己酰化乙二醇壳聚糖/泊洛沙姆复合水凝胶的制备及其药物缓释性能

为减少泊洛沙姆水凝胶的溶胶-凝胶转变温度对浓度的依赖性,以泊洛沙姆(P₄₀₇)为基材,将己酰化乙二醇壳聚糖(HGC)与泊洛沙姆复合,制备了己酰化乙二醇壳聚糖/泊洛沙姆(HGC/P₄₀₇)复合水凝胶,利用FTIR、SEM及试管反转法探讨了HGC/P₄₀₇复合水凝胶的性能,并利用紫外-可见分光光度计(UV-vis)对HGC/P₄₀₇复合水凝胶的体外药物缓释性能进行表征。结果表明,通过控制HGC的加入量,基于3%泊洛沙姆的HGC/P₄₀₇复合水凝胶即可发生溶胶-凝胶转变现象,并使HGC/P₄₀₇复合水凝胶的溶胶-凝胶转变温度处于32~37℃。HGC/P₄₀₇复合水凝胶具有高度孔隙率,孔隙之间相互连通,孔径大小处于10~90μm的范围之内。HGC/P₄₀₇复合水凝胶对抗癌药物吉西他滨的释药量达到82.4%~90.6%,缓释时间可达80 h左右。HGC/P₄₀₇复合水凝胶在可注射药物载体领域具有重要的应用前景。     

前端聚合法制备聚N-异丙基丙烯酰胺/碳纳米管复合水凝胶及其性能

用前端聚合法制备了聚(N-异丙基丙烯酰胺)/多壁碳纳米管(PNIPAM/MWCNTS)复合水凝胶,对产物的微观形貌、温敏性、力学性能和释药性能进行了研究。结果表明,PNIPAM/MWCNTS复合水凝胶具有温度敏感性,MWCNTS的加入不影响水凝胶的低临界转变温度,随MWCNTS含量增加,水凝胶吸水能力降低,力学强度显著提高,当MWCNTS的含量由0%增至10%时,水凝胶的压缩强度从88 k Pa增加到666 k Pa。复合水凝胶具有良好的药物缓释性能。     

一种含纳米银的物理交联壳聚糖-泊洛沙姆膜的制备与表征

为了简单方便地制备出一种柔韧性、吸水能力较好的,并具有一定抑菌特性的薄膜,通过调节溶解在稀醋酸溶液中的壳聚糖-泊洛沙姆溶胶pH值的方法,制备出了具有优良抑菌特性、柔韧性与吸水特性的薄膜。薄膜通过物理交联法制备,并进行了力学测试、薄膜断面SEM测试、吸水能力测试以及抑菌圈试验。测试结果显示,所制备的薄膜的拉伸强度和断裂伸长率与泊洛沙姆和甘油的浓度有关。在薄膜的断面SEM测试中发现,泊洛沙姆的加入,会使凝胶断面出现孔洞,孔洞的最大直径10μm。在吸水能力测试中发现,在PBS溶液中,4‰与6‰泊洛沙姆组和2%甘油组具有更好地吸水能力;而在生理盐水溶液中,8‰泊洛沙姆组和2%甘油组具有更好的吸水能力。在抑菌圈试验中,发现不同泊洛沙姆浓度制备出的薄膜基本上均具有明显的抑菌圈。最后,通过综合以上特性,优选出泊洛沙姆和甘油的浓度分别为6‰和2%。由于其制备的方便性、薄膜较好的柔韧性、吸水性,以及有效的抑菌特性,壳聚糖-泊洛沙姆薄膜有望在烧伤治疗、伤口化脓性感染的治疗方面得以应用。     

注射型壳聚糖温敏相变复合材料的制备及性能研究

制备了一种注射型壳聚糖(CS)温敏相变复合材料,首先采用乳化-化学交联法,以戊二醛为交联剂,制备包载甲氨蝶呤(MTX)的壳聚糖微球,然后采用离子交联法,向CS溶液中滴加50%甘油磷酸钠溶液,制备CS温敏水凝胶。将CS载药微球分散于水凝胶中,制得温敏相变复合材料。结果表明,所制得的微球载药量为12.98%,包封率为32.66%,且粒径均一,分散性良好,具有良好的通针性;水凝胶在37℃下1min内可发生相变,由溶胶转变为凝胶,具有良好的温度敏感性;制备的温敏相变复合材料具有良好的原位注射性,且4h内药物释放率为35.65%,缓释效果明显。     

温度敏感型PCL-Pluronic-PCL水凝胶的合成与性能

通过泊洛沙姆(Pluronic)引发己内酯(ε-CL)开环反应,合成了一种较低分子量的PCL-Pluronic-PCL多嵌段共聚物,并采用FT-IR和1H-NMR对其结构进行表征。这种PCL-Pluronic-PCL共聚物有良好的水溶性,并且当其水溶液浓度高于临界凝胶浓度(CGC)时,随着温度的变化呈现出凝胶-溶胶转变特性。采用试管法测试共聚物水溶液的凝胶-溶胶转变。该共聚物水凝胶在可注射药物控制释放系统等方面有着广泛的潜在应用价值。     

壳聚糖可注射水凝胶制备及药物缓释行为

通过溶胶-凝胶法制得壳聚糖(CS)/β-甘油磷酸钠(GP)可注射水凝胶,研究了不同成胶温度对凝胶机械性能、微观形貌、溶胀性能以及药物缓释性能的影响。结果表明,较高的成胶温度使凝胶内氢键作用增强、有效交联密度增大,导致凝胶的机械性能增强,使凝胶的三维网络更加致密,并延缓了药物的释放时间。当成胶温度为60℃时,CS/GP可注射水凝胶抗拉强度为3.13MPa,平衡溶胀率为6.27g/g;制得的CS/GP/阿司匹林(ASA)载药水凝胶的药物释放速率常数为5.09×10-3/min,具有较好的应用前景。     

壳聚糖基可注射纳米复合凝胶的制备及表征

传统的水凝胶支架面临伤口创伤、感染以及对缺损部位不适应等问题,从而导致支架的失效。可注射温敏水凝胶在注射前为流动的液体,通过注射器注入皮下组织或肌肉组织后,可在注射部位原位凝胶化,具有微创易治疗、可修复深层组织损伤、不破坏修复区供血等优点。通常血管内皮生长因子(VEGF)和基质细胞衍生因子-1(SDF-1)的半衰期较短,若将其装载到纳米颗粒复合凝胶中则可起缓释效果。因此实验制备了壳聚糖基水凝胶,保持壳聚糖和明胶体积比不变,通过加入不同体积的β-甘油磷酸钠,制备出不同组分的壳聚糖基温敏水凝胶体系,研究了不同凝胶的成胶时间、孔隙率以及细胞毒性;并制备了壳聚糖和岩藻聚糖的纳米颗粒,对VEGF和SDF-1进行了装载,并对纳米颗粒的粒径、电位及因子释放做了检测。结果表明壳聚糖基水凝胶具有温敏性且增加β-甘油磷酸钠的量会降低凝胶时间,凝胶电镜观察呈三维网络状,无细胞毒性;纳米颗粒粒径分布较均匀且稳定,在凝胶中有缓释效果。因此,制备安全可靠、有合适响应速度的壳聚糖基纳米复合水凝胶是提高材料性能的一种有效方式,将为今后满足不同需求的医用生物材料提供新的研究方向。     

溶胶法原位复合聚乙烯醇/羟基磷灰石水凝胶的结构与性能研究

研究了制备聚乙烯醇(PVA)/羟基磷灰石(HA)复合水凝胶的溶胶法原位复合技术,将无机纳米粉体的溶胶-凝胶合成反应引入高分子基体。对该法制备的复合水凝胶的相结构、微观形貌和拉伸强度进行了分析,并与物理共混法复合水凝胶加以比较。结果表明,溶胶法原位复合可以在富水基体中制备晶相的HA粉体,且粉体粒径小于200nm,分散良好,复合材料的力学性能也有进一步改善。     

纳米银/壳聚糖复合水凝胶的原位制备、表征及抗菌性能研究

在壳聚糖/1,2-丙二醇凝胶中采用抗坏血酸原位还原硝酸银生成纳米银,进而通过碱液置换得到具有不同纳米银含量的物理交联的纳米银/壳聚糖复合水凝胶.紫外-可见光谱、X射线衍射图谱和低分辨率TEM照片的结果表明,复合水凝胶内形成了分散良好的纳米银.高分辨率TEM照片结果表明纳米银的直径在20～50nm之间,但其结晶状态并不均一.抗菌性实验证明,纳米银/壳聚糖复合水凝胶对大肠杆菌和金黄色葡萄球菌均有抗菌效果.     

pH敏感型黄原胶/聚乙烯醇水凝胶的制备与表征

通过化学交联结合物理交联的方法制备了一种pH敏感型的黄原胶/聚乙烯醇(XG/PVA)复合水凝胶,研究了XG与PVA不同质量比、不同交联剂用量及不同冷冻-解冻循环次数对XG/PVA水凝胶溶胀性能和力学性能的影响。结果表明,XG与PVA质量比为1∶5,交联剂环氧氯丙烷用量为5%,冷冻-解冻循环3次时,XG/PVA复合水凝胶内部结构均匀紧密且具有较高的溶胀性能,此时凝胶的弹性模量和压缩强度达到(26.30±0.03)kPa和(134.36±0.43)kPa。并探讨了该实验条件制备的XG/PVA水凝胶的pH敏感性及pH刺激响应性,并以牛血清蛋白(BSA)为模型进行了体外药物释放性能测试及材料生物相容性实验的研究。结果表明,该凝胶具有良好的pH敏感性及pH刺激响应特性,不同pH环境下可实现体外BSA的控制释放,且具有良好的生物相容性,有望用于药物控释载体。     

Ocular poloxamer-based ciprofloxacin hydrochloride in situ forming gels

The purpose of this study was to develop poloxamer-based in situ gelling formulations of ciprofloxacin hydrochloride (HCl) aiming at prolonging corneal contact time, controlling drug release, enhancing ocular bioavailability, and increasing patient compliance. The in situ forming gels were prepared using different concentrations of poloxamer 407 (P407) and poloxamer 188 (P188). Mucoadhesives such as hydroxypropylmethyl cellulose (HPMC) or hydroxyethyl cellulose (HEC) were added to the formulations to enhance the gel bioadhesion properties. The prepared formulations were evaluated for their in vitro drug release, sol-gel transition temperature, rheological behavior, and mucoadhesion force. The in vivo antimicrobial efficacy of selected ciprofloxacin HCl in situ gelling formulations was studied on infected rabbit's eyes and compared with that of the marketed conventional eye drops. The gelation temperature of the prepared formulations ranged from 28.00 to 34.03 degrees C. Increasing the concentrations of P407, HPMC, and HEC increased the viscosity and mucoadhesion force of the preparations and decreased the in vitro drug release. Ciprofloxacin HCl in situ forming gel formulae composed of P407/P188/HPMC (18/13/1.5%, wt/wt), and P407/P188/HEC (18/13/0.5%, wt/wt) showed optimum release and mucoadhesion properties and improved ocular bioavailability as evidenced by an enhanced therapeutic response compared with the marketed conventional eye drops.     

Ocular Poloxamer-Based Ciprofloxacin Hydrochloride In Situ Forming Gels

The purpose of this study was to develop poloxamer-based in situ gelling formulations of ciprofloxacin hydrochloride (HCl) aiming at prolonging corneal contact time, controlling drug release, enhancing ocular bioavailability, and increasing patient compliance. The in situ forming gels were prepared using different concentrations of poloxamer 407 (P407) and poloxamer 188 (P188). Mucoadhesives such as hydroxypropylmethyl cellulose (HPMC) or hydroxyethyl cellulose (HEC) were added to the formulations to enhance the gel bioadhesion properties. The prepared formulations were evaluated for their in vitro drug release, sol–gel transition temperature, rheological behavior, and mucoadhesion force. The in vivo antimicrobial efficacy of selected ciprofloxacin HCl in situ gelling formulations was studied on infected rabbit's eyes and compared with that of the marketed conventional eye drops. The gelation temperature of the prepared formulations ranged from 28.00 to 34.03°C. Increasing the concentrations of P407, HPMC, and HEC increased the viscosity and mucoadhesion force of the preparations and decreased the in vitro drug release. Ciprofloxacin HCl in situ forming gel formulae composed of P407/P188/HPMC (18/13/1.5%, wt/wt), and P407/P188/HEC (18/13/0.5%, wt/wt) showed optimum release and mucoadhesion properties and improved ocular bioavailability as evidenced by an enhanced therapeutic response compared with the marketed conventional eye drops.     

Hydroxybutyl chitosan thermo-sensitive hydrogel: a potential drug delivery system

Drug delivery mediated by hydrogel has shown great promise in controlled drug release field. We report here the development of a hydroxybutyl chitosan (HBC) thermo-sensitive gel to deliver doxorubicine hydrochloride (DOX·HCl) for cancer treatment. Concentrated HBC aqueous solution could transform into hydrogel within 30 s after injection under physiological temperature in non-chemical fashion. The properties of the HBC gels including chemical structure, surface morphology, and rheologic properties were studied. Gelation temperature and gelation time of HBC could be adjusted by HBC concentrations. The gel erosion rate in vivo was faster than solubilization rate in vitro. The mild inflammatory response caused by implantation of the hydrogel was acceptable. The DOX·HCl (1 mg/ml) loaded HBC gels displayed slow release rates that were independent of the HBC concentration, and significantly reduced viability of 4T-1 cells compared with the HBC gels after 1 day incubation. These results indicate that thermo-sensitive HBC hydrogels have promising potential as an injectable drug carrier for pharmaceutical applications.     

Thermosensitive hydrogel of hydrophobically-modified methylcellulose for intravaginal drug delivery

Hydrogels with the advantages of prolonging drug release and administration convenience are necessary for intravaginal drug delivery to prevent sexual transmission of human immunodeficiency virus and other vaginal infections. In this study, the thermosensitive hydrogel of methylcellulose modified by stearic acid (MCS) were evaluated in the presence of NaCl and phosphates, which exhibited sol-to-gel transition performance at body temperature or even lower. The in vitro cytotoxicity and in vivo mucosal irritation were investigated and the results showed that MCS hydrogel possessed good biocompatibility similar with hydroxyethyl cellulose (HEC) gel. Significantly, the release studies revealed that MCS hydrogel could control tenofovir sustained release for 10 h without burst release, longer than that from HEC gel or poloxamer 407 hydrogel. Therefore, MCS thermosensitive hydrogel would be a promising carrier for intravaginal delivery of antiviral drugs for long time controlled release.     

Preparation and evaluation of in situ gelling ophthalmic drug delivery system for methazolamide

Purpose: In this study, a thermosensitive in situ gelling vehicle was prepared to increase the precorneal resident time and the bioavailability of methazolamide (MTA). Method: Poloxamer analogs were used as the gelling agents, and the in situ gel was obtained by using a cold method. The gelation temperature, rheological properties, in vitro release as well as in vivo evaluation (the elimination of MTA in aqueous humor and intraocular-lowering effect) of the optimized formulations were investigated. Results: The optimum concentrations of poloxamer analogs for the in situ gel-forming delivery system were 21% (w/w) poloxamer 407 and 10% (w/w) poloxamer P188. This formulation was able to flow freely under nonphysiological conditions and underwent sol–gel transition in the cul-de-sac upon placement into the eye. In vitro release studies demonstrated a diffusion-controlled release of MTA from the poloxamer solutions over a period of 10 hours. In vivo evaluation indicated that the poloxamer solutions had a better ability to retain drug than MTA eyedrops did. Conclusion: These results suggested that in situ gelling ophthalmic drug delivery system may hold some promise in ocular MTA delivery.     

Controlled release behaviors of chitosan/α, β- glycerophosphate thermo-sensitive hydrogels

Chitosan/α, β-glycerophosphate (CS/α, β-GP) thermo-sensitive hydrogels presented flowable solution state at low temperature and semisolid hydrogel when the ambient temperature increased. In this research, different concentrations of metronidazole encapsulated, CS and α, β-GP, as well as different acid solvents, were chosen to evaluate their influences on the drug release behaviors from CS/α, β-GP hydrogels. It was found that there was a sustaining release during the first 3 h followed by a plateau. SEM images showed that drugs were located both on the surface and in the interior of hydrogels. The optimal preparation conditions of this hydrogel for drug release were as follows: 1.8% (w/v) CS in HAc solvent, 5.6% (w/v) α, β-GP and 5 g/L metronidazole encapsulation. Cytotoxicity evaluation found no toxic effect. In order to control the release rate, 2.5 g/L chitosan microspheres with spherical shape and smooth surface were incorporated, and it was found that the initial release process was alleviated, while drug concentration had no obvious effect on the release rate. It could be concluded that the metronidzole release behaviors could be optimized according to practical applications.     

壳聚糖/SiO2复合涂层的缓释性能研究

为了了解壳聚糖含量对壳聚糖/SiO2复合涂层缓释性能的影响,将氧氟沙星直接溶于壳聚糖醋酸水溶液中,采用溶胶-凝胶法制备了壳聚糖/SiO2复合涂层。通过扫描电子显微镜(SEM)、透射电子显微镜(TEM)、原子力显微镜(AFM)、比表面积及孔径分析仪和光学接触角测量仪(OCA)进行结构和表面分析,并对载药复合膜的释放性能进行了研究。结果显示复合涂层具有良好的缓释性能,其缓释周期和释放率受到壳聚糖含量的影响。     

Anti-adhesive effect of poloxamer-based thermo-sensitive sol-gel in rabbit laminectomy model

Poloxamer-based thermo-sensitive sol-gel has been developed to reduce the incidence of postoperative scar formation at the laminectomy site. The purpose of this study was to evaluate the anti-adhesive effect of poloxamer based thermo-sensitive sol-gel compared to hyaluronate based solution after laminectomy, using a rabbit model. A thermo-sensitive anti-adhesive with a property of sol-gel transition was manufactured by a physical mixture of Poloxamer188/407, Chitosan and Gelatin. The viscosity in different temperatures was assessed. 72 adult New Zealand rabbits underwent lumbar laminectomy and were randomly divided into experimental (treated with the newly developed agent), positive (treated with hyaluronate based solution), and negative control groups. Each group was subdivided into 1 and 4-week subgroups. Gross and histological evaluations were performed to assess the extent of epidural adhesion. The experimental group showed significantly higher viscosity compared to the positive control group and showed a significant increase of viscosity as the temperature increased. Gross evaluation showed no statistically significant differences between the 1- and 4-week subgroups. However, histologic evaluation showed significant differences both in 1- and 4-week subgroups. Although the 4-week histologic results of the experimental and the positive control subgroups showed no significant difference, both subgroups revealed higher value compared to the negative control subgroup with regard to the ratio of adhesion less than 50?%. The new poloxamer based thermo-sensitive agent showed superior efficacy over the hyaluronate based agent at 1?week postoperatively. At 4?weeks postoperatively, there were no statistically significant differences between the two agents, although both showed efficacy over the sham group.     

Development of the ambroxol gels for enhanced transdermal delivery

Ambroxol is an expectoration improver and mucolytic agent that has been used to treat acute and chronic disorders. However, ambroxol needs to be administered percutaneously in order to avoid systemic adverse effects, such as headache, drowsiness, dizziness, and insomnia, which can occur after oral administration. The aim of this study was to develop a gel preparation containing a permeation enhancer to enhance the delivery of ambroxol. The ambroxol gels were prepared using hydroxypropyl methylcellulose (HPMC) and poloxamer 407. The release characteristics of the drug from the gels were examined according to the receptor medium, drug concentration, and temperature. The rate of drug permeation into the skin was enhanced by incorporating various enhancers such as the ethylene glycols, the propylene glycols, the glycerides, the non-ionic surfactants, and the fatty acids into the gels. The permeation study through mouse skin was examined at 37˚C. The rate of drug release increased with increasing drug concentration and temperature. Among the enhancers used, propylene glycol mono caprylate showed the best enhancing effects. The estimated activation energy of release (Ea), which was calculated from the slope of a log P versus 1000/T plot, was 14.80, 14.22, 13.91, and 12.46 kcal/mol for ambroxol loading doses of 2, 3, 4, and 5%, respectively. The results of this study show that the gel preparation of ambroxol containing a permeation enhancer could be developed for the enhanced transdermal delivery of ambroxol.     

Preparation and properties of an injectable thermo-sensitive double crosslinking hydrogel based on thiolated chitosan/beta-glycerophosphate

An injectable thermo-sensitive double crosslinking hydrogel based on thiolated chitosan (CS-TGA)/beta-glycerophosphate (β-GP) was prepared by combining physical and chemical crosslinking. The effect of the concentrations of CS-TGA and β-GP on gelation temperature of CS-TGA-GP hydrogel was investigated. The gelation and mechanical properties of CS-TGA-GP in situ gel system were studied by oscillatory rheology and unconfined compression testing. By the physical interaction of CS-TGA and β-GP, CS-TGA-GP system undergoes a fast gelation at body temperature within 2 min. In addition, CS-TGA-GP hydrogel contains a low concentration of β-GP, which significantly decreases the toxicity of the gel. Owing to the chemical crosslinking of disulfide bonds, the gel is durable and possesses high-mechanical strength without introducing any potential cytotoxicity. The integrity of CS-TGA-GP hydrogel maintains for more than 30 days both in vitro and in vivo, and the interior morphology visualized by scanning electron microscopy reveals that the gel has interconnected porous network structure. In vitro release behavior of protein from CS-TGA-GP hydrogel was investigated using BSA as model protein. There is a sustained protein release from the gel without any initial burst. In vitro cytotoxicity, hemolysis, and histopathological analysis reveal that the gel is biocompatible. These features indicate that CS-TGA-GP hydrogel is a promising candidate for injectable protein delivery system and biomedical applications.