氢溴酸右美沙芬鼻用热敏凝胶的研究
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摘要
本论文以氢溴酸右美沙芬(dextromethorphan hydrobromide，DMH)为模型药物，对鼻用热敏型在体凝胶进行了研究。鼻腔给药由于具有吸收迅速、避免首过代谢等优点，在近年来已引起广泛关注。将热敏性高分子材料泊洛沙姆407引入鼻腔给药系统，可以使鼻用制剂在室温下为自由流动的液体，给药后在鼻腔温度(33℃)下形成半固体凝胶。这种热敏凝胶剂除了具有一般鼻用制剂的优点以外，还可以明显延长药物在鼻腔的滞留时间。
对DMH的相关性质进行了研究。测定了DMH的溶解度和油／水分配系数，DMH在水、生理盐水和15％泊洛沙姆407水溶液中的表观溶解度分别为17.5，16.7和31.9mg／ml；DMH的表观油／水分配系数随pH值的增加而增大。
以胶凝温度和体外释放为指标对处方进行了筛选，得出DMH鼻用热敏凝胶最佳处方为1.5％DMH+20％Poloxamer407+2.5％PEG6000+0.01％BKC+0.9％NaCl。在该处方下，制剂的胶凝温度在32～33℃之间，体外释放规律符合Higuchi方程。
对DMH热敏凝胶进行了初步稳定性研究。结果表明该制剂在pH小于7.0时较为稳定，同时结合pH与油／水分配系数的关系，将制剂的pH值确定在6.0～7.0。该制剂对热稳定但对光稳定性稍差，提示应在避光容器中保存。
采用大鼠在体鼻腔滞留法对DMH热敏凝胶的鼻腔吸收规律进行了研究，结果表明该制剂的吸收符合一级动力学方程。
采用在体蟾蜍上颚实验模型，通过测定纤毛摆动时间、观察纤毛形态，评价了DMH热敏凝胶的纤毛毒性。结果表明，该制剂对纤毛持续摆动时间略有影响，但不影响其用于鼻腔给药。
The purpose of this paper was to develop a thermosensitive in situ gel including dextromethorphan hydrobromide(DMH) for intranasal administration. Drug delivery by the nasal route has received a lot of attention recently because of its advantages such as rapid absorption, avoidance of first-pass elimination and so on. Poloxamer 407, a thermosensitive high molecular material, was introduced into nasal drug delivery system. This material can make the nasal preparation liquid state at room temperature and a semisolid gel at nasal temperature(33℃). Thermosensitive gel formulation can prolong the nasal residence time of drug greatly except for the merits of traditional nasal preparation.The properties about DMH were studied as an essential part of preformulation. Solubility and oil/water partition coefficient of DMH were determined. The apparent solubility of DMH in water, physiological saline and 15% poloxamer 407 solution was 17.5, 16.7 and 31.9mg/ml, respectively. The apparent oil/water partition coefficient of DMH kept rising with the increasing of pH value.The formulation screening was performed by taking sol-gel transition temperature and in vitro release as indices. The best formulation of DMH thermosensitive gel was 1.5% DMH + 20% poloxamer407 + 2.5% PEG6000 + 0.01% BKC + 0.9% NaCl. In this formulation, the sol-gel transition temperature was between 32～33—℃and the DMH release from thermosensitive gel was accelerated obviously. The in vitro release of DMH followed Higuchi model.The initial stability investigation of DMH thermosensitive gel was carried out. The results indicated the stable pH range was below 7.0 and the best pH for this preparation was 6.0～7.0 according to the relationship between oil/water partition coefficient and pH value. The formulation was stable to heat but a little unstable to light, so it was better for this preparation to be stored in a light-resistant container.
The regulation of nasal absorption of DMH thermosensitive gel was investigated by the rat in situ nasal deposit method. The conclusion was that the absorption process of this preparation fitted to the first-order dynamics process.
To assess the nasal ciliary toxicity of DMH thermosensitive gel, ciliary movement time was determined and ciliary morphology was observed after administration by the hoptoad in situ maxilla mucosa method. The toxicity is very low so that the preparation can be used in nasal administration.
对DMH的相关性质进行了研究。测定了DMH的溶解度和油／水分配系数，DMH在水、生理盐水和15％泊洛沙姆407水溶液中的表观溶解度分别为17.5，16.7和31.9mg／ml；DMH的表观油／水分配系数随pH值的增加而增大。
以胶凝温度和体外释放为指标对处方进行了筛选，得出DMH鼻用热敏凝胶最佳处方为1.5％DMH+20％Poloxamer407+2.5％PEG6000+0.01％BKC+0.9％NaCl。在该处方下，制剂的胶凝温度在32～33℃之间，体外释放规律符合Higuchi方程。
对DMH热敏凝胶进行了初步稳定性研究。结果表明该制剂在pH小于7.0时较为稳定，同时结合pH与油／水分配系数的关系，将制剂的pH值确定在6.0～7.0。该制剂对热稳定但对光稳定性稍差，提示应在避光容器中保存。
采用大鼠在体鼻腔滞留法对DMH热敏凝胶的鼻腔吸收规律进行了研究，结果表明该制剂的吸收符合一级动力学方程。
采用在体蟾蜍上颚实验模型，通过测定纤毛摆动时间、观察纤毛形态，评价了DMH热敏凝胶的纤毛毒性。结果表明，该制剂对纤毛持续摆动时间略有影响，但不影响其用于鼻腔给药。
The purpose of this paper was to develop a thermosensitive in situ gel including dextromethorphan hydrobromide(DMH) for intranasal administration. Drug delivery by the nasal route has received a lot of attention recently because of its advantages such as rapid absorption, avoidance of first-pass elimination and so on. Poloxamer 407, a thermosensitive high molecular material, was introduced into nasal drug delivery system. This material can make the nasal preparation liquid state at room temperature and a semisolid gel at nasal temperature(33℃). Thermosensitive gel formulation can prolong the nasal residence time of drug greatly except for the merits of traditional nasal preparation.The properties about DMH were studied as an essential part of preformulation. Solubility and oil/water partition coefficient of DMH were determined. The apparent solubility of DMH in water, physiological saline and 15% poloxamer 407 solution was 17.5, 16.7 and 31.9mg/ml, respectively. The apparent oil/water partition coefficient of DMH kept rising with the increasing of pH value.The formulation screening was performed by taking sol-gel transition temperature and in vitro release as indices. The best formulation of DMH thermosensitive gel was 1.5% DMH + 20% poloxamer407 + 2.5% PEG6000 + 0.01% BKC + 0.9% NaCl. In this formulation, the sol-gel transition temperature was between 32～33—℃and the DMH release from thermosensitive gel was accelerated obviously. The in vitro release of DMH followed Higuchi model.The initial stability investigation of DMH thermosensitive gel was carried out. The results indicated the stable pH range was below 7.0 and the best pH for this preparation was 6.0～7.0 according to the relationship between oil/water partition coefficient and pH value. The formulation was stable to heat but a little unstable to light, so it was better for this preparation to be stored in a light-resistant container.
The regulation of nasal absorption of DMH thermosensitive gel was investigated by the rat in situ nasal deposit method. The conclusion was that the absorption process of this preparation fitted to the first-order dynamics process.
To assess the nasal ciliary toxicity of DMH thermosensitive gel, ciliary movement time was determined and ciliary morphology was observed after administration by the hoptoad in situ maxilla mucosa method. The toxicity is very low so that the preparation can be used in nasal administration.
引文
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[2] 陆彬．药物新剂型与新技术[M]．第1版．北京：人民卫生出版社，2002：451-462．
[3] 毕殿洲，毛世瑞，陈建明．鼻粘膜给药系统的进展[G]．丹东：东北三省第六届药剂学术会议论文汇编，1996，12-16．
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[5] Chien YW. Novel drug delivery systems[M]. Drugs and the pharmaceutical sciences, 1999, 50: 229-231.
[6] 梁文权．生物药剂学与药物动力学[M]．第1版．北京：人民卫生出版社，2000：64-65．
[7] 王峰，蒋新国．鼻黏膜作为脑内递药途径的研究进展[J]．药学学报，2001，36(8)：636-640．
[8] 相小强，陶涛，陈庆华．透血脑屏障制剂的研究进展[J]．中国新药杂志，2002，11(7)：519-523．
[9] 张彤，徐莲英．经鼻给药制剂研究进展[J]．中西医结合学报，2004，2(3)：223-225．
[10] 蒋新国．药物的鼻腔黏膜吸收[J]．中国新药杂志，2003，12(11)：902-905．
[11] Behl CR, Pimplaskar HK, Sileno AP, et al. Effects of physicochemical properties and other factors on systemic nasal drug delivery[J]. Adv Drug Del Rev, 1998, (29): 89-116.
[12] Martin E, Schipper NGM, Verhoef JC, et al. Nasal mucociliary clearance as a factor in nasal drug delivery[J]. Adv Drug Del Rev, 1998, (29): 13-38.
[13] 毛世瑞，史哲，毕殿洲．安乃近溶液鼻粘膜吸收的研究[J]．中国药学杂志，1997，32(2)：87-90．
[14] 魏刚．体温敏感眼用凝胶的研究[D]．沈阳药科大学博士学位论文，2002．6
[15] 魏刚，徐晖，郑俊民．原位凝胶的形成机制及在药物控制释放领域的应用[J]．中国药学杂志，2004，38(8)：564-568．
[16] 我国医药科技发展现状及前景展望[R]．广州医药集团有限公司网站，http://www.gpc.com.cn/innovate/kjzw.htm, 2005.04.
[17] Gilbert JC, Hadgraft J, Bye A, et al. Drug release from Pluronic F-127 gels[J]. Int J Pharm, 1986, 32: 223-228.
[18] 李柏，凌昌全。泊洛沙姆407研究新进展[J]．中国医药工业杂志，2001，21(12)：752-753．
[19] Bohorquez M, Koch C, Trygstad T, et al. A study of the temperature-dependent micellization of Pluronic F127[J]. J Colloid Interface Sci. 1999, 216(1): 34-40.
[20] Choi HG, Jung JH, Ryu JM, et al. Development of in situ-gelling and mucoadhesive acetaminophen liquid suppository[J]. Int J Pharm, 1998, 165: 33-44.
[21] Choi HG, Oh YK, Kim CK. In situ gelling and mucoadhesive liquid suppository containing acetaminophen: enhanced bioavailability[J]. Int J Pharm, 1998, 165: 23-32.
[22] 王明坤，方晓玲．泊洛沙姆在药剂学中的应用[J]．中国医药工业杂志，2002，33(12)：621-624．
[23] Kim EY, Gao ZG, Park JS, et al. rhEGF/HP-β-CD complex in poloxamer gel for ophthalmic delivery[J]. Int J Pharm, 2002, 233: 159-167.
[24] Wei G, Xu H, Ding PT, et al. Thermosetting gels with modulated gelation temperature for ophthalmic use: rheological and gamma scintingraphic studies[J]. J Controlled Release, 2002, 83(1): 65-72.
[25] Lee BJ, Lee TS, Cha BJ, et al. Percutaneous absorption and histopathology of a poloxamer-based formulation of capsaicin analog[J], Int J Pharm, 1997, 159: 105-114.
[26] 王文俭，蒋雪涛，刘祚永，等．喃氟啶从poloxamer 407凝胶基质中的体外释放[J]．中国临床药学杂志，1998，7(5)：233-235．
[27] Ricei EJ, Lunardi LO, Nanelares DMA, et al. Sustained release of lidocaine from Poloxamer 407 gels[J]. Int J Pharm, 2005, 288: 235-244.
[28] Pisal SS, Paradkar AR, Mahadik KR, et al. Pluronic gels for nasal delivery of Vitamin B12. Part Ⅰ: Preformulation study[J]. Int J Pharm, 2004, 270: 37-45.
[29] 国家基本药物领导小组．国家基本药物(西药)[M]．北京：人民卫生出版社，1999：452．
[30] The United States Pharmacopeial Convention. USP27[K], 2004: 580.
[31] 苑振亭，刘士平，潘志浩，等．氢溴酸右美沙芬制剂的研究概况[J]．军队医药，2000，10(4)：25-28．
[32] 国家食品药品监督管理局网站，http://www.sda.gov.cn.2005.04．
[33] 苏德森，王思玲．物理药剂学[M]．第1版．北京：化学工业出版社，2004：102
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