CN116211799A - 一种局麻药复合物混悬剂 - Google Patents
一种局麻药复合物混悬剂 Download PDFInfo
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- CN116211799A CN116211799A CN202310059656.XA CN202310059656A CN116211799A CN 116211799 A CN116211799 A CN 116211799A CN 202310059656 A CN202310059656 A CN 202310059656A CN 116211799 A CN116211799 A CN 116211799A
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- Prior art keywords
- local anesthetic
- complex
- sodium
- ropivacaine
- suspension
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Abstract
本发明公开了一种局麻药复合物混悬剂,包含局麻药与离子型表面活性剂的疏水复合物以及药学上可接受的辅料;所述的局麻药为酰胺类局麻药或其可药用盐;所述的酰胺类局麻药选自罗哌卡因、布比卡因、利多卡因、左旋布比卡因、甲哌卡因、辛可卡因、吡咯卡因、依替卡因、丙胺卡因中的至少一种;所述的离子型表面活性剂选自油酸、多库酯钠、脱氧胆酸钠、十二烷基硫酸钠、十二烷基苯磺酸钠、癸酸钠中的至少一种;药学上可接受的辅料包括非离子型表面活性剂、稳定剂和助悬剂中的至少一种。本发明的局麻药复合物混悬剂具有长效麻醉效果,可实现一次给药后达到术后疼痛管理的目的。
Description
技术领域
本发明涉及药物制剂领域,尤其涉及一种局麻药复合物混悬剂。
背景技术
尽管不受欢迎,疼痛是手术不可避免的后果。据报道,多达80%的手术患者会出现急性术后疼痛,30%的患者在术后会出现剧烈疼痛。疼痛在手术后的前48小时内最为严重。研究发现,术后较高的急性疼痛几乎使中度慢性疼痛发展的几率增加了两倍,提高心脏和肺部并发症的风险,不利于术后恢复。并且由于住院时间延长、计划外再入院、后续慢性疼痛综合征的出现,术后疼痛控制不佳会导致高昂的医疗费用以及死亡率的增加,是具有重大临床、社会和经济影响的事件。术后疼痛管理市场研究报告显示,术后疼痛管理市场规模在2020年价值315亿美元,预计到2028年将达到480亿美元,从2021年到2028年以5.4%的复合年增长率增长。
慢性疼痛被定义为持续超过6个月的任何疼痛,尽管国际疼痛指南推荐了治疗方法,但超过60%的慢性疼痛患者没有改善或反应不佳,并且经常出现不良反应。而慢性疼痛机制复杂,在临床实践中确定疼痛背后的机制可能具有挑战性或不可能。因此,对术后急性疼痛的有效管理将是预防慢性疼痛的最佳手段之一。事实上,持续时间少于1天的单次注射周围神经阻滞即可减少3个月和12个月的持续乳房切除术后疼痛。一直以来,阿片类药物是缓解急性术后疼痛的金标准,尤其是中度或重度疼痛时。然而,它们容易导致耐受、依赖和成瘾,进一步引起显著不良事件,包括但不限于呼吸系统和中枢神经系统抑制、便秘、恶心和呕吐。
阿片类药物最小化策略包括使用无阿片类麻醉、区域麻醉技术、多模式非阿片类镇痛药和非药物干预等(如早期实施物理治疗和针刺)。用局麻药(LA)浸润手术部位是多模式镇痛方案的重要环节。尽管局部麻醉药具有极好的镇痛效果(相比阿片药物,全身不良反应少得多),但在单次注射后作用持续时间相对较短,最长只可达12小时。若与各种佐剂(右美托咪定、可乐定,特别是地塞米松)联用则可延长至24小时。这归功于佐剂对局部血管收缩、对周围神经的直接影响或全身抗炎过程的启动。但大多数佐剂只能延长镇痛时间0-12h,最多(丁丙诺啡和地塞米松)也只能延长不到24h。不良反应发生的可能性随着给予药物增多而增多,许多佐剂可能会增加瘙痒,恶心/呕吐,低血压症,心动过缓和镇静等副作用的发生率。连续周围神经阻滞是临床上延长局麻药镇痛效力的重要手段,与单次注射局麻药周围神经阻滞相比,疼痛缓解能力与硬膜外镇痛相当,但血流动力学稳定性有所改善。尽管超声引导技术的发展使得导管现在能准确插入神经旁,但外源的导管在插入人体后,总是会不可避免地出现导管相关机械神经刺激、打结、迁移、阻塞或剪切、导管插入部位的液体泄漏或炎症、细菌定植、输液泵故障等问题。
因此,一次给药即可达到与硬膜外镇痛和神经导管连续输注同等镇痛效力,且减少血药浓度波动的局麻药缓释制剂是目前术后长效镇痛领域的焦点。它不仅减少了导管、硬膜穿刺这些侵入性技术带来的副作用和不良的患者依从性,并且通过减少给药总剂量和给药次数大大降低了局麻药全身毒性发生的风险,在术后急性疼痛的控制、单次阻滞后的短暂但强烈的“灼烧感”反弹痛和术后更久的慢性疼痛的预防中占据了重要的地位。国内外已有多项研究介绍了脂质体,混悬液,包合物,凝胶,可注射液体聚合物,聚合物微粒等长效局麻药制剂。在镇痛效力上取得了一定进展,但还存在微球突释严重,肌肉毒性较高;植入物生物相容性差,机械强度不足;水凝胶包封能力弱,降解缓慢;纳米粒溶出过快等问题。
目前已获批上市的长效局麻药制剂包括用于注射的布比卡因多囊室脂质体Exparel、用于植入的含布比卡因的胶原蛋白基质Xaracoll、用于滴注的复方布比卡因/美洛昔康聚合物溶液Zynrelef、用于滴注的含布比卡因的乙酸异丁酸蔗糖酯粘稠溶液Posimir。Exparel已上市十年,但最近的多项研究强调了其只能部分证明与单次给药后常规布比卡因相比术后镇痛持续时间的延长。此外,Exparel载药量有限,需要严格的温度控制,存在保质期相对较短的不足。近两年上市的Xaracoll、Zynrelef、Posimir获批适应症还较少,尚未有严重不良反应的报道,但全面的疗效和安全性还有待探究:Xaracoll植入异物感强且降解缓慢;含有极高剂量布比卡因(660mg)的Posimir的恶心、呕吐和瘀伤的副作用情况不容小觑,且其所用有机溶剂苄醇在神经阻滞中安全性低,镇痛效果也无显著性优势;双效麻醉的Zynrelef疗效在四者中最优,但成本较高,同时合用药物中的美洛昔康直接滴入伤口的安全性还有待检验。
脂质体作为近年来局麻药缓释领域研究最为广泛的一种药物载体,相比非脂质载体具有显著优势,如生物相容性,生物降解性、非免疫原性和相对较低的成本。目前国内已有两项处于临床阶段的局麻药脂质体:绿叶制药公司的罗哌卡因多泡脂质体LY09606正在开展I期临床研究、注射用HR18034罗哌卡因脂质体拟开展Ⅱ期临床研究。
然而,除开脂质体固有的稳定性差,药物突释等不足,包封局麻药的脂质体开发中还会遇到如下问题:一是局麻药水溶性差,临床上常使用的是局麻药盐酸盐水合物,但盐酸盐水合物在制备脂质体时候不易载药,二是直接将脂溶性局麻药主动载药的方式获得的局麻药单室脂质体往往存在载药量低和包封率低的问题。这一方面不利于长期镇痛,另一方面未包封药物可能有毒性风险,其去除也将带来成本升高问题。制得的普通局麻药脂质体往往难以达到较高的载药量和预期的缓控释效果。已经研究过的脂质体制剂的一个共同特征就是LA包封不如其他DDS获得的包封高。
已上市的EXPAREL的生产依赖于复杂的两步双乳化工艺且需要中性脂质,总体而言成本高昂。中国专利202110046374.7公开了一种“油脂-卵磷脂-局麻药-药效增强剂”的罗哌卡因储库组合物,该组合物中的磷脂在局部施用后会受体液刺激完成脂质体的自组装,从而获得了高载药量的局麻药脂质体,在大鼠体内可达到两至三天的镇痛。然而该制剂给药后初始扩散和释放较大,且其中的有机溶剂苯甲醇在局部施用后刺激性大。中国专利202110964079.X公开了一种包载局麻药的近红外响应脂质体温敏凝胶,克服了单纯脂质体缓释能力不足的缺点,实现响应性和可调释放的问题,在体外达到了3天以上的缓慢释放。该脂质体是由DLPC、DSPC、EggPC和胆固醇构成,对罗哌卡因包封率达94%,但其本身粒径较小(200nm)不利于缓释,且局麻药浓度低(罗哌卡因1mg/mL)不利于长效镇痛。尽管额外引入的凝胶对缓释是有利的,但工艺中需要考察的质量指标较多,不利于放大生产。离子梯度脂质体提供比传统脂质体更高的包封效率,专利US20150250724A1公开了一种脂质体内部区域水相的pH(pH6.5柠檬酸溶液/硫酸铵溶液)低于外界水相pH(pH 7.2PBS)的局麻药离子梯度脂质体,该脂质体的平均颗粒直径不小于1μm且具有10层或更多层膜,在给药后至少有不少于3天的镇痛时间。然而离子梯度脂质体工艺复杂、难以工业化生产,内水相偏低的pH值导致稳定性也有待进一步加强。
因此,长效局麻药制剂领域仍需开发更多具有良好生物相容性、可控工艺和稳定的长效麻醉效果的制剂以满足患者的多样术后镇痛需求。
发明内容
本发明提供了一种制备工艺简单可控的局麻药复合物混悬剂,该局麻药复合物混悬剂具有长效麻醉效果,可实现一次给药后达到术后疼痛管理的目的。
一种局麻药复合物混悬剂,包含局麻药与离子型表面活性剂的疏水复合物以及药学上可接受的辅料;
所述的局麻药为酰胺类局麻药或其可药用盐;所述的酰胺类局麻药选自罗哌卡因、布比卡因、利多卡因、左旋布比卡因、甲哌卡因、辛可卡因、吡咯卡因、依替卡因、丙胺卡因中的至少一种;
所述的离子型表面活性剂选自油酸、多库酯钠、脱氧胆酸钠、十二烷基硫酸钠、十二烷基苯磺酸钠、癸酸钠中的至少一种;
药学上可接受的辅料包括非离子型表面活性剂、稳定剂和助悬剂中的至少一种。
局部麻醉剂(LA)是弱碱,在溶液中以带电和非带电形式存在。非带电形式的LA易于扩散进入神经元,而后与电压门控钠通道的胞内部分结合,进而阻断动作电位的传播。但由于受伤,感染或手术,在炎症过程中通常会发生组织酸中毒,并由于炎性因子的存在而维持较长时间,这会减少脂溶性的LA对神经细胞膜的渗透,不利用镇痛效力的维持。临床常用的局麻药盐酸盐水合物水溶性良好,因而在局部注射给药后易于快速扩散入血循环,半衰期较短。并且目前并无市售的局麻药混悬剂可用于术后长效镇痛。
表面活性剂(即具有一端亲水、一端疏水结构)在药学领域中应用十分广泛。发明人发现,在较高的浓度下应用表面活性剂,其可通过疏水作用和胶束等聚集体的形成大大增强LA的溶解度,然而,当发明人应用结构独特的表面活性剂,且控制浓度在临界胶束浓度(CMC)下时,疏水药物中表面活性剂的添加反而导致药物的溶解度进一步下降,具体表现为,向LA的药用盐溶液中加入少量表面活性剂后反而析出了微小晶体形成混悬剂。发明人认为,在CMC以下时,表面活性剂与具有氨基的疏水药物之间基于静电相互作用、疏水作用、范德华力、π-π相互作用等非共价作用形成了疏水性更强的复合物,并在随后的实验中证明了该复合物对于缓释是有利的。
进一步的,所述复合物的形成提高了LA的亲脂性,使其渗透亲脂性膜的能力得到了明显的提高,这对于在手术部位酸性环境中因质子化而脂溶性降低的局麻药是有利的,这将促进其对神经细胞的穿透性,有利于镇痛效力的维持。
本发明中,特定的局麻药与特定的离子型表面活性剂相互作用形成上述疏水性更强的复合物,改善了局麻药的脂溶性,得到制备简单可控的缓释局麻药混悬剂。
所述的局麻药复合物混悬剂的制备方法包括如下步骤:
(1)制备局麻药与离子型表面活性剂的疏水复合物;
(2)向所述的疏水复合物或疏水复合物的溶液中加入药学上可接受的辅料,充分均匀制得局麻药复合物混悬剂。
本发明所使用的局麻药可以是市售纯品,也可由局麻药药用盐制得:将局麻药药用盐水溶液调pH至碱性使局麻药碱析出,而后直接用于后续制备或离心、冻干得到样品后用于后续制备。
优选的,所述的局部麻醉药为罗哌卡因或其可药用盐。布比卡因与罗哌卡因是临床中是应用最为广泛的局麻药。相比布比卡因,罗哌卡因脂溶性更差,所以效价更低,但另一方面也拥有更高的安全边际。在临床实际应用中,同等剂量的罗哌卡因表现出与布比卡因近乎相同的镇痛效力,并且产生的运动阻滞更少,呈现明显的感觉/运动阻滞分离,因此罗哌卡因正逐渐成为临床局部镇痛的更优选。
发明人筛选了局麻药与多种表面活性剂如油酸、多库酯钠、1-羟基-2-萘甲酸钠、胆酸钠、脱氧胆酸、脱氧胆酸钠、石胆酸钠、牛磺脱氧胆酸钠、琥珀酸钠、癸酸钠、十二烷基苯磺酸钠、柠檬酸钠、多聚磷酸钠、聚丙烯酸钠、甘油磷酸钠、萘磺酸钠、对甲苯磺酸钠、环己基氨基磺酸钠、十二烷基硫酸钠、十六烷基磷酸酯、N,N-二棕榈酰-l-赖氨酸、双羟萘酸、硫酸葡聚糖、硬脂基硫酸钠、硬脂酰牛磺酸钠、硬脂酰谷氨酸钠、癸磺酸钠、十四烷基硫酸钠、十六烷基硫酸钠、十八烷基硫酸钠、双羟萘酸钠、胆固醇硫酸钠、海藻酸钠、透明质酸钠、醋酸钠、癸磺酸钠、硬脂酸钠等的结合。发现并非所有表面活性剂都能与局麻药形成疏水复合物,绝大多数表面活性剂发挥的仍是增溶的作用,不利于局麻药的缓释。
为了形成疏水复合物,首先,离子型表面活性剂通过额外的静电作用更有利于复合物的形成,在此基础上,表面活性剂的疏水端疏水性越强(即疏水域较大、较多)以及有额外的氢键位点(羟基)更有利于疏水性复合物的形成。
离子型表面活性剂油酸、多库酯钠、脱氧胆酸钠、十二烷基硫酸钠、十二烷基苯磺酸钠或癸酸钠,均能与局麻药形成疏水复合物。
优选的,所述的离子型表面活性剂为多库酯钠。
具有“强效增溶剂和稳定剂”美誉的多库酯钠在与局麻药形成疏水复合物,减少其溶解性方面也表现了卓越的效果。在低于临界胶束浓度(CMC)的条件下,多库酯钠的磺酸根与局麻药的氨基结合十分牢固,强于羧基与氨基的作用,且其独特的双分支疏水尾链及两个酯基会大大加强与局麻药之间的疏水作用,加之其有利的空间位阻,其与氨基酰胺局麻药形成的复合物在结合域处和空间结构上都十分稳定,表现出了异常优秀的“减溶”效果。反映在结果中,罗哌卡因-多库酯钠复合物混悬剂在体外表现出长达5d的缓慢释放,在小鼠体内表现出长达10d的镇痛效力。这些均说明多库酯钠作为表面活性剂在缓释局麻药领域乃至整个药物制剂领域具有十分广阔的开发应用价值。
优选的,所述的离子型表面活性剂为油酸。
尽管因为疏水链比较单一,油酸与局麻药形成的复合物稳定性一般,但作为天然omega-9脂肪酸的油酸本身特殊的结构即具有一定的镇痛作用,即通过抑制瞬时受体电位香兰素1(TRPV1)通道来减轻瘙痒和疼痛,且其天然来源赋予了其优异的生物相容性,因此局麻药-油酸复合物在长效镇痛制剂的开发中仍具有较大的前景。
优选的,步骤(1)包括:向溶解有离子型表面活性剂的超纯水中缓慢加入局麻药或其药用盐水溶液,搅拌使离子型表面活性剂与局麻药完全结合,形成疏水复合物。
一些离子型表面活性剂溶液与局麻药混合后无明显现象,需要调节pH至微酸/微碱性才会生成复合物。
优选的,步骤(1)中,所述的离子型表面活性剂和局麻药的摩尔用量比为0.2-5:1;进一步优选为1-2:1;最优选为2:1。
步骤(1)中,所述的局麻药与离子型表面活性剂形成的疏水复合物,可以是混悬液、离心后沉淀物或经由本领域其他常规干燥方式如喷雾干燥、冷冻干燥、喷雾冷冻干燥等获得的干粉。
在一些实施方案中,步骤(1)中所述局麻药与离子型表面活性剂的疏水复合物是离心后沉淀物;向溶解有离子型表面活性剂的超纯水中缓慢加入局麻药或其药用盐水溶液,搅拌使离子型表面活性剂与局麻药完全结合,再以12000rpm离心后,用超纯水洗涤离心下来的固体三次,60℃干燥24h得到的所述的疏水复合物。
在一些实施方案中,步骤(1)中所述局麻药与离子型表面活性剂的疏水复合物是冻干粉;向溶解有离子型表面活性剂的超纯水中缓慢加入局麻药或其药用盐水溶液,搅拌使离子型表面活性剂与局麻药完全结合,再-30℃冷冻干燥2天,得到的所述的疏水复合物。
局麻药与离子型表面活性剂形成复合物后,其疏水性提高,因此不可避免地表现出放置一段时间后的聚集和析出,优选的,可以加入药学上可接受的辅料以提高复合物的稳定性。
步骤(2)中,所述的药学上可接受的辅料包括非离子型表面活性剂、生物大分子聚合物和助悬剂中的至少一种。根据不同临床需要,还可进一步含有等渗调节剂、缓冲剂、pH调节剂、防腐剂中的一种或多种。
优选的,所述的非离子型表面活性剂为磷脂(如蛋黄卵磷脂、大豆卵磷脂等)、吐温(如吐温20、吐温40、吐温60、吐温80和吐温85等)、泊洛沙姆(如泊洛沙姆188、泊洛沙姆237、泊洛沙姆338、泊洛沙姆407等)、聚氧乙烯蓖麻油和聚氧乙烯氢化蓖麻油系列(如CremophorEL 40、Cremophor RH 40)、维生素E聚乙二醇琥珀酸酯、15-羟基硬脂酸聚乙二醇酯中的至少一种。
进一步优选的,所述的非离子型表面活性剂为大豆卵磷脂或泊洛沙姆188。
最优选的,所述的非离子型表面活性剂为大豆卵磷脂。
优选的,所述的非离子型表面活性剂与局麻药的质量比为0.1-2:1;进一步优选为0.5-1.2:1;最优选为1:1。
优选的,所述的助悬剂选自阿拉伯胶、西黄蓍胶、卡波姆、海藻酸钠、琼脂、淀粉、甲基纤维素及其钠盐、羧甲基纤维素及其钠盐、羟乙基纤维素及其钠盐、羟丙基纤维素及其钠盐、聚乙烯吡咯烷酮系列(如PVP K15,K30,C30,K90等)、聚乙二醇-400、透明质酸钠中的至少一种。
进一步优选的,所述的助悬剂为羧甲基纤维素钠(CMC-Na)。
优选的,所述的局麻药复合物混悬剂中,助悬剂的浓度为0.2-2%;进一步优选为0.7-1.2%;最优选为1%。
局麻药与离子型表面活性剂所形成疏水复合物的稳定性不足的主要原因是疏水复合物之间的聚集和析出,因此,参考胶囊的设计,为疏水复合物加上外壳将会有助于减少疏水复合物之间的聚集,同时复合物的溶蚀也将有利于缓释。
优选的,所述的稳定剂包括两种电性相反的生物大分子聚合物,其通过电性吸附构成疏水复合物的两层外壳。可将其称为局麻药层层包裹制剂。
优选的,所述的生物大分子聚合物选自聚赖氨酸、聚多巴胺、聚乙二醇、聚丙烯酸、聚乙烯醇、硫酸类肝素、硫酸软骨素、胶原蛋白、结冷胶、黄原胶、多糖如透明质酸、明胶、海藻酸盐、几丁质、壳聚糖、纤维素、果胶、瓜尔豆胶及其衍生物中的至少一种。
一种局麻药层层包裹制剂的制备工艺包括:
a:向疏水复合物的水溶液中加入正电性的生物大分子聚合物溶液,搅拌均匀;
b:向步骤a得到的溶液中加入负电性的生物大分子聚合物溶液,充分搅拌,得到局麻药层层包裹制剂。
在一些实施方式中,a中疏水复合物与正电性的生物大分子聚合物结合的方式可以是向正电性的生物大分子聚合物水溶液中加入疏水复合物的冻干粉。
优选的,正电性的生物大分子聚合物为聚赖氨酸或壳聚糖,负电性的生物大分子聚合物为透明质酸或明胶。
进一步优选的,正电性的生物大分子聚合物为壳聚糖,其是以溶解在1%冰醋酸中的形式加入到疏水复合物的水溶液中,且在执行步骤b以前提前调pH至中性。
优选的,正电性的生物大分子聚合物与局麻药的摩尔比为1-2:1;进一步优选为1.3-1.6:1;最优选为1.5:1。
优选的,正电性的生物大分子聚合物与负电性的生物大分子聚合物的摩尔比为1:1-2;进一步优选为1:1。1-1.4;最优选为3:4。
优选的,负电性的生物大分子聚合物为透明质酸,其质量浓度为1-3%;进一步优选为1-2%;优选为1.5%。
层层包裹制剂的稳定剂加入顺序是有要求的,须先加入正电性生物大分子聚合物包裹疏水复合物,而后再加入负电性生物大分子聚合物包裹。如果先加入负电性生物大分子聚合物,则不易于形成均一的混悬剂,甚至产生沉淀,不利于下一步正电性生物大分子聚合物的包裹。
一种局麻药复合物混悬剂,其制备方法包括如下步骤:
(1)局麻药与离子型表面活性剂在水中在分散条件1下充分混匀制得疏水复合物;
(2)向(1)中疏水复合物或疏水复合物溶液中加入药学上可接受的辅料,在分散条件2下充分混匀制得局麻药复合物混悬剂。
在一些实施方式中,分散条件1可以为:以200-600rpm转速搅拌;优选为以200-500rpm转速搅拌;再优选为以300-400rpm搅拌,最优选为以300rpm转速搅拌。搅拌持续时间为2-24h;优选为4-24h,最优选为12h。
在一些实施方式中,分散条件2可以为:在500-10000rpm转速下进行剪切或搅拌;优选在1000-10000rpm转速下进行剪切;再优选在2000-10000转速下进行剪切;再优选在5000-10000转速下进行剪切;再优选在7000-10000rpm转速下进行剪切;再优选在8000-10000rpm转速下进行剪切。剪切持续时间为10min或更长时间,例如可以是10-30min。
在一些实施方式中,(2)中所述混悬剂的药学上可接受的辅料所用的非离子型表面活性剂优选大豆卵磷脂。其制备方法可以为:向(1)中局麻药复合物溶液或复合物中加入大豆卵磷脂和药学上可接受的辅料,在分散条件2下充分混匀制得混悬剂。还可以为:将大豆卵磷脂在有机溶剂中溶解完全后,在37℃以100rpm的转速旋转蒸发成薄膜。而后用(1)中局麻药复合物溶液水化,得到局麻药复合物磷脂混悬剂,而后加入其他辅料,在分散条件2下充分混匀制得混悬剂。其中,有机溶剂选自可挥发性有机溶剂选自氯仿、二氯甲烷、甲醇、乙醇、乙醚、叔丁醇中的一种以上。
根据本发明的实施方案,(2)中所述药学上可接受的辅料还可进一步含有等渗调节剂、缓冲剂、pH调节剂、防腐剂中的一种或多种,提供适宜的药剂学性质和药理学性质以用于各种形式、各种给药方式的术后镇痛。所述等渗调节剂可以选自氯化钠、葡萄糖、甘露醇、氯化钾、蔗糖、果糖、乳糖、山梨醇中的一种或多种。所述缓冲剂可以选自磷酸盐缓冲液、醋酸盐缓冲液、柠檬酸盐缓冲液、三羟甲基氨基甲烷缓冲液、乳酸盐缓冲液、酒石酸盐缓冲液、组氨酸缓冲液、甘氨酰甘氨酸缓冲液中的一种或多种。所述pH调节剂可以选自上述缓冲剂和盐酸、氢氧化钠中的一种或多种。所述防腐剂可以选自苯酚、间甲酚、苯甲醇、对羟基苯甲酸酯、对羟基苯甲酸甲酯、苯扎氯铵、氯丁醇、硫柳汞、乙二胺四乙酸及其盐、氯甲酚、间甲酚、氯化苄乙氧铵中的一种或多种。
本发明所提供的局麻药复合物混悬剂可以以多种方式给药,如肌肉给药、皮下给药、神经丛给药等,优选皮下注射浸润麻醉。
同现有技术相比,本发明的主要优点有:
(1)本发明所制备的局麻药复合物混悬剂工艺简单可控,易于放大生产。
(2)本发明所制备的局麻药复合物混悬剂所用辅料均为安全性高的辅料,生物相容性高,可直接局部注射浸润麻醉。
(3)本发明所制备的局麻药复合物混悬剂显著改善局麻药水溶液半衰期短的缺点,可在体外缓释24h以上,在体内最高可达到10d的镇痛时长。
(4)本发明所制备的局麻药复合物混悬剂克服了临床所用局麻药水溶液需多次给药的极大不便,将会极大提高患者的依从性。
附图说明
图1为实施例1的罗哌卡因疏水复合物冻干粉,从左至右为罗哌卡因与十二烷基硫酸钠、油酸、癸酸钠、多库酯钠、十二烷基苯磺酸钠、脱氧胆酸钠所形成的复合物;
图2为实施例3的罗哌卡因-多库酯钠复合物磷脂混悬剂;
图3为实施例3的罗哌卡因-多库酯钠复合物磷脂混悬剂粒径分布图;
图4为实施例3的罗哌卡因-多库酯钠复合物磷脂混悬剂的体外释放结果;
图5为实施例5的罗哌卡因-油酸复合物磷脂混悬剂;
图6为实施例5的罗哌卡因-油酸复合物磷脂混悬剂粒径分布图;
图7为实施例5的罗哌卡因-油酸复合物磷脂混悬剂的体外释放结果;
图8为实施例7的罗哌卡因-多库酯钠复合物层层包裹混悬剂,从左至右为罗哌卡因多库酯钠复合物-壳聚糖-明胶制剂、罗哌卡因多库酯钠复合物-壳聚糖-透明质酸制剂、罗哌卡因多库酯钠复合物-聚赖氨酸-明胶制剂、罗哌卡因多库酯钠复合物-聚赖氨酸-透明质酸制剂;
图9为实施例7的罗哌卡因-多库酯钠层层包裹混悬剂的粒径分布图,(a)为罗哌卡因-多库酯钠复合物-聚赖氨酸-透明质酸制剂,(b)为罗哌卡因多库酯钠复合物-壳聚糖-透明质酸制剂;
图10为实施例7的罗哌卡因-多库酯钠复合物层层包裹混悬剂的体外释放结果图;
图11为实施例3的罗哌卡因-多库酯钠复合物磷脂混悬剂的小鼠体内镇痛实验结果图:(a)为机械痛镇痛效力,(b)为热痛镇痛效力;
图12为实施例5的罗哌卡因-油酸复合物磷脂混悬剂的小鼠体内镇痛实验结果图:(a)为机械痛镇痛效力,(b)为热痛镇痛效力。
具体实施方式
术语:
术语“混合”是指采用药学领域公知的搅拌或加热方式使两种以上组分在溶液中均一分布的过程。
术语“w/v”是指溶质以g为单位,溶于100mL水中所表示的质量浓度。1%(w/v)即表示溶质的质量浓度为1g/100mL。
术语“生物相容性”是根据国际标准化组织(International StandardsOrganization,ISO)所定义的生命体组织对非活性材料产生反应的一种性能,一般是指材料与宿主之间的相容性。
术语“释放度”是指药物从缓控释制剂中在规定溶剂中释放的速度和程度。
术语“粒径分布”是指使用BlueWave激光粒度分析仪测得制剂溶液中不同粒径范围内所含粒子的个数。
下面结合附图及具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
实施例1罗哌卡因疏水复合物的制备
(1)称取罗哌卡因2倍用量的离子型表面活性剂,分别溶解于10mL软化水中,而后在连续搅拌的情况下缓慢加入150mg罗哌卡因,以300rpm搅拌过夜使结合完全。如未形成复合物则考虑调pH或加热。复合物形成的结果如表1所示。
(2)取5mL(1)中得到的复合物混悬剂在-30℃冷冻干燥2天得到疏水复合物固体,如图1所示。图1中从左至右为罗哌卡因与十二烷基硫酸钠、油酸、癸酸钠、多库酯钠、十二烷基苯磺酸钠、脱氧胆酸钠所形成的复合物。所得复合物固体为乳白色,塌陷较少,略微粘稠,再分散性良好,遇水很快崩解成小块,涡旋10s即可得乳白混悬液。并且罗哌卡因-油酸复合物冻干粉和罗哌卡因-多库酯钠复合物冻干粉外观光滑平整,色泽均匀,疏松多孔,无塌陷或皱缩,稍加碾磨即可成粉。
表1能形成罗哌卡因复合物混悬剂的部分离子型表面活性剂
实施例2罗哌卡因复合物混悬剂的制备
表2罗哌卡因复合物混悬剂处方
根据表2处方用量,称取离子型表面活性剂溶解于5mL软化水中,而后在连续搅拌的情况下缓慢加入75mg罗哌卡因,以300rpm搅拌过夜得到复合物混悬剂。对于处方10-15,向复合物混悬剂中加入非离子型表面活性剂和助悬剂,以8000rpm剪切15min充分分散,得到最终混悬剂。
对于处方1-9和处方16-26,将大豆卵磷脂在氯仿中溶解完全后,在37℃以100rpm的转速旋转蒸发成薄膜,用复合物混悬剂水化,而后加入助悬剂,以8000rpm剪切15min充分分散,得到最终混悬剂。
实施例3罗哌卡因-多库酯钠复合物磷脂混悬剂的粒径分布
按实施例2制备了处方3的罗哌卡因-多库酯钠复合物磷脂混悬剂,具体用量如下:
(1)称取多库酯钠243.2mg投入5mL超纯水中,50℃水浴1h加热溶解,后加入75mg罗哌卡因,在50℃下以300rpm搅拌过夜充分反应,所得溶液为乳白色。
(2)称取75mg磷脂加入氯仿中,在37℃以100rpm的转速旋转蒸发成薄膜,倒入上述混悬液,水浴超声使充分水化,最后加入适量CMC-Na,以8000rpm剪切15min充分分散后即得目标混悬剂,如图2所示。混悬剂为稠厚的乳白色,可稳定放置72h及以上,沉降后可轻轻振摇,在20s内重新再分散。
使用BlueWave激光粒度分析仪对混悬剂进行粒径和分布情况的考察。其粒径分布如图3所示。结果表明罗哌卡因-多库酯钠复合物磷脂混悬剂的粒径为1926nm,PDI为0.37。
实施例4罗哌卡因-多库酯钠复合物磷脂混悬剂的体外释放
取1mL处方3的罗哌卡因-多库酯钠复合物磷脂混悬剂于透析袋中(MWCO:8000-14000,MD44),透析袋两端均用透析夹夹住,置于含150mL释放介质(含0.2%吐温20的PBS)的烧杯中。烧杯置于37℃,25rpm的恒温气浴振荡中,在预定的时间点取样1mL,同时补充1mL新鲜的流动相。通过紫外分光光度法测量罗哌卡因浓度,计算释放度。结果如图4所示,罗哌卡因-多库酯钠复合物磷脂混悬剂无突释,在24h释放至50%左右,而后缓慢释放,至120h时释放达到顶点的90%。
实施例5罗哌卡因-油酸复合物磷脂混悬剂的粒径分布
按实施例2制备了处方17的罗哌卡因-油酸复合物磷脂混悬剂,具体用量如下:
(1)称取油酸154.4mg(约0.178mL)投入5mL超纯水中,涡旋混匀,后加入75mg罗哌卡因,在室温下以300rpm搅拌过夜充分反应,所得溶液为乳白色。
(2)称取75mg磷脂加入氯仿中,在37℃以100rpm的转速旋转蒸发成薄膜,倒入上述混悬液,水浴超声使充分水化,最后加入适量CMC-Na,以8000rpm剪切15min充分分散后即得目标混悬剂,如图5所示。混悬剂为稠厚的乳白色,可稳定放置72h及以上,沉降后可轻轻振摇,在20s内重新再分散。
使用BlueWave激光粒度分析仪对混悬剂进行粒径和分布情况的考察。其粒径分布如图6所示。结果表明罗哌卡因-油酸复合物磷脂混悬剂的粒径为919.3nm,PDI为0.25。
实施例6罗哌卡因-油酸复合物磷脂混悬剂的体外释放
按实施例4中的方法,取1mL处方17的罗哌卡因-油酸复合物磷脂混悬剂置于透析袋中,于150mL释放介质中考察罗哌卡因-多库酯钠层层包裹混悬剂的体外释放,结果如图7所示。结果表明罗哌卡因-油酸复合物磷脂混悬剂可在体外缓慢释放24h。
实施例7罗哌卡因-多库酯钠层层包裹混悬剂的制备
(1)按实施例1中方法制备罗哌卡因-多库酯钠复合物混悬液,而后在-30℃冷冻干燥两天得到罗哌卡因-多库酯钠复合物冻干粉;
(2)称取90mg聚赖氨酸,完全溶解在5mL超纯水中得到聚赖氨酸溶液;称取105mg壳聚糖(15万道尔顿),完全溶解在5mL1%冰醋酸中得到壳聚糖溶液;
(3)向(1)中聚赖氨酸溶液中加入477.5mg罗哌卡因-多库酯钠复合物冻干粉,以300rpm搅拌2h;将(1)中壳聚糖溶液调pH至中性,向(1)中壳聚糖溶液中加入477.5mg罗哌卡因-多库酯钠复合物冻干粉,以300rpm搅拌2h;
(4)向(3)中两份溶液中分别加入5mL 3%透明质酸溶液,以300rpm搅拌过夜得到罗哌卡因-多库酯钠-透明质酸层层包裹混悬剂。因为加入了透明质酸,所以制剂略带凝胶性状;向(3)中两份溶液中分别加入5mL 3.4%明胶溶液,以300rpm搅拌过夜得到罗哌卡因-多库酯钠-明胶层层包裹混悬剂。因为加入了透明质酸,所以制剂略带凝胶性状。制得的制剂如图8所示,从左至右为罗哌卡因多库酯钠复合物-壳聚糖-明胶制剂、罗哌卡因多库酯钠复合物-壳聚糖-透明质酸制剂、罗哌卡因多库酯钠复合物-聚赖氨酸-明胶制剂、罗哌卡因多库酯钠复合物-聚赖氨酸-透明质酸制剂。罗哌卡因多库酯钠复合物-聚赖氨酸-明胶制剂和罗哌卡因多库酯钠复合物-壳聚糖-明胶制剂不稳定,沉降特别快(1min以内)。
使用BlueWave激光粒度分析仪对两份罗哌卡因多库酯钠复合物-透明质酸层层包裹混悬剂溶液进行粒径和分布情况的考察。结果如图9所示:左图为罗哌卡因-多库酯钠复合物-聚赖氨酸-透明质酸制剂,右图为罗哌卡因多库酯钠复合物-壳聚糖-透明质酸制剂。结果表明罗哌卡因多库酯钠复合物-聚赖氨酸-透明质酸制剂的粒径为1710nm,PDI为0.097,罗哌卡因-多库酯钠复合物-壳聚糖-透明质酸制剂的粒径为1640nm,PDI为0.202。
实施例8罗哌卡因-多库酯钠层层包裹混悬剂的体外释放
按实施例4中的方法,取1mL罗哌卡因-多库酯钠层层包裹混悬剂置于透析袋中,于150mL释放介质中考察罗哌卡因-多库酯钠层层包裹混悬剂的体外释放,如图10所示。结果表明罗哌卡因多库酯钠复合物-聚赖氨酸-透明质酸制剂和罗哌卡因多库酯钠复合物-壳聚糖-透明质酸制剂均可在体外持续释放24h以上。
实施例9罗哌卡因-多库酯钠复合物磷脂混悬剂的小鼠体内镇痛实验
为了进一步验证发明中公开的罗哌卡因复合物混悬剂具有缓释的作用,按照实例3的方案制备了罗哌卡因-多库酯钠复合物磷脂混悬剂样品,采用Von Frey法和热板法进行镇痛试验。
实验方案为:通过坐骨神经阻滞模型进行药效学评价,即在动物神经周围肌肉注射0.2mL局麻药溶液,阻滞动作电位和神经冲动的传导,使该神经控制的区域内产生显著的麻醉镇痛作用。
(1)在造模前三日,每日测量C57BL/6小鼠的基线疼痛值:Von Frey法小鼠50%缩足阈值测试和热板法镇痛测试。去除痛阈异常的动物。将6只雄性小鼠随机分成2组,即对照组:7.5mg/mL盐酸罗哌卡因注射液组、供试品组:罗哌卡因-多库酯钠复合物磷脂混悬剂组。实验前一天在小鼠右腿外侧处剃毛,以备第二天实验。
(2)用异丙醇和生理盐水配置1.25%三溴乙醇溶液并过0.22μm膜,按照150mg/kg的剂量腹腔注射以短暂麻醉小鼠。待小鼠变得安静,翻正反射不明显之后,用医用PE胶带以俯卧姿势固定四肢(注意使右足底面朝上方)。沿纵向轻微剪开右大腿股骨处皮肤,而后使用止血钳钝性解剖股二头肌,暴露坐骨神经。在直视下,将0.2mL局麻药溶液平行注入坐骨神经根或坐骨神经周围的肌肉中,而后用可吸收缝线缝合皮肤。注射后,在预先设置的时间点,对各组小鼠进行感觉神经阻滞的测试,即Von Frey法和热板法。热板法测试应重复三次。
(3)Von Frey法和热板法程序:
Von Frey法:将小鼠置于0.5cm*0.5cm的金属网格篮上,用烧杯限制其活动领域。在小鼠适应10min逐渐安静下来后,按照up and down方法将Von frey纤维丝(力度的标度为0.02、0.04、0.07、0.16、0.4、0.6、1.0、1.4、2.0g)从0.02g标度垂直地刺激右足底中部皮肤,纤维丝接触足底后应加压至呈“S”型或“C”型保持最少3s,最长刺激时间应不超过8s,至小鼠抬脚或逃开,观察其右足反应。缩足或舔足记为阳性反应(“X”),无缩足舔足或不明显均记为阴性反应(“O”)。如果第一根纤维丝刺激后为阴性反应,则使用下一级标度纤维丝进行刺激;反之则使用上一级标度标度纤维丝刺激。将出现转折(即第一次从阴性反应转变至阳性反应)的那一次阴性反应记为起始点,而后连续测量4次,相邻刺激应间隔不少于1min。当2.0g纤维丝刺激也得到阴性反应时应停止测试,直接将后面的PWT值记为4.0g,目的是避免在麻醉效果下刺伤小鼠足部的组织。记录5次刺激所得的“OX”序列和第5次刺激的纤维丝的力度(f),按照公式1-1计算机械痛缩足阈值(即50%机械缩足反应刺激力度,pawwithdrawal threshold,PWT)。
式中,f是最后应用的Von Frey纤维丝的标度值,Xf代表最后一次刺激的强弱,Xf=lg(f*10000)。k值由Dixon统计表提供,是与疼痛模式即OX序列相关的常数。δ是5个刺激的标度以对数单位的平均差异。
热板法:室温下,将小鼠轻置于55℃的恒温加热平台上,开始计时,并观察小鼠反应。一般认为舔足或明显缩足为阳性反应,反之则即为阴性反应。一旦出现阳性反应则立刻停止计时并将小鼠移开热板,记录热潜伏期时间。同一只鼠重复测三次,每两次热板测试之间至少应间隔3分钟,三次结果的平均值代表了小鼠的热潜伏期。若30s仍无阳性反应撤走热板,防止在麻醉情况下烫伤小鼠足底皮肤,此时小鼠热潜伏期记为30s。用最大比例效应(MPE)来分析小鼠的热痛超敏或镇痛,其计算公式如1-2所示:
式中,A是检测时间点处小鼠的平均热潜伏期,B是小鼠的基础热潜伏期即给药前的疼痛基线水平,C代表允许的最长热潜伏期(本公开中为30s)。有效的感觉阻滞时效(有效镇痛时间)为从给药到MPE恢复到50%所持续的时间。
罗哌卡因-多库酯钠复合物磷脂混悬剂的小鼠体内镇痛结果如图11所示。结果表明罗哌卡因-多库酯钠复合物磷脂混悬剂在坐骨神经阻滞中可达到10d以上的显著镇痛效力。
实施例10罗哌卡因-油酸复合物磷脂混悬剂的小鼠体内镇痛实验
按实施例9中的方法,通过坐骨神经阻滞模型评价了罗哌卡因-油酸复合物磷脂混悬剂的小鼠体内镇痛效力,结果如图12所示。结果表明罗哌卡因-油酸复合物磷脂混悬剂在坐骨神经阻滞中可达到24h以上的镇痛效力。
以上所述的实施例对本发明的技术方案和有益效果进行了详细说明,应理解的是以上所述仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充和等同替换等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种局麻药复合物混悬剂,其特征在于,包含局麻药与离子型表面活性剂的疏水复合物以及药学上可接受的辅料;
所述的局麻药为酰胺类局麻药或其可药用盐;所述的酰胺类局麻药选自罗哌卡因、布比卡因、利多卡因、左旋布比卡因、甲哌卡因、辛可卡因、吡咯卡因、依替卡因、丙胺卡因中的至少一种;
所述的离子型表面活性剂选自油酸、多库酯钠、脱氧胆酸钠、十二烷基硫酸钠、十二烷基苯磺酸钠、癸酸钠中的至少一种;
药学上可接受的辅料包括非离子型表面活性剂、稳定剂和助悬剂中的至少一种。
2.根据权利要求1所述的局麻药复合物混悬剂,其特征在于,制备方法包括以下步骤:
(1)制备局麻药与离子型表面活性剂的疏水复合物;
(2)向所述的疏水复合物或疏水复合物的溶液中加入药学上可接受的辅料,充分均匀制得局麻药复合物混悬剂。
3.根据权利要求2所述的局麻药复合物混悬剂,其特征在于,步骤(1)包括:向溶解有离子型表面活性剂的超纯水中缓慢加入局麻药或其药用盐水溶液,搅拌使离子型表面活性剂与局麻药完全结合,形成疏水复合物。
4.根据权利要求1所述的局麻药复合物混悬剂,其特征在于,所述的离子型表面活性剂和局麻药的摩尔用量比为0.2-5:1。
5.根据权利要求1所述的局麻药复合物混悬剂,其特征在于,所述的非离子型表面活性剂为磷脂、吐温、泊洛沙姆、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、维生素E聚乙二醇琥珀酸酯、15-羟基硬脂酸聚乙二醇酯中的至少一种。
6.根据权利要求1或5所述的局麻药复合物混悬剂,其特征在于,所述的非离子型表面活性剂与局麻药的质量比为0.1-2;1。
7.根据权利要求1所述的局麻药复合物混悬剂,其特征在于,所述的稳定剂包括两种电性相反的生物大分子聚合物,其通过电性吸附构成疏水复合物的两层外壳;所述的生物大分子聚合物选自聚赖氨酸、聚多巴胺、聚乙二醇、聚丙烯酸、聚乙烯醇、硫酸类肝素、硫酸软骨素、胶原蛋白、结冷胶、黄原胶、多糖如透明质酸、明胶、海藻酸盐、几丁质、壳聚糖、纤维素、果胶、瓜尔豆胶及其衍生物中的至少一种。
8.根据权利要求7所述的局麻药复合物混悬剂,其特征在于,制备方法包括以下步骤:
(1)制备局麻药与离子型表面活性剂的疏水复合物;
(1-a)向疏水复合物的水溶液中加入正电性的生物大分子聚合物溶液,搅拌均匀;
(1-b)向步骤(1-a)得到的溶液中加入负电性的生物大分子聚合物溶液,充分搅拌,得到局麻药层层包裹制剂;
(2)向局麻药层层包裹制剂中加入药学上可接受的辅料,充分均匀制得局麻药复合物混悬剂。
9.根据权利要求8所述的局麻药复合物混悬剂,其特征在于,正电性的生物大分子聚合物与局麻药的摩尔比为1-2:1;正电性的生物大分子聚合物与负电性的生物大分子聚合物的摩尔比为1:1-2。
10.根据权利要求1所述的局麻药复合物混悬剂,其特征在于,所述的助悬剂选自阿拉伯胶、西黄蓍胶、卡波姆、海藻酸钠、琼脂、淀粉、甲基纤维素及其钠盐、羧甲基纤维素及其钠盐、羟乙基纤维素及其钠盐、羟丙基纤维素及其钠盐、聚乙烯吡咯烷酮、聚乙二醇-400、透明质酸钠中的至少一种。
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