CN1686123A - Pyrolidone hydrochloride drip pill and its preparation method - Google Patents
Pyrolidone hydrochloride drip pill and its preparation method Download PDFInfo
- Publication number
- CN1686123A CN1686123A CN 200510066001 CN200510066001A CN1686123A CN 1686123 A CN1686123 A CN 1686123A CN 200510066001 CN200510066001 CN 200510066001 CN 200510066001 A CN200510066001 A CN 200510066001A CN 1686123 A CN1686123 A CN 1686123A
- Authority
- CN
- China
- Prior art keywords
- polyethylene glycol
- pioglitazone
- substrate
- pioglitazone hydrochloride
- hydrochloride
- 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.)
- Granted
Links
- 239000006187 pill Substances 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 25
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 claims description 95
- 229960002827 pioglitazone hydrochloride Drugs 0.000 claims description 95
- 229920001223 polyethylene glycol Polymers 0.000 claims description 91
- 239000002202 Polyethylene glycol Substances 0.000 claims description 88
- 239000000758 substrate Substances 0.000 claims description 47
- -1 sorbitol anhydride Chemical class 0.000 claims description 44
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 31
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 31
- 229920001983 poloxamer Polymers 0.000 claims description 31
- 229960000502 poloxamer Drugs 0.000 claims description 31
- 150000002148 esters Chemical class 0.000 claims description 30
- 229920002472 Starch Polymers 0.000 claims description 27
- 235000019698 starch Nutrition 0.000 claims description 27
- 239000008107 starch Substances 0.000 claims description 27
- 229920000858 Cyclodextrin Polymers 0.000 claims description 24
- 239000001116 FEMA 4028 Substances 0.000 claims description 24
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 24
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 24
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 24
- 229960004853 betadex Drugs 0.000 claims description 24
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 24
- 229910052708 sodium Inorganic materials 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 229960005095 pioglitazone Drugs 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 13
- 239000001828 Gelatine Substances 0.000 claims description 10
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 10
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 10
- 235000021355 Stearic acid Nutrition 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 229920000159 gelatin Polymers 0.000 claims description 10
- 235000019322 gelatine Nutrition 0.000 claims description 10
- 235000011187 glycerol Nutrition 0.000 claims description 10
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 10
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 10
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 10
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 10
- 239000008117 stearic acid Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 6
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 5
- 241000790917 Dioxys <bee> Species 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
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- 235000015424 sodium Nutrition 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
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- 238000000465 moulding Methods 0.000 claims description 2
- 229920002545 silicone oil Polymers 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 5
- 239000011159 matrix material Substances 0.000 description 58
- 229940023488 pill Drugs 0.000 description 35
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 34
- 102000004877 Insulin Human genes 0.000 description 17
- 108090001061 Insulin Proteins 0.000 description 17
- 229940125396 insulin Drugs 0.000 description 17
- 238000012360 testing method Methods 0.000 description 16
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- 239000004615 ingredient Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 206010022489 Insulin Resistance Diseases 0.000 description 9
- 239000000969 carrier Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 7
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 229940100389 Sulfonylurea Drugs 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 description 4
- 229950009226 ciglitazone Drugs 0.000 description 4
- 239000000428 dust Substances 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 4
- 229960001641 troglitazone Drugs 0.000 description 4
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 4
- 239000003472 antidiabetic agent Substances 0.000 description 3
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- 150000002632 lipids Chemical class 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 3
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
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- 150000004283 biguanides Chemical class 0.000 description 2
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- 150000002304 glucoses Chemical class 0.000 description 2
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- 238000012795 verification Methods 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 102000000340 Glucosyltransferases Human genes 0.000 description 1
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- 229960003105 metformin Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
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- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A dripping pill of bigelietong hydrochloride for treating diabetes is prepared from the bigelietong hydrochloride and the pharmacologically acceptable carrier.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of diabetes, particularly is a kind of drug composition oral preparation that feedstock production forms with the pioglitazone hydrochloride.
Background technology
Type ii diabetes (NIDDM) is the big disease in third place in the world---the common type of diabetes, its main diseases is because of being insulin resistance, so unsuitable life-time service insulinize, and sulfonylurea, biguanides untoward reaction are more obvious, and many patients are difficult for accepting.Kai Fa a class does not stimulate insulin secretion in recent years, by the intensifier target tissue to insulin sensitivity and the hypoglycemic drug of onset is a tetrahydrothiazole diketone derivatives, mainly contain pioglitazone (pioglitazone), troglitazone (troglitazone), ciglitazone (ciglitazone), englitazones (englitazone) etc. can improve insulin resistance in the patient body, correct sugar and lipid metabolic disorder, directly improve high sugared toxicity.It is less that this type of medicine has untoward reaction, can not cause characteristics such as hypoglycemic reaction during treatment, is subjected to clinical extensive concern once coming out.
[pharmacological action] this product is the thiazolidinediones antidiabetic medicine, belongs to euglycemic agent.Mechanism of action is relevant with the existence of insulin, can reduce the insulin resistant of peripheral tissues and liver, increases the processing of the glucose that relies on insulin, and reduces the output of glycogen.Different with sulfonylurea, this product is not the short secretion of an insulin medicine.Its mechanism of action is the exciting microperoxisome growth factor activation receptor y [PPAR-γ] of high selectivity, the transcribing of the insulin related gene of many control glucoses of the activation scalable of PPAR-γ and lipid metabolism.Zoopery shows that this product can reduce hyperglycemia, hyperinsulinemia and the high triglyceride of insulin resistant.The increase that the metabolic alterations that this product causes has caused the tissue of dependence insulin to be replied.Because the effect (promptly reducing insulin resistant) that this product has improved the circulation insulin, so it can not reduce the blood glucose of the animal model that lacks endogenous insulin.
[indication] type 2 diabetes mellitus (or noninsulindependent diabetes, NADDM).
[clinical evaluation] clinical research shows that pioglitazone can improve insulin resistant patient's insulin sensitivity, improves the reactivity of insulin pair cell, and improves glucose disequilibrium in the body.Act on sustainable at least 1 year, in controlled clinical trial, pioglitazone and sulfonylureas, metformin or insulin share, and can improve curative effect.The unusual patient of lipid has also been selected in the clinical trial of pioglitazone, and the patient treats through pioglitazone, can reduce the triacylglycerol level, increase HDL-C, but LDL and TC does not then have conforming change.
The pioglitazone hydrochloride sheet, be to be a kind of oral formulations that chemical raw material is prepared from the pioglitazone hydrochloride, has the insulin sensitivity that improves the insulin resistant patient, improve the reactivity of insulin pair cell, and improve glucose disequilibrium effect in the body, be used for the treatment of the oral tablet of type 2 diabetes mellitus, through clinical verification, determined curative effect is the common drug that clinical and family is used for the treatment of this type of disease.
Owing to reasons such as technologies of preparing, the oral formulations of most drug, exist all after taking that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.In addition, conventional peroral dosage form as tablet, capsule etc., because the technology of granulation is arranged, therefore can produce bigger dust pollution in preparation process, can staff's health be worked the mischief to a certain extent, also can cause certain pollution to environment simultaneously.Moreover, the complex manufacturing of conventional oral formulations, production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
Summary of the invention
Purpose of the present invention is to replenish the existing deficiency that is used for the treatment of the oral drug preparation of type 2 diabetes mellitus, and a kind of bioavailability height is provided, and has a quick release, produce effects is cheap fast, and free of contamination aborning drug composition oral preparation Pyrolidone hydrochloride drip pill.Pyrolidone hydrochloride drip pill involved in the present invention is a chemical raw material with the pioglitazone hydrochloride, is prepared from the pharmaceutically suitable carrier as substrate.Be prepared by the following technical solutions, can obtain Pyrolidone hydrochloride drip pill involved in the present invention:
[preparation method]
1. pioglitazone hydrochloride
[English name] Pioglitazonehydrochloride
[trade name] Actos
[chemical name] (±)-5-[[4-[2-(5-ethyl-2-pyridine radicals) dioxy base] benzyl]-2,4] the thiazolidinedione hydrochlorate
[chemical structural formula]
2. substrate: the mixture of one or more in pharmaceutically suitable carrier such as polyethylene glycols, sorbitol anhydride class, polyoxyethylene sorbitol acid anhydride class, polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
3. proportioning: with g or kg is unit, by weight, and pioglitazone hydrochloride: substrate=1: 1～1: 9;
4. according to the given ratio of prescription, accurately take by weighing pioglitazone hydrochloride and substrate, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing pioglitazone hydrochloride and substrate and/or emulsion and/or suspension;
5. adopt homemade or general drop pill machine (as the TZDW-1 type drop pill machine of Changzheng Tianmin High Science ﹠ Technology Co., Ltd., Beijing's production), and the temperature control system of adjustment drop pill machine, make the water dropper temperature heating of drop pill machine and remain on (50～90) ℃, the temperature cooling of condensing agent also remains on (40～-5) ℃;
6. when treating that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and reaching desired state of temperature, fused solution and/or the emulsion and/or the suspension that will contain pioglitazone hydrochloride and substrate, place in the water dropper jar of drop pill machine, splash in the condensing agent, condensing agent can be any one in liquid paraffin, methyl-silicone oil, the vegetable oil;
7. will shrink the drop pill taking-up of molding by the outlet of drop pill machine, remove the surface condensation agent, be drying to obtain.
[beneficial effect]
Type ii diabetes (NEDDM) is the big disease in third place in the world---the common type of diabetes, its main diseases is because of being insulin resistance, so unsuitable life-time service insulinize, and sulfonylurea, biguanides untoward reaction are more obvious, and many patients are difficult for accepting.Kai Fa a class does not stimulate insulin secretion in recent years, by the intensifier target tissue to insulin sensitivity and the hypoglycemic drug of onset is a tetrahydrothiazole diketone derivatives, mainly contain pioglitazone (pioglitazone), troglitazone (troglitazone), ciglitazone (ciglitazone), englitazones (englitazone) etc. can improve insulin resistance in the patient body, correct sugar and lipid metabolic disorder, directly improve high sugared toxicity.It is less that this type of medicine has untoward reaction, can not cause characteristics such as hypoglycemic reaction during treatment, is subjected to clinical extensive concern once coming out.
The pioglitazone hydrochloride sheet, be to be a kind of oral formulations that chemical raw material is prepared from the pioglitazone hydrochloride, has the insulin sensitivity that improves the insulin resistant patient, improve the reactivity of insulin pair cell, and improve glucose disequilibrium effect in the body, be used for the treatment of the oral tablet of type 2 diabetes mellitus, through clinical verification, determined curative effect is the common drug that clinical and family is used for the treatment of this type of disease.
Owing to reasons such as technologies of preparing, the oral formulations of most drug, exist all after taking that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence the performance of drug effect, also directly affect therapeutic effect.In addition, conventional peroral dosage form as tablet, capsule etc., because the technology of granulation is arranged, therefore can produce bigger dust pollution in preparation process, can staff's health be worked the mischief to a certain extent, also can cause certain pollution to environment simultaneously.Moreover, the complex manufacturing of conventional oral formulations, production cost is higher, thereby patient's drug cost is also improved thereupon, is unfavorable for improving the ability of seeking medical advice of extensive patients, also is unfavorable for improving the general health level of society.
Pyrolidone hydrochloride drip pill involved in the present invention is compared with the pioglitazone hydrochloride sheet has following beneficial effect:
1. Pyrolidone hydrochloride drip pill involved in the present invention; utilize surfactant to be substrate; make solid dispersion with pioglitazone hydrochloride, make medicine be molecule, colloid or microcrystalline state and be scattered in the substrate, the total surface area of medicine increases; and substrate is hydrophilic; medicine is had wetting action, can make that medicine is rapidly molten to loose into microgranule or solution, thereby make the dissolving of medicine and absorb and accelerate; thereby improved bioavailability, brought into play efficient, quick-acting effects etc.
2. Pyrolidone hydrochloride drip pill involved in the present invention, contact promptly with saliva and to dissolve rapidly, and absorb by oral mucosa, not only rapid-action, and the influence of not taken food, promptly all can containing take after meal ante cibum, can not produce any residual harmful substance at gastric yet, thereby make that patient's medication is safer, also have medication convenience, characteristic of accurate simultaneously.
3. Pyrolidone hydrochloride drip pill involved in the present invention mixes pioglitazone hydrochloride mutually with molten matrix, splashes in the not miscible condensed fluid to make.Therefore, the stability of drug height, not facile hydrolysis, oxidation, and the operation be under liquid state, to carry out, no dust pollution is not subject to the influence of crystal formation, thereby has guaranteed the quality of medicine, has increased stability.
4. production technology, the equipment of preparation drop pill are simple, easy to operate, the automaticity height, and labor intensity is low, the production efficiency height.Workshop does not have dust simultaneously, helps labor protection and environmental protection yet.
5. the production cost of preparation drop pill is usually with about 50% of other oral formulations of kind, and compares with oral liquid, and the dosage of drop pill is accurate, thereby makes the patient take metering control easily.
The specific embodiment
Now with several groups of specific embodiments, be described further with regard to the preparation method of Pyrolidone hydrochloride drip pill of the present invention.
[first group: the test of single-matrix]
1. pioglitazone hydrochloride
[English name] Pioglitazonehydrochloride
[chemical name] (±)-5-[[4-[2-(5-ethyl-2-pyridine radicals) dioxy base] benzyl]-2,4] the thiazolidinedione hydrochlorate.
2. substrate: Polyethylene Glycol
1000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, span 40, polyoxyethylene stearate 40 esters, poloxamer, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
3. proportioning: with g or kg is unit, by weight, and pioglitazone hydrochloride: substrate=1: 1～1: 9;
4. the process that provides according to [preparation method] 4～7 is prepared, and can obtain the Pyrolidone hydrochloride drip pill of different size.
[result of the test]
Test 1: for observe pioglitazone hydrochloride and different substrates when 1: 1 the proportioning prepared Pyrolidone hydrochloride drip pill in qualitative difference, according to 1: 1 ratio, with pioglitazone hydrochloride respectively with Polyethylene Glycol
1000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as span 40, polyoxyethylene stearate 40 esters, poloxamer, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 13 pharmaceutical compositions experiments that contain pioglitazone hydrochloride and different substrates, and obtain 13 groups of different experimental results and see Table 1.
Test 2: for observe pioglitazone hydrochloride and different substrates when 1: 3 the proportioning prepared Pyrolidone hydrochloride drip pill in qualitative difference, according to 1: 3 ratio, with pioglitazone hydrochloride respectively with Polyethylene Glycol
1000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as span 40, polyoxyethylene stearate 40 esters, poloxamer, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 13 pharmaceutical compositions experiments that contain pioglitazone hydrochloride and different substrates, and obtain 13 groups of different experimental results and see Table 2.
Test 3: for observe pioglitazone hydrochloride and different substrates when 1: 9 the proportioning prepared Pyrolidone hydrochloride drip pill in qualitative difference, according to 1: 9 ratio, with pioglitazone hydrochloride respectively with Polyethylene Glycol
1000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as span 40, polyoxyethylene stearate 40 esters, poloxamer, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 13 pharmaceutical compositions experiments that contain pioglitazone hydrochloride and different substrates, and obtain 13 groups of different experimental results and see Table 3.
[second group: the test of mixed-matrix]
1. pioglitazone hydrochloride
[English name] Pioglitazonehydrochloride
[chemical name] (±)-5-[[4-[2-(5-ethyl-2-pyridine radicals) dioxy base] benzyl]-2,4] the thiazolidinedione hydrochlorate.
2. substrate:
2.1 Polyethylene Glycol---English name Macrogol,
2.2 polyoxyethylene stearate 40 esters---English name Polyoxyl (40) Stearate,
Molecular formula is with C
17H
35COO (CH
2CH
2O)
nH represents that n is about 40,
2.3 poloxamer---English name Poloxamer, polyoxyethylene poly-oxygen propylene aether,
Molecular formula HO (C
2H
4O)
a(C
3H
6O)
b(C
2H
4O)
cH,
The sodium salt of the starch carboxymethyl ester that 2.4 carboxymethyl starch sodium---English name Carboxymethylstach Sodium, starch generates with the monoxone effect under alkali condition,
2.5 betacyclodextrin---English name Betacyclodextrin, molecular formula C
6H
10O
5, this product is that ring dextrin glucosyl transferase acts on 7 glucoses that starch generates with α-1, the bonded cyclic oligosaccharide of 4-glycosidic bond;
3. proportioning: with g or kg is unit, by weight, and pioglitazone hydrochloride: substrate=1: 1～1: 9;
4. the process that provides according to [preparation method] 4～7 is prepared, and can obtain the different size Pyrolidone hydrochloride drip pill.
[result of the test]
Test 4: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 1 ratio different with the 4 kinds respectively mixing matrix phases of pioglitazone hydrochloride are mixed again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 4.
Test 5: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 3 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 3 ratio different with the 4 kinds respectively mixing matrix phases of pioglitazone hydrochloride are mixed again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 5.
Test 6: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 9 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 9 ratio different with the 4 kinds respectively mixing matrix phases of pioglitazone hydrochloride are mixed again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 6.
Test 7: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 1 ratio different with the 4 kinds respectively mixing matrix phases of pioglitazone hydrochloride are mixed again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 7.
Test 8: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 3 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 3 ratio different with the 4 kinds respectively mixing matrix phases of pioglitazone hydrochloride are mixed again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 8.
Test 9: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 9 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 9 ratio different with the 4 kinds respectively mixing matrix phases of pioglitazone hydrochloride are mixed again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 9.
Test 10: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 1 ratio pioglitazone hydrochloride is mixed mutually with 4 kinds of different mixed-matrixes respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 10.
Test 11: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 3 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 3 ratio pioglitazone hydrochloride is mixed mutually with 4 kinds of different mixed-matrixes respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 11.
Test 12: in order to observe the mass discrepancy of pioglitazone hydrochloride and mixed-matrix prepared Pyrolidone hydrochloride drip pill when 1: 9 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 9 ratio pioglitazone hydrochloride is mixed mutually with 4 kinds of different mixed-matrixes respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that pioglitazone hydrochloride and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 12.
The group practices of table 1 pioglitazone hydrochloride and single-matrix
(pioglitazone hydrochloride: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 1000 | ??50.0 | ??64 | ??＜30 | ??＞10 | ??+ |
| Polyethylene Glycol 4000 | ??50.0 | ??72 | ??＜30 | ??＞10 | ??+ |
| Polyethylene Glycol 6000 | ??50.0 | ??73 | ??＜30 | ??＞10 | ??++ |
| Polyethylene Glycol 10000 | ??50.0 | ??76 | ??＜30 | ??＞10 | ??++ |
| Polyethylene Glycol 20000 | ??50.0 | ??75 | ??＜30 | ??＞10 | ??++ |
| Span 40 | ??50.0 | ??72 | ??＜30 | ??＞10 | ??++ |
| Polyoxyethylene stearate 40 esters | ??50.0 | ??76 | ??＜30 | ??＞10 | ??++ |
| Poloxamer | ??50.0 | ??76 | ??＜30 | ??＞10 | ??++ |
| Sodium lauryl sulphate | ??50.0 | ??73 | ??＞30 | ??＞10 | ??+ |
| Stearic acid | ??50.0 | ??62 | ??＞30 | ??＞10 | ??++ |
| Sodium stearate | ??50.0 | ??63 | ??＞30 | ??＞10 | ??++ |
| Glycerin gelatine | ??50.0 | ??61 | ??＞30 | ??＞10 | ??+ |
| Lac | ??50.0 | ??65 | ??＞30 | ??＞10 | ??+ |
The group practices of 2 pioglitazone hydrochloride and single-matrix
(pioglitazone hydrochloride: substrate=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 1000 | ??25.0 | ??66 | ??＜30 | ??＞10 | ??+ |
| Polyethylene Glycol 4000 | ??25.0 | ??85 | ??＜30 | ??＜10 | ??+++ |
| Polyethylene Glycol 6000 | ??25.0 | ??87 | ??＜30 | ??＜10 | ??+++ |
| Polyethylene Glycol 10000 | ??25.0 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Polyethylene Glycol 20000 | ??25.0 | ??90 | ??＜30 | ??＜10 | ??+++ |
| Span 40 | ??25.0 | ??82 | ??＜30 | ??＞10 | ??++ |
| Polyoxyethylene stearate 40 esters | ??25.0 | ??89 | ??＜30 | ??＜10 | ??++ |
| Poloxamer | ??25.0 | ??85 | ??＜30 | ??＜10 | ??+++ |
| Sodium lauryl sulphate | ??25.0 | ??76 | ??＜30 | ??＞10 | ??++ |
| Stearic acid | ??25.0 | ??73 | ??＞30 | ??＞10 | ??+++ |
| Sodium stearate | ??25.0 | ??71 | ??＞30 | ??＞10 | ??+++ |
| Glycerin gelatine | ??25.0 | ??75 | ??＞30 | ??＞10 | ??+++ |
| Lac | ??25.0 | ??74 | ??＞30 | ??＞10 | ??+++ |
The group practices of table 3 pioglitazone hydrochloride and single-matrix
(pioglitazone hydrochloride: substrate=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 1000 | ??10.0 | ??75 | ??＜30 | ??＞10 | ??+ |
| Polyethylene Glycol 4000 | ??10.0 | ??87 | ??＜30 | ??＜10 | ??+++ |
| Polyethylene Glycol 6000 | ??10.0 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Polyethylene Glycol 10000 | ??10.0 | ??89 | ??＜30 | ??＜10 | ??+++ |
| Polyethylene Glycol 20000 | ??10.0 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Span | ??10.0 | ??85 | ??＜30 | ??＞10 | ??+++ |
| Polyoxyethylene stearate 40 esters | ??10.0 | ??91 | ??＜30 | ??＜10 | ??++ |
| Poloxamer | ??10.0 | ??85 | ??＜30 | ??＜10 | ??+++ |
| Sodium lauryl sulphate | ??10.0 | ??78 | ??＜30 | ??＞10 | ??+++ |
| Stearic acid | ??10.0 | ??75 | ??＞30 | ??＞10 | ??+++ |
| Sodium stearate | ??10.0 | ??73 | ??＞30 | ??＞10 | ??+++ |
| Glycerin gelatine | ??10.0 | ??76 | ??＞30 | ??＞10 | ??+++ |
| Lac | ??10.0 | ??77 | ??＞30 | ??＞10 | ??+++ |
The group practices of table 4 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ??50 | ??84 | ??＜30 | ??＞10 | ??++ |
| Poloxamer: Polyethylene Glycol=1: 1 | ??50 | ??83 | ??＜30 | ??＞10 | ??++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ??50 | ??81 | ??＜30 | ??＞10 | ??++ |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ??50 | ??82 | ??＜30 | ??＞10 | ??+ |
The group practices of table 5 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ??25 | ??85 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 1 | ??25 | ??87 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ??25 | ??85 | ??＜30 | ??＞10 | ??++ |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ??25 | ??87 | ??＜30 | ??＞10 | ??++ |
The group practices of table 6 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ??10 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 1 | ??10 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ??10 | ??89 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ??10 | ??87 | ??＜30 | ??＞10 | ??+++ |
The group practices of table 7 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ??50 | ??88 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 5 | ??50 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ??50 | ??89 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ??50 | ??89 | ??＜30 | ??＜10 | ??++ |
The group practices of table 8 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ??25 | ??86 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 5 | ??25 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ??25 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ??25 | ??90 | ??＜30 | ??＜10 | ??+++ |
The group practices of table 9 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ??10 | ??90 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 5 | ??10 | ??92 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ??10 | ??92 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ??10 | ??89 | ??＜30 | ??＜10 | ??+++ |
The group practices of table 10 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ??50 | ??88 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 10 | ??50 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ??50 | ??87 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ??50 | ??89 | ??＜30 | ??＞10 | ??+++ |
The group practices of table 11 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 3)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ??25 | ??92 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 10 | ??25 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ??25 | ??89 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ??25 | ??90 | ??＜30 | ??＜10 | ??+++ |
The group practices of table 12 pioglitazone hydrochloride and mixed-matrix
(pioglitazone hydrochloride: mixed-matrix=1: 9)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ??10 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Poloxamer: Polyethylene Glycol=1: 10 | ??10 | ??91 | ??＜30 | ??＜10 | ??+++ |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ??10 | ??90 | ??＜30 | ??＜10 | ??+++ |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ??10 | ??92 | ??＜30 | ??＜10 | ??+++ |
1. can be seen by the result in the table: when the ratio of pioglitazone hydrochloride and substrate was 1: 1, its rounding rate, the ball method of double differences was different and index such as hardness is all undesirable, and dissolve scattered time limit influenced not obvious.
2. when the ratio of pioglitazone hydrochloride and substrate is 1: 3, the rounding rate, the ball method of double differences is different and index such as hardness slightly all begins to enter preferable state.
3. when the ratio of pioglitazone hydrochloride and substrate is 1: 9, the rounding rate, the ball method of double differences is different and index such as hardness improves not obvious.
4. the general effect of composite interstitial substance is better than single-matrix.
5. the hardness method for expressing in the subordinate list adopts drop pill is placed on the glass plate, press...withes one's finger it, observes its metamorphosis."+" expression flicking promptly is out of shape, " ++ " expression distortion of firmly pressing, and " +++" expression is indeformable by it.
[reference material]
1. the journey book is weighed, Li Benquan, Ma Hongfu. and pioglitazone treatment diabetes are used progress. and external medical 2001,22 (2) P.108
2. Zou advances greatly, Wang Qijin. pioglitazone hydrochloride. and 469 pages of Chinese Journal of New Drugs the 10th the 6th phases of volume of calendar year 2001.
Claims (5)
1. a pharmaceutical composition pioglitazone drop pill that is used for the treatment of type 2 diabetes mellitus is a raw material with the pioglitazone, be prepared from pharmaceutically suitable carrier as substrate, wherein:
1.1 pioglitazone hydrochloride
[English name] Pioglitazonehydrochloride
[chemical name] (±)-5-[[4-[2-(5-ethyl-2-pyridine radicals) dioxy base] benzyl]-2,4] the thiazolidinedione hydrochlorate
[chemical structural formula]
1.2 substrate: the mixture of one or more in pharmaceutically suitable carrier such as polyethylene glycols, sorbitol anhydride class, polyoxyethylene sorbitol acid anhydride class, polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
1.3 proportioning: with g or kg is unit, by weight, and pioglitazone hydrochloride: substrate=1: 1～1: 9.
2. pioglitazone drop pill as claimed in claim 1 is characterized in that: described substrate is the mixture of Polyethylene Glycol and polyoxyethylene stearate 40 esters or Polyethylene Glycol and poloxamer or Polyethylene Glycol and carboxymethyl starch sodium or Polyethylene Glycol and betacyclodextrin; With g or kg is unit, and by weight, its mixed proportion is polyoxyethylene stearate 40 esters: Polyethylene Glycol or poloxamer: Polyethylene Glycol or carboxymethyl starch sodium: Polyethylene Glycol or betacyclodextrin: Polyethylene Glycol=1: 1～1: 10.
3. any pioglitazone drop pill as claimed in claim 1 or 2 is characterized in that: the mixed proportion of described medicine dry powder and substrate is 1: 1～1: 5.
4. the preparation method of a pioglitazone drop pill is characterized in that being made of following process:
4.1 pioglitazone hydrochloride
[English name] Pioglitazonehydrochloride
[chemical name] (±)-5-[[4-[2-(5-ethyl-2-pyridine radicals) dioxy base] benzyl]-2,4] the thiazolidinedione hydrochlorate.
4.2 substrate: the mixture of one or more in pharmaceutically suitable carrier such as polyethylene glycols, sorbitol anhydride class, polyoxyethylene sorbitol acid anhydride class, polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
4.3 proportioning: with g or kg is unit, by weight, and pioglitazone hydrochloride: substrate=1: 1～1: 9;
4.4, accurately take by weighing pioglitazone hydrochloride and substrate according to the given ratio of prescription, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing pioglitazone hydrochloride and substrate and/or emulsion and/or suspension;
4.5 adjust the temperature control system of drop pill machine, make the water dropper temperature heating of drop pill machine and remain on 50 ℃～90 ℃, the temperature cooling of condensing agent also remains on 40 ℃～-5 ℃;
4.6 when treating in dropping-pill machine head and the condensation column that the temperature of condensing agent reaches desired state of temperature respectively, to contain the fused solution of pioglitazone hydrochloride and substrate and/or emulsion and/or suspension places in the water dropper jar of drop pill machine, splash in the condensing agent, shrink molding promptly.
5. as the preparation method of pioglitazone drop pill as described in the claim 4, it is characterized in that: described condensing agent be methyl-silicone oil or/and liquid paraffin or/and vegetable oil.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102228457A (en) * | 2011-04-25 | 2011-11-02 | 刘树芹 | Pharmaceutical composition for treating diabetes and complication thereof |
| CN103432128A (en) * | 2013-08-26 | 2013-12-11 | 中国人民解放军第150中心医院 | Method for compounding drug-containing layer of pioglitazone hydrochloride controlled-release pellet preparation |
| CN104324004A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Pioglitazone lipidosome combined drug, and large-scale production process thereof |
| CN105456242A (en) * | 2008-03-10 | 2016-04-06 | 雀巢产品技术援助有限公司 | Medium chain dicarboxylic acids, their derivates and metabolic disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1424041A (en) * | 2002-12-19 | 2003-06-18 | 中国人民解放军第二军医大学 | Kakonein preparations and their production |
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2005
- 2005-04-19 CN CNB2005100660017A patent/CN100364533C/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105456242A (en) * | 2008-03-10 | 2016-04-06 | 雀巢产品技术援助有限公司 | Medium chain dicarboxylic acids, their derivates and metabolic disorders |
| CN104324004A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Pioglitazone lipidosome combined drug, and large-scale production process thereof |
| CN102228457A (en) * | 2011-04-25 | 2011-11-02 | 刘树芹 | Pharmaceutical composition for treating diabetes and complication thereof |
| CN102228457B (en) * | 2011-04-25 | 2013-07-24 | 刘树芹 | Pharmaceutical composition for treating diabetes and complication thereof |
| CN103432128A (en) * | 2013-08-26 | 2013-12-11 | 中国人民解放军第150中心医院 | Method for compounding drug-containing layer of pioglitazone hydrochloride controlled-release pellet preparation |
| CN103432128B (en) * | 2013-08-26 | 2015-11-18 | 中国人民解放军第150中心医院 | A kind of compound formulation of pioglitazone hydrochloride sustained-release pellet preparations medicated layer |
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| CN100364533C (en) | 2008-01-30 |
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Assignee: Jiangsu Zhengda Fenghai Pharmaceutical Co., Ltd. Assignor: Beijing Zhengda Oasis Medicine Technology Co., Ltd. Contract fulfillment period: 2008.2.18 to 2025.4.18 Contract record no.: 2008320000313 Denomination of invention: Pyrolidone hydrochloride drip pill and its preparation method Granted publication date: 20080130 License type: Exclusive license Record date: 20080924 |
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