CN1761465B - Method for manufacturing coated formulation - Google Patents
Method for manufacturing coated formulation Download PDFInfo
- Publication number
- CN1761465B CN1761465B CN200480006889.9A CN200480006889A CN1761465B CN 1761465 B CN1761465 B CN 1761465B CN 200480006889 A CN200480006889 A CN 200480006889A CN 1761465 B CN1761465 B CN 1761465B
- Authority
- CN
- China
- Prior art keywords
- preparation
- pioglitazone hydrochloride
- coated formulation
- coating material
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
It is intended to provide a process for producing a preparation coated with pioglitazone hydrochloride which is useful as a remedy for diabetes, etc. and has excellent preparation characteristics such as elution properties of pioglitazone hydrochloride.
Description
Technical field
The present invention relates to the preparation method of the preparation (preparation) that applies with pioglitazone hydrochloride (pioglitazone hydrochloride), described preparation is as the therapeutic agent of diabetes etc.
Background technology
Below be about comprising report as the pharmaceutical composition of the insulin sensitiser thing of thiazolidinedione (thiazolidinedione) chemical compound etc. and biguanide (biguanide).
1) reported a kind of pharmaceutical agent (seeing EP-749751A), it contains the insulin sensitiser thing that combines with at least a following composition, and described composition is alpha-glucosidase inhibitor, aldose reductase inhibitor, biguanide, statin compound, (angle) zamene synthetic inhibitor, special class (fibrate) chemical compound of shellfish, LDL catabolism enhancer and angiotensin-convertion enzyme inhibitor.
2) reported a kind of pharmaceutical composition (seeing WO98/57634), it comprises insulin sensitiser thing, biguanide, hyperglycemia reagent and pharmaceutically acceptable carrier.
3) reported a kind of pharmaceutical composition (seeing WO01/35940), it comprises thiazolidinedione, metformin hydrochloride (metformin hydrochloride) and pharmaceutically acceptable carrier, and wherein thiazolidinedione is prepared on the surface of metformin hydrochloride.
4) a kind of pharmaceutical composition (seeing WO01/35941), it comprises thiazolidinedione, metformin hydrochloride and their own pharmaceutically acceptable carriers, and wherein thiazolidinedione and metformin hydrochloride are dispersed in respectively in the pharmaceutically acceptable carrier.
5) reported a kind of nuclear (core) preparation (seeing WO01/82875), it comprises (a) and contains pioglitazone hydrochloride or its pharmaceutically acceptable salt ground floor as active component, (b) contain the nuclear of biguanide as active component, wherein at least a portion nuclear is wrapped into by described ground floor.
6) reported a kind of nuclear preparation (seeing USP6403121), it comprises the ground floor that contains pioglitazone hydrochloride, this ground floor covers the nuclear that at least a portion contains biguanide, and a kind of in its center and the ground floor or both are dispersed in adjustment release agent (modulating release agent) as in the polysaccharide etc.
Summary of the invention
The preparation method that the purpose of this invention is to provide a kind of preparation that applies with pioglitazone hydrochloride, described preparation can be used as the therapeutic agent of diabetes etc., and storage stability can be excellent, and stripping property (dissolution) excellent performance of the characteristic example hydrochloric acid pioglitazone of said preparation.
The inventor finds, in the preparation that preparation applies with pioglitazone hydrochloride, by applying, can obtain the good coated formulation (coated preparation) of stripping property performance (the especially stripping property performance in 15 minutes of stripping property test beginning) of pioglitazone hydrochloride with the aqueous dispersion of pioglitazone hydrochloride that comprises low viscosity coating material (coating material).The inventor also makes further research based on this discovery, thereby has finished the present invention.
Therefore, the present invention relates to
1) preparation method of coated formulation, it comprises that the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material applies;
2) coated formulation that preparation method above-mentioned 1) obtains;
3) preparation method above-mentioned 1), wherein 5% viscosity in aqueous solution of low viscosity coating material is not more than 35mPas at 20 ℃;
4) preparation method above-mentioned 1), wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer;
5) preparation method above-mentioned 1), wherein the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material applies the nuclear that comprises active component;
6) preparation method above-mentioned 5), wherein active component is the therapeutic agent of diabetes (diabetes);
7) preparation method above-mentioned 6), wherein the treatment of diabetes agent is a biguanide;
8) preparation method above-mentioned 7), wherein biguanide is a metformin hydrochloride;
9) preparation method above-mentioned 5), wherein active component is the therapeutic agent of hyperlipemia;
10) preparation method above-mentioned 9), wherein the therapeutic agent of hyperlipemia is the HMG-CoA reductase inhibitor;
11) a kind of method of improving pioglitazone hydrochloride stripping from the preparation that applies with pioglitazone hydrochloride, the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material when it is included in the described preparation of preparation applies;
12) coated formulation that preparation method above-mentioned 1) obtains, it discharges in 15 minutes in stripping property test and is no less than 50% pioglitazone hydrochloride, and described stripping property test is to use the hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by commentaries on classics basket method (basket method) under 37 ℃, 100rpm;
13) coated formulation that preparation method above-mentioned 1) obtains, it discharges in 15 minutes in stripping property test and is no less than 50% pioglitazone hydrochloride, and described stripping property test is to use the hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by oar method (paddle method) under 37 ℃, 50rpm; Or the like
The particle mean size of the pioglitazone hydrochloride of Shi Yonging is preferably 0.5-500 μ m, more preferably 1-150 μ m in the present invention.
The aqueous dispersion of Shi Yonging can be aqueous solution or waterborne suspension in the present invention.
The concentration of pioglitazone hydrochloride in the aqueous dispersion for example is 1-25% (W/W), is preferably 1-15% (W/W).From the operability that applies, the aspects such as content uniformity of pioglitazone hydrochloride consider that the concentration of these scopes is preferred the coated formulation that obtains.
" aqueous dispersion of pioglitazone hydrochloride " (hereinafter abbreviating dispersion of the present invention sometimes as) comprises the low viscosity coating material.
As what use herein, " low viscosity coating material " refers to, for example the viscosity in aqueous solution of its 5% (W/V) is at 20 ℃ of coating materials that are not more than 35mPas (preferably being not more than 30mPas, more preferably no more than 25mPas).When the concentration of coating material in aqueous solution, measuring condition (as measuring temperature) etc. not simultaneously, the viscosity of coating material also can change.When measuring condition not simultaneously, the coating material of viscosity number in above-mentioned range of viscosities when being transformed into 20 ℃, 5% (W/V) viscosity in aqueous solution is included in " low viscosity coating material " of the present invention.
For " low viscosity coating material ", can mention, for example hydroxypropyl cellulose (grade: SL, SSL (trade mark); Nippon Soda Co., Ltd.), hydroxypropyl emthylcellulose (grade: MW, E, EW (trade mark); Shin-Etsu Chemical Co., Ltd.) (grade: E-3 (trade mark); Nippon Soda Co., Ltd.), hydroxypropyl cellulose (grade: SSL, Nippon Soda Co., Ltd.) and hydroxypropyl emthylcellulose (grade: pre-composition E-3) (grade: SSM (trade mark), Nippon Soda Co., Ltd.), polyvinyl alcohol-polyethyleneglycol-graft copolymer (Kollicoat IR (trade mark), BAS F, Germany) etc.
Above-mentioned coating material can be the mixture of suitable two or more of ratio.When by mixing under proper ratio when being selected from coating material mixture that one or more and one or more high viscosity coating material in the above-mentioned coating material obtains and being " viscosity in aqueous solution of its 5% (W/V) is at 20 ℃ of coating materials that are not more than 35mPas ", this mixture can be used as " low viscosity coating material " of the present invention.As what use herein, " high viscosity coating material " refers to, for example the viscosity in aqueous solution of its 5% (W/V) is at 20 ℃ of coating materials greater than 35mPas.Its instantiation comprises hydroxypropyl cellulose (grade: L (trade mark); Nippon Soda Co., Ltd.) (grade: Klucel EF, Klucel LF (trade mark); Aqualon (USA)), hydroxypropyl emthylcellulose (grade: R (trade mark); Shin-Etsu Chemical Co., Ltd.), or the like.
The low viscosity coating material preferably includes the hydroxypropyl cellulose SL (viscosity of 5% aqueous solution under 20 ℃: about 24mPas; And/or the viscosity of 2% aqueous solution under 20 ℃: 3.0-5.9mPas), the hydroxypropyl cellulose SSL (viscosity of 5% aqueous solution under 20 ℃: about 8mPas; And/or the viscosity of 2% aqueous solution under 20 ℃: 2.0-2.9mPas), polyvinyl alcohol-polyethyleneglycol-graft copolymer [KollicoatIR (trade mark), BASF, the Germany] (viscosity of 5% aqueous solution under 20 ℃: about 18mPas) etc.
The low viscosity coating material can stripping property or is suspended in the dispersion of the present invention.In order to prepare coated formulation effectively at excellent performance aspect the intensity of the content uniformity of pioglitazone hydrochloride and preparation, preferably with the coating material stripping property in dispersion of the present invention.
Dispersion of the present invention can also comprise coating additive (coating additive).For coating additive, can mention, for example opacifier (shading agent) and/or coloring agent such as titanium dioxide (titaniumoxide), Talcum, ferrum oxide etc.; Plasticizer such as Polyethylene Glycol, triethyl citrate, Oleum Ricini, polysorbate etc.; Organic acid such as citric acid, tartaric acid, malic acid, ascorbic acid etc.; Lactose, D-mannitol, the low hydroxypropyl cellulose that replaces, carboxymethylcellulose calcium, crospovidone etc.
When coating additive is non-water-soluble, its particle mean size preferably is not more than 500 μ m, more preferably no more than 150 μ m, especially preferably is not more than 75 μ m.When use has the coating additive of described particle mean size, can obtain the coated formulation of excellent performance aspect the intensity of the content uniformity of pioglitazone hydrochloride and preparation effectively.
The concentration of low viscosity coating material is in dispersion of the present invention, for example 1-30% (W/W), preferably 1-25% (W/W), more preferably 2-25% (W/W).Consider the operability of coating, in the coated formulation that obtains the content uniformity etc. of pioglitazone hydrochloride, the concentration of these scopes is preferred.
The concentration of coating additive is in dispersion of the present invention, for example 0.2-35% (W/W), preferably 0.2-30% (W/W), more preferably 0.5-15% (W/W).Consider the operability of coating, in the coated formulation that obtains the content uniformity etc. of pioglitazone hydrochloride, the concentration of these scopes is preferred.
For the nuclear (hereinafter sometimes be called for short of the present invention nuclear) of desire, for example, can mention solid preparation such as tablet, capsule, granule, powder, lozenge (troche) etc. with the aqueous dispersion coating of the pioglitazone hydrochloride that comprises the low viscosity coating material.Solid preparation can be controlled release formulation, and for example direct delivery formulations discharges lasting preparation (extended release preparation) etc.Solid preparation can contain the conventional additives in the field of pharmaceutical preparations, and can be prepared according to known method.For additive, for example, can mention: excipient, disintegrating agent, binding agent, lubricant, coloring agent, pH regulator agent, surfactant, release continue agent (realease-sustaining agent), stabilizing agent, acidic flavoring agent (sour agent), flavoring agent, fluidizer (glidant) etc.These additives use with field of pharmaceutical preparations amount commonly used.
For excipient, for example, can mention: the starch of starch such as corn starch, potato starch, wheaten starch, rice starch, part pregelization, the starch of pregelization, porous (porous) starch etc.; Sugar and sugar alcohol such as lactose, fructose, glucose, D-mannitol, Sorbitol etc.; Anhydrous calcium phosphate, crystalline cellulose, winnofil, calcium silicates etc.
For disintegrating agent, for example, can mention carboxymethyl cellulose, carboxymethylcellulose calcium, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl starch etc.The use amount of disintegrating agent is preferably the 0.5-25 weight portion for per 100 weight portion solid preparations, more preferably the 1-15 weight portion.
For binding agent, for example, can mention: crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, gummi arabicum pulveratum etc.The use amount of binding agent is preferably the 0.1-50 weight portion for per 100 weight portion solid preparations, more preferably the 0.5-40 weight portion.
The preferred embodiment of lubricant comprises sucrose ester, sodium stearyl fumarate of magnesium stearate, calcium stearate, Talcum, fatty acid etc.
For coloring agent, for example, can mention that food coloring is as edible Huang No. 5, edible red No. 2, No. 2, edible indigo plant etc., food lake colours (food lake colors), ferrum oxide etc.
For the pH regulator agent, can mention citrate, phosphate, carbonate, tartrate, fumarate, acetate, amino acid salts etc.
For surfactant, can mention sodium stearyl sulfate, Tween 80, polyoxyethylene (160) polyoxypropylene (30) glycol (polyoxyethylene (160) polyoxypropylene (30) glycol) etc.
Continue agent for discharging, for example, can mention: cellulosic polymer such as hydroxypropyl cellulose, hydroxypropyl emthylcellulose (preferred hydroxypropyl methylcellulose 2910, hydroxypropyl methylcellulose 2208 etc.), cellulose acetate (preferred acetyl content is the cellulose acetate of 39.3-40%), cellulose diacetate, Triafol T, cellulose acetate propionate, ethyl cellulose, sodium carboxymethyl cellulose, crystalline cellulose sodium, carboxymethyl cellulose etc.; Sodium alginate, CVP Carbopol ETD2050; Acrylic polymer such as aminoalkyl methacrylate copolymer RS (Eudragit RS (trade mark), Rohm Pharma), EUDRAGIT NE 30 D EUDRAGIT NE 30D suspension (Eudragit NE (trade mark), Rohm Pharma) etc., or the like.Discharging lasting agent can comprise, for example, flux enhancer (flux enhancer) (for example: sodium chloride, potassium chloride, sucrose, Sorbitol, D-mannitol, Polyethylene Glycol (preferred PEG400 etc.), propylene glycol, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, polyvinyl alcohol, methacrylate polymer); Plasticizer (for example: glycerol acetate, acetylation mono glycerinate, Oleum Vitis viniferae, olive oil, Oleum sesami, acetyl tributyl citrate, acetyl triethyl citrate, glycerol Sorbitol (glycerin sorbitol), ethyl oxalate, ethyl maleate., DEF, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, glycerin tributyrate), or the like.Discharging the preferred embodiment that continues agent comprises: (1) contains the semipermeable membrane coating of cellulose acetate (preferred acetyl content is the cellulose acetate of 39.3-40%), Polyethylene Glycol (preferred PEG400 etc.) and glycerol acetate; (2) release that contains sodium carboxymethyl cellulose, hydroxypropyl methylcellulose 2910, hydroxypropyl methylcellulose 2208 and avicel cellulose continues compositions; Or the like.
For stabilizing agent, for example, can mention: tocopherol, sodium ethylene diamine tetracetate, nicotiamide, cyclodextrin etc.
For the agent of turning sour, for example, can mention: ascorbic acid, citric acid, tartaric acid, malic acid etc.
For acidic flavoring agent, for example, can mention: menthol, Oleum menthae, Fructus Citri Limoniae oil, vanillin etc.
For fluidizer, for example, can mention: light anhydrous silicic acid (light anhydrous silicicacid), hydrated SiO 2 etc.
Above-mentioned additive can suitable ratio the form of two or more mixture use.
Nuclear of the present invention preferably contains active component.As what use herein, can mention for active component: the therapeutic agent of treatment of diabetes agent, diabetic complication, the therapeutic agent of hyperlipemia, hypotensive agent, anti-obesity agent, diuretic, antithrombotic agent etc.These activating agents can be low molecular weight compound, high molecular weight protein, polypeptide or antibody, vaccine etc.Active component can be the mixture of two or more suitable components of ratio.
The nuclear that contains active component by this way as nuclear of the present invention provide excellent effect as: 1) improved the effect (to the cooperative effect of medicament effect) of pioglitazone hydrochloride or active component, 2) reduced the dosage (comparing the effect that reduces drug dose with the administration of single medicine) of pioglitazone hydrochloride or active component, 3) reduced the side effect (as weight increase effect, ketoacidosis, acidosis) of pioglitazone hydrochloride or active component, or the like.
The example of treatment of diabetes agent comprises: insulin preparation is (as the animal insulin preparation that extracts from the pancreas of cattle, pig; Adopt escherichia coli or yeast by the synthetic human insulin's preparation of technique for gene engineering; Insulin zinc; Insulin zinc protamine, the fragment of insulin or derivant (as INS-1 etc.), or the like), the insulin sensitiser thing is (as pioglitazone or its salt (preferred salt hydrochlorate), rosiglitazone (rosiglitazone) and salt thereof (preferred maleate), GI-262570, reglixane (JTT-501), netoglitazone (MCC-555), YM-440, KRP-297, CS-011, FK-614, the chemical compound of describing among the WO99/58510 (as (E)-4-[4-(5-methyl-2-phenyl-4-oxazolyl methoxyl group) benzyloxy imino group]-the 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.), alpha-glucosidase inhibitor is (as volibose, acarbose, miglitol, emiglitate (emiglitate) etc.), biguanide is (as phenformin, metformin, buformin, or its salt (example hydrochloric acid salt, fumarate, succinate) etc.), and insulin secretagogue (sulfonylureas (as tolbutamide, glibenclamide, Gliclazide, chlorpropamide, tolazamide, glyclopyramide, glimepiride, glipizide, glybuzole etc.), repaglinide, Nateglinide (nateglinide), Mitiglinide (mitiglinide) or its calcium salt hydrate, GLP-1 etc.), dipeptide peptidase (dipeptidylpeptidase) IV inhibitor is (as NVP-DPP-278, PT-100, NVP-DDP-728, LAF237, etc.), β 3 agonist are (as CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140 etc.), dextrin agonist (as Pramlintide etc.), phosphotyrosine phosphatase inhibitor (as vanadic acid sodium etc.), gluconeogenesis inhibitor (as glycogen phosphorylase inhibitors, G-6-Pase inhibitor, glucagon antagonist etc.) and SGLUT (sodium glucose co-transporter 2 is white) inhibitor (as T-1095 etc.).
The example of diabetes complicated Remedies comprises that aldose reductase inhibitor is (as tolrestat; epalrestat; zenarestat; zopolrestat; minalrestat (minalrestat); fidarestat (fidarestat) (SNK-860); CT-112 etc.); neurotrophic factor is (as NGF; NT-3; BDNF etc.), neurotrophin generation-secernent [as the neurotrophin generation-secernent (neurotrophin production-secretion promoters) in WO01/14372, described (as 4-(4-chlorphenyl)-2-(2-methyl isophthalic acid-imidazole radicals)-5-(3-(2-methylphenoxy) propyl group) oxazole etc.)], pkc inhibitor (as LY-333531 etc.); the AGE inhibitor is (as ALT946; pimagedine, pyratoxanthine, N-benzoyl thiazole
Bromide (N-phenacylthiazolium bromide) (ALT766), EXO-226 etc.), active oxygen cleanser (as thioctic acid etc.) and cerebral vasodilator (as tiapride, mexiletine etc.).
The example of remedy for hyperlipemia comprises that the HMG-CoA reductase inhibitor is (as pravastatin; simvastatin; lovastatin; atorvastatin; fluvastatin; fenofibrate; cerivastatin; he cuts down his spit of fland (itavastatin) for she, rosuvastatin (rosuvastatin) (ZD-4522), or their salt is (as sodium salt; calcium salt etc.); or the like), special class (fibrate) chemical compound of shellfish (rolls Bei Te as benzene, beclobrate; binifibrate; cyprofibrate, clinofibrate, clofibrate (clofibrate); clofibric acid; etofibrate, fenofibrate, gemfibrozil; nicofibrate; pirifibrate, Ronifibrate, simfibrate; Etophylline Clofibrate etc.); (angle) squalene synthase inhibitor is (as the chemical compound described among the WO97/10224 (as 1-[[(3R, 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2; the 3-Dimethoxyphenyl)-2-oxygen-1; 2,3,5-tetrahydrochysene-4; the 1-benzooxazepin-3-yl] acetyl group] piperidines-4-acetic acid (1-[[(3R; 5S)-and 1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxy-phenyl)-2-oxo-1; 2; 3,5-tetrahydro-4,1-benzooxazepin-3-yl] acetyl] piperidine-4-acetic acid); Deng); ACAT inhibitor (e.g., Avasimibe, Eflucimibe etc.); anion exchange resin (as colestyramine etc.); probacol, nicotinic acid medicine (as nicomol, niceritrol etc.); EPA-E (ethyl icosapentate); phytosterol class (plant sterols) (as Generol 122 (soysterol), gamma oryzanol (alcohol) etc.), or the like.
The example of hypotensive agent comprises: angiotensin-convertion enzyme inhibitor is (as captopril, enalapril, delapril etc.), the Angiotensin II antagonist (comes ester as Kan Deshatanxi, losartan, Yi Pusatan, valsartan, telmisartan, irbesartan, Tasosartan etc.), and the calcium antagonist (as Manidipine, nifedipine (nifedipine), nicardipine, amlodipine, efonidipine etc.), potassium channel is opened thing (openers) (as levcromakalim, L-27152, AL 0671, NIP-121 etc.), clonidine etc.
The example of anti-obesity agent comprises: act on anti-obesity agent on the central nervous system (as, dexfenfluramine, Fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, Mazindol, phenylpropanolamine, clobenzorex etc.), pancreatic lipase inhibitor (as orlistat etc.), and β 3 agonist (as CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ-40140 etc.), peptide appetite suppressant (peptidic anorexiants) (as leptin, CNTF (cilium neurotrophic factor) etc.), the cholecystokinin agonist is (as Lintitript (lintitript), FPL-15849 etc.), or the like.
The example of diuretic comprises: xanthine derivative is (as sodium salicylate and theobromine, calcium salicylate and theobromine etc.), the thiazide preparation (as ethiazide, cyclopenthiazide, trichloromethyl thiazine (trichloromethyazide), hydrodiuril, hydroflumethiazide, behyd, penflutizide, many thiazines, methyclothiazide etc.), aldosterone antagonist (antialdosterone) preparation (as spironolactone, triamterene etc.), carbonate dehydratase inhibitor (as acetazolamide etc.), chlorobenzene sulfanilamide (chlorobenzenesulfonamide) preparation (as chlortalidone, mefruside, indapamide etc.), azosemide, isosorbide, acidum ethacrynicum, piretanide, bumetanide, furosemide etc.
The example of antithrombotic agent comprises: heparin is (as heparin sodium, calciparine, dalteparin sodium etc.), tromexan ethyl acetate (as warfarin potassium etc.), antithrombotic drug (as aragatroban etc.), and thrombolytics (as urokinase, the different kinases of mercapto (tisokinase), organize the fibrinolysin activator, Nateplase (nateplase), Monteplase (monteplase), pamiteplase (pamiteplase) etc.), anticoagulant (example hydrochloric acid ticlopidine, cilostazol, EPA-E, Beraprost Sodium, sarpogrelate hydrochloride etc.), or the like.
Described active component is preferably the treatment of diabetes agent, more preferably biguanide, especially preferably metformin or its salt (preferred metformin hydrochloride).
In addition, the therapeutic agent of also preferred hyperlipemia is as active component.More preferably the therapeutic agent of hyperlipemia is the HMG-CoA reductase inhibitor.Particularly, preferred simvastatin etc.
The amount of the active component in nuclear of the present invention for example, is the 0.1-100 weight portion for per 100 weight portions nuclear of the present invention, preferred 1-99 weight portion.
Nuclear of the present invention is preferably the tablet that contains active component (preferred treatment of diabetes agent, more preferably biguanide, especially preferably metformin hydrochloride).The shape of tablet can be circle, capsule sheet shape (caplet), ellipse etc.Tablet can prepare by following manner, for example, according to the conventional method that adopts in field of pharmaceutical preparations above-mentioned additive and active component is mixed or pelletize, the mixture of compression forming gained or granule after mixing then.
Here, mixing is that rotary drum mixer etc. carry out by for example blender such as V-type blender, and pelletize uses for example mixed at high speed comminutor, fluidized bed pelletizer etc. to carry out.For compression forming, usually at 5-35kN/cm
2Pressure use down single punching tablet machine (single punch tabletingmachine), rotary tablet machine etc. to carry out punching press.
When the active component in being included in nuclear of the present invention was not the medicament that is administered once every day (for example being the medicament of administration in a day 2 times or 3 times), the nuclear that contains described active component was preferably sustained release formulation.
During the compatibility difference of pioglitazone hydrochloride in being included in nuclear of the present invention and active component, can be with the nuclear that contains active component with coatings such as above-mentioned coating materials.
Nuclear of the present invention is more preferably the sustained release formulation (preferred tablet) that contains biguanide (preferred metformin hydrochloride).For such preparation, for example, can mention the medicament tablet of the controlled release of describing among the WO99/47125, the double-deck controlled release delivery system of describing among the WO99/47128, the controlled release medicinal preparation for oral administration of describing among the USP6340475 etc.
For the sustained release formulation that contains biguanide, preferably:
(1) be coated with the tablet that contains biguanide of semipermeable membrane coating, it contains cellulose acetate (preferred acetyl content is the cellulose acetate of 39.3-40%), Polyethylene Glycol (preferred PEG400 etc.) and triacetin (described semipermeable membrane coating can have hole or aperture);
(2) tablet that obtains by the following method: the sustained-release composition that will contain Carboxymethyl cellulose sodium, hydroxypropyl methylcellulose 2910, hydroxypropyl methylcellulose 2208 and crystalline cellulose is mixed with biguanide, this mixture of compression forming then, or the like.
In preparation method of the present invention, apply according to known method.For example use coating device to apply.
In addition, so apply and make of the present invention checking be generally the 50-99 weight portion, be preferably the 70-99 weight portion, more preferably the 70-98 weight portion in the coated formulation of per 100 weight portion gained.
In addition, " with the preparation of pioglitazone hydrochloride coating " (hereinafter abbreviating coated formulation of the present invention sometimes as) that preparation in accordance with the present invention obtains can apply, purpose is to improve the preparation intensity of coated formulation, improve bitterness, increases light resistance, painted, or the like.Can and use for example above-mentioned coating material etc. to apply this coating according to known method.
For the dosage form of coated formulation of the present invention, for example, can mention tablet, capsule, granule, powder, lozenge etc.The dosage form of coated formulation is preferably tablet.In addition, the shape of tablet can be arbitrarily circle, capsule sheet shape, ellipse etc.In addition, on tablet, can stamp the mark or the letter that are used to discern, and can engrave separator bar so that cut apart.
The amount of the active component in coated formulation of the present invention, for example the coated formulation for per 100 weight portions is generally the 0.01-99 weight portion, is preferably the 0.1-99 weight portion.Especially, when active component is biguanide (preferred metformin hydrochloride), the content of biguanide in coated formulation, for example the coated formulation for per 100 weight portions is generally the 5-98 weight portion, is preferably the 15-96 weight portion.
The content of the pioglitazone hydrochloride in coated formulation of the present invention, for example the coated formulation for per 100 weight portions is generally the 0.01-30 weight portion, is preferably the 0.5-25 weight portion, more preferably the 0.5-10 weight portion.
Coated formulation of the present invention can be mixed with oral and to the medicament of mammal (as mice, rat, rabbit, cat, Canis familiaris L., cattle, horse, monkey, the mankind etc.) safety.
Coated formulation of the present invention the stripping property performance of preparation characteristic (preparation characteristics) example hydrochloric acid pioglitazone (especially after stripping property test beginning to the health administration after at once or 15 minutes after the stripping property performance) etc. aspect performance excellence, and the preventive drug or the therapeutic agent that can be used for following disease, described disease for diabetes for example (as type 1 diabetes, type 2 diabetes mellitus, gestational diabetes etc.), hyperlipemia is (as HTC, hypercholesterolemia, low hdl mass formed by blood stasis (hypo-HDL-emia), hyperlipemia etc. after the meal), glucose tolerance lowers (IGT (impaired glucose tolerance)), diabetic complication is (as neuropathy, nephropathy, retinopathy, cataract, macroangiopathy (macroangiopathy), osteopenia, diabetic coma, infectious disease is (as respiratory tract infection, urinary tract infection, gastrointestinal infection, skin soft-tissue infection, lower limb (inferior limb) infection etc.), the diabetic gangrene, xerostomia, hypoacusis, cerebrovascular disorder, peripheral blood circulation disorder etc.), obesity, osteoporosis, cachexia is (as cancer cachexia, the tuberculosis cachexia, the diabetes cachexia, the hematopathy cachexia, the endocrinopathy cachexia, infectious disease cachexia or the cachexia that causes because of acquired immune deficiency syndrome (AIDS)), fatty liver, hypertension, polycystic ovary syndrome, nephropathy is (as diabetic nephropathy, glomerulonephritis, glomerulosclerosis, the nephrotic syndrome, hypertensive nephrosclerosis, latter stage nephropathy etc.), the muscle nutrition imbalance, myocardial infarction, angina pectoris, the cerebrovascular accident situation is (as cerebral infarction, apoplexy), the glucagon syndrome, syndrome X, hyperinsulinemia, the inductive sense organ disorder of hyperinsulinemia, tumor is (as leukemia, breast carcinoma (breast cancer), carcinoma of prostate, skin carcinoma etc.), irritable bowel trace integration disease, acute or chronic diarrhea, inflammatory diseases is (as the Alzheimer disease, chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis distortion (osteoarthritis cleformans), pain in the lumbar region, gout, postoperative or wound inflammation, the elimination of swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis (comprises non-alcoholic liver fat too much (nonalcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory bowel disease (inflammatory bowel disease), ulcerative colitis etc.), internal organs hypertrophy (visceral obesity) syndrome, arteriosclerosis (as atherosclerosis etc.), or the like.
Coated formulation of the present invention also can be used for the secondary protection (secondaryprevention) (as for example secondary protection of myocardial infarction etc. of cardiovascular pathological changes) of above-mentioned various diseases and hold back the development (develop to diabetes as suppressing impaired glucose tolerance, suppress the arteriosclerotic development of diabetic).
For adult (body weight 60kg), the dosage of coated formulation of the present invention is 7.5-60mg/ days based on the amount of pioglitazone hydrochloride, preferred 15-60mg/ days, and more preferably 15-45mg/ days.
When the nuclear that contains active component when employing obtained coated formulation of the present invention, coated formulation preferably contained effective amount of actives.For example, when active component was biguanide (preferred metformin hydrochloride), for adult (body weight 60kg), effective dose was 125-2550mg/ days, is preferably 250-2550mg/ days.In addition, when active component was HMG-CoA reductase inhibitor (preferred simvastatin, Atorvastatin calcium, fluvastatin sodium), to adult (body weight 60kg), effective dose was 1-100mg/ days, is preferably 5-80mg/ days.
Coated formulation of the present invention can be used in combination with one or more medicaments, described medicament is selected from the treatment of diabetes agent, the therapeutic agent of diabetic complication, the therapeutic agent of hyperlipemia, (hereinafter also abbreviating subsidiary medicine (concomitantdrug) as) such as hypotensive agent, anti-obesity agent, diuretic, antithrombotic agents.Can use above-mentioned with the active component example those as subsidiary medicine.The administration time of coated formulation of the present invention and subsidiary medicine without limits, they can be to administration simultaneously of administration object or the time administration that is staggering.Can suitably determine the dosage of subsidiary medicine according to the dosage of clinical use.In addition, can suitably determine the mixing ratio of coated formulation of the present invention and subsidiary medicine according to administration object, route of administration, target disease, condition, combination (combination) etc.For example, when administration to as if man-hour, the subsidiary operable amount of medicine is 0.01～100 weight portion for the coated formulation of per 1 weight portion.
So use subsidiary medicine that excellent effect is provided, for example: 1) strengthened the effect (do to use at medicament cooperative effect) of coated formulation of the present invention or subsidiary medicine, 2) dosage that has reduced coated formulation of the present invention or subsidiary medicine (is compared with single administration, reduce the effect of drug dose), 3) reduced the side effect (as weight increase effect, ketoacidosis, acidosis) of coated formulation of the present invention or subsidiary medicine, or the like.
The invention still further relates to that " a kind of method that is used for improving pioglitazone hydrochloride from the preparation stripping that applies with pioglitazone hydrochloride, the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material when it is included in the described preparation of preparation applies.”
When preparation that preparation applies with pioglitazone hydrochloride, use preparation method of the present invention can obtain the excellent coated formulation of stripping property performance (especially at once stripping property or the stripping property performance in 15 minutes of stripping property test beginning after the health administration) of pioglitazone hydrochloride.
The invention still further relates to " coated formulation that preparation in accordance with the present invention obtains; it discharges in 15 minutes and is no less than 50% pioglitazone hydrochloride, described stripping property test are to use the hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by changeing the basket method " under 37 ℃, 100rpm in the stripping property test.As what use herein, described stripping property test is what to carry out according to the method for describing among the The JapanesePharmacopoeia 14th Edition.Used " hydrochloric acid-potassium chloride buffer solution (pH 2.0) " as test solution can prepare according to known method.The amount of used hydrochloric acid-potassium chloride buffer solution as test solution is generally 900mL.
" preparation in accordance with the present invention obtain, discharged the coated formulation that is no less than 50% pioglitazone hydrochloride under 37 ℃, 100rpm in the stripping property test (using the hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by changeing the basket method) 15 minutes " can use the mode oral administration identical with the invention described above coated formulation, and to mammal (as mice, rat, rabbit, cat, Canis familiaris L., cattle, horse, monkey, the mankind etc.) safety, identical in target disease, dosage etc. and the invention described above coated formulation wherein.
The invention still further relates to " coated formulation that preparation in accordance with the present invention obtains; it discharges in 15 minutes and is no less than 50% pioglitazone hydrochloride, described stripping property test are to use the hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by the oar method " under 37 ℃, 50rpm in the stripping property test.As what use herein, described stripping property test is what to carry out according to the method for describing among the The Japanese Pharmacopoeia14th Edition.Used " hydrochloric acid-potassium chloride buffer (pH 2.0) " as test solution can prepare according to known method.The amount of the used hydrochloric acid as test solution-potassium chloride buffer is generally 900mL.
" preparation in accordance with the present invention obtain, discharged the coated formulation that is no less than 50% pioglitazone hydrochloride under 37 ℃, 50rpm in the stripping property test (using the hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by the oar method) 15 minutes " can use the mode oral administration identical with the invention described above coated formulation, and to mammal (as mice, rat, rabbit, cat, Canis familiaris L., cattle, horse, monkey, the mankind etc.) safety, identical in target disease, dosage etc. and the invention described above coated formulation wherein.
Describe the present invention in detail below with reference to embodiment, reference example, comparative example and experimental example, they should not be considered to restrictive.
For the formulation additives of in following examples, reference example and comparative example, using (as D-mannitol, corn starch, hydroxypropyl cellulose, magnesium stearate, microcrystalline Cellulose, lactose, hydroxypropyl emthylcellulose, polyethylene glycol 6000, titanium dioxide, low-substituted hydroxypropyl cellulose, Talcum, carboxy methyl cellulose calcium), employing can be satisfied those of The Japanese Pharmacopoeia 14th Edition standard.For triethyl citrate, yellow iron oxide, ferrum oxide and ethylcellulose aqueous dispersion, employing can be satisfied those of Japanese Pharmaceutical Excipients (1998) standard.
Embodiment 1
With hydroxypropyl cellulose (26.4g, grade SSL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 8mPas), polyethylene glycol 6000 (1.32g), titanium dioxide (2.64g) and pioglitazone hydrochloride (16.5g) are dispersed in the water (297g) to obtain coating solution.
The tablet (300g) that will obtain in reference example 1 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 260.9mg with above-mentioned coating solution under 70 ℃ inlet temperature.
Embodiment 2
With hydroxypropyl cellulose (24g, grade SL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 24mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (344.7g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 381mg with above-mentioned coating solution under 75 ℃ inlet temperature.
Embodiment 3
With hydroxypropyl cellulose (24g, grade SSL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 8mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (344.7g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 382mg with above-mentioned coating solution under 75 ℃ inlet temperature.
Embodiment 4
With hydroxypropyl emthylcellulose (24g, grade MW, Shin-Etsu Chemical Co., Ltd.) (the viscosity of 5% aqueous solution under 20 ℃: 21mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (310g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 382mg with above-mentioned coating solution under 70 ℃ inlet temperature.
Embodiment 5
With hydroxypropyl emthylcellulose (24g, grade EW, Shin-Etsu Chemical Co., Ltd.) (the viscosity of 5% aqueous solution under 20 ℃: 12mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (344.7g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 382mg with above-mentioned coating solution under 70 ℃ inlet temperature.
Embodiment 6
With polyvinyl alcohol-polyethyleneglycol-graft copolymer (trade mark: Kollicoat IR, 24g, BAS F, Germany) (viscosity of 5% aqueous solution under 20 ℃: 18mPas), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (200g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 380.5mg with above-mentioned coating solution under 75 ℃ inlet temperature.
Embodiment 7
With hydroxypropyl cellulose (48.0g, grade SL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 24mPas), polyethylene glycol 6000 (2.4g), titanium dioxide (4.8g) and pioglitazone hydrochloride (30.0g) are dispersed in the water (540g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 4 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 459mg with above-mentioned coating solution under 90 ℃ inlet temperature.
Embodiment 8
With polyvinyl alcohol-polyethyleneglycol-graft copolymer (trade mark: Kollicoat IR, 48.0g, BASF, Germany) (the viscosity of 5% aqueous solution under 20 ℃: 18mPas), polyethylene glycol 6000 (2.4g), titanium dioxide (4.8g) and pioglitazone hydrochloride (30.0g) are dispersed in the water (540g) to obtain coating solution.
The tablet (250g) that will obtain in reference example 4 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and is carried out coated with obtaining coated formulation, every heavy 461mg with above-mentioned coating solution under 90 ℃ inlet temperature.
Embodiment 9
With polyvinyl alcohol-polyethyleneglycol-graft copolymer (trade mark: Kollicoat IR, 18.0g, BASF, Germany) (the viscosity of 5% aqueous solution under 20 ℃: 18mPas), titanium dioxide (1.8g), low-substituted hydroxypropyl cellulose (trade mark: L-HPC 31,3.6g, Shin-Etsu Chemical Co., Ltd.) and pioglitazone hydrochloride (11.3g) be dispersed in the water (207g) to obtain coating solution.
Tablet (the 240g that obtains in tablet that will in reference example 5, obtain (30) and the reference example 3, about 800) send into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and under 95 ℃ inlet temperature, apply with above-mentioned coating solution.According to the outward appearance of resulting tablet, select to contain the tablet that obtains in the reference example 5 coated formulation (every 479mg) as nuclear.
Embodiment 10
With hydroxypropyl cellulose (24.0g, grade SSL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 8mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15.0g) are dispersed in the water (350g) to obtain coating solution.
Glucophage XR tablet (trade mark, 30, the tablet that contains the lasting release of 500mg metformin hydrochloride) tablet (250g) of (Bristol-Myers Squibb Company) and acquisition in reference example 3 is sent into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and is applied with above-mentioned coating solution under 70 ℃ inlet temperature.According to the outward appearance of resulting tablet, select to contain Glucophage XR tablet as nuclear and every coated formulation (every weight: 1.086g) that contains metformin hydrochloride 500mg/ pioglitazone hydrochloride 16.53mg.
Embodiment 11
With polyvinyl alcohol-polyethyleneglycol-graft copolymer (trade mark: Kollicoat IR, 36.0g, BASF, Germany) (viscosity of 5% aqueous solution under 20 ℃: 18mPas), titanium dioxide (3.6g) and pioglitazone hydrochloride (22.5g) are dispersed in the water (300g) to obtain coating solution.
Glucophage XR tablet (trade mark, 30, the tablet that contains the lasting release of 500mg metformin hydrochloride) (by Bristol-Myers Squibb Company manufacturing) and the tablet (250g) that obtains in reference example 3 are sent into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and are applied with above-mentioned coating solution under 70 ℃ inlet temperature.According to the outward appearance of resulting tablet, obtain to contain Glucophage XR tablet as nuclear and every coated formulation (every weight: 1.082g) that contains metformin hydrochloride 500mg/ pioglitazone hydrochloride 16.53mg.
Embodiment 12
With hydroxypropyl cellulose (24.0g, grade SL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 24mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15.0g) are dispersed in the water (350g) to obtain coating solution.
The Lipovas tablet 20 (trade marks that will contain the active component simvastatin, 30, BanyuPharmaceutical Co., Ltd., major axis 14.0mm, minor axis 7.5mm, heavy 400mg) and the tablet (250g) of acquisition in the reference example 9 send into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and under 70 ℃ inlet temperature, apply with above-mentioned coating solution.According to the outward appearance of resulting tablet, obtained every coated formulation (every weight: 449mg) that contains simvastatin 20mg/ pioglitazone hydrochloride 17.78mg.
Embodiment 13
With hydroxypropyl cellulose (72g, grade SL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 24mPas), polyethylene glycol 6000 (3.6g), titanium dioxide (7.2g) and pioglitazone hydrochloride (45g) are dispersed in the water (1050g) to obtain coating solution.
The tablet (250g) of acquisition in the tablet (30) that obtains in the reference example 10 and the reference example 9 is sent into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and under 80 ℃ inlet temperature, apply with above-mentioned coating solution.According to the outward appearance of resulting tablet, obtained every coated formulation (every weight: 349mg) that contains simvastatin 15mg/ pioglitazone hydrochloride 16.25mg.
Embodiment 14
Hydroxypropyl cellulose (72g, grade SL, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 24mPas), polyethylene glycol 6000 (3.6g), titanium dioxide (7.2g) and pioglitazone hydrochloride (45g) are dispersed in water (1050g) to obtain coating solution.
The tablet (250g) of acquisition in the tablet (30) that obtains in the reference example 11 and the reference example 9 is sent into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and under 80 ℃ inlet temperature, apply with above-mentioned coating solution.According to the outward appearance of resulting tablet, obtained every coated formulation (every weight: 349mg) that contains Atorvastatin calcium 21mg/ pioglitazone hydrochloride 16.93mg.
Reference example 1
With D-mannitol (2176g) and corn starch (918g) fluidized bed pelletizer (FD-3S that packs into; make by POWREX CORPORATION) and pelletize when sprinkling contains the aqueous solution (1700g) of hydroxypropyl cellulose (102g), next obtain granule by drying steps.Add in the powder (3012g) that obtains microcrystalline Cellulose (160.2g) and magnesium stearate (32g) and mixing.The powder/particle mixture that obtains tablet machine (Correct 19K is made by Kikusui Seisakusho Ltd.) tabletting (size of sheet: 8.5mm φ, compression pressure 9KN/ punching press) is to obtain the tablet of every heavy 244mg.
Reference example 2
With lactose (2470g); corn starch (315g) and carboxymethylcellulose calcium (157.5g) fluidized bed pelletizer (FD-3S that packs into; POWREX CORPORATION makes) and pelletize when sprinkling contains the aqueous solution (1575g) of hydroxypropyl cellulose (94.5g), next obtain granule by drying steps.Add in the powder (2868g) that obtains carboxymethylcellulose calcium (89.3g) and magnesium stearate (17.9g) and stirring.The powder/particle mixture that obtains tablet machine (Correct 19K is made by Kikusui Seisakusho Ltd.) (size of sheet: major axis 12mm, minor axis 7mm, compression pressure 15KN/ punching press) tabletting is to obtain the tablet of every heavy 350mg.
Reference example 3
With lactose (1976g); corn starch (252g) and carboxymethylcellulose calcium (126g) fluidized bed pelletizer (FD-3S that packs into; make by POWREX CORPORATION) and pelletize when sprinkling contains the aqueous solution (1260g) of hydroxypropyl cellulose (75.6g), next obtain granule by drying steps.Add in the powder (2294g) that obtains carboxymethylcellulose calcium (71.4g) and magnesium stearate (14.3g) and stirring.The powder/particle mixture that obtains tablet machine (Correct 19K is made by Kikusui SeisakushoLtd.) (size of sheet: 9mm φ, compression pressure 7KN/ punching press) tabletting is to obtain the tablet of every heavy 300mg.
Reference example 4
The tablet (400g) that obtains in the reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.), under 90 ℃ inlet temperature with comprising ethylcellulose aqueous dispersion (trade mark: Aquacoat, Asahi Kasei Corporation, 148.2g), Talcum (2.2g), triethyl citrate (13.3g), the coating solution of yellow iron oxide (0.36g) and water (231.1g) applies, and obtains the tablet of every heavy 391mg thus.In addition, with hydroxypropyl emthylcellulose (47.3g), polyethylene glycol 6000 (9.5g), titanium dioxide (6.3g) and the solution of ferrum oxide (0.09g) in water (473g) apply these tablets to obtain the tablet of every heavy 416mg under condition same as described above.
Reference example 5
The tablet (400g) that obtains in the reference example 2 is sent into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.), under 58 ℃ inlet temperature with comprising ethylcellulose aqueous dispersion (trade mark: Aquacoat, Asahi Kasei Corporation, 74.1g), Talcum (1.1g), triethyl citrate (6.7g), the coating solution of yellow iron oxide (0.18g) and water (115.6g) applies, and obtains the tablet of every heavy 381mg thus.In addition, with hydroxypropyl emthylcellulose (47.3g), polyethylene glycol 6000 (9.5g), titanium dioxide (6.3g) and the solution of ferrum oxide (0.09g) in water (473g) apply these tablets to obtain the tablet of every heavy 429mg under condition same as described above.
Reference example 6
With hydroxypropyl cellulose (26.4g, grade L, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 42mPas), polyethylene glycol 6000 (1.32g), titanium dioxide (2.64g) and pioglitazone hydrochloride (16.5g) are dispersed in the water (297g) to obtain coating solution.
The tablet (300g) that will in reference example 1, obtain send into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and under 70 ℃ inlet temperature with above-mentioned coating solution coated with the coated formulation that obtains every heavy 262.1mg.
Reference example 7
With hydroxypropyl cellulose (24g, grade L, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 42mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (344.7g) to obtain coating solution.
The tablet (250g) that will in reference example 2, obtain send into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and under 75 ℃ inlet temperature with above-mentioned coating solution coated with the coated formulation that obtains every heavy 382mg.
Reference example 8
With hydroxypropyl emthylcellulose (24g, grade R, Shin-Etsu Chemical Co., Ltd.) (the viscosity of 5% aqueous solution under 20 ℃: 40mPas), polyethylene glycol 6000 (1.2g), titanium dioxide (2.4g) and pioglitazone hydrochloride (15g) are dispersed in the water (270g) to obtain coating solution.
The tablet (250g) that will in reference example 2, obtain send into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and under 70 ℃ inlet temperature with above-mentioned coating solution coated with the coated formulation that obtains every heavy 381.2mg.
Reference example 9
With lactose (41160g); corn starch (5250g) and carboxymethylcellulose calcium (2625g) fluidized bed pelletizer (FD-WSG-60 that packs into; POWREX CORPORATION) and pelletize when sprinkling contains the aqueous solution (31510g) of hydroxypropyl cellulose (1575g), next obtain granule by drying steps.Add in the powder (47910g) that obtains carboxymethylcellulose calcium (1491g) and magnesium stearate (298.2g) and stirring.The powder/particle mixture that obtains uses tablet machine (Correct 19K, Kikusui SeisakushoLtd.) (size of sheet: 7mm φ, compression pressure 5.7KN/ punching press) tabletting to obtain the tablet of every heavy 105mg.
Reference example 10
The Lipovas tablets 5mg (trade mark that will contain the active component simvastatin, BanyuPharmaceutical Co., Ltd., heavy 100mg) in mortar, pulverizes, by universal testing machine (Shimadzu Corporation, UH-10A) (compression pressure 9.5KN/ punching press) use 9.0mm φ drift with the ground powder of 300mg (being equivalent to the 15mg simvastatin) tabletting with R and mould, obtain 30.
Reference example 11
Lipitortablets 5mg (the trade mark that will contain the active component Atorvastatin calcium, YamanouchiPharmaceutical Co., Ltd., heavily about 72mg) in mortar, pulverizes, by universal testing machine (Shimadzu Corporation, UH-10A) (compression pressure 9.5KN/ punching press) use 9.0mm φ drift with the ground powder of 300mg (being equivalent to the 21mg Atorvastatin calcium) tabletting with R and mould, obtain 30.
Comparative example 1
With hydroxypropyl cellulose (48.0g, grade L, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 42mPas), polyethylene glycol 6000 (2.4g), titanium dioxide (4.8g) and pioglitazone hydrochloride (30.0g) are dispersed in the water (540g) to obtain coating solution.
The tablet (250g) that will in reference example 4, obtain send into film applicator (Hicoater-Mini, FreundIndustrial Co.Ltd.) and under 90 ℃ inlet temperature with above-mentioned coating solution coated with the coated formulation that obtains every heavy 459mg.
Comparative example 2
With hydroxypropyl cellulose (48.0g, grade L, Nippon Soda Co., the Ltd.) (viscosity of 5% aqueous solution under 20 ℃: 42mPas), polyethylene glycol 6000 (2.4g), titanium dioxide (4.8g) and pioglitazone hydrochloride (30.0g) are dispersed in the water (700g) to obtain coating solution.
The Lipovas tablet 20 (trade marks that will contain the active component simvastatin, 30, BanyuPharmaceutical Co., Ltd., major axis 14.0mm, minor axis 7.5mm, heavy 400mg) and the tablet (250g) that obtains in the reference example 9 is sent into film applicator (Hicoater-Mini, Freund Industrial Co.Ltd.) and under 70 ℃ inlet temperature with above-mentioned coating solution coating.According to the outward appearance of resulting tablet, obtained every coated formulation (every weight: 445mg) that contains simvastatin 20mg/ pioglitazone hydrochloride 16.23mg.
Experimental example 1
Use 0.3M hydrochloric acid-potassium chloride buffer solution (900mL, 37 ℃, pH 2.0) to estimate the stripping property performance of the pioglitazone hydrochloride of the coated formulation that obtains in the foregoing description by changeing basket method (100rpm).The results are shown in table 1.
The stripping property of [table 1] pioglitazone hydrochloride distributes (profiles) (%)
As shown in table 1, the coated formulation that obtains by preparation method of the present invention demonstrates the stripping property performance of pioglitazone hydrochloride excellence.
Experimental example 2
Use 0.3M hydrochloric acid-potassium chloride buffer solution (900mL, 37 ℃, pH2.0) the stripping property performance of the pioglitazone hydrochloride of the coated formulation that obtains in evaluation the foregoing description and the comparative example by oar method (50rpm).The results are shown in table 2.
The stripping property distribution (%) of [table 2] pioglitazone hydrochloride
As shown in table 2, coated formulation of the present invention demonstrates the stripping property performance of pioglitazone hydrochloride excellence.
Experimental example 3
Estimate the stripping property performance of the pioglitazone hydrochloride of the coated formulation that obtains in the foregoing description and the comparative example in the mode identical with experimental example 2.The results are shown in table 3.
The stripping property distribution (%) of [table 3] pioglitazone hydrochloride
As shown in table 3, coated formulation of the present invention demonstrates the stripping property performance of pioglitazone hydrochloride excellence.
Industrial applicibility
The coated formulation that is obtained by preparation method of the present invention can be used as the therapeutic agent of diabetes etc., and excellent in aspect performances such as the stripping property performances of preparation characteristic example hydrochloric acid Pioglitazone (after especially to the health administration at once the stripping property performance in stripping property or in stripping property test beginning 15 minutes), and storage stability can be excellent.
In addition, preparation in accordance with the present invention can be made the preparation that applies with PIOGITAZONE HYDROCHLORIDE easily. Therefore preparation method of the present invention can be used as the large-scale production that industrial production process is used for above-mentioned coated formulation.
Claims (12)
1. the preparation method of a coated formulation, it comprises that the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material applies, and wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer Kollicoat IR.
2. the preparation method of claim 1, wherein in the time of 20 ℃, 5% viscosity in aqueous solution of low viscosity coating material is not more than 35mPas.
3. the preparation method of claim 1, wherein the aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material applies the nuclear that comprises active component, and wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer Kollicoat IR.
4. the preparation method of claim 3, wherein active component is the treatment of diabetes agent.
5. the preparation method of claim 4, wherein the treatment of diabetes agent is a biguanide.
6. the preparation method of claim 5, wherein biguanide is a metformin hydrochloride.
7. the preparation method of claim 3, wherein active component is the therapeutic agent of hyperlipemia.
8. the preparation method of claim 7, wherein the therapeutic agent of hyperlipemia is the HMG-CoA reductase inhibitor.
9. an improvement is from the method with the pioglitazone hydrochloride stripping property the preparation of pioglitazone hydrochloride coating, aqueous dispersion with the pioglitazone hydrochloride that comprises the low viscosity coating material when it is included in the described preparation of preparation applies, and wherein the low viscosity coating material is hydroxypropyl cellulose SL, hydroxypropyl cellulose SSL or polyvinyl alcohol-polyethyleneglycol-graft copolymer Kollicoat IR.
10. the coated formulation that preparation method obtained of claim 1.
11. the coated formulation of claim 10, it discharges in 15 minutes in the stripping property test and is no less than 50% pioglitazone hydrochloride, and described stripping property test is to use the 37 ℃ of hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by changeing the basket method under 100rpm.
12. the coated formulation of claim 10, it discharges in 15 minutes in the stripping property test and is no less than 50% pioglitazone hydrochloride, and described stripping property test is to use the 37 ℃ of hydrochloric acid-potassium chloride buffer (pH 2.0) as test solution to be undertaken by the oar method under 50rpm.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP020925/2003 | 2003-01-29 | ||
| JP2003020925 | 2003-01-29 | ||
| JP2003276894 | 2003-07-18 | ||
| JP276894/2003 | 2003-07-18 | ||
| JP001128/2004 | 2004-01-06 | ||
| JP2004001128 | 2004-01-06 | ||
| PCT/JP2004/000754 WO2004067001A1 (en) | 2003-01-29 | 2004-01-28 | Process for producing coated preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1761465A CN1761465A (en) | 2006-04-19 |
| CN1761465B true CN1761465B (en) | 2010-10-13 |
Family
ID=36707297
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480006889.9A Expired - Fee Related CN1761465B (en) | 2003-01-29 | 2004-01-28 | Method for manufacturing coated formulation |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1761465B (en) |
| UA (1) | UA86015C2 (en) |
| ZA (1) | ZA200506397B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008018569A1 (en) * | 2006-08-10 | 2008-02-14 | Takeda Pharmaceutical Company Limited | Pharmaceutical composition |
| EP2674149B1 (en) * | 2012-06-15 | 2017-10-04 | Shin-Etsu Chemical Co., Ltd. | Method of preparing composite granule comprising low-substituted hydroxypropyl cellulose and rapid release preparation |
| MX362930B (en) * | 2013-06-17 | 2019-02-26 | Nippon Soda Co | Coating agent containing hydroxyalkyl cellulose. |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996036338A1 (en) * | 1995-05-17 | 1996-11-21 | The Procter & Gamble Company | Bisacodyl dosage form for colonic delivery |
| WO2000016776A1 (en) * | 1998-09-18 | 2000-03-30 | Takeda Chemical Industries, Ltd. | Sustained release oral preparations |
| CN1258217A (en) * | 1997-05-28 | 2000-06-28 | 阿斯特拉公司 | Pharmaceutical formulation of omeprazole |
| US6168806B1 (en) * | 1999-03-05 | 2001-01-02 | Fang-Yu Lee | Orally administrable nifedipine pellet and process for the preparation thereof |
| WO2001035940A2 (en) * | 1999-11-16 | 2001-05-25 | Smithkline Beecham P.L.C. | Pharmaceutical composition comprising a thiazolidinedione-metformin hydrochloride |
| WO2001082875A2 (en) * | 2000-05-01 | 2001-11-08 | Aeropharm Technology, Inc. | A core formulation |
| WO2001082873A2 (en) * | 2000-05-01 | 2001-11-08 | Aeropharm Technology, Inc. | A medicinal aerosol formulation |
| WO2001082904A1 (en) * | 2000-05-01 | 2001-11-08 | Aeropharm Technology, Inc. | A core formulation |
| CN1331605A (en) * | 1998-10-26 | 2002-01-16 | 田边制药株式会社 | Sustained-release particles |
| CN1387848A (en) * | 1993-09-15 | 2003-01-01 | 三共株式会社 | Use of thiazolidinedione for preventing or retaining non-insulin-dependent diabets mellitus (NIDDM) attack |
-
2004
- 2004-01-28 CN CN200480006889.9A patent/CN1761465B/en not_active Expired - Fee Related
- 2004-01-28 ZA ZA200506397A patent/ZA200506397B/en unknown
- 2004-01-28 UA UAA200508346A patent/UA86015C2/en unknown
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1387848A (en) * | 1993-09-15 | 2003-01-01 | 三共株式会社 | Use of thiazolidinedione for preventing or retaining non-insulin-dependent diabets mellitus (NIDDM) attack |
| WO1996036338A1 (en) * | 1995-05-17 | 1996-11-21 | The Procter & Gamble Company | Bisacodyl dosage form for colonic delivery |
| CN1258217A (en) * | 1997-05-28 | 2000-06-28 | 阿斯特拉公司 | Pharmaceutical formulation of omeprazole |
| WO2000016776A1 (en) * | 1998-09-18 | 2000-03-30 | Takeda Chemical Industries, Ltd. | Sustained release oral preparations |
| CN1331605A (en) * | 1998-10-26 | 2002-01-16 | 田边制药株式会社 | Sustained-release particles |
| US6168806B1 (en) * | 1999-03-05 | 2001-01-02 | Fang-Yu Lee | Orally administrable nifedipine pellet and process for the preparation thereof |
| WO2001035940A2 (en) * | 1999-11-16 | 2001-05-25 | Smithkline Beecham P.L.C. | Pharmaceutical composition comprising a thiazolidinedione-metformin hydrochloride |
| WO2001082875A2 (en) * | 2000-05-01 | 2001-11-08 | Aeropharm Technology, Inc. | A core formulation |
| WO2001082873A2 (en) * | 2000-05-01 | 2001-11-08 | Aeropharm Technology, Inc. | A medicinal aerosol formulation |
| WO2001082904A1 (en) * | 2000-05-01 | 2001-11-08 | Aeropharm Technology, Inc. | A core formulation |
Non-Patent Citations (2)
| Title |
|---|
| CN 1387848 A,全文. |
| US 6168806 B1,全文. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1761465A (en) | 2006-04-19 |
| ZA200506397B (en) | 2006-11-29 |
| UA86015C2 (en) | 2009-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2514539C (en) | Process for producing coated preparation | |
| US8263121B2 (en) | Solid pharmaceutical preparation | |
| RU2359671C2 (en) | Method of obtaining of preparation with covering | |
| US9101660B2 (en) | Solid preparation | |
| CN100367960C (en) | Process for producing coated preparation | |
| AU2004285354B2 (en) | Solid preparation comprising an insulin sensitizer, an insulin secretagogue and a polyoxyethylene sorbitan fatty acid ester | |
| CN1761465B (en) | Method for manufacturing coated formulation | |
| JP4567340B2 (en) | Method for producing coated preparation | |
| JP4361461B2 (en) | Solid preparation | |
| JP4478413B2 (en) | Manufacturing method of coated preparation | |
| KR20050017090A (en) | Process for producing coated preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101013 Termination date: 20160128 |
|
| EXPY | Termination of patent right or utility model |