法莫替丁渗透泵制剂的研究
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摘要
法莫替丁(famotidine)是安全、有效的H_2受体拮抗剂类抗胃溃疡药。本文以法莫替丁为模型药物，研究制备了单层渗透泵控释片和双层渗透泵控释片两种缓控释制剂，并对它们的体内外释药行为及释药机理进行了初步的探讨。
本文研制的法莫替丁单层渗透泵控释制剂目前尚未见国内外报道。本文采用单因素试验法考察了多方面因素对于单层渗透泵控释片释药行为的影响。为解决难溶性药物单层渗透泵控释片释放度低的问题，采用柠檬酸改变渗透泵片半透膜内的微环境的pH值，增大了法莫替丁的溶解度，显著提高了释放度，从而达到了较好的控释效果。由于片芯中影响释放的因素较多，所以在单因素考察的基础上，采用正交实验设计优化了片芯处方，得到了体外零级释药特征显著(r=0.9926)的控释片。
在固定包衣工艺参数的条件下，对法莫替丁双层渗透泵控释片的片芯含药层、助推层，衣膜组成，制备工艺，和体外释药条件等因素进行了单因素考察。采用相似因子法判定不同因素对释药行为的影响，其结果表明，在实验考察的范围内，药层聚氧乙烯(PEON1)，助推层中聚维酮用量、聚氧乙烯(WSR1)用量和衣膜中PEG4000含量、膜重量对体外释药影响显著。而释药孔径、介质种类、转速、片芯硬度对于控释片的体外释药行为无显著影响。制得的双层渗透泵控释片释药完全，体外零级释药特征较为显著，重现性良好。
本研究参考有关文献并自己摸索，建立了法莫替丁体内血药浓度测定方法。采用高效液相色谱紫外检测法，对自制的法莫替丁单层渗透泵控释片和双层渗透泵控释片与法莫替丁的普通片进行了三交叉Beagle犬体内药物动力学评价。Beagle犬体内药动学研究结果表明，与市售普通片相比，自制两种控释片的达峰时间延长、峰浓度降低、药物在体内的平均滞留时间延长，达到了生物等效，体内外相关性良好(EOP∶r=0.9514，PPOP∶r=0.9444)。
Famotidine is a structurally safe and efficient antipeptie ulcer drug with H_(2-) receptor antagonists properties. In this paper, famotidine is used as the model drugs to prepare compound monolith osmotic tablet(EOP) and push-pull osmotic pump controlled release tablets(PPOP). Furthermore, the release behaviors of both drugs in vitro and in vivo and the mechanism of two types of controlled release tablets were elementarily studied.
Until now, there was no report about compound famotidine controlled release preparations in the research area of pharmacy. In this paper, compound famotidine controlled release tablets were developed. The effects of many factors including formulation of drug layers, arts of tablets and the condition of drug release on both drug release behaviors of monolith osmotic tablet were investigated, In general, both highly and poorly water-soluble drugs were not good candidates for elementary osmotic delivery. So, it was a great challenge to the pharmacists how to provide EOP with satisfactory controlled release behaviors of famotidine. In this paper, citric acid was used to modulate the solubility of famotidine within the core. In the paper , based on the investigation of factors analysis,orthogonal experiment designs were used to optimize the formulation. The results indicated that the drug release profiles of the optimal formulation had excellent zero-order release character in vitro(r=0.9926) from 0-24 hours.
Under the condition of constant coating parameters, single factor tests were carried out on the formulation of tablet core and coating material, procedure as well as the in vitro release condition ,which affect the release behavivor were analyzed by similar factor method. Results showed that the amount of PEO_(N1) of the drug layer , the amount of PVP and WSR1 in the assist layer, the amount and the kinds of PEG, the weight of coating all influence the drug release behavior ,while the diameter of orifice, the release medium and the method of dissolution had no significant effects. Hardness of tablet core also had no obvious effect on the release behavior of controlled release famotidine tablets. The results indicated that the drug release profiles had good zero-order release character and recuracy in vitro.
The method of detecting drug concentration in plasma was based on the reference and our own exploration. Using the conventional tablets as the references, the pharmacokinetic study of the self-made two kinds of controlled release tablets were performed in six healthy Beagle dogs. After three cross studies, the concentrations of both drugs in plasma of dogs administered with single dose were detected by HPLC methods. The results showed that, T_(max) and MRT of the self-made two kinds of controlled release tablets were delayed, C_(max) were plaied down. Good correlation existed between absorption percentage in vivo and release rate in vitro .
本文研制的法莫替丁单层渗透泵控释制剂目前尚未见国内外报道。本文采用单因素试验法考察了多方面因素对于单层渗透泵控释片释药行为的影响。为解决难溶性药物单层渗透泵控释片释放度低的问题，采用柠檬酸改变渗透泵片半透膜内的微环境的pH值，增大了法莫替丁的溶解度，显著提高了释放度，从而达到了较好的控释效果。由于片芯中影响释放的因素较多，所以在单因素考察的基础上，采用正交实验设计优化了片芯处方，得到了体外零级释药特征显著(r=0.9926)的控释片。
在固定包衣工艺参数的条件下，对法莫替丁双层渗透泵控释片的片芯含药层、助推层，衣膜组成，制备工艺，和体外释药条件等因素进行了单因素考察。采用相似因子法判定不同因素对释药行为的影响，其结果表明，在实验考察的范围内，药层聚氧乙烯(PEON1)，助推层中聚维酮用量、聚氧乙烯(WSR1)用量和衣膜中PEG4000含量、膜重量对体外释药影响显著。而释药孔径、介质种类、转速、片芯硬度对于控释片的体外释药行为无显著影响。制得的双层渗透泵控释片释药完全，体外零级释药特征较为显著，重现性良好。
本研究参考有关文献并自己摸索，建立了法莫替丁体内血药浓度测定方法。采用高效液相色谱紫外检测法，对自制的法莫替丁单层渗透泵控释片和双层渗透泵控释片与法莫替丁的普通片进行了三交叉Beagle犬体内药物动力学评价。Beagle犬体内药动学研究结果表明，与市售普通片相比，自制两种控释片的达峰时间延长、峰浓度降低、药物在体内的平均滞留时间延长，达到了生物等效，体内外相关性良好(EOP∶r=0.9514，PPOP∶r=0.9444)。
Famotidine is a structurally safe and efficient antipeptie ulcer drug with H_(2-) receptor antagonists properties. In this paper, famotidine is used as the model drugs to prepare compound monolith osmotic tablet(EOP) and push-pull osmotic pump controlled release tablets(PPOP). Furthermore, the release behaviors of both drugs in vitro and in vivo and the mechanism of two types of controlled release tablets were elementarily studied.
Until now, there was no report about compound famotidine controlled release preparations in the research area of pharmacy. In this paper, compound famotidine controlled release tablets were developed. The effects of many factors including formulation of drug layers, arts of tablets and the condition of drug release on both drug release behaviors of monolith osmotic tablet were investigated, In general, both highly and poorly water-soluble drugs were not good candidates for elementary osmotic delivery. So, it was a great challenge to the pharmacists how to provide EOP with satisfactory controlled release behaviors of famotidine. In this paper, citric acid was used to modulate the solubility of famotidine within the core. In the paper , based on the investigation of factors analysis,orthogonal experiment designs were used to optimize the formulation. The results indicated that the drug release profiles of the optimal formulation had excellent zero-order release character in vitro(r=0.9926) from 0-24 hours.
Under the condition of constant coating parameters, single factor tests were carried out on the formulation of tablet core and coating material, procedure as well as the in vitro release condition ,which affect the release behavivor were analyzed by similar factor method. Results showed that the amount of PEO_(N1) of the drug layer , the amount of PVP and WSR1 in the assist layer, the amount and the kinds of PEG, the weight of coating all influence the drug release behavior ,while the diameter of orifice, the release medium and the method of dissolution had no significant effects. Hardness of tablet core also had no obvious effect on the release behavior of controlled release famotidine tablets. The results indicated that the drug release profiles had good zero-order release character and recuracy in vitro.
The method of detecting drug concentration in plasma was based on the reference and our own exploration. Using the conventional tablets as the references, the pharmacokinetic study of the self-made two kinds of controlled release tablets were performed in six healthy Beagle dogs. After three cross studies, the concentrations of both drugs in plasma of dogs administered with single dose were detected by HPLC methods. The results showed that, T_(max) and MRT of the self-made two kinds of controlled release tablets were delayed, C_(max) were plaied down. Good correlation existed between absorption percentage in vivo and release rate in vitro .
引文
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[2] Mc Callum.KW, Chremos AN, Kuljian B et al. A novel histamine H2-receptor inhibitor with prolonged antisecretory effect..Dig Dis Sci, 1985, 30 (12) : 1139
[3] Smith JT, Gamal MA, Chremos AN et al. Effect on parietal, nonparietal, and pepsin secretion in man.. Dig Dis Sci, 1985, 30(4) : 308
[4] Langtry HD, Grand SM, Goa KL. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in peptic ulcer disease and other allied diseases. Drugs, 1989, 38(4): 551
[5] 陆彬．药物新剂型与新技术．北京：人民卫生出版社，1998，253-322
[6] F. Theeuwes, Elementary osmotic pump. J. Pharm. Sci. 64 (1975), 1987-1991
[7] Verma RK, Mishra B. Studies on formulation and evaluation of oral osmotic pumps of nimesulide. Pharmazie, 1999, 54: 74
[8] 甘勇．难溶性药物格列吡嗪渗透泵型控释片及流变与溶胀释药机理的研究．沈阳药科大学博士学位论文．2002，27-63
[9] Okimmoto K, Rajewski RA, Stella VJ, et al. Release of testosterone from an osmotic pump tablet utilizing (SBE)_(7m)-β-CD as both a solubilizing and an osmotic pump agent. J Control Release, 1999, 58:29
[10] Liu L, Khang G, Rhee JM, et al. Monolithic osmotic tablet system for nifedipine delivery. J Control Release, 2000, 67(2-3): 309
[11] Janicki S, Cichon R, Jedras Z, et al. Gastrointesting therapeutic system delivering of a insoluble
[12] 郎轶咏，李三鸣，徐璐．尼莫地平渗透泵型控释片的研制及释药影响因素考察[J]．沈阳药科大学学报，2004，21(3)：168-172．
[13] 丁雪鹰，高申，高静等．难溶性药物盐酸尼卡地平单室单层渗透泵片的制备[J]．中国药学杂志，2005，40(4)：286-288
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