CN105919924B - 他克莫司缓释温敏凝胶及其制备方法 - Google Patents
他克莫司缓释温敏凝胶及其制备方法 Download PDFInfo
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- CN105919924B CN105919924B CN201610247835.6A CN201610247835A CN105919924B CN 105919924 B CN105919924 B CN 105919924B CN 201610247835 A CN201610247835 A CN 201610247835A CN 105919924 B CN105919924 B CN 105919924B
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- tacrolimus
- thermo
- sensitive gel
- soluplus
- sustained
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- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 title claims abstract description 70
- 229960001967 tacrolimus Drugs 0.000 title claims abstract description 68
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种他克莫司缓释温敏凝胶及其制备方法,所述的他克莫司缓释温敏凝胶由如下重量百分含量的物料组成:他克莫司0.05%~20%、有机溶剂0.5%~27%、基于Soluplus的温敏凝胶基质余量;本发明所述的他克莫司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,本发明他克莫司缓释温敏凝胶用于局部注射给药或眼部给药,治疗类风湿性关节炎、器官移植或自身免疫性眼病等,疗效显著优于他克莫司泊洛沙姆407温敏凝胶。
Description
(一)技术领域
本发明涉及一种新型的他克莫司缓释温敏凝胶及其制备方法。
(二)背景技术
他克莫司(Tacrolimus,又名FK506),为一种强力的新型免疫抑制剂,主要通过抑制白介素-2(IL-2)的释放,全面抑制T淋巴细胞功能,其抑制作用较环孢素(CsA)强100倍。临床主要用于肝、肾、心、肺、肠、骨髓等器官组织移植;及特应性皮炎(AD)、系统性红斑狼疮(SLE)、自身免疫性眼病等自身免疫性疾病。目前市售剂型主要有胶囊剂、注射剂、软膏、缓释胶囊剂和缓释片剂,等。文献报道的制剂研究有微球(Kojima R,Yoshida T,Tasaki H,Umejima H,Maeda M,Higashi Y,Watanabe S,Oku N.Release mechanisms oftacrolimus-loaded PLGA and PLA microspheres and immunosuppressive effects ofthe microspheres in a rat heart transplantation model.Int J Pharm,2015,492(1-2):20-7),脂质体(Ishii T,Asai T,Oyama D,Agato Y,Yasuda N,Fukuta T,Shimizu K,Minamino T,Oku N.Treatment of cerebral ischemia-reperfusion injury withPEGylated liposomes encapsulating FK506.FASEB J.2013,27(4):1362-70.)、纳米粒(王瑞华,张堂德,孙乐栋.他克莫司固体脂质纳米粒制备及理化性质研究.南方医科大学硕士论文,2012)、β环糊精-F127温敏凝胶(张晶晶,张天虹,宋洪涛.他克莫司体温敏感眼用凝胶的研究,沈阳药科大学硕士论文,2008),等。但他克莫司分子量较大,水溶性较差,市售注射剂为20%聚氧乙烯60蓖麻油(HCO-60)与80%无水乙醇为混合溶剂配制的溶液型注射剂(规格5mg/mL),临用前用0.9%NaCl或5%葡萄糖稀释后静脉滴注,但HCO-60可能导致过敏,且用药过程可能导致药物析出。
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。泊洛沙姆407(Pluronic F127或Lutrol F127或Kolliphor P407,简称F127或P407)为聚氧乙烯-聚氧丙烯-聚氧乙烯(101:56:101)三嵌段共聚物,平均分子量9,840~14,600g/mol,是一种常用的温敏凝胶基质。文献报道,浓度18%时,相变温度23.5℃,泪液稀释后失去胶凝能力;浓度大于20%,泪液稀释后仍能胶凝,但相变温度低于室温,需冷藏后使用;与泊洛沙姆188一起使用可提高胶凝温度,泊洛沙姆407与188二者比例为(23%+10.3%)时,胶凝温度26.8℃,经泪液(泊洛沙姆溶液:泪液=40:7)稀释后胶凝温度34.4℃(张晶晶,张天虹,宋洪涛.他克莫司体温敏感眼用凝胶的研究,沈阳药科大学硕士论文,2008)。尽管加入泊洛沙姆188可提高泊洛沙姆407的相变温度,或加入增稠剂能提高其凝胶机械强度;但泊洛沙姆407温敏凝胶的体内稳定性差,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 deliverysystems for poorly water-soluble drugs.Molecules.2015,20(11):20397-408)。
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。与泊洛沙姆407均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,但分子组成不同,且分子量约为泊洛沙姆407的10倍。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,且能增溶他克莫司形成稳定的给药系统。
故本发明旨在以Soluplus为温敏凝胶基质,提供一种新型的他克莫司温敏凝胶缓释制剂配方组合物,经局部注射给药或眼部给药,治疗类风湿性关节炎、器官移植或自身免疫性眼病等。
(三)发明内容
本发明的目的是提供一种新型的他克莫司缓释温敏凝胶及其制备方法,所述的他克莫司缓释温敏凝胶经局部注射给药或眼部给药,可用于治疗类风湿性关节炎、器官移植或自身免疫性眼病等,且能够提高他克莫司的治疗疗效。
为实现上述目的,本发明采用如下技术方案:
一种他克莫司缓释温敏凝胶,由如下重量百分含量的物料组成:
他克莫司 0.05%~20%
有机溶剂 0.5%~27%
基于Soluplus的温敏凝胶基质余量
优选的,所述他克莫司缓释温敏凝胶由如下重量百分含量的物料组成:
他克莫司 0.45%~4%
有机溶剂 4.7%~22%
基于Soluplus的温敏凝胶基质余量
更加优选的,所述他克莫司缓释温敏凝胶由如下重量百分含量的物料组成:
他克莫司 0.45%~1.0%
有机溶剂 4.7%~9.0%
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他克莫司缓释温敏凝胶中添加其他适宜的组分,主要包括抗氧化剂等稳定剂,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:Soluplus8%~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、等渗的磷酸盐缓冲液、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℃。
本发明所述的他克莫司缓释温敏凝胶可按如下方法进行制备:
按照配方量,将他克莫司溶于有机溶剂中,配制成他克莫司溶液,然后在0~30℃、搅拌条件下,将他克莫司溶液加入基于Soluplus的温敏凝胶基质中,即得所述的他克莫司缓释温敏凝胶(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:本发明所述的他克莫司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,本发明他克莫司缓释温敏凝胶用于局部注射给药或眼部给药,治疗类风湿性关节炎、器官移植或自身免疫性眼病等,疗效显著优于他克莫司泊洛沙姆407温敏凝胶。
(四)附图说明
图1为实施例2中他克莫司-Soluplus与他克莫司-泊洛沙姆407温敏凝胶体外释放度比较;
图2为实施例3中他克莫司-Soluplus与他克莫司-泊洛沙姆407温敏凝胶体内成型性、滞留性和缓释性比较;
图3为实施例4中他克莫司-Soluplus与他克莫司-泊洛沙姆407温敏凝胶抗类风湿性关节炎疗效比较。
(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他克莫司购自华东医药股份有限公司;Soluplus和泊洛沙姆407(商品名Kolliphor P407,简称P407)均由BASF惠赠。
实施例1他克莫司-Soluplus、他克莫司-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,得到均一的分散体系,所得分散体系于0~30℃下依次过0.45μm、0.22μm微孔滤膜除菌,得到温敏凝胶基质体系;将他克莫司溶于乙醇中,配制成他克莫司溶液;再将他克莫司溶液在室温搅拌下,加入Soluplus或泊洛沙姆407温敏凝胶基质体系中,得到他克莫司-Soluplus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,得到均一的分散体系,所得分散体系于0~10℃下依次过0.45μm、0.22μm微孔滤膜除菌,得到温敏凝胶基质体系;将他克莫司溶于乙醇中,配制成他克莫司溶液;再将他克莫司溶液在室温搅拌下,加入泊洛沙姆407温敏凝胶基质体系中,得到他克莫司-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他克莫司-Soluplus、他克莫司-泊洛沙姆407温敏凝胶的配方
实施例2他克莫司-Soluplus、他克莫司-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他克莫司温敏凝胶,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0.5%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法测定他克莫司的浓度。他克莫司-Soluplus与他克莫司-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,他克莫司的累积释放量达60%,48h接近80%。以Soluplus为温敏凝胶基质时,浓度从10%提高至20%,他克莫司的释放量减慢,当Soluplus为20%时,体外48h他克莫司的累积释放量仅6.93%,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他克莫司-Soluplus、他克莫司-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,他克莫司-Soluplus(10%、20%)或他克莫司-F127(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。他克莫司-Soluplus与他克莫司-泊洛沙姆407温敏凝胶体内成型性比较见图2。
结论:20%泊洛沙姆407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23.4±0.9%,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,并测得他克莫司为注射量的76.8±1.6%,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,并测得他克莫司为注射量的55.7±2.0%,d7时发现凝胶几乎完全消失。
由此可见,他克莫司-Soluplus温敏凝胶较相同浓度的他克莫司-泊洛沙姆407温敏凝胶在体内的缓释特性更好。
实施例4他克莫司-Soluplus、他克莫司-泊洛沙姆407温敏凝胶局部注射治疗类风湿性关节炎的疗效比较
雄性SD大鼠40只,体重160g左右,饲养一周后,于单侧右后足皮内注射100μL弗氏完全佐剂(CFA,含灭活的结核杆菌5mg/mL),造模当天作为第0天。隔日测定足肿胀度,当足肿胀度>100%视为类风湿性关节炎造模成功。d7,按照大鼠注射侧足的肿胀度进行分组,每组5只,按他克莫司剂量10mg/kg皮下注射给予温敏凝胶制剂及相应的对照制剂。
给药期间每日用排水法测量同一只大鼠注射侧及对侧的足趾容积及称量体重,给药后隔日测定。具体操作为:以大鼠后足的踝关节上方约1cm处作为浸入水中的上线,固定大鼠,分别将大鼠的左右后肢浸入测量器中,容器中水的重量变化值除以水的密度即为大鼠浸入水中的足体积。同一只大鼠双侧足做对比,计算肿胀度,公式如下:
肿胀度=(Vt-Vt’)/Vt’×100
Vt:造模后第t天注射侧足体积
Vt’:造模后第t天注射足对侧的足体积
他克莫司-Soluplus与他克莫司-泊洛沙姆407温敏凝胶体内抗类风湿性关节炎的疗效比较见图3。
从结果可见,空白凝胶组均未产生治疗效果。
他克莫司-10%Soluplus温敏凝胶组,从d7给药至d11,肿胀度持续下降,其中d10和d11的肿胀度较对照组显著下降(p<0.05);之后肿胀度略有增大,维持在约90%。
他克莫司-20%Soluplus温敏凝胶组,从d7给药至d17,肿胀度持续下降,其中d10~d17的肿胀度较对照组显著下降((p<0.05),之后肿胀度略有增大,维持在约83%。
他克莫司-Soluplus温敏凝胶组抗炎效果显著,而他克莫司-泊洛沙姆407温敏凝胶组未呈现出明显的治疗效果。
Claims (10)
1.一种他克莫司缓释温敏凝胶,其特征在于,所述的他克莫司缓释温敏凝胶由如下重量百分含量的物料组成:
他克莫司 0.05%~20%
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所述的他克莫司缓释温敏凝胶,其特征在于,所述的他克莫司缓释温敏凝胶由如下重量百分含量的物料组成:
他克莫司 0.45%~4%
有机溶剂 4.7%~22%
基于Soluplus的温敏凝胶基质 余量。
3.如权利要求2所述的他克莫司缓释温敏凝胶,其特征在于,所述的他克莫司缓释温敏凝胶由如下重量百分含量的物料组成:
他克莫司 0.45%~1.0%
有机溶剂 4.7%~9.0%
基于Soluplus的温敏凝胶基质 余量。
4.如权利要求1所述的他克莫司缓释温敏凝胶,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所述的他克莫司缓释温敏凝胶,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所述的他克莫司缓释温敏凝胶,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所述的他克莫司缓释温敏凝胶,其特征在于,所述的水相为下列之一:50mM磷酸盐缓冲液、等渗的磷酸盐缓冲液、0.9wt%NaCl溶液。
8.如权利要求1所述的他克莫司缓释温敏凝胶,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所述的他克莫司缓释温敏凝胶,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。
10.一种如权利要求1所述的他克莫司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,将他克莫司溶于有机溶剂中,配制成他克莫司溶液,然后在0~30℃、搅拌条件下,将他克莫司溶液加入基于Soluplus的温敏凝胶基质中,即得所述的他克莫司缓释温敏凝胶,于0~30℃储存。
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