CN102525991A - Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and method for preparing compound preparation containing pioglitazone hydrochloride and metformin hydrochloride - Google Patents
Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and method for preparing compound preparation containing pioglitazone hydrochloride and metformin hydrochloride Download PDFInfo
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- CN102525991A CN102525991A CN2012100379199A CN201210037919A CN102525991A CN 102525991 A CN102525991 A CN 102525991A CN 2012100379199 A CN2012100379199 A CN 2012100379199A CN 201210037919 A CN201210037919 A CN 201210037919A CN 102525991 A CN102525991 A CN 102525991A
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Abstract
The invention relates to a compound preparation which is taken once every day and consists of pioglitazone hydrochloride and metformin hydrochloride and a method for preparing the compound preparation. The compound preparation consists of a controlled release part and an immediate-release part, wherein the metformin hydrochloride is used as the controlled release part, and is prepared into controlled release tablets by using a monolithic osmotic pump technology; the controlled release tablet consists of a medicinal core and a controlled release coat, and a medicine release hole is formed in each of two sides of the tablet; the metformin hydrochloride is released in a zero-level mode; and the pioglitazone hydrochloride is used as the immediate-release part and is wrapped on the outer layers of the metformin hydrochloride controlled release tablets uniformly in a coating mode. According to the compound preparation, the pioglitazone hydrochloride can be dissolved out immediately to exert a curative effect, and the metformin hydrochloride also can be released slowly, so that the blood concentration is stable; the administration frequency is reduced (the compound preparation is taken once every day), and the administration compliance of patients is improved; and the side effect of gastrointestinal tracts is reduced, and the administration safety is improved.
Description
Technical field: the present invention relates to a kind of compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride and preparation method thereof.
Background technology: at present, the common drug of treatment type ii diabetes has biguanides, sulfonylurea, alpha-glucosidase inhibitor, thiazolidinediones etc.Two kinds of OHA pioglitazone hydrochloride and the metformin hydrochloride that the present invention relates to belong to thiazolidinediones and biguanides respectively, and the two blood sugar lowering mechanism is different, and drug combination has synergism.
Metformin hydrochloride mainly acts on islets of langerhans and organizes outward, suppresses the intestinal absorption glucose, increases the utilization of peripheral tissues to glucose, reduces the hepatic glycogen heteroplasia, thereby reaches the purpose of blood sugar lowering.Because its blood sugar reducing function is obvious, does not cause hypoglycemia, can obviously reduce postprandial hyperglycemia, be fit to the type ii diabetes patient, be a line medicine of treatment type ii diabetes; It also improves insulin resistance etc. simultaneously, therefore is used widely clinical.But metformin hydrochloride also has himself shortcoming, and it has t as oral hypoglycemic
1/2Short (2～6h), bioavailability low (40%～60%), dosage is big, and (1000～2550mg/d), every day, medicining times was many, characteristics such as gastrointestinal side effect incidence rate height.
For reaching the minimizing medicining times, reduce blood concentration fluctuation, reduce the purpose of side effect; In water, be prone to dissolving in conjunction with metformin hydrochloride, molecular weight is little, adopts the matrix type slow release that drug release is difficult to control, has to increase the consumption of blocker, cause sheet great, characteristics such as should not take; The present invention is made into a day clothes osmotic pump tablet once, and metformin hydrochloride is zero level and discharges, and reduces gastrointestinal upset, improves patient's compliance.
The patent of An Dekesi drugmaker (CN1158999C) has been described a kind of controlled release tablet of metformin, comprises a drug core, semipermeable membrane layer and at least one release duct.Drug core comprises active component metformin, water miscible binding agent (like polyvidone) and absorption enhancer (like sodium lauryl sulphate).Though this preparation can reach better controlled-release effect, there is the bigger problem of intestinal zest.This is that this absorption enhancer can dissolve the biomembrane lipid because used more sodium lauryl sulphate (2%～10%), weakens intestinal wall, produces the intestinal ill effect in the long-term prescription process.
Pioglitazone hydrochloride acts on peroxisome proliferation activated receptor-γ (PPAR-γ), increases the sensitivity of Insulin receptor INSR.The pioglitazone hydrochloride untoward reaction is little, and can not cause hypoglycemic reaction.It has overcome, and the OHA toxic and side effects was big in the past, and the problem that the patient should not tolerate can be improved overweight people's hyperglycemia and triglyceride, and the effect of blood sugar lowering and insulin resistance is arranged, and obviously improved the metabolism of glucose and fat.
Compound hydrochloric acid pioglitazone metformin hydrochloride controlled release tablet is succeeded in developing by Japan military field drugmaker; And obtain drugs approved by FDA listing in May, 2009; Trade name: ACTOPLUS
XR is mainly used in the treatment of type ii diabetes.
Wu Tian company adopts this compound preparation of elementary osmotic pump technology preparation about the patent (CN100544717C) of compound hydrochloric acid pioglitazone metformin hydrochloride controlled release tablet, and concrete structure comprises a drug core, primary seal coating, semipermeable membrane, secondary seal coating, the second active medicine release layer from the inside to the outside.Although this technical description the method for preparing of compound hydrochloric acid pioglitazone metformin hydrochloride controlled release tablet; But slice, thin piece complex structure, processing step are loaded down with trivial details; And existing the release of elementary osmotic pump release later stage is short of power; Discharge shortcomings such as incomplete, simultaneously equally with patent CN1158999C also used the more irritating ionic surface active agent of intestinal that has, long-term prescription produces the intestinal side effect.
CN102008472A discloses a kind of compound preparation of being made up of pioglitazone hydrochloride and metformin hydrochloride double-layer osmotic pump controlled-release tablet, on structure is formed, comprises successively from the inside to the outside: label, the contagion gown layer of being made up of medicated layer and boosting layer, be with clothing film, pioglitazone hydrochloride release layer and the nonessential aesthstic coat of drug release hole.The double-layer osmotic pump controlled-release technology is adopted in this invention, and the later stage of improving metformin hydrochloride discharges.Yet the preparation technology and the equipment of existing double layer osmotic pump technology are not perfect; This invention exists the feasibility problem of suitability for industrialized production; And the adding of boosting agent has limited the content of every active medicine in the double-layer osmotic pump tablet; Need a day clothes multi-disc just can reach effective dose, not ideal enough aspect raising patient medication compliance.
Problem to the prior art existence; The compound preparation that the present invention is made up of pioglitazone hydrochloride and metformin hydrochloride adopts the elementary osmotic pump technology; Absorption enhancer is replaced with osmotic pressure promoter; Reduce the intestinal side effect that ionic surface active agent produces, and strengthen release later stage power, promote that release is complete.
In addition, the present invention has also simplified the method for preparing of compound controlled release sheet, has saved elementary, secondary seal coating; Dissolution in vitro, the evidence of release degree do not have this two-layered coating; The stripping of pioglitazone hydrochloride and the release of metformin hydrochloride are unaffected, thereby save production cost, and reduce supplementary product consumption simultaneously; The tablet volume is littler, is convenient to the patient and swallows.
The pharmacokinetics result of the test proves compound controlled release sheet of the present invention and commercially available (ACTOPLUS in the Beagle dog body
XR) compare C
Max, T
MaxAnd the equal no difference of science of statistics of AUC, show that said preparation is than successful compound hydrochloric acid pioglitazone metformin hydrochloride controlled release tablet, and easier than prior art, safer, more can improve the medication compliance.
Summary of the invention: the purpose of this invention is to provide a kind of compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride and preparation method thereof.
The invention provides a kind of compound preparation of being made up of pioglitazone hydrochloride and metformin hydrochloride, on structure was formed, it comprised from the inside to the outside successively:
The metformin hydrochloride tablet core;
The clothing film of band drug release hole;
The pioglitazone hydrochloride release layer.
Based on the gross weight of metformin hydrochloride tablet core, said label comprises the metformin hydrochloride of 80～95 weight %, the binding agent of 4～8 weight %, the osmotic pressure promoter of 2～6 weight % and the lubricant of 0.1～1.5 weight %.
Based on the gross weight of used clothing film, said clothing film comprises the polymer of 80～95 weight %, the porogen of 5～20 weight %, the plasticizer of 0～5 weight %.
Based on the gross weight of pioglitazone hydrochloride release layer, said release layer comprises the pioglitazone hydrochloride of 30～70 weight %, the rapid release clothing membrane material of 30～70 weight %, the surfactant of 0.5～2 weight %.
Compound preparation described in the invention, the amount that each preparation unit contains the active ingredient hydrochloric acid metformin has 500mg, 750mg, 850mg, 1000mg, and the amount that contains the active ingredient hydrochloric acid pioglitazone has 15mg, 30mg, 45mg.Two kinds of preferred compound doses are metformin hydrochloride 1000mg, pioglitazone hydrochloride 15mg and metformin hydrochloride 1000mg, pioglitazone hydrochloride 30mg.
Compound preparation described in the invention is made up of metformin hydrochloride controlled release part and pioglitazone hydrochloride immediate release section.
In the compound preparation described in the invention, metformin hydrochloride controlled release part is characterized in that metformin hydrochloride is the elementary osmotic pump sheet, and respectively there is a drug release hole on the two sides of slice, thin piece.In the release in vitro degree was investigated, metformin hydrochloride discharged the 10%～25%, 4th hour on the 2nd hour and discharges release in the 25%～40%, 8th hour more than 50%, and metformin hydrochloride is zero level and discharges.
In the said metformin hydrochloride tablet core, the cohesiveness of adhesive consumption decision label, thus the formability and the hardness of slice, thin piece there is considerable influence.The binding agent of label is selected from one or more in polyvinylpyrrolidone (PVP), hydroxypropyl emthylcellulose, hyprolose, hydroxyethyl-cellulose, the sodium carboxymethyl cellulose, preferred PVP K90.
Elementary osmotic pump exists release later stage osmotic pressure to be short of power usually, causes the problem of drug residue in the release-controlled film, therefore adds the osmotic pressure promoter of proper proportion.The osmotic pressure promoter of label is selected from one or more in sodium chloride, potassium chloride, glucose, sucrose, lactose, mannitol, the sorbitol; Preferred lactose; The formation of the inside and outside permeable pressure head of controlled release tablet can be promoted, the compressibility of metformin hydrochloride can also be improved.
Be suitable for preparing the mixed solution that the typical wetting agent of metformin hydrochloride tablet core among the present invention comprises ethanol, water or second alcohol and water, preferred 70%～90% ethanol can prepare satisfactory wet granular, is unlikely to the sticking technology repeatability that influences again.
Lubricant can improve the outward appearance of particulate flowability and label in the tabletting process, and the lubricant of label is selected from one or more in stearic acid, magnesium stearate, the sodium stearyl fumarate, preferred magnesium stearate.
Said label can adopt the film coating method, forms clothing film at the sheet wicking surface.This clothing film is the key components of osmosis pump control-release system, and it is a kind of semipermeable polymers layer, and the water infiltration is passed through, and medicine, osmotic pressure promoter etc. then can't pass through.The polymeric material of clothing film is selected from one or more in ethyl cellulose, cellulose acetate, the polyacrylic resin, preferred cellulose acetate.
Porogen can increase the moisture permeability of clothing film, and the porogen of clothing film is selected from one or more in Polyethylene Glycol (PEG), glycerol, polyvinylpyrrolidone, propylene glycol, the hyprolose, preferred PEG400.
Plasticizer can improve the pliability and the extensibility of clothing film, reduce controlled release tablet get in the body, behind the medicine dissolution, release-controlled film is because gastrointestinal tract squeezing action and disruptive probability.The plasticizer of clothing film is selected from one or more in dibutyl sebacate, triethyl citrate, dimethyl phthalate, the glyceryl triacetate, preferred glyceryl triacetate.
The coating solvent that is suitable for preparing clothing film among the present invention comprises one or more in acetone, methanol, the water, and preferred acetone: water is 95: 5 mixed solvent.
Said clothing film accounts for 1%～10% of label weight, and preferred 1%～5%.
Metformin hydrochloride osmotic pump tablet according to the invention has a drug release hole at least on the clothing film, preferred two drug release hole reduce to cause single drug release hole to stop up the probability that can't discharge medicine because of tablet adheres to coat of the stomach.
In the compound preparation described in the invention, the pioglitazone hydrochloride immediate release section is characterized in that pioglitazone hydrochloride evenly is wrapped in metformin hydrochloride osmotic pump tablet surface with the form of coating.The outward appearance of this compound recipe sheet is similar with the general thin coated tablet.In dissolution in vitro was investigated, pioglitazone hydrochloride 30min stripping was more than 75%.
The rapid release clothing membrane material of said release layer is selected from one or more in hydroxypropyl emthylcellulose, hyprolose, the polyvinylpyrrolidone, preferred hydroxypropyl emthylcellulose.
Be applicable to that the typical solvent for preparing rapid release clothing film among the present invention is selected from one or more in water, ethanol, methanol, the acetone, preferred water.
Pioglitazone hydrochloride dissolubility in water is very little; It is excessive to be dispersed in the suspension viscosity that forms in the water with rapid release clothing membrane material, is unfavorable for coating, therefore dissolving low quantity of surfactant earlier in water; Add pioglitazone hydrochloride and clothing membrane material more successively, can obtain more suitable coating solution.The surfactant of said release layer is selected from one or more in Tween 80, sorbester p17, sodium lauryl sulphate, the polyoxyethylene castor oil, preferably sodium dodecyl sulfate.
The method for preparing of the compound preparation that pioglitazone hydrochloride of the present invention and metformin hydrochloride are formed may further comprise the steps: the 1. preparation of metformin hydrochloride tablet core; 2. wrap the controlled release clothing; 3. controlled release tablet punching; 4. wrap pioglitazone hydrochloride rapid release clothing.
Metformin hydrochloride, binding agent, the osmotic pressure promoter of prescription ratio are mixed, and wet granule compression tablet makes the metformin hydrochloride tablet core that outward appearance is bright and clean, hardness is suitable; Adopt film-coated technique, label is carried out clothing film coating, drying; Then mechanically or laser each plays a drug release hole on the osmotic pump tablet two sides; Wrap the pioglitazone hydrochloride release layer at last, drying gets said compound preparation.
Compound preparation of the present invention is applicable to takes the type ii diabetes patient that pioglitazone or metformin are not enough to blood sugar control separately; Take this compound preparation once a day; Can keep steadily effective blood drug level; Reduce untoward reaction (like hypoglycemia, GI irritation etc.) incidence rate, reduce medicining times, improve patient's compliance.This method for preparing step is simple simultaneously, is easy to realize suitability for industrialized production.
Description of drawings:
Fig. 1 is that the release profiles of metformin hydrochloride among embodiment 1 compound hydrochloric acid pioglitazone-metformin hydrochloride controlled release tablet and commercially available (ACTOPLUS
XR) compares
Fig. 2 is the stripping curve of pioglitazone hydrochloride in embodiment 1 compound hydrochloric acid pioglitazone-metformin hydrochloride controlled release tablet
Fig. 3 is the release profiles of metformin hydrochloride in embodiment 2 compound hydrochloric acids pioglitazone-metformin hydrochloride controlled release tablet
Fig. 4 is the stripping curve of pioglitazone hydrochloride in embodiment 2 compound hydrochloric acids pioglitazone-metformin hydrochloride controlled release tablet
Fig. 5 is the release profiles of metformin hydrochloride in embodiment 3 compound hydrochloric acids pioglitazone-metformin hydrochloride controlled release tablet
Fig. 6 is the stripping curve of pioglitazone hydrochloride in embodiment 3 compound hydrochloric acids pioglitazone-metformin hydrochloride controlled release tablet
Fig. 7 is the release profiles of metformin hydrochloride in embodiment 4 compound hydrochloric acids pioglitazone-metformin hydrochloride controlled release tablet
Fig. 8 is the stripping curve of pioglitazone hydrochloride in embodiment 4 compound hydrochloric acids pioglitazone-metformin hydrochloride controlled release tablet
Fig. 9 is for receiving in test preparation and the reference preparation metformin hydrochloride at the intravital blood drug level-time graph of Beagle dog
Figure 10 is for receiving in test preparation and the reference preparation pioglitazone hydrochloride at the intravital blood drug level-time graph of Beagle dog
The specific embodiment:
Embodiment 1
Metformin hydrochloride tablet core prescription (1000 amounts)
Clothing film coating fluid prescription (1000 amounts)
Pioglitazone hydrochloride release layer coating fluid prescription (1000 amounts)
Preparation technology:
1. the preparation of metformin hydrochloride tablet core: with supplementary material drying, pulverizing, sieving for standby; Get the supplementary material of recipe quantity, the equivalent mixing of progressively increasing; Add an amount of wetting agent and prepare soft material, granulation; Dry, granulate; Add magnesium stearate, mix homogeneously; Tabletting, hardness 8～10kg.
2. wrap clothing film: in acetone, dissolve cellulose acetate, glyceryl triacetate, dissolving PEG400 and adding in the cellulose acetate solution in the water.Adopt film-coated technique, wrap the clothing film that is about plate core weight 1.6% at the sheet wicking surface, the vacuum drying oven drying is removed residual solvent.
3. controlled release tablet punching: each plays a drug release hole on the coated tablet two sides with the laser boring mode.
4. wrap pioglitazone hydrochloride rapid release clothing: in water, dissolve sodium lauryl sulphate, add pioglitazone hydrochloride and Opadry II 03K19229 again, stir, then the suspension that obtains with film-coated mode bag on above-mentioned controlled release tablet.
The release degree of embodiment 1-embodiment 4 metformin hydrochloride and the determination of dissolution rate method of pioglitazone hydrochloride:
Regulation according to Chinese Pharmacopoeia version in 2010 two appendix XC dissolution method first method and XD drug release determination method first method makes an experiment.Getting pioglitazone hydrochloride-metformin hydrochloride compound controlled release sheet and place and change basket, is dissolution medium with the 0.1mol/L hydrochloric acid solution of 1000ml, and rotating speed is 100rpm; Temperature is (37 ± 0.5) ℃, respectively at 5,10,15,30,60,120min gets liquid 5ml, replenishes equivalent equality of temperature fresh medium simultaneously; Discard the acid solution in above-mentioned each stripping rotor behind the 2h; Is release medium with 1000ml through the distilled water of the degassing, respectively at 4,6,8,12,24h gets liquid 5ml, replenishes equivalent equality of temperature fresh medium simultaneously.Institute's sample thief filters through 0.45 μ m microporous filter membrane, discards filtrating just, gets subsequent filtrate and is diluted to suitable concentration.According to two appendix VB of Chinese Pharmacopoeia version in 2010 HPLC, measure the peak area of metformin hydrochloride and pioglitazone hydrochloride in the 255nm wavelength.In addition respectively precision to take by weighing reference substance an amount of, measure with method, calculate the release degree of metformin hydrochloride and the dissolution of pioglitazone hydrochloride with external standard method.
The dissolution result of the release degree of metformin hydrochloride and pioglitazone hydrochloride sees Fig. 1, Fig. 2 respectively among the embodiment 1, shows that label comprises 88.5% metformin hydrochloride, 6.0% PVP K90,4.5% lactose and 1.0% magnesium stearate; Clothing film comprises 88.9% cellulose acetate, the glyceryl triacetate of 8.9% PEG 400,2.2%; Coating increased weight 1.6% o'clock, and metformin hydrochloride has good controlled-release effect.Release layer comprises 49.4% pioglitazone hydrochloride, when 49.4% Opadry II 03K19229,1.2% sodium lauryl sulphate, can realize the rapid stripping of pioglitazone hydrochloride.
Metformin hydrochloride tablet core prescription (1000 amounts)
Clothing film coating fluid prescription (1000 amounts)
Pioglitazone hydrochloride release layer coating fluid prescription (1000 amounts)
Preparation technology:
1. the preparation of metformin hydrochloride tablet core: with supplementary material drying, pulverizing, sieving for standby; Get the supplementary material of recipe quantity, the equivalent mixing of progressively increasing; Add an amount of wetting agent and prepare soft material, granulation; Dry, granulate; Add magnesium stearate, mix homogeneously; Tabletting, hardness 8～10kg.
2. wrap clothing film: in acetone, dissolve cellulose acetate, glyceryl triacetate, dissolving PEG400 and adding in the cellulose acetate solution in the water.Adopt film-coated technique, wrap the clothing film that is about plate core weight 2.9% at the sheet wicking surface, the vacuum drying oven drying is removed residual solvent.
3. controlled release tablet punching: each plays a drug release hole on the coated tablet two sides with the laser boring mode.
4. wrap pioglitazone hydrochloride rapid release clothing: in water, dissolve sodium lauryl sulphate, add pioglitazone hydrochloride and Opadry II03K19229 again, stir, then the suspension that obtains with film-coated mode bag on above-mentioned controlled release tablet.
The dissolution result of the release degree of metformin hydrochloride and pioglitazone hydrochloride sees Fig. 3, Fig. 4 respectively among the embodiment 2, shows that label comprises 88.5% metformin hydrochloride, 6.0% PVP K90,4.5% lactose and 1.0% magnesium stearate; Clothing film comprises 81.6% cellulose acetate, the glyceryl triacetate of 16.3% PEG 400,2.0%; Coating increased weight 2.9% o'clock, and metformin hydrochloride has good controlled-release effect.Release layer comprises 65.6% pioglitazone hydrochloride, and when 32.8% Opadry II 03K19229,1.6% sodium lauryl sulphate, the stripping of pioglitazone hydrochloride is slower.
Embodiment 3
Metformin hydrochloride tablet core prescription (1000 amounts)
Clothing film coating fluid prescription (1000 amounts)
Pioglitazone hydrochloride release layer coating fluid prescription (1000 amounts)
Preparation technology:
1. the preparation of metformin hydrochloride tablet core: with supplementary material drying, pulverizing, sieving for standby; Get the supplementary material of recipe quantity, the equivalent mixing of progressively increasing; Add an amount of wetting agent and prepare soft material, granulation; Dry, granulate; Add magnesium stearate, mix homogeneously; Tabletting, hardness 8～10kg.
2. wrap clothing film: in acetone, dissolve cellulose acetate, dissolving PEG400 and adding in the cellulose acetate solution in the water.Adopt film-coated technique, wrap the clothing film that is about plate core weight 2.8% at the sheet wicking surface, the vacuum drying oven drying is removed residual solvent.
3. controlled release tablet punching: each plays a drug release hole on the coated tablet two sides with the laser boring mode.
4. wrap pioglitazone hydrochloride rapid release clothing: in water, dissolve sodium lauryl sulphate, add pioglitazone hydrochloride and Opadry II 32K10858 again, stir, then the suspension that obtains with film-coated mode bag on above-mentioned controlled release tablet.
The dissolution result of the release degree of metformin hydrochloride and pioglitazone hydrochloride sees Fig. 5, Fig. 6 respectively among the embodiment 3, shows that label comprises 88.5% metformin hydrochloride, 6.0% PVP K90,4.5% lactose and 1.0% magnesium stearate; Clothing film comprises 83.3% cellulose acetate, 16.7% PEG 400; Coating increased weight 2.8% o'clock, and metformin hydrochloride has good controlled-release effect.Release layer comprises 33.1% pioglitazone hydrochloride, when 66.1% Opadry II 32K10858,0.8% sodium lauryl sulphate, can realize the rapid stripping of pioglitazone hydrochloride.
Metformin hydrochloride tablet core prescription (1000 amounts)
Clothing film coating fluid prescription (1000 amounts)
Pioglitazone hydrochloride release layer coating fluid prescription (1000 amounts)
Preparation technology:
1. the preparation of metformin hydrochloride tablet core: with supplementary material drying, pulverizing, sieving for standby; Get the supplementary material of recipe quantity, the equivalent mixing of progressively increasing; Add an amount of wetting agent and prepare soft material, granulation; Dry, granulate; Add magnesium stearate, mix homogeneously; Tabletting, hardness 8～10kg.
2. wrap clothing film: in acetone, dissolve cellulose acetate, dissolving PEG400 and adding in the cellulose acetate solution in the water.Adopt film-coated technique, wrap the clothing film that is about plate core weight 3.8% at the sheet wicking surface, the vacuum drying oven drying is removed residual solvent.
3. controlled release tablet punching: each plays a drug release hole on the coated tablet two sides with the laser boring mode.
4. wrap pioglitazone hydrochloride rapid release clothing: in water, dissolve sodium lauryl sulphate, add pioglitazone hydrochloride and HPMC E5 again, stir, then the suspension that obtains with film-coated mode bag on above-mentioned controlled release tablet.
The dissolution result of the release degree of metformin hydrochloride and pioglitazone hydrochloride sees Fig. 7, Fig. 8 respectively among the embodiment 4, shows that label comprises 90.9% metformin hydrochloride, 6.0% PVP K90,2.9% lactose and 0.2% magnesium stearate; Clothing film comprises 83.3% cellulose acetate, 16.7% PEG 400; Coating increased weight 3.8% o'clock, and metformin hydrochloride has good controlled-release effect.Release layer comprises 49.4% pioglitazone hydrochloride, and when 49.4% HPMC E5,1.2% sodium lauryl sulphate, the stripping of pioglitazone hydrochloride is slower.
Be the test data of the pharmacokinetics of part preparation of the present invention below:
Selecting six average weights is that the male Beagle dog of (12.0 ± 2.0) kg is as animal subject.The oral pioglitazone hydrochloride of the present invention of dual crossing-6 (every hydrochloric pioglitazone 30mg of metformin hydrochloride compound controlled release sheet at random; Metformin hydrochloride 1000mg; Receive test preparation; Embodiment 1 method preparation) and 6 (every hydrochloric pioglitazone 30mg of ACTOPLUS
XR of Wu Tian company; Metformin hydrochloride 1000mg, reference preparation).Fasting 12h before taking medicine.In 8 administrations on an empty stomach in morning, extract blank blood before the administration.Receive examination and reference preparation group all in 0.5,1,1.5,2,3,4,6,8,12,16,24,36h gets veins of upper extremity blood 3ml and puts in the anticoagulant heparin pipe, the centrifugal 10min of 4000rpm gets upper plasma, it is subsequent use to put-70 ℃ of freezing preservations.
Plasma sample is handled: get pastille blood plasma 50 μ l, add 150 μ l protein precipitants (50/50ng/ml two kinds in target acetonitrile solution), vibration 3min protein precipitation, two times centrifugal (15000rpmmin
-1* 10min centrifugal first time, 18000rpmmin
-1* 5min centrifugal second time) after, shift 80 μ l supernatant to the sample introduction bottle, 10 μ l sample introductions adopt LC-MS/MS working sample content.
Receive in test preparation and the reference preparation metformin hydrochloride and pioglitazone hydrochloride to see Fig. 9, Figure 10 respectively at the intravital blood drug level-time graph of Beagle dog.
In vivo test proves that the rapid stripping of pioglitazone hydrochloride part (receives test preparation T in the compound preparation of the present invention
Max=1.17h, reference preparation T
Max=0.92h), metformin hydrochloride controlled release part can discharge in 24 hours gently.
Claims (8)
1. compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride, on structure was formed, it comprised from the inside to the outside successively:
The metformin hydrochloride tablet core;
The clothing film of band drug release hole;
The pioglitazone hydrochloride release layer.
Wherein,
Based on the gross weight of metformin hydrochloride tablet core, said label comprises the metformin hydrochloride of 80～95 weight %, the binding agent of 4～8 weight %, the osmotic pressure promoter of 2～6 weight % and the lubricant of 0.1～1.5 weight %;
Based on the gross weight of used clothing film, said clothing film comprises the polymer of 80～95 weight %, the porogen of 5～20 weight %, the plasticizer of 0～5 weight %;
Said film weightening finish is 1～10 weight % of label;
Based on the gross weight of pioglitazone hydrochloride release layer, said release layer comprises the pioglitazone hydrochloride of 30～70 weight %, the rapid release clothing membrane material of 30～70 weight %, the surfactant of 0.5～2 weight %.
2. the compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride according to claim 1, metformin hydrochloride is the controlled release part, it is characterized in that metformin hydrochloride is the elementary osmotic pump sheet, respectively there is a drug release hole on the osmotic pump tablet two sides; Pioglitazone hydrochloride is an immediate release section, it is characterized in that pioglitazone hydrochloride evenly is wrapped in metformin hydrochloride osmotic pump tablet surface with the form of coating.The outward appearance of this compound recipe sheet is similar with the general thin coated tablet.
3. the compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride according to claim 1, in said metformin hydrochloride tablet core,
The binding agent of said label is selected from one or more in polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hyprolose, hydroxyethyl-cellulose, the sodium carboxymethyl cellulose;
The osmotic pressure promoter of said label is selected from sodium chloride, potassium chloride, glucose, sucrose, lactose, mannitol, by in the pears alcohol one or more;
The lubricant of said label is selected from one or more in stearic acid, magnesium stearate, the sodium stearyl fumarate.
4. the compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride according to claim 1, in the clothing film of said band drug release hole,
The polymeric material of said clothing film is selected from one or more in ethyl cellulose, cellulose acetate, the polyacrylic resin;
The porogen of said clothing film is selected from one or more in Polyethylene Glycol, glycerol, polyvinylpyrrolidone, propylene glycol, the hyprolose;
The plasticizer of said clothing film is selected from one or more in dibutyl sebacate, triethyl citrate, dimethyl phthalate, the glyceryl triacetate.
5. the compound preparation of forming by pioglitazone hydrochloride and metformin hydrochloride according to claim 1, in said pioglitazone hydrochloride release layer,
The rapid release clothing membrane material of said release layer is selected from one or more in hydroxypropyl emthylcellulose, hyprolose, the polyvinylpyrrolidone;
The surfactant of said release layer is selected from one or more in Tween 80, sorbester p17, sodium lauryl sulphate, the polyoxyethylene castor oil.
6. the compound preparation of being made up of pioglitazone hydrochloride and metformin hydrochloride according to claim 1, the sustained release of wherein said metformin hydrochloride provides 4-8 hour peak serum concentration.
7. the compound preparation of being made up of pioglitazone hydrochloride and metformin hydrochloride according to claim 1, the rapid release of wherein said pioglitazone hydrochloride provides 1-4 hour peak serum concentration.
8. according to the method for preparing of the described compound preparation of being made up of pioglitazone hydrochloride and metformin hydrochloride of claim 1-5, it may further comprise the steps: the 1. preparation of metformin hydrochloride tablet core; 2. wrap clothing film; 3. controlled release tablet punching; 4. wrap pioglitazone hydrochloride rapid release clothing.
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| CN2012100379199A Pending CN102525991A (en) | 2012-02-20 | 2012-02-20 | Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and method for preparing compound preparation containing pioglitazone hydrochloride and metformin hydrochloride |
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| CN (1) | CN102525991A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104473894A (en) * | 2014-12-18 | 2015-04-01 | 浙江华海药业股份有限公司 | Pioglitazone hydrochloride medicine-loading coating preparation and preparation method thereof |
| WO2017156953A1 (en) * | 2016-03-17 | 2017-09-21 | 赛乐医药科技(上海)有限公司 | Metformin hydrochloride osmotic pump tablet and preparation method therefor |
| CN115212180A (en) * | 2022-09-03 | 2022-10-21 | 深圳市信宜特科技有限公司 | Compound preparation of aspirin and clopidogrel hydrogen sulfate and preparation method thereof |
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| US20020064556A1 (en) * | 1998-03-20 | 2002-05-30 | Cheng Xiu Xiu | Controlled release oral tablet having a unitary core |
| CN1726912A (en) * | 2005-07-25 | 2006-02-01 | 天津药物研究院 | Slow release capsule of compound metformin pyrrolidone and preparation method |
| CN102008472A (en) * | 2010-10-18 | 2011-04-13 | 中国科学院上海药物研究所 | Compound pioglitazone hydrochloride/metformin hydrochloride bilayer osmotic pump controlled release preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020064556A1 (en) * | 1998-03-20 | 2002-05-30 | Cheng Xiu Xiu | Controlled release oral tablet having a unitary core |
| CN1726912A (en) * | 2005-07-25 | 2006-02-01 | 天津药物研究院 | Slow release capsule of compound metformin pyrrolidone and preparation method |
| CN102008472A (en) * | 2010-10-18 | 2011-04-13 | 中国科学院上海药物研究所 | Compound pioglitazone hydrochloride/metformin hydrochloride bilayer osmotic pump controlled release preparation and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104473894A (en) * | 2014-12-18 | 2015-04-01 | 浙江华海药业股份有限公司 | Pioglitazone hydrochloride medicine-loading coating preparation and preparation method thereof |
| WO2017156953A1 (en) * | 2016-03-17 | 2017-09-21 | 赛乐医药科技(上海)有限公司 | Metformin hydrochloride osmotic pump tablet and preparation method therefor |
| US10668021B2 (en) | 2016-03-17 | 2020-06-02 | Elite Pharma Technology (Shanghai) Co., Ltd. | Metformin hydrochloride osmotic pump tablet and preparation method therefor |
| CN115212180A (en) * | 2022-09-03 | 2022-10-21 | 深圳市信宜特科技有限公司 | Compound preparation of aspirin and clopidogrel hydrogen sulfate and preparation method thereof |
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