盐酸帕罗西汀肠溶缓释制剂的研制
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摘要
盐酸帕罗西汀是高度选择性的5-羟色胺再摄取抑制剂,用于治疗抑郁症、惊恐症、强迫性观念和行为、创伤后应急性疾病和全身性焦虑症[1–3]。与早期用于治疗抑郁症的三环及四环类抗抑郁药相比较,5-羟色胺再摄取抑制剂急性毒性低且耐受性好,成为老年人治疗抑郁症的一线药物[2]。由于抑郁症患者需要长时间反复服用帕罗西汀,因此研制其肠溶缓控释制剂以提高疗效,降低毒副作用,减轻胃肠道不适,提高患者顺应性。本文进行了盐酸帕罗西汀肠溶缓释片及肠溶缓释微丸的制备的研究。
本研究用紫外分光光度法研究了盐酸帕罗西汀半水合物的理化性质。溶解度实验显示:盐酸帕罗西汀半水合物在水,0.l mol/L HCl,pH7.5 TRIS-NaCl缓冲液溶解度大于1mg/ml;表观油水分配系数随pH的增大而增大。研究建立了高效液相法用于盐酸帕罗西汀肠溶缓释片及肠溶缓释微丸的体外释放度考察及含量测定。
通过单因素考察及正交试验,考察了缓释片组成及工艺因素。以药物在4小时释放完全作为标准,筛选出最佳缓释片处方,确定了以HPMC为缓释片的主要控释材料,微晶纤维素为填充剂,采用湿法制粒法制备颗粒,压制缓释片。对盐酸帕罗西汀缓释片的质量考察,表明了自制缓释片批间的释药行为重现性良好。
考察了释药条件对药物释放的影响,结果发现:释放度试验过程中转篮法与桨法对释药行为无影响;用Higuchi方程对缓释片的释药曲线进行拟合,得到的拟合度R2最大(0.9949),用Ritger-Peppas方程拟合,释放参数n=0.7632,推断药物的释放机制是扩散和骨架溶蚀协同作用的结果。
采用包衣技术制备盐酸帕罗西汀肠溶缓释片。通过衣膜的溶解性及药物释放度决定用Eudragit L100作为肠溶缓释包衣材料,以前2小时释放<10%、第7小时释放完全为判定依据,优化包衣处方及包衣工艺。
对最佳处方制成的肠溶缓释片做了影响因素试验。结果表明,该制剂在光照、高温条件下药物的释放曲线不变,但含量下降;75%高湿条件下药物的释放度发生改变,而含量下降得较少。
以层积法制备盐酸帕罗西汀肠溶缓释微丸,用流化床悬浮包衣法对空白微丸包含药层、缓释层及肠溶层。以释放度为指标,单因素考察确立了包衣工艺参数,采用EC为缓释层,对包衣处方、包衣增重以及热处理时间等影响因素进行了考察,选出最优处方;以Eudragit为肠溶包衣液,对抗粘剂等作了考察,以前2小时释放<10%、第7小时释放完全为判定依据,优化包衣处方及包衣工艺。
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) currently used as an antidepressant drug [1–3]. The lower acute toxicity and improved tolerability of SSRI compared to previously frequently use tri- and tetra-cyclic antidepressants have been major reasons for the recommendation of its use as first-line treatment of depression in the elderly [2]. In this article, the preparation of enteric-coated sustained release tablets and pellets were included to avoid the gastrointestinal tract irritation.
In this study, UV spectrophotometry was used for assay the partition coefficient and solubility of paroxetine. The experiment results showed that paroxetine is easily soluble in water, 0.lmol/L HCl aqueous solution, and pH7.5 TRIS-NaCl buffer solutions. The n-octanol/water partition coefficients increase with pH rising in various physiological pH solutions. And HPLC method was used for in vitro assay during the studies of release and content in tablets and pellets.
Based on single factor investigation and orthogonal design, Hydroxy-propylmethyl cellulose and cellulose microcrystallisate were used to make the sustained tablet core by wet granulation compression; the wetting agent and the compression pressure can make paroxetine release rate change. Based on the quality investigation of the sustained release tablets, the self-prepared tablets between batches have good reproducibility of drug release behavior.
The conditions affecting drug release were investigated. No significant difference in drug release behavior was observed for release study by using basket or paddle method. The mechanism of drug release from this sustained release tablet was investigated. Drug release rate followed the Higuchi equation. And the releasing parameter of the Ritger-Peppas equation equaling to 0.7632(0.45 < n < 0. 89) meant that the release mechanism was a synergism of diffusion and matrix erosion.
The sustained release tablets were coated with Eudragit L100 to avoid to be destroying in the gastric juice. The coating formulation was optimized, having good resistance to acid and the dissolution of the tablet can last 5 hours in artificial intestinal liquid.
The result of stability test showed that the enteric-coated tablet was unstable when exposed to strong light and high temperature. The appearance and drug release did not change, but the quantity decrease significantly. As it exposed to 75% humidity condition, drug release change and quantity decrease slightly.
A fluid-bed spray processor was adopted for coating the pellets. Based on single factor investigation, the coating process variables of drug lay, sustained release lay, and enteric-coated lay were determined. Ethyl cellulose was selected as the main material for sustained release lay. And the categories and dosage of ethyl cellulose, curing time, etc were investigated. The coating formulation was optimized; the dissolution of the pellets can last 5 hours in artificial intestinal liquid. Eudragit L100 was selected for the excellent drug release. The coating formulation was optimized, having good resistance to acid and quickly dissolving in artificial intestinal liquid. The anti-tacking agent talc, curing time were studied.
本研究用紫外分光光度法研究了盐酸帕罗西汀半水合物的理化性质。溶解度实验显示:盐酸帕罗西汀半水合物在水,0.l mol/L HCl,pH7.5 TRIS-NaCl缓冲液溶解度大于1mg/ml;表观油水分配系数随pH的增大而增大。研究建立了高效液相法用于盐酸帕罗西汀肠溶缓释片及肠溶缓释微丸的体外释放度考察及含量测定。
通过单因素考察及正交试验,考察了缓释片组成及工艺因素。以药物在4小时释放完全作为标准,筛选出最佳缓释片处方,确定了以HPMC为缓释片的主要控释材料,微晶纤维素为填充剂,采用湿法制粒法制备颗粒,压制缓释片。对盐酸帕罗西汀缓释片的质量考察,表明了自制缓释片批间的释药行为重现性良好。
考察了释药条件对药物释放的影响,结果发现:释放度试验过程中转篮法与桨法对释药行为无影响;用Higuchi方程对缓释片的释药曲线进行拟合,得到的拟合度R2最大(0.9949),用Ritger-Peppas方程拟合,释放参数n=0.7632,推断药物的释放机制是扩散和骨架溶蚀协同作用的结果。
采用包衣技术制备盐酸帕罗西汀肠溶缓释片。通过衣膜的溶解性及药物释放度决定用Eudragit L100作为肠溶缓释包衣材料,以前2小时释放<10%、第7小时释放完全为判定依据,优化包衣处方及包衣工艺。
对最佳处方制成的肠溶缓释片做了影响因素试验。结果表明,该制剂在光照、高温条件下药物的释放曲线不变,但含量下降;75%高湿条件下药物的释放度发生改变,而含量下降得较少。
以层积法制备盐酸帕罗西汀肠溶缓释微丸,用流化床悬浮包衣法对空白微丸包含药层、缓释层及肠溶层。以释放度为指标,单因素考察确立了包衣工艺参数,采用EC为缓释层,对包衣处方、包衣增重以及热处理时间等影响因素进行了考察,选出最优处方;以Eudragit为肠溶包衣液,对抗粘剂等作了考察,以前2小时释放<10%、第7小时释放完全为判定依据,优化包衣处方及包衣工艺。
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) currently used as an antidepressant drug [1–3]. The lower acute toxicity and improved tolerability of SSRI compared to previously frequently use tri- and tetra-cyclic antidepressants have been major reasons for the recommendation of its use as first-line treatment of depression in the elderly [2]. In this article, the preparation of enteric-coated sustained release tablets and pellets were included to avoid the gastrointestinal tract irritation.
In this study, UV spectrophotometry was used for assay the partition coefficient and solubility of paroxetine. The experiment results showed that paroxetine is easily soluble in water, 0.lmol/L HCl aqueous solution, and pH7.5 TRIS-NaCl buffer solutions. The n-octanol/water partition coefficients increase with pH rising in various physiological pH solutions. And HPLC method was used for in vitro assay during the studies of release and content in tablets and pellets.
Based on single factor investigation and orthogonal design, Hydroxy-propylmethyl cellulose and cellulose microcrystallisate were used to make the sustained tablet core by wet granulation compression; the wetting agent and the compression pressure can make paroxetine release rate change. Based on the quality investigation of the sustained release tablets, the self-prepared tablets between batches have good reproducibility of drug release behavior.
The conditions affecting drug release were investigated. No significant difference in drug release behavior was observed for release study by using basket or paddle method. The mechanism of drug release from this sustained release tablet was investigated. Drug release rate followed the Higuchi equation. And the releasing parameter of the Ritger-Peppas equation equaling to 0.7632(0.45 < n < 0. 89) meant that the release mechanism was a synergism of diffusion and matrix erosion.
The sustained release tablets were coated with Eudragit L100 to avoid to be destroying in the gastric juice. The coating formulation was optimized, having good resistance to acid and the dissolution of the tablet can last 5 hours in artificial intestinal liquid.
The result of stability test showed that the enteric-coated tablet was unstable when exposed to strong light and high temperature. The appearance and drug release did not change, but the quantity decrease significantly. As it exposed to 75% humidity condition, drug release change and quantity decrease slightly.
A fluid-bed spray processor was adopted for coating the pellets. Based on single factor investigation, the coating process variables of drug lay, sustained release lay, and enteric-coated lay were determined. Ethyl cellulose was selected as the main material for sustained release lay. And the categories and dosage of ethyl cellulose, curing time, etc were investigated. The coating formulation was optimized; the dissolution of the pellets can last 5 hours in artificial intestinal liquid. Eudragit L100 was selected for the excellent drug release. The coating formulation was optimized, having good resistance to acid and quickly dissolving in artificial intestinal liquid. The anti-tacking agent talc, curing time were studied.
引文
[1] Holliday SM, Plosker GL. Paroxetine. A review of its pharmacology, therapeutic use in depression and therapeutic potential in diabetic neuropathy[J]. Drugs Aging,1993,(3):278–99.
[2] Gottfries CG, Karlsson I, Nyth A-L. Treatment of depression in elderly patients with and without dementia disorders[J]. Int Clin Psychopharmacol,1992,6(Suppl 5):354–9.
[3] Lane R, Baldwin D, Preskom S. The SSRIs: advantages, disadvantages and differences[J]. J Psychopharmacol, 1995,9(Suppl):5–11.
[4] Sharon Rosenzweig-Lipson et al., Differentiating antidepressants of the future: Efficacy and safety [J]. Pharmacology & Therapeutics,2007,113(1): 134-153
[5] 高春生,梅兴国.微丸压片技术的研究进展[J].中国药学杂志, 2006,41(3):163-166.
[6] 伍成祥,徐峰.浅析微丸在固体口服缓释控释制剂中的应用[J].山东医药工业,2000,19(5):36-38.
[7] Rajesh Gandhi, Chaman Lal Kaul, Ramesh Panchagnula.Extrusion and spheronization in the development of oral controlled-releasedosage forms[J]. PSTT, 1999,2(4):160-170.
[8] Jittima Chatchawalsaisina, Fridrun Podczeckb, J. Michael Newton.The preparation by extrusion/spheronization and the properties of pellets containing drugs, microcrystalline cellulose and glyceryl monostearate[J]. European Journal of Pharmaceutical Sciences,2005, 24(1):35–48.
[9] Nuttanan Sinchaipanid, Varaporn Junyaprasert, Ampol Mitrevej. Application of hot-melt coating for controlled release of propranolol hydrochloride pellets[J]. Powder Technology, 2004,141(3):203– 209.
[10] Obara Sakae, Maruyama Naosuke, Nishiyama Yuichi, et al. Dry coating: an innovative enteric coating method using a cellulose derivative [J]. Eur J Pharm Biopharm, 1999, 47(1): 51-59.
[11]孙桂芝,曹智华,刘文,等.维骨康胶囊中微丸制备工艺研究[J].中成药,2005,27(4):394-397.
[12] Thaned Pongjanyakul, Natalie J. Medlicott,,Ian G. Tucker. Melted glyceryl palmitostearate (GPS) pellets for protein delivery[J]. International Journal ofPharmaceutics,2004, 271(1-2):53–62.
[13] Moore JW, F lanner HH. Mathematical comparison of dissolution profiles[J]. Pharmaceutical Technology, 1996,6(1): 64.
[14] Lecomte, F., Siepmann, J., Walther, M., et al. Polymer blends used for the coating of multiparticulates: Comparison of aqueous and organic coating techniques[J]. Pharmaceutical Research,2004, 21(1): 882-890.
[15] Zhang Z Y, Ping Q N, Xiao B, et al. Microencapsulation and characterization of tramadol-resin somplexes[J]. J Control Release, 2000, 66(2-3): 107.
[16]沈德凤,张启兴,唐艳秋.用乙基纤维素 (EC)制备硝苯地平(Nifedipine)缓释固体分散体的研究[J]. 黑龙江医药科学,2002,25(1):78.
[17]Hutchings DE, Sakr A. Influence on pH and plasticizers on drug release from ethylcellulose pseudo latex coated pellets[J]. J P harm Sci, 1994, 83 (10):1386.
[18]金描真,张志宏.不同规格羟丙基甲基纤维素作为片剂薄膜衣材料的研究. 广东医药学院学报[J],1993,9(1):35-37.
[19] Qing-Ri Cao, Han-Gon Choi, Dong-Chool Kim, et al. Release behavior and photo-image of nifedipine tablet coated with high viscosity grade hydroxypropylmethylcellulose: effect of coating conditions. International Journal of Pharmaceutics[J],2004, 274(1-2 ): 107–117.
[2] Gottfries CG, Karlsson I, Nyth A-L. Treatment of depression in elderly patients with and without dementia disorders[J]. Int Clin Psychopharmacol,1992,6(Suppl 5):354–9.
[3] Lane R, Baldwin D, Preskom S. The SSRIs: advantages, disadvantages and differences[J]. J Psychopharmacol, 1995,9(Suppl):5–11.
[4] Sharon Rosenzweig-Lipson et al., Differentiating antidepressants of the future: Efficacy and safety [J]. Pharmacology & Therapeutics,2007,113(1): 134-153
[5] 高春生,梅兴国.微丸压片技术的研究进展[J].中国药学杂志, 2006,41(3):163-166.
[6] 伍成祥,徐峰.浅析微丸在固体口服缓释控释制剂中的应用[J].山东医药工业,2000,19(5):36-38.
[7] Rajesh Gandhi, Chaman Lal Kaul, Ramesh Panchagnula.Extrusion and spheronization in the development of oral controlled-releasedosage forms[J]. PSTT, 1999,2(4):160-170.
[8] Jittima Chatchawalsaisina, Fridrun Podczeckb, J. Michael Newton.The preparation by extrusion/spheronization and the properties of pellets containing drugs, microcrystalline cellulose and glyceryl monostearate[J]. European Journal of Pharmaceutical Sciences,2005, 24(1):35–48.
[9] Nuttanan Sinchaipanid, Varaporn Junyaprasert, Ampol Mitrevej. Application of hot-melt coating for controlled release of propranolol hydrochloride pellets[J]. Powder Technology, 2004,141(3):203– 209.
[10] Obara Sakae, Maruyama Naosuke, Nishiyama Yuichi, et al. Dry coating: an innovative enteric coating method using a cellulose derivative [J]. Eur J Pharm Biopharm, 1999, 47(1): 51-59.
[11]孙桂芝,曹智华,刘文,等.维骨康胶囊中微丸制备工艺研究[J].中成药,2005,27(4):394-397.
[12] Thaned Pongjanyakul, Natalie J. Medlicott,,Ian G. Tucker. Melted glyceryl palmitostearate (GPS) pellets for protein delivery[J]. International Journal ofPharmaceutics,2004, 271(1-2):53–62.
[13] Moore JW, F lanner HH. Mathematical comparison of dissolution profiles[J]. Pharmaceutical Technology, 1996,6(1): 64.
[14] Lecomte, F., Siepmann, J., Walther, M., et al. Polymer blends used for the coating of multiparticulates: Comparison of aqueous and organic coating techniques[J]. Pharmaceutical Research,2004, 21(1): 882-890.
[15] Zhang Z Y, Ping Q N, Xiao B, et al. Microencapsulation and characterization of tramadol-resin somplexes[J]. J Control Release, 2000, 66(2-3): 107.
[16]沈德凤,张启兴,唐艳秋.用乙基纤维素 (EC)制备硝苯地平(Nifedipine)缓释固体分散体的研究[J]. 黑龙江医药科学,2002,25(1):78.
[17]Hutchings DE, Sakr A. Influence on pH and plasticizers on drug release from ethylcellulose pseudo latex coated pellets[J]. J P harm Sci, 1994, 83 (10):1386.
[18]金描真,张志宏.不同规格羟丙基甲基纤维素作为片剂薄膜衣材料的研究. 广东医药学院学报[J],1993,9(1):35-37.
[19] Qing-Ri Cao, Han-Gon Choi, Dong-Chool Kim, et al. Release behavior and photo-image of nifedipine tablet coated with high viscosity grade hydroxypropylmethylcellulose: effect of coating conditions. International Journal of Pharmaceutics[J],2004, 274(1-2 ): 107–117.