CN101991585B - 治疗类风湿性关节炎的透皮吸收涂膜剂及其制备方法 - Google Patents
治疗类风湿性关节炎的透皮吸收涂膜剂及其制备方法 Download PDFInfo
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Abstract
一种治疗类风湿性关节炎的透皮吸收涂膜剂及其制备方法，由治疗类风湿性关节炎的主药、药物溶剂、粘合剂、成膜剂和透皮吸收促渗剂组成。治疗类风湿性关节炎的主药为雷公藤内酯醇和缓解类风湿性关节炎疼痛的镇痛药盐酸利多卡因。该涂膜剂药理作用全面，恰好阻断类风湿性关节炎疾病发展的主要病理环节，针对性强，药理效果持久，且制备方法简单。
Description
技术领域
本发明涉及药物制剂领域及制剂方法，尤其是涉及一种治疗类风湿性关节炎兼具局部镇痛的透皮吸收涂膜剂及其制备方法。
背景技术
雷公藤内酯醇(triptolide)是从卫矛科雷公藤属植物雷公藤中提取的化学成分。从药理作用来看：(1)雷公藤内酯醇既具有非特异性抗炎免疫作用，又具有以抑制为主的免疫作用。(2)对急、慢性炎症均有明显的抑制作用，而且与垂体--系统有关，主要是通过垂体引起ACTH释放，增强肾上腺皮质分泌功能。(3)应用于佐剂关节炎的研究表明：对大鼠佐剂关节炎具有明显抑制作用，大鼠佐剂关节炎是研究类风湿药物的动物模型，它的组织病理变化与人的类风湿性关节炎极为相似。总之，雷公藤内酯醇的药理作用全面，恰好阻断类风湿性关节炎疾病发展的主要病理环节，针对性强，疗效显著。它不仅兼具症状缓解与病情缓解的双重作用，还具有类激素样作用和免疫调节作用，但它又非激素，集多类药物的多种作用于一身，是两类抗类风湿性关节炎西药和激素类药无法比拟的。利多卡因是临床上应用广泛的局部镇痛药，可起到缓解类风湿性关节炎患者疼痛的症状，减轻病人的痛苦。
目前，关于涂膜剂的研究报导及专利已有不少，但专门针对雷公藤内酯醇以及利多卡因的涂膜剂却没有，因此也没有其制备方法。
发明内容
本发明目的在于提供一种治疗类风湿性关节炎的透皮吸收涂膜剂，该涂膜剂的主药能长时间地持续释放，药理效果持久，且配方简单。
治疗类风湿性关节炎的透皮吸收涂膜剂技术方案为：
一种治疗类风湿性关节炎的透皮吸收涂膜剂，其中含有治疗类风湿性关节炎的主药、药物溶剂、粘合剂、成膜剂和透皮吸收促渗剂，治疗类风湿性关节炎的主药为雷公藤内酯醇和缓解类风湿性关节炎疼痛的镇痛药盐酸利多卡因。
所述治疗类风湿性关节炎的透皮吸收涂膜剂各组成成份的最佳重量配比为：主药(1)∶主药(2)∶药物溶剂∶透皮吸收促渗剂∶粘合剂和成膜剂∶溶剂＝0.01～0.2‰∶1～2‰∶3～8％∶1～10％∶13～18％∶65～81％。
本发明还提供一种治疗类风湿性关节炎的透皮吸收涂膜剂的配方，为雷公藤内酯醇3.0mg、盐酸利多卡因1.2g、羊毛脂2.0g、PVA-124 4.0g、CMC-Na 1.0g、甘油3.0g、氮酮2.0g、双蒸水80ml。
本发明同时提供一种治疗类风湿性关节炎的透皮吸收涂膜剂的制备方法，即(1)用20ml双蒸水溶解1.0g的CMC-Na并放置24h；(2)将雷公藤内酯醇3mg溶于2ml无水乙醇，在水浴上加热至溶解，再溶于2.0g羊毛脂中，在水浴上加热至溶解；(3)用10ml水溶解1.2g的盐酸利多卡因；(4)用50ml双蒸水溶解4.0g的PVA-124，水浴上加热约20min溶解，加入盐酸利多卡因水溶液，加入CMC-Na水溶液，加入雷公藤内酯醇的乙醇羊毛脂溶液，加热约10min，挥去乙醇，加入3.0g甘油，加入2.0g氮酮，搅拌1h，得涂膜剂60g，分装即成。
有益效果：
本透皮吸收涂膜剂
(1)药物经皮吸收，直接进入体循环，避免药物受肝肠首过作用；
(2)不受胃肠道各种因素的影响，也不直接对胃肠道造成刺激或其它不利影响；
(3)具有缓释长效特点，可达24小时，每日只需给药一次；
(4)使用极为方便，无需口服或注射；
(5)安全，几乎无一般用药的毒性反应，特别是避开了雷公藤内酯醇的毒性；
(6)如果在使用过程中出现不良反应，还可立即擦去、终止给药。
本透皮吸收涂膜剂制备方法简单，投资少，无须购置大型设备和采用复杂的工艺。
具体实施方式
治疗类风湿性关节炎的透皮吸收涂膜剂由治疗类风湿性关节炎的主药、药物溶剂、粘合剂、成膜剂和透皮吸收促渗剂组成，主药为雷公藤内酯醇和缓解类风湿性关节炎疼痛的镇痛药盐酸利多卡因。
药物溶剂是从一元醇、二元醇、三元醇、酯类中选择1种或2种及以上。
药物溶剂为乙醇、丙二醇、甘油、1，2丙二醇、聚乙二醇、异丙醇、2-辛基十二烷醇、吡咯烷酮、N-甲基-2-吡咯烷酮中的1种或2种。
粘合剂和成膜剂为聚乙烯醇PVA-124、聚乙烯醇PVA-1788、聚乙烯醇PVA-0588、PVA-1750、聚乙吡咯烷酮、CMC-Na、HPMC、聚乙二醇PEG-400、明胶、卡波姆-940、玉米朊、聚乙烯醇缩丁醛、聚丙烯酸树脂III中的1种或2种或3种。
透皮吸收促渗剂为月桂醇、月桂氮唑酮(氮酮)、冰片、樟脑、肉豆蔻酸异丙酯(IPM)其中的1种或2种。
治疗类风湿性关节炎的透皮吸收涂膜剂各组成成份的最佳重量配比为：主药(1)∶主药(2)∶药物溶剂∶透皮吸收促渗剂∶粘合剂和成膜剂∶溶剂＝0.01～0.2‰∶1～2‰∶3～8％∶1～10％∶13～18％∶65～81％。
一种治疗类风湿性关节炎的透皮吸收涂膜剂的配方为：
雷公藤内酯醇 3.0mg
盐酸利多卡因 1.2g
羊毛脂 2.0g
PVA-124 4.0g
CMC-Na 1.0g
甘油 3.0g
氮酮 2.0g
双蒸水 80ml
60g/瓶
治疗类风湿性关节炎的透皮吸收涂膜剂的制备方法为：(1)用20ml双蒸水溶解1.0g的CMC-Na并放置24h；(2)将雷公藤内酯醇3mg溶于2ml无水乙醇，在水浴上加热至溶解，再溶于2.0g羊毛脂中，在水浴上加热至溶解；(3)用10ml水溶解1.2g的盐酸利多卡因；(4)用50ml双蒸水溶解4.0g的PVA-124，水浴上加热约20min溶解，加入盐酸利多卡因水溶液，加入CMC-Na水溶液，加入雷公藤内酯醇的乙醇羊毛脂溶液，加热约10min，挥去乙醇，加入3.0g甘油，加入2.0g氮酮，搅拌1h，得涂膜剂60g，分装即成。
试验例1：对佐剂关节炎大鼠原发性关节肿胀率的影响试验：
雄性大鼠50只，体重170±20g，随机分成5组，每组10只，分别为雷公藤内酯醇涂膜剂中，低剂量组(100ug/g，50ug/g)，2.5％酮基布洛芬(凝胶)阳性药对照组，赋形剂对照组，正常对照组(未注射佐剂大鼠)，分组后将大鼠分别单独装入特制筒内.后腿及尾部伸出筒外，按″毛细血管放大测量法″测定大鼠右后足容积.在右后足趾及踝关节部位(原发侧)涂药，正常对照组不涂任何制剂，对照组涂赋形剂，约0.8g/只，每日一次，连续给药7天，于第二次涂药后30min注射佐剂致炎.测量致炎后18h，d3，d6，d8左后足(佐剂注射侧)容积并按下式计算肿胀率，与赋形剂组比较进行统计学测验：
肿胀率％＝(致炎后足容积-致炎前足容积)/致炎前足容积×100％
雷公藤内酯醇涂膜剂对大鼠佐剂关节炎原发病变的影响(n＝10，X±SD)：
与赋形剂组比较＊P＜0.05，＊＊P＜0.01与正常对照组比较△△P＜0.01.
结果表明与正常组比较，赋形剂组(模型)组致炎后右足明显肿胀(P＜0.01)；与赋形剂组比较雷公藤内酯醇涂膜剂在100ug/g、50ug/g均可明显抑制佐剂关节炎大鼠右后足肿胀(P＜0.05)，且起效快持续时间长，有剂量依赖关系，二种剂量与酮基布洛芬比较抑制佐剂关节炎大鼠原发性病变作用相似，无明显差异(P＜0.05)。雷公藤内酯醇涂膜剂对原发性佐剂关节炎大鼠关节肿胀的抑制作用，提示雷公藤内酯醇涂膜剂对该疾病早期病变有一定改善作用。
试验例2：对佐剂关节炎大鼠继发性关节肿胀率的影响试验：
雄性大鼠170±15g，每鼠试验前测左后足(继发侧)容积(同原发病变)，在佐剂(酮基布洛芬)注射(右足)后d17测左后足(继发侧)容积，选择有继发性病变的大鼠50只。按佐足肿胀程度均匀分5组(见表2)每组10只。另取10只同样未注射佐剂大鼠为正常对照组，受试药分涂于左右后足部，涂药剂量，涂药范围，同原发病变，每日涂药一次连续12d。自给药之日起每隔4d测量大鼠左足(佐剂注射对测)容积，计算肿胀率，与赋形剂组比较进行统计学测验。
雷公藤内酯醇涂膜剂对大鼠佐剂关节炎继发病变的影响(n＝10，X±SD)：
与赋形剂组比较＊P＜0.05，＊＊P＜0.01与正常对照组比较△△P＜0.01.
结果表明与正常组比较，赋形剂组(模型)组在致炎后继发侧足肿胀明显增加(P＜0.01)；与赋形剂组比较雷公藤内酯醇涂膜剂在100ug/g、50ug/g及酮基布洛芬组均可明显抑制佐剂关节炎大鼠的继发性足肿胀(P＜0.05)，并随剂量增加作用增强，且这两个剂量组的抑制作用与酮基布洛芬组相似，无明显差异(P＜0.05)。
本发明中，如有必要，还可以适当添加可用于涂膜剂或可以使用的添加剂，如苹果酸、磷酸、柠檬酸、酒石酸、乳酸、二乙醇胺、三乙醇胺、二异丙醇胺等PH调节剂；缩水梨糖醇脂肪酸酯、甘油脂肪酸酯、聚氧乙烯加氢蓖麻、聚氧乙烯硬脂基醚、聚氧乙基月桂基醚、月桂基硫酸钠等表面活性剂；羊毛脂、石蜡、橄揽油、杏仁油、聚异戊二烯、丙二醇、菜子油等软化剂；氧化锌、硫酸铝等收敛剂；对羟基苯甲酸丙酯等防腐剂。
本发明的透皮吸收涂膜剂，可采用涂膜剂制备技术领域中一般采用的方法来制备。
本发明中对装涂膜剂使用的容器没有特别的规定，一般装量为20ml，30ml，60ml，100ml。
Claims (2)
1.一种治疗类风湿性关节炎的透皮吸收涂膜剂，其特征在于该涂膜剂的配方为：雷公藤内酯醇3.0mg、盐酸利多卡因1.2g、羊毛脂2.0g、PVA-124 4.0g、CMC-Na 1.0g、甘油3.0g、氮酮 2.0g、双蒸水 80mL。
2.如权利要求1所述的透皮吸收涂膜剂的制备方法，其特征在于：
（1）用20mL双蒸水溶解1.0g的CMC-Na并放置24h；
（2）将雷公藤内酯醇3mg溶于2mL无水乙醇，在水浴上加热至溶解，再溶于2.0g羊毛脂中，在水浴上加热至溶解；
（3）用10mL双蒸水溶解1.2g的盐酸利多卡因；
（4）用50mL双蒸水溶解4.0g的PVA-124，水浴上加热20min溶解，加入盐酸利多卡因水溶液，加入CMC-Na水溶液，加入雷公藤内酯醇的乙醇羊毛脂溶液，加热10min，挥去乙醇，加入3.0g甘油，加入2.0g氮酮，搅拌1h，得涂膜剂60g，分装即成。
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