CN1686125A - Rogelinone drip pill and its preparation method - Google Patents
Rogelinone drip pill and its preparation method Download PDFInfo
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- CN1686125A CN1686125A CN 200510068274 CN200510068274A CN1686125A CN 1686125 A CN1686125 A CN 1686125A CN 200510068274 CN200510068274 CN 200510068274 CN 200510068274 A CN200510068274 A CN 200510068274A CN 1686125 A CN1686125 A CN 1686125A
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- polyethylene glycol
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Abstract
A dripping pill of Luogelietong for treating diabetes B is prepared from Luogelietong or its salts and the pharmacologically acceptable carrier. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of diabetes, is the medicine part a kind of drug composition oral preparation that is prepared from that forms alive with rosiglitazone or its esters particularly.
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), rosiglitazone (rosiglitazone), troglitazone (troglitazone), ciglitazone (ciglitazone), englitazone (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.
Rosiglitazone (rosiglitazone) chemically belongs to thiazolidinediones, and foreign literature incorporates this class thiazolidines antidiabetic compound into glitazones (glitazone) into.Glitazone is a class new oral antidiabetic medicine, and its anti-diabetic effect mainly shows as increases the sensitivity of target tissue to insulin, improves insulin resistant, so be called as euglycemic agent.Rosiglitazone is to the existing report of experiment of heritability insulin resistant model and high fat human insulin opposing model, but the direct sensitization of its insulin and the effect of immunity insulin resistant model do not appeared in the newspapers.This experiment is observed the antidiabetic effect of rosiglitazone by IDDM (insulin dependent diabetes mellitus (IDDM)) rat model and immunity insulin resistant model.
Experimental result shows: rosiglitazone 1,3, and the continuous gastric infusion 8d of 10 a μ molkg-13 dosage group all fails to reduce normal rat blood glucose, also fails to reduce blood glucose in diabetic rats due to the chain assistant rhzomorph; But and with low dose of insulin condition under, the continuous gastric infusion 8d of rosiglitazone 3,10 μ molkg-1 can reduce chain and help blood glucose in diabetic rats due to the rhzomorph; Behind the continuous gastric infusion 8d of rosiglitazone 10 μ molkg-1, detect with positive sugared tongs technology, the glucose infusion speed under the inferior high and high insulin state of immunity insulin resistant model all obtains.Conclusion: rosiglitazone has insulin-sensitizing effect and insulin resistant improvement effect.
Its esters commonly used clinically is as the raw material of rosiglitazone pharmaceutical preparation, as: the rosiglitazone maleate sheet, be to be a kind of oral formulations that chemical raw material is prepared from the rosiglitazone maleate, have the insulin sensitivity that improves the insulin resistant patient, improve the reactivity of insulin pair cell, and improve glucose disequilibrium effect in the body, the oral tablet that is used for the treatment 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 Rogelinone drip pill.Rogelinone drip pill involved in the present invention is an active constituents of medicine with rosiglitazone or its esters, 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. rosiglitazone maleate (used rosiglitazone maleate here, also can use rosiglitazone or other salt)
[English name] rosiglitazone maleate
[chemical name] (±)-5-[[4-[2-(methyl-2-pyridine amino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione (Z)-2-butylene diacid salt
[molecular formula] C
18H
19N
3O
3SC
4H
4O
4
[molecular weight] 473.52
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 rosiglitazone or its esters: substrate=1: 1～1: 9;
4. according to the given ratio of prescription, accurately take by weighing rosiglitazone or its esters and substrate, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing rosiglitazone 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 rosiglitazone 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 (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), rosiglitazone (rosiglitazone), troglitazone (troglitazone), ciglitazone (ciglitazone), englitazone (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.
Rosiglitazone (rosiglitazone) chemically belongs to thiazolidinediones, and foreign literature incorporates this class thiazolidines antidiabetic compound into glitazones (glitazone) into.Glitazone is a class new oral antidiabetic medicine, and its anti-diabetic effect mainly shows as increases the sensitivity of target tissue to insulin, improves insulin resistant, so be called as euglycemic agent.Rosiglitazone is to the existing report of experiment of heritability insulin resistant model and high fat human insulin opposing model, but the direct sensitization of its insulin and the effect of immunity insulin resistant model do not appeared in the newspapers.This experiment is observed the antidiabetic effect of rosiglitazone by IDDM (insulin dependent diabetes mellitus (IDDM)) rat model and immunity insulin resistant model.
Its esters commonly used clinically is as the raw material of rosiglitazone pharmaceutical preparation, as: the rosiglitazone maleate sheet, be to be a kind of oral formulations that chemical raw material is prepared from the rosiglitazone maleate, have the insulin sensitivity that improves the insulin resistant patient, improve the reactivity of insulin pair cell, and improve glucose disequilibrium effect in the body, the oral tablet that is used for the treatment 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. Rogelinone drip pill involved in the present invention; utilize surfactant to be substrate; make solid dispersion with rosiglitazone or its esters, 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. Rogelinone 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. Rogelinone 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 Rogelinone drip pill of the present invention.
[first group: the test of single-matrix]
1. rosiglitazone maleate
[English name] rosiglitazone maleate
[chemical name] (±)-5-[[4-[2-(methyl-2-pyridine amino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione (Z)-2-butylene diacid salt
[molecular formula] C
18H
19N
3O
3SC
4H
4O
4
[molecular weight] 473.52
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 get the rosiglitazone maleate drop pill of different size.
[result of the test]
Test 1: for observe rosiglitazone maleate and different substrates when 1: 1 the proportioning prepared rosiglitazone maleate drop pill in qualitative difference, according to 1: 1 ratio, with rosiglitazone maleate 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 rosiglitazone maleate and different substrates, and obtain 13 groups of different experimental results and see Table 1.
Test 2: for observe rosiglitazone maleate and different substrates when 1: 3 the proportioning prepared rosiglitazone maleate drop pill in qualitative difference, according to 1: 3 ratio, with rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate drop pill in qualitative difference, according to 1: 9 ratio, with rosiglitazone maleate 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 rosiglitazone maleate and different substrates, and obtain 13 groups of different experimental results and see Table 3.
[second group: the test of mixed-matrix]
1. rosiglitazone maleate
[English name] rosiglitazone maleate
[chemical name] (±)-5-[[4-[2-(methyl-2-pyridine amino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione (Z)-2-butylene diacid salt
[molecular formula] C
18H
19N
3O
3SC
4H
4O
4
[molecular weight] 473.52
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, get final product different size rosiglitazone maleate drop pill.
[result of the test]
Test 4: in order to observe the mass discrepancy of rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix prepared rosiglitazone maleate drop 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 rosiglitazone maleate 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 rosiglitazone maleate and mixed-matrix constituted, and obtain 4 groups of different experimental results and see Table 12.
The group practices of table 1 rosiglitazone maleate and single-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and single-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and single-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
Rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate and mixed-matrix
(rosiglitazone maleate: 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 rosiglitazone maleate 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 rosiglitazone maleate 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 rosiglitazone maleate 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]
Luo Moulun, Guo Yuxiao, Hu Yinghui, Lin Zhibin. the insulin-sensitizing effect of rosiglitazone and insulin resistant improvement effect. Chinese Pharmacological circular 2000Aug; 16 (4): 425～8P.524.
Claims (6)
1. a pharmaceutical composition Rogelinone drip pill that is used for the treatment of type 2 diabetes mellitus is an active constituents of medicine with rosiglitazone or its esters, be prepared from pharmaceutically suitable carrier as substrate, wherein:
1. rosiglitazone: English name rosiglitazone
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. Rogelinone drip pill as claimed in claim 1 is characterized in that: described active constituents of medicine is a rosiglitazone maleate, and specific definition is as follows:
[English name] rosiglitazone maleate
[chemical name] (±)-5-[[4-[2-(methyl-2-pyridine amino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione (Z)-2-butylene diacid salt
[molecular formula] C
18H
19N
3O
3SC
4H
4O
4
[molecular weight] 473.52.
3. as claim 1 or the described any Rogelinone drip pill of claim 2, it 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.
4. any Rogelinone drip pill as claimed in claim 1 or 2 is characterized in that: the mixed proportion of described active constituents of medicine and substrate is 1: 1～1: 5.
5. the preparation method of a Rogelinone drip pill is characterized in that being made of following process:
5.1 rosiglitazone maleate
[English name] rosiglitazone maleate
[chemical name] (±)-5-[[4-[2-(methyl-2-pyridine amino) ethyoxyl] phenyl] methyl]-2,4-thiazolidinedione (Z)-2-butylene diacid salt
[molecular formula] C
18H
19N
3O
3SC
4H
4O
4
[molecular weight] 473.52
5.2 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;
5.3 proportioning: with g or kg is unit, by weight, and rosiglitazone maleate: substrate=1: 1～1: 9;
5.4, accurately take by weighing rosiglitazone maleate 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 rosiglitazone maleate and substrate and/or emulsion and/or suspension;
5.5 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 ℃;
5.6 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 rosiglitazone maleate 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.
6. as the preparation method of Rogelinone drip pill as described in the claim 5, it is characterized in that: described condensing agent be methyl-silicone oil or/and liquid paraffin or/and vegetable oil.
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|---|---|---|---|
| CN 200510068274 CN1686125A (en) | 2005-05-08 | 2005-05-08 | Rogelinone drip pill and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102389427A (en) * | 2011-10-10 | 2012-03-28 | 成都恒瑞制药有限公司 | Solid oral preparation containing rosiglitazone and cetirizine hydrochloride |
| CN104324002A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Rosiglitazone lipidosome combined drug, and large-scale production technology and application thereof |
-
2005
- 2005-05-08 CN CN 200510068274 patent/CN1686125A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104324002A (en) * | 2010-07-29 | 2015-02-04 | 湖南康都制药有限公司 | Rosiglitazone lipidosome combined drug, and large-scale production technology and application thereof |
| CN102389427A (en) * | 2011-10-10 | 2012-03-28 | 成都恒瑞制药有限公司 | Solid oral preparation containing rosiglitazone and cetirizine hydrochloride |
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