CN114983927A - 一种温度敏感型即型凝胶系统及其制备方法和用途 - Google Patents
一种温度敏感型即型凝胶系统及其制备方法和用途 Download PDFInfo
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- CN114983927A CN114983927A CN202110231392.2A CN202110231392A CN114983927A CN 114983927 A CN114983927 A CN 114983927A CN 202110231392 A CN202110231392 A CN 202110231392A CN 114983927 A CN114983927 A CN 114983927A
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Abstract
本发明属药物制剂技术领域，涉及一种温度敏感型即型凝胶系统及其制备与应用，所述的温度敏感型即型凝胶系统由泊洛沙姆、维生素E、乳酸、三乙醇胺和水或缓冲溶液组成，其相转变温度在28～37℃之间，在环境温度从室温迅速提升至体温后20～150秒内凝固成半固体凝胶，本发明的即型凝胶进入腔道深处后在黏膜褶皱上形成的凝胶形态能延长药物与黏膜接触时间，增加药物渗透进入黏膜或与腔道表面病原体相互作用的机会，适用于多种黏膜途径，进一步可制备用于阴道给药、直肠给药或鼻腔给药制剂。
Description
技术领域
本发明属于药物制剂技术领域，涉及一种温度敏感型即型凝胶系统，具体涉及一种具有适于腔道用药的相变速度及相变温度的温度敏感型即型凝胶及其制备方法和作为药物活性分子载体的应用。
背景技术
现有技术公开了温度敏感型即型凝胶是适用于多种给药途径的新型制剂形式，在室温(或更低温度)下为液体，在体温时为凝胶态，可在给药局部形成药物储库，缓慢释放药物，持久发挥疗效。
泊洛沙姆407是温度敏感型凝胶材料中研究和应用最多的种类之一，已有公开的专利，包括以泊洛沙姆类为单一凝胶基质的专利(CN109846816A，CN111467302A，CN111632025A)，有将泊洛沙姆类与其他高分子合用以获得更好缓释效果的专利(CN111388411A，CN111434340A，CN110743003A，CN110151680A，CN109646394A)，也有将泊洛沙姆类与其他高分子合用以调节其相转变温度的专利。
本申请的研究团队在温度敏感型即型凝胶的应用实践中发现，如果温度敏感型即型凝胶的相转变速度过快，从给药容器向腔道中推药的过程中，前段被推出的即型凝胶在体腔体温作用下急速凝固，会妨碍了后段凝胶的推出。另一方面，相转变速度过快的温度敏感型即型凝胶对黏膜褶皱覆盖不充分，因为还没来得及流进黏膜褶皱之前就已经凝固了，几乎不能发挥即型凝胶的优点。有研究发现，泊洛沙姆407溶解于纯水中构成的即型凝胶存在相转变速度过快的问题，腔道给药过程中容易凝固，给药不便，更难以进入腔道深处及黏膜褶皱。因此，研究人员认为，除了适宜的相转变温度和缓释效果之外，温度敏感型即型凝胶还应该具有适宜的相转变速度。
综合检索文献，目前，基于维生素E、乳酸、三乙醇胺和泊洛沙姆407组合的即型凝胶的制备及其作为药物活性分子的载体用于黏膜途径给药的应用尚未见报道。
基于现有技术的现状及存在的问题，本申请的发明人拟提供一种温度敏感型即型凝胶系统，具体涉及一种具有适于腔道用药的相变速度及相变温度的温度敏感型即型凝胶及其制备方法和作为药物活性分子载体的应用。
发明内容
本发明的目的是基于现有技术的现状及存在的问题，提供一种温度敏感型即型凝胶系统，具体涉及一种具有适于腔道用药的相变速度及相变温度的温度敏感型即型凝胶及其制备方法，所述温度敏感型即型凝胶系统可以作为药物活性分子的载体，应用于腔道途径给药。
本发明利用安全性良好的维生素E、乳酸和三乙醇胺等成分对泊洛沙姆407溶解于纯水中构成的即型凝胶进行了改良，在满足适宜各种给药途径所需pH的前提下，获得适合实际需要的相转变温度和速度，可作为药物活性分子的载体，用于阴道、鼻腔和直肠等多种黏膜途径给药。
本发明提供了一种温度敏感型即型凝胶系统，其特征在于，由泊洛沙姆、维生素E、乳酸、三乙醇胺和水组成，所述的温度敏感型即型凝胶系统相转变温度在28～37℃之间，在环境温度从室温至体温后20～150秒凝固成半固体凝胶。
本发明中，所述的泊洛沙姆是泊洛沙姆407，或是泊洛沙姆407和泊洛沙姆188的组合。
本发明中，泊洛沙姆407含量为16～30％(w/w)，泊洛沙姆188含量为0～15％(w/w)，维生素E含量为0.01～1％，乳酸含量为1.0～3.0％(w/w)，三乙醇胺含量为0～2％(w/w)，其余为纯水。
本发明中，所述的温度敏感型即型凝胶系统含有药物，包括抗肿瘤药物、癌前干预药物、抗感染药物、解热镇痛药、性激素类或糖皮质激素；药物含量范围为0～5％(w/w)；
所述的抗肿瘤药物，选自紫杉醇、多西他赛、盐酸博莱霉素、硫酸长春新碱、伊立替康、盐酸阿霉素、伊立替康、伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、尼洛替尼、拉帕替尼、帕唑帕尼、埃克替尼、凡德他尼、维罗非尼、克唑替尼、阿西替尼、伯舒替尼、卡博替尼、普纳替尼、瑞戈非尼、拉多替尼、达拉非尼、曲美替尼、阿法替尼、依鲁替尼、色瑞替尼、阿来替尼、阿帕替尼、尼达尼布、乐伐替尼、奥希替尼、奥莫替尼、姜黄素、长春碱、长春新碱、长春瑞滨等；
所述的癌前干预药物，选自重组人干扰素α-2b等；
所述的抗感染药物，选自阿昔洛韦、更昔洛韦、甲硝唑、奥硝唑等；
所述的解热镇痛药，选自吲哚美辛、布洛芬等；
所述的性激素类，选自雌二醇、雌三醇等；
所述的糖皮质激素，选自曲安奈德、布地奈德等。
本发明中，所述的温度敏感型即型凝胶系统，进一步包含抑菌剂、渗透压调节剂和缓冲盐；所述抑菌剂为尼泊金类，其含量为0～0.25％(w/w)，或为薄荷油，其含量为0～0.08％(w/w)；所述渗透压调节剂为氯化钠，其含量为0～2.7％(w/w)；所述缓冲盐为醋酸/醋酸钠、枸橼酸/枸橼酸钠、酒石酸/酒石酸钠、磷酸氢二钠/磷酸二氢钠或相应钾盐，其含量为0～3.0％(w/w)。
本发明还提供上述即型凝胶的制备及其载药方法，其包括：
步骤1.以冷置溶解法制备即型凝胶基质：
以适量纯水稀释处方量的乳酸得稀乳酸溶液，按一定的重量比加入泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解、得透明、无色、低温下为粘稠液体、温度升高至体温时会凝固成半固体的均相体系，按处方量加入维生素E，置于4℃冰浴中机械搅拌，待体系分散均匀透明后，再以三乙醇胺将pH调至所需范围(因目标给药途径而异，用于阴道给药者pH应在3.5～5.0，用于直肠及鼻腔给药者，pH应在7.0～8.0)，即得即型凝胶基质。
步骤2.以分散法进行载药：
1)如药物为水溶性药物，按处方量称取药物，加至适量按步骤1所述制备的即型凝胶基质中，置于4℃冰浴中机械搅拌，待药物充分溶解，得均相体系，如pH偏离预设范围，以三乙醇胺或乳酸将pH调回预设范围。
2)如药物为疏水性药物，以适当方法将药物微粉化后，按处方量取药物加至适量按步骤1所述制备的即型凝胶基质中，置于4℃冰浴中机械搅拌，待药物充分分散均匀即得。
上述方法能得到具有适宜热敏凝胶化温度及速度的载药凝胶，可以液体状态进行阴道给药、直肠给药和鼻腔给药等途径给药，进入腔道深处，充分覆盖黏膜褶皱，随后因温度相变后所得的凝胶形态能延长药物与黏膜接触时间，增加药物渗透进入黏膜或与腔道表面病原体相互作用的机会，充分发挥药物效果。
本发明所提供的即型凝胶利用泊洛沙姆407和维生素E之间的相互作用调节了即型凝胶的温度敏感性，选择了与该凝胶体系相容性良好的乳酸和三乙醇胺作为缓冲对，获得符合具体给药途径的pH(如适合阴道给药的酸性pH和适合鼻腔给药的中性pH)。
本发明所提供的即型凝胶在室温下粘度低于10cP，流动性好，环境温度从室温迅速提升至体温后需几十秒才会凝固成凝胶(同泊洛沙姆407浓度的泊洛沙姆407/纯水或缓冲盐体系发生该相变的时间不到1秒)，可以以液体状态给到腔道深处及黏膜褶皱后再凝固，能满足多种黏膜途径给药的实际需要。
本发明所提供的即型凝胶进入腔道深处后在黏膜褶皱上形成的凝胶形态能延长药物与黏膜接触时间，增加药物渗透进入黏膜或与腔道表面病原体相互作用的机会，适用于多种黏膜途径，包括阴道给药、直肠给药和鼻腔给药等：阴道给药适用于针对宫颈癌术前化疗或保守治疗的抗肿瘤药物、宫颈癌癌前干预药物、针对生殖道感染的抗病毒、抗滴虫、抗真菌药物等；直肠给药适用于针对痔疮的消炎药物、针对直肠癌术前化疗的抗肿瘤药物、旨在全身吸收后降温抗炎的解热镇痛药等；鼻腔给药适用于能直接作用于经呼吸道传播病原体的活性物质、旨在全身吸收后起效的镇痛药、能缓解过敏性鼻炎黏膜症状的抗炎抗过敏药物及活性成分。
附图说明
图1温度升高时(首先在25℃平衡温度10分钟，随后在10秒内从25℃升温至37℃，从温度达到37℃时开始记录)所述即型凝胶基质的弹性模量随时间的变化(对照为同浓度F127水溶液)。
图2温度升高时(首先在25℃平衡温度10分钟，随后在10秒内从25℃升温至37℃，从温度达到37℃时开始记录)所述即型凝胶基质的粘性模量随时间的变化(对照为同浓度F127水溶液)。
图3实施例1所述即型凝胶弹性模量随温度升高的变化。
图4实施例1所述即型凝胶粘性模量随温度升高的变化。
具体实施方式
以下实施例是用来说明本发明的，不应被认为是以任何方式对本发明的限制。
实施例1即型凝胶基质(阴道用)
以38mL纯水与1.0g乳酸混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，再以三乙醇胺将pH调至4.5，加纯水至50g，搅拌均匀，即得。该即型凝胶凝胶化温度为31℃，从室温(25℃)加热至37℃时凝胶化速度适中，弹性模量达到2000Pa需要39秒，粘性模量达到1000Pa需要56s(同浓度泊洛沙姆407水溶液发生上述变化均不到3秒)。该基质适合用于阴道给药。
实施例2即型凝胶基质(直肠用)
以38mL纯水与1g乳酸混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，再以三乙醇胺将pH调至7，加纯水至50g，搅拌均匀，即得。该即型凝胶凝胶化温度为31℃，从室温(25℃)加热至37℃时凝胶化速度适中，弹性模量达到2000Pa需要31秒，粘性模量达到1000Pa需要103s(同浓度泊洛沙姆407水溶液发生上述变化均不到3秒)。该基质适用于直肠给药。
实施例3即型凝胶基质(鼻腔用)
以38mL纯水与1g乳酸混合后，加入8.0g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，加纯水至50g，以三乙醇胺将pH调至7，搅拌均匀，即得。该基质适用于鼻腔给药。
实施例4紫杉醇即型凝胶
以38mL纯水与1g乳酸混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，加入紫杉醇100mg(微粉化)，以三乙醇胺将pH调至3.5～4.5，加纯水至50g，于4℃冰浴中机械搅拌均匀即得。本实施例适用于阴道内给药。
实施例5盐酸博莱霉素/硫酸长春新碱复方即型凝胶
以38mL纯水与1g乳酸混合后，加入8.0g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，加入盐酸博莱霉素0.4g和硫酸长春新碱0.02mg，置于4℃冰浴中机械搅拌均匀，使药物完全溶解后，以三乙醇胺将pH调至3.5～4.5，加纯水至50g，于4℃冰浴中机械搅拌均匀，即得。本实施例适用于阴道内给药治疗。
实施例6伊马替尼即型凝胶
以38mL纯水与1g乳酸混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入75mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，加入伊马替尼1.0g(微粉化)，置于4℃冰浴中机械搅拌均匀后，以三乙醇胺将pH调至3.5～4.5，加纯水至50g，于4℃冰浴中机械搅拌均匀，即得。本实施例适用于阴道内给药。
实施例7苦参即型凝胶
以38mL纯水与1g乳酸混合后，加入9.0g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解，得即型凝胶基质。另取苦参总碱1.0mg，混入前述即型凝胶基质，置于4℃冰浴中机械搅拌均匀，使药物完全溶解后，以三乙醇胺将pH调至3.5～4.5，加纯水至50g，于4℃冰浴中机械搅拌均匀，即得。本实施例适用于阴道内给药。
实施例8雌三醇即型凝胶
以38mL纯水与1g乳酸混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，加入雌三醇40mg(微粉化)，置于4℃冰浴中机械搅拌均匀后，以三乙醇胺将pH调至3.5～4.5，加纯水至50g，即得。本实施例适用于阴道内给药。
实施例9重组人干扰素α-2b即型凝胶
以38mL纯水与1g乳酸(约0.83mL)混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解，以三乙醇胺将pH调至3.5～4.5，加入重组人干扰素α-2b400万单位，混入前述即型凝胶基质，置于4℃冰浴中机械搅拌均匀，使药物完全溶解后，加纯水至50g，即得。本实施例适用于阴道内给药。
实施例10吲哚美辛即型凝胶
以38mL纯水与1g乳酸混合后，加入8.5g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，加入雌三醇40mg(微粉化)，置于4℃冰浴中机械搅拌均匀后，以三乙醇胺将pH调至7.0，加纯水至50g，即得。本实施例适用于直肠内给药。
实施例11鼻腔给药用布地奈德即型凝胶
以38mL纯水与1g乳酸混合后，加入8.0g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解，加入布地奈德40mg(微粉化)，置于4℃冰浴中机械搅拌均匀，以三乙醇胺将pH调至7.0～8.0，加纯水至50g，于4℃冰浴中机械搅拌均匀即得。本实施例适用于鼻腔给药。
实施例12鼻腔给药用曲安奈德即型凝胶
以38mL纯水与1g乳酸混合后，加入8.0g泊洛沙姆407，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解，加入曲安奈德40mg(微粉化)，置于4℃冰浴中机械搅拌均匀，以三乙醇胺将pH调至7.0～8.0，加纯水至50g，于4℃冰浴中机械搅拌均匀即得。本实施例适用于鼻腔给药。
实施例13即型凝胶基质(阴道用)
以35mL纯水与1.0g乳酸混合后，加入9.0g泊洛沙姆407和0.5g泊洛沙姆188，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，再以三乙醇胺将pH调至4.5，加纯水至50g，搅拌均匀，即得。
实施例14即型凝胶基质(直肠用)
以38mL纯水与1g乳酸混合后，加入9.0g泊洛沙姆407和0.5g泊洛沙姆188，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解后，再以三乙醇胺将pH调至7，加纯水至50g，搅拌均匀，即得。该基质适用于直肠给药。
实施例15重组人干扰素α-2b即型凝胶
以38mL纯水与1g乳酸(约0.83mL)混合后，加入9.0g泊洛沙姆407和0.5g泊洛沙姆188，所得混合物以机械搅拌混合均匀后，于4℃静置，待固形物完全溶解后，加入80mg维生素E，置于4℃冰浴中机械搅拌，待维生素E充分分散溶解，以三乙醇胺将pH调至3.5～4.5，加入重组人干扰素α-2b 400万单位，混入前述即型凝胶基质，置于4℃冰浴中机械搅拌均匀，使药物完全溶解后，加纯水至50g，即得。本实施例制得的重组人干扰素α-2b即型凝胶适用于阴道内给药。
Claims (11)
1.一种温度敏感型即型凝胶系统，其特征在于，由泊洛沙姆、维生素E、乳酸、三乙醇胺和水组成；
所述的泊洛沙姆是泊洛沙姆407，或是泊洛沙姆407和泊洛沙姆188的组合；组分中的泊洛沙姆407含量为16～30％(w/w)，泊洛沙姆188含量为0～15％(w/w)，维生素E含量为0.01～1％，乳酸含量为1.0～3.0％(w/w)，三乙醇胺含量为0～2％(w/w)，其余为纯水；
所述的温度敏感型即型凝胶系统相转变温度在28～37℃之间，在环境温度从室温至体温后20～150秒凝固成半固体凝胶。
2.根据权利要求1所述的温度敏感型即型凝胶系统，其特征在于，所述的温度敏感型即型凝胶系统含有药物，包括抗肿瘤药物、癌前干预药物、抗感染药物、解热镇痛药、性激素类或糖皮质激素。
3.根据权利要求2所述的温度敏感型即型凝胶系统，其特征在于，药物含量范围为0～5％(w/w)。
4.根据权利要求2所述的温度敏感型即型凝胶系统，其特征在于，所述的抗肿瘤药物选自紫杉醇、多西他赛、盐酸博莱霉素、硫酸长春新碱、伊立替康、盐酸阿霉素、伊立替康、伊马替尼、吉非替尼、厄洛替尼、索拉非尼、舒尼替尼、达沙替尼、尼洛替尼、拉帕替尼、帕唑帕尼、埃克替尼、凡德他尼、维罗非尼、克唑替尼、阿西替尼、伯舒替尼、卡博替尼、普纳替尼、瑞戈非尼、拉多替尼、达拉非尼、曲美替尼、阿法替尼、依鲁替尼、色瑞替尼、阿来替尼、阿帕替尼、尼达尼布、乐伐替尼、奥希替尼、奥莫替尼、姜黄素、长春碱、长春新碱或长春瑞滨；
所述的癌前干预药物选自重组人干扰素α-2b；
所述的抗感染药物选自阿昔洛韦、更昔洛韦、甲硝唑或奥硝唑；
所述的解热镇痛药选自吲哚美辛或布洛芬；
所述的性激素类选自雌二醇或雌三醇；
所述的糖皮质激素选自曲安奈德或布地奈德。
5.根据权利要求2所述的温度敏感型即型凝胶系统，其特征在于，还包含抑菌剂、渗透压调节剂和缓冲盐。
6.根据权利要求5所述的温度敏感型即型凝胶系统，其特征在于，所述抑菌剂为尼泊金类，其含量为0～0.25％(w/w)，或为薄荷油，其含量为0～0.08％(w/w)。
7.根据权利要求5所述的温度敏感型即型凝胶系统，其特征在于，所述渗透压调节剂为氯化钠，其含量为0～2.7％(w/w)。
8.根据权利要求5所述的温度敏感型即型凝胶系统，其特征在于，所述缓冲盐为醋酸/醋酸钠、枸橼酸/枸橼酸钠、酒石酸/酒石酸钠、磷酸氢二钠/磷酸二氢钠或相应钾盐，其含量为0～3.0％(w/w)。
9.根据权利要求1～8所述的温度敏感型即型凝胶系统的制备方法，其特征在于，其包括：
第一步：以冷置溶解法制备即型凝胶基质，即以适量纯水稀释处方量的乳酸得稀乳酸溶液，按一定的重量比加入泊洛沙姆，机械搅拌混合均匀后于4℃静置，待固形物完全溶解后，按处方量加入维生素E，机械搅拌混合均匀后于4℃静置，即得；
第二步：以分散法进行载药，即按处方量称取药物，加至适量按第一步所制基质中，置于4℃冰浴中机械搅拌，待药物充分溶解或分散，最后以三乙醇胺将pH调至所需范围，即得。
10.根据权利要求9所述的温度敏感型即型凝胶的制备方法，其特征在于，所述制备方法中如药物为难溶性药物，则先对药物微粉化后再混入凝胶基质。
11.权利要求1-8任一所述的温度敏感型即型凝胶在制备用于阴道给药、直肠给药或鼻腔给药制剂中的用途。
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| CN116869927A (zh) * | 2023-09-06 | 2023-10-13 | 中国医学科学院北京协和医院 | 一种用于治疗嗜酸性食管炎的食道温敏凝胶 |
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| US20040151774A1 (en) * | 2002-10-31 | 2004-08-05 | Pauletti Giovanni M. | Therapeutic compositions for drug delivery to and through covering epithelia |
| CN105381469A (zh) * | 2015-11-03 | 2016-03-09 | 温州医科大学 | 一种用于治疗脑部疾病的药物制剂 |
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| CN116115557A (zh) * | 2023-02-03 | 2023-05-16 | 安徽农业大学 | 一种常山酮温敏凝胶复合物及其制备方法与应用 |
| CN116869927A (zh) * | 2023-09-06 | 2023-10-13 | 中国医学科学院北京协和医院 | 一种用于治疗嗜酸性食管炎的食道温敏凝胶 |
| CN116869927B (zh) * | 2023-09-06 | 2023-11-10 | 中国医学科学院北京协和医院 | 一种用于治疗嗜酸性食管炎的食道温敏凝胶 |
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