以丙烯酸树脂材料为载体的水溶性药物控制释放体系的研究
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摘要
本论文以盐酸二甲双胍为水溶性模型药物,研究了用丙烯酸树脂作为的载体材料制备了其缓释微球及以其为骨架材料制备缓释骨架片,并对制备的微球和缓释骨架片进行了一系列的表征及体外药物释放行为的研究。
本论文的主要工作和结果为:
1.采用W1/O/W2、W/O1/O2、S/O1/O2型乳液-溶剂蒸发法制备了载有盐酸二甲双胍的丙烯酸树脂微球。盐酸二甲双胍具有较强的水溶性,采用W1/O/W2所得微球的包封率很低,改变制备工艺,比如增加聚合物浓度及在外水相中加NaCl时,包封率提高均不明显,最大包封率小于5%。因此采用W1/O/W2法很难得到高包封率的盐酸二甲双胍微球。W/O1/O2乳液-溶剂蒸发法得到了几乎同样结果,分析其原因是因为盐酸二甲双胍易溶于水,制备初乳时油水界面的存在,乳剂很容易破裂,内水相析出,从而导致MH包封率的下降。为了减少盐酸二甲双胍在微球制备过程中的损失,我们又考察了S/O1/O2乳液-溶剂蒸发法制备微球,结果所得微球的包封率有所改善。改变制备工艺,比如改变投料比,在内油相中增加丙酮、改变乳化剂和分散剂的用量时,微球的包封率都可达99%以上。但通过实验发现,S/O1/O2法制备的载药微球在体外释放过程中突释效应明显,达到50%左右,主要原因是微球表面或近表面存在一定的药物。微球释药速度快,2h的累积释放量是95%左右。
2.在已有乳液-溶剂蒸发法方法基础上,我们考虑在盐酸二甲双胍与高分子缓释层之间引入疏水性的隔离层油相,在盐酸二甲双胍药物粉末的表面形成一层隔离油层,减缓微球外界溶媒的浸入。发明了一种新型乳液-溶剂蒸发法(S/O1/O2/O3型),可以解决包埋水溶性药物的微球所遇到的问题。和传统的乳液-溶剂蒸发法相比,该工艺具有如下优势:水溶性药物粉末集中分布在隔离油相内,随后被疏水性高分子溶液的二次包裹,包封率可以接近于100%,不仅使水溶性药物在疏水性高分子微球中包封率大大提高,也使隔离层油相对水溶性药物的泄漏和快速释放得以阻滞,具有明显的控释效果。
3.在采用S/O/O/O型乳液-溶剂蒸发法制得盐酸二甲双胍/丙烯酸树脂控释微球的同时,我们考虑了降低盐酸二甲双胍的溶解度,将盐酸二甲双胍容纳于疏水性的乙酰基-β-环糊精的空腔内,生成超分子化固体包合物,降低盐酸二甲双胍在水中溶解度,制得具有缓释作用的环糊精包合物。对于包合物的制备方法采用研磨法、旋转蒸发法和叔丁醇/水共溶剂冻干法,MH与TA-β-CD摩尔比为1:1。用差示热扫描法和X射线粉末衍射法对所得到的包合物进行鉴定,并考察了MH/TA-β-CD环糊精包合物的释药行为。结果显示,不同制备方法的包合物中药物与环糊精之间的相互作用力大小如下:共溶剂冻干法>旋转蒸发法>研磨法>物理混合物,体外释放度试验也证实这一点。MH原料药、物理混合、研磨法、旋转蒸发法和叔丁醇/水共溶剂冻干法制备的包合物释药100%所需的时间分别是1,3,60,240和420min。将共溶剂冻干法制备包合物进一步与其他高分子缓释材料联合应用后,可以制备出零级释药特征明显的MH包合物缓释骨架片
The aim of this paper is preparing the water-insoluble drug metformin hydrochloride (MH)-loaded microspheres and sustained-release matrix tablets , using polymethacrylates as the matrices. The microspheres and matrix tablets obtained were characterized by SEM, DSC and XRD and in vitro drug release was studied as well.
Major work and the result of this paper are:
1.Preparation of MH-loaded Eudragit○R RS PO(Eu RS) microspheres using W1/O/W2、W/O1/O2、S/O1/O2 double emulsion solvent evaporation method. Because MH was highly soluble in water, the entrapment efficiency of microspheres prepared by W/O/W double emulsion solvent evaporation method was very low. Increasing the polymer concentration and introducing NaCl into outer water phase resulted in no increase in the entrapment efficiency, and the maximal entrapment efficiency is about 5%.Consequently, W/O1/O2 double emulsion solvent evaporation method was utilized and similar results were observed, the droplets were apt to broke and most of MH was diffused into water phase might be responsible for these results. In order to avoid MH loss during the process of solvent evaporation, We investigated S/O1/O2 emulsion solvent evaporation method. the entrapment efficiency of microspheres prepared by S/O1/O2 emulsion solvent evaporation method was improved. Changing polymer /MH ratio,increasing the amount of acetone﹑Span-80 and magnesium stearate, the entrapment efficiency of microspheres was about 99% in these cases.The S/O1/O2 type microspheres showed a significant burst effect (about 50%),with 95% of the drug released within 2h of the test period.The initial burst was attributed to release of the drug from the surface regions of the microspheres.
2.Based on W1/O/W2、W/O1/O2、S/O1/O2multiple emulsion solvent evaporation method, the protected oil phase introduced between MH and polymer sustained release layer. The protected oil phase covered on the surface of MH power which can slowdown the release medium infiltration, and solved a rapid burst release of the drug and low entrapment efficiency during prepareing water soluble drugs containing microspheres. The S/O1/O2/O3 type multiple emulsion solvent evaporation method has advantages as follow: Entrapment efficiency was achieved approximately 100%.The S/O1/O2/O3 type microspheres successfully prevented the leakage of water soluble drugs, and achieved evident drug retarding property in vivo. These results was attributed to the barrier effect of the vegetable oils phase which separated the MH power from the EtOH phase.
3. In the same time, we considered decreasing the solubility of MH. Triacetyl-β-cyclodextrin (TA-β-CD),a hydrophobic CD derivative practically insoluble in water, were prepared to evaluate their suitability for the development of a sustained-release dosage form of the drug. MH was set into TA-β-CD molecular cavity as guest.This inlusion complex supermolecular system can decrease guest’s solubility and soluable velocity. The MH/TA-β-CD products were selected as the best candidates for a suitable prolonged-release oral dosage form of MH. Equimolar MH/TA-β-CD solid compounds were obtained by different techniques, i.e. kneading, Co-evaporating and cosolvent lyophilization, in order to investigate and compare their effectiveness and influence on the physical chemical properties of the final products. Differential scanning calorimetry and X-ray power diffractometry were used for the solid-state characterization of the different MH/TA-β-CD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. According to the results of solid-state studies, the ability of the different preparation methods to promote effective interactions between drug and CD varied in the order: cosolvent lyophilization> co-evaporating> kneading> physical mixture. The same effectiveness rank order was observed also in dissolution studies. In fact the time to dissolve 100% varied increased from 1 min,for pure drug, to 3,60,240 up to 420 min for physically-mixed, keaded, co-evaporated, cosolvent lyophilization products, respectively. The resultant ternary complex could be subsequently incorporated in hydrophobic matrix tablets to achieve zero-order drug release systems.
本论文的主要工作和结果为:
1.采用W1/O/W2、W/O1/O2、S/O1/O2型乳液-溶剂蒸发法制备了载有盐酸二甲双胍的丙烯酸树脂微球。盐酸二甲双胍具有较强的水溶性,采用W1/O/W2所得微球的包封率很低,改变制备工艺,比如增加聚合物浓度及在外水相中加NaCl时,包封率提高均不明显,最大包封率小于5%。因此采用W1/O/W2法很难得到高包封率的盐酸二甲双胍微球。W/O1/O2乳液-溶剂蒸发法得到了几乎同样结果,分析其原因是因为盐酸二甲双胍易溶于水,制备初乳时油水界面的存在,乳剂很容易破裂,内水相析出,从而导致MH包封率的下降。为了减少盐酸二甲双胍在微球制备过程中的损失,我们又考察了S/O1/O2乳液-溶剂蒸发法制备微球,结果所得微球的包封率有所改善。改变制备工艺,比如改变投料比,在内油相中增加丙酮、改变乳化剂和分散剂的用量时,微球的包封率都可达99%以上。但通过实验发现,S/O1/O2法制备的载药微球在体外释放过程中突释效应明显,达到50%左右,主要原因是微球表面或近表面存在一定的药物。微球释药速度快,2h的累积释放量是95%左右。
2.在已有乳液-溶剂蒸发法方法基础上,我们考虑在盐酸二甲双胍与高分子缓释层之间引入疏水性的隔离层油相,在盐酸二甲双胍药物粉末的表面形成一层隔离油层,减缓微球外界溶媒的浸入。发明了一种新型乳液-溶剂蒸发法(S/O1/O2/O3型),可以解决包埋水溶性药物的微球所遇到的问题。和传统的乳液-溶剂蒸发法相比,该工艺具有如下优势:水溶性药物粉末集中分布在隔离油相内,随后被疏水性高分子溶液的二次包裹,包封率可以接近于100%,不仅使水溶性药物在疏水性高分子微球中包封率大大提高,也使隔离层油相对水溶性药物的泄漏和快速释放得以阻滞,具有明显的控释效果。
3.在采用S/O/O/O型乳液-溶剂蒸发法制得盐酸二甲双胍/丙烯酸树脂控释微球的同时,我们考虑了降低盐酸二甲双胍的溶解度,将盐酸二甲双胍容纳于疏水性的乙酰基-β-环糊精的空腔内,生成超分子化固体包合物,降低盐酸二甲双胍在水中溶解度,制得具有缓释作用的环糊精包合物。对于包合物的制备方法采用研磨法、旋转蒸发法和叔丁醇/水共溶剂冻干法,MH与TA-β-CD摩尔比为1:1。用差示热扫描法和X射线粉末衍射法对所得到的包合物进行鉴定,并考察了MH/TA-β-CD环糊精包合物的释药行为。结果显示,不同制备方法的包合物中药物与环糊精之间的相互作用力大小如下:共溶剂冻干法>旋转蒸发法>研磨法>物理混合物,体外释放度试验也证实这一点。MH原料药、物理混合、研磨法、旋转蒸发法和叔丁醇/水共溶剂冻干法制备的包合物释药100%所需的时间分别是1,3,60,240和420min。将共溶剂冻干法制备包合物进一步与其他高分子缓释材料联合应用后,可以制备出零级释药特征明显的MH包合物缓释骨架片
The aim of this paper is preparing the water-insoluble drug metformin hydrochloride (MH)-loaded microspheres and sustained-release matrix tablets , using polymethacrylates as the matrices. The microspheres and matrix tablets obtained were characterized by SEM, DSC and XRD and in vitro drug release was studied as well.
Major work and the result of this paper are:
1.Preparation of MH-loaded Eudragit○R RS PO(Eu RS) microspheres using W1/O/W2、W/O1/O2、S/O1/O2 double emulsion solvent evaporation method. Because MH was highly soluble in water, the entrapment efficiency of microspheres prepared by W/O/W double emulsion solvent evaporation method was very low. Increasing the polymer concentration and introducing NaCl into outer water phase resulted in no increase in the entrapment efficiency, and the maximal entrapment efficiency is about 5%.Consequently, W/O1/O2 double emulsion solvent evaporation method was utilized and similar results were observed, the droplets were apt to broke and most of MH was diffused into water phase might be responsible for these results. In order to avoid MH loss during the process of solvent evaporation, We investigated S/O1/O2 emulsion solvent evaporation method. the entrapment efficiency of microspheres prepared by S/O1/O2 emulsion solvent evaporation method was improved. Changing polymer /MH ratio,increasing the amount of acetone﹑Span-80 and magnesium stearate, the entrapment efficiency of microspheres was about 99% in these cases.The S/O1/O2 type microspheres showed a significant burst effect (about 50%),with 95% of the drug released within 2h of the test period.The initial burst was attributed to release of the drug from the surface regions of the microspheres.
2.Based on W1/O/W2、W/O1/O2、S/O1/O2multiple emulsion solvent evaporation method, the protected oil phase introduced between MH and polymer sustained release layer. The protected oil phase covered on the surface of MH power which can slowdown the release medium infiltration, and solved a rapid burst release of the drug and low entrapment efficiency during prepareing water soluble drugs containing microspheres. The S/O1/O2/O3 type multiple emulsion solvent evaporation method has advantages as follow: Entrapment efficiency was achieved approximately 100%.The S/O1/O2/O3 type microspheres successfully prevented the leakage of water soluble drugs, and achieved evident drug retarding property in vivo. These results was attributed to the barrier effect of the vegetable oils phase which separated the MH power from the EtOH phase.
3. In the same time, we considered decreasing the solubility of MH. Triacetyl-β-cyclodextrin (TA-β-CD),a hydrophobic CD derivative practically insoluble in water, were prepared to evaluate their suitability for the development of a sustained-release dosage form of the drug. MH was set into TA-β-CD molecular cavity as guest.This inlusion complex supermolecular system can decrease guest’s solubility and soluable velocity. The MH/TA-β-CD products were selected as the best candidates for a suitable prolonged-release oral dosage form of MH. Equimolar MH/TA-β-CD solid compounds were obtained by different techniques, i.e. kneading, Co-evaporating and cosolvent lyophilization, in order to investigate and compare their effectiveness and influence on the physical chemical properties of the final products. Differential scanning calorimetry and X-ray power diffractometry were used for the solid-state characterization of the different MH/TA-β-CD systems, whereas their in vitro dissolution properties were determined according to the dispersed amount method. According to the results of solid-state studies, the ability of the different preparation methods to promote effective interactions between drug and CD varied in the order: cosolvent lyophilization> co-evaporating> kneading> physical mixture. The same effectiveness rank order was observed also in dissolution studies. In fact the time to dissolve 100% varied increased from 1 min,for pure drug, to 3,60,240 up to 420 min for physically-mixed, keaded, co-evaporated, cosolvent lyophilization products, respectively. The resultant ternary complex could be subsequently incorporated in hydrophobic matrix tablets to achieve zero-order drug release systems.
引文
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[2]郑巧东,高春燕,陈欢林.药物控制释放研究及应用[J].浙江化工,2003,34 (5):26～29.
[3]赵京波,杨万泰. 合成生物降解性聚酯研究的进展[J].高分子通报,1996,(2):11～15.
[4]王德中.功能高分子材料[M].北京:中国物质出版社.1998:309.
[5]杨亚楠,尹静波,刘芳.高分子材料在药物控制释放方面的应用吉林工学院学报[J].2001, 22 (3):38～40.
[6]J Kost.Pulsed And Self-Regulated Drug Delivery CRC Press.Lnc.1990.
[7] Sergio Freitas,Hans P Merkle,Bruno Gande.Microencapsulation by solvent extraction/evaporation : reviewing the state of the art of microsphere preparation process technology[J].J.Controlled Release,2005,102:313～333.
[8]Sturrenon C,Carlfors J,Edsman K et al. Preparation of biodegradable poly (lactic - co- glycolic) acid microsphere and their in vitro release of timolol maleate[J].Int J Pharm,1993,89:235.
[9]Raghavendra C,Mundargi,Srirangarajan S,et al.Development and evalua -tion of novel biodegradable microspheres based on poly (D,L-lactide -co-glycolide) and poly( ε -caprolactone) for controlled delivery of doxycycline in the treatment of human periodontal pocket: In vitro and in vivo studies[J].J.Controlled Release,2007,119:59～68.
[10]Lagarce F,Garcion E,Faisant N,et al.Development and characterization of interleukin -18 -loaded biodegradable microspheres[J].Int J Pharm, 2006,314:179～188.
[11]Ika O, Shomizu Y, Ikada Y, Watanabe S, Natsume T, Wada R, Hyon S H, Hitonic S. Biodegradation and antitumor effect of adriamycin-containing poly (L-lactic acid) microspheres[J]. Biomaterials ,1991,(12):757～762.
[12]Kyo M, Hyon S H, Ikada Y. Effects of preparation conditions of cisplatin-loaded microspheres on the in vitro release[J]. J control release,1995,(35):73～82.
[13]Jung-Hwa Lee ,Tae Gwan Park,Hoo-Kyun Choi. Effect of formulation and processing variables on the characteristics of microspheres for water - soluble drugs prepared by w/o/o double emulsion solvent diffusion method[J]. Int J Pharm,2000,196:75～83.
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