CN103446063B - A kind of compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and preparation technology - Google Patents
A kind of compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and preparation technology Download PDFInfo
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Abstract
The compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and a preparation technology, prepare diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill respectively; Diabecron sustained-release micropill and the mixing of pioglitazone hydrochloride sustained-release micropill are done drug release rate experiment, qualified products are made compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, loads in hard capsule or be pressed into tablet; Make blood sugar decreasing effect desirable, the toxic and side effects of medicine can be reduced, continual and steady blood sugar decreasing effect can be reached in vivo, be conducive to the compliance improving patient, there is higher bioavailability and stable blood drug level, effectively can improve clinical efficacy, for domestic and international diabetics provides better dosage regimen and curative effect.
Description
Technical field
The present invention relates to diabetes pharmaceutical technology sectors, especially a kind of compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and preparation technology.
Background technology
Diabetes (diabetes) be by the various virulence factor of inherited genetic factors, immunologic function disorder, infected by microbes and toxin thereof, free radical toxin, Nervous and Mental Factors etc. act on body cause hypoinsulinism, insulin resistant etc. and cause a series of metabolism disorder syndrome such as sugar, protein, fat, water and eletrolytes.The performance such as be main feature clinically with hyperglycemia, polyuria, polydipsia, polyphagia can appear in model case, become thin, i.e. " three-many-one-little " symptom; Diabetes (blood glucose), once control badly can cause complication, cause the exhaustion pathological changes at the positions such as kidney, eye, foot, and cannot cure; Diabetes have become commonly encountered diseases and the frequently-occurring disease in China and even the world, and have become one of the highest disease of M & M.Diabetes are divided into amphitypy, and I type is insulin dependent diabetes mellitus (IDDM), and II type is non-insulin-dependent diabetes mellitus.Wherein II type non-insulin-dependent diabetes mellitus patient is in the majority, accounts for patient populations's more than 90%.
Metformin hydrochloride is a kind of biguanides oral antidiabetic drug, for the treatment of non-insulin-dependent diabetes mellitus.This medicine mainly acts on islets of langerhans and organizes outward, suppresses enterocyte to absorb glucose, increases surrounding tissue to the sensitivity of 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 hepatic gluconeogenesis, reduces plasma glucagon level.Pioglitazone hydrochloride is 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 of peripheral tissues's Glucose transporter-1 and glucose transporter 4 etc. to synthesize with albumen, increase picked-up and the transhipment of basal glucose, thus change insulin resistant and play hypoglycemic activity.Metformin hydrochloride and pioglitazone hydrochloride can improve insulin resistant from different approaches.When pioglitazone hydrochloride and metformin hydrochloride coupling, pioglitazone improves the sensitivity of tissue to insulin, and the effect of the anerobic glycolysis and increase surrounding tissue insulin and its receptors bind that make metformin hydrochloride improve surrounding tissue better plays.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 is the features such as concise production process, drug loading are large, good fluidity, favorable reproducibility, good stability, be widely used in medicine sustained and controlled release preparation.Sustained-release micro-pill capsules preparation is developed rapidly in recent years, and domestic had the more report about slow release capsule preparation, and the Related product such as slow releasing capsule, enteric coated capsule is at commercial type.But relatively less to the research of compound sustained release capsules, the domestic listing also not ratifying compound sustained release capsules at present; The domestic existing listing of common compound tablet of metformin hydrochloride and pioglitazone hydrochloride, its compound slow-release tablet also obtained U.S. FDA approval in 2009, but there is no report to the research of compound sustained-release pellet capsule is domestic.
Number of patent application is the compound preparation that the patent document of 20101051.527.0 discloses a kind of pioglitazone hydrochloride and metformin hydrochloride double-layer osmotic pump controlled-release tablet composition, structure composition comprises from the inside to the outside successively: the label be made up of medicated layer and boosting layer, contagion gown layer, with the clothing film of drug release hole, pioglitazone hydrochloride release layer and nonessential aesthstic coat, this invention adopts double-layer osmotic pump controlled-release technology, improve the later stage release of metformin hydrochloride, but the preparation technology of existing double layer osmotic pump technology and equipment not perfect, this invention also exists the feasibility problems of suitability for industrialized production, and in double-layer osmotic pump tablet propellant add the content limiting every sheet active medicine, need to take multi-disc day and just can reach effective dose, undesirable in raising patient medication compliance.
In view of the foregoing, now invent a kind of compound formulation and preparation technology of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations, sustained release and drug release behavior effect comparatively stably in vivo can be reached, 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 improve the compliance of patient, for domestic and international diabetics provides better dosage regimen and curative effect.
Summary of the invention
The object of the invention is 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, blood drug level is stablized, and there is higher bioavailability, can clinical efficacy be improved, reduce medicining times, continual and steady blood sugar decreasing effect can be reached, can also compliance be improved, reduce untoward reaction.
The present invention to achieve these goals, adopt following technical scheme: a kind of compound formulation of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations and preparation technology, diabecron sustained-release micropill forms by containing pill core and slow release layer two parts, be made up of metformin hydrochloride, filler and binding agent containing pill core, slow release layer is made up of slow-release material and porogen, pioglitazone hydrochloride sustained-release micropill by celphere, medicated layer and slow release layer three part form, medicated layer is made up of pioglitazone hydrochloride, binding agent, solubilizing agent, and slow release layer is made up of slow-release material and porogen, assembly percentage by weight is: metformin hydrochloride 20.0-35.0%, for the filler 15.0-37.5% of diabecron sustained-release micropill, for the binding agent 0.2-2.5% of diabecron sustained-release micropill, for the slow-release material 2.3-8.4% of diabecron sustained-release micropill, for the porogen 0.01-1.0% of diabecron sustained-release micropill, celphere 35.1-41.7%, pioglitazone hydrochloride 6.5-14.3%, for the binding agent 0.7-1.0% of pioglitazone hydrochloride sustained-release micropill, for the solubilizing agent 0.05-0.6% of pioglitazone hydrochloride sustained-release micropill, for the slow-release material 1.9-6.5% of pioglitazone hydrochloride sustained-release micropill, for the porogen 0.6-2.5% of pioglitazone hydrochloride sustained-release micropill, above each component by weight ratio sum is 100%,
Described filler is microcrystalline Cellulose, lactose, sucrose, starch, wherein one or more combination; Described binding agent is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin, wherein one or more combination; Described solubilizing agent is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate, wherein one or more combination; Described slow-release material is crylic acid resin aqueous dispersion especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material, wherein one or more combination; Described porogen is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate, wherein one or more combination;
By metformin hydrochloride, filler and binding agent mix homogeneously, make soft material, extrusion spheronization method or centrifugal granulation is adopted to be prepared into metformin hydrochloride containing pill core, containing pill core, preheating is carried out to metformin hydrochloride, slow release layer coating solution is sprayed onto metformin hydrochloride containing on pill core, is prepared into diabecron sustained-release micropill; By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by being prepared into pioglitazone hydrochloride containing pill core to celphere medicine-feeding, containing pill core, preheating is carried out to pioglitazone hydrochloride, slow release layer coating solution is sprayed onto pioglitazone hydrochloride containing on pill core, is prepared into pioglitazone hydrochloride sustained-release micropill; Do drug release rate experiment to diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill, drug release rate is qualified products within the scope of standard drug release; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are made compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, loads in hard capsule 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 mixed 80 mesh sieves fully to mix, in the material of mixing, add 6-9% (g/ml) binder solution make soft material, adopt extrusion spheronization method extruder that soft material is squeezed into bar, bar is added to round as a ball rear formation micropill in spheronizator, take out drying in oven 6-9 hour that micropill is placed in 30-45 DEG C, be prepared into dry metformin hydrochloride containing pill core, sieving out particle diameter is that 18 ~ 24 objects are containing pill core, for subsequent use, slow-release material adding distil water is diluted to the solution of solid content 8-12%, slow release layer coating solution is prepared into, get for subsequent use containing after pill core is placed in fluidized-bed coating machine preheating, be sprayed onto by slow release layer coating solution and carry out coating containing on pill core, be prepared into diabecron sustained-release micropill after stirring, fluidized-bed coating machine parameter setting is, inlet temperature 35-38 DEG C, atomizing pressure 1 ~ 2bar, air blast frequency 20 ~ 30 hertz, hydrojet speed 0.8 ~ 1.0mL/min, coating weight gain 8 ~ 12%,
The preparation technology of pioglitazone hydrochloride sustained-release micropill: take pioglitazone hydrochloride crude drug, dissolve with 50-65ml EtOH Sonicate and be prepared into pastille alcoholic solution, 0.1-0.8g binding agent is dissolved in 30-50ml water, 0.01-0.07g solubilizing agent is added in binder aqueous solution, stirring and dissolving, mixed aqueous solution containing binding agent and solubilizing agent is slowly joined in pastille alcoholic solution and is prepared into alcohol water mixed solution, stir while adding, by alcohol water mixed solution high speed shear homogenize 3-7min, be prepared into pastille suspension; 80-110g celphere is placed in fluidized-bed coating machine and is preheated to 35-45 DEG C, preheat duration time is 4-8 minute, pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, pastille suspension is added medicine to celphere, sieve obtained containing pill core, sieving out particle diameter is that 18 ~ 24 objects contain pill core, for subsequent use; Slow-release material adding distil water is diluted to the solution of solid content 8-12%, high speed shear homogenize, adds porogen, is prepared into slow release layer coating solution after stirring; Get and be for subsequent usely placed in fluidized-bed coating machine be preheated to 35-45 DEG C containing pill core, preheat duration time is 3-7 minute, is sprayed onto by slow release layer coating solution and carries out coating containing on pill core, be prepared into pioglitazone hydrochloride sustained-release micropill; Fluidized-bed coating machine parameter setting is: inlet temperature 35-38 DEG C, atomizing pressure 1 ~ 2bar, air blast frequency 20 ~ 30 hertz, hydrojet speed 0.8 ~ 1.0mL/min, coating weight gain 4 ~ 10%;
Drug release rate is tested: test according to the regulation of Chinese Pharmacopoeia version in 2010 two annex XC dissolution method first methods and XD drug release determination method, take metformin hydrochloride micropill and pioglitazone hydrochloride micropill, quality is equal to a compound sustained release capsules, be placed in digestion instrument and turn basket, release medium is the Hcl solution of 0.1mol/L and the Na3P04 solution of 0.2mol/L, the temperature of release medium controls at 37 ± 0.5 DEG C, digestion instrument is turned the Hcl solution 650-800ml that basket is placed in 0.1mol/L, turning basket rotating speed is 100r/min, the Na3P04 solution 200-350ml of 0.2mol/L is added after release 2h, the pH value of Na3P04 solution is 5-7, change release medium to complete in 4-6min, digestion instrument turns basket and rotates until experiment in 24 hours stops after terminating in release medium, at scheduled time slot sampling 4-6ml, add isopyknic release medium simultaneously, filter with the microporous filter membrane of 0.6-0.9 μm, discard the first filtrate that small part contains filtering residue, get subsequent filtrate for subsequent use, sample introduction 15-30 μ l carries out HPLC analysis,
Drug release rate is tested: the drug release rate of diabecron sustained-release pellet preparations is: discharge 1-15% after 2 hours, 14-28% is discharged after 4 hours, 22-43% is discharged after 6 hours, 35-60% is discharged 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, release is greater than 90%; The drug release rate of pioglitazone hydrochloride sustained-release pellet preparations is: discharge 0.1-5% after 2 hours, 0.8-15% is discharged after 4 hours, 2-20% is discharged after 6 hours, 15-43% is discharged 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, release is greater than 85%.
The invention has the beneficial effects as follows: the diameter that micropill is made up 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, indivedual micropill preparation on error or defect be unlikely to affect greatly the drug release behavior of overall preparation, because there is larger contact surface on medicine and gastrointestinal tract surface, absorption is good and little to the zest of local, simultaneously, micropill is different from tablet, the former does not affect by gastric emptying factor substantially, therefore the infiltration rate of medicine is even, and individual bioavailability difference is little; Micropill has the advantages such as uniform particle sizes, good fluidity, not easily crushing, particularly fine pellet core surface coatings, make location, slow release or controlled release preparation, technique are simple, other solid preparations can be avoided as uneven in coatings such as tablets, the risk of medicine pulse may be caused; The compound capsule be made up of the micropill of different pharmaceutical, can increase the stability of medicine, improves curative effect, reduce poisonous side effect of medicine etc.
Metformin hydrochloride gastrointestinal absorption is rapid, and metabolism is fast, day medication dose large and action time is short.Bioavailability is only 50-60%, Tmax1-3 hour, and dosage increases absorption minimizing, and dosage and blood concentration are without linear correlation, and clinical being difficult to grasps dosage and effect; Take food and reduce absorbtivity and postpone peak time, peak serum concentration reduces by 40%, and necessary (medicine) being taken before meal use, peak concentration changes greatly, and the patients with NIDDM of normal renal function can differ 1 times with the patients with NIDDM of renal dysfunction.Therefore be difficult to grasp dosage and effect; If make slow releasing preparation, drug release is slow, absorbs constant, and dosage is good with blood drug level dependency, is clinically easy to grasp relation of dosage and effect.
Pioglitazone hydrochloride ordinary preparation, after oral administration, under fasting conditions, can measure pioglitazone hydrochloride in serum after 30 minutes, within 2 hours, reach peak concentration, food can by peak concentration time retardation by 3 ~ 4 hours, then medicine is eliminated in vivo fast, and Drug therapy window is narrower.After pioglitazone hydrochloride is prepared into slow releasing preparation, the plasma concentration of medicine can be maintained for a long time in treatment window.Can effectively control medicine blood drug level, blood drug level is stablized, and there is higher bioavailability, can clinical efficacy be improved, reduce medicining times, continual and steady blood sugar decreasing effect can be reached, can also compliance be improved, reduce untoward reaction.
Metformin hydrochloride water solublity is fabulous, and with the slow release layer coating material of Aquacoat product Sulisi (Surelease) as metformin hydrochloride, when being used alone, the rete permeance property of formation is better, and drug release effect is steady.Therefore, by the release speed regulating coating film thickness to control medicine, the drug release rate that diabecron sustained-release micropill reaches desirable is made.
Pioglitazone hydrochloride water solublity is bad, with the slow release layer coating material of Aquacoat product Sulisi (Surelease) as pioglitazone hydrochloride, when being used alone, 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 slow release layer coating solution, preferred hypromellose (HPMC-E3) is as porogen, make it in clothing film, form aquation passage thus improve clothing permeability of the membrane, make the drug release rate that pioglitazone hydrochloride sustained-release micropill reaches desirable.
Metformin hydrochloride adds a certain proportion of lactose containing in pill core, can prevent from separating out metformin hydrochloride crystal containing making due to the extremely strong water solublity of medicine in pill core dry run containing pill wicking surface; 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 being mixed by a certain percentage, adopt pharmaceutically customary way, can directly load in hard capsule, other pharmaceutic adjuvant can also be added and be pressed into tablet.
The present invention is mixed in prescribed dose and ratio, by the compound slow release preparation that Drug combinations different for metformin hydrochloride and pioglitazone hydrochloride two kinds of hypoglycemic activities is made, metformin hydrochloride and pioglitazone hydrochloride is made to play its synergism, make blood sugar decreasing effect desirable, the toxic and side effects of medicine can be reduced, reduce medicining times every day, take medicine every day once, continual and steady blood sugar decreasing effect can be reached in vivo, be conducive to the compliance improving patient, there is higher bioavailability and stable blood drug level, effectively can improve clinical efficacy.
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.
Detailed description of the invention
Below in conjunction with accompanying drawing and detailed description of the invention, the present invention is described in further detail:
Embodiment 1
Diabecron sustained-release micropill forms by containing pill core and slow release layer two parts, and be made up of metformin hydrochloride, filler and binding agent containing pill core, slow release layer is made up of slow-release material and porogen, pioglitazone hydrochloride sustained-release micropill by celphere, medicated layer and slow release layer three part form, medicated layer is made up of pioglitazone hydrochloride, binding agent, solubilizing agent, and slow release layer is made up of slow-release material and porogen, assembly percentage by weight is: metformin hydrochloride 20.0-35.0%, for the filler 15.0-37.5% of diabecron sustained-release micropill, for the binding agent 0.2-2.5% of diabecron sustained-release micropill, for the slow-release material 2.3-8.4% of diabecron sustained-release micropill, for the porogen 0.01-1.0% of diabecron sustained-release micropill, celphere 35.1-41.7%, pioglitazone hydrochloride 6.5-14.3%, for the binding agent 0.7-1.0% of pioglitazone hydrochloride sustained-release micropill, for the solubilizing agent 0.05-0.6% of pioglitazone hydrochloride sustained-release micropill, for the slow-release material 1.9-6.5% of pioglitazone hydrochloride sustained-release micropill, for the porogen 0.6-2.5% of pioglitazone hydrochloride sustained-release micropill, above each component by weight ratio sum is 100%,
Described filler is microcrystalline Cellulose, lactose, sucrose, starch, wherein one or more combination; Described binding agent is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin, wherein one or more combination; Described solubilizing agent is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate, wherein one or more combination; Described slow-release material is crylic acid resin aqueous dispersion especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material, wherein one or more combination; Described porogen is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate, wherein one or more combination;
By metformin hydrochloride, filler and binding agent mix homogeneously, make soft material, extrusion spheronization method or centrifugal granulation is adopted to be prepared into metformin hydrochloride containing pill core, containing pill core, preheating is carried out to metformin hydrochloride, slow release layer coating solution is sprayed onto metformin hydrochloride containing on pill core, is prepared into diabecron sustained-release micropill; By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by being prepared into pioglitazone hydrochloride containing pill core to celphere medicine-feeding, containing pill core, preheating is carried out to pioglitazone hydrochloride, slow release layer coating solution is sprayed onto pioglitazone hydrochloride containing on pill core, is prepared into pioglitazone hydrochloride sustained-release micropill; Do drug release rate experiment to diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill, drug release rate is qualified products within the scope of standard drug release; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are made compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, loads in hard capsule 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 mixed 80 mesh sieves fully to mix, in the material of mixing, add 6-9% (g/ml) binder solution make soft material, adopt extrusion spheronization method extruder that soft material is squeezed into bar, bar is added to round as a ball rear formation micropill in spheronizator, take out drying in oven 6-9 hour that micropill is placed in 30-45 DEG C, be prepared into dry metformin hydrochloride containing pill core, sieving out particle diameter is that 18 ~ 24 objects are containing pill core, for subsequent use, slow-release material adding distil water is diluted to the solution of solid content 8-12%, slow release layer coating solution is prepared into, get for subsequent use containing after pill core is placed in fluidized-bed coating machine preheating, be sprayed onto by slow release layer coating solution and carry out coating containing on pill core, be prepared into diabecron sustained-release micropill after stirring, fluidized-bed coating machine parameter setting is, inlet temperature 35-38 DEG C, atomizing pressure 1 ~ 2bar, air blast frequency 20 ~ 30 hertz, hydrojet speed 0.8 ~ 1.0mL/min, coating weight gain 8 ~ 12%,
The preparation technology of pioglitazone hydrochloride sustained-release micropill: take pioglitazone hydrochloride crude drug, dissolve with 50-65ml EtOH Sonicate and be prepared into pastille alcoholic solution, 0.1-0.8g binding agent is dissolved in 30-50ml water, 0.01-0.07g solubilizing agent is added in binder aqueous solution, stirring and dissolving, mixed aqueous solution containing binding agent and solubilizing agent is slowly joined in pastille alcoholic solution and is prepared into alcohol water mixed solution, stir while adding, by alcohol water mixed solution high speed shear homogenize 3-7min, be prepared into pastille suspension; 80-110g celphere is placed in fluidized-bed coating machine and is preheated to 35-45 DEG C, preheat duration time is 4-8 minute, pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, pastille suspension is added medicine to celphere, sieve obtained containing pill core, sieving out particle diameter is that 18 ~ 24 objects contain pill core, for subsequent use; Slow-release material adding distil water is diluted to the solution of solid content 8-12%, high speed shear homogenize, adds porogen, is prepared into slow release layer coating solution after stirring; Get and be for subsequent usely placed in fluidized-bed coating machine be preheated to 35-45 DEG C containing pill core, preheat duration time is 3-7 minute, is sprayed onto by slow release layer coating solution and carries out coating containing on pill core, be prepared into pioglitazone hydrochloride sustained-release micropill; Fluidized-bed coating machine parameter setting is: inlet temperature 35-38 DEG C, atomizing pressure 1 ~ 2bar, air blast frequency 20 ~ 30 hertz, hydrojet speed 0.8 ~ 1.0mL/min, coating weight gain 4 ~ 10%;
Drug release rate is tested: test according to the regulation of Chinese Pharmacopoeia version in 2010 two annex XC dissolution method first methods and XD drug release determination method, take metformin hydrochloride micropill and pioglitazone hydrochloride micropill, quality is equal to a compound sustained release capsules, be placed in digestion instrument and turn basket, release medium is the Hcl solution of 0.1mol/L and the Na3P04 solution of 0.2mol/L, the temperature of release medium controls at 37 ± 0.5 DEG C, digestion instrument is turned the Hcl solution 650-800ml that basket is placed in 0.1mol/L, turning basket rotating speed is 100r/min, the Na3P04 solution 200-350ml of 0.2mol/L is added after release 2h, the pH value of Na3P04 solution is 5-7, change release medium to complete in 4-6min, digestion instrument turns basket and rotates until experiment in 24 hours stops after terminating in release medium, at scheduled time slot sampling 4-6ml, add isopyknic release medium simultaneously, filter with the microporous filter membrane of 0.6-0.9 μm, discard the first filtrate that small part contains filtering residue, get subsequent filtrate for subsequent use, sample introduction 15-30 μ l carries out HPLC analysis,
Drug release rate is tested: the drug release rate of diabecron sustained-release pellet preparations is: discharge 1-15% after 2 hours, 14-28% is discharged after 4 hours, 22-43% is discharged after 6 hours, 35-60% is discharged 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, release is greater than 90%; The drug release rate of pioglitazone hydrochloride sustained-release pellet preparations is: discharge 0.1-5% after 2 hours, 0.8-15% is discharged after 4 hours, 2-20% is discharged after 6 hours, 15-43% is discharged 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, release is greater than 85%.
Claims (2)
1. the preparation method of a compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations, it is characterized in that: diabecron sustained-release micropill forms by containing pill core and slow release layer two parts, be made up of metformin hydrochloride, filler and binding agent containing pill core, slow release layer is made up of slow-release material and porogen, pioglitazone hydrochloride sustained-release micropill by celphere, medicated layer and slow release layer three part form, medicated layer is made up of pioglitazone hydrochloride, binding agent, solubilizing agent, and slow release layer is made up of slow-release material and porogen, assembly percentage by weight is: metformin hydrochloride 20.0-35.0%, for the filler 15.0-37.5% of diabecron sustained-release micropill, for the binding agent 0.2-2.5% of diabecron sustained-release micropill, for the slow-release material 2.3-8.4% of diabecron sustained-release micropill, for the porogen 0.01-1.0% of diabecron sustained-release micropill, celphere 35.1-41.7%, pioglitazone hydrochloride 6.5-14.3%, for the binding agent 0.7-1.0% of pioglitazone hydrochloride sustained-release micropill, for the solubilizing agent 0.05-0.6% of pioglitazone hydrochloride sustained-release micropill, for the slow-release material 1.9-6.5% of pioglitazone hydrochloride sustained-release micropill, for the porogen 0.6-2.5% of pioglitazone hydrochloride sustained-release micropill, above each component by weight ratio sum is 100%,
Described filler is microcrystalline Cellulose, lactose, sucrose, starch, wherein one or more combination; Described binding agent is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin, wherein one or more combination; Described solubilizing agent is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate, wherein one or more combination; Described slow-release material is crylic acid resin aqueous dispersion especially strange, Aquacoat product Sulisi, cellulose acetate, wherein one or more combination; Described porogen is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate, wherein one or more combination;
By metformin hydrochloride, filler and binding agent mix homogeneously, make soft material, extrusion spheronization method or centrifugal granulation is adopted to be prepared into metformin hydrochloride containing pill core, containing pill core, preheating is carried out to metformin hydrochloride, slow release layer coating solution is sprayed onto metformin hydrochloride containing on pill core, is prepared into diabecron sustained-release micropill; By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by being prepared into pioglitazone hydrochloride containing pill core to celphere medicine-feeding, containing pill core, preheating is carried out to pioglitazone hydrochloride, slow release layer coating solution is sprayed onto pioglitazone hydrochloride containing on pill core, is prepared into pioglitazone hydrochloride sustained-release micropill; Do drug release rate experiment to diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill, drug release rate is qualified products within the scope of standard drug release; Diabecron sustained-release micropill and pioglitazone hydrochloride sustained-release micropill are made compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations by assembly weight percentage mix, loads in hard capsule or be pressed into tablet;
Test according to the regulation of Chinese Pharmacopoeia version in 2010 two annex XC dissolution method first methods and XD drug release determination method, take metformin hydrochloride micropill and pioglitazone hydrochloride micropill, quality is equal to a compound sustained release capsules, be placed in digestion instrument and turn basket, release medium is the HCl solution of 0.1mol/L and the Na3PO4 solution of 0.2mol/L, the temperature of release medium controls at 37 ± 0.5 DEG C, digestion instrument is turned the HCl solution 650-800ml that basket is placed in 0.1mol/L, turning basket rotating speed is 100r/min, the Na3PO4 solution 200-350ml of 0.2mol/L is added after release 2h, the pH value of Na3PO4 solution is 5-7, change release medium to complete in 4-6min, digestion instrument turns basket and rotates until experiment in 24 hours stops after terminating in release medium, at scheduled time slot sampling 4-6ml, add isopyknic release medium simultaneously, filter with the microporous filter membrane of 0.6-0.9 μm, discard the first filtrate that small part contains filtering residue, get subsequent filtrate for subsequent use, sample introduction 15-30 μ l carries out HPLC analysis,
The drug release rate of diabecron sustained-release micropill is: discharge 1-15% after 2 hours, 14-28% is discharged after 4 hours, 22-43% is discharged after 6 hours, 35-60% is discharged 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, release is greater than 90%; The drug release rate of pioglitazone hydrochloride sustained-release micropill is: discharge 0.1-5% after 2 hours, 0.8-15% is discharged after 4 hours, 2-20% is discharged after 6 hours, 15-43% is discharged 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, release is greater than 85%.
2. the preparation method of a kind of compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations according to claim 1, it is characterized in that: take metformin hydrochloride crude drug and filler, grind respectively and cross 120 mesh sieves, then mixed 80 mesh sieves fully to mix, in the material of mixing, add 6-9% binder solution make soft material, adopt extrusion spheronization method extruder that soft material is squeezed into bar, bar is added to round as a ball rear formation micropill in spheronizator, take out drying in oven 6-9 hour that micropill is placed in 30-45 DEG C, be prepared into dry metformin hydrochloride containing pill core, sieving out particle diameter is that 18 ~ 24 objects are containing pill core, for subsequent use, slow-release material adding distil water is diluted to the solution of solid content 8-12%, slow release layer coating solution is prepared into, get for subsequent use containing after pill core is placed in fluidized-bed coating machine preheating, be sprayed onto by slow release layer coating solution and carry out coating containing on pill core, be prepared into diabecron sustained-release micropill after stirring, fluidized-bed coating machine parameter setting is, inlet temperature 35-38 DEG C, atomizing pressure 1 ~ 2bar, air blast frequency 20 ~ 30 hertz, hydrojet speed 0.8 ~ 1.0mL/min, coating weight gain 8 ~ 12%.
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| 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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| 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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