秋水仙碱口服缓控释剂型研究
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摘要
秋水仙碱作为治疗痛风急性发作的特效药应用历史悠久,但其治疗指数范围窄(血药浓度为0.5～3ng·ml~(-1)),临床需频繁服用且常见胃肠道毒副反应,患者用药顺应性差;目前其口服上市产品仅有普通片剂,国内外均未见其口服新型给药系统的研究报道。若将其制成口服缓控释制剂则有望在保持药效的同时减少毒副反应、使患者乐于用药。
目的:本文以临床治疗急性痛风有特效而毒性较大的秋水仙碱为模型药物,拟选取三种代表性的缓控释给药技术将其制成新型口服制剂(渗透泵控释片、亲水凝胶骨架片、胃滞留缓释片),通过体内外综合比较和评价,优选出能够兼顾患者用药顺应性和生物利用度的新剂型。为秋水仙碱新型口服给药系统的开发奠定基础,也为此类药物口服缓控释制剂的研究提供参考。
方法:重点比较不同剂型的体外释药行为及其口服后的药物动力学参数和生物利用度差异,将体外释放度和体内药动学相结合进行综合评价。
1.考察秋水仙碱的体内外分析方法以及相关制剂含量测定和体外释放度测定方法。
2.测定秋水仙碱溶解度;采用大鼠在体肠段单向灌流技术考察秋水仙碱的肠吸收特性;比较常用亲水性高分子辅料的黏度、吸水膨胀和溶蚀等特性,以便为后期各剂型处方工艺研究奠定基础。
3.分别通过单因素考察筛选出影响体外释药行为的主要处方和工艺因素,经正交或均匀设计优化以上因素,确定渗透泵控释片、亲水凝胶骨架片以及胃滞留缓释片的处方工艺参数。
4.测定三种制剂的体外释放度,考察影响体外释药行为的主要因素,明确体外释药机制。
5.以LC-MS法测定并比较Beagle犬口服秋水仙碱市售片和三种制剂后的体内生物利用度和药物动力学参数。
结果
1.建立了简便、准确、可靠的RP-HPLC法用于分析秋水仙碱样品,并以《中国药典(2005版)》所载小杯法测定制剂的体外释放度。
2.秋水仙碱微溶于水,其溶解度随介质pH值和渗透压而变化较大;秋水仙碱在大鼠各肠段均有不同程度的吸收但在结肠段吸收较差,其吸收速率小、且不具有浓度依赖性;不同种类或同类而聚合度不同的高分子材料,其黏度、吸水后的膨胀性能以及在水中的溶蚀速率存在差异。
3.采用聚氧乙烯为主要片芯辅料制成的秋水仙碱推拉渗透泵控释片的体外释药零级特征显著(2～16h,r=0.9942,F_(16)＞90%)。含替代辅料的新处方的释药行为零级特征也较显著(2～16h,r=0.9956,F_(16)＞80%)。该制剂的体外释药几乎不受环境因素影响,释药机制以膨胀压和渗透压差为主。
4.采用两种规格聚氧乙烯为亲水凝胶材料制成的骨架片的体外释药速率为7.27%·h~(-1),释药完全,但释药行为易受环境因素影响。其释药机制是凝胶扩散和骨架溶蚀协同作用的结果。
5.秋水仙碱胃滞留片的缓释特征显著,体外释药过程包括扩散和溶蚀机制,其良好的漂浮性能源于处方所含的泡腾剂以及聚氧乙烯凝胶材料产生的“静水动力平衡系统”,其胃滞留性能依赖于系统的体积膨胀和漂浮性能。
6.三种剂型的血药浓度波动程度和相对生物利用度大小顺序依次为:渗透泵片＜骨架片＜胃滞留片。前两者虽然血药浓度更平稳,但因错过了最佳吸收部位而与普通片剂不等效。后者较长时间滞留胃内同时缓慢释药,能兼顾安全和有效性。
结论:综上,胃滞留缓释片的处方和工艺较为简便,体外释药较稳定且完全,体内血药浓度较快达到有效限度、波动较小、能更长时间维持在治疗指数范围内,且相对生物利用度较高,因此相对渗透泵控释片和亲水凝胶骨架片更适于秋水仙碱的口服缓控释给药。即将秋水仙碱研制成胃滞留缓控释给药系统可望提高患者用药顺应性、确保临床用药安全有效。
创新点
1.初步比较了常用亲水性高分子辅料的吸水膨胀和溶蚀性能;
2.制备了秋水仙碱口服渗透泵控释片、亲水凝胶骨架片和胃滞留缓释片,并分别考察了体外释放度和释药机制,比较其犬体内药物动力学特性。
3.优选出胃滞留缓控释给药系统为秋水仙碱口服制剂研发的适宜剂型。
Colchicine has been used for centuries in acute gout arthritis,its therapeutics index is very narrow(0.5～3ng·ml~(-1)),but it need frequent administration and usually shows side effects in gastrointestinal tract and poor patient-compliance.Common tablet is the only oral dosage form in market and there is no literature about oral drug delivery systems(DDS) till now.Fewer adverse reactions and better patient-compliance would be expected if we develop colchicine into oral sustained/controlled release system.
Aims:
Three new oral dosage forms of colchicine will be prepared by modern drug delivery technology,be compared and evaluated by in vitro and in vivo test,and one of them will be choosed to be the most preferred dosage form for colchicine.We hope to build foundation for new oral DDS development of colchicine and to offer reference for similar research.
Methods:
The drug release profile,pharmacokinetic parameters and bioavailability of three different dosage forms were compared and evaluated by drug release in vitro and pharmacokinetic parameters in vivo.
1.Methods for sample assay and drug release test in vitro were established.
2.Solubility and absorption properties of colchicine were studied by single-pass intestinal perfusion technique in rats.Viscosity,swelling and erosion properties of hydrophilic polymer commonly used were tested as the basis for formulation and process design.
3.The formulations and process of three dosage forms were studied by single-factor test and optimized by orthogonal or uniform design.
4.Drug relase profiles in vitro,key influencing factors and release mechanism of three preparations were studied.
5.The pharmacokinetic parameters and bioavailability of common tablet and three different preparations in Beagle dogs were studied by LC-MS.
Results:
1.RP-HPLC methodology for analysis of colchicine samples was established with appropriate convenience and accuracy.The cup method in Chinese Pharmacopoeia(Edition 2005) was adopted for in vitro release test of colchicine preparations.
2.Colchicine is sparingly soluble in water and its solubility changed markedly in solvents with different pH and osmotic pressure.Colchicine absorbed in whole rat intestinal and lactose improved its absorption,its absorption rate constant(K_a) were jejunum＞duodenum＞ileum＞colon,and were independent of the concentrations of colchicine in perfusion.Polymers with different units and polymerization degree differed in viscosity,swelling and erosion properties in water.
3.Colchicine osmotically controlled release tablets with PEO as main core ingredients showed excellent zero-order release profile in vitro(2～16h,r=0.9942, F_(16)＞90%),and the new formulation with alternative excipients as well(2～16h, r=0.9956,F_(16)＞80%).Its drug release profile can hardly influenced and drug release mechanism based on swelling pressure and osmotic pressure.
4.Colchicine hydrogel matrix tablet composed of PEO released drug completely with the rate of 7.27%·h~(-1).Its release profile can be influenced and drug release mechanism was the result of matrix erosion and gel diffusion.
5.Colchicine gastro retentive tablet showed markedly sustained-release characteristics with the mechanism of diffusion and erosion.Its floating property was based on the effervescent agents and PEO as "hydrodynamically balanced systems", and its gastric retention ability relied on size expanding and system floating properties.
6.The drug concentration fluctuation in plasma and relative bioavailability of three dosage forms showed bellowed:osmotic-pump tablet＜matrix tablet＜gastro retentive tablet.The former two showed more steady plasma drug concentration but not bioequivalent with common tablet,and the latter showed prolonged gastric retention time and was more safe and effective.
Conclusions:
Taken together,the results suggest that gastro retentive sustained-release tablet is more acceptable dosage form for oral sustained/controlled delivery of colchicine than osmotic-pump tablet and hydrogel matrix tablet,in which its formulation and process being more convenient,drug release in vitro being more complete,drug concentration in plasma being more steady and keeping longer period in range of therapeutic index,higher relative bioavailability in vivo.In other words,gastro retentive delivery system of colchicine is expected to improve patient-compliance and to be more safe and effective clinically.
Innovations:
1.Swelling and erosion properties of common hydrophilic polymers in water were compared initially.
2.Osmotically controlled-release tablets,hydrogel matrix tablets and gastro retentive sustained-release tablets of colchicines were prepared,their drug release mechanism in vitro were discussed,their relative bioavailability and pharmacokinetic parameters were studied.
3.Gastro retentive drug delivery system was found to be the best dosage form for research and development of oral products for colchicine.
目的:本文以临床治疗急性痛风有特效而毒性较大的秋水仙碱为模型药物,拟选取三种代表性的缓控释给药技术将其制成新型口服制剂(渗透泵控释片、亲水凝胶骨架片、胃滞留缓释片),通过体内外综合比较和评价,优选出能够兼顾患者用药顺应性和生物利用度的新剂型。为秋水仙碱新型口服给药系统的开发奠定基础,也为此类药物口服缓控释制剂的研究提供参考。
方法:重点比较不同剂型的体外释药行为及其口服后的药物动力学参数和生物利用度差异,将体外释放度和体内药动学相结合进行综合评价。
1.考察秋水仙碱的体内外分析方法以及相关制剂含量测定和体外释放度测定方法。
2.测定秋水仙碱溶解度;采用大鼠在体肠段单向灌流技术考察秋水仙碱的肠吸收特性;比较常用亲水性高分子辅料的黏度、吸水膨胀和溶蚀等特性,以便为后期各剂型处方工艺研究奠定基础。
3.分别通过单因素考察筛选出影响体外释药行为的主要处方和工艺因素,经正交或均匀设计优化以上因素,确定渗透泵控释片、亲水凝胶骨架片以及胃滞留缓释片的处方工艺参数。
4.测定三种制剂的体外释放度,考察影响体外释药行为的主要因素,明确体外释药机制。
5.以LC-MS法测定并比较Beagle犬口服秋水仙碱市售片和三种制剂后的体内生物利用度和药物动力学参数。
结果
1.建立了简便、准确、可靠的RP-HPLC法用于分析秋水仙碱样品,并以《中国药典(2005版)》所载小杯法测定制剂的体外释放度。
2.秋水仙碱微溶于水,其溶解度随介质pH值和渗透压而变化较大;秋水仙碱在大鼠各肠段均有不同程度的吸收但在结肠段吸收较差,其吸收速率小、且不具有浓度依赖性;不同种类或同类而聚合度不同的高分子材料,其黏度、吸水后的膨胀性能以及在水中的溶蚀速率存在差异。
3.采用聚氧乙烯为主要片芯辅料制成的秋水仙碱推拉渗透泵控释片的体外释药零级特征显著(2～16h,r=0.9942,F_(16)＞90%)。含替代辅料的新处方的释药行为零级特征也较显著(2～16h,r=0.9956,F_(16)＞80%)。该制剂的体外释药几乎不受环境因素影响,释药机制以膨胀压和渗透压差为主。
4.采用两种规格聚氧乙烯为亲水凝胶材料制成的骨架片的体外释药速率为7.27%·h~(-1),释药完全,但释药行为易受环境因素影响。其释药机制是凝胶扩散和骨架溶蚀协同作用的结果。
5.秋水仙碱胃滞留片的缓释特征显著,体外释药过程包括扩散和溶蚀机制,其良好的漂浮性能源于处方所含的泡腾剂以及聚氧乙烯凝胶材料产生的“静水动力平衡系统”,其胃滞留性能依赖于系统的体积膨胀和漂浮性能。
6.三种剂型的血药浓度波动程度和相对生物利用度大小顺序依次为:渗透泵片＜骨架片＜胃滞留片。前两者虽然血药浓度更平稳,但因错过了最佳吸收部位而与普通片剂不等效。后者较长时间滞留胃内同时缓慢释药,能兼顾安全和有效性。
结论:综上,胃滞留缓释片的处方和工艺较为简便,体外释药较稳定且完全,体内血药浓度较快达到有效限度、波动较小、能更长时间维持在治疗指数范围内,且相对生物利用度较高,因此相对渗透泵控释片和亲水凝胶骨架片更适于秋水仙碱的口服缓控释给药。即将秋水仙碱研制成胃滞留缓控释给药系统可望提高患者用药顺应性、确保临床用药安全有效。
创新点
1.初步比较了常用亲水性高分子辅料的吸水膨胀和溶蚀性能;
2.制备了秋水仙碱口服渗透泵控释片、亲水凝胶骨架片和胃滞留缓释片,并分别考察了体外释放度和释药机制,比较其犬体内药物动力学特性。
3.优选出胃滞留缓控释给药系统为秋水仙碱口服制剂研发的适宜剂型。
Colchicine has been used for centuries in acute gout arthritis,its therapeutics index is very narrow(0.5～3ng·ml~(-1)),but it need frequent administration and usually shows side effects in gastrointestinal tract and poor patient-compliance.Common tablet is the only oral dosage form in market and there is no literature about oral drug delivery systems(DDS) till now.Fewer adverse reactions and better patient-compliance would be expected if we develop colchicine into oral sustained/controlled release system.
Aims:
Three new oral dosage forms of colchicine will be prepared by modern drug delivery technology,be compared and evaluated by in vitro and in vivo test,and one of them will be choosed to be the most preferred dosage form for colchicine.We hope to build foundation for new oral DDS development of colchicine and to offer reference for similar research.
Methods:
The drug release profile,pharmacokinetic parameters and bioavailability of three different dosage forms were compared and evaluated by drug release in vitro and pharmacokinetic parameters in vivo.
1.Methods for sample assay and drug release test in vitro were established.
2.Solubility and absorption properties of colchicine were studied by single-pass intestinal perfusion technique in rats.Viscosity,swelling and erosion properties of hydrophilic polymer commonly used were tested as the basis for formulation and process design.
3.The formulations and process of three dosage forms were studied by single-factor test and optimized by orthogonal or uniform design.
4.Drug relase profiles in vitro,key influencing factors and release mechanism of three preparations were studied.
5.The pharmacokinetic parameters and bioavailability of common tablet and three different preparations in Beagle dogs were studied by LC-MS.
Results:
1.RP-HPLC methodology for analysis of colchicine samples was established with appropriate convenience and accuracy.The cup method in Chinese Pharmacopoeia(Edition 2005) was adopted for in vitro release test of colchicine preparations.
2.Colchicine is sparingly soluble in water and its solubility changed markedly in solvents with different pH and osmotic pressure.Colchicine absorbed in whole rat intestinal and lactose improved its absorption,its absorption rate constant(K_a) were jejunum＞duodenum＞ileum＞colon,and were independent of the concentrations of colchicine in perfusion.Polymers with different units and polymerization degree differed in viscosity,swelling and erosion properties in water.
3.Colchicine osmotically controlled release tablets with PEO as main core ingredients showed excellent zero-order release profile in vitro(2～16h,r=0.9942, F_(16)＞90%),and the new formulation with alternative excipients as well(2～16h, r=0.9956,F_(16)＞80%).Its drug release profile can hardly influenced and drug release mechanism based on swelling pressure and osmotic pressure.
4.Colchicine hydrogel matrix tablet composed of PEO released drug completely with the rate of 7.27%·h~(-1).Its release profile can be influenced and drug release mechanism was the result of matrix erosion and gel diffusion.
5.Colchicine gastro retentive tablet showed markedly sustained-release characteristics with the mechanism of diffusion and erosion.Its floating property was based on the effervescent agents and PEO as "hydrodynamically balanced systems", and its gastric retention ability relied on size expanding and system floating properties.
6.The drug concentration fluctuation in plasma and relative bioavailability of three dosage forms showed bellowed:osmotic-pump tablet＜matrix tablet＜gastro retentive tablet.The former two showed more steady plasma drug concentration but not bioequivalent with common tablet,and the latter showed prolonged gastric retention time and was more safe and effective.
Conclusions:
Taken together,the results suggest that gastro retentive sustained-release tablet is more acceptable dosage form for oral sustained/controlled delivery of colchicine than osmotic-pump tablet and hydrogel matrix tablet,in which its formulation and process being more convenient,drug release in vitro being more complete,drug concentration in plasma being more steady and keeping longer period in range of therapeutic index,higher relative bioavailability in vivo.In other words,gastro retentive delivery system of colchicine is expected to improve patient-compliance and to be more safe and effective clinically.
Innovations:
1.Swelling and erosion properties of common hydrophilic polymers in water were compared initially.
2.Osmotically controlled-release tablets,hydrogel matrix tablets and gastro retentive sustained-release tablets of colchicines were prepared,their drug release mechanism in vitro were discussed,their relative bioavailability and pharmacokinetic parameters were studied.
3.Gastro retentive drug delivery system was found to be the best dosage form for research and development of oral products for colchicine.
引文
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25 Nie S F,Pan W S,Yang X G,et al.Evaluation of gravimetry in the rat single-pass intestinal perfusion technique.Chinese J New Drugs(中国新药杂志),2005,14:1176-1179.
26 Sutton C S,Rinaldi T S,Vukovinsky K E,et al.Comparison of the gravimetric,phenol red,and 14C-PEG-3350 methods to determine water absorption in the rat single-pass intestinal perfusion model.AAPS Pharm Sci,2001:25-32.
27 R.C.罗,P.J.舍斯基,P.J.韦勒.郑俊民译.药用辅料手册(原著第四版):化学工业出版社.
28 Niel E,Scherrmann J M.Colchicine today.Joint Bone Spine,2006:672-678.
29 Ungell A L,Nylander S,Bergstrand S,et al.Membrane transport of drags in different regions of the intestinal tract of the rat.J Pharm Sci,1998:360-366.
30 Valanzuela B,Cher A,Carreteropr,et al.Profile of P-Glycoprotein Distribution in the Rat and Its Possible Influence on the Salbutamol Intestinal Absorption Process.J Pharm Sci,2004:1641-1648.
31 Nakayama A,Eguchi O,Hatakeyama M,et al.Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat intestine.Biol Pharm Bull,1999,22:535-538.
32 Fagerholm U,Johansson M,Lennernas H.Comparison between permeability coefficients in rat and human jejunum.Pharm Re,1996,13:1336-1342.
33 Sabouraud A,Chappey O,Dupin T,et al.Binding of colchicine and thiocolchicoside to human serum proteins and blood cells.Intl Clin Pharmacol Ther,1994:429-432.
34 郑俊民.药用高分子材料学.化学工业出版社.1992:45.
35 刘清飞,罗国安,王义明.缓控释制剂释放度相似性评价方法的应用进展.Chin Pharm J(中国药学杂志),2006,41:1121-1124.
36 刘军田,陈修毅.缓控释骨架片药物体外释放行为的评价方法.齐鲁药事,2005,24:178-179.
37 吴涛,潘卫,庄殿友,等.硫酸沙丁胺醇口服渗透泵控释片的制备及体外释放度考察.沈阳药科大学学报,1999,16:79-83.
38 丁富新,江田民,昝佳,等.功能高分子在新型给药系统中的应用.精细化工Fine Chemicals,2004,21:924-927.
39 Frank G,Laser Drilling Enables Advanced Drug Delivery Systems,www.coherent.com/Downloads/Pharma%20Mfg%20Magazine%20Tablet%20Drilling.pdf.
40 En-Xian Lu,Zhi-Qiang Jiang,Qi-Zhi Zhang,Xin-Guo Jiang.A water-insoluble drug monolithic osmotic tablet system utilizing gum arabic as an osmotic,suspending and expanding agent.Journal of Controlled Release,2003:375-382.
41 李琳,翟国松,张伟,等.格列吡嗪缓释片的制备及体外释放度的考察.中国药剂学杂志,2007,5:161-167.
42 苏德森,王思玲.物理药剂学[M].北京:化学工业出版社,2004:120-122.
43 Kim CJ.Effects of drag solubility,drug loading,and polymer molecular weight on drug release from Poiyox tablets[J].Drug Dev Ind Pharzll,1998,24(7):645-651.
44 Zoe Wagenaar.Accidental colchicine poisoning in a dog.Can Vet J,2004;45:55-57.
45 N.Washington,C.Washington,C.G.Wilson.Physiological Pharmaceutics.Ⅱ.New York:Taylor and Francis,2001.
46 Eytan A Klausner,Eran Lavy,Michael Friedman,Amnon Hoffman.Expandable gastroretentive dosage forms.Journal of Controlled Release,2003:143-162.
47 http://zyy.njutcm.edu.cn/client/info_newsl.asp?txt_id=70.
48 http://www.roche.com.tw/medicine/70.htm.
49 Brijesh S.Dave,Avani F.Amin,Madhabhai M.Patel.Gastroretentive Drug Delivery System of Ranitidine Hydrochloride:Formulation and In Vitro Evaluation.AAPS PharmSciTech,2004,5:34.
50 Gastric retention controlled drug delivery system.In:Dudhara et al,ed.US.
51 I R Wilding and S P Newman. Giving Decisions More Precisions in Drag Development: Use of Radionuclide Imaging. Drag Delivery Systems & Sciences, 2001,1:5-10.
52 http://www.spherics.com/pdfs/Gabapentin_CR_CRSAbstract.pdf.
53 Klausner, E.A. et al. Novel levodopa gastroretentive dosage form: in vivo evaluation in dogs. J Control Release, 2003:117-126.
54 Gusler et al. Optimal polymer mixtures for gastric retentive tablets. In: Depomed,Inc, ed. US.
55 Shell et al. Extending the duration of drug release within the stomach during the fed mode. In: DepoMed,Inc,ed. US.
56 Berner et al. Methods of treating non-nociceptive pain states with gastric retentive gabapentin. In:DepoMed,Inc, ed.
57 Shell et al. Extending the duration of drag release within the stomach during the fed mode. US.
58 Berner et al. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms. In:DepoMed,Inc, ed. US.
59 Wong,et al. Prolonged release active agent dosage form adapted for gastric retention. In: Alza, ed. US.
60 J Chen, W E Blevins, H Park and K Park. Gastric Retention Properties of Superporous Hydrogel Composites.Journal of Controlled Release, 2000:39-51.
2 Yan Gong,Christian Gluud.Colchicine for Primary Biliary Cirrhosis:A Cochrane Hepato-biliary Group Systematic Review of Randomized Clinical Trials.American Journal of Gastroenterology,2005:1876- 1885.
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4 Eldad Ben,-Chetrit,Nlicha Levy.Colchieine:1998 Update.Seminars in Arthritis and Rheumatism,1998,28:48-59.
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6 Geraldine M.Ferron,Mydam Rochdi,William J.Jusko,Jean-Michel Scherrmann.Oral Absorption Characteristics and Pharmacokinetics of Coichicine in Healthy Volunteers after Single and Multiple Doses.J Clin Pharmacol,1996:874-883.
7 Rochdi M,Sabouraud A,Girre C,Venet R,Scherrmann JM.Pharmacokinetics and absolute bioavailability of colchicine after iv and oral administration in healthy human volunteers and elderly subjents.Eur J Clin Pharmacol,1994:3511-3540.
8 Sabouraud A,Chappey O,Dupin T,Scherrmann JM.Colchicine disposition in human leukocytes after single and multiple oral administration.Clin Pharmacol Ther,1993:360-367.
9 孙铭,方淑昌,朱争艳,等.秋水仙碱纳米控释微粒抗肿瘤的实验研究.天津医药,2001,29:727-732.
10 张仲海,吴少华,夏天,等.外磁场引导定位秋水仙碱-磁微粒对裸鼠乳腺癌的抑制作用.第四军医大学学报,1995,16:114-116.
11 Joshua D.Bagnato,Alanna L.Eilers,Robert A.Horton,Charles B.Grissom.Synthesis and Characterization of a Cobalamin-Colchicine Conjugate as a Novel Tumor-Targeted Cytotoxin.J Org Chem,2004:8987-8996.
12 Sabine M.W.van Rossenberg,Karen M.Sliedregt-Bol,Gerben Koning,et al.Improvement of Hepatocyte-Specific Gene Expression by a Targeted Colchicine Prodrug.Chem BioChem,2003:633-639.
13 尹潍,程志强,高志红,等.秋水仙碱贴膜治疗急性痛风性关节炎.中国新药与临床杂志,2001,20:373-374.
14 陈秋红,侯世祥.不同基质和透皮促进剂对秋水仙碱凝胶剂体外透皮特性的影响.华西药学杂志,2005,20:521-524.
15 Viness Pillay.Novel formulation approaches in the design strategy,development and evaluation of oral controlled release drug delivery systems[Dr]Temple University,2000.
16 www.ficci.com/media-room/speeches-presentations/2002/sep/sep-indiachem-lupin.PPT.
17 刘薇,周建平,吕慧侠.窄吸收窗药物缓释制剂的研发进展.药学进展,2006,30:212-216.
18 毕瑞.“吸收窗”现象与制剂学研究进展.国外医学药学分册,2006,33:67-70.
19 中华人民共和国药典(二部),2005.412.
20 http://www.inchem.org/documents/pims/pharm/colchic.htm#PartTitle:1.%20%20NAME.
21 http://www.inchem.org/documents/pims/pharm/colchic.htm.
22 Bittner B,Fullhardt P,Zuercher G,Bravo Gonzal RC,Mountfield RJ.Improvement of the oral bioavailability of colchicine in rats by co-administration of D-a-tocopherol polyethylene glycol 1000 succinate and polyethoxylated derivative of 12-hydroxy-stearic acid.Drug Res,2002:684-688.
23 张婷婷,徐文,胡生亮,等.水飞蓟宾在不同介质中平衡溶解度和表观油水分配系数的测定.中国药学杂志,2006,41:1569-1571.
24 王晶,袁悦,王岩.吲哚拉新多晶型的制备及溶解度的研究.中国药剂学杂志,2005,3:9-12.
25 Nie S F,Pan W S,Yang X G,et al.Evaluation of gravimetry in the rat single-pass intestinal perfusion technique.Chinese J New Drugs(中国新药杂志),2005,14:1176-1179.
26 Sutton C S,Rinaldi T S,Vukovinsky K E,et al.Comparison of the gravimetric,phenol red,and 14C-PEG-3350 methods to determine water absorption in the rat single-pass intestinal perfusion model.AAPS Pharm Sci,2001:25-32.
27 R.C.罗,P.J.舍斯基,P.J.韦勒.郑俊民译.药用辅料手册(原著第四版):化学工业出版社.
28 Niel E,Scherrmann J M.Colchicine today.Joint Bone Spine,2006:672-678.
29 Ungell A L,Nylander S,Bergstrand S,et al.Membrane transport of drags in different regions of the intestinal tract of the rat.J Pharm Sci,1998:360-366.
30 Valanzuela B,Cher A,Carreteropr,et al.Profile of P-Glycoprotein Distribution in the Rat and Its Possible Influence on the Salbutamol Intestinal Absorption Process.J Pharm Sci,2004:1641-1648.
31 Nakayama A,Eguchi O,Hatakeyama M,et al.Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat intestine.Biol Pharm Bull,1999,22:535-538.
32 Fagerholm U,Johansson M,Lennernas H.Comparison between permeability coefficients in rat and human jejunum.Pharm Re,1996,13:1336-1342.
33 Sabouraud A,Chappey O,Dupin T,et al.Binding of colchicine and thiocolchicoside to human serum proteins and blood cells.Intl Clin Pharmacol Ther,1994:429-432.
34 郑俊民.药用高分子材料学.化学工业出版社.1992:45.
35 刘清飞,罗国安,王义明.缓控释制剂释放度相似性评价方法的应用进展.Chin Pharm J(中国药学杂志),2006,41:1121-1124.
36 刘军田,陈修毅.缓控释骨架片药物体外释放行为的评价方法.齐鲁药事,2005,24:178-179.
37 吴涛,潘卫,庄殿友,等.硫酸沙丁胺醇口服渗透泵控释片的制备及体外释放度考察.沈阳药科大学学报,1999,16:79-83.
38 丁富新,江田民,昝佳,等.功能高分子在新型给药系统中的应用.精细化工Fine Chemicals,2004,21:924-927.
39 Frank G,Laser Drilling Enables Advanced Drug Delivery Systems,www.coherent.com/Downloads/Pharma%20Mfg%20Magazine%20Tablet%20Drilling.pdf.
40 En-Xian Lu,Zhi-Qiang Jiang,Qi-Zhi Zhang,Xin-Guo Jiang.A water-insoluble drug monolithic osmotic tablet system utilizing gum arabic as an osmotic,suspending and expanding agent.Journal of Controlled Release,2003:375-382.
41 李琳,翟国松,张伟,等.格列吡嗪缓释片的制备及体外释放度的考察.中国药剂学杂志,2007,5:161-167.
42 苏德森,王思玲.物理药剂学[M].北京:化学工业出版社,2004:120-122.
43 Kim CJ.Effects of drag solubility,drug loading,and polymer molecular weight on drug release from Poiyox tablets[J].Drug Dev Ind Pharzll,1998,24(7):645-651.
44 Zoe Wagenaar.Accidental colchicine poisoning in a dog.Can Vet J,2004;45:55-57.
45 N.Washington,C.Washington,C.G.Wilson.Physiological Pharmaceutics.Ⅱ.New York:Taylor and Francis,2001.
46 Eytan A Klausner,Eran Lavy,Michael Friedman,Amnon Hoffman.Expandable gastroretentive dosage forms.Journal of Controlled Release,2003:143-162.
47 http://zyy.njutcm.edu.cn/client/info_newsl.asp?txt_id=70.
48 http://www.roche.com.tw/medicine/70.htm.
49 Brijesh S.Dave,Avani F.Amin,Madhabhai M.Patel.Gastroretentive Drug Delivery System of Ranitidine Hydrochloride:Formulation and In Vitro Evaluation.AAPS PharmSciTech,2004,5:34.
50 Gastric retention controlled drug delivery system.In:Dudhara et al,ed.US.
51 I R Wilding and S P Newman. Giving Decisions More Precisions in Drag Development: Use of Radionuclide Imaging. Drag Delivery Systems & Sciences, 2001,1:5-10.
52 http://www.spherics.com/pdfs/Gabapentin_CR_CRSAbstract.pdf.
53 Klausner, E.A. et al. Novel levodopa gastroretentive dosage form: in vivo evaluation in dogs. J Control Release, 2003:117-126.
54 Gusler et al. Optimal polymer mixtures for gastric retentive tablets. In: Depomed,Inc, ed. US.
55 Shell et al. Extending the duration of drug release within the stomach during the fed mode. In: DepoMed,Inc,ed. US.
56 Berner et al. Methods of treating non-nociceptive pain states with gastric retentive gabapentin. In:DepoMed,Inc, ed.
57 Shell et al. Extending the duration of drag release within the stomach during the fed mode. US.
58 Berner et al. Tablet shapes to enhance gastric retention of swellable controlled-release oral dosage forms. In:DepoMed,Inc, ed. US.
59 Wong,et al. Prolonged release active agent dosage form adapted for gastric retention. In: Alza, ed. US.
60 J Chen, W E Blevins, H Park and K Park. Gastric Retention Properties of Superporous Hydrogel Composites.Journal of Controlled Release, 2000:39-51.