一种pH敏感水凝胶的性质及用于胰岛素口服给药的研究

目的研究pH敏感水凝胶的性质及其用于胰岛素口服给药的降血糖作用。方法制备了聚(甲基丙烯酸 泊洛沙姆 )共聚物水凝胶 ;在不同pH值的介质中研究凝胶溶胀、药物扩散和药物释放性质 ;含胰岛素的凝胶经口服给予糖尿病大鼠。结果水凝胶具有 pH敏感的性质 ;糖尿病大鼠口服给予含胰岛素的聚合物后有明显的剂量依赖的降血糖作用。结论这种水凝胶有望用作药物传递的载体。     

pH/温度双敏感水凝胶合成与释药性质研究

目的:合成一种同时具有pH和温度敏感性的水凝胶,并研究其载药、释药机理.方法:利用反相悬浮聚合法合成基于温度敏感材料N-异丙基丙烯酰胺、pH敏感材料甲基丙烯酸与N,N'-亚甲基双丙烯酰胺的共聚物,以双氯芬酸钠为模型药,测定在不同溶剂中水凝胶的载药能力;并测定了在不同pH环境(pH1,pH4和pH7)、不同温度下(25℃和37℃),双敏感水凝胶的释放性质.结果:实验表明药物在低温、低pH条件下保持收缩状态,药物基本不能从中释放;在高温、高pH状态下药物迅速释放,凝胶微球有较强的温度/pH敏感性质.结论:所得双敏感水凝胶具有显著的pH/温度敏感性质,可应用于药物口服给药.     

聚(甲基丙烯酸-co-泊洛沙姆)水凝胶的溶胀和药物释放性质

以自由基溶液聚合方法制备了聚 (甲基丙烯酸 co 泊洛沙姆 )共聚物水凝胶 ,研究凝胶的溶胀和模型药物氢溴酸右美沙芬 (DMP)和维生素B1 2 的释放性质。凝胶的溶胀和药物释放具有pH 依赖的特征 ,在中性或碱性介质中的溶胀和药物释放速率要高于酸性介质中。在中性或碱性介质中 ,凝胶的溶胀为非Fick或零级过程 ,对于组成适当的水凝胶 ,在数小时内以零级动力学过程释放药物。     

亲水凝胶在药物制剂中的应用

羟丙基甲基纤维素及卡泊波树脂遇水后均可形成亲水凝胶,在缓释制剂中通过亲水凝胶层控制药物的释放。本文影响亲水凝胶控制药物释放的因素如辅料本身的性质,药物的性质以及介质等进行了综术,并着重介绍了羟丙基甲基纤维素在骨架制剂和包衣中的作用,以及卡泊波树脂在固体缓释制剂和口服蛋白给药系统中的应用及最新进展。     

温度敏感型水凝胶

目的综述以PNIPAm水凝胶为代表的温度敏感型水凝胶的性质及其在药学方面的应用。方法针对目前存在的问题,阅读国内外相关文献资料,进行分析整理和归纳。结果聚(N-异丙基丙烯酰胺)(PNIPAm)水凝胶具有一个较低临界溶解温度(LCST,33℃)或相转变温度(Ttr),具有温度敏感特性。PNIPAm水凝胶的这种特殊性能己被广泛应用在许多领域中,如药物的控制释放。结论人们对于这类凝胶的敏感机制尚未取得共识,其在应用领域的研究尚有待于进一步的开发。     

基于动态共价键的多糖水凝胶在药物递送及组织修复中的应用研究进展

水凝胶具有良好的生物相容性和生物降解性,广泛应用于药物递送、伤口敷料和组织工程等生物医学领域。按照材料来源可分为合成材料水凝胶和天然材料水凝胶,其中天然多糖水凝胶不仅可以作为材料应用,还具有独特的药理活性和较好的机械性能,逐渐成为首选材料。动态共价键水凝胶由于其结构灵活性、自愈合性能和环境响应性备受关注。本文对采用动态键方式的天然多糖水凝胶体系进行归类和总结,并对该类水凝胶在药物递送以及组织修复方面的研究现状进行概述,以期为新型多糖水凝胶的临床应用提供借鉴。     

温度敏感型水凝胶

目的 综述以PNIPAm水凝胶为代表的温度敏感型水凝胶的性质及其在药学方面的应用.方法 针对目前存在的问题,阅读国内外相关文献资料,进行分析整理和归纳.结果 聚(N-异丙基丙烯酰胺)(PNIPAm)水凝胶具有一个较低临界溶解温度(LCST,33℃)或相转变温度(Ttr),具有温度敏感特性.PNIPAm水凝胶的这种特殊性能己被广泛应用在许多领域中,如药物的控制释放.结论 人们对于这类凝胶的敏感机制尚未取得共识,其在应用领域的研究尚有待于进一步的开发.     

聚（甲基丙烯酸-co-泊洛沙姆）水凝胶的平衡溶胀和药物扩散性质

以自由基溶液聚合方法制备了聚(甲基丙烯酸-co-泊洛沙姆)共聚物水凝胶,研究凝胶的平衡溶胀性质及模型药物(VB12)在溶胀和收缩状态水凝胶中的扩散性质。随着甲基丙烯酸与泊洛沙姆中乙氧基单元氢键络合的形成和解离,水凝胶表现出pH敏感的溶胀性质和药物扩散性质。酸性介质中凝胶的平衡溶胀率低;中性和碱性时(介质pH高于凝胶溶胀转变的pH),凝胶的平衡溶胀率急剧增大。络合状态水凝胶中,VB12的扩散系数在10-10 to 10-7 cm2s-1范围;而溶胀状态时,VB12的扩散系数在210-6 cm2s-1左右。聚合反应条件以及共聚单体的组成等对水凝胶的结构和溶胀性质、溶质的扩散性质明显影响。凝胶的平衡溶胀率与溶质的扩散系数之间的关系可以用自由体积理论描述,对于甲基丙烯酸和乙氧基的摩尔比>1和<1的水凝胶,lnD与1/H-1分别符合不同的线性方程。     

基于水凝胶的核酸药物负载策略的研究进展

基因治疗在癌症以及遗传疾病的治疗中具有广阔的应用前景,基因治疗的关键在于如何实现将核酸药物精准递送至靶部位。近年来,研究人员致力于将核酸药物负载于水凝胶中,以实现全身或局部的基因递送。水凝胶系统由于其良好的生物相容性、高效的核酸药物负载能力和局部定位控制释放等优势,为核酸药物的递送提供了有效的工具,在实体瘤和再生医学领域具有巨大的潜力。本文综述了近年来水凝胶系统作为核酸药物载体的研究,并重点探讨基于水凝胶的核酸药物负载策略,以期为基于水凝胶的核酸药物递送系统的研究提供参考。     

环境敏感性水凝胶的研究进展及其在给药系统中的应用

环境敏感性水凝胶是一类“感知”外界环境微小的物理和化学刺激后,自身性质发生明显改变的聚合物。分为温度敏感性水凝胶、pH敏感性水凝胶、葡萄糖敏感性水凝胶、电场敏感性水凝胶和光敏感性水凝胶等几类。本文对这几类重要的环境敏感性水凝胶的结构、性质、应用进行了综述,并阐明了各类水凝胶的局限性和发展方向。     

In-vivo drug delivery of 5-fluorouracil using poly(2-hydroxyethyl methacrylate-co-acrylamide) hydrogels

Poly(2-hydroxyethyl methacrylate-co-acrylamide) hydrogels crosslinked with ethylen glycol dimethacrylate were used as devices for the in-vivo drug release of 5-fluorouracil (5-FU). Drug-loaded hydrogels were subcutaneously implanted in the back of Wistar rats. All hydrogel discs reached an equilibrium swelling degree, which was slightly larger than that determined in-vitro. After 30 days of implantation, the hydrogel discs were transparent, and without fracture or apparent degradation. In addition, a fibrous capsule was not detected around the hydrogels that had greater hydration degrees. Release of 5-FU from these hydrogels allows the drug to remain in the plasma from 1 to 5 days, in spite of its short plasma half-life (15 min). This was an improvement of up to 98-times compared with the intraperitoneal drug administration. Administration of 5-FU by implantation of 2-hydroxyethylmethacrylate-co-acrylamide copolymeric hydrogels seems to be a good candidate for 5-FU therapy, since the drug released results in a therapeutically suitable plasma concentration of 5-FU for an extended period of time, despite the short half-life of the drug.     

Preparation and characterization of superporous hydrogels as gastroretentive drug delivery system for rosiglitazone maleate

BACKGROUND AND THE PURPOSE OF THE STUDY: Many drugs which have narrow therapeutic window and are absorbed mainly in stomach have been developed as gastroretentive delivery system. Rosiglitazone maleate, an anti-diabetic, is highly unstable at basic pH and is extensively absorbed from the stomach. Hence there is a need to develop a gastroretentive system. In this study a superporous hydrogel was developed as a gastroretentive drug delivery system. METHODS: Chitosan/poly(vinyl alcohol) interpenetrating polymer network type superporous hydrogels were prepared using a gas foaming method employing glyoxal as the crosslinking agent for Rosiglitazone maleate. Sodium bicarbonate was applied as a foaming agent to introduce the porous structure. Swelling behaviors of superporous hydrogel in acidic solution were studied to investigate their applications for gastric retention device. The optimum preparation condition of superporous hydrogels was obtained from the gelation kinetics. FT-IR, scanning electron microscopy, porosity and swelling ratio studies were used to characterize these polymers. In vitro drug release studies were also carried out. RESULTS: The introduction of a small amount of Poly(Vinyl Alcohol) enhanced the mechanical strength but slightly reduced the swelling ratio. The prepared superporous hydrogels were highly sensitive to pH of swelling media, and showed reversible swelling and de-swelling behaviors maintaining their mechanical stability. The degradation kinetics in simulated gastric fluid showed that it had biodegradability. Swelling was dependent on the amount of chitosan and crosslinker. The drug release from superporous hydrogels was sustained for 6 hrs. MAJOR CONCLUSION: The studies showed that chitosan-based superporous hydrogels could be used as a gastroretentive drug delivery system for rosiglitazone maleate in view of their swelling and prolonged drug release characteristics in acidic pH.     

Diffusion and binding of 5-fluorouracil in non-ionic hydrogels with interpolymer complexation

Hydrogen-bonded interpolymer complexes can be used for development of novel dosage forms. In this study, two types of crosslinked hydrogels, copolymer networks of N-vinyl pyrrolidone and acrylamide (PVP-co-PAM) and interpenetrating polymer networks (IPN) composed of crosslinked PVP-co-PAM and poly(vinyl alcohol) (PVA), were synthesized at three different degrees of crosslinking. The side chain groups in such polymers can form non-ionic complexes through H-bonding, resulting in additional "crosslinks" in the hydrogels. Both kinds of hydrogels have significantly larger swelling sensitivities than the networks formed with ionizable side chains. In the IPNs, introduction of the PVA chains into the PVP-co-PAM networks raises the permeability, indicating more open pores. The permeability decreases with the increasing degree of crosslinking of the copolymer. For probing the drug binding in the hydrogels, Fourier transform infrared spectra (FTIR) difference spectroscopy indicated the presence of significant H-bonding interactions between 5-fluorouracil (5-FU) and the side chains of the polymers. Such interactions are larger in the PVP-co-PAM copolymers than in the IPN hydrogels, thereby causing an additional source of the slower release kinetics in the copolymer hydrogels as revealed by the Peppas model, albeit both types of the networks followed a non-Fickian transport mechanism.     

Drug-delivery study and estimation of polymer-solvent interaction parameter for bisacrylate ester-modified Pluronic hydrogels

In this study, Pluronic F127 hydrogels were characterised as an injectable system for the controlled release of drugs with variable molecular weights (FITC-Dextran at 70 and 40 kDa). In addition, the polymer-solvent interaction parameter (chi) was successfully estimated. Pluronic hydrogels (10-25 wt.%) were redox cured and their swelling behaviour investigated in PBS (pH 7.45) at 37 degrees C. After swelling to equilibrium, the hydrogels were compressed and the rubber-elasticity theory was applied to evaluate chi. Tensile tests proved the hydrogels were elastic and their chi values ranged between 0.50 and 0.53. The full drug load could be delivered over a period of approximately 15 h suggesting that redox cured Pluronic F127 hydrogels can function as injectable systems for controlled and sustained release of macromolecules.     

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.     

Controlled Release of Hepatocyte Growth Factor from Gelatin Hydrogels Based on Hydrogel Degradation

This paper investigates the controlled release of hepatocyte growth factor (HGF) by biodegradable gelatin hydrogels and their HGF-induced angiogenic effect. Hydrogels of different degradabilities were prepared through chemical crosslinking gelatin with varied amounts of glutaraldehyde. When the gelatin hydrogels were radioiodinated and subcutaneously implanted into the back of mice, the remaining radioactivity of the hydrogels decreased with time. However, the remaining period became longer when the concentration of glutaraldehyde used for hydrogel preparation increased. Following implantation of gelatin hydrogels incorporating ¹²⁵I-labeled HGF, the HGF radioactivity retained in the mouse subcutis for longer time periods as the glutaraldehyde concentration becomes higher. The time profile of HGF remaining in every gelatin hydrogel was in good accordance with that of hydrogel degradation, indicating HGF release as a result of hydrogel biodegradation. The gelatin hydrogel incorporating HGF histologically induced angiogenic change around the implanted hydrogel. Gelatin hydrogels incorporating 5 and 10 jig HGF significantly enhanced the number of capillaries newly formed around the implanted site. This was in marked contrast to free HGF of same dose form and HGF-free, empty gelatin hydrogel. The gelatin hydrogel incorporating HGF induced VEGF around the implanted site. In vitro bioassay revealed that HGF molecules interacting with gelatin, still exhibited the biological activity. The interacted HGF would be released from gelatin hydrogels only when they were degraded to generate water-soluble gelatin fragments. It is possible that the HGF associating gelatin fragments of bioactivating, results in induced angiogenic effect.     

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.     

Investigation of active substance release from poly(ethylene oxide) hydrogels

The uptake and controlled release of model active substances from poly(ethylene oxide), (PEO), hydrogels synthesized by irradiation were investigated. For the characterization of network structure of PEO hydrogels, swelling properties in water and the number average molecular weight between crosslinks were determined. Salicylic acid, phthalic acid and resorcinol were used as model substances for their controlled release from PEO hydrogels. The effects of dose rate, total dose and chemical structure of active substance on the uptake and release have been studied. The active substance uptake capacity of hydrogels was found to be lowest for phthalic acid and highest for resorcinol in the gel system obtained by irradiation both at low and high dose rates. The release was lowest both in rate and in total amounts in hydrogels containing phthalic acid, more in those with salicylic acid and highest in those with resorcinol. The physical and chemical factors affecting the release of model compounds such as the network structure of hydrogels and hydrogen bond formation between the adsorbent and PEO chains were discussed.     

Controlled release of hepatocyte growth factor from gelatin hydrogels based on hydrogel degradation

This paper investigates the controlled release of hepatocyte growth factor (HGF) by biodegradable gelatin hydrogels and their HGF-induced angiogenic effect. Hydrogels of different degradabilities were prepared through chemical crosslinking gelatin with varied amounts of glutaraldehyde. When the gelatin hydrogels were radioiodinated and subcutaneously implanted into the back of mice, the remaining radioactivity of the hydrogels decreased with time. However, the remaining period became longer when the concentration of glutaraldehyde used for hydrogel preparation increased. Following implantation of gelatin hydrogels incorporating 125I-labeled HGF, the HGF radioactivity retained in the mouse subcutis for longer time periods as the glutaraldehyde concentration becomes higher. The time profile of HGF remaining in every gelatin hydrogel was in good accordance with that of hydrogel degradation, indicating HGF release as a result of hydrogel biodegradation. The gelatin hydrogel incorporating HGF histologically induced angiogenic change around the implanted hydrogel. Gelatin hydrogels incorporating 5 and 10 microg HGF significantly enhanced the number of capillaries newly formed around the implanted site. This was in marked contrast to free HGF of same dose form and HGF-free, empty gelatin hydrogel. The gelatin hydrogel incorporating HGF induced VEGF around the implanted site. In vitro bioassay revealed that HGF molecules interacting with gelatin, still exhibited the biological activity. The interacted HGF would be released from gelatin hydrogels only when they were degraded to generate water-soluble gelatin fragments. It is possible that the HGF associating gelatin fragments of bioactivating, results in induced angiogenic effect.     

Characterization of Methacrylated Inulin Hydrogels Designed for Colon Targeting: In Vitro Release of BSA

Purpose. To characterize methacrylated inulin hydrogels with respect to their release properties. Methods. Proteins (bovine serum albumin or lysozyme) were used as model drugs and were loaded during or after hydrogel formation. Parameters such as the drug loading method, the molecular weight of the proteins, the initial drug loading concentration, the hydrogel feed composition, degree of substitution, and size of the hydrogel were investigated by determining the release of the model proteins from the hydrogels in a phosphate buffer solution. The biodegradable properties were investigated by studying the release of bovine serum albumin in a solution of inulinase. Results. In vitro protein release from methacrylated hydrogels was influenced by factors such as the drug loading procedure and the molecular weight and loading concentration of the proteins. The feed composition and degree of substitution of inulin seem to be crucial in controlling both the extent and the rate of release. Protein release was clearly enhanced in the presence of inulinase, indicating the biodegradable properties of methacrylated inulin hydrogels. Conclusions. Several hydrogels show interesting properties with respect to the development of a colon-specific drug delivery system.