| Objective: Diltiazem hydrochloride(DIL) is a benzothiazepine derivative with calcium-channel activity, which can prevent circadian angina pectoris. The main products in China are ordinary tablets, sustained-release tablets and injections. According to chronopharmacokinetics and the gastrointestinal pH in normal human subjects, the tablets in this paper were designed to time controlled release with a predetermined lag time by the method of multiply film-coated.Method: The systems consisted of a protected layer, a less water permeable layer and a fast disintegrate core tablet. Through the pre-experiment, the core of time-controlled release tablets of diltiazem hydrochloride (TCT-DIL) was designed. Based on the analysis of the factors which were relative to the lag time of TCT-DIL dissolved in phosphate buffer pH 6.8, the orthogonal experiment design L9(34)was used to select the less water permeable layer of TCT-DIL, which consisted of ethylcellulose, Eurdragit L100 S100, et al.The scanning electron photomicrographs of surfaces ofTCT-DIL were taken before and after dissolution.The content of diltiazem in TCT-DIL was determined by High-performance Liquid Chromatograph (HPLC) with Ultraviolet detector. Diltiazem hydrochloride was reference. The liquid chromatograph is equipped with a 240nm detector and a DIKMA C18 ( 4.6mm X 250mm,5um ) column. Mobile phase is a suitable filtered mixture of methyl alcohol-water(75:25). The flow rate is about 1.0ml per minute. The correlation of the linear range was good between 20 and 220 u g/ml, C =2.284677 X 10-5A-3.181635(n=5), r =0.9980.The column efficiency is not less than 3000 theoretical plates. The recoveries of external standard were 101.62%, 100.60%, 100.99%, respectively. RSD: 1.94%, 1.86%, 1.67%, respectively.Cylindrical basket method was employed in the experiment of dissolution test.The concentration of diltiazem in dissolution of TCT-DIL was determined at 240nm by Ultraviolet spectrophotometer. The best formulation and technology were obtained by terms of the speed of dissolution of TCT-DIL in phosphate buffer pH6.8.The optimal formation of TCT-DIL(60mg) and reference tablets(60mg) were given in a single dose to four healthy volunteers in a cross-over way. The diltiazem concentrations in plasma were determined by HPLC with Ultraviolet detector. The parameters were fitted and calculated by 3P87program. Diazepam was reference. Chromatograph system-trie liquid chromatograph is equipped with a 240nm detector and a DIKMA CIS ( 4.6mm X 250mm,5um ) column. Mobile phase is a suitable filtered mixture of acetonitrile-methyl alcohol-ammonium acetate solution(5:2:3).The flow rate is about 1.0ml per minute. The correlation of the linear range was good between 5 and 95ng/ml, C = 164.093613 As/Ai-8.903321,r=0.9990.The recoveries of reference solution were 98.98%, 99.56% and 101.00%, respectively.RSD:1.62%, 0.92% , 3.66%,respectively.The chemical and physical stability of the optimal formation of TCT-DIL was investigated, including stress testing (high humidity testing, optical testing, high temperature testing), accelerated testing and long-term testing.Results: The results of orthogonal experiment design were found. The lag time of TCT-DIL was mainly determined by composition of the less water permeable layer, that is the proportion of ethylcellulose and Eurdragit L100/S100. The amount of plastizer was important than the thickness of the less water permeable layer.The surface of TCT-DIL was no significant change when it was put into 0.1M HCL and into phosphate buffer pH 6.8. Some small cracks were found in the surface of TCT-DIL when it was put into phosphate buffer pH 7.2.The cumulative release percentage of diltiazem of TCT-DIL(60mg) in 0.1M HCL after 2 hours is less then 10% and in phosphate buffer pH6.8 after 4 hours is less then 10% .The cumulative release percentage in phosphate buffer pH7.2 after 6 hours is more then 75%.The parameter of TMAX and the lag time was significantly different (p<0.01) then control HEXINSHUANG, other...
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