復(fù)方鹽酸二甲雙胍—格列齊特滲透泵膠囊的研究
發(fā)布時間：2019-01-26 10:55
【摘要】：糖尿病是一種需要終生治療的慢性疾病,在目前醫(yī)學(xué)水平下無法實現(xiàn)對其進行根治,給患者和全社會帶來了日益沉重的經(jīng)濟和醫(yī)療負擔(dān)。因此研發(fā)治療糖尿病的藥物,不僅可以滿足廣大糖尿病患者治療的需要,而且具有很好的市場前景。格列齊特與鹽酸二甲雙胍組成的復(fù)方制劑,二者作用機理互補,聯(lián)合應(yīng)用可加強降糖效果。鹽酸二甲雙胍格列齊特復(fù)合制劑避免了餐前餐后服藥的麻煩,患者順應(yīng)性更強。近年來緩控釋給藥系統(tǒng)由于其可改善患者用藥的安全性和順應(yīng)性在藥物研發(fā)中占重要地位。滲透泵制劑是以滲透壓為釋藥動力,零級釋放為動力學(xué)特征的一種制劑。與滲透泵片劑相比,滲透泵控釋膠囊劑優(yōu)勢明顯:制備工藝相對簡單,生產(chǎn)效率高;囊殼和內(nèi)容物可分別制備,便于工業(yè)化生產(chǎn)。目的:研究鹽酸二甲雙胍格列齊特滲透泵膠囊的處方和制備工藝,制備質(zhì)量穩(wěn)定的鹽酸二甲雙胍格列齊特滲透泵膠囊。方法:建立同時測定鹽酸二甲雙胍與格列齊特HPLC體外定量分析方法,同時測定鹽酸二甲雙胍與格列齊特。采用蘸膠法制備滲透泵膠囊殼,以相似因子f2為指標(biāo),對囊芯處方的鹽酸二甲雙胍含藥層、格列齊特含藥層、助推層,滲透泵膠囊殼組成及蘸膠次數(shù)進行進行單因素考察;根據(jù)單因素考察結(jié)果采用正交設(shè)計法進行處方優(yōu)化,對最優(yōu)處方進行處方驗證�？疾祗w外釋放條件對釋放影響,并對釋藥機理進行考察。參照中國藥典附錄要求對滲透泵膠囊殼進行質(zhì)量評價計初步穩(wěn)定性考察;分別建立鹽酸二甲雙胍與格列齊特HPLC體內(nèi)定量分析方法,對復(fù)方鹽酸二甲雙胍—格列齊特滲透泵膠囊進行Beagle犬體內(nèi)的藥動學(xué)研究。結(jié)果:(1)建立了鹽酸二甲雙胍與格列齊特HPLC體外定量分析方法,在所選定的色譜條件下,鹽酸二甲雙胍和格列齊特能達到良好分離且峰形良好,本方法能夠更準(zhǔn)確、有效、簡便地測定鹽酸二甲雙胍及格列齊特的含量。(2)經(jīng)單因素考察及正交優(yōu)化囊芯最優(yōu)處方為:PVP—K90用量為25mg,PEO wsr N-80用量為55mg,助推層PEOwsr-303用量為70mg,Na Cl的用量為35mg;滲透泵膠囊殼的處方和制備工藝為:CA濃度為8%(W/V),PEG6000為35%(w/w,占醋酸纖維素比重),TEC為2%(w/w,占醋酸纖維素比重),蘸膠三次,自然干燥。(3)所制備的滲透泵膠囊殼外觀整潔,無粘連、變形或破裂現(xiàn)象,色澤均勻,無斑點,無異臭,松緊度、脆碎度、干燥失重等均符合中國藥典要求。所制備滲透泵膠囊殼高溫及光照下外觀及柔韌性仍較好,但在高濕條件下膠囊殼會變?yōu)榘咨煌该鳡睢?4)在Beagle犬體內(nèi)的藥動學(xué)研究中,自制滲透泵制劑中鹽酸二甲雙胍及格列齊特血藥濃度較市售普通片劑平穩(wěn),Cmax低于普通制劑,Tmax增長,t1/2延長,MRT延長,體內(nèi)滯留時間延長,表明滲透泵制劑與市售普通片劑相比具有緩釋特性,可延長作用時間。結(jié)論:鹽酸二甲雙胍—格列齊特滲透泵膠囊的處方及工藝可行,膠囊殼質(zhì)量符合中國藥典要求,滲透泵膠囊穩(wěn)定性較好,鹽酸二甲雙胍—格列齊特滲透泵膠囊與市售普通片劑相比具有延長作用時間,有一定的緩釋作用,顯著提高了生物利用度。
[Abstract]:Diabetes is a chronic disease that requires life-long treatment, which can not be radically cured at present, and has brought an increasingly heavy economic and medical burden to both the patient and the whole society. therefore, the medicine for treating diabetes can not only meet the needs of the treatment of the patients with diabetes, but also has a good market prospect. The compound preparation, which is composed of gliclazide and dimethyldihydrochloride, is complementary to the mechanism of action, and the combined application can enhance the blood sugar-lowering effect. The compound preparation of the disibutalin hydrochloride avoids the trouble of taking the medicine after the pre-meal meal, and the patient has stronger compliance. In recent years, the slow-release drug delivery system has an important role in drug research and development because of its improved safety and compliance. the osmotic pump preparation is a preparation with the osmotic pressure as the drug release power and the zero order release as the kinetic characteristic. Compared with the osmotic pump tablet, the osmotic pump controlled-release capsule has the advantages of relatively simple preparation process and high production efficiency, and the capsule shell and the contents can be respectively prepared and are convenient for industrial production. Objective: To study the formulation and the preparation process of the capsules of the disibutrazil hydrochloride and the preparation of the capsules with stable quality. Methods: The quantitative method for the in vitro quantitative analysis was established for the simultaneous determination of dicyandiamide hydrochloride and glinzi by HPLC. The capsule shell of the osmotic pump was prepared by the dipping method, and the composition of the drug-containing layer, the drug-containing layer, the boosting layer, the capsule shell of the osmotic pump and the number of dipping glue were investigated by using the similar factor f2 as the index. According to the single factor, the orthogonal design method was used to optimize the prescription, and the prescription was verified by the prescription. The effect of in vitro release condition on the release was investigated, and the mechanism of drug release was investigated. The initial stability of the osmotic pump capsule shell was studied with reference to the appendix of the Chinese pharmacopoeia. The method of quantitative analysis was established in the method of the in-vivo quantitative analysis of the disimethine hydrochloride and the gatzitt HPLC, and the pharmacokinetics in Beagle dogs were studied. Results: (1) The method of in-vitro quantitative analysis was established for the method of the in-vitro quantitative analysis of dimethoxy-dicyandiamide hydrochloride and glinzitt. Under the selected chromatographic conditions, the dimethoxy-dicyandiamide hydrochloride and the gliclazide can be well separated and the peak-shape is good, and the method can be more accurate and effective, and the content of the dimethyl double-pass and the passing column of the hydrochloric acid is simply determined. (2) The optimal prescription of the single factor investigation and the orthogonal optimized capsule core is as follows: the dosage of PVP-K90 is 25mg, the dosage of PEO wsr N-80 is 55mg, the dosage of the boosting layer PEOwsr-303 is 70mg, the dosage of the Na Cl is 35mg, the prescription and the preparation process of the osmotic pump capsule shell are as follows: the CA concentration is 8% (W/ V) and the PEG6000 is 35% (w/ w, (the specific gravity of cellulose acetate), the TEC is 2% (w/ w, the specific gravity of cellulose acetate), the dipping glue is dipped for three times and is naturally dried. (3) The prepared osmotic pump capsule shell has the advantages of neat appearance, no adhesion, deformation or rupture, uniform color, no spot, no abnormal smell, tightness, friability, loss of drying, and the like, and meets the requirements of the Chinese pharmacopoeia. The prepared osmotic pump capsule shell has good appearance and flexibility under high temperature and light, but the capsule shell becomes white and opaque under the condition of high wet condition. (4) In the study of the pharmacokinetics of the Beagle dog, the concentration of the disimethin hydrochloride in the self-made osmotic pump preparation is stable, the Cmax is lower than that of the common preparation, the Tmax is increased, the t1/ 2 is prolonged, the MRT is prolonged, the retention time in the body is prolonged, It is shown that the osmotic pump preparation has a sustained-release characteristic compared with the conventional tablet sold in the market, and the working time can be prolonged. Conclusion: The formulation and process of the capsule of the disibutalin hydrochloride are in accordance with the requirements of the Chinese pharmacopoeia, the stability of the osmotic pump capsule is good, and the two-and-one-and-one-step osmotic pump capsules have an extended working time as compared with the conventional tablets sold in the market. has certain sustained-release effect, and the bioavailability is obviously improved.
【學(xué)位授予單位】：安徽中醫(yī)藥大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R943
[Abstract]:Diabetes is a chronic disease that requires life-long treatment, which can not be radically cured at present, and has brought an increasingly heavy economic and medical burden to both the patient and the whole society. therefore, the medicine for treating diabetes can not only meet the needs of the treatment of the patients with diabetes, but also has a good market prospect. The compound preparation, which is composed of gliclazide and dimethyldihydrochloride, is complementary to the mechanism of action, and the combined application can enhance the blood sugar-lowering effect. The compound preparation of the disibutalin hydrochloride avoids the trouble of taking the medicine after the pre-meal meal, and the patient has stronger compliance. In recent years, the slow-release drug delivery system has an important role in drug research and development because of its improved safety and compliance. the osmotic pump preparation is a preparation with the osmotic pressure as the drug release power and the zero order release as the kinetic characteristic. Compared with the osmotic pump tablet, the osmotic pump controlled-release capsule has the advantages of relatively simple preparation process and high production efficiency, and the capsule shell and the contents can be respectively prepared and are convenient for industrial production. Objective: To study the formulation and the preparation process of the capsules of the disibutrazil hydrochloride and the preparation of the capsules with stable quality. Methods: The quantitative method for the in vitro quantitative analysis was established for the simultaneous determination of dicyandiamide hydrochloride and glinzi by HPLC. The capsule shell of the osmotic pump was prepared by the dipping method, and the composition of the drug-containing layer, the drug-containing layer, the boosting layer, the capsule shell of the osmotic pump and the number of dipping glue were investigated by using the similar factor f2 as the index. According to the single factor, the orthogonal design method was used to optimize the prescription, and the prescription was verified by the prescription. The effect of in vitro release condition on the release was investigated, and the mechanism of drug release was investigated. The initial stability of the osmotic pump capsule shell was studied with reference to the appendix of the Chinese pharmacopoeia. The method of quantitative analysis was established in the method of the in-vivo quantitative analysis of the disimethine hydrochloride and the gatzitt HPLC, and the pharmacokinetics in Beagle dogs were studied. Results: (1) The method of in-vitro quantitative analysis was established for the method of the in-vitro quantitative analysis of dimethoxy-dicyandiamide hydrochloride and glinzitt. Under the selected chromatographic conditions, the dimethoxy-dicyandiamide hydrochloride and the gliclazide can be well separated and the peak-shape is good, and the method can be more accurate and effective, and the content of the dimethyl double-pass and the passing column of the hydrochloric acid is simply determined. (2) The optimal prescription of the single factor investigation and the orthogonal optimized capsule core is as follows: the dosage of PVP-K90 is 25mg, the dosage of PEO wsr N-80 is 55mg, the dosage of the boosting layer PEOwsr-303 is 70mg, the dosage of the Na Cl is 35mg, the prescription and the preparation process of the osmotic pump capsule shell are as follows: the CA concentration is 8% (W/ V) and the PEG6000 is 35% (w/ w, (the specific gravity of cellulose acetate), the TEC is 2% (w/ w, the specific gravity of cellulose acetate), the dipping glue is dipped for three times and is naturally dried. (3) The prepared osmotic pump capsule shell has the advantages of neat appearance, no adhesion, deformation or rupture, uniform color, no spot, no abnormal smell, tightness, friability, loss of drying, and the like, and meets the requirements of the Chinese pharmacopoeia. The prepared osmotic pump capsule shell has good appearance and flexibility under high temperature and light, but the capsule shell becomes white and opaque under the condition of high wet condition. (4) In the study of the pharmacokinetics of the Beagle dog, the concentration of the disimethin hydrochloride in the self-made osmotic pump preparation is stable, the Cmax is lower than that of the common preparation, the Tmax is increased, the t1/ 2 is prolonged, the MRT is prolonged, the retention time in the body is prolonged, It is shown that the osmotic pump preparation has a sustained-release characteristic compared with the conventional tablet sold in the market, and the working time can be prolonged. Conclusion: The formulation and process of the capsule of the disibutalin hydrochloride are in accordance with the requirements of the Chinese pharmacopoeia, the stability of the osmotic pump capsule is good, and the two-and-one-and-one-step osmotic pump capsules have an extended working time as compared with the conventional tablets sold in the market. has certain sustained-release effect, and the bioavailability is obviously improved.
【學(xué)位授予單位】：安徽中醫(yī)藥大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2016
【分類號】：R943
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