温敏/pH敏共聚物瓜耳胶-异丙基丙烯酰氨的制备及其水凝胶性质研究

目的:合成了新型温敏/pH敏感型高分子材料异丙基丙烯酰氨-g-瓜耳胶(PNIAAr-g-GG),并对其性质进行研究.方法:采用链引发法制备了异丙基丙烯酰氨-g-瓜耳胶共聚物,以戊二醛为交联剂制备了聚合物凝胶及其温敏游离膜,并用红外光谱与热重分析对聚合物结构进行确证;采用黏度法测定了聚合物的低温溶解温度(lower critical solution temperature,LCST);考察了离子强度对聚合物LCST的影响,温度对温敏膜药物透过性的影响,同时考察了温度、离子强度及pH值对聚合物凝胶释药的影响.结果:聚合物的LCST为37.5℃,且随溶液中离子强度的增高而线性降低;当温度高于聚合物LCST时,凝胶中药物释放速率减慢,药物经膜的透过性增加;凝胶释药速率随溶出介质中离子强度的增高而降低,随介质pH值降低而加快.结论:异丙基丙烯酰氨-g-瓜耳胶凝胶骨架片具有明显的温度敏感性及pH敏感性.     

接枝共聚物瓜耳胶-g-丙烯酰胺-丙烯酸的制备及pH敏感性研究

目的制备pH敏感型聚合物瓜耳胶-g-丙烯酰胺-丙烯酸(GG-g-PAAm-AAc,GPAA),并对其结构进行表征。方法采用链引发聚合法制备GPAA;用IR及NMR对GPAA结构进行表征;由元素分析结果计算丙烯酰胺接入率;端基滴定法测定丙烯酸的接入率。以酮洛芬为模型药物,GPAA为骨架材料制备酮洛芬脉冲控释片,采用γ闪烁示踪技术对其体内释药情况进行研究。结果GPAA中丙烯酰胺的接入率为36.4%,丙烯酸的接入率为24.7%;酮洛芬脉冲控释片在胃内基本不释药,进入小肠后,药物逐渐释放,亮点逐渐扩散,7 h药物已释放大部分。结论作者合成的GPAA具有明显的pH敏感性,是一种碱敏感型聚合物,具有广阔的应用前景。     

外用温敏水凝胶基质的研究进展

本文依据近年来国内外相关文献资料,进行归纳总结。综述了几种外用温敏性制剂的基质及各自特性,在给药系统中的应用等方面的研究进展。作为一种新型的药物传递系统,温敏性制剂凭借其独特的优势,在药剂学领域有着广阔的应用前景。     

胰岛素超多孔水凝胶控释制剂的制备及其检测

目的 制备一种可实现控释的超多孔水凝胶,以胰岛素为模型药,考察超多孔水凝胶的载药、释药性能,初探给药途径及药效.方法 采用聚合物互穿网络法制备超多孔水凝胶(SPH-IPN);通过傅立叶变换红外光谱和核磁共振碳谱考察凝胶的结构;通过测定溶胀比、孔隙率考察凝胶的性能;并以胰岛素为模型药研究超多孔水凝胶的载药量及载药后的药效...     

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.     

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N-异丙基丙烯酰胺类温敏凝胶的制备及其对萘普生钠的缓释作用

目的：制备聚N-异丙基丙烯酰胺类的两种温敏凝胶：聚N-异丙基丙烯酰胺均聚水凝胶和N-异丙基丙烯酰胺-甲基丙烯酰胺共聚水凝胶，并考察其性质和对萘普生钠的缓释作用。方法：在氮气保护下制备两种水凝胶，测定和比较交联剂和甲基丙烯酰胺含量对凝胶溶胀度及临界相转变温度的影响。并以两种水凝胶为载体，在模拟人体肠液环境下进行萘普生钠的体外释放实验。结果和结论：交联剂用量增大时，凝胶溶胀度下降；甲基丙烯酰胺含量增加时，共聚水凝胶溶胀度增加，临界相转变温度提高。亲水性共聚水凝胶对药物的释放稳定持久，释药量大，具缓释作用。     

pH及温度双重敏感性聚(N-异丙基丙烯酰胺-烯丙胺)纳米水凝胶的制备与表征

利用聚合沉淀法制备聚（N-异丙基丙烯酰胺-烯丙胺）（PNIPA-co-NH2）纳米水凝胶。考察了其粒径分布，并以500nm处的透光率表征PNIPA-co-NH2的低临界溶解温度（LCST，Tc）和pH敏感性。结果表明，通过调节表面活性剂十二烷基硫酸钠用量和烯丙胺单体的投料比可控制纳米水凝胶的粒径和Tco标记上荧光素后，PNIPA-co-NH2的紫外光谱发生明显改变。     

环境敏感型水凝胶在药物递送中的应用

环境敏感型水凝胶是近年来发展迅速的一种药物递送新剂型,它能基于不同生理环境在用药局部形成黏附性较好的半固体,局部滞留时间长有利于持续释药,且制备工艺简单易于实现工业化.本综述从其分类、常用聚合物和给药途径角度总结归纳了环境敏感型水凝胶的最新研究进展:根据响应因素环境敏感型水凝胶具体可分为温度、pH、离子、光及多重敏感型...     

胰岛素纳米粒温敏凝胶的制备及体外释药性能

目的:制备胰岛素壳聚糖温度敏感型原位凝胶(INS-CS-NP-TISG)并进行体外释药动学考察。方法:采用离子凝胶化法制备胰岛素壳聚糖纳米粒;均匀设计法优化其处方及制备工艺,观察形态,测定粒径、表面电位、包封率和载药量;冷法配液的方法制备温度敏感型原位凝胶,改进透析袋-恒温水浴法研究胰岛素壳聚糖纳米粒温度敏感型原位凝胶溶液的体外释药动学。结果:优化制得的纳米粒呈类球形,均匀圆整,分散性好;平均粒径为(255.3±143.5)nm,在175.2~349.6nm范围内的纳米粒子达99.4%,大小均匀,分布较窄;高效液相色谱法(HPLC)测定胰岛素壳聚糖纳米粒平均包封率和载药量分别为75.84%与58.52%;表面电位(ζ)为+32.67;在人工鼻黏液中,胰岛素壳聚糖纳米粒温度敏感型原位凝胶的体外释药符合双相动力学方程,且持续释药24h。结论:选用合适的处方制备胰岛素壳聚糖纳米粒温度敏感型原位凝胶,方法简便,药物载药量高,具有较好的生物黏附性,并有一定的缓释作用。     

Injectable hybrid delivery system composed of gellan gum,nanoparticles and gentamicin for the localized treatment of bone infections

ABSTRACT

Objectives: Bone infections are treated with antibiotics administered intravenously, antibiotic-releasing bone cements or collagen sponges placed directly in the infected area. These approaches render limited effectiveness due to the lack of site specificity and invasiveness of implanting cements and sponges. To address these limitations, we developed a novel polysaccharide hydrogel-based injectable system that enables controlled delivery of gentamicin (GENT). Its advantages are minimal invasiveness, and localized and finely regulated release of the drug.

Methods: GENT was incorporated both directly within the gellan gum hydrogel and into poly(L-lactide-co-glycolide) nanoparticles embedded into the hydrogel.

Results: We confirmed the injectability of the system and measured extrusion force was 15.6 ± 1.0 N, which is suitable for injections. The system set properly after the injection as shown by rheological measurements. Desired burst release of the drug was observed within the first 12 h and the dose reached ~27% of total GENT. Subsequently, GENT was released gradually and sustainably: ~60% of initial dose within 90 days. In vitro studies confirmed antimicrobial activity of the system against Staphylococcus spp. and cytocompatibility with osteoblast-like cells.

Conclusions: Developed injectable system enables minimally invasive, local and sustained delivery of the pharmaceutically relevant doses of GENT to combat bone infections.     

Investigation of solute permeation across hydrogels composed of poly(methyl vinyl ether‐co‐maleic acid) and poly(ethylene glycol)

Objectives Swelling kinetics and solute permeation (theophylline, vitamin B₁₂ and fluorescein sodium) of hydrogels composed of poly(methyl vinyl ether‐co‐maleic acid) (PMVE/MA) and poly(ethylene glycol) (PEG) are presented. Methods The effects of PMVE/MA and PEG 10 000 content on swelling behaviour (percentage swelling, the type of diffusion and swelling rate constant) were investigated in 0.1 m phosphate buffer. Network parameters, such as average molecular weight between crosslinks (M_c) and crosslink density, were evaluated. Key findings The percentage swelling and M_c of hydrogels increased with decrease in PMVE/MA content, where the water diffusion mechanism into the hydrogels was Class‐II type. In contrast, increase in PMVE/MA content caused an increase in the crosslink density. Permeation of theophylline, vitamin B₁₂ and fluorescein sodium, with increasing hydrodynamic radii, was studied through the equilibrium swollen hydrogels composed of PMVE/MA and PEG. In general, the permeability and diffusion coefficients of all three solutes decreased with increase in the PMVE/MA content. In addition, permeability and diffusion coefficient values increased with decreases in the hydrodynamic radii of the solute molecules. Conclusions The hydrogels have shown a change in swelling behaviour, crosslink density, M_c and solute permeation with change in PMVE/MA content, thus suggesting a potential application in controlled drug‐delivery systems.     

聚谷氨酸-顺铂复合物的制备及其生物活性

本文介绍了制备一种γ-聚谷氨酸-顺铂复合物，并考察其体外的抗肿瘤活性。主要通过生物发酵法获得γ-聚谷氨酸，酸降解法得到小分子γ-聚谷氨酸；利用PCR方法检测γ-聚谷氨酸-顺铂复合物对DNA的作用；利用MTT法来检测该复合物的体外抗肿瘤作用；利用流式细胞仪检测其对细胞凋亡的作用；利用小鼠体内实验检测其体内毒性作用。实验结果表明：成功获得γ-聚谷氨酸-顺铂复合物，该复合物载药率达10%～12%；该复合物对人肝癌细胞BEL7404、人非小细胞肺癌细胞H446和人结肠癌细胞RKO均具有显著的杀伤作用，能引起细胞凋亡(出现凋亡峰)；并且小鼠体内毒性试验表明该聚谷氨酸-顺铂复合物的毒性要比游离顺铂低。因此，γ-聚谷氨酸-顺铂复合物是一种有效的抗肿瘤药物，具有潜在的临床应用价值；生物发酵的γ-聚谷氨酸可用于药物载体，赋予药物新的特点。     

Endocytosis and Interaction of Poly (Amidoamine) Dendrimers with Caco-2 Cells

Purpose To investigate the internalization and subcellular trafficking of fluorescently labeled poly (amidoamine) (PAMAM) dendrimers in intestinal cell monolayers. Materials and methods PAMAM dendrimers with positive or negative surface charge were conjugated to fluorescein isothiocyanate (FITC) and visualized for colocalization with endocytosis markers using confocal microscopy. Effect of concentration, generation and charge on the morphology of microvilli was observed using transmission electron microscopy. Results Both cationic and anionic PAMAM dendrimers internalized within 20 min, and differentially colocalized with endocytosis markers clathrin, EEA-1, and LAMP-1. Transmission electron microscopy analysis showed a concentration-, generation- and surface charge-dependent effect on microvilli morphology. Conclusion These studies provide visual evidence that endocytic mechanism(s) contribute to the internalization and subcellular trafficking of PAMAM dendrimers across the intestinal cells, and that appropriate selection of PAMAM dendrimers based on surface charge, concentration and generation number allows the application of these polymers for oral drug delivery.     

Synthesis and characterization of copolymers of methylmethacrylate and 2-hydroxyethyl methacrylate for the aqueous solubilization of Paclitaxel

The aim of the present work is the modification of a hydrophobic polymeric macromolecule, polymethylmethacrylate, by introducing hydrophilic moieties of 2-hydroxyethyl methacrylate within the polymer chain. Synthesis, characterization, and drug delivery control capabilities exerted on a highly hydrophobic drug (Paclitaxel) are illustrated. In particular, the dependency of the drug delivery kinetic on the fraction of hydrophilic units inserted in the copolymer chain was studied. Results showed that it is possible to have an increase of the kinetic delivery introducing hydrophilic units. In addition, a double control, diffusive and due to the relaxation of the molecules, on drug delivery was obtained.     

In vivo pharmacokinetic study for the assessment of poly(L-aspartic acid) as a drug carrier for colon-specific drug delivery

Glucocorticoids remain one of the mainstays of therapy for acute attacks of inflammatory bowel disease despite systemic side effects that limit their use. Prodrugs that selectively deliver glucocorticoids to the colon may lower the required dose and side effects. Because enzymes of gut microflora are able to cleave certain peptide and ester bonds, the ability of an ester prodrug consisting of dexamethasone (DX) as model drug and poly(L-aspartic acid) (weight-average mol wt=30,000) as drug carrier was investigated to selectively release the drug in the large intestine. Prodrug and drug solutions (1.18 mg DX/ml DMSO) were administered to two groups of male Sprague-Dawley rats by intragastric infusion using an ALZET^® osmotic pump. All rats were infused for sufficient time to achieve steady state in both blood and GI-tract tissues. DX concentrations in blood and tissue samples were measured with HPLC. The steady state DX concentrations at these sites were used to calculate a drug delivery index (DDI). DX blood concentrations were significantly lower (p<0.05) after intragastric administration of the prodrug. Moreover, prodrug administration resulted in significantly higher DX concentrations in the cecum and colon mucosa and the cecum muscle tissue compared to DX administration (p<0.05). The prodrug led to an increase of the DX concentration in the large intestinal tissues by factors of 1.3–2.0 and to an 1.3-fold decrease of DX blood concentrations. Thus, this novel conjugate should both increase efficacy and reduce toxicity to some extent.     

Effect of poly (ethylene oxide)‐poly (propylene oxide)‐poly (ethylene oxide) micelles on pharmacokinetics and intestinal toxicity of irinotecan hydrochloride: potential involvement of breast cancer resistance protein (ABCG2)

Objectives Intestinal toxicity and low levels of systemic drug exposure are among the major problems associated with tumour therapy. We have developed poly (ethylene oxide)‐poly (propylene oxide)‐poly (ethylene oxide) (PEO‐PPO‐PEO) micelles loaded with irinotecan hydrochloride (CPT‐11) hoping to decrease CPT‐11‐induced intestinal toxicity while increasing its systemic exposure. In addition, we have investigated the potential involvement of breast cancer resistance protein (BCRP) in biliary excretion, pharmacokinetics, and intestinal toxicity of CPT‐11. Methods PEO‐PPO‐PEO micelles were prepared using PEO₂₀‐PPO₇₀‐PEO₂₀ and lecithin. The effect of PEO‐PPO‐PEO micelles on BCRP‐mediated cellular accumulation and transport efflux of CPT‐11 was evaluated in MDCKII/BCRP cells. The biliary excretion, intestinal damage, and pharmacokinetic study of CPT‐11‐loaded PEO‐PPO‐PEO micelles were investigated in rats. Key findings The obtained micelles could effectively inhibit BCRP‐mediated CPT‐11 efflux in MDCKII/BCRP cells, and significantly decrease the drug biliary excretion in rats. Moreover, intestinal toxicity, assessed by microscopic examination of pathological damage, was ameliorated in rats injected with PEO‐PPO‐PEO micelles compared with rats injected with CPT‐11 alone. Treatment with PEO‐PPO‐PEO micelles resulted in prolonged circulation time in blood and increased bioavailability of CPT‐11 and SN‐38 (7‐ethyl‐10‐hydroxycamptothecin). Conclusions PEO‐PPO‐PEO micelles were identified as promising carriers able to reduce intestinal toxicity and increase antitumour therapeutic effect of CPT‐11. The study indicated a potential involvement of BCRP in CPT‐11 pharmacokinetics and CPT‐11‐induced intestinal toxicity.     

Natural and synthetic poly(malic acid)-based derivates: a family of versatile biopolymers for the design of drug nanocarriers

Abstract

The field of specific drug delivery is an expanding research domain. Besides the use of liposomes formed from various lipids, natural and synthetic polymers have been developed to prepare more efficient drug delivery systems either under macromolecular prodrugs or under particulate nanovectors. To ameliorate the biocompatibility of such nanocarriers, degradable natural or synthetic polymers have attracted the interest of many researchers. In this context, poly(malic acid) (PMLA) extracted from microorganisms or synthesized from malic or aspartic acid was used to prepare water-soluble drug carriers or nanoparticles. Within this review, both the preparation and the applications of PMLA derivatives are described emphasizing the in vitro and in vivo assays. The results obtained by several groups highlight the interest of such polyesters in the field of drug delivery.     

Direct Evidence That Polysorbate-80-Coated Poly(Butylcyanoacrylate) Nanoparticles Deliver Drugs to the CNS via Specific Mechanisms Requiring Prior Binding of Drug to the Nanoparticles

Purpose. It has recently been suggested that the poly(butylcyanoacrylate) (PBCA) nanoparticle drug delivery system has a generalized toxic effect on the blood-brain barrier (BBB) (8) and that this effect forms the basis of an apparent enhanced drug delivery to the brain. The purpose of this study is to explore more fully the mechanism by which PBCA nanoparticles can deliver drugs to the brain. Methods. Both in vivo and in vitro methods have been applied to examine the possible toxic effects of PBCA nanoparticles and polysorbate-80 on cerebral endothelial cells. Human, bovine, and rat models have been used in this study. Results. In bovine primary cerebral endothelial cells, nontoxic levels of PBCA particles and polysorbate-80 did not increase paracellular transport of sucrose and inulin in the monolayers. Electron microscopic studies confirm cell viability. In vivo studies using the antinociceptive opioid peptide dalargin showed that both empty PBCA nanoparticles and polysorbate-80 did not allow dalargin to enter the brain in quantities sufficient to cause antinociception. Only dalargin preadsorbed to PBCA nanoparticles was able to induce an antinociceptive effect in the animals. Conclusion. At concentrations of PBCA nanoparticles and polysorbate-80 that achieve significant drug delivery to the brain, there is little in vivo or in vitro evidence to suggest that a generalized toxic effect on the BBB is the primary mechanism for drug delivery to the brain. The fact that dalargin has to be preadsorbed onto nanoparticles before it is effective in inducing antinociception suggests specific mechanisms of delivery to the CNS rather than a simple disruption of the BBB allowing a diffusional drug entry.