嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1的pH和温度敏感性质及体外释药特性考察

目的 为嵌段共聚物磺胺甲嘧啶低聚物-聚-ε-己内酯-丙交酯-聚乙二醇-聚-ε-己内酯-丙交酯-磺胺甲嘧啶低聚物(sulfamerazine oligomers-poly(ε-caprolactone-co-DL-lactide-b-ethyleneglycol-b-ε-caprolactone-co-DL-lactide)-sulfamerazine oligomers,OSM1-PCLA-PEG-PCLA-OSM1)作为缓控释给药系统的载体提供依据.方法 采用激光粒度仪对不同pH和温度下嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1胶束粒径大小、分布进行考察;通过表面张力和相转变温度测定对其临界胶束浓度和溶液-凝胶相转变行为进行考察;以5 -氟尿嘧啶为模型药,通过透射电镜观察载药和空白共聚物胶束形态;采用物理混合法制备5 -氟尿嘧啶载药水凝胶;采用HPLC法测定载药水凝胶中药物释放速率.结果 嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1胶束溶液具有pH和温度双重敏感的性质,在一定pH和温度条件下可发生溶液-凝胶相转变;5 -氟尿嘧啶载药水凝胶体外释放可持续9 d,具有较好的缓释作用.结论 pH和温度双重敏感型嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1作为注射缓释给药系统载体材料具有良好的应用前景.     

重组人血管内皮抑制素温敏凝胶的制备及其体外释放度研究

目的制备重组人血管内皮抑制素（rh-endostatin）温度敏感型缓释凝胶制剂并考察其体外释放。方法以聚丙交酯-乙交酯-聚乙二醇嵌段共聚物（PLGA-PEG-PLGA）为载体材料制备rh-endostatin温敏凝胶,采用高效液相色谱法（HPLC）测定rh-endostatin温敏凝胶体外释药量。结果 rh-endostatin温敏凝胶在释放介质PBS（含0.02%NaN3）中,开始2h内释放了17.34%,第一天释放了26.44%,之后药物释放逐渐平稳,七天共释放了65.66%。持续至第十八天累积释放了87.05%。结论 PLGA-PEG-PLGA温敏型凝胶是重组人血管内皮抑制素局部注射给药较理想的缓释载体。     

可注射5-氟尿嘧啶缓释凝胶体外释放及其大鼠体内药动学研究

目的:制备可注射5-氟尿嘧啶(FU)缓释凝胶,并研究其体外释药及体内药动学特征。方法:以pH/温度双重敏感生物可降解嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1为载体材料,采用物理混合法制备5-FU缓释凝胶。考察载药量和共聚物浓度对其体外释药情况的影响。采用高效液相色谱法分别测定大鼠皮下注射5-FU水溶液(参比制剂)及缓释凝胶(受试制剂)后不同时间点的血药浓度,绘制药-时曲线,计算药动学参数。结果:5-FU在载药量为0.5%,共聚物浓度为15%、20%、25%的缓释凝胶中第9天时平均累积释放百分率为89.66%、87.59%、80.85%;载药量为0.2%、0.5%、1%,共聚物浓度为25%的缓释凝胶中第9天时平均累积释放百分率为75.30%、80.85%、86.90%;参比制剂与受试制剂在大鼠体内tmax分别为0.25、0.50h,Cmax分别为72.7、31.1μg·mL-1,AUC(0～)t分别为44.5、342.4mg·h·mL-1,MRT分别为0.57、27.2h。结论:5-FU缓释凝胶中5-FU体外释放呈现Higuchi动力学特征,表现为以扩散控制型为主的释药模式;释药初期,载药量对释药速率影响较大;释药后期,共聚物浓度对释药速率影响较大。皮下注射给药后,与水溶液相比,缓释凝胶可持续释药3d,具有良好的缓释作用。     

温度敏感型聚酯/聚乙二醇三嵌段生物可降解共聚物的降解性能及药物释放的影响因素研究进展

温度敏感型生物可降解水凝胶作为一种注射缓释给药系统的新型载体己受到越来越多的关注,聚酯(A嵌段)/聚乙二醇(B嵌段)三嵌段共聚物是目前最常用的温度敏感型聚合物,具有良好的生物相容性和生物降解性.本文综述了聚乙二醇嵌段含量、聚酯嵌段种类、共聚物凝胶水溶液浓度、处方中添加剂、药物与共聚物分子间的作用力、载药量及制剂形状、介质pH及温度等因素对聚酯/聚乙二醇三嵌段共聚物降解速率及药物释放速率的影响,为聚酯/聚乙二醇三嵌段共聚物水凝胶注射剂开发过程中共聚物降解速率和药物释放速率的调节提供有价值的思路与科学依据.     

嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1的pH和温度敏感性质及体外释药特性考察

目的 为嵌段共聚物磺胺甲嘧啶低聚物-聚-ε-己内酯-丙交酯-聚乙二醇-聚-ε-己内酯-丙交酯-磺胺甲嘧啶低聚物（sulfamerazine oligomers-poly(ε-caprolactone-co-DL-lactide-b-ethyleneglycol-b-ε-caprolactone-co-DL-lactide)-sulfamerazine oligomers,OSM₁-PCLA-PEG-PCLA-OSM1)作为缓控释给药系统的载体提供依据。方法 采用激光粒度仪对不同pH和温度下嵌段共聚物OSM₁-PCLA-PEG-PCLA-OSM₁胶束粒径大小、分布进行考察;通过表面张力和相转变温度测定对其临界胶束浓度和溶液-凝胶相转变行为进行考察;以5-氟尿嘧啶为模型药,通过透射电镜观察载药和空白共聚物胶束形态;采用物理混合法制备5-氟尿嘧啶载药水凝胶;采用HPLC法测定载药水凝胶中药物释放速率。结果 嵌段共聚物OSM₁-PCLA-PEG-PCLA-OSM₁胶束溶液具有pH和温度双重敏感的性质,在一定pH和温度条件下可发生溶液-凝胶相转变;5-氟尿嘧啶载药水凝胶体外释放可持续9 d,具有较好的缓释作用。结论 pH和温度双重敏感型嵌段共聚物OSM₁-PCLA-PEG-PCLA-OSM₁作为注射缓释给药系统载体材料具有良好的应用前景。     

可注射更昔洛韦温敏型原位凝胶剂的研究

构建温敏型三嵌段共聚物,研究其理化性质以及用其制备的可注射更昔洛韦温敏型原位凝胶剂的制剂特性。以聚乙二醇（PEG）作为亲水嵌段．丙交酯（LA）和β-丁内酯（β-BL）的无规共聚物PBLA作为疏水嵌段．采用开环聚合法合成温敏型三嵌段共聚物PBLA-PEG-PBLA,并对其理化性质进行表征,考察其溶液的胶凝温度／临界凝胶浓度、流变学性质、通针性和溶蚀行为以及以更昔洛韦作为模型药物、用其制得的可注射载药温敏型原位凝胶剂的体外释放特性。合成的PBLA-PEG-PBLA嵌段共聚物重均分子质量在6000左右,多分散系数为1．5左右;其溶液临界凝胶浓度（g·mL^-1）为5％-10％,质量浓度（g·mL^-1）在10％～25％时胶凝温度为31～35℃,接近并略低于体温：其凝胶在低温下储能模量与黏度较小,当温度接近相转变温度后两者迅速增大：其载药凝胶剂累计释放量经拟合显示遵循一级动力学方程,并呈扩散释药机制。较低质量浓度[10％15％（g·mL^-1）的PBLA—PEG—PBLA更符合玻璃体注射要求,更适用于制备可注射载药温敏型原位凝胶剂。     

玻璃体内注射用地塞米松微球的制备

目的为治疗增殖性玻璃体视网膜病变,制备玻璃体内注射用地塞米松微球。方法以生物可降解乙交酯和丙交酯的无规共聚物(PLGA)为载体材料,采用W/O型乳化-溶剂挥发方法制备地塞米松微微球。研究影响微球制备的工艺条件,考察了微球的粒径大小与分布、载药量和包封率,评价载药微球的体外释放行为。结果微球形态完整,表面光滑,微球的粒径范围为4.70±1.6μm,载药量为(15.5±0.32)%,包封率为(78.8±1.3)%。体外释药13d约90%,属扩散-溶蚀机制。结论制备方法可行,地塞米松PLGA微球具有药物缓释作用。可以作为玻璃体内注射用地塞米松的给药载体。     

注射用利培酮微球的研制及体外释放的研究

目的 制备注射用利培酮微球,并对其体外释放进行研究。方法 以丙交酯乙交酯共聚物(PLGA)为载体材料,选用乳化溶剂挥发法制备注射用利培酮微球,并采用f₂相似因子考察不同处方的自制样品和参比制剂的体外释放曲线相似性。结果 通过调整二氯甲烷用量,筛选出了最佳处方,其微球释放曲线与参比制剂的相似性大于50。结论 成功制备了注射用利培酮微球,自制的利培酮微球与参比制剂的体外释放行为相似。     

地塞米松眼部植入剂的制备

以生物可降解的乙交酯-丙交酯共聚物(PLGA)为载体,用溶剂法制备了地塞米松眼部植入剂。考察了处方中PLGA的构成和重均分子量、药物含量及释放调节剂对植入剂体外释放的影响。结果表明用分子量较小、乙交酯和丙交酯的摩尔比为50:50的PLGA制备的植入剂体外释药较快;提高药物含量、选用亲水性调节剂或乳酸也能加快体外释放。     

PLGA的结构和分子量对纳曲酮微球体外释药的影响

制备了分子量、比旋度、摩尔比及分子链末端修饰不同的丙交酯-乙交酯共聚物,并测定理化参数.以其为载体制备纳曲酮微球,比较了体外释药速率.结果表明,用分子量较小、有光学活性、单体摩尔比较小、分子链末端未酯化的共聚物制备的微球体外释药速率较快.     

Sustained release of bee venom peptide from biodegradable thermosensitive PLGA-PEG-PLGA triblock copolymer-based hydrogels in vitro

Biodegradable thermosensitive poly (DL-lactide-co-glycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized from monomers of DL-lactide, glycolide and polyethylene glycol and were evaluated for sustained release of bee venom peptide in vitro. The resulting copolymers are soluble in water to form free flowing fluid at room temperature but become hydrogels at body temperature. The gelation temperature of the copolymer solutions can be influenced by the concentration and DL-lactide/glycolide molar ratio of the copolymers. The release of bee venom peptide from the copolymer-based hydrogel and hydrogel degradation in the phosphate buffer (pH 7.4) was studied at 37 degrees C under agitation. Bee venom peptide was released from the copolymer-based hydrogels over 40 days in vitro and the variation of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer did not significantly affect the release rate of bee venom peptide (P > 0.05). The hydrogels undergo slower degradation and then faster degradation rate during the whole release stage. Accordingly, the mechanism of bee venom peptide was Fickian diffusion during initial stage and then may be a combination of diffusion and degradation. The synthesized copolymers have the advantage of gelation temperature over the ReGel system. These results indicate that the PLGA-PEG-PLGA copolymer-based hydrogel could be a promising platform for sustained delivery of bee venom peptide.     

Injectable thermosensitive PLGA-PEG-PLGA triblock copolymers-based hydrogels as carriers for interleukin-2

Thermosensitive PLGA-PEG-PLGA triblock copolymers with the DL-lactide/glycolide molar ratio ranging from 6/1 to 15/1 were synthesized by bulk copolymerization of DL-lactide, glycolide and PEG1500. The resulting copolymers are soluble in water to form a freely flowing fluid at room temperature but become hydrogels at body temperature. The release of IL-2 from the copolymer-based hydrogel in the phosphate buffer (pH 7.2) was studied at 37 degrees C under agitation. IL-2 was released from the copolymer-based hydrogels over 20 days in vitro and the release rate decreased with increasing copolymer concentration. The change of DL-lactide/glycolide molar ratio in the PLGA block of the copolymer had little effect on the IL-2 release. The released IL-2 remained 57-90% of its original activity during the release period. To evaluate the anti-tumor effect of the IL-2 loaded copolymer, solutions were injected subcutaneously to H22 tumor-bearing mice. IL-2 loaded copolymer hydrogel for in vivo use showed good anti-tumor effect. These results indicate that the thermosensitive PLGA-PEG-PLGA triblock copolymers could be a promising platform for sustained delivery of IL-2.     

Injectable and biodegradable poly(organophosphazene) gel containing silibinin: its physicochemical properties and anticancer activity

The biodegradable poly(organophosphazene) hydrogels were developed as a locally injectable drug carrier for a hydrophobic silibinin to overcome its limited bioavailability. The aqueous solution of poly(organophosphazene) enhanced the solubility of silibinin up to 2000 times compared with that of phosphate buffered saline (0.0415 vs. 84.55 mg/mL). Both aqueous polymer solutions with and without silibinin showed a sol-gel transition as a function of temperature. A faster in vitro degradation rate of the gel and drug release rate from the gel at pH 6.8 than those at pH 7.4 were observed when the degradation and release study on hydrogels were conducted at 37 °C. Silibinin was sustainedly released from the hydrogel mainly by a diffusion-controlled mechanism. The silibinin released from the hydrogel was shown to be effective considering the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In the HT-29 xenografted mice model, the intratumorally injected hydrogel containing silibinin exhibited a good antitumor effect in comparison with the control groups. The Western blotting indicated that one of the reasons for the enhanced antitumor effect of the hydrogel system was the sustained antiangiogenic effect of silibinin. The poly(organophosphazene) gels are expected to be an effective candidate of the locally injectable drug carrier for silibinin.     

Effect of bee venom peptide-copolymer interactions on thermosensitive hydrogel delivery systems

The objectives of this study were to investigate the potential interactions between the model protein drug (bee venom peptide, BVP) and thermosensitive poly(dl-lactide-co-glycolide-b-ethyleneglycol-b-dl-lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers and to examine the drug-copolymer interactions on the in vitro drug release and hydrogel degradation. The PLGA-PEG-PLGA copolymers were synthesized by ring-opening copolymerization of dl-lactide and glycolide with PEG as an initiator. Drug-copolymer co-precipitate blends were prepared and analyzed by Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) to characterize the specific interactions between drug and copolymer. For the better understanding the drug-copolymer interactions on drug release, insulin was selected for comparison. The release of the two protein drugs from the copolymer-based hydrogels and hydrogel degradation was studied at 37 degrees C under agitation. The results of FTIR and XRD indicated that the hydrogen bonding interactions existed between the NH group of BVP and CO group of the copolymers. The insulin and BVP released from the copolymer hydrogel over 15 and 40 days, respectively. The BVP-copolymer interactions retarded the BVP release rate and degradation of hydrogel, but did not significantly affect the biological activity of BVP. These results indicate that the drug-copolymer interactions need to be considered when attempting to use PLGA-PEG-PLGA hydrogels as sustained delivery carriers of protein or peptide drugs.     

Pharmacokinetic Evaluation of Thermosensitive Sustained Release Formulations Developed for Subcutaneous Delivery of Protein Therapeutics

Injectable, thermosensitive hydrogels, constructed from cross-linked polymers, can offset the limitations of other sustained release delivery systems, overcome constrains of available therapies, and improve patient compliance to chronic therapy. The goal of this project was to identify and evaluate such sustained release, in situ formulations that can help achieve prolonged exposure of protein therapeutics with a short systemic half-life. Natural polymers were used to develop injectable, thermosensitive in situ hydrogels and single-chain variable fragment (scFv) of trastuzumab was used as the model protein with a short half-life. The three polymer combinations tested were: (1) Chitosan and β-glycerophosphate, (2) Chitosan, β-glycerophosphate, and Hyaluronic Acid, and (3) Hyaluronic Acid and Dextran. In vitro drug release experiments were conducted, using different combinations of various polymer concentrations and different drug loading amounts, to identify optimal combinations with prolonged and controlled drug release while exhibiting minimal burst release effect. Select formulations were injected subcutaneously in normal mice to evaluate the pharmacokinetics of scFv for 14 days and identify drug release kinetics in vivo. A two-compartment PK model was also established to quantitatively characterize the release kinetics and disposition of scFv following in vivo administration of the hydrogels. The scFv was undetectable in plasma after 4 and 24 hours following intravenous and subcutaneous administration, respectively. However, all three hydrogel systems were found to provide controlled release of scFv in vivo and maintain detectable concentrations of scFv for at least 14 days. The results suggested that subcutaneous injection of thermosensitive in situ hydrogels may be used to achieve sustained exposure of protein therapeutics which have a very short half-life and thus require frequent administration.     

In situ Hydrogels Prepared by Photo-initiated Crosslinking of Acrylated Polymers for Local Delivery of Antitumor Drugs

A triblock copolymer was synthesized by ring opening polymerization of ε‐caprolactone in the presence of poly(ethylene glycol) (PEG). The resulted PCL-PEG-PCL triblock copolymer, PEG and monomethoxy (MPEG) were functionalized by end group acrylation. NMR and FT-IR analyses evidenced the successful synthesis and functionalization of polymers. A series of photo-crosslinked hydrogels composed of acrylated PEG-PCL-Acr and MPEG-Acr or PEG-Acr were prepared by exposure to visible light using lithium phenyl-2,4,6-trimethylbenzoylphosphinate as initiator. The hydrogels present a porous and interconnected structure as shown by SEM. The swelling performance of hydrogels is closely related to the crosslinking density and hydrophilic content. Addition of MPEG or PEG results in increase in water absorption capacity of hydrogels. In vitro degradation of hydrogels was realized in the presence of a lipase from porcine pancreas. Various degradation rates were obtained which mainly depend on the hydrogel composition. MTT assay confirmed the good biocompatibility of hydrogels. Importantly, in situ gelation was achieved by irradiation of a precursor solution injected in the abdomen of mice. Doxorubicin (DOX) was selected as a model antitumor drug to evaluate the potential of hydrogels in cancer therapy. Drug-loaded hydrogels were prepared by in situ encapsulation. In vitro drug release studies showed a sustained release during 28 days with small burst release. DOX-loaded hydrogels exhibit antitumor activity against A529 lung cancer cells comparable to free drug, suggesting that injectable in situ hydrogel with tunable properties could be most promising for local drug delivery in cancer therapy.     

Development of thermo-sensitive injectable hydrogel with sustained release of doxorubicin: rheological characterization and in vivo evaluation in rats

To develop a thermo-sensitive injectable hydrogel that is easy to administer, gels quickly in the body, and allows sustained release of the drug, various poloxamer-based hydrogels containing doxorubicin were prepared with poloxamer and hydrochloric acid under light protection using the cold method. Their rheological characterization, dissolution, and pharmacokinetics after intramuscular administration to rats were evaluated. Hydrochloric acid decreased the viscosity and retarded the gelation time of the injectable gel. The drug was dissolved from the hydrogels by Fickian diffusion through the extramicellar aqueous channels of the gel matrix. P 188 and hydrochloric acid barely affected the dissolution mechanism. However, P 188 increased and hydrochloric acid decreased the dissolution rate of the drug from the injectable gels. The thermo-sensitive injectable gel composed of 0.6% doxorubicin, 15% P 407, 6% P 188, and 0.1% hydrochloric acid was easy to administer intramuscularly and gelled quickly in the body. Moreover, it maintained the plasma concentrations of drug for 60 h and gave an ~ 5-fold higher AUC compared to doxorubicin solution. Thus, it would be useful for delivering doxorubicin in a pattern that allows sustained release for a long time, leading to better bioavailability.     

Injectable block copolymer hydrogels for sustained release of a PEGylated drug

The paper employs the spontaneous physical gelling property of a biodegradable polymer in water to prepare an injectable sustained release carrier for a PEGylated drug. A series of thermogelling PLGA-PEG-PLGA triblock copolymers were synthesized. The PEGylated camptothecin (CPT) was also prepared and employed as the model of a PEGylated drug, and the solubility of this hydrophobic drug was significantly enhanced to over 150mg/mL. The model drug was completely entrapped into the polymeric hydrogel, and the sustained release lasted for 1 month. The mechanism of the sustained release was diffusion-controlled at the first stage and then was the combination of diffusion and degradation at the late stage. In vivo anti-tumor tests in mice further confirmed the efficacy of the model PEGylated drug released from the hydrogel. This work also revealed the specificity of the PEGylated drug in such a kind of carrier systems by decreasing the critical gelling temperature and increasing the viscosity of the sol. Due to the very convenient drug formulation and highly tunable release rate, an injectable carrier platform for PEGylated drugs is thus set up.     

Migration of marrow stromal cells in response to sustained release of stromal-derived factor-1α from poly(lactide ethylene oxide fumarate) hydrogels

Stromal derived factor-1α (SDF-1α) is an important chemokine in stem cell trafficking and plays a critical role in the homing of bone marrow stromal (BMS) cells. However, its use in tissue regeneration is limited by its relatively short half-life and the time-dependent nature of cell homing to the site of injury. The objective of this work was to investigate the release characteristics of SDF-1α from degradable poly(lactide ethylene oxide fumarate) (PLEOF) hydrogels and to determine the effect of sustained release of SDF-1α on migration of BMS cells. Three PLEOF hydrogels with poly(l-lactide) (PLA) fractions of 6%, 9%, and 24% by weight were synthesized. After the addition of chemokine, the polymerizing mixture was crosslinked to produce SDF-1α loaded PLEOF hydrogels. The hydrogels were characterized with respect to sol fraction, water uptake, degradation, SDF-1α loading efficiency and release kinetics, and migration rate of bone marrow stromal (BMS) cells. The more hydrophilic hydrogels with 6% and 9% PLA fraction had a pronounced burst release followed by a period of sustained release by diffusion for 21 days. The more hydrophobic hydrogel with 24% PLA fraction had a less pronounced burst release and displayed a slow but constant release by diffusion between days 1 and 9 followed by a fast release by diffusion-degradation from days 9 to 18. The fraction of active SDF-1α released from 6%, 9%, and 24% hydrogels after 21 days was 34.3%, 32.3%, and 35.8%, respectively. The migration of BMS cells in response to time-released SDF-1α closely followed the protein release kinetics from the hydrogels. The biodegradable PLEOF hydrogel may potentially be useful as a delivery matrix for sustained release of SDF-1α in the proliferative phase of healing for recruitment of progenitor cells in tissue engineering applications.     

Hyaluronic Acid and Graphene Oxide-incorporated Hyaluronic Acid Hydrogels for Electrically Stimulated Release of Anticancer Tamoxifen Citrate

Transdermal drug delivery is the transport of drug across the skin and into the systemic circulation. Patch is a one of transdermal device that is used to attach on skin and contains drug. The drug matrices from hyaluronic acid (HA) and graphene oxide (GO) incorporated HA hydrogel were fabricated for the release of tamoxifen citrate (TMX) as the anticancer drug under applied electrical field. The pristine HA hydrogels as the matrix and GO as the drug encapsulation host were fabricated for transdermal patch by the solution casting using citric acid as the chemical crosslinker. In vitro drug release experiment was investigated by utilizing the modified Franz-diffusion cell under the effects of crosslinking ratio, electric potential, and GO. The TMX release behaviors from the hydrogels were found to be from the three mechanisms: the pure Fickian diffusion; the anomalous or non-Fickian diffusion; and Super case II transport depending on the crosslinking conditions. The TMX diffusion and release amount from the pristine HA hydrogels were increased with smaller crosslinking ratios. With applied electrical potential, the enhanced TMX diffusion and release amount were observed when compared to that without due to the electro-repulsive force. Furthermore, the TMX diffusion from the HA hydrogel with GO as the drug encapsulation host was higher by two orders of magnitude than without GO.