美洛昔康贴剂的研究
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摘要
新型非甾体抗炎药美洛昔康临床主要用于治疗风湿性、类风湿性关节炎及骨炎。作为第一个上市的环氧合酶-2抑制剂，美洛昔康因对炎症介质诱导的环氧合酶-2(COX-2)有高度选择性抑制作用，而具有抗炎效果好，且胃肠道副作用小等优点。但近年来研究证实COX-2在调控肾功能中起重要作用，故COX-2抑制剂可能产生严重的肾脏副作用。国内外上市剂型有片剂、胶囊、注射剂，另有凝胶剂在研。为了方便老年人及肾功能不全病人用药，提高用药安全性及病人顺应性，本文研制了美洛昔康贴剂。
美洛昔康在正辛醇／水中logP为1.91，属于脂溶性小分子药物，适于局部给药。本文采用紫外分光光度法对美洛昔康在不同pH溶液中溶解度(10h)进行测定的同时，采用水平扩散池对不同pH介质中美洛昔康经离体鼠皮的扩散行为进行了比较，结果表明稳态流量随pH值升高而增加；渗透系数比较结果：非解离形药物比离子形更易穿透皮肤，但首要条件是药物要具备一定溶解度。
在此基础上，以pH8的磷酸盐缓冲液作为研究介质，研究了几种常用的渗透促进剂对美洛昔康的经离体大鼠皮肤渗透性的促进作用，结果发现氮酮促渗作用最为显著，但天然物质薄荷亦有明显促渗作用；采用微渗析取样技术联合高效液相色谱测定法研究了氮酮及薄荷对大鼠在体的美洛昔康溶液经皮渗透性的促进作用。结果表明，扩散池法与微渗析法对美洛昔康经皮渗透行为的评价具良好的相关性。
本文在对贴剂各项指标测定方法进行了方法学考察的基础上，采用DSC及TG证实了基质型贴剂常用辅料与药物间无配伍变化；考察
沈阳药科大学硕士学位论文 摘 要
了压敏胶型号、增塑剂、交联剂及药物含量对贴剂粘性及释药性影响，
以药物的体外渗透性为主要考察指标，综合考虑贴剂的初粘性、持粘
性等性能，采用正交试验设计方法对贴剂处方进行了优化，并对优化
后处方工艺的质量重现性进行了全面考察，结果本文所制备贴剂压敏
胶成膜均匀，粘性适中，释药迅速完全，可保持皮肤表面较高的药物
浓度，根据Guy等人对贴剂的定性标准，属皮肤控释型基质型贴剂。
采用局部组织活检方祛，利用HPLC分析技术对大鼠口服或局部给
药后美洛昔康在血浆、皮肤及肌肉等组织的分布进行了研究。实验结
果表明贴剂给药后血药浓度虽远低于口服给药者，且无明显的峰谷，
但局部深层组织中药物的分布高于口服者，说明局部给药在获得较高
的局部组织浓度的同时，避免了较高血药浓度所致的副作用。口服组
Ts；；n／P与T．u。c；丫P均远小于贴剂组，故贴剂给药后药物传递到局部深层
组织主要是药物的直接渗透，并非血液平衡系统传递。本文以微渗析
技术对贴剂给药后裸鼠真皮中游离药物浓度进行了在体测定，实验结
果表明微渗析所测游离药物浓度远低于局部组织活检祛所测总浓度，
提示局部给药时药物与角蛋白有较高结合率。
Meloxicam is a new NSAID. In contrast with other NSAIDs currently available,it appears to have greater inhibitory activity against the inducible isoform of cyclo-oxygenase(COX-2), which is implicated in the inflammatory response, than against the constitutive isoform (COX-1),inhibition of which is associated with gastrointestinal and renal adverse events and inhibition of platelet aggregation. However, it was reported recently that the COX-2inhibitor could cause the danger renal harm because of its important actor in regulating and controlling the renal function. In order to adapt the need of large amount of rheumatoid arthritis and ostoarthritis patients with renal and gastrointestinal suffer, the Meloxicam transdermal film was formulated and studied.
The PBS with pH8 was used as permeation medium. The enhancement of ten kinds of permeation enhancers for Meloxicam across full thickness rat skin was studied with modified Valia-Chien diffusion cell. And the steady-state fluxes (Js) and enhancement ratios (ER) for Meloxicam through the rat skin being treated by variable enhancers were compared with control. It was indicated that the enhancement effects of the oil-soluble enhancers were not more significant than water-soluble ones, while their lag time was longer than the later. The synergistic effect between Azone and propylene glycol (PG) were confirmed by comparing the enhancement of Azone using PG as solvent with using ethanol. The enhancements of Azone and Menthe oil were also studied with ethanol as solvent and found to be dependent on the concentration of the enhancers. Cutaneous microdialysis technique was applied to study the enhancements of Azone
and Menthe Oil for the permeation of meloxicam across the skin of rat in vivo. On the same time a sensitive HPLC method was developed and used to determine meloxicam in the dialysate. A good relationship was found in the study for permeability of meloxicam between the method of diffusion cell, which is used to study the permeation of meloxicam across the full excised rat skin, and microdialysis technique.
The methodology for determination the quality of meloxicam patch such as adhesion, content , release and permeation, etc., were studied first. The DSC and TG technique were used to study the contraindication between the drug and excipients and it is showed they were compatible with each other. With acrylic polymers E100 as adhesive vehicle, the formulation and procedure of meloxicam patch was studied. Optimal formulation was achieved by orthogonal experiment with the permeability of the drug across the excised hairless mouse skin and adhesion of the patch as index of the optimization. It was showed that the permeation kinetics of meloxicam across the hairless mouse skin belonged to zero-order pattern.
After topical administration of the patch, drug disposition in local deep tissues (skin, muscle) and plasma was investigated with HPLC technique, and the examination was implemented simultaneously following oral administration. The Cmax and AUC in plasma p.o. were found more higher than topical administration. However, the Cmax and AUC in skin and muscle p.o were more lower than topical administration, which showed that topical administration of meloxicam was superior to the oral administration in achieving higher drug concentration in local deep tissues, avoiding high plasma concentration and reducing side effects.
On the other hand , cutaneous microdialysis technique was used to
study the drug delivery across the hairless skin invo after the administration of meloxicam patch. It was demonstrated that the free drug concentration in dermis determined by microdialysis was far lower than the total concentration in skin and muscle found by biopsy, which suggested that there could be a high protein bound ratio in skin following topical administration.
美洛昔康在正辛醇／水中logP为1.91，属于脂溶性小分子药物，适于局部给药。本文采用紫外分光光度法对美洛昔康在不同pH溶液中溶解度(10h)进行测定的同时，采用水平扩散池对不同pH介质中美洛昔康经离体鼠皮的扩散行为进行了比较，结果表明稳态流量随pH值升高而增加；渗透系数比较结果：非解离形药物比离子形更易穿透皮肤，但首要条件是药物要具备一定溶解度。
在此基础上，以pH8的磷酸盐缓冲液作为研究介质，研究了几种常用的渗透促进剂对美洛昔康的经离体大鼠皮肤渗透性的促进作用，结果发现氮酮促渗作用最为显著，但天然物质薄荷亦有明显促渗作用；采用微渗析取样技术联合高效液相色谱测定法研究了氮酮及薄荷对大鼠在体的美洛昔康溶液经皮渗透性的促进作用。结果表明，扩散池法与微渗析法对美洛昔康经皮渗透行为的评价具良好的相关性。
本文在对贴剂各项指标测定方法进行了方法学考察的基础上，采用DSC及TG证实了基质型贴剂常用辅料与药物间无配伍变化；考察
沈阳药科大学硕士学位论文 摘 要
了压敏胶型号、增塑剂、交联剂及药物含量对贴剂粘性及释药性影响，
以药物的体外渗透性为主要考察指标，综合考虑贴剂的初粘性、持粘
性等性能，采用正交试验设计方法对贴剂处方进行了优化，并对优化
后处方工艺的质量重现性进行了全面考察，结果本文所制备贴剂压敏
胶成膜均匀，粘性适中，释药迅速完全，可保持皮肤表面较高的药物
浓度，根据Guy等人对贴剂的定性标准，属皮肤控释型基质型贴剂。
采用局部组织活检方祛，利用HPLC分析技术对大鼠口服或局部给
药后美洛昔康在血浆、皮肤及肌肉等组织的分布进行了研究。实验结
果表明贴剂给药后血药浓度虽远低于口服给药者，且无明显的峰谷，
但局部深层组织中药物的分布高于口服者，说明局部给药在获得较高
的局部组织浓度的同时，避免了较高血药浓度所致的副作用。口服组
Ts；；n／P与T．u。c；丫P均远小于贴剂组，故贴剂给药后药物传递到局部深层
组织主要是药物的直接渗透，并非血液平衡系统传递。本文以微渗析
技术对贴剂给药后裸鼠真皮中游离药物浓度进行了在体测定，实验结
果表明微渗析所测游离药物浓度远低于局部组织活检祛所测总浓度，
提示局部给药时药物与角蛋白有较高结合率。
Meloxicam is a new NSAID. In contrast with other NSAIDs currently available,it appears to have greater inhibitory activity against the inducible isoform of cyclo-oxygenase(COX-2), which is implicated in the inflammatory response, than against the constitutive isoform (COX-1),inhibition of which is associated with gastrointestinal and renal adverse events and inhibition of platelet aggregation. However, it was reported recently that the COX-2inhibitor could cause the danger renal harm because of its important actor in regulating and controlling the renal function. In order to adapt the need of large amount of rheumatoid arthritis and ostoarthritis patients with renal and gastrointestinal suffer, the Meloxicam transdermal film was formulated and studied.
The PBS with pH8 was used as permeation medium. The enhancement of ten kinds of permeation enhancers for Meloxicam across full thickness rat skin was studied with modified Valia-Chien diffusion cell. And the steady-state fluxes (Js) and enhancement ratios (ER) for Meloxicam through the rat skin being treated by variable enhancers were compared with control. It was indicated that the enhancement effects of the oil-soluble enhancers were not more significant than water-soluble ones, while their lag time was longer than the later. The synergistic effect between Azone and propylene glycol (PG) were confirmed by comparing the enhancement of Azone using PG as solvent with using ethanol. The enhancements of Azone and Menthe oil were also studied with ethanol as solvent and found to be dependent on the concentration of the enhancers. Cutaneous microdialysis technique was applied to study the enhancements of Azone
and Menthe Oil for the permeation of meloxicam across the skin of rat in vivo. On the same time a sensitive HPLC method was developed and used to determine meloxicam in the dialysate. A good relationship was found in the study for permeability of meloxicam between the method of diffusion cell, which is used to study the permeation of meloxicam across the full excised rat skin, and microdialysis technique.
The methodology for determination the quality of meloxicam patch such as adhesion, content , release and permeation, etc., were studied first. The DSC and TG technique were used to study the contraindication between the drug and excipients and it is showed they were compatible with each other. With acrylic polymers E100 as adhesive vehicle, the formulation and procedure of meloxicam patch was studied. Optimal formulation was achieved by orthogonal experiment with the permeability of the drug across the excised hairless mouse skin and adhesion of the patch as index of the optimization. It was showed that the permeation kinetics of meloxicam across the hairless mouse skin belonged to zero-order pattern.
After topical administration of the patch, drug disposition in local deep tissues (skin, muscle) and plasma was investigated with HPLC technique, and the examination was implemented simultaneously following oral administration. The Cmax and AUC in plasma p.o. were found more higher than topical administration. However, the Cmax and AUC in skin and muscle p.o were more lower than topical administration, which showed that topical administration of meloxicam was superior to the oral administration in achieving higher drug concentration in local deep tissues, avoiding high plasma concentration and reducing side effects.
On the other hand , cutaneous microdialysis technique was used to
study the drug delivery across the hairless skin invo after the administration of meloxicam patch. It was demonstrated that the free drug concentration in dermis determined by microdialysis was far lower than the total concentration in skin and muscle found by biopsy, which suggested that there could be a high protein bound ratio in skin following topical administration.
引文
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[3] The First Selective COX-2 Inhibitor—Meloxicam[J].China Contemporary Medcine 2001, Vol. 7(2):70～71.
[4] 徐海燕，钟大放，肇丽梅等．美洛昔康在中国健康受试者体内的药物动力学研究[J]．药学学报Acta Pharmaceutica Sinica 2001, 36(1): 71～73.
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[10] COX-2抑制剂损害肾功能[J]国外医学药学分册2001年2月Vol28(1)．
[11] Summary of the product characteristics, http://www3.mpa.se
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[2] 王平，顾振纶．新型非甾体抗炎药——美洛昔康[J]．中国新药与临订杂志，2000年11月，19(6)：499～501。
[3] The First Selective COX-2 Inhibitor—Meloxicam[J].China Contemporary Medcine 2001, Vol. 7(2):70～71.
[4] 徐海燕，钟大放，肇丽梅等．美洛昔康在中国健康受试者体内的药物动力学研究[J]．药学学报Acta Pharmaceutica Sinica 2001, 36(1): 71～73.
[5] 王庆利，盛春元，赵桂宏，新型非甾体抗炎药COX-2选择性抑制剂的研究及应用进展[J]．中国药房，2001，12(5)：305～306．
[6] Stuart Noble and Julia A. Balfour Meloxicam, Drugs[J]. 1996,5(3), 424-430.
[7] British Pharmacopoeia[Z]. 1998, 936～937.
[8] D.TURCK, W. ROTH and U. BUSCH. A REVIEW OF THE CLINICAL PHARMACOKINETICS OF MELOXICAM[J]. British Journal of Rheumatology 1996;35 (Suppl. 1): 13～16.
[9] P. STEI, B.KRUSS, J.WIEGLEB, etc...Local Tissue Tolerability of meloxicam, A new NSAID: Indications for Parenteral, Dermal and Mucosal Administration. [J]. British Journal of Rheumatology 1996; 35 (Suppl. 1): 44～50.
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