CN105796482A - 紫杉醇缓释温敏凝胶及其制备方法 - Google Patents
紫杉醇缓释温敏凝胶及其制备方法 Download PDFInfo
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- CN105796482A CN105796482A CN201610247459.0A CN201610247459A CN105796482A CN 105796482 A CN105796482 A CN 105796482A CN 201610247459 A CN201610247459 A CN 201610247459A CN 105796482 A CN105796482 A CN 105796482A
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- paclitaxel
- thermosensitive hydrogel
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Inorganic Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种紫杉醇缓释温敏凝胶及其制备方法,所述的紫杉醇缓释温敏凝胶由如下重量百分含量的物料组成:紫杉醇0.01%~5%、有机溶剂0.5%~27%、基于Soluplus的温敏凝胶基质余量;本发明所述的紫杉醇缓释温敏凝胶体系的相变温度较泊洛沙姆407温敏凝胶的胶凝温度更接近体温,不仅方便给药,且体内形成的凝胶强度较泊洛沙姆407温敏凝胶强度大,皮下注射后至少可维持7天药物缓释,而泊洛沙姆407仅约1天,本发明紫杉醇缓释温敏凝胶经瘤旁局部注射或实体瘤摘除部位给药,能够提高癌症的治疗疗效,降低全身毒副作用,疗效显著优于紫杉醇‑泊洛沙姆407温敏凝胶。
Description
(一)技术领域
本发明涉及一种新型的紫杉醇缓释温敏凝胶及其制备方法。
(二)背景技术
紫杉醇是一种常用的广谱抗癌药,主要用于卵巢癌、乳腺癌、小细胞肺癌、前列腺癌、及淋巴癌等的治疗。紫杉醇水中溶解度极低,约0.3μg/mL;且存在严重毒副作用,限制了其临床用药剂量和用药周期。目前市售制剂主要有注射液(Taxol)、脂质体(力扑素)、纳米混悬制剂(白蛋白结合型)和聚合物胶束均为静脉注射给药。
温敏凝胶系指在室温下呈流动液体状态,在体温下迅速相变形成凝胶的一种新型载药体系,用于局部注射给药,可延长药物在用药部位的滞留时间,缓慢释放药物而提高疗效,降低全身毒副作用。目前公开报道的紫杉醇温敏凝胶主要有:紫杉醇脂质体-泊洛沙姆407(Pluronic F127或Lutrol F127,简称F127)温敏凝胶(Mao Y,Li X,Chen G,Wang S.Thermosensitive hydrogel system with paclitaxel liposomes used in localized drug deliverysystem for in situ treatment of tumor:better antitumor efficacy and lower toxicity.J Pharm Sci.2015,doi:10.1002);紫杉醇纳米粒-泊洛沙姆407+188温敏凝胶(Hu H,Lin Z,He B,Dai W,Wang X,Wang J,Zhang X,Zhang H,Zhang Q.A novel localized co-delivery system withlapatinib microparticles and paclitaxel nanoparticles in a peritumorally injectable in situ hydrogel.J Control Release,2015,220(Pt):189-200.;Shen M,Xu YY,Sun Y,Han BS,Duan YR.Preparation of a thermosensitive gel composed of a mPEG-PLGA-PLL-cRGD nanodrug deliverysystem for pancreatic tumor therapy.ACS Appl Mater Interfaces,2015,7(37):20530-7.);紫杉醇纳米脂质体-壳聚糖温敏凝胶(Mahajan M,Utreja P,Jain SK.Paclitaxel loaded nanoliposomes inthermosensitive hydrogel:a dual approach for sustained and localized delivery.Anticancer AgentsMed Chem,2015,Epub.);紫杉醇MPEG-PCL胶束-PEG-PCL-PEG温敏凝胶(Wu Z,Zou X,Yang L,Lin S,Fan J,Yang B,Sun X,Wan Q,Chen Y,Fu S.Thermosensitive hydrogel used indual drug delivery system with paclitaxel-loaded micelles for in situ treatment of lung cancer.Colloids Surf B Biointerfaces,2014,122:90-8.。王伟伟,董岸杰.环醚侧基修饰的PCL/PEG嵌段共聚物可注射温敏凝胶及肿瘤局部给药的研究,天津大学,博士论文);紫杉醇-PLGA-b-PEG-b-PLGA温敏凝胶(Cho H,Kwon GS.Thermosensitivepoly-(d,l-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(d,l-lactide-co-glycolide)hydrogels for multi-drug delivery.J Drug Target.2014,22(7):669-77.);紫杉醇-Poly(organophosphazene)温敏凝胶(Kim JH,Lee JH,Kim KS,Na K,Song SC,Lee J,Kuh HJ.Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts.Arch Pharm Res,2013,36(1):94-101.);紫杉醇-N-异丙基丙烯酰胺-PEG-N-异丙基丙烯酰胺三嵌段聚合物(pNIPAm-PEG-pNIPAm)温敏凝胶(de Graaf AJ1,Azevedo Próspero dos SantosII,Pieters EH,Rijkers DT,van Nostrum CF,Vermonden T,Kok RJ,Hennink WE,MastrobattistaE.A micelle-shedding thermosensitive hydrogel as sustained release formulation.J ControlRelease,2012,162(3):582-90.);紫杉醇-癸酸-PEG-癸酸温敏凝胶(Zhang J,Liang Y,Li N,LiX,Hu R,Xing J,Deng L,Hu F,Dong A.Thermosensitive hydrogel based on poly(ether-esteranhydride)nanoparticle as drug delivery system:preparation,characterization andbiocompatibility.Colloids Surf B Biointerfaces,2012,96:56-61.);紫杉醇-DSPC-EPC温敏磷脂凝胶(Grant J,Zahedi P,Tsallas A,Allen C.Thermosensitive depot-forming injectablephosphatidylcholine blends tailored for localized drug delivery.J Pharm Sci,2013,102(10):3623-31.)。
但由于紫杉醇水中溶解度低,温敏凝胶大多分子量小,强度不足,体内稳定性差,易解聚,导致体内释药速率太快(McKenzie M,Betts D,Suh A,Bui K,Kim LD,Cho H.Hydrogel-based drug delivery systems for poorly water-soluble drugs.Molecules.2015,20(11):20397-408)。故文献报道的紫杉醇温敏凝胶大多先将紫杉醇载入适宜的载体如脂质体、纳米粒、聚合物胶束或环糊精主分子,再与温敏凝胶混合。
聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(商品名Soluplus)为N-乙烯基-ε-己内酰胺-乙酸乙烯酯-聚乙二醇(57:30:13)共聚而成,分子量为90,000~140,000g/mol,是BASF公司2009年研发上市的一种新型高分子材料。Soluplus为两亲性非离子型药用高分子材料,具有增溶、空间稳定及热敏等作用。目前尚没有Soluplus作为温敏凝胶的研究报道。我们发现Soluplus凝胶不仅具有温敏的特点,且能增溶紫杉醇形成稳定的给药系统。
故本发明旨在以Soluplus为温敏凝胶基质,提供一种新型的紫杉醇温敏凝胶缓释制剂配方组合物,经瘤旁局部注射或实体瘤摘除部位给药,提高癌症的治疗疗效,降低全身毒副作用。
(三)发明内容
本发明的目的是提供一种新型的紫杉醇缓释温敏凝胶及其制备方法,所述的紫杉醇缓释温敏凝胶经瘤旁局部注射或实体瘤摘除部位给药,提高癌症的治疗疗效,降低全身毒副作用。
为实现上述目的,本发明采用如下技术方案:
一种紫杉醇缓释温敏凝胶,由如下重量百分含量的物料组成:
紫杉醇 0.01%~5%
有机溶剂 0.5%~27%
基于Soluplus的温敏凝胶基质 余量
优选的,所述紫杉醇缓释温敏凝胶由如下重量百分含量的物料组成:
紫杉醇 0.05%~3%
有机溶剂 0.69%~20%
基于Soluplus的温敏凝胶基质 余量
更加优选的,所述紫杉醇缓释温敏凝胶由如下重量百分含量的物料组成:
紫杉醇 0.1%~1.0%
有机溶剂 5%~15%
基于Soluplus的温敏凝胶基质 余量
此外,还可以根据需要在本发明所述的紫杉醇缓释温敏凝胶中添加其他适宜的组分,主要包括氧化剂等稳定剂,其他适宜组分的添加量可根据药学上可接受的量确定。
本发明中,所述的有机溶剂为与水互溶的有机溶剂,具体可选自甲醇、乙醇、丙酮、二甲亚砜、甘油、四氢呋喃、二甲基甲酰胺、乙二醇、正丁醇中的一种或两种以上任意比例的混合溶剂,优选乙醇。
本发明中,所述基于Soluplus的温敏凝胶基质在25℃以下呈流动的液态分散体系,通针性良好,可注射给药,胶凝温度为25~37℃,优选30~35℃。
所述基于Soluplus的温敏凝胶基质由如下重量百分含量的物料组成:Soluplus 8%~50%、水相余量。
优选的,所述基于Soluplus的温敏凝胶基质由如下重量百分含量的物料组成:Soluplus10%~40%、水相余量。
特别优选的,所述基于Soluplus的温敏凝胶基质由如下重量百分含量的物料组成:Soluplus 10%~30%、水相余量。
此外,还可以根据需要在所述基于Soluplus的温敏凝胶基质中添加其它适宜的辅料,主要包括增稠剂如环糊精、HPMC、MC、HPC等,辅料的用量可根据药学上可接受的量确定。
所述的水相由等渗调节剂和/或pH调节剂溶于水中配制而成,所述水相的渗透压为0~400mOsmol/kg(优选200~300mOsmol/kg),pH值为3.0~9.0(优选4.0~7.6)。
用于配制水相的水通常为注射用水或灭菌注射用水,优选灭菌注射用水。
所述的等渗调节剂为氯化钠、氯化钾、葡萄糖、果糖、乳糖、蔗糖中的至少一种,优选氯化钠。
所述的pH调节剂为磷酸二氢钠、磷酸二氢钾、磷酸氢二钠、磷酸氢二钾、氢氧化钠、盐酸、柠檬酸、酒石酸中的至少一种,优选磷酸二氢钠、氢氧化钠或盐酸。
具体的,优选所述的水相为下列之一:50mM磷酸盐缓冲液、等渗压磷酸盐缓冲液、0.9wt%NaCl溶液。
所述50mM磷酸盐缓冲液的配制方法为:取NaH2PO4 7.8重量份,加1000重量份脱气的注射用水溶解,再用NaOH调节pH至7.4,即得。
所述等渗的磷酸盐缓冲液的配制方法为:取NaCl 8重量份、KH2PO4 0.2重量份、Na2HPO4·12H2O 2.9重量份、KCl 0.2重量份,加1000重量份脱气的注射用水溶解,用NaOH调节pH至7.4,即得。
所述基于Soluplus的温敏凝胶基质的制备方法为:按照配方量,将Soluplus(及根据需要适宜的辅料)加入水相中,于4℃溶胀并搅拌均匀,得到淡蓝色乳光的分散体系,所得分散体系依次过0.45μm、0.22μm微孔滤膜除菌,即得所述基于Soluplus的温敏凝胶基质;所述制备方法的操作温度及所得基于Soluplus的温敏凝胶基质的储存温度一般为0~30℃。
本发明所述的紫杉醇缓释温敏凝胶可按如下方法进行制备:
按照配方量,将紫杉醇溶于有机溶剂中,配制成紫杉醇溶液,然后在0~30℃、搅拌条件下,将紫杉醇溶液加入基于Soluplus的温敏凝胶基质中,即得所述的紫杉醇缓释温敏凝胶(外观呈淡蓝色乳光的分散体系),于0~30℃储存。
与现有技术相比,本发明的有益效果在于:本发明所述的紫杉醇缓释温敏凝胶体系的相变温度较泊洛沙姆407温敏凝胶的胶凝温度更接近体温,不仅方便给药,且体内形成的凝胶强度较泊洛沙姆407温敏凝胶强度大,皮下注射后至少可维持7天药物缓释,而泊洛沙姆407仅约1天,本发明紫杉醇缓释温敏凝胶经瘤旁局部注射或实体瘤摘除部位给药,能够提高癌症的治疗疗效,降低全身毒副作用,疗效显著优于紫杉醇-泊洛沙姆407温敏凝胶。
(四)附图说明
图1为实施例2中紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶体外释放度比较;
图2为实施例3中紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶体内成型性、滞留性和缓释性比较。
(五)具体实施方式
下面通过具体实施例对本发明作进一步说明,但本发明的保护范围并不仅限于此。
以下实施例中用到的紫杉醇购自江苏红豆杉生物科技股份有限公司,Soluplus和泊洛沙姆407(商品名Kolliphor P407,简称P407)均由BASF惠赠。
实施例1紫杉醇-Soluplus、紫杉醇-泊洛沙姆407温敏凝胶的制备
等渗的磷酸盐缓冲液按如下方法配制:称取NaCl 8g、KH2PO4 0.2g、Na2HPO4·12H2O2.9g、KCl 0.2g加入容器中,然后加1000mL脱气的注射用水溶解,用NaOH调节pH至7.4,即可。
将Soluplus加入等渗的磷酸盐缓冲液中,于4℃溶胀,得均一的分散体系,所得分散体系于0~30℃下依次过0.45μm和0.22μm微孔滤膜除菌,作为温敏凝胶基质体系;将紫杉醇溶于乙醇中,配制成紫杉醇溶液;再将紫杉醇溶液在室温搅拌下,加入Soluplus温敏凝胶基质体系中,得到紫杉醇-Soluplus或紫杉醇-泊洛沙姆407温敏凝胶(0~30℃储存备用,呈均匀分散的分散体系)。
将泊洛沙姆407加入等渗的磷酸盐缓冲液中,于4℃溶胀,得均一的分散体系,所得分散体系于0~10℃下依次过0.45μm和0.22μm微孔滤膜除菌,作为温敏凝胶基质体系;将紫杉醇溶于乙醇中,配制成紫杉醇溶液;再将紫杉醇溶液在室温搅拌下,加入泊洛沙姆407温敏凝胶基质体系中,得到紫杉醇-泊洛沙姆407温敏凝胶(0~10℃储存备用,呈均匀分散的分散体系)。
凝胶配方见表1。
表1紫杉醇-Soluplus、紫杉醇-泊洛沙姆407温敏凝胶的配方
配方编号 | 紫杉醇 | 无水乙醇 | Soluplus | 泊洛沙姆407 | 等渗的磷酸盐缓冲液 |
1 | 0.05g | 1ml | 10g | ---- | 90g |
2 | 0.5g | 7ml | 10g | ---- | 90g |
3 | 1.5g | 21ml | 10g | ---- | 90g |
4 | 0.05g | 1ml | 15g | ---- | 85g |
5 | 0.5g | 7ml | 15g | ---- | 85g |
6 | 1.5g | 21ml | 15g | ---- | 85g |
7 | 0.05g | 1ml | 20g | ---- | 80g |
8 | 0.5g | 7ml | 20g | ---- | 80g |
9 | 1.5g | 21ml | 20g | ---- | 80g |
10 | 0.05g | 1ml | 30g | ---- | 70g |
11 | 0.5g | 7ml | 30g | ---- | 70g |
12 | 1.5g | 21ml | 30g | ---- | 70g |
13 | 0.5g | 1ml | ---- | 20g | 80g |
14 | 1.5g | 7ml | ---- | 25g | 75g |
实施例2紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶的体外释放度测定
取实施例1配制的温敏凝胶制剂,采用无膜释放度测定法。分别精密称取0.2mL紫杉醇温敏凝胶,置于试管中,于37℃静置5min,待其完全胶凝;加入4mL相同温度的pH7.4PBS溶液(含0.1%Tween80,w/v),水浴恒温振荡(37℃、100rpm),不同时间点取样1mL,并补加同温度新鲜介质1mL。样品于10,000rpm离心5min,取上清液,HPLC法测定紫杉醇的浓度。紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶体外释放度比较见图1。
结论:以20%泊洛沙姆407为温敏凝胶基质时,体外释放6h,紫杉醇的累积释放量达60%,48h接近90%。以Soluplus为温敏凝胶基质时,浓度从10%提高至20%,紫杉醇的释放量减慢,当Soluplus 20%时,体外48h紫杉醇的累积释放量仅16.7%,可能因Soluplus的分子量约为泊洛沙姆407的10倍,二者浓度相同时,Soluplus胶凝形成的凝胶强度更大,故释药速率慢。
实施例3紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶的体内成型性、滞留性与释放度比较
分别将实施例1中,紫杉醇-Soluplus(10%、20%)或紫杉醇-泊洛沙姆407(20%)温敏凝胶,经4.5号针头注射0.2mL于小鼠(ICR,雄性,体重30±5g,浙江省医学科学院)背部皮下,每组3只,定时处死小鼠,剖开皮下并观察制剂在体内的胶凝情况,并采用HPLC法测定残留凝胶中的药物含量。紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶体内成型性比较见图2。
结论:20%F127载药凝胶皮下注射后6h,注射局部仅有极少量凝胶残留,HPLC法测得残留药物浓度仅为注射量的25.7±2.3%,且18h时完全消失。
皮下注射10%Soluplus载药凝胶,24h时仍有较多凝胶残留,并测得紫杉醇为注射量的74.3±3.5%,d3时发现凝胶几乎完全消失。
皮下注射20%Soluplus载药凝胶,d3时发现凝胶仍有较多残留,并测得紫杉醇为注射量的51.6±3.2%,d7时发现凝胶几乎完全消失。
由此可见,紫杉醇-Soluplus温敏凝胶较相同浓度的紫杉醇-泊洛沙姆407温敏凝胶在体内的缓释特性更好。
实施例4紫杉醇-Soluplus与紫杉醇-泊洛沙姆407温敏凝胶局部注射抗癌疗效的比较
S180细胞经小鼠腹腔传代,无菌条件下取其腹水,生理盐水稀释,台盼蓝染色,细胞计数板计数,并调整细胞浓度至每毫升含S180细胞1.0×107个的悬液。取细胞悬液0.1ml,经皮下注射接种于雌性ICR小鼠右背侧,接种当天为第0天,记作d0。25±2℃条件下饲养,自由饮水、饮食。监测肿瘤生长情况,测量肿瘤的大小。
当肿瘤体积达到100~200mm3时,按肿瘤体积将荷瘤小鼠随机分为生理盐水空白对照组、空白Soluplus温敏凝胶组、空白泊洛沙姆407温敏凝胶组、配方8制剂(紫杉醇-20%Soluplus温敏凝胶)、配方13制剂(紫杉醇-20%泊洛沙姆407温敏凝胶),每组10只,分别经瘤旁注射给予生理盐水或空白温敏凝胶(每只0.1mL);紫杉醇温敏凝胶,剂量20mg·kg-1。于给药后15天处死小鼠,摘取肿瘤,称重,计算抑瘤率。
结果:与生理盐水空白对照组相比,空白Soluplus和泊洛沙姆407温敏凝胶均没有抑瘤作用,紫杉醇-20%Soluplus温敏凝胶抑瘤率为70±10%,紫杉醇-20%泊洛沙姆407温敏凝胶抑瘤率为40±6.8%。说明紫杉醇-20%Soluplus温敏凝胶显著优于紫杉醇-20%泊洛沙姆407温敏凝胶。
Claims (10)
1.一种紫杉醇缓释温敏凝胶,其特征在于,所述的紫杉醇缓释温敏凝胶由如下重量百分含量的物料组成:
紫杉醇 0.01%~5%
有机溶剂 0.5%~27%
基于Soluplus的温敏凝胶基质余量
其中,所述的有机溶剂为:甲醇、乙醇、丙酮、二甲亚砜、甘油、四氢呋喃、二甲基甲酰胺、乙二醇、正丁醇中的一种或两种以上任意比例的混合溶剂;
所述基于Soluplus的温敏凝胶基质由如下重量百分含量的物料组成:Soluplus 8%~50%、水相余量;所述的水相由等渗调节剂和/或pH调节剂溶于水中配制而成,所述水相的渗透压为0~400mOsmol/kg,pH值为3.0~9.0。
2.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述的紫杉醇缓释温敏凝胶由如下重量百分含量的物料组成:
紫杉醇 0.05%~3%
有机溶剂 0.69%~20%
基于Soluplus的温敏凝胶基质余量。
3.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述的紫杉醇缓释温敏凝胶由如下重量百分含量的物料组成:
紫杉醇 0.1%~1.0%
有机溶剂 5%~15%
基于Soluplus的温敏凝胶基质余量。
4.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,用于配制所述水相的水为注射用水或灭菌注射用水。
5.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述的等渗调节剂为氯化钠、氯化钾、葡萄糖、果糖、乳糖、蔗糖中的至少一种。
6.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述的pH调节剂为磷酸二氢钠、磷酸二氢钾、磷酸氢二钠、磷酸氢二钾、氢氧化钠、盐酸、柠檬酸、酒石酸中的至少一种。
7.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述的水相为下列之一:50mM磷酸盐缓冲液、等渗压磷酸盐缓冲液、0.9wt%NaCl溶液。
8.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述基于Soluplus的温敏凝胶基质由如下重量百分含量的物料组成:Soluplus 10%~40%、水相余量。
9.如权利要求1所述的紫杉醇缓释温敏凝胶,其特征在于,所述基于Soluplus的温敏凝胶基质的制备方法为:
按照配方量,将Soluplus加入水相中,于4℃溶胀并搅拌均匀,得到淡蓝色乳光的分散体系,所得分散体系依次过0.45μm、0.22μm微孔滤膜除菌,即得所述基于Soluplus的温敏凝胶基质。
10.如权利要求1所述的紫杉醇缓释温敏凝胶的制备方法,其特征在于,所述的制备方法为:
按照配方量,将紫杉醇溶于有机溶剂中,配制成紫杉醇溶液,然后在0~30℃、搅拌条件下,将紫杉醇溶液加入基于Soluplus的温敏凝胶基质中,即得所述的紫杉醇缓释温敏凝胶,于0~30℃储存。
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