CN103446063A - Assembly method and preparation technology of compound metformin hydrochloride and pioglitazone hydrochloride slow-release micro-pellet preparation - Google Patents
Assembly method and preparation technology of compound metformin hydrochloride and pioglitazone hydrochloride slow-release micro-pellet preparation Download PDFInfo
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- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 title claims abstract description 94
- 229960002827 pioglitazone hydrochloride Drugs 0.000 title claims abstract description 94
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 61
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 61
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- 239000003814 drug Substances 0.000 claims abstract description 76
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 58
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an assembly method and a preparation technology of a compound metformin hydrochloride and pioglitazone hydrochloride slow-release micro-pellet preparation. The preparation technology comprises the following steps: respectively preparing metformin hydrochloride slow-release micro-pellets and pioglitazone hydrochloride slow-release micro-pellets; mixing the metformin hydrochloride slow-release micro-pellets with the pioglitazone hydrochloride slow-release micro-pellets, and carrying out a drug release experiment; mixing qualified products according to the assembly weight percent, so as to prepare the compound metformin hydrochloride and pioglitazone hydrochloride slow-release micro-pellet preparation; loading into hard capsules or pressing into tablets. Therefore, the hypoglycemic effect is ideal; the toxic and side effects of the drug can be reduced; the sustained and steady hypoglycemic effect can be achieved inside a body; the compliance of a sufferer is improved; the preparation has high bioavailability and stable blood concentration; the clinical treatment effect can be effectively improved; better dosage regimen and curative effect are provided for diabetes patients at home and abroad.
Description
Technical field
The present invention relates to diabetes pharmaceutical technology field, especially a kind of compound formulation and preparation technology of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations.
Background technology
Diabetes (diabetes) are to act on that body causes hypoinsulinism, insulin resistant etc. and a series of metabolism disorder syndromes such as the sugar that causes, protein, fat, power and water Xie Zhi by inherited genetic factors, immunologic function disorder, infected by microbes and toxin thereof, free radical toxin, Nervous and Mental Factors etc. various virulence factors.Take hyperglycemia clinically as main feature, the performance such as polyuria, polydipsia, polyphagia can appear in model case, become thin, i.e. " three-many-one-little " symptom; Diabetes (blood glucose) cause complication once control bad meeting, cause the exhaustion pathological changes at the positions such as kidney, eye, foot, and can't cure; Diabetes have become commonly encountered diseases and the frequently-occurring disease in China and even the world, and have become one of disease that M & M is the highest.Diabetes are divided into amphitypy, and the I type is insulin dependent diabetes mellitus (IDDM), and the II type is non-insulin-dependent diabetes mellitus.Wherein II type non-insulin-dependent diabetes mellitus patient is in the majority, accounts for more than 90% of patient's sum.
Metformin hydrochloride is a kind of biguanides oral antidiabetic drug, for the treatment of non-insulin-dependent diabetes mellitus.This medicine Main Function is organized outside islets of langerhans, suppresses enterocyte and absorbs glucose, increases the sensitivity of surrounding tissue to insulin, increases non-insulin and relies on gluconeogenesis function of liver.The hypoglycemic activity of biguanides does not rely on normal islet function and B cell, but increases the anerobic glycolysis of glucose, suppresses the hepatic glycogen heteroplasia, reduces blood plasma glucagon level.Pioglitazone hydrochloride is the Studies of The Insulin Sensitizer Thiazolidinediones medicine, and it can increase insulin sensitivity, reduces blood glucose.The competitive peroxide activator enzyme paraphyte receptor of such medicine energy, regulate transcribing of Insulin sensitivity gene, increase transcribing with albumen of peripheral tissues's glucose transporter 1 and glucose transporter 4 etc. synthetic, increase picked-up and the transhipment of basic glucose, thereby change insulin resistant and performance hypoglycemic activity.Metformin hydrochloride and pioglitazone hydrochloride can improve insulin resistant from different approach.When pioglitazone hydrochloride and metformin hydrochloride coupling, pioglitazone has improved the sensitivity of tissue to insulin, and the anerobic glycolysis that makes metformin hydrochloride improve surrounding tissue is better brought into play with the effect that increases surrounding tissue insulin and its receptors bind.The time limit of the two hypoglycemic activity supplements mutually, and curative effect superposes mutually, and side effect offsets.It is the good combination that treatment onset type Ⅱdiabetes mellitus especially improves insulin resistant.
Pellet capsule belongs to polydisperse system, each dosage is usually containing tens or a hundreds of micropill, micropill is compared with the slow-release tablet of a unit drug-supplying system, there are the characteristics such as concise production process, drug loading are large, good fluidity, favorable reproducibility, good stability, be widely used in the medicine sustained and controlled release preparation.The sustained-release micro-pill capsules preparation is developed rapidly in recent years, and domestic had a more report about slow release capsule preparation, and the Related products such as slow releasing capsule, enteric coated capsule are being sold on the market.But the research to compound sustained release capsules is relatively less, the domestic listing of also not ratifying compound sustained release capsules at present; The domestic existing listing of the common compound tablet of metformin hydrochloride and pioglitazone hydrochloride, its compound slow-release tablet also obtained the U.S. FDA approval in 2009, but to the domestic report that there is no of the research of compound sustained-release pellet capsule.
The patent document that number of patent application is 20101051.527.0 discloses the compound preparation of a kind of pioglitazone hydrochloride and metformin hydrochloride double-layer osmotic pump controlled-release tablet composition, on forming, structure comprises successively from the inside to the outside: the label formed by medicated layer and boosting layer, the contagion gown layer, clothing film with drug release hole, pioglitazone hydrochloride release layer and nonessential aesthstic coat, this invention adopts the double-layer osmotic pump controlled-release technology, the later stage of improving metformin hydrochloride discharges, yet 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 in double-layer osmotic pump tablet, propellant adds the content that has limited every active medicine, need day to take multi-disc and just can reach effective dose, undesirable aspect raising patient medication compliance.
In view of the foregoing, now invent out a kind of compound formulation and preparation technology of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations, can reach and continue in vivo release and drug release behavior effect comparatively stably, stable its bioavailability that makes of drug release behavior improves relatively, the compound recipe combination of two kinds of micropills makes its better efficacy, poisonous side effect of medicine reduces, and hypoglycemic effect is better.Within one day, be administered once and improved patient's compliance, for domestic and international diabetics provides better dosage regimen and curative effect.
Summary of the invention
The objective of the invention is in order to overcome deficiency of the prior art, a kind of compound formulation and preparation technology of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations are provided, can effectively control medicine blood drug level, make blood drug level stable, and there is higher bioavailability, can improve clinical efficacy, reduce medicining times, can reach continual and steady blood sugar decreasing effect, can also improve compliance, reduce untoward reaction.
The present invention to achieve these goals, adopt following technical scheme: a kind of compound formulation and preparation technology of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations, the diabecron sustained-release micropill is by forming containing pill core and slow release layer two parts, containing pill core, metformin hydrochloride, filler and binding agent, consist of, slow release layer is comprised of slow-release material and porogen, the pioglitazone hydrochloride sustained-release micropill is comprised of celphere, medicated layer and slow release layer three parts, and medicated layer is comprised of pioglitazone hydrochloride, binding agent, solubilizing agent, and slow release layer is comprised of slow-release material and porogen, the assembly percentage by weight is: metformin hydrochloride 20.0-35.0%, filler 15.0-37.5% for the diabecron sustained-release micropill, binding agent 0.2-2.5% for the diabecron sustained-release micropill, slow-release material 2.3-8.4% for the diabecron sustained-release micropill, porogen 0.01-1.0% for the diabecron sustained-release micropill, celphere 35.1-41.7%, pioglitazone hydrochloride 6.5-14.3%, binding agent 0.7-1.0% for the pioglitazone hydrochloride sustained-release micropill, solubilizing agent 0.05-0.6% for the pioglitazone hydrochloride sustained-release micropill, slow-release material 1.9-6.5% for the pioglitazone hydrochloride sustained-release micropill, porogen 0.6-2.5% for the pioglitazone hydrochloride sustained-release micropill, above each component sum by weight ratio is 100%.
The filler of buying from market is microcrystalline Cellulose, lactose, sucrose, starch " the wherein combination of one or more "; The binding agent of buying from market is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin " the wherein combination of one or more "; The solubilizing agent of buying from market is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate " the wherein combination of one or more "; The slow-release material of buying from market is especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material " the wherein combination of one or more " of crylic acid resin aqueous dispersion; The porogen of buying from market is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate " the wherein combination of one or more ".
By metformin hydrochloride, filler and binding agent mix homogeneously, make soft material, spheronization is extruded in employing or centrifugal granulation is prepared into metformin hydrochloride containing pill core, metformin hydrochloride is carried out to preheating containing pill core, the slow release layer coating solution is sprayed onto to metformin hydrochloride containing on pill core, is prepared into the diabecron sustained-release micropill; By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by to celphere, medicine-feeding is prepared into pioglitazone hydrochloride containing pill core, pioglitazone hydrochloride is carried out to preheating containing pill core, the slow release layer coating solution is sprayed onto to pioglitazone hydrochloride containing on pill core, is prepared into the pioglitazone hydrochloride sustained-release micropill; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are done to the drug release rate experiment, and drug release rate is qualified products in standard drug release scope; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are made to compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, in the hard capsule of packing into or be pressed into tablet.
The preparation technology of diabecron sustained-release micropill: take metformin hydrochloride crude drug and filler, grind respectively and cross 120 mesh sieves, then mixing 80 mesh sieves fully mixes, adding 6-9%(g/ml in the material mixed) binder solution makes soft material, employing is extruded spheronization, with extruder, soft material is squeezed into to bar, bar is added to round as a ball rear formation micropill in spheronizator, the taking-up micropill is placed in 30-45 ℃ drying in oven 6-9 hour, be prepared into dry metformin hydrochloride containing pill core, sieving out particle diameter is that 18～24 purposes are containing pill core, standby, the slow-release material adding distil water is diluted to the solution of solid content 8-12%, be prepared into the slow release layer coating solution after stirring, get and standbyly containing after pill core is placed in the fluidized-bed coating machine preheating, the slow release layer coating solution is sprayed onto containing carrying out coating on pill core, be prepared into the diabecron sustained-release micropill, the fluidized-bed coating machine parameter setting is, inlet temperature 35-38 ℃, atomizing pressure 1～2bar, 20～30 hertz of air blast frequencies, hydrojet speed 0.8～1.0mL/min, coating weightening finish 8～12%.
The preparation technology of pioglitazone hydrochloride sustained-release micropill: take the pioglitazone hydrochloride crude drug, be prepared into the pastille alcoholic solution with 50-65ml ethanol ultrasonic dissolution, the 0.1-0.8g binding agent is dissolved in 30-50ml water, add the 0.01-0.07g solubilizing agent in binder aqueous solution, stirring and dissolving, the mixed aqueous solution that contains binding agent and solubilizing agent is slowly joined in the pastille alcoholic solution and is prepared into pure water mixed solution, when adding, stirred, by pure water mixed solution high speed shear homogenize 3-7min, be prepared into the pastille suspension; The 80-110g celphere is placed in to fluidized-bed coating machine and is preheated to 35-45 ℃, pre-thermal endurance is 4-8 minute, the pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, the pastille suspension is added medicine to celphere, by obtained, containing pill core, sieve, sieving out particle diameter is that 18～24 purposes contain pill core, standby; The slow-release material adding distil water is diluted to the solution of solid content 8-12%, the high speed shear homogenize, add porogen, is prepared into the slow release layer coating solution after stirring; Get and standbyly containing pill core, be placed in fluidized-bed coating machine and be preheated to 35-45 ℃, pre-thermal endurance is 3-7 minute, and the slow release layer coating solution is sprayed onto containing carrying out coating on pill core, is prepared into the pioglitazone hydrochloride sustained-release micropill; The fluidized-bed coating machine parameter setting is: inlet temperature 35-38 ℃, atomizing pressure 1～2 bar, 20～30 hertz of air blast frequencies, hydrojet speed 0.8～1.0mL/min, coating weightening finish 4～10%.
The drug release rate test: the regulation according to Chinese Pharmacopoeia two appendix XC dissolution method first methods of version in 2010 and XD drug release determination method is tested, take metformin hydrochloride micropill and pioglitazone hydrochloride micropill, quality and a compound sustained release capsules are equal to, be placed in digestion instrument and turn basket, the Hcl solution that release medium is 0.1mol/L and the Na3P04 solution of 0.2mol/L, the temperature of release medium is controlled at 37 ± 0.5 ℃, digestion instrument is turned to the Hcl solution 650-800ml that basket is placed in 0.1mol/L, turning the basket rotating speed is 100r/min, the Na3P04 solution 200-350ml that adds 0.2 mol/L after release 2h, the pH value of Na3P04 solution is 5-7, change release medium completes in 4-6min, digestion instrument turns that basket rotates in release medium until experiment in 24 hours stops after finishing, at scheduled time slot sampling 4-6ml, add isopyknic release medium simultaneously, with the microporous filter membrane of 0.6-0.9 μ m, filtered, discard the first filtrate that small part contains filtering residue, get subsequent filtrate standby, sample introduction 15-30 μ l carries out the HPLC analysis.
The drug release rate test: the drug release rate of diabecron sustained-release pellet preparations is: after 2 hours, discharge 1-15%, discharge 14-28% after 4 hours, discharge 22-43% after 6 hours, discharge 35-60% after 8 hours, discharge 42-68% after 10 hours, after 12 hours, discharge 54-78%, after 14 hours, discharge 62-80%, discharge 71-90% after 18 hours, after 24 hours, discharge and be greater than 90%; The drug release rate of pioglitazone hydrochloride sustained-release pellet preparations is: after 2 hours, discharge 0.1-5%, discharge 0.8-15% after 4 hours, discharge 2-20% after 6 hours, discharge 15-43% after 8 hours, discharge 27-51% after 10 hours, after 12 hours, discharge 42-65%, after 14 hours, discharge 50-80%, discharge 72-90% after 18 hours, after 24 hours, discharge and be greater than 85%.
The invention has the beneficial effects as follows: the diameter that micropill is comprised of medicine and adjuvant is about the small entity of spherical shape of 1mm.Micropill belongs to polydisperse system, each dosage is usually containing tens or a hundreds of micropill, error or the defect of indivedual micropills in preparation is unlikely to the drug release behavior of whole preparation is affected greatly, because there is larger contact surface on medicine and gastrointestinal tract surface, absorb good and little to local zest, simultaneously, micropill is different from tablet, the former is not affected by the gastric emptying factor basically, therefore the infiltration rate of medicine is even, individual bioavailability difference is little; Micropill has the advantages such as particle diameter is even, good fluidity, difficult crushing, particularly the fine pellet core surface coatings, make location, slow release or controlled release preparation, technique is simple, can avoid other solid preparations as inhomogeneous as coatings such as tablets, may cause the risk of medicine pulse; The compound capsule formed by the micropill of different pharmaceutical, can increase medicine stability, improve curative effect, reduce poisonous side effect of medicine etc.
The metformin hydrochloride gastrointestinal absorbs rapidly, and metabolism is fast, and day medication dose is large and action time is short.Bioavailability is only 50-60%, Tmax 1-3 hour, and dosage increase to absorb reduces, and dosage is relevant without linearity to blood concentration, clinically is difficult to grasp dosage and effect; Take food and reduce absorbtivity and postpone peak time, the serum peak concentration reduces by 40%, necessary (medicine) being taken before meal use, and peak concentration changes greatly, and the patients with NIDDM of normal renal function and the patients with NIDDM of renal dysfunction can differ 1 times.Therefore be difficult to grasp dosage and effect; If make slow releasing preparation, drug release is slow, absorbs constantly, and dosage and blood drug level dependency are good, clinically is easy to grasp relation of dosage and effect.
The pioglitazone hydrochloride ordinary preparation, after oral administration, on an empty stomach in situation, can in serum, measure pioglitazone hydrochloride after 30 minutes, within 2 hours, reach peak concentration, food can be by peak concentration time retardation to 3～4 hour, then medicine is eliminated in vivo fast, and the Drug therapy window is narrower.After pioglitazone hydrochloride is prepared into to slow releasing preparation, can maintain for a long time the plasma concentration of medicine in the treatment window.Can effectively control medicine blood drug level, make blood drug level stable, and there is higher bioavailability, can improve clinical efficacy, reduce medicining times, can reach continual and steady blood sugar decreasing effect, can also improve compliance, reduce untoward reaction.
The metformin hydrochloride water solublity is fabulous, the slow release layer coating material with Aquacoat product Sulisi (Surelease) as metformin hydrochloride, and while using separately, the rete permeance property of formation is better, and the drug release effect is steady.Therefore, control the release speed of medicine by regulating the coating film thickness, make the diabecron sustained-release micropill reach desirable drug release rate.
The pioglitazone hydrochloride water solublity is bad, slow release layer coating material with Aquacoat product Sulisi (Surelease) as pioglitazone hydrochloride, while using separately, the rete permeance property formed is poor, cause the release of medicine slower, and do not have adequate thickness easily cause prominent release with drug release too fast, therefore, the present invention adds a certain amount of water-soluble polymer in the slow release layer coating solution, preferably hypromellose (HPMC-E3) is as porogen, thereby make it form the aquation passage in the clothing film and improve the clothing permeability of the membrane, make the pioglitazone hydrochloride sustained-release micropill reach desirable drug release rate.
Metformin hydrochloride adds a certain proportion of lactose containing in pill core, can prevent from making to separate out the metformin hydrochloride crystal containing the pill wicking surface containing the extremely strong water solublity due to medicine in the pill core dry run; Pioglitazone hydrochloride, due to indissoluble in water, so add a certain proportion of sodium lauryl sulphate in medicated layer, can improve drug release rate and the degree of slow-release micro-pill.
After diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are mixed by a certain percentage, adopt pharmaceutically customary way, in the hard capsule of can directly packing into, can also add other pharmaceutic adjuvant and be pressed into tablet.
The present invention is that dosage and ratio are mixed in accordance with regulations, the compound slow release preparation that two kinds of different Drug combinations of hypoglycemic activity of metformin hydrochloride and pioglitazone hydrochloride are made, make metformin hydrochloride and pioglitazone hydrochloride bring into play its synergism, make the blood sugar decreasing effect ideal, can reduce the toxic and side effects of medicine, reduce medicining times every day, after taking medicine every day once, can reach in vivo continual and steady blood sugar decreasing effect, be conducive to improve patient's compliance, there is higher bioavailability and stable blood drug level, can effectively improve clinical efficacy.
The accompanying drawing explanation
Below in conjunction with accompanying drawing, the invention will be further described:
Fig. 1 is, diabecron sustained-release micropill preparation technology flow chart;
Fig. 2 is, pioglitazone hydrochloride sustained-release micropill preparation technology flow chart.
The specific embodiment
Below in conjunction with accompanying drawing and the specific embodiment, the present invention is described in further detail:
Embodiment 1
The diabecron sustained-release micropill, by forming containing pill core and slow release layer two parts, is comprised of metformin hydrochloride, filler and binding agent containing pill core, and slow release layer is comprised of slow-release material and porogen, the pioglitazone hydrochloride sustained-release micropill is comprised of celphere, medicated layer and slow release layer three parts, and medicated layer is comprised of pioglitazone hydrochloride, binding agent, solubilizing agent, and slow release layer is comprised of slow-release material and porogen, the assembly percentage by weight is: metformin hydrochloride 20.0-35.0%, filler 15.0-37.5% for the diabecron sustained-release micropill, binding agent 0.2-2.5% for the diabecron sustained-release micropill, slow-release material 2.3-8.4% for the diabecron sustained-release micropill, porogen 0.01-1.0% for the diabecron sustained-release micropill, celphere 35.1-41.7%, pioglitazone hydrochloride 6.5-14.3%, binding agent 0.7-1.0% for the pioglitazone hydrochloride sustained-release micropill, solubilizing agent 0.05-0.6% for the pioglitazone hydrochloride sustained-release micropill, slow-release material 1.9-6.5% for the pioglitazone hydrochloride sustained-release micropill, porogen 0.6-2.5% for the pioglitazone hydrochloride sustained-release micropill, above each component sum by weight ratio is 100%.
Embodiment 2
The filler of buying from market is microcrystalline Cellulose, lactose, sucrose, starch " the wherein combination of one or more "; The binding agent of buying from market is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin " the wherein combination of one or more "; The solubilizing agent of buying from market is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate " the wherein combination of one or more "; The slow-release material of buying from market is especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material " the wherein combination of one or more " of crylic acid resin aqueous dispersion; The porogen of buying from market is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate " the wherein combination of one or more ".
Embodiment 3
By metformin hydrochloride, filler and binding agent mix homogeneously, make soft material, spheronization is extruded in employing or centrifugal granulation is prepared into metformin hydrochloride containing pill core, metformin hydrochloride is carried out to preheating containing pill core, the slow release layer coating solution is sprayed onto to metformin hydrochloride containing on pill core, is prepared into the diabecron sustained-release micropill; By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by to celphere, medicine-feeding is prepared into pioglitazone hydrochloride containing pill core, pioglitazone hydrochloride is carried out to preheating containing pill core, the slow release layer coating solution is sprayed onto to pioglitazone hydrochloride containing on pill core, is prepared into the pioglitazone hydrochloride sustained-release micropill; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are done to the drug release rate experiment, and drug release rate is qualified products in standard drug release scope; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are made to compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, in the hard capsule of packing into or be pressed into tablet.
Embodiment 4
The preparation technology of diabecron sustained-release micropill: take metformin hydrochloride crude drug and filler, grind respectively and cross 120 mesh sieves, then mixing 80 mesh sieves fully mixes, adding 6-9%(g/ml in the material mixed) binder solution makes soft material, employing is extruded spheronization, with extruder, soft material is squeezed into to bar, bar is added to round as a ball rear formation micropill in spheronizator, the taking-up micropill is placed in 30-45 ℃ drying in oven 6-9 hour, be prepared into dry metformin hydrochloride containing pill core, sieving out particle diameter is that 18～24 purposes are containing pill core, standby, the slow-release material adding distil water is diluted to the solution of solid content 8-12%, be prepared into the slow release layer coating solution after stirring, get and standbyly containing after pill core is placed in the fluidized-bed coating machine preheating, the slow release layer coating solution is sprayed onto containing carrying out coating on pill core, be prepared into the diabecron sustained-release micropill, the fluidized-bed coating machine parameter setting is, inlet temperature 35-38 ℃, atomizing pressure 1～2bar, 20～30 hertz of air blast frequencies, hydrojet speed 0.8～1.0mL/min, coating weightening finish 8～12%.
Embodiment 5
The preparation technology of pioglitazone hydrochloride sustained-release micropill: take the pioglitazone hydrochloride crude drug, be prepared into the pastille alcoholic solution with 50-65ml ethanol ultrasonic dissolution, the 0.1-0.8g binding agent is dissolved in 30-50ml water, add the 0.01-0.07g solubilizing agent in binder aqueous solution, stirring and dissolving, the mixed aqueous solution that contains binding agent and solubilizing agent is slowly joined in the pastille alcoholic solution and is prepared into pure water mixed solution, when adding, stirred, by pure water mixed solution high speed shear homogenize 3-7min, be prepared into the pastille suspension; The 80-110g celphere is placed in to fluidized-bed coating machine and is preheated to 35-45 ℃, pre-thermal endurance is 4-8 minute, the pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, the pastille suspension is added medicine to celphere, by obtained, containing pill core, sieve, sieving out particle diameter is that 18～24 purposes contain pill core, standby; The slow-release material adding distil water is diluted to the solution of solid content 8-12%, the high speed shear homogenize, add porogen, is prepared into the slow release layer coating solution after stirring; Get and standbyly containing pill core, be placed in fluidized-bed coating machine and be preheated to 35-45 ℃, pre-thermal endurance is 3-7 minute, and the slow release layer coating solution is sprayed onto containing carrying out coating on pill core, is prepared into the pioglitazone hydrochloride sustained-release micropill; The fluidized-bed coating machine parameter setting is: inlet temperature 35-38 ℃, atomizing pressure 1～2 bar, 20～30 hertz of air blast frequencies, hydrojet speed 0.8～1.0mL/min, coating weightening finish 4～10%.
Embodiment 6
The drug release rate test: the regulation according to Chinese Pharmacopoeia two appendix XC dissolution method first methods of version in 2010 and XD drug release determination method is tested, take metformin hydrochloride micropill and pioglitazone hydrochloride micropill, quality and a compound sustained release capsules are equal to, be placed in digestion instrument and turn basket, the Hcl solution that release medium is 0.1mol/L and the Na3P04 solution of 0.2mol/L, the temperature of release medium is controlled at 37 ± 0.5 ℃, digestion instrument is turned to the Hcl solution 650-800ml that basket is placed in 0.1mol/L, turning the basket rotating speed is 100r/min, the Na3P04 solution 200-350ml that adds 0.2 mol/L after release 2h, the pH value of Na3P04 solution is 5-7, change release medium completes in 4-6min, digestion instrument turns that basket rotates in release medium until experiment in 24 hours stops after finishing, at scheduled time slot sampling 4-6ml, add isopyknic release medium simultaneously, with the microporous filter membrane of 0.6-0.9 μ m, filtered, discard the first filtrate that small part contains filtering residue, get subsequent filtrate standby, sample introduction 15-30 μ l carries out the HPLC analysis.
Embodiment 7
The drug release rate test: the drug release rate of diabecron sustained-release pellet preparations is: after 2 hours, discharge 1-15%, discharge 14-28% after 4 hours, discharge 22-43% after 6 hours, discharge 35-60% after 8 hours, discharge 42-68% after 10 hours, after 12 hours, discharge 54-78%, after 14 hours, discharge 62-80%, discharge 71-90% after 18 hours, after 24 hours, discharge and be greater than 90%; The drug release rate of pioglitazone hydrochloride sustained-release pellet preparations is: after 2 hours, discharge 0.1-5%, discharge 0.8-15% after 4 hours, discharge 2-20% after 6 hours, discharge 15-43% after 8 hours, discharge 27-51% after 10 hours, after 12 hours, discharge 42-65%, after 14 hours, discharge 50-80%, discharge 72-90% after 18 hours, after 24 hours, discharge and be greater than 85%.
Claims (7)
1. the compound formulation of a compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations, it is characterized in that: the diabecron sustained-release micropill is by forming containing pill core and slow release layer two parts, containing pill core, metformin hydrochloride, filler and binding agent, consist of, slow release layer is comprised of slow-release material and porogen, the pioglitazone hydrochloride sustained-release micropill is comprised of celphere, medicated layer and slow release layer three parts, and medicated layer is comprised of pioglitazone hydrochloride, binding agent, solubilizing agent, and slow release layer is comprised of slow-release material and porogen, the assembly percentage by weight is: metformin hydrochloride 20.0-35.0%, filler 15.0-37.5% for the diabecron sustained-release micropill, binding agent 0.2-2.5% for the diabecron sustained-release micropill, slow-release material 2.3-8.4% for the diabecron sustained-release micropill, porogen 0.01-1.0% for the diabecron sustained-release micropill, celphere 35.1-41.7%, pioglitazone hydrochloride 6.5-14.3%, binding agent 0.7-1.0% for the pioglitazone hydrochloride sustained-release micropill, solubilizing agent 0.05-0.6% for the pioglitazone hydrochloride sustained-release micropill, slow-release material 1.9-6.5% for the pioglitazone hydrochloride sustained-release micropill, porogen 0.6-2.5% for the pioglitazone hydrochloride sustained-release micropill, above each component sum by weight ratio is 100%.
2. the compound formulation of a kind of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations according to claim 1, is characterized in that: from the filler of market purchase, be microcrystalline Cellulose, lactose, sucrose, starch " the wherein combination of one or more "; The binding agent of buying from market is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin " the wherein combination of one or more "; The solubilizing agent of buying from market is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate " the wherein combination of one or more "; The slow-release material of buying from market is especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material " the wherein combination of one or more " of crylic acid resin aqueous dispersion; The porogen of buying from market is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate " the wherein combination of one or more ".
3. the preparation technology of a compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations, it is characterized in that: by metformin hydrochloride, filler and binding agent mix homogeneously, make soft material, spheronization is extruded in employing or centrifugal granulation is prepared into metformin hydrochloride containing pill core, metformin hydrochloride is carried out to preheating containing pill core, the slow release layer coating solution is sprayed onto to metformin hydrochloride containing on pill core, is prepared into the diabecron sustained-release micropill; By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by to celphere, medicine-feeding is prepared into pioglitazone hydrochloride containing pill core, pioglitazone hydrochloride is carried out to preheating containing pill core, the slow release layer coating solution is sprayed onto to pioglitazone hydrochloride containing on pill core, is prepared into the pioglitazone hydrochloride sustained-release micropill; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are done to the drug release rate experiment, and drug release rate is qualified products in standard drug release scope; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are made to compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, in the hard capsule of packing into or be pressed into tablet.
4. the preparation technology of a kind of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations diabecron sustained-release micropill according to claim 3, it is characterized in that: take metformin hydrochloride crude drug and filler, grind respectively and cross 120 mesh sieves, then mixing 80 mesh sieves fully mixes, in the material mixed, add the 6-9%g/ml binder solution to make soft material, employing is extruded spheronization, with extruder, soft material is squeezed into to bar, bar is added to round as a ball rear formation micropill in spheronizator, the taking-up micropill is placed in 30-45 ℃ drying in oven 6-9 hour, be prepared into dry metformin hydrochloride containing pill core, sieving out particle diameter is that 18～24 purposes are containing pill core, standby, the slow-release material adding distil water is diluted to the solution of solid content 8-12%, be prepared into the slow release layer coating solution after stirring, get and standbyly containing after pill core is placed in the fluidized-bed coating machine preheating, the slow release layer coating solution is sprayed onto containing carrying out coating on pill core, be prepared into the diabecron sustained-release micropill, the fluidized-bed coating machine parameter setting is, inlet temperature 35-38 ℃, atomizing pressure 1～2bar, 20～30 hertz of air blast frequencies, hydrojet speed 0.8～1.0mL/min, coating weightening finish 8～12%.
5. the preparation technology of a kind of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations pioglitazone hydrochloride sustained-release micropill according to claim 3, it is characterized in that: take the pioglitazone hydrochloride crude drug, be prepared into the pastille alcoholic solution with 50-65ml ethanol ultrasonic dissolution, the 0.1-0.8g binding agent is dissolved in 30-50ml water, add the 0.01-0.07g solubilizing agent in binder aqueous solution, stirring and dissolving, the mixed aqueous solution that contains binding agent and solubilizing agent is slowly joined in the pastille alcoholic solution and is prepared into pure water mixed solution, when adding, stirred, by pure water mixed solution high speed shear homogenize 3-7min, be prepared into the pastille suspension, the 80-110g celphere is placed in to fluidized-bed coating machine and is preheated to 35-45 ℃, pre-thermal endurance is 4-8 minute, the pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, the pastille suspension is added medicine to celphere, by obtained, containing pill core, sieve, sieving out particle diameter is that 18～24 purposes contain pill core, standby, the slow-release material adding distil water is diluted to the solution of solid content 8-12%, the high speed shear homogenize, add porogen, is prepared into the slow release layer coating solution after stirring, get and standbyly containing pill core, be placed in fluidized-bed coating machine and be preheated to 35-45 ℃, pre-thermal endurance is 3-7 minute, and the slow release layer coating solution is sprayed onto containing carrying out coating on pill core, is prepared into the pioglitazone hydrochloride sustained-release micropill, the fluidized-bed coating machine parameter setting is: inlet temperature 35-38 ℃, atomizing pressure 1～2 bar, 20～30 hertz of air blast frequencies, hydrojet speed 0.8～1.0mL/min, coating weightening finish 4～10%.
6. the drug release rate of a kind of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations according to claim 3 test, it is characterized in that: the regulation according to Chinese Pharmacopoeia two appendix XC dissolution method first methods of version in 2010 and XD drug release determination method is tested, take metformin hydrochloride micropill and pioglitazone hydrochloride micropill, quality and a compound sustained release capsules are equal to, be placed in digestion instrument and turn basket, the Hcl solution that release medium is 0.1mol/L and the Na3P04 solution of 0.2mol/L, the temperature of release medium is controlled at 37 ± 0.5 ℃, digestion instrument is turned to the Hcl solution 650-800ml that basket is placed in 0.1mol/L, turning the basket rotating speed is 100r/min, the Na3P04 solution 200-350ml that adds 0.2 mol/L after release 2h, the pH value of Na3P04 solution is 5-7, change release medium completes in 4-6min, digestion instrument turns that basket rotates in release medium until experiment in 24 hours stops after finishing, at scheduled time slot sampling 4-6ml, add isopyknic release medium simultaneously, with the microporous filter membrane of 0.6-0.9 μ m, filtered, discard the first filtrate that small part contains filtering residue, get subsequent filtrate standby, sample introduction 15-30 μ l carries out the HPLC analysis.
7. the drug release rate of a kind of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations according to claim 3 test, it is characterized in that: the drug release rate of diabecron sustained-release pellet preparations is: after 2 hours, discharge 1-15%, discharge 14-28% after 4 hours, discharge 22-43% after 6 hours, discharge 35-60% after 8 hours, discharge 42-68% after 10 hours, discharge 54-78% after 12 hours, discharge 62-80% after 14 hours, discharge 71-90% after 18 hours, after 24 hours, discharge and be greater than 90%; The drug release rate of pioglitazone hydrochloride sustained-release pellet preparations is: after 2 hours, discharge 0.1-5%, discharge 0.8-15% after 4 hours, discharge 2-20% after 6 hours, discharge 15-43% after 8 hours, discharge 27-51% after 10 hours, after 12 hours, discharge 42-65%, after 14 hours, discharge 50-80%, discharge 72-90% after 18 hours, after 24 hours, discharge and be greater than 85%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310377236.2A CN103446063B (en) | 2013-08-26 | 2013-08-26 | A kind of compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and preparation technology |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310377236.2A CN103446063B (en) | 2013-08-26 | 2013-08-26 | A kind of compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and preparation technology |
Publications (2)
| Publication Number | Publication Date |
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| CN103446063A true CN103446063A (en) | 2013-12-18 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030724A (en) * | 2015-08-20 | 2015-11-11 | 杭州成邦医药科技有限公司 | Composition of anti-diabetic drugs |
| CN109475656A (en) * | 2016-07-12 | 2019-03-15 | 优格创新与发展研究 | Allow the dressing of the controlled extended release of melbine |
| CN110801443A (en) * | 2019-12-03 | 2020-02-18 | 仁和堂药业有限公司 | Metformin hydrochloride sustained-release preparation and quality detection method thereof |
| CN112461947A (en) * | 2020-10-27 | 2021-03-09 | 山东省药学科学院 | Method for measuring dissolution curve of pioglitazone hydrochloride tablet |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101269040A (en) * | 2008-05-16 | 2008-09-24 | 北京正大绿洲医药科技有限公司 | Pioglitazone hydrochloride sustained-release dropping pill and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101269040A (en) * | 2008-05-16 | 2008-09-24 | 北京正大绿洲医药科技有限公司 | Pioglitazone hydrochloride sustained-release dropping pill and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030724A (en) * | 2015-08-20 | 2015-11-11 | 杭州成邦医药科技有限公司 | Composition of anti-diabetic drugs |
| CN109475656A (en) * | 2016-07-12 | 2019-03-15 | 优格创新与发展研究 | Allow the dressing of the controlled extended release of melbine |
| CN110801443A (en) * | 2019-12-03 | 2020-02-18 | 仁和堂药业有限公司 | Metformin hydrochloride sustained-release preparation and quality detection method thereof |
| CN112461947A (en) * | 2020-10-27 | 2021-03-09 | 山东省药学科学院 | Method for measuring dissolution curve of pioglitazone hydrochloride tablet |
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