复方对乙酰氨基酚双层缓释片的研究
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摘要
盐酸曲马多由于其毒副作用小，无耐受性，无成瘾性和无戒断症状而越来越广泛的应用于急慢性疼痛的治疗。近年来研究结果表明，当其与对乙酰氨基酚合用时，显示了协同的镇痛效果并且可以减少副作用的发生。本文依据国外上市的复方对乙酰氨基酚／盐酸曲马多普通片，研制了日服两次的复方对乙酰氨基酚／盐酸曲马多双层缓释片。并分别采用体内、体外方法对其进行了科学评价。
建立了紫外分光光度法用于对乙酰氨基酚、盐酸曲马多基本理化性质、片剂的释放度和含量的测定；建立了高效液相色谱法，用于检测体内血药浓度，对乙酰氨基酚和盐酸曲马多的提取回收率分别为97.01％，97.95％。以上方法准确可靠，方便快捷，很好地满足了本研究中的各项分析要求。
在处方前研究中，测定了对乙酰氨基酚、盐酸曲马多在不同介质中的溶解度，不同pH值下的油／水分配系数，在此基础上，重点考察了影响盐酸曲马多缓释片释放的各个因素。主要影响因素是HPMC K4M和十八醇的用量。本文根据对乙酰氨基酚盐酸曲马多具有协同作用的前提，以HPMC为主要缓释材料，制备了对乙酰氨基酚曲马多双层缓释片，对双层缓释片的处方组分分别采用了均匀设计法、分数法等进行优化，以优化处方制备的双层缓释片体外释放度试验结果显示对乙酰氨基酚体外释放行为符合non-Fick扩散释放机制，骨架溶蚀机制起主导作用，而盐酸曲马多体外释放行为符合Higuchi方程。
复方对乙酰氨基酚双层缓释片的初步稳定性试验表明，其对光、热、
沈阳药科大学硕士学位论文 摘要
湿和空气等均较稳定，含量、释放度均无明显变化。加速试验结果预测
其有效期可达二年。
家犬口服双层缓释片后吸收动力学及生物利用度研究结果显示，单
剂量给药后双层缓释片中的对乙酚氨基酚和盐酸曲马多的相对生物利用
度分别为99．68％和97．19％，体外释放百分数和体内吸收百分数之间呈现
出点．点线性相关。
Tramadol hydrochloride was widely used to the therapy of acute and chronic pain as its low side effects. Recently clinical research proved that the combination of tramadol hydrochloride and acetaminophen could provide analgesia equal to or greater than the sum of the components with a resultant reduction in the required dose of each agent and lead to reduced incidents of side effects as well. The two drugs produced analgesic activities through different mechanisms with tramadol having opiate-like properties and acetaminophen having prostaglandin inhibition properties. To reduce the side effects and maintain relatively constant plasma concentration, two-layer sustained release tablets of twice daily administration was designed and prepared by using hydroxypropyl methyl cellulose (HPMC) and octadecyl alcohol (OA) as basic matrix material.
According to the literature, Ultraviolet (UV) spectrophotomatry method was developed for determination of physicochemical properties, content and drug release; High-performance liquid chromatography (HPLC) method with UV detection was applied to the plasma concentration of tramadol and acetaminophen in dogs. The extraction recovery of tramadol HC1 and acetaminophen was 97.95% and 97.01%, respectively.
In the preformulation researches, the physicochemical properties of tramadol HC1 and acetaminophen were investigated, which benefit pharmaceutical design. Based on the researches of preformulation, single-factor tests were carried out to study the influences of formulation and manufacture process on the release of tramadol HC1 and acetaminophen, and two-layer tablets were prepared with HPMC and OA as the release
controlling material. Uniform design method as well as the fraction method were applied for the formulation optimization. The way of acetaminophen released from two-layer tablets could be described as non-Fickian diffusion, which was mainly by matrix erosion. And the release of tramadol followed Higuchi equation.
Stability studies of preparation demonstrated that light, temperature, humidity and air had little effect on compound two-layer sustained release tablets.
The studies of pharmacokinetics of compound two-layer sustained release tablets in dogs verified that the desired purpose of sustained release was achieved, which proved this formulation was successful. The plasma concentration maintained for about 24h. Its relative bioavailability was between 80.0% and 120.0%, The result of statistic analysis showed that tramadol HC1 and acetaminophen was bioequivalent with reference preparation. The release of tramadol HC1 and acetaminophen in vitro is correlative with the absorption fraction in vivo.
建立了紫外分光光度法用于对乙酰氨基酚、盐酸曲马多基本理化性质、片剂的释放度和含量的测定；建立了高效液相色谱法，用于检测体内血药浓度，对乙酰氨基酚和盐酸曲马多的提取回收率分别为97.01％，97.95％。以上方法准确可靠，方便快捷，很好地满足了本研究中的各项分析要求。
在处方前研究中，测定了对乙酰氨基酚、盐酸曲马多在不同介质中的溶解度，不同pH值下的油／水分配系数，在此基础上，重点考察了影响盐酸曲马多缓释片释放的各个因素。主要影响因素是HPMC K4M和十八醇的用量。本文根据对乙酰氨基酚盐酸曲马多具有协同作用的前提，以HPMC为主要缓释材料，制备了对乙酰氨基酚曲马多双层缓释片，对双层缓释片的处方组分分别采用了均匀设计法、分数法等进行优化，以优化处方制备的双层缓释片体外释放度试验结果显示对乙酰氨基酚体外释放行为符合non-Fick扩散释放机制，骨架溶蚀机制起主导作用，而盐酸曲马多体外释放行为符合Higuchi方程。
复方对乙酰氨基酚双层缓释片的初步稳定性试验表明，其对光、热、
沈阳药科大学硕士学位论文 摘要
湿和空气等均较稳定，含量、释放度均无明显变化。加速试验结果预测
其有效期可达二年。
家犬口服双层缓释片后吸收动力学及生物利用度研究结果显示，单
剂量给药后双层缓释片中的对乙酚氨基酚和盐酸曲马多的相对生物利用
度分别为99．68％和97．19％，体外释放百分数和体内吸收百分数之间呈现
出点．点线性相关。
Tramadol hydrochloride was widely used to the therapy of acute and chronic pain as its low side effects. Recently clinical research proved that the combination of tramadol hydrochloride and acetaminophen could provide analgesia equal to or greater than the sum of the components with a resultant reduction in the required dose of each agent and lead to reduced incidents of side effects as well. The two drugs produced analgesic activities through different mechanisms with tramadol having opiate-like properties and acetaminophen having prostaglandin inhibition properties. To reduce the side effects and maintain relatively constant plasma concentration, two-layer sustained release tablets of twice daily administration was designed and prepared by using hydroxypropyl methyl cellulose (HPMC) and octadecyl alcohol (OA) as basic matrix material.
According to the literature, Ultraviolet (UV) spectrophotomatry method was developed for determination of physicochemical properties, content and drug release; High-performance liquid chromatography (HPLC) method with UV detection was applied to the plasma concentration of tramadol and acetaminophen in dogs. The extraction recovery of tramadol HC1 and acetaminophen was 97.95% and 97.01%, respectively.
In the preformulation researches, the physicochemical properties of tramadol HC1 and acetaminophen were investigated, which benefit pharmaceutical design. Based on the researches of preformulation, single-factor tests were carried out to study the influences of formulation and manufacture process on the release of tramadol HC1 and acetaminophen, and two-layer tablets were prepared with HPMC and OA as the release
controlling material. Uniform design method as well as the fraction method were applied for the formulation optimization. The way of acetaminophen released from two-layer tablets could be described as non-Fickian diffusion, which was mainly by matrix erosion. And the release of tramadol followed Higuchi equation.
Stability studies of preparation demonstrated that light, temperature, humidity and air had little effect on compound two-layer sustained release tablets.
The studies of pharmacokinetics of compound two-layer sustained release tablets in dogs verified that the desired purpose of sustained release was achieved, which proved this formulation was successful. The plasma concentration maintained for about 24h. Its relative bioavailability was between 80.0% and 120.0%, The result of statistic analysis showed that tramadol HC1 and acetaminophen was bioequivalent with reference preparation. The release of tramadol HC1 and acetaminophen in vitro is correlative with the absorption fraction in vivo.
引文
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[3] Yamakita H, Matsukawa Y, Maejima T,et al. Preparation of controlled release granules of TA-5707F using entericpolymers and ethlcellulose, and their in vivo evaluation. Biol. Pharm. Bull., 1996, 19 (1): 106-113
[4] Dong ZC, Jiang XT. Effect of physical-chemical properties of HPMC on dissolution from hydrophilic matrix tablets. Yaoxue Xuebao (Acta Pharm Sinica), 1994, 29 (12): 920-924
[5] Yamakita H, Maejima T,Osawa T. In vitro/in vivo evalution of two series of TA-5707F controlled release matrix tablets prepared with hydroxypropyl methyl cellulose derivatives with entero-soluble or gel-formation properties. Biol. Pharm. Bull., 1995, 18 (10): 1409-1416
[6] Gao P, Nixon PR,Skoug JW. Difusion in HPMC gels Ⅱ. Prediction of drug release rates from hydrophilic matric extended release dosage forms. Pharm. Res., 1995, 12 (7): 965-971
[7] Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropyl on water penetration into amatrix system. Int. J. Pharm., 1991, 73 (2): 111-116
[8] Wan LSC, Heng PWS, Wong LF. Relationship between swelling and drug release in a hydrophilic matrix. Drug Dev. Ind. Pharm., 1993, 19 (10): 1201-1210
[9] Bettini R, Colombo P, Masssimo G, et al. Swelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effexts. Eur. J. Pharm. Sci., 1994, 2 (3): 213-219
[10] Colombo P, Bettini R, Masssimo G, et al. Drug diffusion front movement is important in drug release control from swellable matrix tablets. J. Pharm. Sci.,
1995, 84 (8): 991-997
[11] Wan LSC, Heng PWS, Wong LF. Matrix swelling: A simple model describing extent of swelling of HPMC matrices. Int. J. Pharm., 1995, 116 (2): 159-168
[12] Colombo P. Swellable matrices for oral controlled release: an update on delivery mechanism. Eur. J. Pharm. Sci., 1998, 6 (suppl.1): 11-17
[13] Tsai,Tsuimin, Ho,Hsiu-O, Kao,Ching-Cheng, et al. Film-forming polymer granulated excipients as mtric materials for the production of pellets by extrusion/spheronization. Chin. Pharm. J., (Taipei)1997, 49 (4): 249-257
[14] Tsai,Tsuimin, San,Yu-Ping, Ho,Hsiu-O.Film-forming polymer-granulated excipient as the matrix materials for controlled-release dosage forms. J. Controlled Release, 1998, 51 (2, 3): 289-299
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[18] Nath BS, Venkatesh, Hiremath D. Formulation and evaluation of sustained release dosage form of theophylline using a combined hydrophobic and hydrophobic and hydrophilic matrix. Indian J. Pharm. Sci., 2000, 62 (1): 33-36
[19] 苑振亭，王晓文，赵中华，等．氢溴酸右美沙芬缓释片的制备及释放度研究．中国医院药学杂志，1999，19(10)：598-601
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[23] Raffa.Robert B.Opioid and Nonopioid Components Independently Contribute to the Mechanism of Action of Tramadol, an 'Atypical' Opioid Analgesic. J.
Pharm..Exp.Ther. 1992, 260 (1): 275-285
[24] Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinefic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993, 46 (8): 313-40
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[2] Zahirul M, Khan I. Resent trend and progress in sustained or controlled oral delivery of some water soluble drugs: morphine salts, diltiazem and captopril. Drug Dev. Ind. Pharm., 1995, 21 (9): 1037-1070
[3] Yamakita H, Matsukawa Y, Maejima T,et al. Preparation of controlled release granules of TA-5707F using entericpolymers and ethlcellulose, and their in vivo evaluation. Biol. Pharm. Bull., 1996, 19 (1): 106-113
[4] Dong ZC, Jiang XT. Effect of physical-chemical properties of HPMC on dissolution from hydrophilic matrix tablets. Yaoxue Xuebao (Acta Pharm Sinica), 1994, 29 (12): 920-924
[5] Yamakita H, Maejima T,Osawa T. In vitro/in vivo evalution of two series of TA-5707F controlled release matrix tablets prepared with hydroxypropyl methyl cellulose derivatives with entero-soluble or gel-formation properties. Biol. Pharm. Bull., 1995, 18 (10): 1409-1416
[6] Gao P, Nixon PR,Skoug JW. Difusion in HPMC gels Ⅱ. Prediction of drug release rates from hydrophilic matric extended release dosage forms. Pharm. Res., 1995, 12 (7): 965-971
[7] Wan LSC, Heng PWS, Wong LF. The effect of hydroxypropyl on water penetration into amatrix system. Int. J. Pharm., 1991, 73 (2): 111-116
[8] Wan LSC, Heng PWS, Wong LF. Relationship between swelling and drug release in a hydrophilic matrix. Drug Dev. Ind. Pharm., 1993, 19 (10): 1201-1210
[9] Bettini R, Colombo P, Masssimo G, et al. Swelling and drug release in hydrogel matrices: polymer viscosity and matrix porosity effexts. Eur. J. Pharm. Sci., 1994, 2 (3): 213-219
[10] Colombo P, Bettini R, Masssimo G, et al. Drug diffusion front movement is important in drug release control from swellable matrix tablets. J. Pharm. Sci.,
1995, 84 (8): 991-997
[11] Wan LSC, Heng PWS, Wong LF. Matrix swelling: A simple model describing extent of swelling of HPMC matrices. Int. J. Pharm., 1995, 116 (2): 159-168
[12] Colombo P. Swellable matrices for oral controlled release: an update on delivery mechanism. Eur. J. Pharm. Sci., 1998, 6 (suppl.1): 11-17
[13] Tsai,Tsuimin, Ho,Hsiu-O, Kao,Ching-Cheng, et al. Film-forming polymer granulated excipients as mtric materials for the production of pellets by extrusion/spheronization. Chin. Pharm. J., (Taipei)1997, 49 (4): 249-257
[14] Tsai,Tsuimin, San,Yu-Ping, Ho,Hsiu-O.Film-forming polymer-granulated excipient as the matrix materials for controlled-release dosage forms. J. Controlled Release, 1998, 51 (2, 3): 289-299
[15] Choi Hyun Soon, Jiang Ge, Lee Gye Won, et al. The preparation of controlled-releasse mierocapsules for captopril and their dissolution characteristics. Yakche Hakhoechi, 1998, 28 (1): 7-13
[16] 张淑秋，冷光，谢茵，等．卡托普利控释微丸的研制及其体外释放研究．山西医科大学学报，1997，28(1)：16-18
[17] 曾环想，潘卫三，陈济民，等．法莫替丁缓释片的制备工艺及其体外释放特性的研究．中国药学杂志，1997，32(4)：213-215
[18] Nath BS, Venkatesh, Hiremath D. Formulation and evaluation of sustained release dosage form of theophylline using a combined hydrophobic and hydrophobic and hydrophilic matrix. Indian J. Pharm. Sci., 2000, 62 (1): 33-36
[19] 苑振亭，王晓文，赵中华，等．氢溴酸右美沙芬缓释片的制备及释放度研究．中国医院药学杂志，1999，19(10)：598-601
[20] 张淑秋，谢茵，郝正华，等．卡托普利缓释片的研究．中国药学杂志，1996，31(11)：668-669
[21] 杨阳等．镇痛新药曲马多的药理和临床研究近况．中国药理学通报，1994，10(5)：396-398
[22] Dayer P, Collart L, Desmeules J. The pharmacology oftramadol. Drugs. 1994,47 (suppl.1 ): 3-7
[23] Raffa.Robert B.Opioid and Nonopioid Components Independently Contribute to the Mechanism of Action of Tramadol, an 'Atypical' Opioid Analgesic. J.
Pharm..Exp.Ther. 1992, 260 (1): 275-285
[24] Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinefic properties, and therapeutic potential in acute and chronic pain states. Drugs. 1993, 46 (8): 313-40
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