CN117085112A - 一种无针注射用齐考诺肽及其制备方法 - Google Patents
一种无针注射用齐考诺肽及其制备方法 Download PDFInfo
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- CN117085112A CN117085112A CN202210508231.8A CN202210508231A CN117085112A CN 117085112 A CN117085112 A CN 117085112A CN 202210508231 A CN202210508231 A CN 202210508231A CN 117085112 A CN117085112 A CN 117085112A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明属于药物制剂技术领域,公开了一种无针注射用齐考诺肽及其制备方法。通过本发明的方法制备得到的无针注射用齐考诺肽,经无针注射器械注射后,可直接穿透皮肤表面与皮肤角质层,将齐考诺肽递送入血以发挥药效,改变齐考诺肽仅能鞘内注射的临床现状,同时无针注射的特点可以使连续多次无痛感给药,用于慢性疼痛的齐考诺肽可长时间经皮注射发挥止痛效果而不产生皮下硬结。
Description
技术领域
本发属于药物制剂领域,特别涉及一种无针注射用齐考诺肽及其制备方法。
背景技术
慢性疼痛一般特指疼痛周期超过一个月以上,影响机体生理、心理健康的症状,目前已成为困扰人类健康的重要因素之一,也因此被人成为不死的癌症。当常规止疼不能控制时,可以通过种植泵经鞘内注射镇痛药物例如齐考诺肽等进行治疗。
齐考诺肽是一种源自锥蜗牛的神经毒性肽,用于治疗不能耐受或对如鞘内注射吗啡和全身镇痛药等的其他治疗方法反应不佳的严重慢性疼痛患者。
齐考诺肽于2004年12月28日获得FDA批准上市销售,目前所上市的所有制剂均采用鞘内注射的给药方式。鞘内注射由于其治疗方式和操作手段的特殊性,决定了患者在接受治疗的过程中依从性极低,整个治疗过程需要专门人员进行,注射过程繁琐,且容易对患者产生创面以及注射恐惧,以及鞘内注射还有可能引发部分注射并发症,特别的,对于慢性疼痛的等需要长期治疗的疾病,需要定期进行给药,更需要一种简单、安全、高效、依从性高的给药手段。
发明内容
针对以上现有技术的缺陷,本发明解决的技术问题是提供一种用于慢性疼痛治疗无针注射用齐考诺肽,还提出一种用于慢性疼痛治疗无针注射用齐考诺肽的制备方法。
为解决本发明的技术问题,本发明提供一种用于慢性疼痛治疗的无针注射用齐考诺肽,其特征在于:
所述无针注射用齐考诺肽为液体形式,所述无针注射用齐考诺肽包括活性物质、改性组分与溶剂组分;
所述的活性物质选自齐考诺肽;
所述的改性组分选自改性组分A,改性组分B,改性组分C中的一种或多种;
所述改性组分A为体系稳定剂,选自透明质酸钠、壳聚糖、黄原胶和明胶中的一种或多种;所述改性组分B为增、助、潜溶剂,选自丙二醇、丙三醇、聚山梨酯、司盘和泊洛沙姆中的一种或多种;所述改性组分C为功能剂,选自叶酸、透明质酸、冰片、安息香和苏合香脂中的一种或多种;
所述的溶剂组分选自溶剂组分A、溶剂组分B中的一种或多种;
所述溶剂组分A选自葡萄糖、氯化钠、磷酸盐、枸橼酸,盐酸、氢氧化钠中的一种或多种;所述溶剂组分B选自注射用水、磷酸盐缓冲液、生理盐水和葡萄糖溶液中的一种或多种。
其特征还在于,所述齐考诺肽的终浓度为50~280mg/mL。
进一步,本发明还提供一种无针注射用齐考诺肽的制备方法,包含以下步骤:
第一,将活性物质齐考诺肽按一定比例直接溶于溶剂组分;
第二,将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽;
其中,制备方法可根据改性材料的的具体种类选择薄膜蒸发法、超声匀质法、乳化法、蒸发法、液液注入法;
第三,将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整,pH调整至5.5~8.2,渗透压调整至250~400mOsm/kg;
第四,将上述调整好pH、渗透压的注射用齐考诺肽无菌处理、分装后即得;
其中,无菌处理可根据具体条件选择滤膜过滤法、高压灭菌法、无菌灌装法;
进一步,本发明还提供一种无针注射用齐考诺肽的使用方法,所述的无针注射用齐考诺肽在制备治疗慢性疼痛药物中的应用;所述无针注射用齐考诺肽可根据需求,调整每日给药次数,调整每日使用剂量,每日最大剂量不超过0.5mg/kg体重;
本发明的有益之处在于:
通过本发明的方法制备得到的一种用于慢性疼痛治疗的无针注射用齐考诺肽适合需要多次给药的慢性疾病,使用者无痛感,注射部位不产生硬结;同时,本发明的方法制备得到的一种用于慢性疼痛治疗的无针注射用齐考诺肽经无针注射器械给药后,可以获得一种更好的药物扩散特性,药物呈弥散形式进入体内其特点是改变了齐考诺肽临床上只能通过鞘内注射的单一的给药方式,给药方式更加灵活,不会造成二次创伤、其他损伤或其他并发症。
通过本发明的方法制备得到的一种用于慢性疼痛治疗的无针注射用齐考诺肽经改性组分改性后,可以保护齐考诺肽结构的稳定性,进行保证药效的稳定性。
通过本发明的方法制备得到的一种用于慢性疼痛治疗的无针注射用齐考诺肽经改性组分改性后,可以促进载有齐考诺肽的微粒更容易的透过血脑屏障、血脊屏障,进而在脑脊液、全身范围内发挥药效。
附图说明
图1按本发明实施例2制备方法制备得到的无针注射用齐考诺肽的半成品示意图;
图2按本发明实施例2制备方法制备得到的并灌装后的无针注射用齐考诺肽成品示意图;
图3适用于本发明实施例灌装后的无针注射用齐考诺肽的无针注射器械实物图;
图4齐考诺肽高效液相色谱图;
图5高效液相色谱法测得齐考诺肽脑脊液含量结果图
具体实施方式
下面通过实施例对本发明作进一步的详细说明,旨在用于说明本发明而非限定本发明。并且,需要特别指出的是,对于本领域技术人员而言,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也同样落入本发明的保护范围之内。
实施例1:一种无针注射用齐考诺肽的制备
1、处方(1000mL)
2、将活性物质齐考诺肽按一定比例直接溶于溶剂组分:称取齐考诺肽100g,加入500mL注射用水,在匀速搅拌下充分溶解至视野下无可视颗粒;
3、将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽:称取透明质酸钠0.1g与壳聚糖0.05g加入300mL注射用水中,经高速匀质法充分溶解溶胀,并将此溶液加入至上述齐考诺肽溶液中,二者在高速剪切下混合均匀;
4、将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整:其中,加入余量磷酸盐缓冲液200mL,并使用溶剂组分A中物质将pH调整至7.0,使用溶剂组分B将渗透压调整至300mOsm/kg;
5、将上述调整好pH、渗透压的注射用齐考诺肽经无菌滤膜无菌滤过、分装后即得;
使用时,患者借助无针注射器械直接将无针注射用齐考诺肽注射于局部慢性疼痛时的患处或全身慢性疼痛时的适处。
实施例2:一种无针注射用齐考诺肽的制备
1、处方(1000mL)
2、将活性物质齐考诺肽按一定比例直接溶于溶剂组分:称取齐考诺肽200g,加入500mL磷酸盐缓冲液,在匀速搅拌下充分溶解至视野下无可视颗粒;
3、将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽:称取0.05g泊洛沙姆188,与0.5g冰片加入500mL葡萄糖缓冲液中,经高速匀质法充分溶解溶胀,并将此溶液以液液注入法加入至上述齐考诺肽溶液中,二者在高速剪切下混合均匀;
4、将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整:其中,使用溶剂组分A中物质将pH调整至6.8,使用溶剂组分B将渗透压调整至320mOsm/kg;
5、将上述调整好pH、渗透压的注射用齐考诺肽经无菌滤膜无菌滤过、分装后即得;
使用时,患者借助无针注射器械直接将无针注射用齐考诺肽注射于局部慢性疼痛时的患处或全身慢性疼痛时的适处。
实施例3:一种无针注射用齐考诺肽的制备
1、处方(1000mL)
2、将活性物质齐考诺肽按一定比例直接溶于溶剂组分:称取齐考诺肽50g,加入200mL注射用水,在匀速搅拌下充分溶解至视野下无可视颗粒;
3、将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽:称取黄原胶0.01g加入500mL注射用水中,经高速匀质法充分溶解溶胀,再向其中加入0.5mL丙二醇和0.1mL司盘80,充分混匀后将此溶液加入至上述齐考诺肽溶液中,二者在高速剪切下混合均匀;
4、将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整:其中,加入余量注射用水300mL,并使用溶剂组分A中物质将pH调整至8.0,使用溶剂组分B将渗透压调整至360mOsm/kg;
5、将上述调整好pH、渗透压的注射用齐考诺肽经无菌滤膜无菌滤过、分装后即得;
使用时,患者借助无针注射器械直接将无针注射用齐考诺肽注射于局部慢性疼痛时的患处或全身慢性疼痛时的适处。
实施例4:一种无针注射用齐考诺肽的制备
1、处方(1000mL)
2、将活性物质齐考诺肽按一定比例直接溶于溶剂组分:称取齐考诺肽200g,加入600mL注射用水,在匀速搅拌下充分溶解至视野下无可视颗粒;
3、将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽:称取明胶0.02g加入200mL注射用水中,经高速匀质法充分溶解溶胀,将0.3mL司盘80与0.05g苏合香脂在200mL葡萄糖溶液中充分溶解,与上述明胶溶液混匀后,将此溶液加入至上述齐考诺肽溶液中,二者在高速剪切下混合均匀;
4、将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整:其中,使用溶剂组分A中物质将pH调整至5.8,使用溶剂组分B将渗透压调整至280mOsm/kg;
5、将上述调整好pH、渗透压的注射用齐考诺肽经无菌滤膜无菌滤过、分装后即得;
使用时,患者借助无针注射器械直接将无针注射用齐考诺肽注射于局部慢性疼痛时的患处或全身慢性疼痛时的适处。
实施例5:一种无针注射用齐考诺肽的制备
1、处方(1000mL)
2、将活性物质齐考诺肽按一定比例直接溶于溶剂组分:称取齐考诺肽180g,加入450mL注射用水,在匀速搅拌下充分溶解至视野下无可视颗粒;
3、将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽:称取黄原胶0.001g与壳聚糖0.001g冰片加入200mL注射用水中,经高速匀质法充分溶解溶胀;取安息香0.01g,冰片0.01g和叶酸0.01g,加入上述溶液中,搅拌下充分溶解,待全部溶解后,将此溶液加入至上述齐考诺肽溶液中,二者在高速剪切下混合均匀;
4、将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整:其中,加入余量磷酸盐缓冲液350mL,并使用溶剂组分A中物质将pH调整至6.8,使用溶剂组分B将渗透压调整至315mOsm/kg;
5、将上述调整好pH、渗透压的注射用齐考诺肽经无菌滤膜无菌滤过、分装后即得;
使用时,患者借助无针注射器械直接将无针注射用齐考诺肽注射于局部慢性疼痛时的患处或全身慢性疼痛时的适处。
实验例1:本发明一种无针注射用齐考诺肽皮肤穿透能力与皮下扩散能力的研究
使用SD大鼠腹部皮肤评估无针注射用齐考诺肽的体外皮肤穿透能力,本实验例使用的齐考诺肽样品为实施例2制备得到的无针注射用齐考诺肽,搭配的无针注射器械为北京某企业已上市的无针注射器械。首先,取下SD大鼠腹部皮肤,除毛,并将其固定在泡沫板上。将本发明的无针注射用齐考诺肽经无针注射器械紧贴皮肤,并注射至大鼠皮肤内。随后,取走无针注射器械,滤纸吸取大鼠皮肤表面残留液体,借助放大镜观察注射针口。而后将注射部位大鼠皮肤经0.6cm角膜环钻取下,组织处理后借助高效液相色谱仪进行含量分析。
结果显示,本发明实施例2的无针注射用齐考诺肽注射入皮肤后,大鼠皮肤表面无残留液体发现,借助放大镜观察结果显示大鼠皮肤仅有一微小创口,其创口远小于1mL注射器针头造成的皮肤创口,说明本方法下注射用齐考诺肽全部注射进入体内,促进了药物经皮传递。
实验例2:本发明一种无针注射用齐考诺肽的大鼠个体安全性与组织刺激性的研究
本实验例使用的齐考诺肽样品为实施例2制备得到的无针注射用齐考诺肽,搭配的无针注射器械为北京某企业已上市的无针注射器械。雄性SD大鼠(体重200~250g)按数字随机表法设置分组,(1)齐考诺肽鞘内注射给药组、(2)齐考诺肽无针注射给药组、(3)齐考诺肽有针注射给药组。每组6只,分别使用下述分组设置中的药物对大鼠进行给药,给药后饲养一定时间,观察大鼠的行为状态,以及存活状态。以上,所有组别给药的齐考诺肽量相同,均为0.2mg。之后处死大鼠,取脑、心、肝、脾、肺、肾组织进行H&E染色,观察比较各组织的病理状态。
结果显示,各组SD大鼠在给药后均未出现死亡的情况,说明本发明实施例2的无针注射用齐考诺肽同对照组一样安全性良好。组织病理学结果显示,本发明实施例2的无针注射用齐考诺肽在给药后,未见明显的淋巴细胞浸润,未见组织损伤或坏死,同样表明本发明的无针注射用齐考诺肽具有良好的安全性。
大鼠个体安全性与组织刺激性结果表
实验例3:本发明一种无针注射用齐考诺肽在脑脊液中的药物分布研究
本实验例使用的齐考诺肽样品为实施例2制备得到的无针注射用齐考诺肽,搭配的无针注射器械为北京某企业已上市的无针注射器械。雄性SD大鼠(体重200~250g)按数字随机表法设置分组,(1)齐考诺肽鞘内注射给药组、(2)齐考诺肽无针注射给药组。每组30只,分别使用下述分组设置中的药物对大鼠进行给药,给药后饲养72h,在饲养过程中,于给药后0.5/1/2/4/8/12/24/36/48/72h每组各处死3只大鼠,取脑脊液,组织处理后借助高效液相色谱法测定脑脊液中齐考诺肽的含量,高效液相色谱谱图如图4所示。
结果如图5所示:鞘内注射组可以更快的在脑脊液中达到齐考诺肽的药物峰值,并且能达到的Cmax也高于无针注射给药组,但是无针注射组中也在脑脊液中获得了齐考诺肽的数据,虽然整体药物吸收略低于鞘内注射组,但也可以达到有效的药物浓度,而且由于无针注射可供患者自行给药,降低了治疗成本,并且免去了鞘内注射有可能产生的手术失败或引起的并发症,相较而言,不会产生更高的成本。
实验例4:本发明一种无针注射用齐考诺肽的药效学的研究
本实验例使用的齐考诺肽样品为实施例2制备得到的无针注射用齐考诺肽,搭配的无针注射器械为北京某企业已上市的无针注射器械。选用SPF级SD大鼠,体质量200~250g,模型建立参照H.B.Jia等文献报道,按1500mg/kg对大鼠进行腹膜内注射注射乌拉坦麻醉大鼠,俯卧固定于操作台,腹下垫薄垫,局部剃毛消毒,沿L4-6脊柱中线切皮,钝性分离脊柱右侧肌肉组织,切除L5横突,暴露并识别L5脊神经,用3-0的丝线结扎并切断右侧腰5脊神经,缝合并关闭切口。假手术组除了不切断L5脊神经以外,其余操作与手术组完全相同,术中及术后恢复均置大鼠与恒温电子电热毯保温。于术后第7~14天,给予不同分组的药物干预,给药时间每天上午7:00~8:00。
雄性SD大鼠(体重200~250g)按数字随机表法分为如下组,每组6只:(1)假手术组(假手术+等量生理盐水口服及腹腔注射)、(2)L5SNT组(L5脊神经切断+等量生理盐水口服及腹腔注射)、(3)齐考诺肽注射给药组(L5SNT+齐考诺肽鞘内注射释药剂量约5mg/d)、(4)无针注射用齐考诺肽高浓度组(L5SNT+无针注射用齐考诺肽释药剂量约20mg/d)、(5)无针注射用齐考诺肽低浓度组(L5SNT+无针注射用齐考诺肽释药剂量约5mg/d)。所有大鼠均术后第7d开始药物干预,连续7d。
动物造模前第3天、造模当天、造模后第7天开始给药后6小时进行热刺激撤足潜伏值的测定,使用足底测试仪检测大鼠后肢足跟部皮肤对热伤害性刺激的反应。每只大鼠热刺激强度以正常大鼠光照15s左右出现撤足反应为宜,为防止长时间热刺激造成组织损伤,热光源自动关闭时间为20s,实验期间,每5min作为时间间隔对大鼠双侧后足各测3次,3次撤足潜伏期取平均值,并做统计学分析。
无针注射用齐考诺肽的药效学结果
结果表明,在造模前,各SD大鼠的热刺激撤足潜伏值均约为10.0s,造模后,假手术组(假手术+等量生理盐水口服及腹腔注射)热刺激撤足潜伏值仍约为11.0,各手术组则均降低至8.2s,在造模之后7天开始给药,给药前再次测定各组大鼠的热刺激撤足潜伏值,其结果基本维持造模后的热刺激撤足潜伏值与机械刺激撤足域。各组按实验设定进行给药,给药后6小时再次测定大鼠的热刺激撤足潜伏值,假手术组热刺激撤足潜伏值仍约为11.0s,造模组则约为8.0s,各给药组热刺激撤足潜伏值与机械刺激撤足域均有上升,其中,齐考诺肽注射给药组(L5SNT+齐考诺肽鞘内注射)约为12.2s、78g,无针注射用齐考诺肽高浓度组(L5SNT+无针注射用齐考诺肽释药剂量约20mg/d)约为14.6s、86g,无针注射用齐考诺肽低浓度组(L5SNT+无针注射用齐考诺肽释药剂量约5mg/d)约为9.8s、66g。说明本发明的无针注射用齐考诺肽低高剂量组的药物作用效果呈现浓度依赖性,在一定的范围内,给药剂量越高,药物的治疗慢性疼痛的效果越好,在相同浓度下,效果略低于齐考诺肽鞘内注射组,但其却可以避免许多齐考诺肽鞘内注射带来的不便与危害。总体来看,说明本发明实施例2的无针注射用齐考诺肽具有良好的缓解、治疗慢性疼痛的效果。
实验例5:本发明一种无针注射用齐考诺肽的志愿者疼痛感受与止疼效果研究
本实验例使用的齐考诺肽样品为实施例2制备得到的无针注射用齐考诺肽,搭配的无针注射器械为北京某企业已上市的无针注射器械。本实验例全部志愿者为招募自由自愿加入,并充分阅读知晓知情同意书,实验过程符合伦理福利要求。所有志愿者均在教授使用方法后自行给药,并在给药后分别反馈给药时疼痛感(结果以-,+,++表示,其中-表示无痛感,++表示痛感强)、给药后24小时内止疼效果(结果以-,+,++表示,其中-表示无效,++表示效果很好)与接受程度。结果如下:
Claims (5)
1.一种无针注射用齐考诺肽药物组合物,其特征在于,
所述无针注射用齐考诺肽药物组合物为液体形式,所述无针注射用齐考诺肽药物组合物包括活性物质、改性组分与溶剂组分;
所述的活性物质选自齐考诺肽;
所述的改性组分选自改性组分A,改性组分B,改性组分C中的一种或多种;
所述改性组分A为体系稳定剂,选自透明质酸钠、壳聚糖、黄原胶和明胶中的一种或多种;所述改性组分B为增、助、潜溶剂,选自丙二醇、丙三醇、聚山梨酯、司盘和泊洛沙姆中的一种或多种;所述改性组分C为功能剂,选自叶酸、透明质酸、冰片、安息香和苏合香脂中的一种或多种;
所述的溶剂组分选自溶剂组分A、溶剂组分B中的一种或多种;
所述溶剂组分A选自葡萄糖、氯化钠、磷酸盐、枸橼酸,盐酸、氢氧化钠中的一种或多种;所述溶剂组分B选自注射用水、磷酸盐缓冲液、生理盐水和葡萄糖溶液中的一种或多种。
2.根据权利要求1所述的无针注射用齐考诺肽药物组合物,其特征在于,
其中,所述齐考诺肽的终浓度为50~280mg/mL。
3.权利要求1-2任一项所述的无针注射用齐考诺肽药物组合物的制备方法,其特征在于,
所述无针注射用齐考诺肽药物组合物的制备方法包含以下步骤:
第一,将活性物质齐考诺肽按一定比例直接溶于溶剂组分;
第二,将改性组分中的一种或几种加入到上述溶液中,经制备得到具有长期稳定性质的注射用齐考诺肽;
其中,制备方法可根据改性材料的的具体种类选择薄膜蒸发法、超声匀质法、乳化法、蒸发法、液液注入法;
第三,将上述经制备得到具有长期稳定性质的注射用齐考诺肽进行pH、渗透压的调整,pH调整至5.5~8.2,渗透压调整至250~400mOsm/kg;
第四,将上述调整好pH、渗透压的注射用齐考诺肽无菌处理、分装后即得;
其中,无菌处理可根据具体条件选择滤膜过滤法、高压灭菌法、无菌灌装法。
4.权利要求1-2任一项所述的无针注射用齐考诺肽药物组合物的使用方法,其特征在于,
其中,所述无针注射用齐考诺肽药物组合物可根据需求,调整每日给药次数,调整每日使用剂量,每日最大剂量不超过0.5mg/kg体重。
5.根据权利要求1-2任一项所述的无针注射用齐考诺肽药物组合物在制备治疗慢性疼痛药物中的应用。
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