聚氨酯生物吸收材料及其作为缓释药物载体的研究

合成了一系列新的紫外光固化生物吸收性聚氨酯水凝胶网络，测定了材料的含水率及水解性能，并以之为载体，研究了对异烟肼的药物缓释性能。结果表明，该水凝胶的含水率及降解速率与其结构有关，该水凝胶对异烟肼具有缓释作用，释放行为受扩散控制并符合Ｈｉｇｕｃｈｉ方程，表观扩散系数与水凝胶的含水率有关。     

Synthesis and Characterization of Sterculia Gum Based pH Responsive Drug Delivery System for Use in Colon Cancer

The present study deals with the modification of sterculia gum to develop the novel colon specific delivery system for use in colon cancer. The sterculia and acrylic acid based hydrogels were synthesized and characterized with FTIR, SEMs, TGA and swelling behavior. Swelling studies of the hydrogels were carried out as a function of reaction parameters such as monomer concentration, initiator concentration, amount of sterculia gum and crosslinker concentration and nature of swelling mediums. Swelling kinetics of the hydrogels and in vitro release dynamics of anticancer model drug methotrexate from the hydrogels were studied to evaluate the swelling mechanism and drug release mechanism from the drug-loaded hydrogels. The values of diffusion exponent for the release of drug were 0.883, 0.910 and 0.787 in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. The release of drug from the polymer matrix occurred through a non -Fickian type diffusion mechanism.     

Experimental Study and Numerical Modeling of Rheological and Flow Behavior of Xanthan Gum Solutions Using Artificial Neural Network

This study investigated effect of temperature, concentration, and shear rate on rheological properties of xanthan gum aqueous solutions using a Couette viscometer at temperatures between 25°C and 55°C and concentrations of 0.25 wt% to 1.0 wt%. The Herschel–Bulkley model described very well the non-Newtonian behavior of xanthan gum solutions. Shear rate, temperature, and concentration affected apparent viscosity and an equation was proposed for the temperature and concentration effect valid for each shear rate. This article also presents an artificial neural network (ANN) model to predict apparent viscosity. Based on statistical analysis, the ANN method estimated viscosity with high accuracy and low error.     

冷冻/解冻制备的聚乙烯醇水凝胶的结构和流变性研究

研究了冷冻/解冻法制备的不同浓度(5wt%～25wt%)聚乙烯醇(PVA)水凝胶的结构和流变行为之间的关系.由XRD确定了凝胶中PVA的结晶度和晶粒尺寸.用应力流变仪研究了凝胶的流变行为,包括动态模量和蠕变等.在频率为1Hz和低应力的条件下,测量了凝胶的储能模量和损耗模量.在该试验条件下,PVA水凝胶的形变是完全可以回复的.低频率区和低应变区的储能模量随浓度增加而变大,但当浓度超过20wt%时,储能模量增加速率明显降低.由PVA水凝胶在1Hz时的储能模量和结晶度的数据,理论分析得到了形成PVA水凝胶的最低PVA浓度和最小结晶度.当PVA浓度低于15wt%时,储能模量主要由PVA的微晶控制,分子链间的氢键影响很小.通过低应变区储能模量的数值计算出了凝胶网孔尺寸的结构参数.同时对不同温度下PVA水凝胶的储能模量数据进行了标度分析.PVA水凝胶的蠕变行为显示,随浓度提高,凝胶的蠕变黏弹性由线性向非线性转变.     

Swelling and drug release behavior of poly(2-hydroxyethyl methacrylate/itaconic acid) copolymeric hydrogels obtained by gamma irradiation

The new copolymeric hydrogels based on 2-hydroxyethyl methacrylate (HEMA) and itaconic acid (IA) were prepared by gamma irradiation, in order to examine the potential use of these hydrogels in controlled drug release systems. The influence of IA content in the gel on the swelling characteristics and the releasing behavior of hydrogels, and the effect of different drugs, theophylline (TPH) and fenethylline hydrochloride (FE), on the releasing behavior of P(HEMA/IA) matrix were investigated in vitro. The diffusion exponents for swelling and drug release indicate that the mechanisms of buffer uptake and drug release are governed by Fickian diffusion. The swelling kinetics and, therefore, the release rate depends on the matrix swelling degree. The drug release was faster for copolymeric hydrogels with a higher content of itaconic acid. Furthermore, the drug release for TPH as model drug was faster due to a smaller molecular size and a weaker interaction of the TPH molecules with(in) the P(HEMA/IA) copolymeric networks.     

Photopolymerization of alicyclic methacrylate hydrogels for controlled release

Alicyclic hydroxy methacrylate monomer, o‐hydroxycyclohexyl methacrylate (HCMA), was synthesized and characterized by Fourier transformed infrared spectroscopy (FT‐IR) and proton nuclear magnetic resonance spectroscopy (¹H‐NMR). Photopolymerization kinetics of HCMA was investigated via real‐time infrared spectroscopy (RT‐IR). Polymeric network hydrogels based on hydroxyethyl methacrylate (HEMA) and HCMA were prepared by using the photopolymerization technique. Mechanical strength, swelling characteristic, and controlled release behavior of hydrogels with various feed compositions were studied. Poly(HEMA‐co‐HCMA) hydrogel had higher storage modulus than that of poly(HEMA) hydrogel as investigated by dynamic mechanical analysis (DMA). Acid orange 8 was used as a model drug for the investigation of drug release behavior of copolymeric hydrogels. Results indicated that increase in HCMA ratio in hydrogel composition could reduce the swelling rate and prolong the release time. Scanning electron microscopy (SEM) was also utilized to study the surface morphology of hydrogels, and the results indicated that HCMA content influenced pore diameter on the hydrogel surface. Copyright © 2008 John Wiley & Sons, Ltd.     

Effect of Sodium Alginate on the Properties of Thermosensitive Hydrogels

Sodium alginate (SA ) was combined with poly(N ‐isopropylacrylamide) (PNIPAAm ) to prepare thermosensitive hydrogels through semi‐interpenetrating polymer network (semi‐IPN ) and fully interpenetrating polymer network (full‐IPN ). The thermosensitive, swelling, mechanical, and thermal properties of pure PNIPAAm , SA /PNIPAAm semi‐IPN , and Ca‐alginate/PNIPAAm full‐IPN hydrogels were investigated. The formation of semi‐IPN and full‐IPN significantly improved the hydrogels’ swelling capability and mechanical properties without altering their thermosensitivity. 5‐Fluorouracil (5‐Fu) was selected as a model drug to study the release behaviors of the hydrogels. It was found that in vitro controlled drug release from semi‐IPN hydrogels showed an initial release burst, followed by a slower and sustained release, before reaching equilibrium. Full‐IPN hydrogels showed slow and sustained release during the whole process. Temperature and pH were found to affect the rate of drug release. Ca‐alginate/PNIPAAm full‐IPN hydrogels have potential application as drug delivery matrices in controlled drug release.     

Design of sterculia gum based double potential antidiarrheal drug delivery system

In view of the antidiarrheal properties of sterculia gum and ornidazole, an attempt has been made to synthesize novel hydrogels by functionalization of sterculia gum with poly(vinylpyrrolidone) (PVP) for release of the model antidiarrheal drug ornidazole. These hydrogels were characterized with FTIR, SEM, TGA and swelling behavior. Swelling kinetics of the hydrogels and in vitro release dynamics of ornidazole from the drug loaded hydrogels have been studied to determine the mechanism of swelling and drug release from the drug loaded hydrogels. A Fickian diffusion mechanism has been observed for the release of drug from the hydrogels. These hydrogels may have dual actions for the treatment of diarrhea.     

Adsorption and controlled release of Chlortetracycline HCl by using multifunctional polymeric hydrogels

Adsorption and controlled release of Chlortetracycline HCl to and from multifunctional polymeric materials (HEMA/MAA) hydrogels were investigated. P(HEMA/MAA) hydrogels were synthesized by gamma radiation-induced copolymerization of 2-hydroxyethylmethacrylate (HEMA) and methacrylic acid (MAA) in aqueous solution. The influence of copolymer composition and pH value of the surrounding medium on the type of water diffusion into the glassy polymer were discussed. Drug, Chlortetracycline HCl containing hydrogels, with different drug concentration to polymer ratios, was loaded by direct adsorption method. The influence of MAA content in the gel on the adsorption capacities of hydrogel was studied. Chlortetracycline HCl adsorption capacity of hydrogels was found to increase from 8 to 138 mg Chlortetracycline HCl per gram dry gel with increasing amount of MAA in the gel system and drug concentration. The effect of pH on the releasing behavior of Chlortetracycline HCl from gel matrix was investigated. In vitro drug release studies in different buffer solutions show that the basic parameters affecting the drug release behavior of hydrogel are the pH of the solution and MAA content of hydrogel.     

Novel poly(N‐isopropylacrylamide)/clay/poly(acrylamide) IPN hydrogels with the response rate and drug release controlled by clay content

Novel interpenetrating network (IPN) hydrogels (PNIPAAm/clay/PAAm hydrogels) based on poly(N‐isopropylacrylamide) (PNIPAAm) crosslinked by inorganic clay and poly(acrylamide) (PAAm) crosslinked by organic crosslinker were prepared in situ by ultraviolet (UV) irradiation polymerization. The effects of clay content on temperature dependence of equilibrium swelling ratio, deswelling behavior, thermal behavior, and the interior morphology of resultant IPN hydrogels were investigated with the help of Fourier transform infrared spectroscopy, differential scanning calorimeter (DSC), scanning electron microscope (SEM). Study on temperature dependence of equilibrium swelling ratio showed that all IPN hydrogels exhibited temperature‐sensitivity. DSC further revealed that the temperature‐sensitivity was weakened with increasing amount of clay. Study on deswelling behavior revealed that IPN hydrogels had much faster response rate when comparing with PNIPAAm/clay hydrogels, and the response rate of IPN hydrogels could be controlled by clay content. SEM revealed that there existed difference in the interior morphology of IPN hydrogels between 20 [below lower critical solution temperature (LCST)] and 50 °C (above LCST), and this difference would become obvious with a decrease in clay content. For the standpoint of applications, oscillating swelling/deswelling behavior was investigated to determine whether properties of IPN hydrogels would be stable for potential applications. Bovine serum albumin (BSA) was used as model drug for in vitro experiment, the release data suggested that the controlled drug release could be achieved by modulating clay content. © 2008 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47: 96–106, 2009     

Controlled Drug Release from Gelatin-Sodium Carboxymethylcellulose Interpenetrating Polymer Networks

Hydrogels of uncrosslinked gelatin, crosslinked gelatin (Gelx), and various compositions of semi-interpenetrating polymer network of cross-linked gelatin with uncross-linked sodium carboxymethylcellulose [Gelx-NaCMC] were investigated as potential matrices for substrate delivery. Simultaneous swelling behavior and controlled drug release under enzymatic conditions (erodible) were monitored for hydrogels of [Gelx-NaCMC] and Gelx. Results indicated a first order release indicating that the processes (rate of drug diffusion and degradation) do not follow the same kinetics.     

Biodegradable in situ gel-forming controlled vancomycin delivery system based on a thermosensitive mPEG-PLCPPA hydrogel

In this study, a biodegradable in situ gel-forming controlled drug delivery system based on a thermosensitive methoxy polyethylene glycol-co-poly (lactic acid-co-aromatic anhydride) (mPEG-PLCPPA) hydrogel was studied. The hydrogels were formed by micelle aggregation with rising temperature. The hydrogels underwent a temperature-dependent sol–gel–sol transition, which was a flowing sol at ambient temperature and a non-flowing gel at the physiological body temperature. The residual weight and pH value changes after degradation and the viscosity properties of the hydrogel were investigated. The in vitro release behavior of vancomycin from the mPEG-PLCPPA hydrogels at different concentrations was also investigated. The results showed that the mPEG-PLCPPA amphiphilic copolymer could self-assemble to form micelles at low concentrations, and that the particle sizes gradually increased with increasing temperature. The hydrogel maintained a stable degradation rate and provided a moderate pH microenvironment after degradation for 30 days. Vancomycin sustained a stable release profile from the hydrogel over a 10-day period. Furthermore, good biocompatibility was proven by MTT assay and live and dead test. Therefore, the mPEG-PLCPPA hydrogel shows promise as an injectable local antibiotic delivery system.     

TEMPERATURE AND pH RESPONSE, AND SWELLING BEHAVIOR OF POROUS ACRYLONITRILE-ACRYLIC ACID COPOLYMER HYDROGELS

Macroporous acrylonitrile-acrylic acid （AN-AA） copolymer hydrogels were synthesized by flee-radical solution polymerizations, using ammonium persulfate （APS）/N,N,N＇,N＇-tetramethylethylenediamine （TEMED） redox initiator system and alcohols porogens. The morphology, temperature and pH sensitive swelling behavior, and swelling kinetics of the resulting hydrogels were investigated. It was found that alcohol type and concentration had great influences on the pore structure and porosity of hydrogels. The pore size of hydrogel increases with the moderate increase of the length of alcohol alkyl chain. However, a further increase of alkyl length would result in the formation of cauliflower-like structure and the decrease of pore size. The porosity of hydrogels increases with the increase of porogen concentration in the polymerization medium. The hydrogels with macroporous structure swell or shrink much faster in response to the change of pH in comparison with the conventional hydrogel without macroporous structure. Furthermore, the response rate is closely related to the porosity of the hydrogels, which could be easily controlled by modulating the concentration of the porogen in the medium. The circular swelling behavior of hydrogels indicated the formation of a relaxing three-dimensional network.     

Investigation of drug release from thermo‐ and pH‐sensitive poly(N‐isopropylacrylamide/itaconic acid) copolymeric hydrogels

N‐Isopropylacrylamide/itaconic acid copolymeric hydrogels were prepared by irradiation of the ternary mixtures of N‐isopropylacrylamide/itaconic acid/water by γ‐rays at ambient temperature. The dependence of swelling properties and phase transitions on the comonomer concentration and temperature were investigated. The hydrogels showed both temperature and pH responses. The effect of comonomer concentration on the uptake and release behavior of the hydrogels was studied. Methylene blue (MB) was used as a model drug for the investigation of drug uptake and release behavior of the hydrogels. The release studies showed that the basic parameters affecting the drug release behavior of the hydrogels were pH and temperature of the solution. Copyright © 2004 John Wiley & Sons, Ltd.     

Synthesis and physicochemical characterization of biodegradable and pH‐responsive hydrogels based on polyphosphoester for protein delivery

In this work, a series of biodegradable and pH‐responsive hydrogels based on polyphosphoester and poly(acrylic acid) are presented. A novel biodegradable macrocrosslinker α‐methacryloyloxyethyl ω‐acryloyl poly(ethyl ethylene phosphate) (HEMA‐PEOP‐Ac) was synthesized by first ring‐opening polymerization of the cyclic monomer 2‐ethoxy‐2‐oxo‐1,3,2‐dioxaphospholane using HEMA as the initiator and Sn(Oct)₂ as catalyst, and subsequent conversion of hydroxyl into vinyl group. The hydrogels were then fabricated by the copolymerization of the macromonomer with acrylic acid, and their swelling/deswelling and degradation behaviors were investigated. The results demonstrated that the crosslinking density and pH values of media strongly influenced both the swelling ratio and the degradation rate of the hydrogels. The rheological properties of these hydrogels were also studied from which the storage modulus (G′) showed clear dependence on the crosslinking density. MTT and “live/dead” assay showed that these hydrogels were compatible to fibroblast cells, not exhibiting apparent cytotoxicity even at high concentrations. Moreover, in vitro bovine serum albumin release from these hydrogels was also investigated, and it could be found that the release profiles showed a burst effect followed by a continuous release phase, and the release rate was inversely proportional to the crosslinking density of hydrogels. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 1919–1930, 2010     

The controlled release behavior and pH‐ and thermo‐sensitivity of alginate/poly(vinyl alcohol) blended hydrogels

Poly(vinyl alcohol) (PVA) was blended with sodium alginate (Alg) in various ratios and crosslinked with calcium chloride and made into hydrogel membranes. The dependence of the swelling behavior of these Alg‐Ca/PVA hydrogels on pH was investigated. The temperature‐dependent swelling behavior of the semi‐interpenetrating network (semi‐IPN) hydrogels was examined at temperatures from 2 to 45°C and the enthalpy of mixing (ΔH_mix) was determined at various temperatures. The molecular structure of the hydrogels was studied by infrared spectroscopy and their water structure in the semi‐IPN hydrogels was measured by differential scanning calorimetry (DSC). The influence of Ca²⁺ content on the network structure of Alg‐Ca/PVA hydrogels was investigated in terms of the compressive elastic modulus, effective crosslinking density, and the polymer–solvent interaction parameter based on the Flory theory. The loading of alizarin red S (ARS) followed the Langmuir isotherm mechanism and the release kinetics of ARS from the Alg‐Ca/PVA hydrogels followed the Fickian diffusion mechanism. Copyright © 2008 John Wiley & Sons, Ltd.     

pH敏感型聚谷氨酸/透明质酸基互穿网络医用水凝胶的制备及表征

生物材料是推动生物医学领域日新月异变化的基石,医用水凝胶作为重要成员,近年来表现出蓬勃发展的态势。文章介绍了一种新型可注射的、以生物相容性方法交联的聚谷氨酸(Poly (γ-glutamic acid), PGA)/透明质酸(Hyaluronic acid, HA)复合水凝胶。研究首先采用EDC/NHS方法合成了酪胺(Tyramine,Ty)接枝聚谷氨酸的PGA-Ty前体大分子及半胱胺(Cysteamine, CA)修饰透明质酸的HA-CA前体大分子。两种前体大分子的结构分别使用核磁和红外进行了确证。得到的两种前体大分子在低浓度双氧水和辣根过氧化物酶(Horseradish Peroxidase, HRP)的共同作用下,于水相中交联得到互穿网络(Interpenetrating Network, IPN)水凝胶。实验对IPN水凝胶样品的系列性能,如平衡含水量、内部形貌、酶降解速率以及力学性能等进行了测试,并选取了盐酸四环素为药物模型对凝胶的体外药物释放行为、体外抗菌效果进行了测评。凝胶材料的细胞毒性及凝胶支架对细胞3D培养的效果证明其生物相容性优异,体外包埋的细胞经72h培养,未表现出明显细胞毒性。系列数据证明,该种水凝胶可以设计成为pH敏感型的药物控释载体材料,并因其良好的生物相容性,也有作为细胞支架、创伤辅料等其它生物医用材料的潜力。     

Synthesis and release profile analysis of thermo-sensitive albumin hydrogels

Novel thermo-responsive hydrophilic microspheres were prepared by free radical polymerization of methacrylate bovine serum albumin and N-isopropylacrylamide, as cross-linker and functional monomer, respectively. The incorporation of monomers in the network was confirmed by infrared spectroscopy, while the network density and shape of hydrogels strictly depend on concentration of monomers in the polymerization feed. The thermal analyses showed negative thermo-responsive behavior with pronounced water affinity of microspheres at temperature lower than lower critical solution temperature (LCST). The in vitro release studies of drug-loaded thermo-sensitive hydrogels were performed. Experimental data showed, for the copolymers with functional monomer/cross-linker ratio ≤ 1, a predominant drug release in the collapsed state, while the copolymers with functional monomer/cross-linker ratio > 1 showed prominent drug release in the swollen state. Below the hydrogel LCST, drug release through the swollen polymeric networks was observed, while a squeezing-out effect at temperature above the LCST was predominant.     

Controlled and targeted delivery of diclofenac sodium to the intestine from pH-Responsive chitosan/poly(vinyl alcohol) interpenetrating polymeric network hydrogels

pH-Responsive hydrogels comprised of chitosan and poly(vinyl alcohol) were explored for the controlled delivery of diclofenac sodium (DS) to the intestine. To regulate the drug delivery, preformed solid inclusion complex of DS with ß-cyclodextrin (ß-CD) was added into the hydrogels. Negligible drug release was observed in the simulated gastric fluid and sustained release in the intestinal fluid. The preliminary kinetics revealed that the drug release follows anomalous transport mechanism which is influenced by the presence of ß-CD. The pH-specific release behavior of these hydrogels suggests them to be ideal candidates for oral controlled delivery of DS to the intestine.     

温敏性乙二醇壳聚糖水凝胶的制备及药物缓释性能

以乙二醇壳聚糖为原料, 乙酸酐为酰化剂, 通过N-乙酰化反应, 制得了新型温敏性高分子乙酰化乙二醇壳聚糖. 通过核磁共振氢谱(¹H NMR)、 傅里叶变换红外光谱(FTIR)及试管倒置法对乙酰化乙二醇壳聚糖的结构及温敏性进行了表征, 通过扫描电子显微镜(SEM)和紫外-可见分光光度计(UV-Vis)对水凝胶的微观形貌和体外药物释放性能进行了研究. 结果表明, 随着反应时间和乙酸酐与乙二醇壳聚糖氨基摩尔比的增加, 产物的乙酰度逐渐增加; 乙酰化乙二醇壳聚糖溶液具有热可逆温敏性溶胶-凝胶转变行为, 可以通过控制乙酰化乙二醇壳聚糖的乙酰度和溶液浓度, 使溶胶-凝胶转变温度处于室温至体温(25~37 ℃)之间; 乙酰化乙二醇壳聚糖水凝胶具有“高度孔隙化且孔隙之间相互连通”的结构特点, 通过控制乙酰度和溶液浓度, 可使其孔径大小处于1~40 μm范围内; 乙酰化乙二醇壳聚糖水凝胶的乙酰度为89.90%时, 质量分数为5%~7%的水凝胶对抗癌药物吉西他滨具有缓释作用, 载药凝胶的释药时间可达3~5 d. 乙酰化乙二醇壳聚糖有望在药物释放及组织工程等领域得到广泛应用.