粉防己碱海藻酸钙缓释凝胶小球的研制
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摘要
目前，海藻酸钠与二价钙离子交联反应形成的海藻酸钙凝胶小球作为药物的载体日益受到广泛的应用。本文以中药钙拮抗剂粉防己碱(tetrandrine,TET)为模型药，制备了TET海藻酸钙凝胶小球；并以丙烯酸树脂Eudragit RS 30D和Eudragit RL 30D作为衣膜材料，采用流化床包衣技术制备了TET缓释凝胶小球；通过体内、外分析方法对其进行了较为科学、准确的评价。本文主要进行了以下几个方面的研究：
(1)建立了紫外分光光度法用于TET的基本理化性质、制剂含量、体外释放度的考察；建立了高效液相色谱法考察原料药的初步稳定性、TET溶液稳定性及体内血药浓度的检测；首次建立原子发射光谱法用于研究海藻酸钙凝胶小球的释放机制。以上方法专属性强、灵敏度高、方便快捷，符合各项分析研究的要求。
(2)首次采用了酸性染料比色法研究大鼠在体肠吸收情况。初步推断TET在小肠中的吸收动力学为一级吸收，TET在大鼠体内主要以被动扩散方式吸收，这为剂型设计提供了前提和依据。
(3)在处方设计前工作中，对与口服固体缓释制剂设计相关的原料药的理化性质进行了考察。测定了TET在水、0.1mol／L盐酸及pH6.8磷酸盐缓冲液(PBS)中的平衡溶解度(37℃)和不同pH值下正辛醇／水系统中的表观油／水分配系数P_(app)；原料药初步稳定性考察表明了TET对热、水分、空气稳定，对光有所不稳定；TET的水、0.1mol／L盐酸和pH6.8磷酸盐缓冲溶液在24h内稳定。
(4)制剂学方面分为两部分：首先，以包封率、载药量、药物释放度及粉体学性质为质量指标，对海藻酸钙凝胶小球处方和工艺因素进行了单因
沈阳药科大学硕士学位论文 摘要
素考察，在此基础上通过Lg（3’）正交设计筛选出最优处方。其次，采用
流化床包衣技术，在单因素考察的基础上通过全面搭配试验筛选出符合要
求的包衣液处方，进行包衣达到了预期日服两次的缓释目的。缓释凝胶小
球体外释放行为符合non－Fickian扩散释放机制，骨架溶蚀机制起主导作用。
（）本文考察了海藻酸钠的基本理化性质，测定了海藻酸钠的含量为
96．13％，特性粘度和平均摩尔质量分别为 0．1916Pa．s和 3．10x10’，GM值
为0．65，为海藻酸钙凝胶小球作为药物载体的基础研究提供了依据。
K）家犬药物动力学研究表明自制TET海藻酸钙凝胶小球在体内具有
明显的缓释效果，血药浓度平稳，达峰时间滞后，Tm。和C＿分别为5石7h。
2．75ng／L，相对生物利用度为106．13％，体内外相关性良好（，0．9798人
Calcium alginate gel beads were widely used as drug carriers, which were obtained by the gelation of sodium alginate with divalent cation as Ca2+. Tetrandrine (TET), the calcium antagonists of Traditional Chinese Medicine, was selected as model drug to prepare calcium alginate gel beads. The coating process was performed on a fluid bed spray coater with Eudragit RS 30D and Eudragit RL 30D as the coating materials. The researches made were as follows:
(1) Ultraviolet (UV) spectrophotometry method was developed for determination of physicochemical properties, content and drug release; High-performance liquid chromatography (HPLC) method with UV detection was applied to detect the stability of TET powder and solution as well as the plasma concentration of TET in dogs. Atomic emission spectrometry (AES) method was firstly adopted to study the release mechanism of calcium alginate. Analytical methods above were precise, simple and reliable.
(2) Acid-dye colorimetric method was firstly applied to study the absorption of TET from intestine by utilizing intestinal absorption experiment of rats in situ. The results suggested that the intestinal absorption of TET was suitable for first-order kinetics via passive transport mechanism.
(3) In the preformulation research the physicochemical properties of TET were investigated, which were connected closely with dosage form design. Equilibrium solubility(37 C)in distilled water, 0.1mol/L hydrochloric acid (HC1), pH6.8 phosphate buffer solution (PBS) and apparent oil-water partition coefficient in different pH value were determined relatively. Exposed to temperature, moisture and oxygen except light, the content of TET remained unchanged. And the stability of TET in water, 0.1mol/L HC1 and pH6.8 PBS
were good within 24 hours.
(4) The preparation design was divided into two parts. The influences of formulation and manufacture on the entrapment efficiency, degree of circularity and drug release of gel beads were studied firstly, and orthogonal test was used to optimize the formulation. Then based on the studies of coating factors, the coating formulation was obtained by full design test. The way of TET released from gel beads could be described as non Fickian diffusion, which was mainly by matrix erosion.
(5) To study the physicochemical parameters of sodium alginate, the content, intrinsic viscosity , average molecular weight and G/M value were determined, which were 96.13%, 0.1916Pas-1, 3.10+105 and 0.65, respectively.
(6) The studies of pharmacokinetics in dogs indicated that the desired purpose of sustained release was achieved. Plasma concentration maintained relatively constant for more than 12 hours. Its relative bioavailability was 106.13%. The release of sustained released gel beads in vitro was correlative with absorption fraction in vivo well.
(1)建立了紫外分光光度法用于TET的基本理化性质、制剂含量、体外释放度的考察；建立了高效液相色谱法考察原料药的初步稳定性、TET溶液稳定性及体内血药浓度的检测；首次建立原子发射光谱法用于研究海藻酸钙凝胶小球的释放机制。以上方法专属性强、灵敏度高、方便快捷，符合各项分析研究的要求。
(2)首次采用了酸性染料比色法研究大鼠在体肠吸收情况。初步推断TET在小肠中的吸收动力学为一级吸收，TET在大鼠体内主要以被动扩散方式吸收，这为剂型设计提供了前提和依据。
(3)在处方设计前工作中，对与口服固体缓释制剂设计相关的原料药的理化性质进行了考察。测定了TET在水、0.1mol／L盐酸及pH6.8磷酸盐缓冲液(PBS)中的平衡溶解度(37℃)和不同pH值下正辛醇／水系统中的表观油／水分配系数P_(app)；原料药初步稳定性考察表明了TET对热、水分、空气稳定，对光有所不稳定；TET的水、0.1mol／L盐酸和pH6.8磷酸盐缓冲溶液在24h内稳定。
(4)制剂学方面分为两部分：首先，以包封率、载药量、药物释放度及粉体学性质为质量指标，对海藻酸钙凝胶小球处方和工艺因素进行了单因
沈阳药科大学硕士学位论文 摘要
素考察，在此基础上通过Lg（3’）正交设计筛选出最优处方。其次，采用
流化床包衣技术，在单因素考察的基础上通过全面搭配试验筛选出符合要
求的包衣液处方，进行包衣达到了预期日服两次的缓释目的。缓释凝胶小
球体外释放行为符合non－Fickian扩散释放机制，骨架溶蚀机制起主导作用。
（）本文考察了海藻酸钠的基本理化性质，测定了海藻酸钠的含量为
96．13％，特性粘度和平均摩尔质量分别为 0．1916Pa．s和 3．10x10’，GM值
为0．65，为海藻酸钙凝胶小球作为药物载体的基础研究提供了依据。
K）家犬药物动力学研究表明自制TET海藻酸钙凝胶小球在体内具有
明显的缓释效果，血药浓度平稳，达峰时间滞后，Tm。和C＿分别为5石7h。
2．75ng／L，相对生物利用度为106．13％，体内外相关性良好（，0．9798人
Calcium alginate gel beads were widely used as drug carriers, which were obtained by the gelation of sodium alginate with divalent cation as Ca2+. Tetrandrine (TET), the calcium antagonists of Traditional Chinese Medicine, was selected as model drug to prepare calcium alginate gel beads. The coating process was performed on a fluid bed spray coater with Eudragit RS 30D and Eudragit RL 30D as the coating materials. The researches made were as follows:
(1) Ultraviolet (UV) spectrophotometry method was developed for determination of physicochemical properties, content and drug release; High-performance liquid chromatography (HPLC) method with UV detection was applied to detect the stability of TET powder and solution as well as the plasma concentration of TET in dogs. Atomic emission spectrometry (AES) method was firstly adopted to study the release mechanism of calcium alginate. Analytical methods above were precise, simple and reliable.
(2) Acid-dye colorimetric method was firstly applied to study the absorption of TET from intestine by utilizing intestinal absorption experiment of rats in situ. The results suggested that the intestinal absorption of TET was suitable for first-order kinetics via passive transport mechanism.
(3) In the preformulation research the physicochemical properties of TET were investigated, which were connected closely with dosage form design. Equilibrium solubility(37 C)in distilled water, 0.1mol/L hydrochloric acid (HC1), pH6.8 phosphate buffer solution (PBS) and apparent oil-water partition coefficient in different pH value were determined relatively. Exposed to temperature, moisture and oxygen except light, the content of TET remained unchanged. And the stability of TET in water, 0.1mol/L HC1 and pH6.8 PBS
were good within 24 hours.
(4) The preparation design was divided into two parts. The influences of formulation and manufacture on the entrapment efficiency, degree of circularity and drug release of gel beads were studied firstly, and orthogonal test was used to optimize the formulation. Then based on the studies of coating factors, the coating formulation was obtained by full design test. The way of TET released from gel beads could be described as non Fickian diffusion, which was mainly by matrix erosion.
(5) To study the physicochemical parameters of sodium alginate, the content, intrinsic viscosity , average molecular weight and G/M value were determined, which were 96.13%, 0.1916Pas-1, 3.10+105 and 0.65, respectively.
(6) The studies of pharmacokinetics in dogs indicated that the desired purpose of sustained release was achieved. Plasma concentration maintained relatively constant for more than 12 hours. Its relative bioavailability was 106.13%. The release of sustained released gel beads in vitro was correlative with absorption fraction in vivo well.
引文
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[2] 张钧寿．缓／控释制剂的国外研究动向．中国新药杂志，1996，5(3)：161-163．
[3] 平其能．口服缓释及控释制剂发展动态．药学进展，1995，19(3)：140-143．
[4] 陆彬主编．药物新剂型与新技术．北京：人民卫生出版社，1998，2．
[5] 崔福德主编．药剂学．北京：中国医药科技出版社，2002，511．
[6] Fiona A. Johnson, Duncan Q. M. Craig, Amanda D. Mercer. Characterization of the block structure and molecular weight of sodium alginate. J. Pharm. Pharmacol., 1997, 49 (7): 639-643.
[7] 何林，蒋学华，李屯．粘膜给药系统质量评价．中国药学杂志，1998，33(2)：68-72．
[8] 马萍，孙淑英．一种新的缓释载体-海藻酸钙小球的研究概况．国外医药-合成药、生化药、制剂分册，1998，19(3)：190-194．
[9] S. Al-Musa, D. Abu Fara, A. A. Badwan. J. controlled Release, 1999, 57 (3): 223-232.
[10] Tone Qsteberg, Ellen Marie Lund, Christina Graffer. Int. J. Pharm., 1994, 112 (3): 241-243.
[11] Huang Renjie. Strait Pharmaceueical J., 2001, 13 (1): 11-12.
[12] Sumihiro Shiraishi, Terukolmai. Biol. Pharm. Bull., 1993, 16(11): 1164-1168.
[13] 冯鹏，王亦农，马建林．肽类药物口服剂型材料及控制释放性能研究．离子交换与吸附，1999，15(1)：64-70．
[14] D. Lemoine, F. Wauters, S. Bouehend. Int. J. Pham., 1998, 176 (1): 9-19.
[15] 吴雪梅，邓意辉．阿霉素海藻酸钙凝球微丸的释放性．沈阳药科大学学报．1998，15(4)：279-280．
[16] 全国钙拮抗剂临床应用进展专题研讨会记要．中华心血管病杂志．1996，24(2)：85-87．
[17] 王序．现代生物分析法对常用中药的筛选．北京医科大学学报，1986，18(1)：31-33．
[18] Ichikawak. Chem. Pham. Bull., 1989, 37 (2): 345-350.
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