| Levodopa(LD)is a drug in the treatment of Parkinson’s disease.Because its absorption site is mainly in the stomach and the proximal small intestine,it can be fully absorbed by prolonging the residence time.The combination of benserazide hydrochloride with levodopa to inhibit decarboxylation and increase the concentration of levodopa in the central system.LD and benserazide hydrochloride were used as model drugs in this study.Single factor experiments were conducted to investigate the effects of core formulation and coating formulation on the drug release behavior of microporous osmotic pump capsules.The quality and pharmacokinetics of the capsules were also evaluated.The formulation of levodopa controlled-release granule(a capsule)was determined as follows:levodopa 100 mg,penetration enhancersodium chloride 80mg,lactose 20 mg,bleachercetyl alcohol 40 mg,8%PVP eth anol solution as binder,adding appropriate amount of binder into the above mixed excip ients to make soft material,then granulated by 24 mesh sieve.The levodopa granules were obtained by drying at 30℃for 4 h and sieved through 20 mesh.At the same time,the formulation of benserazide hydrochloride granules(a capsule)was determined as follows:28.5mg benserazide hydrochloride(equivalent to 25.0 mg benserazide),10 mg stearic acid as a blocking agent,8%PVP ethanol solution as a bi nder,an appropriate amount of binder was added to the above mixed excipients to make soft material,then granulated by 24 mesh,dried at 30℃for 4 h,sieved through 20 mesh to obtain benserazide granules.The above two kinds of granules were mixed according to the ratio of main drug content of 4:1,and added into 0~#capsule shell.The coating material was 6%cellulose acetate acetone solution,the amount of porogen poloxamer 188was 60%(based on the weight of CA,w/w),the coating weight was increa sed by12%,and the capsule was coated with a coating pot to prepare the gastric floating microporous osmotic pump controlled-release capsule of levodopa and benserazide hydrochloride,which made levodopa and benserazide hydrochloride release simultaneously.The mathematical model fitting showed that the drug release behavior of the preparation was close to zero order release characteristics,and the goodness of fit R~2 was 0.993.At the same time,this paper also prepared the gastric floating microporous osmotic pump capsule with ethyl cellulose as coating material.Using thein vitrocumulative release as an indicator,the factors such as porogen and weight gain of the coating were investigated.The optimal formulation of coating solution was determined as follows:the coating material was6%ethyl cellulose(EC)ethanol solution(by volume of absolute ethanol,w/v),the amount of porogen polyvinylpyrrolidone(PVP)was 60%(by weight of EC,w/w),and 15%coating weight.The cumulative release rate reached 97%af ter 12 h.By comparison,the free membrane prepared with C A as coating material was more tenacious,and the coating membrane remained intact after 12 hours of dissolution.Therefore,CA was used as coating material to prepare osmotic pump capsules.The pharmacokinetics of levodopa and benserazide hydrochloride gas tric floating microporous osmotic pump controlled-release capsules was studied in beagle dogs with commerical tablets as reference preparation.The plasma concentration of levodopa and benserazide hydrochloride was determined by HPLC.The AUC of levodopa was 69.31±3.61(μg·h/ml)and 28.87±2.58(μg·h/ml)in the self-made capsule and commerical tablet,respectively.The Cmax was 7.84±0.3 4(μg/ml)and9.21±1.04(μg/ml),respectively.The relative bioavailability was(267.55±34.54)%.The results of pharmacokinetic study in dogs showed that the preparation had better sustained-release effect and higher relative bioavailability compared with the commercial tablets. |
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