CN101843617B - Slow release preparation of compound Repaglinide-metformin hydrochloride - Google Patents
Slow release preparation of compound Repaglinide-metformin hydrochloride Download PDFInfo
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- CN101843617B CN101843617B CN2010101184216A CN201010118421A CN101843617B CN 101843617 B CN101843617 B CN 101843617B CN 2010101184216 A CN2010101184216 A CN 2010101184216A CN 201010118421 A CN201010118421 A CN 201010118421A CN 101843617 B CN101843617 B CN 101843617B
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- metformin hydrochloride
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Abstract
The invention relates to a slow release preparation of compound Repaglinide-metformin hydrochloride and a preparation method thereof, which mainly solve the problem of the synchronous slow release of insoluble medicament Repaglinide and water-soluble medicament metformin hydrochloride. The preparation method uses hydroxypropyl methylcellulose, glyceride behenate, ethylcellulose and the like as framework materials and comprises the steps of: respectively pelletizing the Repaglinide and the metformin hydrochloride, pressing into bilayer tablets or respectively pressing into small tablets, and encapsulating into capsules. The prepared compound slow release preparation not only can improve the curative effect based on the complementation between medicament action mechanisms and decrease the dose of each individual component to reduce toxic or side effects of the medicaments, cut also can slow down the release of the medicaments, stabilize the blood concentration, reduce the administration frequency, and improve the compliance of patients.
Description
Technical field: the present invention relates to slow releasing preparation of compound Repaglinide-metformin hydrochloride and preparation method thereof.
Background technology: diabetes be a kind of be the endocrine metabolism property disease of characteristic with the hyperglycemia, usually cause damage, functional defect and the depletion of human body various tissues, particularly eyes, kidney, nerve, heart and blood vessel.The sickness rate of diabetes is relevant with life style, dietary structure and age factor etc., and improves the gesture that is comprehensive rising with living standard.Yet the pathogenesis of diabetes is still not fully aware of at present, and the pathology characteristics that demonstrate according to the patient can be divided into two types: type i diabetes, i.e. insulin-dependent (IDDM), this kind of patient must rely on exogenous insulin and earn a bare living, belong to heavy; Type ii diabetes, i.e. non-insulin-depending type (NIDDM), this kind of patient must not rely on exogenous insulin and earn a bare living; Majority is the adult, but also is found in teenager, and the patient is fat mostly; Insulin receptor INSR is insensitive, and it accounts for more than 80% of diabetes cases at least.
Repaglinide is a kind of new oral hypoglycemic medicine of methyl benzene methanamine benzoic acid family, it through with the beta Cell of islet film on specific receptor combine, promote the ATP dependency K on the islet cells film
+Pathway closure suppresses K
+From the β cell drain, make the cell membrane depolarization, thus the Ca that open voltage relies on
2+Passage makes extracellular Ca
2+In the entering cell, promote insulin secretion, the sugar that reduces the type ii diabetes patient closes hemoglobin and blood sugar level, can in tissue, not accumulate, and has safety preferably.Metformin hydrochloride does not directly stimulate the insulin secretion of beta Cell of islet; But through suppressing intestinal to absorption, the hepatocellular gluconeogenesis of glucose with improve body to insulin sensitivity; Increase of picked-up and the utilization of peripheral tissues such as fat, muscle, can obviously reduce empty stomach and post-prandial glycemia and can not cause hypoglycemia glucose.Because mechanism of action is complementary, repaglinide and metformin hydrochloride have synergism aspect blood sugar lowering, existing at present compound Repaglinide-metformin hydrochloride ordinary tablet listing.Yet repaglinide and metformin hydrochloride half-life are all shorter, and common compound recipe sheet need be taken medicine 3 times every day, and diabetes need long-term prescription, therefore bring inconvenience to the patient, and are prone to cause the drug level big defective of undulatory property in vivo.
Summary of the invention: the present invention is the slow releasing preparation of a kind of compound Repaglinide-metformin hydrochloride of development, mainly is the problem that solves insoluble drug repaglinide and water soluble drug metformin hydrochloride synchronous slow.The repaglinide dissolubility is little, and the dissolubility in water is 0.005mg/mL, and metformin hydrochloride is a water soluble drug, can cause the metformin hydrochloride rate of releasing drug suitable if adopt conventional technology to carry out tabletting, and repaglinide will can not discharge.And the repaglinide rate of releasing drug is suitable, will lose control of the release of metformin hydrochloride, and cause the prominent of metformin hydrochloride to be released.Realize two medicines synchronous slow in vivo; Adopt conventional technology to carry out tabletting and obviously can not satisfy its synchronous slow in vivo and in vitro; Therefore, the present invention adopts different framework material compacting double-layer sustained release tablets respectively with repaglinide, metformin hydrochloride, obtains the formulation and technology that two medicines all have suitable rate of releasing drug; Perhaps repaglinide, metformin hydrochloride are adopted different framework material compressed minitablets respectively respectively, then fill capsule proportionally.The present invention with hydroxypropyl emthylcellulose, Rikemal B 200, ethyl cellulose, acrylic resin, Ka Bopu, octadecanol, hexadecanol, stearic acid, sodium carboxymethyl cellulose, sodium alginate, polyox etc. as framework material with repaglinide, the metformin hydrochloride compacting double-layer tablet of granulating respectively; Perhaps distinguish compressed minitablets, carry out the fill capsule, made compound slow release preparation; Not only can improve curative effect through the complementation between the mechanism of drug action; Thereby reduce each one-component consumption the toxic and side effects of medicine is reduced, also can delay the release of medicine, steadily blood drug level; Reduce administration number of times, improve patient's compliance.Because the dissolubility of repaglinide in water is merely 0.005mg/mL; Also can earlier repaglinide be prepared into solid dispersion or clathrate; As separately or unite preparation repaglinide solid dispersion such as adopting PEG, PVP, HPMC, lactose, mannitol; Perhaps adopt β-CD or HP-β-CD to prepare the repaglinide clathrate, the ratio of repaglinide and carrier is 1: 1～20, to improve the dissolubility of crude drug; Then dispersion prepared or clathrate and above-mentioned framework material and all the other adjuvants are mixed with its slow releasing preparation, again itself and diabecron sustained-release granule are pressed into compound slow release preparation at last.
The compound slow release preparation of Repaglinide-metformin hydrochloride, the principal agent composition of said preparation is repaglinide and metformin hydrochloride.Repaglinide: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or the ratio that wherein makes up arbitrarily are 0.1: 1-30; Metformin hydrochloride: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or the ratio that wherein makes up arbitrarily are 1: 0.5-3.
Wherein adding hydrophilic gel matrix material is hydroxypropyl emthylcellulose, Ka Bopu, sodium carboxymethyl cellulose, sodium alginate, Polyox or wherein combination arbitrarily; Wax lipid framework material is octadecanol, hexadecanol, Rikemal B 200, stearic acid or wherein combination arbitrarily; Insoluble framework material is ethyl cellulose, acrylic resin or wherein combination arbitrarily.
The compound slow release preparation of Repaglinide-metformin hydrochloride; It is characterized in that repaglinide: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, Ka Bopu, sodium alginate, octadecanol, hexadecanol, sodium carboxymethyl cellulose, stearic acid, Polyox, acrylic resin or the ratio that wherein makes up arbitrarily are 0.1: 1～30.Wherein, preferred framework material is hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, octadecanol, Polyox, acrylic resin, and preferred repaglinide and framework material ratio are 0.1: 2～25; Metformin hydrochloride: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, Ka Bopu, sodium alginate, octadecanol, hexadecanol, sodium carboxymethyl cellulose, stearic acid, Polyox, acrylic resin or the ratio that wherein makes up arbitrarily are 1: 0.5-3.Wherein, preferred framework material is hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, octadecanol, Polyox, acrylic resin, sodium carboxymethyl cellulose, and preferred metformin hydrochloride and framework material ratio are 1: 0.7-2.
This compound slow release preparation can also add methylcellulose, lactose, microcrystalline Cellulose, starch, Icing Sugar, polyvinylpyrrolidone, sodium lauryl sulphate, tween, span, lecithin, sucrose ester, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, poloxamer, sodium bicarbonate, sodium carbonate, basic magnesium carbonate or wherein combination arbitrarily, and by being routinely added to binding agent, wetting agent and lubricant.
Repaglinide can adopt in PEG, PVP, HPMC, lactose, the mannitol one or more for preparing carriers repaglinide solid dispersion earlier; Perhaps adopting β-CD or HP-β-CD is preparing carriers repaglinide clathrate, and the ratio of repaglinide and carrier is 1: 1～20.Wherein, preferred carrier is PVP, and the ratio of preferred repaglinide and PVP is 1: 3～15.Add the slow releasing preparation that framework material makes repaglinide again after making solid dispersion or clathrate, again itself and metformin hydrochloride are processed compound slow release preparation at last.
The compound slow release preparation of Repaglinide-metformin hydrochloride can be oral sustained release, controlled release tablet, comprises double-deck matrix tablet and Entogastric lingering sheet; Said preparation can also be oral sustained release, controlled release capsule, and wherein implant is the matrix type small pieces of repaglinide and metformin hydrochloride.
The present invention also provides a kind of method for preparing of compound slow release preparation of Repaglinide-metformin hydrochloride; Earlier with metformin hydrochloride: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein make up arbitrarily: after 0.5-3 mixes with 1; Direct compression, or adopt the dry granulation tabletting, or adopt wet granule compression tablet, or adopt the solid dispersion method pelletizing press sheet to make the diabecron sustained-release layer; Again with repaglinide: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein make up arbitrarily: after 1-30 mixes with 0.1; Direct compression, or adopt the dry granulation tabletting, or adopt wet granule compression tablet, or adopt the solid dispersion method pelletizing press sheet on the diabecron sustained-release layer; Make the compound Repaglinide-metformin hydrochloride double-layer sustained release tablets; Perhaps earlier respectively repaglinide and metformin hydrochloride and corresponding adjuvant are pressed into the matrix type small pieces, again according to its dose ratio fill capsule.
Description of drawings:
Fig. 1 is embodiment 1 a compound Repaglinide-metformin hydrochloride double-layer sustained release tablets release profiles
Fig. 2 is the double-deck intra-gastric floating tablet release profiles of embodiment 2 compound Repaglinide-metformin hydrochlorides
Fig. 3 is embodiment 3 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets release profiles
Fig. 4 is embodiment 4 compound Repaglinide-metformin hydrochloride two-layer release-controlled tablet release profiles
Fig. 5 is embodiment 5 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets release profiles
Fig. 6 is embodiment 6 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets release profiles
Fig. 7 is embodiment 7 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets release profiles
Fig. 8 is the double-deck intra-gastric floating tablet release profiles of embodiment 8 compound Repaglinide-metformin hydrochlorides
Fig. 9 is the double-deck intra-gastric floating tablet release profiles of embodiment 9 compound Repaglinide-metformin hydrochlorides
Figure 10 is the double-deck intra-gastric floating tablet release profiles of embodiment 10 compound Repaglinide-metformin hydrochlorides
Figure 11 is the double-deck intra-gastric floating tablet release profiles of embodiment 11 compound Repaglinide-metformin hydrochlorides
Figure 12 is the double-deck intra-gastric floating tablet release profiles of embodiment 12 compound Repaglinide-metformin hydrochlorides
Figure 13 is the double-deck intra-gastric floating tablet release profiles of embodiment 13 compound Repaglinide-metformin hydrochlorides
Figure 14 is the double-deck intra-gastric floating tablet release profiles of embodiment 14 compound Repaglinide-metformin hydrochlorides
Figure 15 is embodiment 15 compound Repaglinide-metformin hydrochloride slow releasing capsule release profiles
Figure 16 is embodiment 16 compound Repaglinide-metformin hydrochloride slow releasing capsule release profiles
Figure 17 is embodiment 19 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets release profiles
The specific embodiment:
The preparation of embodiment 1 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 3g
Hydroxypropyl emthylcellulose (K4M) 75g
Microcrystalline Cellulose 30g
Magnesium stearate 1g
Binding agent: 5%PVP80% alcoholic solution
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 200g
Microcrystalline Cellulose 100g
Magnesium stearate 10g
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, hydroxypropyl emthylcellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting on the diabecron sustained-release layer gets double-layer sustained release tablets.
By " 2005 editions two appendix XD three therapeutic methods of traditional Chinese medicine of Chinese pharmacopoeia adopt the device of dissolution method (the appendix XC three therapeutic methods of traditional Chinese medicine), get the compound Repaglinide-metformin hydrochloride double-layer sustained release tablets, are release medium with the hydrochloric acid solution of 100ml 0.1mol/L; Rotating speed is that per minute 50 changes, respectively at 1,2, and 4; Got solution 5ml in 8,12,14,24 hours; Add the fresh medium of uniform temp, equal volume simultaneously, institute's sample thief filters immediately, gets subsequent filtrate and measures.It is an amount of to get reference substance, calculates the release degree by external standard method.The result sees accompanying drawing 1, shows repaglinide: hydroxypropyl emthylcellulose (K4M)=0.1: 2.5, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M)=1: 0.8 has the good slow release effect.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 2 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 2g
Hydroxypropyl emthylcellulose (K4M) 40g
Octadecanol 100g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 1g
Binding agent: 5%PVP80% alcoholic solution
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 150g
Octadecanol 100g
Sodium bicarbonate 30g
Microcrystalline Cellulose 100g
Magnesium stearate 10g
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, the granulation of sieving; Dry; Granulate adds magnesium stearate, mix homogeneously; Tabletting on the diabecron sustained-release layer gets double-deck intra-gastric floating tablet.In gastric juice, rise always and float.The result sees accompanying drawing 2, shows repaglinide: hydroxypropyl emthylcellulose (K4M): octadecanol=0.1: 2: 5, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): octadecanol=1: 0.6: 0.4 has the good slow release effect.
The preparation of embodiment 3 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 1g
Ethyl cellulose 100g
Microcrystalline Cellulose 50g
Magnesium stearate 1g
Binding agent: 5%PVP80% alcoholic solution
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 300g
Microcrystalline Cellulose 150g
Magnesium stearate 30g
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, ethyl cellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting on the diabecron sustained-release layer gets double-layer sustained release tablets.The result sees accompanying drawing 3, shows repaglinide: ethyl cellulose=0.1: 10, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M)=1: 1.2 has the good slow release effect.
The preparation of embodiment 4 compound Repaglinide-metformin hydrochloride two-layer release-controlled tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 2g
Polyox?N60K 150g
Microcrystalline Cellulose 100g
Magnesium stearate 1g
Binding agent: dehydrated alcohol
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Polyox?N60K 200g
Microcrystalline Cellulose 100g
Magnesium stearate 10g
Binding agent: dehydrated alcohol
Preparation technology:
Metformin hydrochloride, Polyox N60K, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, Polyox N60K, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting on the diabecron sustained-release layer gets two-layer release-controlled tablet.The result sees accompanying drawing 4, shows repaglinide: Polyox N60K=0.1: 7.5, and metformin hydrochloride: Polyox N60K=1: 0.8, have good controlled-release effect.
The preparation of embodiment 5 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 1g
Rikemal B 200 100g
Microcrystalline Cellulose 50g
Magnesium stearate 2g
Binding agent: 10%PVP80% alcoholic solution
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Rikemal B 200 300g
Microcrystalline Cellulose 150g
Magnesium stearate 30g
Binding agent: 10%PVP80% alcoholic solution
Preparation technology:
Metformin hydrochloride, Rikemal B 200, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, Rikemal B 200, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting on the diabecron sustained-release layer gets double-layer sustained release tablets.The result sees accompanying drawing 5, shows repaglinide: Rikemal B 200=0.1: 10, metformin hydrochloride: Rikemal B 200=1: 1.2 has the good slow release effect.
The preparation of embodiment 6 compound Repaglinide-metformin hydrochloride two-layer release-controlled tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 1g
Eudragit?RS 100g
Microcrystalline Cellulose 50g
Magnesium stearate 2g
Binding agent: 10%PVP80% alcoholic solution
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Eudragit?RS 300g
Microcrystalline Cellulose 150g
Magnesium stearate 30g
Binding agent: 10%PVP80% alcoholic solution
Preparation technology:
Metformin hydrochloride, Eudragit RS, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, EudragitRS, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting on the diabecron sustained-release layer gets two-layer release-controlled tablet.The result sees accompanying drawing 6, shows repaglinide: Eudragit RS=0.1: 10, and metformin hydrochloride: Eudragit RS=1: 1.2, have the good slow release effect.
The preparation of embodiment 7 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 0.5g
Ethyl cellulose 100g
Microcrystalline Cellulose 50g
Magnesium stearate 2g
Binding agent: 10%PVP80% alcoholic solution
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Ethyl cellulose 300g
Microcrystalline Cellulose 150g
Magnesium stearate 30g
Binding agent: 10%PVP80% alcoholic solution
Preparation technology:
Metformin hydrochloride, ethyl cellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Repaglinide, ethyl cellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting on the diabecron sustained-release layer gets double-layer sustained release tablets.The result sees accompanying drawing 7, shows repaglinide: ethyl cellulose=0.1: 20, metformin hydrochloride: ethyl cellulose=1: 1.2 has the good slow release effect.
Repaglinide dissolubility in the hydrochloric acid of 0.1mol/L can reach 600mg/100mL; Yet dissolubility is merely 0.5mg/100mL in pure water; Belong to insoluble drug, can add surfactant, like sodium lauryl sulphate, tween, span, lecithin, sucrose ester, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, poloxamer etc.; Perhaps adopt some new techniques on the galenic pharmacy; As separately or unite adopt PEG, PVP, HPMC, mannitol, lactose etc. as preparing carriers repaglinide solid dispersion, adopt β-CD, HP-β-CD to prepare clathrate, improve its dissolubility, increase the stripping of medicine in gastrointestinal tract.Embodiment 8 to embodiment 14 is that carrier adopts solvent method to be prepared into solid dispersion with the polyvinylpyrrolidone with repaglinide earlier; Mix with all the other adjuvants again; On the diabecron sustained-release layer, suppress the compound Repaglinide-metformin hydrochloride double-layer sustained release tablets at last; Embodiment 17 is that carrier adopts the method for dissolving to be prepared into solid dispersion with the Polyethylene Glycol with repaglinide earlier, mixes with all the other adjuvants again and suppresses repaglinide slow release small pieces, at last again with the common fill capsule of diabecron sustained-release small pieces; Embodiment 18 is that carrier adopts polishing to be prepared into cyclodextrin clathrate with repaglinide with β-CD earlier; Mix compacting repaglinide slow release small pieces again with all the other adjuvants, at last again with the common fill capsule of diabecron sustained-release small pieces, when improving dissolubility, all can reach the good slow release effect.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 8 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 1g
Polyvinylpyrrolidone (K30) 10g
Hydroxypropyl emthylcellulose (K4M) 30g
Octadecanol 100g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 150g
Octadecanol 100g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 8, shows repaglinide: hydroxypropyl emthylcellulose (K4M): octadecanol=0.1: 3: 10, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): octadecanol=1: 0.6: 0.4 has the good slow release effect.In simulated gastric fluid, rise immediately and float and floating always.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 9 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 1g
Polyvinylpyrrolidone (K30) 10g
Sodium carboxymethyl cellulose 200g
Octadecanol 50g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 100g
Octadecanol 100g
Ethyl cellulose 50g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, ethyl cellulose, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate 45 ℃ of dryings; Granulate; Add magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, sodium carboxymethyl cellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 9, shows repaglinide: sodium carboxymethyl cellulose: octadecanol=0.1: 20: 5, and metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): ethyl cellulose: octadecanol=1: 0.4: 0.2: 0.4, have the good slow release effect.In gastric juice, rise immediately and float and floating always.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 10 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 2g
Polyvinylpyrrolidone (K30) 20g
Octadecanol 200g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 100g
Octadecanol 100g
Rikemal B 200 50g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, Rikemal B 200, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate 45 ℃ of dryings; Granulate; Add magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 10, shows repaglinide: octadecanol=0.1: 10, and metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): Rikemal B 200: octadecanol=1: 0.4: 0.2: 0.4, have the good slow release effect.In simulated gastric fluid, rise immediately and float and floating always.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 11 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 3g
Polyvinylpyrrolidone (K30) 30g
Eugragit?RS 30g
Octadecanol 100g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 100g
Octadecanol 100g
Eugragit?RS 50g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, Eugragit RS, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate 45 ℃ of dryings; Granulate; Add magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, Eugragit RS, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 11, shows repaglinide: Eugragit RS: octadecanol=0.1: 1: 3.3, and metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): Eugragit RS: octadecanol=1: 0.4: 0.2: 0.4, have the good slow release effect.In simulated gastric fluid, rise immediately and float and floating always.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 12 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 1g
Polyvinylpyrrolidone (K30) 10g
Hydroxypropyl emthylcellulose (K15M) 30g
Octadecanol 100g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K15M) 150g
Octadecanol 100g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate 45 ℃ of dryings; Granulate; Add magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 12, shows repaglinide: hydroxypropyl emthylcellulose (K15M): octadecanol=0.1: 3: 10, metformin hydrochloride: hydroxypropyl emthylcellulose (K15M): octadecanol=1: 0.6: 0.4 has the good slow release effect.In simulated gastric fluid, rise immediately and float and floating always.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 13 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 2g
Polyvinylpyrrolidone (K30) 20g
Hydroxypropyl emthylcellulose (K100M) 30g
Octadecanol 100g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 100g
Ethyl cellulose 50g
Octadecanol 100g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, ethyl cellulose, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate 45 ℃ of dryings; Granulate; Add magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose, magnesium stearate are pressed equivalent incremental method mixing; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 13; Show repaglinide: hydroxypropyl emthylcellulose (K100M): octadecanol=0.1: 1.5: 5; Metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): ethyl cellulose: octadecanol=1: 0.4: 0.2: 0.4, have the good slow release effect.In gastric juice, rise immediately and float and floating always.
The preparation (1000 amounts) of the double-deck intra-gastric floating tablet of embodiment 14 compound Repaglinide-metformin hydrochlorides
Repaglinide layer prescription:
Repaglinide 2g
Polyvinylpyrrolidone (K30) 20g
Hydroxypropyl emthylcellulose (K4M) 40g
Octadecanol 100g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K4M) 150g
Octadecanol 100g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 30g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, polyvinylpyrrolidone, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate 45 ℃ of dryings; Granulate; Add magnesium stearate, mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, hydroxypropyl emthylcellulose, octadecanol, sodium bicarbonate, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-deck intra-gastric floating tablet.The result sees accompanying drawing 14, shows repaglinide: hydroxypropyl emthylcellulose (K4M): octadecanol=0.1: 2: 5, metformin hydrochloride: hydroxypropyl emthylcellulose (K4M): octadecanol=1: 0.6: 0.4 has the good slow release effect.In simulated gastric fluid, rise immediately and float and floating always.
The preparation of embodiment 15 compound Repaglinide-metformin hydrochloride slow releasing capsule
The little tablet recipe of repaglinide (1000 amounts):
Repaglinide 1g
Hydroxypropyl emthylcellulose (K100M) 25g
Microcrystalline Cellulose 60g
Magnesium stearate 2g
The little tablet recipe of metformin hydrochloride (5000 amounts):
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 250g
Polyvinylpyrrolidone (K30) 20g
Magnesium stearate 30g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Repaglinide, hydroxypropyl emthylcellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously, direct powder compression; Metformin hydrochloride, hydroxypropyl emthylcellulose, polyvinylpyrrolidone by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, tabletting.1 repaglinide small pieces and 5 metformin hydrochloride small pieces are poured in the capsules.The result sees accompanying drawing 15, shows repaglinide: hydroxypropyl emthylcellulose (K100M)=0.1: 2.5, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M)=1: 1 has the good slow release effect.
The preparation of embodiment 16 compound Repaglinide-metformin hydrochloride slow releasing capsule
The little tablet recipe of repaglinide (1000 amounts):
Repaglinide 0.5g
Sodium lauryl sulphate 10g
Hydroxypropyl emthylcellulose (K4M) 20g
Sodium alginate 10g
Microcrystalline Cellulose 30g
Lactose 30g
Magnesium stearate 2g
Binding agent: 1%HPMC90% alcoholic solution
The little tablet recipe of metformin hydrochloride (5000 amounts):
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 250g
Polyvinylpyrrolidone (K30) 20g
Magnesium stearate 30g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Repaglinide, sodium lauryl sulphate, hydroxypropyl emthylcellulose, sodium alginate, lactose, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, tabletting; Metformin hydrochloride, hydroxypropyl emthylcellulose, polyvinylpyrrolidone by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, tabletting.1 repaglinide small pieces and 5 metformin hydrochloride small pieces are poured in the capsules.The result sees accompanying drawing 16, shows repaglinide: hydroxypropyl emthylcellulose (K4M): sodium alginate=0.1: 2: 1, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M)=1: 1 has the good slow release effect.
The preparation of embodiment 17 compound Repaglinide-metformin hydrochloride slow releasing capsule
The little tablet recipe of repaglinide (1000 amounts):
Repaglinide 1.5g
Macrogol 4000 15g
Ethyl cellulose 100g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
The little tablet recipe of metformin hydrochloride (5000 amounts):
Metformin hydrochloride 250g
Ethyl cellulose 500g
Polyvinylpyrrolidone (K30) 20g
Magnesium stearate 30g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Adopt fusion method to prepare solid dispersion repaglinide, Polyethylene Glycol, pulverized 100 mesh sieves, repaglinide solid dispersion, ethyl cellulose, microcrystalline Cellulose by equivalent incremental method mixing, are added the magnesium stearate mix homogeneously, direct powder compression; Metformin hydrochloride, ethyl cellulose, polyvinylpyrrolidone by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, tabletting.1 repaglinide small pieces and 5 metformin hydrochloride small pieces are poured in the capsules.Repaglinide: ethyl cellulose=0.1: 10, metformin hydrochloride: ethyl cellulose=1: 2 reaches effective slow release.
The preparation of embodiment 18 compound Repaglinide-metformin hydrochloride gastric floating capsules
The little tablet recipe of repaglinide (1000 amounts):
Repaglinide 1g
β-CD 15g
Hydroxypropyl emthylcellulose (K4M) 30g
Hexadecanol 50g
Sodium bicarbonate 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
The little tablet recipe of metformin hydrochloride (5000 amounts):
Metformin hydrochloride 250g
Hydroxypropyl emthylcellulose (K100M) 200g
Hexadecanol 50g
Sodium bicarbonate 30g
Polyvinylpyrrolidone (K30) 20g
Magnesium stearate 30g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Adopt polishing to prepare cyclodextrin clathrate repaglinide, β-CD; Pulverized 100 mesh sieves; Repaglinide cyclodextrin clathrate, hydroxypropyl emthylcellulose, hexadecanol, sodium bicarbonate, microcrystalline Cellulose are pressed equivalent incremental method mixing; Add the magnesium stearate mix homogeneously, direct powder compression; Metformin hydrochloride, hydroxypropyl emthylcellulose, hexadecanol, sodium bicarbonate, polyvinylpyrrolidone by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate, 45 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, tabletting.1 repaglinide small pieces and 5 metformin hydrochloride small pieces are poured in the capsules.Repaglinide: hydroxypropyl emthylcellulose (K4M): hexadecanol=0.1: 3: 5, metformin hydrochloride: hydroxypropyl emthylcellulose (K100M): hexadecanol=1: 0.8: 0.2 reaches effective slow release.
The preparation of embodiment 19 compound Repaglinide-metformin hydrochloride double-layer sustained release tablets (1000 amounts)
Repaglinide layer prescription:
Repaglinide 2g
Polyvinylpyrrolidone (K30) 10g
Hydroxypropyl emthylcellulose (K4M) 10g
Lactose 10g
Microcrystalline Cellulose 30g
Magnesium stearate 2g
Metformin hydrochloride layer prescription:
Metformin hydrochloride 250g
Ethyl cellulose 100g
Polyvinylpyrrolidone (K30) 20g
Microcrystalline Cellulose 100g
Magnesium stearate 20g
Binding agent: 1%HPMC90% alcoholic solution
Preparation technology:
Metformin hydrochloride, ethyl cellulose, polyvinylpyrrolidone, microcrystalline Cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate; 60 ℃ of dryings, granulate adds magnesium stearate; Mix homogeneously, compacting diabecron sustained-release layer.Adopt solvent method to prepare solid dispersion repaglinide, polyvinylpyrrolidone; Pulverized 100 mesh sieves; Repaglinide solid dispersion, hydroxypropyl emthylcellulose, lactose, microcrystalline Cellulose by equivalent incremental method mixing, are added magnesium stearate, mix homogeneously; Powder is direct compression on the diabecron sustained-release layer, gets double-layer sustained release tablets.Repaglinide: hydroxypropyl emthylcellulose (K4M)=0.1: 0.5, metformin hydrochloride: ethyl cellulose=1: 0.4, slow releasing function is not obvious, can not effectively control the release of medicine.
The preparation of embodiment 20 compound Repaglinide-metformin hydrochloride ordinary tablets (1000 amounts)
Repaglinide 1g
Metformin hydrochloride 250g
Lactose 300g
Microcrystalline Cellulose 100g
Low-substituted hydroxypropyl cellulose 50g
Magnesium stearate 20g
Binding agent: 5%PVP80% alcoholic solution
Preparation technology:
Repaglinide, metformin hydrochloride, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose by equivalent incremental method mixing, are added suitable amount of adhesive and prepare soft material, cross 18 mesh sieves and granulate.60 ℃ of dryings, granulate adds magnesium stearate, mix homogeneously, tabletting.The stripping 85% in 10 minutes of repaglinide and metformin hydrochloride.
Claims (9)
1. the slow releasing preparation of compound Repaglinide-metformin hydrochloride is characterized in that: repaglinide: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein arbitrarily the ratio of combination be 0.1: 1-30; Metformin hydrochloride: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or the ratio that wherein makes up arbitrarily are 1: 0.5-3, said hydrophilic gel matrix material are hydroxypropyl emthylcellulose, Ka Bopu, sodium carboxymethyl cellulose, sodium alginate, Polyox or wherein combination arbitrarily; Wax lipid framework material is octadecanol, hexadecanol, Rikemal B 200, stearic acid or wherein combination arbitrarily; Insoluble framework material is ethyl cellulose, acrylic resin or wherein combination arbitrarily.
2. slow releasing preparation according to claim 1 is characterized in that: repaglinide: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, Ka Bopu, sodium alginate, octadecanol, hexadecanol, sodium carboxymethyl cellulose, stearic acid, Polyox, acrylic resin or the ratio that wherein makes up arbitrarily are 0.1: 1～30; Metformin hydrochloride: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, Ka Bopu, sodium alginate, octadecanol, hexadecanol, sodium carboxymethyl cellulose, stearic acid, Polyox, acrylic resin or the ratio that wherein makes up arbitrarily are 1: 0.5-3.
3. according to any described slow releasing preparation of claim 1-2, it is characterized in that: repaglinide: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, octadecanol, Polyox, acrylic resin one or more ratio wherein is 0.1: 2～25; Metformin hydrochloride: hydroxypropyl emthylcellulose, ethyl cellulose, Rikemal B 200, octadecanol, Polyox, acrylic resin, sodium carboxymethyl cellulose one or more ratio wherein is 1: 0.7-2.
4. slow releasing preparation according to claim 1 is characterized in that: further add methylcellulose, lactose, microcrystalline Cellulose, starch, Icing Sugar, polyvinylpyrrolidone, sodium lauryl sulphate, tween, span, lecithin, sucrose ester, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, poloxamer, sodium bicarbonate, sodium carbonate, basic magnesium carbonate or wherein combination arbitrarily.
5. slow releasing preparation according to claim 1; It is characterized in that: repaglinide unites that to adopt PEG, PVP, HPMC, lactose, mannitol be preparing carriers repaglinide solid dispersion; Perhaps adopting β-CD or HP-β-CD is preparing carriers repaglinide clathrate, and wherein the ratio of repaglinide and carrier is 1: 1～20.
6. slow releasing preparation according to claim 5 is characterized in that: the carrier of repaglinide solid dispersion is PVP, and the ratio of repaglinide: PVP is 1: 3～15.
7. slow releasing preparation according to claim 1 is characterized in that: said preparation is oral sustained release, controlled release tablet or oral sustained release, controlled release capsule, and wherein implant is the matrix type small pieces of repaglinide and metformin hydrochloride.
8. slow releasing preparation according to claim 7 is characterized in that oral sustained release, controlled release tablet are double-deck matrix tablet or Entogastric lingering sheet.
9. according to the method for preparing of any described slow releasing preparation of claim 1-8; It is characterized in that: earlier with metformin hydrochloride: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein make up arbitrarily: after 0.5-3 mixes with 1; Direct compression, or adopt the dry granulation tabletting, or adopt wet granule compression tablet, or adopt the solid dispersion method pelletizing press sheet to make the diabecron sustained-release layer; Again with repaglinide: hydrophilic gel matrix material, wax lipid framework material, insoluble framework material or wherein make up arbitrarily: after 1-30 mixes with 0.1; Direct compression, or adopt the dry granulation tabletting, or adopt wet granule compression tablet, or adopt the solid dispersion method pelletizing press sheet on the diabecron sustained-release layer; Make the compound Repaglinide-metformin hydrochloride double-layer sustained release tablets; Perhaps earlier respectively repaglinide and metformin hydrochloride and corresponding adjuvant are pressed into the matrix type small pieces, promptly get according to its dose ratio fill again.
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| CN102247370B (en) * | 2011-05-19 | 2013-04-17 | 中国药科大学 | Compound repaglinide-metformin hydrochloride controlled release preparation |
| CN102784127B (en) * | 2011-05-20 | 2014-07-16 | 江苏豪森医药集团连云港宏创医药有限公司 | Solid pharmaceutical composition, preparation method and application |
| CN103027900B (en) * | 2012-09-27 | 2014-12-03 | 江苏豪森药业股份有限公司 | Repaglinide tablet and preparation method thereof |
| CN103432129B (en) * | 2013-08-26 | 2016-01-27 | 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 |
| CN103432131A (en) * | 2013-09-11 | 2013-12-11 | 中国药科大学 | Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and preparing method thereof |
| CN106309444A (en) * | 2016-09-27 | 2017-01-11 | 山东明仁福瑞达制药股份有限公司 | Preparation method of composition of repaglinide and metformin hydrochloride |
| CN110938961A (en) * | 2019-11-30 | 2020-03-31 | 绍兴恒辉布业有限公司 | Production process of polar fleece knitted fabric |
| CN111388438A (en) * | 2020-05-08 | 2020-07-10 | 福建东瑞制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
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| CN1209101C (en) * | 2003-11-19 | 2005-07-06 | 广州市医药工业研究所 | Metformin hydrochloride sustained-release tablet and method for preparing the same |
| CN1817341A (en) * | 2005-02-04 | 2006-08-16 | 周卓和 | Solid sustained preparation of miglinon and its preparing method |
| CN1985819A (en) * | 2006-11-21 | 2007-06-27 | 北京润德康医药技术有限公司 | Slow released preparation containing metformin hydrochloride and gliclazide and its preparing process |
| CN101383011A (en) * | 2007-09-05 | 2009-03-11 | 乐金电子（昆山）电脑有限公司 | Short circuit prevention device connecting slot for storage medium |
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| CN101278919B (en) * | 2008-05-06 | 2012-01-18 | 中国药科大学 | Metformin hydrochloride and Glipizide sustained-release pellet and method of preparing the same |
| CN101283993A (en) * | 2008-06-10 | 2008-10-15 | 北京赛诺源医药科技有限公司 | Use of the diabecron sustained-release tablet in treating the type 2 diabetes mellitus |
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