可植入温敏水凝胶的合成及性质研究

目的:合成满足植入给药载体要求的温度敏感型PLGA-PEG-PLGA嵌段共聚物,并对其结构和性质进行研究.方法:采用开环聚合法,以不同比例的丙交酯、乙交酯和PEG为原料,异辛酸亚锡为催化剂,合成PLGA-PEG-PLGA嵌段共聚物.通过考察不同嵌段共聚物的相变温度和黏度,筛选确定符合植入给药载体要求的合成条件和投料比例.结果:合成的凝胶材料,经FTIR和1H-NMR检测,材料符合PLGA-PEGPLGA嵌段共聚物特征.经筛选,按丙交酯-乙交酯-PEG 1500(6:1:3)的质量比投料,0.1%(W/W)催化剂用量,在真空条件下140℃反应12 h,可以得到满足植入给药要求的栽体材料.结论:采用开环聚合法,可以合成温敏型PIGA-PFGA嵌段共聚物,其相变温度可过改变丙交酯、乙交酯投料比例和PEG的相对分子质量在一定范围内调节.实验合成的共聚物在质量分教为20%时.相变温度35℃,黏度与55%甘油水溶液相当,形成的凝胶具备一定的刚性,材料无有机溶剂残留,符合植入蛤药载体的要求.     

用于关节腔注射的马钱子碱壳聚糖温敏凝胶的研究

利用壳聚糖-甘油-饱和硼砂溶液为主要材料构建一种用于关节腔注射、具有缓释作用的壳聚糖反相温敏水凝胶系统,并对其理化性质和生物相容性进行初步研究。以凝胶的形成和胶凝时间为指标,考察壳聚糖浓度、壳聚糖与甘油的比例、pH值等因素对水凝胶理化性质的影响,并对其体外释放行为、流变学、生物相容性等特性进行表征。温敏凝胶在常温下为溶胶态,当处于37℃时转变为凝胶态,并具有一定的缓释效果,生物相容性较高。     

醋酸曲安奈德温敏凝胶药效学及滞留性

目的：制备关节腔注射用醋酸曲安奈德TAA温敏凝胶,考察其药效学和滞留性。方法：采用物理混合法制得TAA温敏凝胶,建立老鼠皮下气囊炎症模型,给予不同组分药物治疗后,通过对比皮下囊物理特征、组织切片的相关评价以及elisa试剂盒检测炎性因子TNF-α水平等来考察所制备的TAA温敏凝胶药效学及缓释性能,并通过小动物活体成像实验评价其滞留性。结果：药效学结果显示制备的TAA温敏凝胶相比于市售TAA混悬液对于气囊滑膜炎模型的炎症抑制作用更强、作用时间更持久。小动物活体成像实验结果显示制备的TAA温敏凝胶在体内滞留时间能达到9 d以上,能够达到缓释药物的目的,适用于关节腔局部用药的要求。结论：所制备的TAA温敏凝胶的炎症抑制作用强且持久,缓释效果及滞留性良好,有望成为新的关节腔给药传递系统。     

注射用N'-十二烷酰异烟肼温敏凝胶的处方前研究

目的合成异烟肼的活性衍生物N'-十二烷酰异烟肼并对其进行处方前研究,为注射用N'-十二烷酰异烟肼温敏凝胶的处方设计提供基础。方法采用~1H-NMR、LC-MS、UV和HPLC对合成的N'-十二烷酰异烟肼进行确证和纯度测定。并用HPLC法测定N'-十二烷酰异烟肼的油水分配系数、在不同溶剂中的平衡溶解度、稳定性等理化性质。结果所得的N'-十二烷酰异烟肼纯度大于99%,~1H-NMR、LC-MS、UV确证其结构正确。N'-十二烷酰异烟肼溶液在高温(60℃)和强光(4500 Lx)条件下稳定,Log P为3.48,难溶于水,在相应的溶出介质中满足漏槽条件。结论建立的分析方法准确可靠,处方前研究表明N'-十二烷酰异烟肼原料药较稳定。     

壳聚糖季铵盐温敏凝胶的制备及性能考察

目的 研究壳聚糖季铵盐温敏凝胶及性质.方法 采用试管倾斜法测定胶凝时间,考察壳聚糖季铵盐的浓度、体积比、温度等对胶凝时间的影响,采用吸光度经时变化法测定相变动力学,并用透析法测定载药凝胶的体外释放.结果 56％ GPS/2％ HTCC体积配比1:5、温度37℃时,胶凝时间为3.53min,钙黄绿素载药凝胶具有良好的缓释...     

Synthesis and characterization of grafted thermosensitive hydrogels for heating activated controlled release

Poly(N-isopropylacrylamide), PNIPAAm, hydrogels are negatively thermosensitive which means that they have an expanded hydrogel structure at low temperatures and a shrunken structure at high temperatures. Based on this negative thermosensitivity of PNIPAAm, a drug delivery system with PNIPAAm oligomers grafted onto poly(hydroxyethyl methacrylate) PHEMA, a thermally nonresponsive polymer was designed. Poly(hydroxyethyl methacrylate-g-N-isopropylacrylamide), P(HEMA-g-NIPAAm) hydrogels were synthesized to control the release of an imbedded drug. This new grafted system exhibited high diffusivity at temperatures greater than the lower critical solution temperature (LCST) of the PNIPAAm oligomers. Utilizing PNIPAAm's LCST of approximately 34 degrees C, the release rate was controlled by the temperature of the release medium. The LCST of PNIPAAm was tuned by making copolymers with hydrophobic butyl methacrylate (BMA). Theophylline and inulin release profiles were studied using PHEMA, PNIPAAm and P(HEMA-g-NIPAAm) at three temperatures with drug diffusion coefficients determined as a function of temperature and drug type. The molecular weights between crosslinks and mesh sizes of PHEMA hydrogels were calculated using Flory-Rehner and rubber-elasticity theories.     

可生物降解的盐酸米诺环素微球凝胶的研制及其含量测定方法

目的制备盐酸米诺环素微球的功能性壳聚糖温敏凝胶.方法将小分子药物米诺环素先制备成盐酸米诺环素微球,共混于壳聚糖温敏凝胶中,观察其理化性质及释药性能;并建立药物的HPLC测定方法.结果通过试验筛选微球、凝胶制备工艺,温敏凝胶系统的流变学性质几乎未受加入药物的影响;实验制得的缓释凝胶,T50%可延长至4.24 d;HPLC方法如下线性范围为99～495 ng·mL-1,标准曲线为A=1 170.6C 52 235,r=0.999 5.结论本实验为可生物降解的盐酸米诺环素微球凝胶的进一步研究奠定了初步基础.     

Postfabrication encapsulation of model protein drugs in a negatively thermosensitive hydrogel

A postfabrication encapsulation technique was developed for loading model protein drugs into an intelligent and biodegradable hydrogel film, which exhibits negative thermosensitivity with a desirable phase transition temperature between refrigerator temperature and body temperature. The hydrogel comprises mainly poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) block copolymer, and oligo(lactide). The model proteins Hemoglobin and Bovine Serum Albumin were loaded into the hydrogel films by soaking the gels at 4 degrees C, at which the hydrogel film was swollen. The loaded drug was released gradually in PBS at 37 degrees C, where the hydrogel film was shrunken. Because the hydrogel is biodegradable, the loaded drug could be released completely. It is confirmed that proteins can, in their native structures, be included in the hydrogel via the present technique, as characterized by FTIR, Raman spectrum, UV/VIS spectrum, and circular dichroism spectrum. The highlight of our approach is avoidance of high temperatures and organic solvents in encapsulation, making it ideal for protein drug delivery systems.     

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.     

A thermosensitive chitosan-based hydrogel for the local delivery of paclitaxel.

A novel injectable thermosensitive in situ gelling hydrogel has been developed. The system, which falls under the BST-Gel platform technology developed at Biosyntech Inc. (Laval, QC, Canada), consists of a chitosan solution (C) neutralized with beta-glycerophosphate (GP) that is liquid at room temperature but gels when heated to body temperature. We propose to use this thermosensitive hydrogel for the sustained release of paclitaxel at tumor resection sites in order to prevent local tumor recurrence. The in vitro release profiles demonstrated controlled delivery over 1 month. The initial drug loading substantially affected the release. Local delivery of paclitaxel from the formulation injected intratumorally was investigated using EMT-6 tumors implanted subcutaneously on Balb/c mice. These experiments showed that one intratumoral injection of the thermosensitive hydrogel containing paclitaxel was as efficacious as four intravenous injections of Taxol in inhibiting the growth of EMT-6 cancer cells in mice, but in a less toxic manner. Further histological analysis revealed that while the proportion of necrotic areas was similar for the C/GP/paclitaxel and the Taxol-treated tumors, a disparity between tumor-associated inflammatory cell populations may suggest differing anti-tumor mechanisms.     

Investigation of a new injectable thermosensitive hydrogel loading solid lipid nanoparticles

For improving the effectiveness of cancer chemotherapy and avoiding rapid clearance of solid lipid nonoparticles (SLN) from the systemic circulation following systemic administration, 2-methoxyestradiol (2-ME) as model drug, PLGA-PEG-PLGA as hydrogel material, an injectable SLN loaded hydrogel was developed. Integrity of SLN within and released from the hydrogel was confirmed by direct visualization by a scanning electron microscope (SEM), particle size measurement by laser light scattering, and free drug concentration in the release medium by ultracentrifugation. Moreover, in vitro release, thermo-sensitive properties and rheological behavior were investigated. The results indicated that SLN were stable in the hydrogel. In the release medium, most 2-ME existed in the SLN and intact 2-ME SLN could be released from the hydrogel for a prolonged period over 46 days. Their concentration showed a significant effect on the release rate, in contrast to particle size and pH value of the release medium. In addition, the SLN loaded hydrogel could still exhibit reversible thermo-sensitive properties and better syringeability. These results suggested that the SLN loaded hydrogel could transport SLN to the target site and control prolonged release of SLN, which may increase the efficacy of cancer chemotherapy.     

Preparation and characterization of Tegafur magnetic thermosensitive liposomes

The purpose was to study the preparation and properties of tegafur magnetic thermosensitive liposomes. The method was to employ an improved chemical coprecipitation method for preparing nano-magnetic particles and a reverse-phase evaporation and ultrasonic method for preparing tegafur magnetic thermosensitive liposomes. The results showed that tegafur magnetic thermosensitive liposomes were prepared successfully. They had comparatively strong magnetism and superparamagnetism, and their temperature showed a linear positive correlation with dosages and the field strength under a current value. The conclusion was that tegafur magnetic thermosensitive liposomes with comparatively small particle size, superparamagnetism and comparatively strong magnetism were prepared successfully.     

Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts

Poly(organophosphazene), a novel thermosensitive hydrogel, is an injectable drug delivery system (DDS) that transforms from sol to gel at body temperature. Paclitaxel (PTX) is a mitotic inhibitor used in the treatment of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60 mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6 % w/w into a 10 % w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90 % of the dose, respectively, in a sustained manner over 4 weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6 weeks, and the PTX concentration in the tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound tumor growth after 14 days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14 days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone.     

大黄素温敏凝胶治疗慢性牙周炎临床观察

目的 观察大黄素温敏凝胶治疗慢性牙周炎的临床疗效及安全性. 方法 选取40例慢性牙周炎患者采用同一口腔内病情相同牙齿的自身对照研究设计,分成观察组40个牙和对照组40个牙,观察两组治疗前后各阶段各项临床指标的变化情况. 结果 观察组和对照组在治疗前各项临床指标差异均无统计学意义（均P＞0.05）;在治疗后第6周时,两组PLI、SBI、PD、AL、MD与治疗前比较均有显著改善（t=39.06、62.76、20.50、8.05、158.32、31.45、46.53、8.43、8.08、8.03,均P＜0.01）,而观察组较对照组改善更为明显（t=31.50、27.91、3.92、7.38、20.09,均P＜0.01）;在治疗后第12周时,两组PLI均有所反弹,但与治疗后6周时差异无统计学意义（P＞0.05）,观察组与对照组之间差异有统计学意义（t=23.39,P＜0.01）;治疗后第12周时观察组SBI、PD、AL、MD较治疗后第6周时有明显改善（t=3.50、21.18、9.93、9.05,均P＜0.01）,与对照组差异均有统计学意义（t=30.69、5.76、13.41、25.60,均P＜0.01）. 结论 大黄素温敏凝胶可以有效控制慢性牙周炎引起的各种临床症状.     

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated.

Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics.

Results: The formulations showed rapid gelation (4–7 min) at 30–35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110–150 kDa led to generation of optimum spray with lower Dv₅₀, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions.

Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.     

Drug release characteristics of physically cross-linked thermosensitive poly(N-vinylcaprolactam) hydrogel particles

The effect of physical cross-linking was studied on the formation and properties of thermosensitive polymer particles of poly(N-vinylcaprolactam), PVCL, and PVCL grafted with poly(ethylene oxide) macromonomer, PVCL-graft-C(11)EO(42). Loading and release of model drugs into/from the hydrogel particles were evaluated. Thermosensitive particles were stabilized by cross-linkers, the most feasible of which was salicylic acid (SA). At 23 degrees C, below the lower critical solution temperature (LCST) of the thermosensitive polymers, stability of the hydrogels was poor, whereas at 37 degrees C stable hydrogel particles were formed. All the drugs and also the cross-linker (SA) were released more efficiently from the PVCL particles compared to the PVCL-graft-C(11)EO(42) particles. Drug concentration and pH affected clearly the rate and extent of drug release in physiological buffer. The higher drug release from the PVCL was based on the more open gel-like structure as opposed to PVCL-graft-C(11)EO(42) particles. Complex formation between the cross-linker and the polymers was due to the hydrogen bonding between the hydroxyl groups of SA and H-bond acceptors of the PVCL. In the case of PVCL-graft-C(11)EO(42), the ethylene oxide chain provided more opportunities for H-bonding in comparison to the pure PVCL, creating more stable complexes (more tightly packed particles) leading to sustained drug release.     

Alginate nanogels-based thermosensitive hydrogel to improve antidepressant-like effects of albiflorin via intranasal delivery

Depression is a primary public health problem. However, current antidepressants work slowly, and together with side effects. Herein, the alginate nanogels were constructed to load albiflorin (albiflorin nanogels), which further formed albiflorin nanogel loaded self-assembled thermosensitive hydrogel system (albiflorin-NGSTH) and were used to improve its antidepressant effects. The nanogel showed a nano-scaled particle size and stronger antioxidant activity. Rheological studies showed that albiflorin-NGSTH had a sol-gel transition at approximately 28 °C. Albiflorin-NGSTH quickly entered the brain by intranasal delivery, and had a continuously release for albiflorin. Preliminary results of mice behavioral despair tests found that albiflorin-NGSTH had no effects on independent exploratory behavior and anxiety of the mice, and significantly decreased immobility duration of the mice in tail suspension test (TST). Moreover, the intranasally administrated albiflorin-NGSTH at a low dose improved depressive behavior, decreased levels of proinflammatory cytokines, and repaired neuronal damage of chronic unpredictable mild stress (CUMS) rats, which indicated an excellent potential for depression therapy. The treatment of albiflorin-NGSTH on depressive disorder was achieved by regulating signal pathway related to depression. Therefore, albiflorin-NGSTH has an excellent potential for clinical application in intranasal drug delivery systems.     

In vitro and in vivo evaluation of thermosensitive chitosan hydrogel for sustained release of insulin

Injectable In situ gel-forming chitosan/β-glycerol phosphate (CS/β-Gp) solution can be introduced into the body in a minimally invasive manner prior to solidifying within the target tissue. This hydrogel is a good candidate for achieving a prolonged drug delivery system for insulin considering its high molecular weight. In addition to the physicochemical characterization of this hydrogel, in vitro and in vivo applications were studied as a sustained insulin delivery system. In the in vitro release studies, 19–63% of total insulin was released from the CS/β-Gp hydrogel within 150?h at different β-Gp and insulin concentrations. The best formulation was selected for in vivo experimentation to control the plasma glucose of diabetic mice models. The hypoglycemic effect of this formulation following subcutaneous injection in diabetic mice lasted 5?d, significantly longer than that of free insulin solution which lasted several hours.     

温度敏感性水凝胶携带阿利吉仑对心肌梗死后大鼠左室重构的影响

目的探讨水凝胶携带肾素抑制剂阿利吉仑对心肌梗死后大鼠心室重构的影响。方法 70只Wistar大鼠随机分成5组:假手术组(Sham组,0只)、磷酸缓冲液组(Pbs组,15只)、磷酸缓冲液+阿利吉仑组(Pbs+a组,15只)、水凝胶组(Gel组,15只)和水凝胶+阿利吉仑组(Gel+a组,15只),后4组大鼠分别在心梗模型制作成功后,于心肌梗死区周边注射等体积的磷酸缓冲液、含有1.5 mg阿利吉仑的磷酸缓冲液、1.5%的温度敏感性水凝胶和含有1.5 mg阿利吉仑的1.5%温度敏感性水凝胶;而假手术组只穿线不结扎,心肌梗死4周后,用病理切片方法统计心梗面积和胶原容积分数;Western blot的方法检测心肌梗死后心肌组织中MMP-2、M M P-9、TIM P、TGF-β的蛋白含量。结果心肌梗死4周后,56只大鼠存活,其中Sham组8只、Pbs组11只、Pbs+a组12只、Gel组12只、Gel+a组13只;Gel+a组的心梗面积和胶原容积分数明显低于Pbs组(P<0.01);心肌组织中MMP-2、MMP-9、TGF-β的蛋白含量明显低于Pbs组(P<0.05);而心肌组织中TIMP的含量明显高于Pbs组(P<0.05);Gel+a组这些作用被进一步增强。结论温度敏感性水凝胶携带阿利吉仑比单纯应用水凝胶更能改善心肌梗死后大鼠的心室重构,具有协同的心肌保护作用。其可能机制是通过影响MMP-2、MMP-9、TIM P-1的活性及下调TGF-β的表达来影响胶原代谢,减少胶原的合成来改善心室重构及心肌梗死后的心功能。