Study On The Controlled Release Tablets Of Sinomenine Hydrochloride

Object:Sinomenine(SM) main effective component in rhizome of orientvine stem of Menispermaceae in traditional Chinese medicine. It is present commonly used to cure rheumatism, rheumatoid arthritis, pyelonephritis, with its muriate used clinically. Because of its histamine release action and long treatment period. After a long-term administration, part of patients emerge pruritus, rubeosis, pain, aggravated engorge, and accompany with skin rash,sweating, stomachache, Stomach discomfort and so on. After administrating, the drug density in blood of ordinary enteric-coated tablet of SM is very slow in the initial stage, a quick release following, with drug density in blood suddenly heightening to appear a evident peak value.The characteristics of gel-matrix retard tablets of SM contain the stable rug density in blood in vivo reduced administration frequency and long persistence time. venenosusly adverse reaction in cinlical is obviouse and mainly show as comparatively grave gastrointestinal tract hypersensitive response, especially stimulus to stomach mucous membrane, while general external preparations are too hard to permeate skin into cavity or diseased region to get satisfactory therapeutic effect. so it is essential to develop pharmaceutics investigation to make up above-mentioned defects. How to ease adverse reaction and stimulus, on base of low administration frequency, so as to develop a high performance prolonged action low-toxic drug or preparation, is a extensively studied topic in recent years. Method:By means of SM as the model drug, Two different preparation technologies of SM enteric-coated controlled release preparation has been developed. gel-matrix retard enteric-coated controlled release tablets and enteric membrane-controlled release tablets. In the process of initial study of gel-matrix retard enteric-coated controlled release tablets, we progress single-factor investigation to prescription factors which has effects to its release, while in the process of initial study of enteric membrane-controlled release tablets, we adopt membrane-coated controlled and second order controlled release technology. First,by single-factor experiment, we take the blocking agent, loading agent, binding agent in tablet core and coating material, hole-digging agent, plastifier, antisticking agent in coating solution as influential factors. Subsequently, composite score with zero-order release correlation coefficient and release degree after being normalizated conduct as synthetic index. Even design was used to optimize the dosage of microcrystalline cellulose and ethyl cellulose which have notable effects to release degree of tablet core. Center compound design was used to optimize the ratio of coating material in coating solution and the dosage of hole-digging agent. Last, in condition of fixing the prescription of tablet core and coating solution, coating craft of membrane-coated controlled release tablets was progressed by single-factor investigation, as a result, a kind of simple, stable, feasible preparation craft of enteric membrane-controlled release tablets were achieved. We also initially studied the drug release mechanism and pathway in vitro. Adopting random crossover trial design, SM enteric-coated tablet as reference drug, with single dose schedule, pharmacokinetics and relative bioavailability in Beagles in vivo and its vivo-vitro dependability were researched.Result:In vitro experiment of releasing degree demonstrated that varieties and dosages of framework material HPMC, varieties of filler and its proportion have significant effects on releasing degree, on contrary, dosages of dextrin and varieties of adhesive material in the prescription have no significance on releasing degree of the enteric gel-matrix controlled-release tablets of SM, hence, the equation of Higuchi was fundamentally matched to the release profile of enteric gel-matrix controlled-release tablets in vitro, which was not according to zero level equation in constant speed. However, the dosages of filler Microcry Stalline Cellulose (MCC) and retarder Ethyl Cellulose (EC) in the enteric membrane-controlled release tablets have significant effects on releasing degree, at the same time, the increasing dosages of acrylic resins RL and intestine-dissolved adjuvant HPMCP in the coating solution, the increasing thickness of coating were correspondingly obviously declining its releasing rates of the enteric membrane-controlled release tablets, when thickness of coating and dosages of HPMCP reached to a certain degree, the release profile was consistent with zero level equation in vitro.The investigation on the rule of drug releasing of the enteric membrane-controlled release tablets in vitro indicated that drug releasing degree was sensitive to pH value of the medium, while stirring rates had no effect on drug releasing behavior. Curve model fitting of drug releasing and the research of drug releasing mechanism displayed that dynamics of drug releasing shows zero level equation, the pathway of this drug releasing mainly through port-hole which caused by intestine-dissolved adjuvant locating on the coat membrane, it also released by the permeability among tangle chains of coating material polymer, so we presumed the releasing mechanisms of enteric membrane-controlled release tablets of SM were mainly osmotic pump mechanism and distension.The experiment of pharmacokinetics of common enteric coated tablet and enteric membrane-controlled release tablets of SM in vivo of Beagle dog with single dose indicated that the relative bioavailability in enteric membrane-controlled release tablets were 86.0%, the pharmacokinetics parameters of test group and reference group were AUC0→1 (6839.906±563.215) h·μg/L vs (8566.049±1479.603) h·μg/L; Cmax(660.1±47.611)μg/L vs (1862.325±121.149)μg/L;Tmax(7.5±0.577) vs (4.375±0.25); Tlag (2.658±0.836) vs (2.042±0.201); MRT (15.00±1.27) vs (7.281±0.907), respectively. The one-way ANOVA and one-sided test were used for analyzing the data, the results indicated that there were no significant differences in AUC0→1, while significantly different in Cmax of both groups. However, the parameters of Tmax had no significant differences between test and reference group by analysis of the no-parametric test.As pharmacokinetics process in vivo of this preparation shown one compartment mode, calibration curve was constructed by linear regression percentage of accumulated releasing in vitro(Q%) verse absorption ratio in vivo (Fa) in the calibration curve with the method of Wagner-Nelson in this paper. The calibration curve was well linear with correlation coefficient(r=0.9545), there were satisfactory relativity between releasing experiment in vitro and absorption in vivo in the enteric membrane-controlled release tablets of SM. Hence, there is great significance for controlling the quality of drug preparation by using the releasing parameters in vitro to predict the dynamic rules of drug release in vivo.Conclusion:The drug releasing of the enteric membrane-controlled release tablets of SM in vitro was consistent with zero level equation, the surrounding environment had little effect on its releasing behavior, the preparation technology was stable and reproducible. Compared with the common enteric coated tablets, the enteric membrane-controlled release tablets could reduce the administration frequency, prolong its half-life period and significantly reduce the fluctuated degree, meanwhile, had the satisfactory relativity both in vivo and in vitro, it could also predict the basic drug absorption in vivo through the information of drug releasing in vitro. As this enteric membrane-controlled release tablets of SM reached the expecting result of well controlled releasing, it could be used generally and industrialized production in future.