关节腔注射用温敏性凝胶药物缓释制剂研究
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摘要
在最近十年的研究中,基于温敏性聚合物的可注射凝胶受到了越来越多的关注。在新型药物载体的应用方面,可注射的温敏性凝胶具备临床使用方便、载药量高、不含有机溶剂、良好的药物缓释性能及较低的全身毒性等优点。这种新型药物递送体系在给药前,呈可流动的水溶胶状态；在注射后,其会在生理条件下快速地发生凝胶转变,在局部形成药物缓释储库,从而延长药物在给药部位的滞留时间。
类风湿性关节炎等关节炎疾病使众多患者致病,患者通常要忍受关节疼痛和关节功能减退,严重影响患者的活动能力和生活质量。目前,关节炎疾病的治疗主要通过口服、肌肉注射及关节腔内注射等给药方式。其中,在患病的关节处直接给药可以为在患处局部形成较高的药物浓度,同时降低全身性的副作用提供了可能。尽管如此,关节腔内注射给药的临床治疗效果并不理想,一方面是关节腔内给药后药物在关节腔内的清除速率极快,另一方面是关节腔反复给药将增加关节腔感染机率。很多研究对关节腔注射用缓释制剂进行了尝试性改进,如将治疗性药物包载入脂质体、聚合物微球以及纳米粒等。尽管这种新型的缓释制剂比传统剂型在效果上有了提高,但其自身仍存在一些明显的缺陷,比如,该剂型在注射给药后在关节腔内滞留时间较短；材料降解产物会破坏关节腔生理环境等。为了克服以上缺点,许多学者致力于更长效的关节腔药物递送体系的研究。
本研究构建了一种基于生物可降解的聚己内酯—聚乙二醇—聚己内酯(PCL-PEG-PCL)温敏凝胶的注射用缓释药物递送体系,以期开发出新型关节腔注射用局部给药缓释制剂。
本文的主要研究内容如下：
1.合成具有不同PCL和PEG嵌段组成的温敏性PCL-PEG-PCL三嵌段共聚物
本文合成了一系列具有不同PEG和PCL嵌段长度的PCL-PEG-PCL三嵌段共聚物,并通过核磁共振氢谱及凝胶渗透色谱对其组成、结构及分子量进行了表征。核磁共振及凝胶渗透色谱测定结果表明合成的共聚物组成与初始投料比一致,符合设计的温敏性PCL-PEG-PCL嵌段聚合物结构。
2.PCL-PEG-PCL温敏凝胶的温敏性能研究
本文合成的所有PCL-PEG-PCL嵌段共聚物均具备良好的溶胶-凝胶转变能力。根据实验结果绘制的溶胶-凝胶转变相图,PCL-PEG-PCL温敏凝胶的溶胶-凝胶转变能力与聚合物本身的化学组成及凝胶的浓度密切相关。在相同的凝胶浓度条件下,固定亲水的PEG嵌段长度,增加疏水的PCL嵌段长度会降低PCL-PEG-PCL温敏凝胶的溶胶-凝胶相变温度；对于同一化学组成的PCL-PEG-PCL温敏凝胶来说,提高凝胶浓度可以降低其溶胶-凝胶相变温度。另外,PCL-PEG-PCL温敏凝胶所具备的良好的原位成胶能力及极短的体外成胶时间也在实验中得到了验证,从而为PCL-PEG-PCL温敏凝胶作为理想的注射用药物递送体系打下了基础。
3. PCL-PEG-PCL温敏凝胶的药物体外释放行为研究
本文分别考察了PCL-PEG-PCL温敏凝胶对亲水性蛋白药物牛血清白蛋白和疏水性抗肿瘤药物紫杉醇的体外释放行为。结果表明PCL-PEG-PCL温敏凝胶对两种类型的药物均显示了良好、可控的缓释性能,即可以通过改变聚合物中的PCL嵌段和PEG嵌段长度或凝胶浓度和初始载药量控制载药PCL-PEG-PCL温敏凝胶的药物体外缓释行为。此外,PCL-PEG-PCL温敏凝胶对蛋白药物活性的影响也得到了考察,模型蛋白辣根过氧化酶的活性实验证明蛋白活性不受药物载体的影响,在整个体外释放过程中保持了完好的生理活性。
4. PCL-PEG-PCL温敏凝胶作为关节腔内注射用缓释制剂的初步探讨
在PCL-PEG-PCL温敏凝胶的生物相容性实验中,证明了PCL-PEG-PCL温敏凝胶在关节腔滑膜中未引发炎症,具备理想的体内生物相容性。PCL-PEG-PCL温敏凝胶的体内生物降解实验中,PCL-PEG-PCL温敏凝胶可以在小鼠体内以凝胶状态存在约45天,并最终完全降解。考察了包载有甲氨喋呤的PCL-PEG-PCL温敏凝胶的体外释放行为；在动物实验中,考察了关节腔内注射包载有甲氨喋呤的PCL-PEG-PCL温敏凝胶后,大鼠的体内药代动力学。结果表明,载药PCL-PEG-PCL温敏凝胶在体外释放试验中对甲氨喋呤显示了良好的缓释性能；在体内实验中,载药PCL-PEG-PCL温敏凝胶可以减缓甲氨喋呤的清除速率,实现药物在关节腔内的缓释作用。
由于具备理想的温敏性能、可控的药物缓释能力以及良好的生物降解性能和生物相容性,PCL-PEG-PCL温敏凝胶是一种极具潜力的关节腔内注射用药物缓释体系,从而为改善类风湿性关节炎等疾病的临床疗效发挥重大的作用。
During the last decade, thermosensitive polymers-based injectable thermosensitive hydrogels received an increasing attention as controlled drug carriers because of their many advantages such as the convenience of application, high drug loading, no organic solvents, sustained drug release behavior and less systemic toxicity. These drug delivery systems are flowable aqueous solution before administration, but once injected, they rapidly form gel under physiological conditions and hence an in situ "drug depot" forms. In situ gel formation after the topical injection of aqueous solutions of such thermosensitive polymers resulted in a significantly prolonged drug residence time.
Inflammatory arthritis diseases such as rheumatoid arthritis (RA) affect an enormous number of individuals. Patients afflicted with the disease may experience pain and loss of joint function with associated deleterious effects on patient activity level and lifestyle habits. Treatment of arthritis disease is achieved through oral, parenteral or intra-articular drugs. The direct drug delivery to an affected joint offers the possibility of reaching high drug concentrations at the action site with limited systemic toxicity. However, the undeniable clinical efficacy of intra-articular injections is somehow restricted either by the rapid efflux of drugs from the joint cavity after injections or by the need of repeated injections, possibly causing joint instability and infections. Retention of drugs in the joints using controlled release delivery system offers an exciting option for intra-articular drug delivery. Researchers thus have tried to encapsulate the drugs into different drug delivery systems such as liposomes, nanoparticles and microparticles.Though more promising than drug suspensions, these systems also faced a major drawback of short retention in the joint due to synovial capillary and lymphatic drainage, which takes place within a few days after injection. To overcome these limitations, many researches have been carried out to find more controlled and prolonged drug delivery to the joint.
In this study, we have constructed a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogels, which offered a great potential to develop a kind of novel topical articular-administrated drug delivery system.
The major contents of this paper are shown as follows:
1. Synthesis, characterization of a series of thermosensitive PCL-PEG-PCL triblock copolymers with different PCL and PEG block lengths.
A series of thermosensitive PCL-PEG-PCL copolymers with different molecular compositions were synthesized by ring-opening polymerization method, and their structure was characterized via 1H-NMR and GPC techniques. The results calculated from 1H-NMR and GPC indicated that EG/CL ratios were consistent with the initial feed ratios, which offered a strong proof to their compositions and molecular structure.
2. Thermosensitivity characterization of PCL-PEG-PCL hydrogels.
All synthesized PCL-PEG-PCL triblock copolymers in this study exhibited a temperature-dependent reversible sol-to-gel transition in water. The phase diagrams revealed that the sol-to-gel transition behavior of PCL-PEG-PCL triblock copolymers in aqueous solutions was highly dependent on their chemical compositions and copolymer concentrations:ⅰ) increasing the length of hydrophobic PCL block with a fixed PEG block length resulted in a lower sol-to-gel transition temperature at a given copolymer concentration.ⅱ) an increase in the copolymer concentration shifted sol-to-gel transitions to the lower temperature. Furthermore, both the short enough gelation time and in situ gel-forming ability of thermosensitive PCL-PEG-PCL hydrogels were confirmed, which were prerequisite for a promising injectable drug delivery system.
3. In vitro drug release behavior of thermosensitive PCL-PEG-PCL hydrogels.
In this chapter, the in vitro release behavior of both hydrophilic protein drug (BSA) and hydrophobic chemo drug (Paclitaxel) from thermosensitive PCL-PEG-PCL hydrogels were investigated. The results revealed that the in vitro drug release rate from the PCL-PEG-PCL hydrogels was controllable by altering either the PEG and PCL block lengths or the hydrogel concentrations and initial drug loadings. Besides, a suitable controlled delivery system should be able to release protein in its biologically active form. In protein activity test, the released model protein (HRP) was confirmed to conserve its biological activity by specific enzymatic activity assay. 4. Injectable thermosensitive hydrogels for intra-articular delivery of methotrexate
The in vivo biodegradability study suggested that the synthesized PCL-PEG-PCL hydrogels were able to persist about 45 days and provide an extended drug release period. The in vivo biocompatibility of PCL-PEG-PCL hydrogels was evaluated, indicating no obvious inflammatory infiltrattion occurred in the synovial membrane.
Sustained drug release behaviors from thermosensitive methotrexate loaded PCL-PEG-PCL hydrogels in both in vitro and in vivo (intra-articular injection in rats) experiments were observed. The pharmacokinetics data suggested that the methotrexate loaded hydrogel was able to slow down the clearance of methotrexate and control the methotrexate release in the joint cavity.
Owing to great thermosensitivity, controllable drug release behaviors, biocompatibility and biodegradability of these PCL-PEG-PCL copolymers, these developed PCL-PEG-PCL hydrogels can be applied as a promising in situ gel-forming controlled drug delivery system for the intra-articular injection and pave a way to improve the therapeutic efficacy of rheumatoid arthritis clinically.
类风湿性关节炎等关节炎疾病使众多患者致病,患者通常要忍受关节疼痛和关节功能减退,严重影响患者的活动能力和生活质量。目前,关节炎疾病的治疗主要通过口服、肌肉注射及关节腔内注射等给药方式。其中,在患病的关节处直接给药可以为在患处局部形成较高的药物浓度,同时降低全身性的副作用提供了可能。尽管如此,关节腔内注射给药的临床治疗效果并不理想,一方面是关节腔内给药后药物在关节腔内的清除速率极快,另一方面是关节腔反复给药将增加关节腔感染机率。很多研究对关节腔注射用缓释制剂进行了尝试性改进,如将治疗性药物包载入脂质体、聚合物微球以及纳米粒等。尽管这种新型的缓释制剂比传统剂型在效果上有了提高,但其自身仍存在一些明显的缺陷,比如,该剂型在注射给药后在关节腔内滞留时间较短；材料降解产物会破坏关节腔生理环境等。为了克服以上缺点,许多学者致力于更长效的关节腔药物递送体系的研究。
本研究构建了一种基于生物可降解的聚己内酯—聚乙二醇—聚己内酯(PCL-PEG-PCL)温敏凝胶的注射用缓释药物递送体系,以期开发出新型关节腔注射用局部给药缓释制剂。
本文的主要研究内容如下：
1.合成具有不同PCL和PEG嵌段组成的温敏性PCL-PEG-PCL三嵌段共聚物
本文合成了一系列具有不同PEG和PCL嵌段长度的PCL-PEG-PCL三嵌段共聚物,并通过核磁共振氢谱及凝胶渗透色谱对其组成、结构及分子量进行了表征。核磁共振及凝胶渗透色谱测定结果表明合成的共聚物组成与初始投料比一致,符合设计的温敏性PCL-PEG-PCL嵌段聚合物结构。
2.PCL-PEG-PCL温敏凝胶的温敏性能研究
本文合成的所有PCL-PEG-PCL嵌段共聚物均具备良好的溶胶-凝胶转变能力。根据实验结果绘制的溶胶-凝胶转变相图,PCL-PEG-PCL温敏凝胶的溶胶-凝胶转变能力与聚合物本身的化学组成及凝胶的浓度密切相关。在相同的凝胶浓度条件下,固定亲水的PEG嵌段长度,增加疏水的PCL嵌段长度会降低PCL-PEG-PCL温敏凝胶的溶胶-凝胶相变温度；对于同一化学组成的PCL-PEG-PCL温敏凝胶来说,提高凝胶浓度可以降低其溶胶-凝胶相变温度。另外,PCL-PEG-PCL温敏凝胶所具备的良好的原位成胶能力及极短的体外成胶时间也在实验中得到了验证,从而为PCL-PEG-PCL温敏凝胶作为理想的注射用药物递送体系打下了基础。
3. PCL-PEG-PCL温敏凝胶的药物体外释放行为研究
本文分别考察了PCL-PEG-PCL温敏凝胶对亲水性蛋白药物牛血清白蛋白和疏水性抗肿瘤药物紫杉醇的体外释放行为。结果表明PCL-PEG-PCL温敏凝胶对两种类型的药物均显示了良好、可控的缓释性能,即可以通过改变聚合物中的PCL嵌段和PEG嵌段长度或凝胶浓度和初始载药量控制载药PCL-PEG-PCL温敏凝胶的药物体外缓释行为。此外,PCL-PEG-PCL温敏凝胶对蛋白药物活性的影响也得到了考察,模型蛋白辣根过氧化酶的活性实验证明蛋白活性不受药物载体的影响,在整个体外释放过程中保持了完好的生理活性。
4. PCL-PEG-PCL温敏凝胶作为关节腔内注射用缓释制剂的初步探讨
在PCL-PEG-PCL温敏凝胶的生物相容性实验中,证明了PCL-PEG-PCL温敏凝胶在关节腔滑膜中未引发炎症,具备理想的体内生物相容性。PCL-PEG-PCL温敏凝胶的体内生物降解实验中,PCL-PEG-PCL温敏凝胶可以在小鼠体内以凝胶状态存在约45天,并最终完全降解。考察了包载有甲氨喋呤的PCL-PEG-PCL温敏凝胶的体外释放行为；在动物实验中,考察了关节腔内注射包载有甲氨喋呤的PCL-PEG-PCL温敏凝胶后,大鼠的体内药代动力学。结果表明,载药PCL-PEG-PCL温敏凝胶在体外释放试验中对甲氨喋呤显示了良好的缓释性能；在体内实验中,载药PCL-PEG-PCL温敏凝胶可以减缓甲氨喋呤的清除速率,实现药物在关节腔内的缓释作用。
由于具备理想的温敏性能、可控的药物缓释能力以及良好的生物降解性能和生物相容性,PCL-PEG-PCL温敏凝胶是一种极具潜力的关节腔内注射用药物缓释体系,从而为改善类风湿性关节炎等疾病的临床疗效发挥重大的作用。
During the last decade, thermosensitive polymers-based injectable thermosensitive hydrogels received an increasing attention as controlled drug carriers because of their many advantages such as the convenience of application, high drug loading, no organic solvents, sustained drug release behavior and less systemic toxicity. These drug delivery systems are flowable aqueous solution before administration, but once injected, they rapidly form gel under physiological conditions and hence an in situ "drug depot" forms. In situ gel formation after the topical injection of aqueous solutions of such thermosensitive polymers resulted in a significantly prolonged drug residence time.
Inflammatory arthritis diseases such as rheumatoid arthritis (RA) affect an enormous number of individuals. Patients afflicted with the disease may experience pain and loss of joint function with associated deleterious effects on patient activity level and lifestyle habits. Treatment of arthritis disease is achieved through oral, parenteral or intra-articular drugs. The direct drug delivery to an affected joint offers the possibility of reaching high drug concentrations at the action site with limited systemic toxicity. However, the undeniable clinical efficacy of intra-articular injections is somehow restricted either by the rapid efflux of drugs from the joint cavity after injections or by the need of repeated injections, possibly causing joint instability and infections. Retention of drugs in the joints using controlled release delivery system offers an exciting option for intra-articular drug delivery. Researchers thus have tried to encapsulate the drugs into different drug delivery systems such as liposomes, nanoparticles and microparticles.Though more promising than drug suspensions, these systems also faced a major drawback of short retention in the joint due to synovial capillary and lymphatic drainage, which takes place within a few days after injection. To overcome these limitations, many researches have been carried out to find more controlled and prolonged drug delivery to the joint.
In this study, we have constructed a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogels, which offered a great potential to develop a kind of novel topical articular-administrated drug delivery system.
The major contents of this paper are shown as follows:
1. Synthesis, characterization of a series of thermosensitive PCL-PEG-PCL triblock copolymers with different PCL and PEG block lengths.
A series of thermosensitive PCL-PEG-PCL copolymers with different molecular compositions were synthesized by ring-opening polymerization method, and their structure was characterized via 1H-NMR and GPC techniques. The results calculated from 1H-NMR and GPC indicated that EG/CL ratios were consistent with the initial feed ratios, which offered a strong proof to their compositions and molecular structure.
2. Thermosensitivity characterization of PCL-PEG-PCL hydrogels.
All synthesized PCL-PEG-PCL triblock copolymers in this study exhibited a temperature-dependent reversible sol-to-gel transition in water. The phase diagrams revealed that the sol-to-gel transition behavior of PCL-PEG-PCL triblock copolymers in aqueous solutions was highly dependent on their chemical compositions and copolymer concentrations:ⅰ) increasing the length of hydrophobic PCL block with a fixed PEG block length resulted in a lower sol-to-gel transition temperature at a given copolymer concentration.ⅱ) an increase in the copolymer concentration shifted sol-to-gel transitions to the lower temperature. Furthermore, both the short enough gelation time and in situ gel-forming ability of thermosensitive PCL-PEG-PCL hydrogels were confirmed, which were prerequisite for a promising injectable drug delivery system.
3. In vitro drug release behavior of thermosensitive PCL-PEG-PCL hydrogels.
In this chapter, the in vitro release behavior of both hydrophilic protein drug (BSA) and hydrophobic chemo drug (Paclitaxel) from thermosensitive PCL-PEG-PCL hydrogels were investigated. The results revealed that the in vitro drug release rate from the PCL-PEG-PCL hydrogels was controllable by altering either the PEG and PCL block lengths or the hydrogel concentrations and initial drug loadings. Besides, a suitable controlled delivery system should be able to release protein in its biologically active form. In protein activity test, the released model protein (HRP) was confirmed to conserve its biological activity by specific enzymatic activity assay. 4. Injectable thermosensitive hydrogels for intra-articular delivery of methotrexate
The in vivo biodegradability study suggested that the synthesized PCL-PEG-PCL hydrogels were able to persist about 45 days and provide an extended drug release period. The in vivo biocompatibility of PCL-PEG-PCL hydrogels was evaluated, indicating no obvious inflammatory infiltrattion occurred in the synovial membrane.
Sustained drug release behaviors from thermosensitive methotrexate loaded PCL-PEG-PCL hydrogels in both in vitro and in vivo (intra-articular injection in rats) experiments were observed. The pharmacokinetics data suggested that the methotrexate loaded hydrogel was able to slow down the clearance of methotrexate and control the methotrexate release in the joint cavity.
Owing to great thermosensitivity, controllable drug release behaviors, biocompatibility and biodegradability of these PCL-PEG-PCL copolymers, these developed PCL-PEG-PCL hydrogels can be applied as a promising in situ gel-forming controlled drug delivery system for the intra-articular injection and pave a way to improve the therapeutic efficacy of rheumatoid arthritis clinically.
引文
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