CN103462903B - A kind of preparation technology of pioglitazone hydrochloride sustained-release pellet preparations - Google Patents
A kind of preparation technology of pioglitazone hydrochloride sustained-release pellet preparations Download PDFInfo
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- CN103462903B CN103462903B CN201310377195.7A CN201310377195A CN103462903B CN 103462903 B CN103462903 B CN 103462903B CN 201310377195 A CN201310377195 A CN 201310377195A CN 103462903 B CN103462903 B CN 103462903B
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Abstract
The compound formulation of a kind of pioglitazone hydrochloride sustained-release pellet preparations and preparation technology, by pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by hydrochloric acid pioglitazone pellet core being prepared by celphere medicine-feeding, pioglitazone hydrochloride pellet core is preheated, slow release layer coating solution is sprayed onto in pioglitazone hydrochloride pellet core, prepares hydrochloric acid pioglitazone slow-release micro-pill；Obtained compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations is mixed with diabecron sustained-release micropill, 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 improving the compliance of patient, there is higher bioavailability and stable blood drug level, clinical efficacy can be effectively improved, better dosage regimen and curative effect are provided for domestic and international diabetics。
Description
Technical field
The present invention relates to diabetes pharmaceutical technology field, the preparation technology of especially a kind of pioglitazone hydrochloride sustained-release pellet preparations。
Background technology
Diabetes (diabetes) be by inherited genetic factors, immunologic function disorder, microorganism infection and the various virulence factors of toxin, free radical toxin, Nervous and Mental Factors etc. thereof act on body cause hypoinsulinism, insulin resistant etc. and cause sugar, protein, fat, a series of metabolism disorder syndromes such as power and water Xie Zhi。Clinically with hyperglycemia for main feature, the performances such as model case may occur in which polyuria, polydipsia, polyphagia, become thin, i.e. three-many-one-little symptom；Diabetes (blood glucose), once control bad to 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 or 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 more than the 90% of patient populations。
Metformin hydrochloride is a kind of biguanides oral antidiabetic drug, for the treatment of non-insulin-dependent diabetes mellitus。This medicine mainly acts on and organizes outside islets of langerhans, it is suppressed that enterocyte absorbs glucose, increases the surrounding tissue sensitivity to insulin, increases non-insulin and relies on gluconeogenesis function of liver。The hypoglycemic activity of biguanides is independent of normal islet function and B cell, and is to increase 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。Such competitive peroxide activator enzyme paraphyte receptor of 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 changing insulin resistant and playing hypoglycemic activity, metformin hydrochloride and pioglitazone hydrochloride can improve insulin resistant from different approaches。When pioglitazone hydrochloride and metformin hydrochloride coupling, pioglitazone improves the tissue sensitivity to insulin so that the effect that the anerobic glycolysis of metformin hydrochloride raising surrounding tissue and increase surrounding tissue insulin are combined with its receptor better plays。The time limit of the two hypoglycemic activity supplements mutually, and curative effect is overlapped mutually, and side effect offsets。It is treat onset type Ⅱdiabetes mellitus especially to improve the good combination of insulin resistant。
Pellet capsule belongs to polydisperse system, each dosage is generally containing tens or hundreds of micropill, the slow-release tablet of micropill and a unit drug-supplying system is compared, there is the feature such as concise production process, drug loading big, 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 the research of compound sustained release capsules is relatively fewer, the domestic listing but without approval 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。
The patent document that number of patent application is 20101051.527.0 discloses a kind of pioglitazone hydrochloride and the compound preparation of metformin hydrochloride double-layer osmotic pump controlled-release tablet composition, include successively from the inside to the outside on structure forms: the label being made up of medicated layer and boosting layer, contagion gown layer, clothing film with 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 are not perfect, this invention also exists the feasibility problems of industrialized production, and the addition of propellant limits the content of every active medicine in double-layer osmotic pump tablet, need to take multi-disc day and can be only achieved effective dose, undesirable improving in patient medication compliance。
In view of the foregoing, now invent the preparation technology of a kind of pioglitazone hydrochloride sustained-release pellet preparations, obtained compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations is mixed with diabecron sustained-release micropill, sustained release and drug release behavior effect comparatively smoothly in vivo can be reached, stablizing of drug release behavior makes its bioavailability relatively improve, the compound recipe combination of two kinds of micropills makes its better efficacy, and poisonous side effect of medicine reduces, and hypoglycemic effect is better。Within one day, it is administered once and improves the compliance of patient, better dosage regimen and curative effect are provided for domestic and international diabetics。
Summary of the invention
The invention aims to overcome deficiency of the prior art, the preparation technology of a kind of pioglitazone hydrochloride sustained-release pellet preparations is provided, obtained compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations is mixed with diabecron sustained-release micropill, medicine blood drug level can be efficiently controlled, make blood drug level stable, and there is higher bioavailability, clinical efficacy can be improved, reduce medicining times, continual and steady blood sugar decreasing effect can be reached, compliance can also be improved, reduce untoward reaction。
The present invention to achieve these goals, adopts the following technical scheme that the preparation technology of a kind of pioglitazone hydrochloride sustained-release pellet preparations, and pioglitazone hydrochloride sustained-release micropill is made up of celphere, medicated layer and slow release layer three part；Medicated layer is made up of pioglitazone hydrochloride, binding agent, solubilizing agent；Slow release layer is made up of slow-release material and porogen；Set of weights amount percentage ratio is: celphere 70.2-83.3%, pioglitazone hydrochloride 13.0-28.6%, binding agent 1.4-2.0%, solubilizing agent 0.1-1.2%, slow-release material 3.8-13.0%, porogen 1.2-5.0%, above each component sum by weight ratio is 100%；
Described binding agent is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin one of which or several combinations；Described solubilizing agent is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate one of which or several combinations；Described slow-release material is crylic acid resin aqueous dispersion especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material one of which or several combinations；Described porogen is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate one of which or several combinations；
By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by hydrochloric acid pioglitazone pellet core being prepared by celphere medicine-feeding, pioglitazone hydrochloride pellet core is preheated, slow release layer coating solution is sprayed onto in pioglitazone hydrochloride pellet core, prepares hydrochloric acid pioglitazone slow-release micro-pill；
The preparation technology of pastille suspension: weigh pioglitazone hydrochloride crude drug, pastille alcoholic solution is prepared into EtOH Sonicate dissolving, the binding agent of described set of weights amount is dissolved in the water, binder aqueous solution adds the solubilizing agent of described set of weights amount, stirring and dissolving, alcohol water mixed solution is prepared into being slowly added in pastille alcoholic solution containing binding agent with the mixed aqueous solution of solubilizing agent, it is stirred while adding, alcohol water mixed solution high speed shear is homogenized 3-7min, prepares into pastille suspension；
The preparation technology of pellet core: the celphere of described set of weights amount is placed in fluidized-bed coating machine and is preheated to 35-45 DEG C, pre-thermal endurance is 4-8 minute, pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, celphere is added medicine to by pastille suspension, obtained pellet core is sieved, screens out the pellet core that particle diameter is 18～24 orders；
The preparation technology of slow release layer coating solution: slow-release material adding distilled water diluting and becomes the solution of solid content 8-12%, high speed shear homogenizes, adds porogen, prepares into slow release layer coating solution after stirring；
Taking standby pellet core to be placed in fluidized-bed coating machine and be preheated to 35-45 DEG C, pre-thermal endurance is 3-7 minute, is sprayed onto in pellet core by slow release layer coating solution and carries out coating, prepares hydrochloric acid pioglitazone slow-release micro-pill；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%。
The invention has the beneficial effects as follows: the diameter that micropill is made up of medicine and adjuvant is about the small shape entity of 1mm。Require to carry out drug ratio according to different treatments, the error in preparation of indivedual micropills or defect are unlikely to the drug release behavior of overall preparation is affected greatly, owing to there is bigger contact surface on medicine and gastrointestinal tract surface, absorb good and the zest of local is little, meanwhile, micropill is different from tablet, and the former is not substantially affected by the impact of gastric emptying factor, therefore the infiltration rate of medicine is uniform, individual bioavailability difference is little；Micropill has the advantage such as uniform particle sizes, good fluidity, not easily crushing, particularly fine pellet core surface coatings, to make location, slow release or controlled release preparation, technique simple, the coatings such as other solid preparations such as tablet can be avoided uneven, it is possible to cause the risk of medicine pulse；The compound capsule being made up of the micropill of different pharmaceutical, can increase the stability of medicine, improve curative effect, reduction poisonous side effect of medicine etc.。
Pioglitazone hydrochloride ordinary preparation, after oral administration, under fasting conditions, can measuring pioglitazone hydrochloride after 30 minutes in serum, within 2 hours, reach peak concentration, food can by peak concentration time retardation to 3～4 hour, then medicine quickly eliminates in vivo, 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。Medicine blood drug level can be efficiently controlled, make blood drug level stable, and there is higher bioavailability, clinical efficacy can be improved, reduce medicining times, continual and steady blood sugar decreasing effect can be reached, moreover it is possible to improve compliance, reduce untoward reaction。
Pioglitazone hydrochloride water solublity is bad, with Aquacoat product Sulisi (Surelease) the slow release layer coating material as pioglitazone hydrochloride, when being used alone, the rete permeance property formed is poor, cause that the release of medicine is slower, being easily caused again without adequate thickness prominent release too fast with drug release, 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, it is made to form aquation passage in clothing film thus improving clothing permeability of the membrane, pioglitazone hydrochloride sustained-release micropill is made to reach desirable drug release rate。
Pioglitazone hydrochloride is due to indissoluble in water, so adding a certain proportion of sodium lauryl sulphate in medicated layer, it is possible to improve drug release rate and the degree of slow-release micro-pill。
Obtained compound metformin hydrochloride pioglitazone hydrochloride sustained-release pellet preparations is mixed with diabecron sustained-release micropill, sustained release and drug release behavior effect comparatively smoothly in vivo can be reached, stablizing of drug release behavior makes its bioavailability relatively improve, 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, it is administered once and improves the compliance of patient, better dosage regimen and curative effect are provided for domestic and international diabetics。
Accompanying drawing explanation
Below in conjunction with accompanying drawing, the invention will be further described:
Fig. 1 is, 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
Pioglitazone hydrochloride sustained-release micropill is made up of celphere, medicated layer and slow release layer three part；Medicated layer is made up of pioglitazone hydrochloride, binding agent, solubilizing agent；Slow release layer is made up of slow-release material and porogen；Set of weights amount percentage ratio is: celphere 70.2-83.3%, pioglitazone hydrochloride 13.0-28.6%, binding agent 1.4-2.0%, solubilizing agent 0.1-1.2%, slow-release material 3.8-13.0%, porogen 1.2-5.0%, above each component sum by weight ratio is 100%；
Described binding agent is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin one of which or several combinations；Described solubilizing agent is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate one of which or several combinations；Described slow-release material is crylic acid resin aqueous dispersion especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material one of which or several combinations；Described porogen is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate one of which or several combinations；
By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by hydrochloric acid pioglitazone pellet core being prepared by celphere medicine-feeding, pioglitazone hydrochloride pellet core is preheated, slow release layer coating solution is sprayed onto in pioglitazone hydrochloride pellet core, prepares hydrochloric acid pioglitazone slow-release micro-pill；
The preparation technology of pastille suspension: weigh pioglitazone hydrochloride crude drug, pastille alcoholic solution is prepared into EtOH Sonicate dissolving, the binding agent of described set of weights amount is dissolved in the water, binder aqueous solution adds the solubilizing agent of described set of weights amount, stirring and dissolving, alcohol water mixed solution is prepared into being slowly added in pastille alcoholic solution containing binding agent with the mixed aqueous solution of solubilizing agent, it is stirred while adding, alcohol water mixed solution high speed shear is homogenized 3-7min, prepares into pastille suspension；
The preparation technology of pellet core: the celphere of described set of weights amount is placed in fluidized-bed coating machine and is preheated to 35-45 DEG C, pre-thermal endurance is 4-8 minute, pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, celphere is added medicine to by pastille suspension, obtained pellet core is sieved, screens out the pellet core that particle diameter is 18～24 orders；
The preparation technology of slow release layer coating solution: slow-release material adding distilled water diluting and becomes the solution of solid content 8-12%, high speed shear homogenizes, adds porogen, prepares into slow release layer coating solution after stirring；
Taking standby pellet core to be placed in fluidized-bed coating machine and be preheated to 35-45 DEG C, pre-thermal endurance is 3-7 minute, is sprayed onto in pellet core by slow release layer coating solution and carries out coating, prepares hydrochloric acid pioglitazone slow-release micro-pill；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%。
Claims (1)
1. the preparation technology of a pioglitazone hydrochloride sustained-release pellet preparations, it is characterised in that: pioglitazone hydrochloride sustained-release micropill is made up of celphere, medicated layer and slow release layer three part；Medicated layer is made up of pioglitazone hydrochloride, binding agent, solubilizing agent；Slow release layer is made up of slow-release material and porogen；Set of weights amount percentage ratio is: celphere 70.2-83.3%, pioglitazone hydrochloride 13.0-28.6%, binding agent 1.4-2.0%, solubilizing agent 0.1-1.2%, slow-release material 3.8-13.0%, porogen 1.2-5.0%, above each component sum by weight ratio is 100%；
Described binding agent is hypromellose, polyvidone, carboxymethyl cellulose, methylcellulose, ethyl cellulose, Polyethylene Glycol, sucrose solution, sodium alginate, gelatin one of which or several combinations；Described solubilizing agent is Polysorbate, sorbitan fatty acid ester, sodium lauryl sulphate one of which or several combinations；Described slow-release material is crylic acid resin aqueous dispersion especially strange, Aquacoat product Sulisi, cellulose acetate and matrix material one of which or several combinations；Described porogen is hypromellose, polyvinyl alcohol, sodium chloride, polyvidone, mannitol, lactose, sodium lauryl sulphate one of which or several combinations；
By pioglitazone hydrochloride, solubilizing agent and binding agent mix homogeneously, by hydrochloric acid pioglitazone pellet core being prepared by celphere medicine-feeding, pioglitazone hydrochloride pellet core is preheated, slow release layer coating solution is sprayed onto in pioglitazone hydrochloride pellet core, prepares hydrochloric acid pioglitazone slow-release micro-pill；
Weigh pioglitazone hydrochloride crude drug, pastille alcoholic solution is prepared into EtOH Sonicate dissolving, the binding agent of described set of weights amount is dissolved in the water, binder aqueous solution adds the solubilizing agent of described set of weights amount, stirring and dissolving, prepares into alcohol water mixed solution being slowly added in pastille alcoholic solution containing binding agent with the mixed aqueous solution of solubilizing agent, is stirred while addition, alcohol water mixed solution high speed shear is homogenized 3-7min, prepares into pastille suspension；
The celphere of described set of weights amount is placed in fluidized-bed coating machine and is preheated to 35-45 DEG C, pre-thermal endurance is 4-8 minute, pastille suspension at the uniform velocity stirs in magnetic stirring apparatus, celphere is added medicine to by pastille suspension, obtained pellet core is sieved, screens out the pellet core that particle diameter is 18～24 orders；
Slow-release material adding distilled water diluting and becomes the solution of solid content 8-12%, high speed shear homogenizes, and adds porogen, prepares into slow release layer coating solution after stirring；
Taking standby pellet core to be placed in fluidized-bed coating machine and be preheated to 35-45 DEG C, pre-thermal endurance is 3-7 minute, is sprayed onto in pellet core by slow release layer coating solution and carries out coating, prepares hydrochloric acid pioglitazone slow-release micro-pill；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%。
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| 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 |
| CN102058557A (en) * | 2009-11-18 | 2011-05-18 | 天津药物研究院 | Multicomponent sustained-release preparation and preparation method thereof |
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| 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 |
| CN102058557A (en) * | 2009-11-18 | 2011-05-18 | 天津药物研究院 | Multicomponent sustained-release preparation and preparation method thereof |
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