天麻素固体缓控释制剂的研究
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摘要
本文以天麻素(Gastrodin)为模型药物，制备了天麻素缓释片、渗透泵型控释片，并利用流化床设备制备了天麻素缓释微丸。对天麻素渗透泵型控释片和缓释微丸进行了Beagle犬体内药物动力学研究。
采用单向灌流技术考察天麻素大鼠在体肠吸收性质。结果表明灌流速度对药物吸收速度常数(K_a)和药物表观吸收系数(P_(app))值有显著影响；药物浓度在15～150μg／ml范围内对K_a和P_(app)值无显著影响。天麻素在全肠道均有吸收；与其它肠段相比，天麻素在结肠的吸收量明显降低。
本文选用羟丙甲基纤维素(HPMC)、羧甲基纤维素钠(CMC-Na)等辅料，从处方因素和工艺因素方面详细考察了各种因素对天麻素缓释片释放行为的影响，并在此基础上制备了天麻素缓释片。
在固定包衣工艺参数的条件下，对天麻素渗透泵型控释片片芯组成、衣膜处方、制备工艺和体外释药条件等因素对天麻素渗透泵型控释片释药行为的影响进行了考察。影响因素实验结果表明：Nacl的用量、PEG的种类和用量、衣膜重量对天麻素渗透泵型控释片的体外释药行为有较大影响；而释药孔径、片芯硬度、释放介质种类、转速对天麻素渗透泵型控释片的体外释药行为影响较小。
在天麻素缓释微丸的处方研究中，以粉体学参数和产率为考察指标，采用Hasaan转换求得“归一值”，并对含药丸芯进行单因素考察，确定理想的含药丸芯处方和工艺参数。最后以Eudragit~(?)RS为骨架和包衣材料制备天麻素膜控骨架杂化型缓释微丸。
采用高效液相色谱法，对自制天麻素渗透泵型控释片、缓释微丸和市售普通片进行三交叉Beagle犬体内药物动力学评价。单剂量给药的实验结果表明：天麻素普通片、渗透泵片和缓释微丸的血药浓度曲线下面积AUC(μg·h／ml)分别为1043.76±215.49、1016.45±331.30和882.52±196.81；最大血药浓度C_(max)(μg／ml)分别为193.87±21.79、114.27±24.03和94.18±25.19；达峰时间T_(max)(h)分别为2.17±0.52、5.17±0.98和5.00±0.89；两种自制制剂相对生物利用度分别为97.20％和84.28％；生物等效性分析结果表明两种自制制剂和普通片均生物等效；体内外相关性判定表明两种自制制剂体内外相关性均良好(r=0.9890、0.9732)。
In this paper, gastrodin was selected as the model drug to prepare sustained-release tablets(ST), osmotic pump controlled-release tablets(OPT) and sustained-release pellets(SP). At last, the pharmacokinetic study of OPT and SP was performed.
The in situ rat intestinal absorption property of gastrodin was investigated by means of single-pass intestinal perfusion technque in order to supply biopharmaceutical bases for drug formulation design. The results showed that perfusion flow rate could significantly affect the values of K_a and P_(app); drug concentration ranged from 15 to 150 μg·ml~(-1) had no significantly effect on the values of Ka and Papp. Gastrodin can be ingested in the whole intestines and the absorption of it was good at the upper and middle intestinal segments while the absorption at the underpart was not so good as other parts.
In the formulation study of ST, HPMC, CMC-Na were used to make the tablets. The effects of many factors including formulation and technique on the release behavior of tablets were investigated. Based on the results of single factor tests, an optimal self-prepared ST was screened.
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 behavior of OPT. Results showed that the amount of NaCl, the amount and the kind 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
采用单向灌流技术考察天麻素大鼠在体肠吸收性质。结果表明灌流速度对药物吸收速度常数(K_a)和药物表观吸收系数(P_(app))值有显著影响；药物浓度在15～150μg／ml范围内对K_a和P_(app)值无显著影响。天麻素在全肠道均有吸收；与其它肠段相比，天麻素在结肠的吸收量明显降低。
本文选用羟丙甲基纤维素(HPMC)、羧甲基纤维素钠(CMC-Na)等辅料，从处方因素和工艺因素方面详细考察了各种因素对天麻素缓释片释放行为的影响，并在此基础上制备了天麻素缓释片。
在固定包衣工艺参数的条件下，对天麻素渗透泵型控释片片芯组成、衣膜处方、制备工艺和体外释药条件等因素对天麻素渗透泵型控释片释药行为的影响进行了考察。影响因素实验结果表明：Nacl的用量、PEG的种类和用量、衣膜重量对天麻素渗透泵型控释片的体外释药行为有较大影响；而释药孔径、片芯硬度、释放介质种类、转速对天麻素渗透泵型控释片的体外释药行为影响较小。
在天麻素缓释微丸的处方研究中，以粉体学参数和产率为考察指标，采用Hasaan转换求得“归一值”，并对含药丸芯进行单因素考察，确定理想的含药丸芯处方和工艺参数。最后以Eudragit~(?)RS为骨架和包衣材料制备天麻素膜控骨架杂化型缓释微丸。
采用高效液相色谱法，对自制天麻素渗透泵型控释片、缓释微丸和市售普通片进行三交叉Beagle犬体内药物动力学评价。单剂量给药的实验结果表明：天麻素普通片、渗透泵片和缓释微丸的血药浓度曲线下面积AUC(μg·h／ml)分别为1043.76±215.49、1016.45±331.30和882.52±196.81；最大血药浓度C_(max)(μg／ml)分别为193.87±21.79、114.27±24.03和94.18±25.19；达峰时间T_(max)(h)分别为2.17±0.52、5.17±0.98和5.00±0.89；两种自制制剂相对生物利用度分别为97.20％和84.28％；生物等效性分析结果表明两种自制制剂和普通片均生物等效；体内外相关性判定表明两种自制制剂体内外相关性均良好(r=0.9890、0.9732)。
In this paper, gastrodin was selected as the model drug to prepare sustained-release tablets(ST), osmotic pump controlled-release tablets(OPT) and sustained-release pellets(SP). At last, the pharmacokinetic study of OPT and SP was performed.
The in situ rat intestinal absorption property of gastrodin was investigated by means of single-pass intestinal perfusion technque in order to supply biopharmaceutical bases for drug formulation design. The results showed that perfusion flow rate could significantly affect the values of K_a and P_(app); drug concentration ranged from 15 to 150 μg·ml~(-1) had no significantly effect on the values of Ka and Papp. Gastrodin can be ingested in the whole intestines and the absorption of it was good at the upper and middle intestinal segments while the absorption at the underpart was not so good as other parts.
In the formulation study of ST, HPMC, CMC-Na were used to make the tablets. The effects of many factors including formulation and technique on the release behavior of tablets were investigated. Based on the results of single factor tests, an optimal self-prepared ST was screened.
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 behavior of OPT. Results showed that the amount of NaCl, the amount and the kind 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
引文
[1] 岑信钊．天麻的化学成分与药理作用研究进展．中药材[J]．2005．28(10)：958-962
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[2] 游金辉，谭天秩，匡安仁，钟裕国，何沙．3H—天麻甙元和3H—天麻素在小鼠体内的分布和代谢．华西医科大学学报[J]．1994，25(3)：325-328
[3] 岑信钊．天麻的化学成分与药理作用研究进展．中药材[J]．2005．28(10)：958-962
[4] Anon. W-Ayerst introduces naprelan in US. Scrip[J]. 1996, (2137): 21
[5] Anon. New product launches in the UK. Scrip[J]. 1996, (2181): 20
[6] Anon. Product news in brief: cystrin CR approved in Finland. Scrip [J]. 1997, (2280): 19
[7] Anon. First once-daily venlafaxine launched [J]. Scrip, 1997, (2266): 20
[8] 陈庆华．聚合物作为微丸包衣材料的应用研究[J]．中国医药工业杂志．1997，28(4)：191-194
[9] G S Isaac. Pharmaceutical Pelletization Technology. New York, Marcel Dekker, 1989:187-189
[10] G S Isaac. Pharmaceutical Pelletization Technology. New York, Marcel Dekker, 1989:145-146
[11] Garg S.Osmotically controlled oral drug delivery.Drug Dev Ind Pharm[J],2000, 26(7): 695-708
[12] Giancarlo Santus, Baker RW. Osmotic drug delivery: a review of the patent literature. J Control Release [J].1995, 35(1): 1-21
[13] Mcclelland GA, Sutton SC, Engle K, et al. The controlled porosity osmotic pump. Pharm Res[J]. 1991, 8:88
[14] Lindemulder B,Gupta SK.Singls-andmultiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCI) formulation.J Clin Pharmacol[J]. 2000, 48 (1): 71-78
[15] Esteban R,Bornancini ER.Effect of alkyl chain length and degree of substitution on the complexation of sulfoalkyl ether-β-cyclodextrin with steroids[J]. J Pharm Sci, 1997, 86(2): 220-224
[16] Jeong Ku, Bong Lee, John M.Rhee, et al. Nifedipine controlled delivery by sandwiched osmotic tablet system. J Control Release[J]. 2000, 68(3): 145-156
[17] F.Theeuwes Osmotic dispenser with gas generating means. US Patent[P]: 4036228,July 19,1977
[18] Herbig SM, Cardinal JR, Korsmeyer RW, et al. Asymmetric-membrane tablet coatings for osmotic drug delivery. J Control Release[J]. 1995, 35(1): 127-136
[19] Chen CM,Lee DY, Xie J. Conrolled release formulation for water insoluble drugs in which a passage-way is formed in situ[P]. US Patent: 5736159, 1998-04-07
[20] Gilson K. Monolithic osmotic tablet system for nifedipine. J Control Release[J]. 2000, 67(2): 309-322
[21] Jensen JL, Appel LE, Clair JH, et al. Variables that affect the mechanism of drug release from osmotic pumps coated with acrylate/methacrylate copolymer latexes. J Pharm Sci[J]. 1995, 84(5): 530
[22] 平其能，胡一桥，周建平，等．现代药剂学．第一版[M]．北京：中国医药工业出版社，2001
[23] Chilko D,Howard S.On the analysis of dissolution rate [J]. Drug Dev Ind Pharm,1986,12(7): 969-992
[24] Shah VP, Tsong Y, Sathe P, et al. In vitro dissolution profile comparison-statistics and analysis of the similarity factor, f_2 [J]. Pharm Res, 1998, 15(6): 889-896
[25] Gohel MC, Panchal MK. Novel use of similarity factors f_2 and Sd for the development of diltiazem HCL modified-release tablets using a 32 factorail design [J]. Drug Dev Ind Pharm, 2002, 28(1): 77-87
[26] Gabrielsson J, Nystrom A, Lundstedt T. Application of Multivariate analysis in pharmaceutical development work [J]. Drug Dev Ind Pharm, 2000, 26(3): 275-296
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