CN108354903A - 一种局部麻醉镇痛缓释递药系统及其制备方法和应用 - Google Patents
一种局部麻醉镇痛缓释递药系统及其制备方法和应用 Download PDFInfo
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- CN108354903A CN108354903A CN201810320900.2A CN201810320900A CN108354903A CN 108354903 A CN108354903 A CN 108354903A CN 201810320900 A CN201810320900 A CN 201810320900A CN 108354903 A CN108354903 A CN 108354903A
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Abstract
本发明公开了一种新型局部麻醉镇痛缓释递药系统，包括内水相、外水相、油相、有机溶剂、等渗调节剂和pH调节剂，内水相包括镇痛剂、药物溶剂和药物增溶剂；镇痛剂选自布比卡因、左布比卡因、罗哌卡因、利多卡因、比卡因或甲哌卡因中的一种，且镇痛剂为游离碱形式或酸盐形式；药物溶剂选自含N或P的无机酸；药物增溶剂选自糖或环状有机酸中的一种或多种；本发明制备的多囊脂质体包封率和载药量高，粒径均一，缓释效果好。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种局部麻醉镇痛缓释递药系统及其制备方法和应用。
背景技术
目前临床局部麻醉药物主要有酯类和酰胺类，这些药物作用时间一般在3小时以下，若需要长时间镇痛则要持续给药以维持合适的血药浓度。若将此类药物制备成具有缓释功能的制剂，如微球、多囊脂质体，则可以使镇痛效果持续很长时间，同时也提高了患者的耐受性。专利号为CN102274183B的中国专利提出了两种多囊脂质体制备方法，第一种方法是将药物活性成分与渗透压调节剂溶于水制得内水相，加入由脂质溶于有机溶剂制得的脂质相，制得油包水初乳，之后在油包水初乳上层加入含有渗透压调节剂的外水相，制得水包油包水复乳，之后除去复乳中的有机溶剂即可。该方法在制备过程加入了辅助乳化剂，主要为右旋糖酐、聚乙烯吡咯烷酮等片剂常用表面活性剂，pH调节剂为本技术领域常用酸。第二种方法与上述不同之处在于其载药过程是将药物溶解于外水相，通过多囊脂质体内外渗透压差载药，而不是在制备W/O时加入药物。该方法类似于普通脂质体pH梯度法载药或离子梯度载药，由于多囊脂质体为多数小囊存在于一个大囊的结构，在利用该技术载药时，必然是外层小囊内优先载入药物，而在外层小囊载药后，大囊内层的小囊体载入药物的渗透压会降低，那么多囊脂质体大囊内必然有部分小囊内无活性药物填充，另外，多囊脂质体与普通脂质体的不同之处在于其含有甘油三酯等油性成分，存在于每一个囊体的骨架结构中，该专利是将药物溶解于外水相，那么水性药物从外水相进入内水相的过程中势必会受到甘油三酯的干扰，药物无法顺利进入多囊脂质体内部，且该专利所述药物活性成分主要为艾塞那肽、拓扑替康等在碱性条件下不稳定的药物。
基于此，本发明提供一种含酰胺类局部麻醉镇痛剂的多囊脂质体制备思路，从而制备出包封率更高、稳定性更好的多囊脂质体产品。
发明内容
本发明所要解决的技术问题是提供一种更好的多囊脂质体及其制备方法，从而制备出包封率更高、稳定性更好、适合多种需求的多囊脂质体产品。
为实现上述目的，本发明采用以下技术方案：
一种新型局部麻醉镇痛缓释递药系统，包括内水相、外水相、油相、有机溶剂、等渗调节剂和pH调节剂，所述内水相包括镇痛剂、药物溶剂和药物增溶剂；其中外水相最终被除去，最后加入等渗调节剂和pH调节剂得到本发明的缓释递药系统。
所述镇痛剂选自布比卡因、左布比卡因、罗哌卡因、利多卡因或甲哌卡因中的一种。
所述药物溶剂选自含N、P的无机酸，优选硝酸和磷酸。
所述药物增溶剂选自糖或环状有机酸，优选环状有机酸；所述糖选自蔗糖、葡萄糖、果糖等单糖或者二元糖，所述环状有机酸选自维生素C、烟酸、没食子酸或葡萄糖醛酸。
所述外水相选自糖、环状有机酸、有机碱或反絮凝剂中的一种或多种；所述有机碱选自赖氨酸或精氨酸；所述反絮凝剂选自柠檬酸盐、酒石酸盐或磷酸盐。
所述油相包括合成磷脂、合成磷脂酰甘油、胆固醇和甘油脂；所述合成磷脂选自DEPC(二芥酰基卵磷脂)、DOPC(二油酰基卵磷脂)、DPPC(二棕榈酰基卵磷脂)、DSPC(二硬脂酰基磷脂酰胆碱)或DMPC(二肉豆蔻酰基卵磷脂)中的一种或多种；所述合成磷脂酰甘油选自DPPG(1,2-棕榈酰磷脂酰甘油)、DOPG(二油酰磷脂酰甘油)、DMPG(二肉豆蔻酰磷脂酰甘油)或DSPG(二硬脂酰磷脂酰甘油)中的一种或多种；所述甘油脂选自三油酸甘油脂或三辛酸甘油酯。
所述有机溶剂选自三氯甲烷、乙醚或正己烷等与水不互溶的有机溶剂，优选三氯甲烷或乙醚。
所述等渗调节剂选自0.9％氯化钠注射液、5％甘露醇注射液、乳酸钠林格注射液或5％葡萄糖注射液；等渗调节剂用于调节脂质体混悬液的渗透压，使其达到等渗状态。其中乳酸钠林格注射液为乳酸钠、氯化钠、氯化钾、氯化钙的混合溶液，每种物质有其固定的量，为本技术领域所熟知的溶液。
所述pH调节剂是浓度为0.1M～1M的碱性物质，优选氢氧化钠、三乙胺、赖氨酸、精氨酸或组氨酸。
所述的新型局部麻醉镇痛缓释递药系统，各组分的用量范围如下：
所述内水相共5ml，包括镇痛剂5mg～500mg、药物溶剂1ml～5ml和药物增溶剂5mg～500mg；所述外水相共100ml，选自糖0.01g～10g、环状有机酸0.1g～10g、有机碱0.1g～10g或反絮凝剂0.1g～10g中的一种或多种配制成的水溶液；所述油相共5ml，包括合成磷脂5mg～400mg、合成磷脂酰甘油0.5mg～250mg、胆固醇2.5mg～250mg和甘油脂2.5mg～250mg；所述有机溶剂选自三氯甲烷0.5ml～50ml、乙醚0.5ml～50ml或正己烷0.5ml～50ml中的一种或多种。
优选的，所述新型局部麻醉镇痛缓释递药系统，各组分的用量范围如下：
所述内水相共5ml，包括镇痛剂25mg～300mg、药物溶剂1ml～5ml和药物增溶剂25mg～250mg；所述外水相共100ml，选自糖1g～5g、环状有机酸1g～5g、有机碱1g～3g或反絮凝剂1g～5g中的一种或多种配成水溶液；所述油相共5ml，包括合成磷脂25mg～150mg、合成磷脂酰甘油5mg～100mg、胆固醇5mg～125mg和甘油脂1mg～150mg；所述有机溶剂选自三氯甲烷1.5ml～45ml、乙醚1.5ml～45ml或正己烷1.5ml～45ml中的一种或多种。
所述的新型局部麻醉镇痛缓释递药系统，制备方法包含以下步骤：
(1)内水相的制备
称取一定量的镇痛剂，若镇痛剂为游离碱形式，加入处方量的药物溶剂和药物增溶剂，使镇痛剂完全溶解；若镇痛剂为酸盐形式，将镇痛剂所含酸根替换为含N或P的酸根，然后按上述方法操作。
(2)外水相的制备
称取一定量的外水相各物质，加水溶解，其中有机碱用来调节外水相pH值。
(3)油相的制备
称取处方量的合成磷脂酰胆碱、合成磷脂酰甘油、胆固醇和甘油酯，用有机溶剂溶解，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，二者体积比为1:10-10:1，在10000-16000rpm条件下，剪切5-20min，得初乳。
(5)复乳的制备
量取一定量的初乳，按初乳与外水相体积比1:5-1:50配比将初乳加入外水相，1000-4000rpm剪切5-60s，然后继续迅速加入初乳5-20倍体积的外水相，在20-40℃下，用40-90L/min的氮气吹5-30min，或20-40℃下，旋转蒸发；除去有机溶剂，收集脂质体中间体，100-20000rpm下离心10-30min，弃去上清液，用大量的等渗调节剂冲洗，用pH调节剂调至5.0～8.0，得多囊脂质体，所得多囊脂质体粒径范围为1～50μm。
在符合本领域基础思想的前提下，本发明中上述技术特征任意组合均可得到较优的多囊脂质体制剂。
本发明的有益效果：本发明根据分子结构提出制备特定药物多囊脂质体所必须满足的条件，药物结构不同，所需药物增溶剂不同，酰胺类局麻药结构含苯环、吡啶环，故选择环状有机酸作为药物的增溶剂效果较好，另吡啶环上有N原子，故药物溶剂选含N、P在同一族的无机酸，才可制备出收率高的多囊脂质体。本发明制备的多囊脂质体包封率和载药量高，粒径均一，缓释效果好。本发明的多囊脂质体可用于制备如降糖药物、抗抑郁药、心血管疾病用药等需要长期给药的慢性病药物。
附图说明：
图1为左布比卡因多囊脂质体在400倍光学显微镜下的外观形态图；
图2为左布比卡因多囊脂质体在200倍光学显微镜下的外观形态图；
图3为左布比卡因多囊脂质体给药后48h平均针刺无痛反应数对比图；
图4为左布比卡因多囊脂质体给药48h后针刺平均无痛无反应数百分比(％)对比图。
具体实施方式
以下结合附图对本发明做进一步的详细描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
实施例1
处方组成：
多囊脂质体的制备方法如下：
(1)内水相的制备
称取一定量的盐酸左布比卡因，用水溶解后加入1M的氢氧化钠，待无更多不溶物出现时，过滤收集固体，用注射用水洗至中性，60℃烘干，向固体粉末中加入内水相的其他物质，加入3ml 1M磷酸，溶解后加水至5ml，得水相。
(2)外水相的制备
称取上表外水相烟酸和柠檬酸钠，加入80ml水溶解，用精氨酸调节pH至7.4，加水至100ml，得外水相。
(3)油相的制备
称取上表油相各物质，用5ml三氯甲烷与乙醚的混合溶液溶解(体积比3:2)，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，在13000rpm下，剪切10min，得初乳。
(5)复乳的制备
量取5ml初乳，迅速倒入20ml外水相，3000rpm剪切60s，然后继续迅速加入80ml外水相，在30℃下，用80L/min的氮气吹20min，除去有机溶剂，收集多囊脂质体中间体，用大量的0.9％的NaCl溶液冲洗，用1M氢氧化钠调节脂质体混悬液的pH为7.4，得多囊脂质体，所得多囊脂质体平均为30μm。
实施例2
处方组成：
多囊脂质体的制备方法如下：
(1)内水相的制备
称取200mg布比卡因，加入内水相的其他物质，加入2.5ml 1M硝酸，溶解后加水至5ml，得水相。
(2)外水相的制备
称取上表外水相葡萄糖醛酸、蔗糖和柠檬酸钠，加入80ml水溶解，用精氨酸调节pH至8.0，加水至100ml，得外水相。
(3)油相的制备
称取上表油相各物质，用5ml三氯甲烷与乙醚的混合溶液溶解(体积比4:1)，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，在16000rpm下，剪切8min，得初乳。
(5)复乳的制备
量取5ml初乳，迅速倒入20ml外水相，2000rpm剪切30s，然后继续迅速加入80ml外水相，35℃旋蒸除去有机溶剂，收集多囊脂质体中间体，用大量的5％的葡萄糖溶液冲洗，用0.8M三乙胺调节脂质体混悬液的pH为6.8，得多囊脂质体，所得多囊脂质体平均为43μm。
实施例3
处方组成：
多囊脂质体的制备方法如下：
(1)内水相的制备
称取250mg罗哌卡因，加入内水相的其他物质，加入3.5ml 1M磷酸，溶解后加水至5ml，得水相。
(2)外水相的制备
称取上表外水相维生素C、蔗糖和酒石酸钠，加入80ml水溶解，用赖氨酸调节pH至8.5，加水至100ml，得外水相。
(3)油相的制备
称取上表油相各物质，用5ml三氯甲烷溶解，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，在13000rpm下，剪切10min，得初乳。
(5)复乳的制备
量取5ml初乳，迅速倒入20ml外水相，3000rpm剪切15s，然后继续迅速加入80ml外水相，37℃旋蒸除去有机溶剂，收集多囊脂质体中间体，用大量的5％的甘露醇溶液冲洗，用0.2M赖氨酸调节脂质体混悬液的pH为7.2，得多囊脂质体，所得多囊脂质体平均为24μm。
实施例4
处方组成：
多囊脂质体的制备方法如下：
(1)内水相的制备
称取300mg利多卡因，加入内水相的其他物质，加入4ml 1M硝酸，溶解后加水至5ml，得水相。
(2)外水相的制备
称取上表外水相维生素C、葡萄糖醛酸、磷酸二氢钠和葡萄糖，加入80ml水溶解，用组氨酸调节pH至9.0，加水至100ml，得外水相。
(3)油相的制备
称取上表油相各物质，用5ml三氯甲烷和乙醚的混合溶液(体积比1:4)溶解，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，在10000rpm下，剪切15min，得初乳。
(5)复乳的制备
量取5ml初乳，迅速倒入20ml外水相，4000rpm剪切15s，然后继续迅速加入80ml外水相，35℃水浴，100L/min氮气吹15min除去有机溶剂，收集多囊脂质体中间体，用大量的乳酸钠林格溶液冲洗，用0.5M精氨酸调节脂质体混悬液的pH为7.4，得多囊脂质体，所得多囊脂质体平均为45μm。
实施例5
处方组成：
多囊脂质体的制备方法如下：
(1)内水相的制备
称取180mg甲哌卡因，加入内水相的其他物质，加入3ml 1M磷酸，溶解后加水至5ml，得水相。
(2)外水相的制备
称取上表外水相葡萄糖醛酸和磷酸氢二钠，加入100ml水溶解，用赖氨酸调节pH至7.0，加水至150ml，得外水相。
(3)油相的制备
称取上表油相各物质，用5ml正己烷和乙醚的混合溶液(体积比3:2)溶解，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，在16000rpm下，剪切20min，得初乳。
(5)复乳的制备
量取5ml初乳，迅速倒入30ml外水相，4000rpm剪切60s，然后继续迅速加入120ml外水相，30℃水浴，旋转蒸发除去有机溶剂，收集多囊脂质体中间体，用大量的5％的葡萄糖溶液冲洗，用0.2M组氨酸调节脂质体混悬液的pH为7.4，得多囊脂质体，所得多囊所得脂质体平均为15μm。
实施例6
处方组成：
多囊脂质体的制备方法如下：
(1)内水相的制备
称取220mg左布比卡因，加入内水相的其他物质，加入2ml 1M磷酸，溶解后加水至5ml，得水相。
(2)外水相的制备
称取上表外水相维生素C、蔗糖、磷酸氢二钠和磷酸二氢钠盐，加入100ml水溶解，用精氨酸调节pH至7.0，加水至150ml，得外水相。
(3)油相的制备
称取上表油相各物质，用5ml正己烷和三氯甲烷的混合溶液(体积比3:2)溶解，得油相。
(4)初乳的制备
将配制好的内水相加入到油相中，在15000rpm下，剪切10min，得初乳。
(5)复乳的制备
量取5ml初乳，迅速倒入30ml外水相，8000rpm剪切25s，然后继续迅速加入120ml外水相，35℃水浴，旋转蒸发除去有机溶剂，收集多囊脂质体中间体，用大量的0.9％氯化钠溶液冲洗，用0.1M氢氧化钠调节脂质体混悬液的pH为7.0，得多囊脂质体，所得多囊脂质体平均为18μm。
实施例7
左布比卡因多囊脂质体显微结构观察
按上述实施例1制备左布比卡因多囊脂质体，取一滴于载玻片上，盖上盖玻片，分别在400倍和200倍显微镜下观察，拍摄左布比卡因多囊脂质体显微结构图，如图1和图2所示。图谱显示，多囊脂质体形态规则呈圆整的球状体，内部有多个小囊泡构成。囊膜完整、清晰可见，多囊粒径整体较均一。
实施例8
左布比卡因多囊脂质体的含量与包封率测定
采用高效液相色谱测定左布比卡因多囊脂质体的含量，色谱条件如下：
色谱柱：Agilent C18column(150mm*4.6mm*5μm)；以0.02mol/L磷酸盐缓冲液(取磷酸二氢钾2.72g与氢氧化钠0.75g，加水1000ml使其溶解，调节pH值至8.0)-乙腈(50:50)为流动相；检测波长为240nm；流速为1.0ml/min；柱温为35℃，进样量：20μl。左布比卡因峰与相邻杂质峰的分离度应大于1.5。
左布比卡因多囊脂质体的包封率测定具体方法如下：
精密量取左布比卡因多囊脂质体混悬液1.0ml，加入1.0ml 0.9％NaCl溶液，混匀后，精密移取0.1ml，置于10ml容量瓶中，加甲醇2ml，破乳振摇并用流动相稀释至刻度，摇匀。用HPLC测定左布比卡因多囊脂质体中总药量(W总)。其余样品于3000rpm离心10min，精密移取上清液0.1ml，置10ml容量瓶中，加甲醇2ml破乳振摇，用流动相稀释至刻度，摇匀，吸取20μl，按照上述色谱条件操作，测定左布比卡因多囊脂质体中游离药物含量(W上清)。
根据公式计算左布比卡因多囊脂质体包封率(EE％)：包封率(EE％)＝(W总-W上清)/W总×100％。按照上述方法测定实施例中多囊脂质体的包封率，见下表：
实施例9
左布比卡因多囊脂质体药效对比
实验动物为30周豚鼠，体重300-500g，雄性。实验前豚鼠应在独立环境，保持室温(23±1)℃及12～12h明/暗光照(晨起8:00为光照)静养3天适应环境。
实验方法：将豚鼠(9只)背部皮肤6cm×10cm的毛剃净。标记泡疹范围，每只豚鼠标记4个区域，左上为生理盐水，右上为空白多囊脂质体，左下为盐酸左布比卡因注射液、右下为自制左布比卡因多囊脂质体。实验分为三个剂量组，即低剂量10mg/ml、中剂量15mg/ml、高剂量20mg/ml，每组3只豚鼠。每个标记区域皮内注射给药注射体积为0.35ml。形成皮下泡疹，15min后测试豚鼠对针刺的反应。对每个泡疹内进行17次针刺，针刺间隔3-5s，测试时间点分别为：注射后1min、15min、30min和3h、6h、9h、12h、18h、21h、24h、30h、48h，共12个时间点。每只豚鼠每个区域受的针刺总数为204次，对豚鼠不能做出反应的针刺进行计数。累加48h内12个时间点没有产生反应的针刺数，以总和为分子，以针刺总数204为分母形成的数值反映麻醉程度。计算每组豚鼠的无反应次数的平均百分比，数值越大，麻醉作用越强；计算数值越小，麻醉作用越弱。左布比卡因多囊脂质体低剂量、中剂量、高剂量组给药48h后不同时间点平均针刺计数结果见表1及附图2。针刺平均无痛反应数百分比(％)结果见表2及附图3。
表1：左布比卡因多囊脂质体不同时间点平均针刺计数统计表
表2：左布比卡因多囊脂质体不同时间点平均无痛反应数百分比(％)结果
左布比卡因多囊脂质体药效学实验证实，左布比卡因多囊脂质体48小时内的针刺无痛反应数(分别为10mg/ml：79.90％，13.3mg/ml：82.35％，20mg/ml：85.78％)明显高于盐酸左布比卡因注射液(28.59％)，作用时间大于24小时，可见，将左布比卡因制备成具有缓释功能的多囊脂质体混悬液，用于术后镇痛是可以实现的。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.一种新型局部麻醉镇痛缓释递药系统，包括内水相、外水相、油相、有机溶剂、等渗调节剂和pH调节剂，所述内水相包括镇痛剂、药物溶剂和药物增溶剂；所述镇痛剂选自布比卡因、左布比卡因、罗哌卡因、利多卡因或甲哌卡因中的一种，且所述镇痛剂为游离碱形式或酸盐形式；所述药物溶剂选自含N或P的无机酸；所述药物增溶剂选自糖或环状有机酸中的一种或多种。
2.根据权利要求1所述的一种新型局部麻醉镇痛缓释递药系统，所述外水相选自糖、环状有机酸、有机碱或反絮凝剂中的一种或多种配制成的水溶液；所述油相包括合成磷脂、合成磷脂酰甘油、胆固醇和甘油脂；所述有机溶剂选自三氯甲烷、正己烷或乙醚中的一种或多种；所述等渗调节剂选自0.9％氯化钠注射液、5％甘露醇注射液、乳酸钠林格注射液或5％葡萄糖注射液；所述pH调节剂选自氢氧化钠、三乙胺、赖氨酸、精氨酸或组氨酸。
3.根据权利要求2所述的一种新型局部麻醉镇痛缓释递药系统，所述糖选自葡萄糖、果糖或蔗糖；所述环状有机酸选自维生素C、烟酸、没食子酸或葡萄糖醛酸；所述有机碱选自赖氨酸、精氨酸或组氨酸；所述反絮凝剂选自柠檬酸盐、酒石酸盐或磷酸盐；所述合成磷脂选自DEPC、DOPC、DPPC、DSPC或DMPC中的一种或多种；所述合成磷脂酰甘油选自DPPG、DOPG、DMPG或DSPG中的一种或多种；所述甘油脂选自三油酸甘油脂或三辛酸甘油酯。
4.根据权利要求2所述的一种新型局部麻醉镇痛缓释递药系统，所述各组分的用量范围如下：所述内水相共5ml，包括镇痛剂5mg～500mg、药物溶剂1ml～5ml和药物增溶剂5mg～500mg；所述外水相共100ml，选自糖0.01g～10g、环状有机酸0.1g～10g、有机碱0.1g～10g或反絮凝剂0.1g～10g中的一种或多种；所述油相共5ml，包括合成磷脂5mg～400mg、合成磷脂酰甘油0.5mg～250mg、胆固醇2.5mg～250mg和甘油脂2.5mg～250mg；所述有机溶剂选自三氯甲烷0.5ml～50ml、乙醚0.5ml～50ml或正己烷0.5ml～50ml中的一种或多种。
5.根据权利要求4所述的一种新型局部麻醉镇痛缓释递药系统，所述各组分的用量范围如下：所述内水相共5ml，包括镇痛剂25mg～300mg、药物溶剂1ml～5ml和药物增溶剂25mg～250mg；所述外水相共100ml，选自糖1g～5g、环状有机酸1g～5g、有机碱1g～3g或反絮凝剂1g～5g中的一种或多种配成水溶液；所述油相共5ml，包括合成磷脂25mg～150mg、合成磷脂酰甘油5mg～100mg、胆固醇5mg～125mg和甘油脂1mg～150mg；所述有机溶剂选自三氯甲烷1.5ml～45ml、乙醚1.5ml～45ml或正己烷1.5ml～45ml中的一种或多种。
6.根据权利要求4或5所述的一种新型局部麻醉镇痛缓释递药系统，制备方法包含以下步骤：
(1)内水相的制备
称取一定量的镇痛剂，若镇痛剂为游离碱形式，加入处方量的药物溶剂和药物增溶剂，使镇痛剂完全溶解；若镇痛剂为酸盐形式，将镇痛剂所含酸根替换为含N或P的酸根，然后按上述方法操作；
(2)外水相的制备
称取一定量的外水相各物质，加水溶解，其中有机碱用来调节外水相pH值；
(3)油相的制备
称取处方量的合成磷脂酰胆碱、合成磷脂酰甘油、胆固醇和甘油酯，用有机溶剂溶解，得油相；
(4)初乳的制备
将配制好的内水相加入到油相中，二者体积比为1:10-10:1，在10000-16000rpm条件下，剪切5-20min，得初乳；
(5)复乳的制备
量取一定量的初乳，按初乳与外水相体积比1:5-1:50配比将初乳加入外水相，1000-4000rpm剪切5-60s，然后继续迅速加入初乳5-20倍体积的外水相，在20-40℃下，用40-90L/min的氮气吹5-30min，或20-40℃下，旋转蒸发；除去有机溶剂，收集多囊脂质体中间体，100-20000rpm下离心10-30min，弃去上清液，用等渗调节剂冲洗，用pH调节剂调至5.0～8.0，得多囊脂质体，所得多囊脂质体粒径范围为1～50μm。
7.根据权利要求1所述的一种新型局部麻醉镇痛缓释递药系统，其给药途径为局部注射给药。
8.根据权利要求1所述的一种新型局部麻醉镇痛缓释递药系统，用于手术前麻醉及手术后镇痛。
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| CN110045034A (zh) * | 2019-04-30 | 2019-07-23 | 江苏东南纳米材料有限公司 | 一种高效液相色谱测定二芥酰磷脂酰胆碱含量的方法 |
| CN110179752A (zh) * | 2019-05-31 | 2019-08-30 | 常州莱特豪斯生物医药科技有限公司 | 高浓度布比卡因多囊脂质体及其制备工艺、配液系统 |
| CN111388418A (zh) * | 2018-12-31 | 2020-07-10 | 北京泰德制药股份有限公司 | 一种含有罗哌卡因或其药用盐的药物组合物 |
| WO2020211762A1 (zh) * | 2019-04-15 | 2020-10-22 | 湖州依诺唯新药物制剂有限公司 | 脂性药物制剂及其应用 |
| CN113976052A (zh) * | 2021-11-03 | 2022-01-28 | 健进制药有限公司 | 一种多囊脂质体制备系统及其制备方法 |
| CN114948877A (zh) * | 2022-05-30 | 2022-08-30 | 华裕(无锡)制药有限公司 | 一种盐酸罗哌卡因脂质体注射液及其制备方法 |
| CN115804771A (zh) * | 2021-12-17 | 2023-03-17 | 佐建锋 | 一种具有长效缓释作用的脂质释药系统及其制备方法 |
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| CN113116823B (zh) * | 2019-12-30 | 2024-02-20 | 江苏恒瑞医药股份有限公司 | 一种脂质体及其制备方法 |
| US11033495B1 (en) | 2021-01-22 | 2021-06-15 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| WO2022159564A1 (en) * | 2021-01-22 | 2022-07-28 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US11278494B1 (en) | 2021-01-22 | 2022-03-22 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| US12151024B2 (en) | 2021-01-22 | 2024-11-26 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
| CN114469734B (zh) * | 2021-10-13 | 2023-08-04 | 成都科建生物医药有限公司 | 一种蒽环类药物脂质体的制备装置与制备方法 |
| EP4415713A1 (en) * | 2021-10-14 | 2024-08-21 | Pacira Pharmaceuticals, Inc. | Bupivacaine multivesicular liposome formulations and uses thereof |
| US12156940B1 (en) | 2024-05-20 | 2024-12-03 | Pacira Pharmaceuticals, Inc. | Manufacturing of bupivacaine multivesicular liposomes |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111388418A (zh) * | 2018-12-31 | 2020-07-10 | 北京泰德制药股份有限公司 | 一种含有罗哌卡因或其药用盐的药物组合物 |
| CN111388418B (zh) * | 2018-12-31 | 2022-09-06 | 北京泰德制药股份有限公司 | 一种含有罗哌卡因或其药用盐的药物组合物 |
| WO2020211762A1 (zh) * | 2019-04-15 | 2020-10-22 | 湖州依诺唯新药物制剂有限公司 | 脂性药物制剂及其应用 |
| CN111840553A (zh) * | 2019-04-15 | 2020-10-30 | 湖州依诺唯新药物制剂有限公司 | 脂性药物制剂及其应用 |
| CN110045034A (zh) * | 2019-04-30 | 2019-07-23 | 江苏东南纳米材料有限公司 | 一种高效液相色谱测定二芥酰磷脂酰胆碱含量的方法 |
| CN110179752A (zh) * | 2019-05-31 | 2019-08-30 | 常州莱特豪斯生物医药科技有限公司 | 高浓度布比卡因多囊脂质体及其制备工艺、配液系统 |
| CN110179752B (zh) * | 2019-05-31 | 2024-02-20 | 常州吾合生物医药有限责任公司 | 高浓度布比卡因多囊脂质体及其制备工艺、配液系统 |
| CN113976052A (zh) * | 2021-11-03 | 2022-01-28 | 健进制药有限公司 | 一种多囊脂质体制备系统及其制备方法 |
| CN115804771A (zh) * | 2021-12-17 | 2023-03-17 | 佐建锋 | 一种具有长效缓释作用的脂质释药系统及其制备方法 |
| CN114948877A (zh) * | 2022-05-30 | 2022-08-30 | 华裕(无锡)制药有限公司 | 一种盐酸罗哌卡因脂质体注射液及其制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3572070A1 (en) | 2019-11-27 |
| EP3572070A4 (en) | 2020-01-01 |
| WO2019196129A1 (zh) | 2019-10-17 |
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