CN103768062B - A kind of repaglinide and the compound preparation of metformin hydrochloride - Google Patents
A kind of repaglinide and the compound preparation of metformin hydrochloride Download PDFInfo
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- CN103768062B CN103768062B CN201210407014.6A CN201210407014A CN103768062B CN 103768062 B CN103768062 B CN 103768062B CN 201210407014 A CN201210407014 A CN 201210407014A CN 103768062 B CN103768062 B CN 103768062B
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Abstract
The present invention relates to the preparation method of a kind of repaglinide and metformin hydrochloride compound preparation, repaglinide is dissolved in ethanol, alkaline agent and solubilizing agent and is dissolved in water by the present invention, then is added separately in metformin hydrochloride and other adjuvants, makes tablet.The problems such as it is bad that the present invention solves repaglinide dissolution, uniformity of dosage units difference, are suitable for industrialization large-scale production.
Description
Technical field
The present invention relates to treat the preparation method of a kind of compound preparation of diabetes, concrete is, a kind of repaglinide and
The preparation method of the compound preparation of metformin hydrochloride.
Background technology
Diabetes have become one of 5 kinds of the highest diseases of whole world M & M, especially with the development such as Chinese, African
Chinese Home increase is the most notable.Diabetes once control bad to cause complication, cause the position exhaustion pathological changes such as kidney, eye, foot,
And cannot cure.Diabetes can be divided into insulin-dependent diabetes (1 type) and noninsulindependent diabetes (2 type) two
Kind, in the diabetics that quantity sharply increases, type 2 diabetes mellitus at least accounts for more than the 90% of patient populations.Type 1 diabetes is suffered from
Person treats with insulin at present, and major part type 2 diabetes mellitus patient is with stimulating the sulfonylureas of β cell function or with strengthening patient couple
The medicament of the structure sensitive properties of insulin or treat with insulin.
Repaglinide is a kind of Drugs Promoting Insulin Secretion, and the specific receptor on beta Cell of islet film is combined, and promotes and is subject to
The ATP sensitive potassium channel of body coupling is closed, and suppression potassium ion is from β cell drain, membrane depolarization, and calcium channel is open, calcium
Stream in ion, promotes insulin secretion.Repaglinide effect is faster than sulfonylurea, therefore hypoglycemic activity is very fast after the meal, is first
The glucose regulator taken during individual dining, maximum advantage is can to imitate the physiological secretion of insulin, the most effectively
Control postprandial hyperglycemia.
Metformin hydrochloride has the glucose tolerance improving type 2 diabetes mellitus patient, reduces the work of basis and post-prandial glycemia
With.This medicine can promote fatty tissue ingestion of glucose, reduces glucose at the absorption of intestinal and gluconeogenesis, glucagon suppression
Release etc., thus improve the sensitivity of insulin, metformin hydrochloride will not be to type 2 diabetes mellitus patient or the patient of euglycemia
Produce hypoglycemia.
Repaglinide and metformin hydrochloride use in conjunction can preferably reduce blood glucose, and repaglinide reduces stimulating pancreas
The blood glucose of uelralante；Metformin reduce basis and level of postprandial blood sugar, combine two kinds of different mechanism of action with
Medicine is effectively improved the glycemic control of type 2 diabetes mellitus patient.
Existing document reports repaglinide and metformin hydrochloride technical problem present in the preparation process, Rui Gelie
When how to combine with metformin hydrochloride, repaglinide content is several milligrams, and metformin content is up to 500mg, makes at the two
It is easy to generation during Bei can not mix completely, the problem causing uniformity of dosage units difference；It addition, repaglinide dissolves in water
Spend the least, only 0.005mg/mL, and metformin hydrochloride is water soluble drug, so makes the pharmaceutical preparation prepared in dissolution
Dissolution in journey is asynchronous, make repaglinide and metformin hydrochloride over the course for the treatment of can not onset simultaneously, affect medicine and send out
Wave its synergy.
CN101516347A discloses repaglinide is dissolved in water with solubilizing agent, binding agent, alkaline agent, spray dried
Dry, the powder and the filler that obtain are mixed to prepare repaglinide pre-formulation, by metformin and binding agent, solvent, water solublity dilution
Agent prepares metformin granule, then by equal to repaglinide pre-formulation and metformin granule, filler, disintegrating agent, mix lubricant
Even, tabletting, obtain repaglinide metformin pharmaceutical composition.But repaglinide dissolubility in water is the least, by itself and its
It is less, more that his composition is dissolved in repaglinide specification in the effect that water can not be uniformly mixed, particularly compound preparation jointly
Add that to result in its mixing uneven.
CN101756971A discloses metformin hydrochloride is mixed homogeneously with filler, binding agent, by repaglinide
Being dissolved in ethanol in addition said mixture, soft material processed, add disintegrating agent, mix lubricant uniformly, tabletting obtains repaglinide salt
Acid dimethyldiguanide tablet.During in the method, repaglinide is dissolved in ethanol, increase when mixing with metformin hydrochloride and adjuvant
Contact area, improves its uniformity of dosage units, but the product dissolution that this technique prepares is the most undesirable.
Summary of the invention
The present invention, by substantial amounts of experiment, develops a kind of repaglinide and the preparation side of metformin hydrochloride compound preparation
Method, the present invention solves repaglinide and metformin hydrochloride and prepares and be difficult to mixing in production process, and uniformity of dosage units is low, dissolution
Spend low, the problems such as dissolution is asynchronous.Repaglinide is dissolved in ethanol obtaining solution A by the present invention, and a small amount of repaglinide is with molecule
Form be uniformly dispersed in ethanol so that it is with the mixed process of metformin hydrochloride and adjuvant in increase contact area,
Make repaglinide mix homogeneously with metformin hydrochloride, keep good uniformity of dosage units；It addition, prescription adds alkaline agent,
Its objective is to ensure the PH dependent/non-dependent of preparation dissolution so that process in leaching stably continues；The addition of solubilizing agent promotes product
Dissolution, the particularly dissolution of the repaglinide of poorly water-soluble, reasonable disposition alkaline agent and solubilizing agent consumption, it is possible to make Rui Ge
Arrange dissolution the most Tong Bu with metformin hydrochloride, play drug effect, and the PH no dependence to dissolution environment simultaneously, preferably play
Repaglinide and the drug synergism of metformin.For avoiding repaglinide to react with alkaline agent and solubilizing agent, and by
Relatively big with the difference of the two dissolution properties in repaglinide, repaglinide is dissolved in the most respectively solvent and makes solution, then add successively
Enter in the solid mixture of prescription, the effect of alkaline agent and solubilizing agent can not only be given full play to, it also avoid related substance
Increase, it is ensured that the quality of the pharmaceutical preparations.It addition, the Adding Way of disintegrating agent also provides guarantee for product quality in preparation process,
The present invention adds in using disintegrating agent and the method for additional combination, first will be added in disintegrating agent in metformin solid mixture, then
Being applied in the granule of repaglinide and metformin hydrochloride, disintegrate occurs in granule and between granule simultaneously, can make to prepare
Tablet be easier to disintegrate, add the dissolution of active component.The present invention, only can be real with conventional equipment in production technology
Existing, reduce production cost, be suitable for industrialization large-scale production.
The present invention the specific scheme is that
A kind of repaglinide and the preparation method of metformin hydrochloride compound preparation, it is characterised in that described concrete steps
For:
(1) repaglinide is dissolved in ethanol, obtains solution A；
(2) by soluble in water to alkaline agent and solubilizing agent, solution B is obtained；
(3) by metformin hydrochloride, diluent, disintegrating agent, binding agent mix homogeneously, mixed powder C is obtained；
(4) in above-mentioned mixed powder C, it is sequentially added into solution A and solution B, mixing, prepare medicine-containing particle；
(5) disintegrating agent, mix homogeneously, tabletting are added.
Above-mentioned alkaline agent is meglumine；Solubilizing agent is poloxamer, Tween 80, sodium lauryl sulphate, is wherein preferably
Poloxamer.
Above-mentioned diluent is several in calcium hydrogen phosphate, pregelatinized Starch, sorbitol, mannitol；Disintegrating agent is carboxylic first
One or more in Starch Sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone；Binding agent is polyvidone, hydroxy propyl cellulose
One or more in element, hypromellose, sodium carboxymethyl cellulose.
Above-mentioned diluent is calcium hydrogen phosphate and sorbitol；Disintegrating agent is carboxymethylstach sodium；Binding agent is polyvidone.
For improving particle flow, can also add lubricant in said method step (5), wherein lubricant is stearic acid
Magnesium, micropowder silica gel, Pulvis Talci.
Above-mentioned preparation method if desired can coating.
In above-mentioned preparation method, each amounts of components is: repaglinide 1 part, alkaline agent 0.3-0.8 part, solubilizing agent 0.3-1 part,
Metformin hydrochloride 500 parts, diluent 60-85 part, disintegrating agent 15-30 part, binding agent 15-30 part.
In above-mentioned preparation method, each amounts of components is: repaglinide 2 parts, alkaline agent 0.7-1.3 part, solubilizing agent 0.8-1.5
Part, metformin hydrochloride 500 parts, diluent 60-85 part, disintegrating agent 15-30 part, binding agent 15-30 part.
In above-mentioned solution A, repaglinide is 1:10-25 with the mass ratio of ethanol.
Above-mentioned solution B neutral and alkali agent and the quality of solubilizing agent and the mass ratio with water are 1:5-16.
Detailed description of the invention
Embodiment 1
(1) repaglinide of 1g is dissolved in the ethanol of 15g, obtains solution A；
(2) by 0.5g meglumine, 0.6g poloxamer is dissolved in the water of 15g, obtains solution B；
(3) by 500g metformin hydrochloride, 60g calcium hydrogen phosphate, 10g sorbitol, 10g carboxymethylstach sodium, 20g polyvidone
Mix homogeneously, obtains mixed powder C；
(4) in above-mentioned mixed powder C, it is sequentially added into solution A and solution B, stirring, prepare medicine-containing particle；
(5) in the granule that step (4) prepares, 10g carboxymethylstach sodium and 4g magnesium stearate, mix homogeneously, tabletting are added.
Embodiment 2
| Component | Weight |
| Repaglinide | 1g |
| Meglumine | 0.3g |
| Tween 80 | 0.3g |
| Metformin hydrochloride | 500g |
| Pregelatinized Starch | 50g |
| Sorbitol | 10g |
| Low-substituted hydroxypropyl cellulose (inside adds) | 7g |
| Hydroxypropyl cellulose | 15g |
| Polyvinylpolypyrrolidone (additional) | 8g |
| Micropowder silica gel | 2g |
| Ethanol | 10g |
| Water | 3g |
Preparation method is with embodiment 1
Embodiment 3
| Component | Weight |
| Repaglinide | 1g |
| Meglumine | 0.8g |
| Sodium lauryl sulphate | 1g |
| Metformin hydrochloride | 500g |
| Calcium hydrogen phosphate | 70g |
| Mannitol | 15g |
| Polyvinylpolypyrrolidone (inside adds) | 15g |
| Hydroxypropyl cellulose | 15g |
| Sodium carboxymethyl cellulose | 15g |
| Carboxymethylstach sodium (additional) | 15g |
| Pulvis Talci | 6g |
| Ethanol | 25g |
| Water | 28g |
Preparation method is with embodiment 1
Embodiment 4
| Component | Weight |
| Repaglinide | 2g |
| Meglumine | 1g |
| Poloxamer | 1.2g |
| Metformin hydrochloride | 500g |
| Calcium hydrogen phosphate | 62g |
| Sorbitol | 12g |
| Carboxymethylstach sodium (inside adds) | 10g |
| Polyvidone | 20g |
| Carboxymethylstach sodium (additional) | 12g |
| Magnesium stearate | 4.5g |
| Ethanol | 33g |
| Water | 22g |
Preparation method is with embodiment 1
Embodiment 5
| Component | Weight |
| Repaglinide | 2g |
| Meglumine | 0.7g |
| Sodium lauryl sulphate | 0.9g |
| Metformin hydrochloride | 500g |
| Pregelatinized Starch | 50g |
| Mannitol | 10g |
| Carboxymethylstach sodium (inside adds) | 8g |
| Hypromellose | 16g |
| Polyvinylpolypyrrolidone (additional) | 8g |
| Magnesium stearate | 2.5g |
| Ethanol | 20g |
| Water | 9g |
Preparation method is with embodiment 1
Embodiment 6
| Component | Weight |
| Repaglinide | 2g |
| Meglumine | 1.3g |
| Tween 80 | 1g |
| Poloxamer | 0.5g |
| Metformin hydrochloride | 500g |
| Calcium hydrogen phosphate | 75g |
| Sorbitol | 10g |
| Polyvinylpolypyrrolidone (inside adds) | 15g |
| Polyvidone | 30g |
| Polyvinylpolypyrrolidone (additional) | 15g |
| Magnesium stearate | 6g |
| Ethanol | 48g |
| Water | 42g |
Preparation method is with embodiment 1
Comparative example 1
1g repaglinide, 0.6g poloxamer and 0.5g meglumine are dissolved in pure water and are spray-dried, get Rui Ge
Arrange how powder.
By 500g metformin hydrochloride, 60g calcium hydrogen phosphate, 10g sorbitol, 10g carboxymethylstach sodium, 20g polyvidone is closing
With pure water pelletize and be dried in suitable high-shear mixer.
Repaglinide powder and metformin hydrochloride granule are mixed with 10g carboxymethylstach sodium, by hard for this mixture 4g
Fatty acid magnesium lubricates, tabletting.
Comparative example 2
By 500g metformin hydrochloride, 0.5g meglumine, 0.6g poloxamer, 60g calcium hydrogen phosphate, 10g sorbitol, 10g
Carboxymethylstach sodium, 20g polyvidone mix homogeneously, add the ethanol solution containing 1g repaglinide, after stirring, add purified water
Soft material the most processed, pelletizes, and is dried, and adds 10g carboxymethylstach sodium and 4g magnesium stearate, mix homogeneously, tabletting.
To above-described embodiment sample and comparative example 1, the uniformity of dosage units (%) of comparative example 2 gained sample is carried out
Test, result is as follows:
Result of the test shows, the repaglinide prepared by the present invention and the uniformity of dosage units of metformin hydrochloride compound preparation
Being better than the compound preparation that comparative example 1 and 2 provider's methods of comparative example prepare, active component is uniformly dispersed, and meets and contains
Amount uniformity prescription.
With reference to two annex XC the first methods of China's coastal port, by embodiment gained sample and comparative example 1, right
Dissolution in vitro (%) test is carried out respectively than embodiment 2 gained sample.Result is as follows:
Understanding according to this test, embodiment gained sample is compared with comparative example's gained sample, and within a short period of time has
Preferably dissolution, and two kinds of active component synchronization dissolutions, it is possible to preferably play the collaborative work of two kinds of active constituents of medicine
With.
To above-described embodiment gained sample and comparative example 1, the relevant thing of repaglinide in comparative example 2 gained sample
Matter (%) content is measured.Result is as follows:
Understanding according to this test, the relevant content of material of sample obtained by the present invention is preferable, hence it is evident that be better than comparative example.
Claims (5)
1. a repaglinide and the preparation method of metformin hydrochloride compound preparation, it is characterised in that described in concretely comprise the following steps:
(1) repaglinide is dissolved in ethanol, obtains solution A；
(2) by soluble in water to alkaline agent and solubilizing agent, solution B is obtained；
(3) by metformin hydrochloride, diluent, disintegrating agent, binding agent mix homogeneously, mixed powder C is obtained；
(4) in above-mentioned mixed powder C, it is sequentially added into solution A and solution B, mixing, prepare medicine-containing particle；
(5) disintegrating agent, mix homogeneously, tabletting are added；
Wherein, described alkaline agent is meglumine；Solubilizing agent is poloxamer, Tween 80, sodium lauryl sulphate；Diluent is selected from
Calcium hydrogen phosphate, pregelatinized Starch, sorbitol, mannitol；Disintegrating agent is selected from carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, friendship
Connection polyvidone；Binding agent is selected from polyvidone, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose；Described each component
Consumption is: repaglinide 1 part, alkaline agent 0.3-0.8 part, solubilizing agent 0.3-1 part, metformin hydrochloride 500 parts, diluent 60-
85 parts, disintegrating agent 15-30 part, binding agent 15-30 part；Or described each amounts of components is: repaglinide 2 parts, alkaline agent 0.7-1.3
Part, solubilizing agent 0.8-1.5 part, metformin hydrochloride 500 parts, diluent 60-85 part, disintegrating agent 15-30 part, binding agent 15-30
Part.
Preparation method the most according to claim 1, it is characterised in that described solubilizing agent is poloxamer.
Preparation method the most according to claim 1, it is characterised in that described diluent is calcium hydrogen phosphate and sorbitol；
Disintegrating agent is carboxymethylstach sodium；Binding agent is polyvidone.
Preparation method the most according to claim 1, it is characterised in that repaglinide and the quality of ethanol in described solution A
Ratio is 1:10-25.
Preparation method the most according to claim 1, it is characterised in that described solution B neutral and alkali agent and the quality of solubilizing agent
And be 1:5-16 with the mass ratio of water.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210407014.6A CN103768062B (en) | 2012-10-24 | 2012-10-24 | A kind of repaglinide and the compound preparation of metformin hydrochloride |
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| CN201210407014.6A CN103768062B (en) | 2012-10-24 | 2012-10-24 | A kind of repaglinide and the compound preparation of metformin hydrochloride |
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| CN103768062A CN103768062A (en) | 2014-05-07 |
| CN103768062B true CN103768062B (en) | 2016-10-19 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
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- 2012-10-24 CN CN201210407014.6A patent/CN103768062B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101516347A (en) * | 2006-09-29 | 2009-08-26 | 诺沃-诺迪斯克有限公司 | Pharmaceutical formulation comprising metformin and repaglinide |
| CN102319245A (en) * | 2011-07-08 | 2012-01-18 | 杭州华东医药集团生物工程研究所有限公司 | Composition containing repaglinide and metformin hydrochloride and preparation thereof |
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| CN103768062A (en) | 2014-05-07 |
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Address after: 101113 Beijing Guangyuan Tongzhou District Industrial Development Zone in Tongzhou Street No. 8 Patentee after: Beijing Fuyuan Pharmaceutical Co., Ltd. Address before: 101113 Beijing Guangyuan Tongzhou District Industrial Development Zone in Tongzhou Street No. 8 Patentee before: Beijing Winsunny Pharmaceutical Co., Ltd. |
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