method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 ° C., 50 rpm. Coatings "can be safely orally administered to mammals (eg, mice, rats, rabbits, cats, dogs, cows, horses, monkeys, humans, etc.) as in the coatings of the invention mentioned above, wherein the target disease, Doses and the like are the same as in the coatings of the present invention mentioned above.

The present invention is described in more detail by the following examples, reference examples and experimental examples, but should not be considered as limiting.

As a formulation additive (e.g., D-mannitol, corn starch, hydroxypropyl cellulose, magnesium stearate, crystalline cellulose, polyvinylpyrrolidone polyethylene glycol 6000, titanium oxide) used in the following examples and reference examples, Japan We used those that could meet the standards of the 14th Pharmacopoeia.

Example 1

Polyvinylpyrrolidone (K-30) (18.9 g), polyethylene glycol 6000 (3.6 g) and pioglitazone hydrochloride (7.5 g, average particle size 12 μm) were dispersed in ethanol (170 g) to obtain a coating solution.

Glucophage XR tablet (trade name) (300 g) (sustained-release tablet containing 500 mg of metformin hydrochloride) (manufactured by Bristol-Myers Squibb) was supplied to a film coating apparatus (Hicoater-Mini, Freund Industrial Co. Ltd.), Coating at the inlet temperature of 80 ° C. with the mentioned coating solution (spray rate: 1.0 g / min) gave a coating containing 500 mg of metformin hydrochloride / 16.53 mg of pioglitazone hydrochloride.

Example 2

Hydroxypropyl cellulose (26.4 g, Grade L, Nippon Soda Co., Ltd.), polyethylene glycol 6000 (1.32 g), titanium oxide (2.64 g) and pioglitazone hydrochloride (16.5 g) in ethanol (297 g) Dispersion gave a coating solution.

The tablet (300 g) obtained in Reference Example 1 was fed to a film coating apparatus (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above-mentioned coating solution at an inlet temperature of 60 ° C., weighing 260 mg per tablet. A coating agent was obtained.

Example 3

Hydroxypropyl cellulose (26.4 g, grade SSL, Nippon Soda Co., Ltd.), polyethylene glycol 6000 (1.32 g), titanium oxide (2.64 g) and pioglitazone hydrochloride (16.5 g) in ethanol (297 g) Dispersion gave a coating solution.

The tablet (250 g) obtained in Reference Example 1 was supplied to a film coating apparatus (Hicoater-Mini, Freund Industrial Co. Ltd.) and coated with the above-mentioned coating solution at an inlet temperature of 60 ° C., weighing 259.7 mg per tablet. A coating agent was obtained.

Reference Example 1

D-mannitol (2176 g) and corn starch (918 g) were charged to a fluid bed granulation-dryer (FD-3S, manufactured by POWREX CORPORATION) and sprayed with an aqueous solution (1700 g) containing hydroxypropyl cellulose (102 g). After granulation, granules were obtained through a drying step. Crystalline cellulose (160.2 g) and magnesium stearate (32 g) were added to the obtained granulated powder (3012 g) and mixed. The granulated powder mixture obtained was purified by tablet press (Correct 19K, manufactured by Kikusui Seisakusho Ltd.) to obtain tablets weighing 244 mg per tablet (tablet size: 8.5 mm φ, compression pressure 9KN / punch).

Experimental Example 1

The coatings obtained in Example 1 mentioned above were evaluated for solubility of pioglitazone hydrochloride by a rotating basket method (100 rpm) using 0.3 M hydrochloric acid-potassium chloride buffer (900 mL, 37 ° C., pH 2.0). The results are shown in Table 1.

Dissolution of pioglitazone hydrochloride (%) time 15 mins 30 minutes 45 mins 60 mins Example 1 69.3 77.7 85.5 91.4

As shown in Table 1, the coatings obtained by the production process of the present invention showed good pioglitazone hydrochloride solubility.

Experimental Example 2

The coatings obtained in Examples 2 and 3 mentioned above were subjected to the solubility of pioglitazone hydrochloride by puddle method (50 rpm) using 0.3 M hydrochloric acid-potassium chloride buffer (900 mL, 37 ° C., pH 2.0). Evaluated. The results are shown in Table 2.

Dissolution of pioglitazone hydrochloride (%) time 15 mins 30 minutes 45 mins 60 mins Example 2 69 93 99 101 Example 3 72 97 99 100

As shown in Table 2, the coatings obtained by the production process of the present invention showed excellent pioglitazone hydrochloride solubility.

The coating agent obtained by the production method of the present invention is useful as an antidiabetic agent and the like, and is excellent in the characteristics of the preparation, such as solubility of pioglitazone hydrochloride.

Claims (12)

A process for producing a coating comprising a coating with a dispersion of pioglitazone hydrochloride in an organic solvent, the coating substrate being soluble in an organic solvent. A coating obtained according to the method of claim 1. The process of claim 1 comprising coating the core containing the active ingredient with a dispersion of pioglitazone hydrochloride in an organic solvent, which contains a coating substrate soluble in the organic solvent. The method according to claim 3, wherein the active ingredient is a diabetes therapeutic agent. The method of claim 4, wherein the diabetes treatment agent is biguanide. 6. The process of claim 5 wherein the biguanide is metformin hydrochloride. The process according to claim 1, wherein the organic solvent is an alcohol or a ketone. The process according to claim 1, wherein the organic solvent is ethanol. The method of claim 1 wherein the coating substrate soluble in the organic solvent is polyvinylpyrrolidone. A method for improving the dissolution of pioglitazone hydrochloride from a formulation coated with pioglitazone hydrochloride, comprising coating with a dispersion of pioglitazone hydrochloride in an organic solvent containing a coating substrate soluble in an organic solvent at the time of preparation of the formulation. How to include. The coating agent obtained according to the preparation method of claim 1, wherein at least 50% of pioglitazone hydrochloride in a dissolution test by a rotating basket method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 ° C. and 100 rpm. Coatings exhibiting dissolution. The coating agent obtained according to the preparation method of claim 1, wherein at least 50% of pioglitazone hydrochloride is eluted within 15 minutes in a dissolution test by a puddle method using hydrochloric acid-potassium chloride buffer (pH 2.0) as a test solution at 37 ° C. and 50 rpm. Coating agent.