CN109316602A - 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用 - Google Patents
一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用 Download PDFInfo
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- CN109316602A CN109316602A CN201811346227.6A CN201811346227A CN109316602A CN 109316602 A CN109316602 A CN 109316602A CN 201811346227 A CN201811346227 A CN 201811346227A CN 109316602 A CN109316602 A CN 109316602A
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Abstract
本发明属于药学领域,主要涉及一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用。本发明所述系统的主药是局部麻醉药物和非甾体抗炎药的组合物,还包括溶媒及相应的缓释材料。主药采用局部麻醉药与非甾体抗炎药复方,局部麻醉药可以弥补单独使用非甾体抗炎药时镇痛效果弱的缺点;而局麻药可以通过降低机体的痛觉敏感来增强局部麻醉药的镇痛效果、抑制炎症反应促进伤口愈合;另外,二者合用可以降低两者的给药剂量从而减少各自的不良反应。
Description
技术领域
本发明属于药学领域,主要涉及一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用。
背景技术
由手术、刀伤、烧伤等引起的伤害性疼痛,是临床上最常见的并且最需紧急处理的急性疼痛。这种疼痛如果得不到及时控制,不仅对患者的心理及生理各器官功能产生重大的影响,如:焦虑、失眠、烦躁不安、恶心呕吐、尿潴留、免疫抑制、出现肺部并发症、血压升高以及心肌缺血危险增加等。目前,临床上有高达70%的患者对术后镇痛效果不满意,而且25%-55%的术后急性痛会发展成慢性疼痛,持续疼痛时间达半年乃至数十年,甚至导致残障。
因此,为减轻创伤患者的疼痛、稳定患者的各器官功能、改善患者愈后和缩短患者的住院时间,对于伤害性疼痛的镇痛,尤其是长效镇痛,是临床急待解决的问题。
目前,临床镇痛的药物以及其在长效镇痛方面的特点如下:
阿片类镇痛药类,如:吗啡、丁丙诺啡、曲马多、芬太尼、舒芬太尼、阿芬太尼、瑞芬太尼等。该类药起效迅速、镇痛作用强,无器官毒性,维持时间短,作用时间为几分钟到几小时不等(<6小时)。但是该类药物的副作用大,对于术后痛等需要长效镇痛的症状,长期反复使用的副作用非常严重,如:恶心呕吐、呼吸抑制、耐受、身体依赖、便秘、尿潴留、精神错乱等;另外该类药物也引发术后痛觉敏化,使病人对镇痛药的需求量明显增加。
局部麻醉药,主要通过椎管内用药、局部浸润、区域神经丛或外周神经阻滞的方法给药。其代表药物有:罗哌卡因、利多卡因、布比卡因、左布比卡因、普鲁卡因、丁卡因、等。其中,罗哌卡因的镇痛效果确切、作用时间长、毒性低、“感觉-运动神经分离”的现象最为明显且,是用于术后镇痛的理想药物。术后痛通常在术后或麻醉作用消失后开始产生,一般持续时间为3-7天,其中前3天的痛觉最为剧烈,也是术后镇痛的关键期。但是,罗哌卡因的作用时间为8小时作用,对于术后镇痛是远远不够的。因此,临床上一般采用硬膜外自控镇痛,即,以恒定速度注入镇痛药物,并根据需要追加药量,极大地提高了患者的顺应性。但是,该方法所耗费的人力物力成本较高。
非甾体抗炎药,根据给药方式可以分为两类:口服药物和注射药物。口服药物主要包括:布洛芬、美洛昔康、塞来昔布、氯诺昔康、双氯酚酸等;注射药物主要包括:帕瑞昔布、氯诺昔康、氟比诺芬酯和酮咯酸等。该类药物主要用于中小手术后的镇痛。但是对于大手术的术后痛,该类药物的镇痛作用不明显,需要与其他类镇痛药(阿片类或者局部麻醉类)合用,才能达到效果。
因此,相对于阿片类镇痛药,局部麻醉药和非甾体抗炎药均为长效镇痛的理想药物。我们于2013年申请了专利-无成瘾性镇痛缓释递药系统的组方及制备方法,专利号为CN103142458,申请了对局部麻醉药的缓释递药系统的组方和制备方法进行专利保护。之后,于2018年我们公司又申请了专利-一种以磷脂-混溶剂-油为载体的局部麻醉药缓释制剂与制备方法,申请号为201810592597.1,在之前专利的基础上对组方进行了改进,在组方中加入磷脂并申请了专利保护。在这两个专利的基础上,我们发现局部麻醉药在合用了非甾体抗炎药后,递药系统的镇痛作用更加优越,还可以促进伤口愈合,主要表现为:
1.非甾体抗炎药可以增强局麻药的镇痛作用。组织损伤后,由于脊髓和外周前列腺素的合成和分泌导致机体对刺激的反应阈值下降,痛觉感受器对组胺、缓激肽等其他致痛物质的敏感性增强从而加重疼痛。因此,非载体抗炎药可以通过抑制前列腺素引起的痛觉敏感而增强局麻药的镇痛作用。
2.非甾体抗炎药可以激活内源性的阿片神经内啡肽系统,增强镇痛效果,且不会出现阿片类镇痛药的副作用。
3.非甾体抗炎药的抗炎效果可以促进伤口愈合,加快患者康复。
4.手术后,炎症反应,尤其是外周和中枢神经系统的炎症反应,对于机体由急性痛向术后慢性疼痛有着非常重要的作用。因此,早期及时地抑制术后炎症反应对于有效抑制术后慢性疼痛的产生,改善患者的生活质量有着非常重要的意义。
5.与非甾体抗炎药合用后,局部麻醉药和非甾体抗炎药的给药剂量均可有所降低,减少两者的毒副作用。
临床调查显示,目前临床上用于长效镇痛的药物比较单一,均为水性制剂,作用时间短。本发明联合应用了局部麻醉药和非甾体抗炎药并制备成缓释制剂来达成持久镇痛并促进伤口愈合的目的。将二者制备成复方缓释制剂不仅可以丰富临床镇痛药物品种、方便给药,还可以拓展其临床应用范围,减少临床给药次数,降低临床不良反应,促进伤口愈合,凸显出很好的临床开发前景,另外本发明的制剂制备工艺简单可控、生产成本低、便于实现产业化。
基于以上发现,我们开发了一类局部麻醉药与非甾体抗炎药复方缓释递药系统,该递药系统可以用于刀伤、手术后的长效镇痛并促进伤口愈合。
发明内容
本发明的目的在于提供一种长效镇痛并促进伤口愈合的复方缓释递药系统。
该系统的主药是局部麻醉药物和非甾体抗炎药的组合物,还包括溶媒及相应的缓释材料。主药采用局部麻醉药与非甾体抗炎药复方,局部麻醉药可以弥补单独使用非甾体抗炎药时镇痛效果弱的缺点;而局麻药可以通过降低机体的痛觉敏感来增强局部麻醉药的镇痛效果、抑制炎症反应促进伤口愈合;另外,二者合用可以降低两者的给药剂量从而减少各自的不良反应。
本发明的递药系统的特征为:油溶液型递药系统,制剂稳定,均一性较好。
本发明所述的复方缓释递药系统,由局部麻醉药、非甾体抗炎药、溶媒和缓释材料组成,其中,局麻药的浓度为10-100mg/ml,非甾体抗炎药的浓度为 2-30mg/ml,溶媒的比例为10%-70%(v/v),剩下的为缓释材料,其中缓释材料由磷脂和油构成,二者体积的比例范围为4:1~1:4。
优选的,本发明所述的复方缓释递药系统,由以下成分组成:局麻药的浓度为10-80mg/ml,非甾体抗炎药的浓度为4-30mg/ml,溶媒的比例为10%-60%(v/v),剩下的为缓释材料,其中缓释材料由磷脂和油构成,二者体积的比例范围为 3:1~1:3。
进一步优选的,本发明所述的复方缓释递药系统,由以下成分组成:局麻药的浓度为10-50mg/ml,非甾体抗炎药的浓度为12-20mg/ml,溶媒的比例为10%-50% (v/v),剩下的为缓释材料,其中缓释材料由磷脂和油构成,二者体积的比例范围为2:1~1:2。
最优选的,局麻药的浓度为40mg/ml,非甾体抗炎药的浓度为20mg/ml。
其中,局部麻醉药主要包括:布比卡因、左布比卡因、罗哌卡因、利多卡因、布鲁卡因的游离碱或其相应的盐,其盐类主要包括盐酸盐、甲磺酸盐、硫酸盐、枸橼酸盐、富马酸盐、乳酸盐、乙基磺酸盐、琥珀酸盐、谷氨酸盐、水杨酸盐、苯磺酸盐、柠檬酸盐、马来酸盐等;局部麻醉药可以是其中一种、两种或者两种以上的组合物。其中,优选为罗哌卡因的游离碱及其相应的盐,最优选为罗哌卡因的游离碱。
其中,非甾体抗炎药包括:布洛芬、舒林酸、依托度酸、吡罗昔康、美洛昔康、氯诺昔康、酮咯酸、氨基比林、帕瑞昔布、塞来昔布、尼美舒利、氟比洛芬酯;非甾体抗炎药可以是其中一种、两种或者两种以上的混合物;其存在形式可以是游离状态,也可以是其与酸或碱结合成相应的盐。
其中,溶媒指可以溶解主药(包括局部麻醉药和非甾体抗炎药)的一种、两种或两种以上的混合物;包括:苯甲醇、乙醇、丙二醇,甘油、乙酸乙酯、乳酸乙酯、苯甲酸苄酯、四氢呋喃聚乙烯醚,(分子量为200-600Da的)液态聚乙二醇中的一种、两种或两种以上的混合物。
本发明所述的缓释材料由磷脂和油组成。
其中磷脂为天然和/或合成磷脂,以及氢化磷脂,优选地,所述磷脂选自以下一种或多种:蛋黄卵磷脂、大豆卵磷脂、磷脂酰胆碱、二油酰基卵磷脂、二棕榈酰卵磷脂、二硬酯酰卵磷脂、二肉豆蔻酰磷脂酰乙醇胺、二棕榈酰磷脂酰乙醇胺、二肉豆蔻酰磷脂酰丝氨酸、二硬酯酰磷脂酰乙醇胺、蛋黄磷脂酰胆碱、多烯磷脂酰胆碱、甘油磷脂酰胆碱、氢化大豆磷脂、氢化蛋黄磷酯、二油酰基磷脂酰丝氨酸、磷脂酸、二棕榈酰磷脂酸、磷脂酰乙醇胺、蛋黄磷脂酰甘油、磷脂酰肌醇;优选为蛋黄卵磷脂、大豆卵磷脂、磷脂酰胆碱、氢化大豆磷脂中的一种、两种或者两种以上的混合物;最优选为蛋黄卵磷脂。
其中,油可以选自植物油或人工合成油脂或两者的混合物;
其中植物油包括:大豆油、蓖麻油、氢化蓖麻油、磺化蓖麻油、聚氧乙烯蓖麻油、芝麻油、花生油、棉籽油、玉米油、橄榄油、葵花子油、茶油、棕榈油、沙棘油、鱼油、大蒜油、红花油的一种、两种或者两种以上的混合物;优选为蓖麻油、大豆油、橄榄油、芝麻油、玉米油的一种、两种或者两种以上的混合物;更优选为蓖麻油、大豆油或者二者混合物。
其中人工合成油脂包括:中链油、油酸乙酯、三乙酸甘油酯、中长链油、单乙酸甘油酯、苯甲酸苄酯、肉豆蔻酸异丙酯、枸橼酸三丁酯、烷基(C12-C15) 苯甲酯、苯乙酸苄酯、辛酸乙酯、没食子酸丁二酯、没食子酸乙酯、没食子酸丙酯、肉豆蔻酸甲酯、异戊基棕榈酸酯、丙酸乙酯、丙酸异戊酯、丙酸苄酯、N- 甲基-2-吡咯烷酮、油酸及油酸酯;优选为油酸乙酯或中链油或二者的混合物。
最优选的,本发明复方缓释递药系统由以下成分组成:局麻药的浓度为 40mg/ml,非甾体抗炎药的浓度为20mg/ml,溶媒的比例为30-40%(v/v),剩下的为缓释材料,其中缓释材料由磷脂和油构成,二者体积的比例范围为2:1~1:2。
具体的,本发明复方缓释递药系统由以下成分组成:
组方1:
组方2:
组方3:
组方4:
组方5:
组方6:
组方7:
组方8:
组方9:
组方10:
组方11:
本发明的另一个目的在于提供复方缓释递药系统的制备方法,包括以下步骤:
(1)药液制备:将精密称取一定量的局部麻醉药和非甾体抗炎药物溶解于一定体积的溶媒中,超声、搅拌、剪切、振摇或者涡旋至药物完全溶解,然后添加处方量磷脂,超声、搅拌、剪切、振摇或涡旋至磷脂完全溶解,最后添加油,超声、搅拌、剪切或涡旋混匀制备出所需缓释递药系统原液;
(2)无菌分装:在无菌条件下,将制备好的药液过微孔滤膜除去杂质、除菌,然后在无菌氮气的保护下分装在容器中,压塞、压盖,可得用于镇痛的复方递药系统,放置于2-8℃下保存;
其中,所述步骤(2)中,所述递药系统还包括包材;优选地,所述包材选自以下一种或多种:西林瓶、安瓶、可填充式注射器、卡式瓶,
其中,所述步骤(2)中,所述微孔滤膜的孔径为0.2μm。
本发明的另一个目的在于提供复方缓释递药系统在制备治疗刀伤、枪伤、手术、烧伤后镇痛和/或促进伤口的愈合的药物中的应用。
本发明所述的复方缓释递药系统具有促进伤口的愈合的作用。
本发明所述的可持久镇痛并促进伤口愈合的复方缓释递药系统的实施方法为:伤口附近神经节点注射、肌肉或皮下单点或多点注射、神经根部注射、喷洒浸润止痛、切口涂抹、借助输液泵连续或间断给药。
本发明为长效油性注射剂,是将药物在溶媒的帮助下溶解在油性基质中,注射到体内后,油性制剂在注射部位形成局部贮库,溶解的药物分子随后从油性制剂中被分配进入水性间隙液,随后被吸收进入血液。除了油剂之外,缓释材料中也加入了适宜量的磷脂,其可以作为分散剂、乳化剂和稳定剂,具有增加递药系统中物质之间的互溶性、控制药物突释并延长药物释放时间的作用。
具体实施方式
通过下列实验例和实施例进一步就本发明组方、制备方法、用途进行说明,但不作为本发明的限制。
由于之前的专利如:CN103142458,CN108159055等,已经对同种类型的空白载药体系中各个辅料(溶媒、磷脂和油)的互溶性及配比做了很深入的研究,本专利将不再进行这一部分的研究,直接利用之前的最优配比进行如下试验。
试验例1局麻药与非甾体抗炎药的组合物在载药体系中的溶解性试验
称取配方量的局麻药和非甾体抗炎药,依次加入配方量的溶剂,盖塞,振摇至完全溶解;再加入配方量的磷脂,盖塞,振摇至完全溶解后加入适量的油,摇匀即可。放置2-8℃保存,观察48小时后主药的析出情况并记录,结果如表1所示。
表1药物制剂稳定性试验结果
实验结果显示:局部麻醉药(≤8%)和非甾体抗炎药(≤3%)的组合物在以上载药体系中比较稳定,在2~8℃放置48h后均无药物析出,具有较好的溶解性。
试验例2不同组方的局麻药和/或非甾体抗炎药复方制剂感觉神经阻滞试验 (热板法)
(1)动物的选择
通过热板法对体重230~250g,健康的雌性SD大鼠进行实验前筛选。将热板升温至(56±1)℃,将大鼠的其中一只后足置于其上,其另外一只后足则处于实验室室温条件中,观察并记录其受试足缩回的时间。随后以同样方法测定大鼠的另外一只后足。每只后足交替测定,间隔5分钟,各测定三次取平均值,记为基础痛阈值。如缩足时间测定结果超过5.0秒,则该大鼠基础痛阈值不符合要求,应予以剔除。
(2)分组与给药
取36只大鼠进行试验,本实验共分为6组,各组分别为生理盐水组-组1、罗哌卡因和帕瑞昔布组合物注射液-组2、罗哌卡因缓释制剂-组3(处方选自专利 CN103142458)、罗哌卡因缓释制剂-组4(处方选自申请号为201810592597.1的专利)、帕瑞昔布缓释制剂-组5、罗哌卡因和帕瑞昔布复方缓释制剂-组6(具体组方与规格见表2),各组分别在大鼠右坐骨神经干周围注入相应药物,各组给药总量均为10mg/kg。
表2不同局部麻醉药和/或非甾体抗炎药复方缓释制剂处方
(3)方法与评价
局麻药和非甾体抗炎药的复方制剂对于大鼠坐骨神经具有明显的阻滞作用,考察各组大鼠给药后感觉阻滞变化情况,并进行全面的比较与评价。为避免出现实验动物机体损伤,如热板实验中大鼠超过15s仍未出现缩足现象,应使其离开热板,并将实验结果记为15s。
(4)统计学方法
用SPSS10.0软件进行统计分析,χ2检验及组间t检验,P<0.05为有统计学意义,P<0.01表示具有显著统计学意义。
(5)感觉神经阻滞的结果评价
实验结果如表3,局麻药和非甾体抗炎药复方制剂的局部麻醉实验考察中,感觉神经阻滞表现出明显的缓释效果。与空白对照组(组1)相比,局麻药缓释制剂组(组3、组4)、非甾体抗炎药制剂组(组5)、局麻药和非甾体抗炎药复方缓释制剂(组6)有一定的持续性镇痛作用;其中,非甾体抗炎药制剂组(组5) 的镇痛强度弱于其他组;局麻药和非甾体抗炎药复方缓释制剂(组6)的镇痛时间最长,可持续48小时甚至72小时以上。局麻药缓释制剂中磷脂的加入(组4vs组 3)可以相对增强镇痛作用,延长药物的释放时间。局麻药和非甾体抗炎药复方缓释制剂组与其注射液组(组2)比较,可显著增强复方药物的镇痛作用及镇痛时间。
表3不同给药组对大鼠肌注感觉神经阻滞时间统计(n=6)
试验例3不同组方的局麻药和/或非甾体抗炎药复方制剂对大鼠伤口愈合的影响
(1)实验分组与给药剂量:SD大鼠,230~250g,雄性,36只左右,适应性饲养2-3天后,依照体重筛选并随机分为6组,每组为6只,各组分别为生理盐水组-组1、罗哌卡因和帕瑞昔布组合物注射液-组2、罗哌卡因缓释制剂-组3(处方选自专利CN103142458)、罗哌卡因缓释制剂-组4(处方选自申请号为 201810592597.1的专利)、帕瑞昔布缓释制剂-组5、罗哌卡因和帕瑞昔布复方缓释制剂-组6(具体组方与规格见表2),给药量为0.5ml/只。
(2)基本实验过程:试验动物在进行筛选和依照体重分组后,各实验组大鼠先进行背部脱毛,次日手术建立2cm*1cm大鼠背部全层缺损创面模型并计为 D0,拍照记录。随机分组,按组给药,给药方式为创口附近多点肌肉注射。
(3)观测指标:分别在给药后D1,D3,D7,D14,D21不同时间点观测各组大鼠创面愈合的情况,并依照创面愈合面积与恢复情况进行评分。
表4不同给药组对SD大鼠伤口愈合情况评分(n=6)
分组 | D1 | D3 | D7 | D14 | D21 |
组1 | - | 19.76% | 50.14% | 83.75% | 97.68% |
组2 | - | 28.45% | 58.26% | 84.63% | 97.54% |
组3 | - | 22.65% | 54.24% | 83.55% | 98.55% |
组4 | - | 23.52% | 53.83% | 85.84% | 96.01% |
组5 | - | 33.75% | 65.43% | 96.01% | 96.52% |
组6 | - | 32.35% | 69.10% | 97.34% | 98.65% |
(4)结果评价:对于不同组别、不同观测点SD大鼠创面愈合情况进行对比性评价,结果表明,局麻药和非甾体抗炎药复方缓释制剂(组6)对SD大鼠伤口愈合具有显著促进作用。与对照组(组1)和局麻药缓释制剂组(组3,组4)相比,含有非甾体抗炎药的缓释制剂组,即:非甾体抗炎药制剂组(组5)、局麻药和非甾体抗炎药复方缓释制剂组(组6)中大鼠的伤口愈合速度显著加快,说明非甾体抗炎药的加入可显著加快伤口愈合。局麻药和非甾体抗炎药组合物缓释制剂组(组6)与其注射液组(组2)比较,能够显著加快伤口的愈合,说明药物的缓释对于伤口愈合有着十分重要的意义。
试验例4肌肉刺激性试验
试验前1周,观察家兔的精神状态、食欲、体温等是否正常。采用家兔股四头肌注法,取健康6只家兔平均分成3组,每组3只,雌雄兼有,体重2~2.5kg,分别在第1组家兔左侧后肢股四头肌处注射局麻药和非甾体抗炎药复方缓释制剂 (组6)注射液(罗哌卡因30mg/ml:帕瑞昔布15mg/ml)1mL,第2组家兔左侧后肢股四头肌处注射灭菌生理盐水1mL。在给药后2、7和15d分别取每组家兔各1 只处死,解剖取股四头肌,纵向切开,观察注射部位肌肉的组织变化,如充血、红肿、变性、坏死等。量取病变直径,按照肌肉组织刺激反应的评定标准进行评定。另外取两侧注射部位肌肉组织,常规处理后,作病理组织学检查。结果评定标准见表5。当家兔的平均反应分值在2级以下,可判定为符合规定,该产品可用作肌肉注射,平均反应分值大于2级,可判定为不符合规定,该产品不可用作肌肉注射。
表5肌肉组织反应分级
试验结果
采用家兔股四头肌注法,在给药后2、7和15d,眼观无肿胀,触摸注射部位无硬结。剖检后取股四头肌,纵向切开,观察注射部位肌肉组织的反应情况,确定反应级数(见表5),平均分级为1级,小于2级,生理盐水对照组为0级,给家兔股四头肌注射灭菌生理盐水,肌肉组织与正常肌肉组织相同;注射局麻药和非甾体抗炎药复方制剂2、7和15d后注射部位未出现肌肉组织红肿、充血等刺激性反应,家兔精神状态表现良好。显微镜下观察肌纤维组织横纹清晰、结构完整,无变性、坏死和炎性反应,与生理盐水对照组比较未见明显的病理变化。
表6注射液对家兔股四头肌试验结果
试验例5不同组方的局麻药和/或非甾体抗炎药复方制剂对大鼠伤口炎症反应的影响
(1)动物模型的建立
取48只大鼠做切口痛模型,腹腔注射水合氯醛麻醉后,用10%的碘伏对大鼠左后肢皮肤进行消毒,然后用手术刀片从大鼠足底近端0.5cm处做一个长约1cm 的纵切口,切口皮肤和筋膜,用眼科镊挑起足底肌肉并纵向切割,保持肌肉的起止和附着完整,用纱布按压止血后缝合皮肤。
(2)分组与给药
本实验共分为6组,各组分别为生理盐水组-组1、罗哌卡因缓释制剂-组3(处方选自专利CN103142458)、罗哌卡因缓释制剂-组4(处方选自申请号为 201810592597.1的专利)、帕瑞昔布缓释制剂-组5、罗哌卡因和帕瑞昔布复方缓释制剂-组6(具体组方与规格见表2)各组分别在大鼠造模后立即在伤口右侧0.5cm 处注入相应药物,各组给药总量均为10mg/kg。
(3)观测指标
分别在给药后4h和24h各组处死6只,取给药侧脊髓腰彭大处,组织匀浆后,用酶联免疫吸附试验(ELISA)检测炎症因子TNF-α、IL-1β,IL-6的表达水平。
(4)统计学方法
用SPSS10.0软件进行统计分析,多组均数间比较采用单因素方差分析 (ANOVA),P<0.05为有统计学意义,P<0.01为有显著统计学意义。
(5)伤口附近炎症反应的评价
切口附近各炎症因子的表达情况见表7,与对照组(组1)和局麻药缓释制剂组(组3)相比,含有非甾体抗炎药的缓释制剂组,即:非甾体抗炎药制剂组(组4)、局麻药和非甾体抗炎药复方缓释制剂组(组5)中大鼠切口附近各炎症因子的表达显著降低。
表7不同给药组切口附近TNF-α、IL-1β,IL-6的表达水平
试验例6复方中局麻药与非甾体抗炎药剂量筛选实验
(1)不同组方的局部麻醉药和非甾体抗炎药复方缓释制剂的制备
根据表8中的处方,分别制备不同局部麻醉药和非甾体抗炎药复方缓释制剂。
表8不同局部麻醉药和非甾体抗炎药复方缓释制剂处方
(2)不同组方的局部麻醉药和非甾体抗炎药复方缓释制剂的药效学研究
根据试验例2中的热板法评估不同处方的复方缓释制剂对于大鼠感觉神经的阻滞作用,根据试验例3中的方法测定不同处方的复方缓释制剂对于大鼠伤口愈合的影响,根据试验例5中的方法测定不同处方的复方缓释制剂对于鼠伤口炎症反应的影响。
试验结果:
(i)不同组方的局部麻醉药和非甾体抗炎药复方缓释制剂对于大鼠感觉神经的阻滞作用
表9不同处方的复方缓释制剂对于大鼠伤口炎症反应的影响
不同组方的复方缓释制剂对于大鼠感觉神经的阻滞作用如表9所示,(1) 组1到组6的复方缓释制剂对于大鼠感觉神经阻滞作用显著强于组7到组9的复方缓释制剂的作用,说明,复方制剂中高、中((80mg/ml、40mg/ml)剂量的局麻药对于复方制剂的神经阻滞作用显著强于复方制剂中低剂量的局麻药(20mg/ml) 的神经阻滞作用。(2)组1到组3的复方缓释制剂与组4到组6的复方缓释制剂对于大鼠感觉神经阻滞作用没有明显的差别,说明中等剂量的局麻药 (40mg/ml)对于大鼠感觉神经阻滞作用与高剂量的局麻药(80mg/ml)对于大鼠感觉神经阻滞作用相当。(3)组1、组2、组3的复方缓释制剂对于大鼠感觉神经阻滞作用没有明显的差别,同样的,组4、组5、组6的复方缓释制剂对于大鼠感觉神经阻滞作用没有明显的差别,说明,在高、中剂量局麻药下,不同剂量的非甾体抗炎药对于复方制剂的神经阻滞作用没有显著的影响。
(ii)不同组方的局部麻醉药和非甾体抗炎药复方缓释制剂对于大鼠伤口愈合的影响
表10不同处方的复方缓释制剂对于大鼠伤口愈合的影响
分组 | D1 | D3 | D7 | D14 | D21 |
组1 | - | 34.26% | 72.61% | 95.37% | 97.68% |
组2 | - | 36.05% | 71.96% | 94.68% | 97.54% |
组3 | - | 29.65% | 56.94% | 85.35% | 97.55% |
组4 | - | 33.58% | 73.13% | 95.24% | 96.25% |
组5 | - | 35.62% | 72.42% | 96.31% | 96.62% |
组6 | - | 28.35% | 58.13% | 87.34% | 98.25% |
组7 | - | 34.92% | 73.25% | 96.21% | 98.72% |
组8 | - | 35.06% | 73.61% | 95.96% | 96.24% |
组9 | - | 29.76% | 56.34% | 86.73% | 97.34% |
不同组方的复方缓释制剂对于大鼠伤口愈合的影响如表10所示,(1)组1、组2、组4、组5、组7和组8中的复方缓释制剂对于大鼠伤口愈合的促进作用显著强于组3、组6和组9中的复方缓释制剂的作用,说明,复方制剂中高、中 (30mg/ml、20mg/ml)剂量的非甾体抗炎药对于复方制剂的促进伤口愈合作用显著强于复方制剂中低剂量的非甾体抗炎药(10mg/ml)的促进伤口愈合作用。(2) 组1和组2相比,组4和组5相比,复方缓释制剂对于大鼠伤口愈合的促进作用没有明显的差别,说明中等剂量的非甾体抗炎药(20mg/ml)对于大鼠伤口愈合的促进作用与高剂量的非甾体抗炎药(30mg/ml)对于大鼠伤口愈合的促进作用相当。(3)组1、组4与组7中的复方缓释制剂对于大鼠伤口愈合的促进作用没有明显的差别,同样的,组2、组5与组8的复方缓释制剂对于大鼠伤口愈合的促进作用没有明显的差别,说明,在高、中剂量非甾体抗炎药下,不同剂量的局部麻醉药对于复方制剂的促进伤口愈合作用没有显著的影响。
(iii)不同组方的局部麻醉药和非甾体抗炎药复方缓释制剂对于大鼠伤口炎症反应的影响
表11不同处方的复方缓释制剂对于大鼠伤口炎症反应的影响
不同组方的复方缓释制剂对于大鼠伤口炎症反应的影响如表11所示,(1) 组1、组2、组4、组5、组7和组8中的复方缓释制剂对于抑制大鼠伤口炎症反应的作用显著强于组3、组6和组9中的复方缓释制剂的作用,说明,复方制剂中高、中(30mg/ml、20mg/ml)剂量的非甾体抗炎药对于复方制剂的抑制大鼠伤口炎症反应的作用显著强于复方制剂中低剂量的非甾体抗炎药(10mg/ml)的抑制大鼠伤口炎症反应的作用。(2)组1和组2相比,组4和组5相比,复方缓释制剂对于大鼠伤口炎症反应的抑制作用没有明显的差别,说明中等剂量的非甾体抗炎药(20mg/ml)对于抑制大鼠伤口炎症反应的作用与高剂量的非甾体抗炎药(30mg/ml)对于抑制大鼠伤口炎症反应的作用相当。(3)组1、组4、与组7 中的复方缓释制剂对于抑制大鼠伤口炎症反应的作用没有明显的差别,同样的,组2、组5、组8的复方缓释制剂对于抑制大鼠伤口炎症反应的作用没有明显的差别,说明,在高、中剂量非甾体抗炎药下,不同剂量的局部麻醉药对于复方制剂的抑制大鼠伤口炎症反应的作用没有显著的影响。
综述所述,试验例6中第5组的复方制剂的药效最佳,即:中等剂量的局部麻醉药(40mg/ml)和中等剂量的非甾体抗炎药(20mg/ml)所组成的的局部麻醉药与非甾体抗炎药复方制剂的药效最佳,如:最佳的神经阻滞作用,促进伤口愈合作用和抑制伤口炎症反应的作用。
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Claims (10)
1.一种长效镇痛并促进伤口愈合的复方缓释递药系统,由局部麻醉药、非甾体抗炎药、溶媒和缓释材料组成,其中,局麻药的浓度为10-100mg/ml,非甾体抗炎药的浓度为2-30mg/ml,溶媒的比例为10%-70%(v/v),剩下的为缓释材料,其中,局部麻醉药选自:布比卡因、左布比卡因、罗哌卡因、利多卡因、布鲁卡因中的一种或多种;
其中,非甾体抗炎药物选自:布洛芬、舒林酸、依托度酸、吡罗昔康、美洛昔康、氯诺昔康、酮咯酸、氨基比林、帕瑞昔布、塞来昔布、尼美舒利、氟比洛芬酯中的一种或多种;
其中,溶媒选自:乙醇、苯甲醇、丙二醇,甘油、乙酸乙酯、乳酸乙酯、四氢呋喃聚乙烯醚和聚乙二醇(分子量200-600Da)中的一种或多种;
其中,缓释材料由磷脂和油构成。
2.根据权利要求1所述的复方缓释递药系统,其特征在于,由以下成分组成:局麻药的浓度为10-80mg/ml,非甾体抗炎药的浓度为4-30mg/ml,溶媒的比例为10%-60%(v/v),剩下的为缓释材料。
3.根据权利要求1所述的复方缓释递药系统,其特征在于,由以下成分组成:局麻药的浓度为10-50mg/ml,非甾体抗炎药的浓度为12-20mg/ml,溶媒的比例为10%-50%(v/v),剩下的为缓释材料。
4.根据权利要求1所述的复方缓释递药系统,其特征在于,局麻药的浓度为40mg/ml,非甾体抗炎药的浓度为20mg/ml。
5.根据权利要求1所述的复方缓释递药系统,其特征在于,
局部麻醉药选自:布比卡因、左布比卡因、罗哌卡因中的一种或多种;
非甾体抗炎药物选自:氯诺昔康、酮咯酸、帕瑞昔布和氟比洛芬酯中的一种或多种;
溶媒选自:乙醇、苯甲醇、乳酸乙酯和苯甲酸苄酯中的一种或多种,
缓释材料由磷脂和油组成,其中磷脂为天然和/或合成磷脂,以及氢化磷脂,优选地,所述磷脂选自以下一种或多种:蛋黄卵磷脂、大豆卵磷脂、磷脂酰胆碱、二油酰基卵磷脂、二棕榈酰卵磷脂、二硬酯酰卵磷脂、二肉豆蔻酰磷脂酰乙醇胺、二棕榈酰磷脂酰乙醇胺、二肉豆蔻酰磷脂酰丝氨酸、二硬酯酰磷脂酰乙醇胺、蛋黄磷脂酰胆碱、多烯磷脂酰胆碱、甘油磷脂酰胆碱、氢化大豆磷脂、氢化蛋黄磷酯、二油酰基磷脂酰丝氨酸、磷脂酸、二棕榈酰磷脂酸、磷脂酰乙醇胺、蛋黄磷脂酰甘油、磷脂酰肌醇;
其中,油可以选自植物油或人工合成油脂或两者的混合物;
其中植物油包括:大豆油、蓖麻油、氢化蓖麻油、磺化蓖麻油、聚氧乙烯蓖麻油、芝麻油、花生油、棉籽油、玉米油、橄榄油、葵花子油、茶油、棕榈油、沙棘油、鱼油、大蒜油、红花油的一种、两种或者两种以上的混合物;
其中,人工合成油脂包括:中链油、油酸乙酯、三乙酸甘油酯、中长链油、单乙酸甘油酯、苯甲酸苄酯、肉豆蔻酸异丙酯、枸橼酸三丁酯、烷基(C12-C15)苯甲酯、苯乙酸苄酯、辛酸乙酯、没食子酸丁二酯、没食子酸乙酯、没食子酸丙酯、肉豆蔻酸甲酯、异戊基棕榈酸酯、丙酸乙酯、丙酸异戊酯、丙酸苄酯、N-甲基-2-吡咯烷酮、油酸及油酸酯。
6.根据权利要求1所述的复方缓释递药系统,其特征在于,
磷脂选自:蛋黄卵磷脂、大豆卵磷脂、磷脂酰胆碱、氢化大豆磷脂中的一种、两种或者两种以上的混合物;
植物油选自:蓖麻油、大豆油、橄榄油、芝麻油、玉米油的一种、两种或者两种以上的混合物;
人工合成油脂选自油酸乙酯、中链油中的一种或两种混合物。
7.根据权利要求1所述的复方缓释递药系统,其特征在于,局部麻醉药或者非甾体抗炎药,可以是它的游离碱及其相应的盐;其盐包括甲磺酸盐、盐酸盐、枸橼酸盐、硫酸盐、乳酸盐、琥珀酸盐、富马酸盐、谷氨酸盐、乙基磺酸盐、苯磺酸盐、柠檬酸盐、水杨酸盐、马来酸盐等;其中,优选为甲磺酸盐、盐酸盐、枸橼酸盐和马来酸盐;最优选为甲磺酸盐和盐酸盐。
8.根据权利要求1所述的复方缓释递药系统,其特征在于,由以下成分组成:组方1:
组方2:
组方3:
组方4:
组方5:
组方6:
组方7:
组方8:
组方9:
组方10:
组方11:
9.权利要求1至8任一项所述的复方缓释递药系统的制备方法,其特征在于,包括以下步骤:
(1)药液制备:将精密称取一定量的局部麻醉药和非甾体抗炎药物溶解于一定体积的溶媒中,超声、搅拌、剪切、振摇或者涡旋至药物完全溶解,然后添加处方量磷脂,超声、搅拌、剪切、振摇或涡旋至磷脂完全溶解,最后添加油,超声、搅拌、剪切或涡旋混匀制备出所需缓释递药系统原液;
(2)无菌分装:在无菌条件下,将制备好的药液过微孔滤膜除去杂质、除菌,然后在无菌氮气的保护下分装在容器中,压塞、压盖,可得用于镇痛的复方递药系统,放置于2-8℃下保存;
其中,所述步骤(2)中,所述递药系统还包括包材;优选地,所述包材选自以下一种或多种:西林瓶、安瓶、可填充式注射器、卡式瓶,
其中,所述步骤(2)中,所述微孔滤膜的孔径为0.2μm。
10.权利要求1所述的复方缓释递药系统在制备治疗刀伤、枪伤、手术、烧伤后镇痛和/或促进伤口的愈合的药物中的应用。
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