环境感应型可生物降解药物控释系统的研究进展

环境感应型可生物降解药物控释系统具有智能化、效率高和使用方便等特点,在药物控制释放研究领域越来越受瞩目。本文基于国内外大量研究文献,对环境感应型可生物降解药物控释系统进行了综述,着重介绍了温度和pH敏感型可生物降解智能化高分子给药系统的研究进展。     

口服胰岛素载体的高分子生物材料

背景：利用具有生物相容性和生物可降解性的高分子材料作为载体,通过化学结合或物理包裹胰岛素,可提高胰岛素在体内的稳定性和生物利用度。 目的：从类型、制备方法、特征、药理作用等方面综述国内外口服胰岛素载体的高分子材料的研究进展。 方法：由作者应用计算机检索中国知网数据库、PubMed数据库和Elsevier 数据库2002年1月至2013年2月,与高分子生物材料和口服胰岛素载体相关的文章,中文关键词为“高分子生物材料、口服胰岛素、载体”,英文关键词为“polymeric biomaterials,oral insulin,carrier”。 结果与结论：目前,主要用于口服胰岛素系统控缓释的高分子生物材料可分为天然高分子生物材料和合成高分子生物材料两大类。用于口服胰岛素载体研究的天然高分子材料,以壳聚糖、藻酸盐多见。合成高分子生物材料中聚酯类、聚丙烯酸酯类及其共聚物,因具有良好的生物相容性、生物降解性和生理性能,被用作口服胰岛素制剂的载体材料的研究报道较多。国内外有关口服胰岛素制剂的研究报道虽多,也有一些商品型口服胰岛素进入临床试验阶段,但至今尚未见到实际应用的临床报告。其主要原因是作为载体的高分子材料、胰岛素的生物利用度低、制剂的质量标准及稳定性问题尚未解决。因此,未来的研究将主要集中在：载体材料的选择或者对现有高分子聚合物进行物理和化学的修饰,研发出新型的聚合物基材料作为载体,以避免胃肠道对胰岛素的破坏和改善胰岛素在体内的吸收,获得理想的释药速度和良好缓控释效果。     

短期胰岛素治疗新发Ⅱ型糖尿病的临床观察

目的观察短期胰岛素治疗对新发Ⅱ型糖尿病病人的胰岛β细胞功能和血糖控制的影响。方法采用自身前后对照，观察18例新诊断Ⅱ型糖尿病人接受短期胰岛素强化治疗前后血糖及C肽释放试验的变化，了解胰岛素治疗前后胰岛β细胞功能的变化。结果经短期胰岛素治疗后，患者血糖明显下降，各点C肽水平明显升高，且有高峰出现，胰岛β细胞功能有恢复。结论对明显高血糖的新发Ⅱ型糖尿病患者短期胰岛素治疗，能显著改善其胰岛β细胞功能，有利于以后长远控制好血糖。     

药用高分子材料智能控释系统的研究

药用高分子材料智能控制释放系统是利用智能高分子材料作为药物的载体，与药物一起构成高分子微包囊药物制剂或高分子纳米级包囊药物制剂，此制剂植入人体后，受外界环境的pH值、温度、化学物质、光、电、磁等的刺激，聚合物载体材料的自身性质会随之发生变化。由此可控制药物脉冲释放，从而达到药物控制智能化的目的。本文概述了药用高分子材料智能控释系统的制备及应用研究。     

温敏型智能化靶向式药物载体研究(II)——具有温敏开关的微囊

采用环境感应式微囊作为智能化靶向式药物载体 ,可以实现药物的定点、定时、定量控制释放。本文研究了膜孔内接枝聚异丙基丙烯酰胺 (PNIPAM)“开关”的温敏型控制释放微囊载体的制备 ,并对其进行了温度感应控释性能实验。实验中采用界面聚合法制备聚酰胺多孔微囊 ,然后利用等离子体接枝填孔聚合法将PNIPAM接枝在微囊壁的膜孔中。研究结果表明 ,这种接枝了PNIPAM“开关”的微囊具有温度感应特性 ,其利用膜孔内PNI PAM接枝链的膨胀 收缩特性实现了感温性控制释放。当环境温度低于PNIPAM的低临界溶解温度 (LCST)时 ,膜孔内PNIPAM分子链膨胀而使膜孔呈“关闭”状态 ,从而限制囊内溶质分子通过 ,于是释放速率慢 ;而当环境温度高于LCST时 ,PNIPAM分子链变为收缩状态而使膜孔“开启” ,为微囊内溶质分子的释放敞开通道 ,于是释放速率快。     

温敏型智能化靶向式药物载体研究(Ⅱ)-具有温敏开关的微囊

采用环境感应式微囊作为智能化靶向式药物载体，可以实现药物的定点、定时、定量控制释放。本文研究了膜孔内接枝聚异丙基丙烯酰胺(PNIPAM)“开关”的温敏型控制释放微囊载体的制备，并对其进行了温度感应控释性能实验。实验中采用界面聚合法制备聚酰胺多孔微囊，然后利用等离子体接枝填孔聚合法将PNIPAM接枝在微囊壁的膜孔中。研究结果表明，这种接枝了PNIPAM“开关”的微囊具有温度感应特性，其利用膜孔内PNIPAM接枝链的膨胀一收缩特性实现了感温性控制释放。当环境温度低于PNIPAM的低临界溶解温度(LCST)时，膜孔内PNIPAM分子链膨胀而使膜孔呈“关闭”状态，从而限制囊内溶质分子通过，于是释放速率慢；而当环境温度高于LCST时，PNIPAM分子链变为收缩状态而使膜孔“开启”，为微囊内溶质分子的释放敞开通道，于是释放速率快。     

医用高分子载体材料在抗肿瘤药物中的应用

背景:介绍医用高分子载体材料的种类及生物学特性,评价其在抗肿瘤药物中的应用。方法:用计算机检索中国期刊全文数据库(1990/2009)和Pubmed数据库(1990/2009),以"高分子材料,抗肿瘤药物,载体"或"polymer,anticancer drug,carrier"为检索词进行检索。纳入主题内容与医用高分子载体材料的生物学特性及其在抗肿瘤药物中的应用联系紧密的文章;排除Meta分析及重复性研究。结果:对文献进行筛选质量评价,共纳入24篇文章。从医用高分子载体材料的生物学特性及其在抗肿瘤药物中的应用进行总结。医用高分子载体材料是随着药物学研究、生物材料科学和临床医学的发展而新兴的给药技术。高分子材料优良的生物相容性、生物可降解性、降解速率的可调节性以及良好的可加工性能,都为药物制剂的创新提供了便利和可能。药物载体材料的结构,提高载药效率,以及它在体内的分布情况和生物降解性能、降解产物对机体的影响等问题都需要深入研究。抗肿瘤药物高分子载体的研究重点目前在于寻找选择性更强、疗效更好的载药材料。结论:医用高分子载体材料可以通过剂型改变,控制药物释放速度,从而使释放到体内的药物浓度比较稳定,还可以通过释放体系使药物送达体内特定部位,而对身体其他部位不起作用。     

胰岛素治疗46例2型糖尿病临床分析

目的 观察胰岛素治疗对2型糖尿病患者血糖控制的效果。方法：对46例2型糖尿病患者短期皮下注射胰岛素强化治疗后继续胰岛素联合口服降糖药物治疗，边用药、边监测血糖，观察用药7-14天，并跟踪半年。结果 血糖达到理想控制状态，胰岛素治疗后患者的空腹血糖、餐后2小时血糖、HbA，C明显低于治疗前，P〈0．01。其中7例只需饮食、运动治疗便可获得良好的血糖控制。结论 2型糖尿病患者在糖尿痛教育、饮食控制、运动疗法、监测血糖的基础上，通过适当的胰岛素治疗，其病情均可得到良好的控制，并保护健存的胰岛B细胞功能，且副作用轻微。     

维生素K对糖代谢的影响

近期研究显示维生素K在控制血糖方面能起到积极的作用.摄入较低剂量维生素K1的小鼠比高维生素K1饮食的小鼠血糖高,且其胰岛素的释放高峰较后者延迟.临床试验也证实健康年轻男性短时间补充维生素K能改善胰岛素的作用及促进外周组织对血糖的代谢.对于维生素K影响血糖代谢的潜在机制尚未完全明了,但近期研究显示可能与骨钙素活性有关.     

2型糖尿病三种胰岛素治疗方法的比较

目的 观察三种胰岛素治疗方法对新发2型糖尿病病人的胰岛β 细胞功能和血糖控制的影响。方法将94例新诊断2型糖尿病人随机分为三组，进行诺和灵R胰岛素泵持续皮下输注治疗（A组，CSⅡ组）、诺和灵R联合诺和灵N（低精蛋白锌人胰岛素）每天多次皮下注射治疗（B组，MSⅡ组）和诺和灵30R每天2次预混胰岛素注射治疗（c组），比较治疗2周后血糖控制水平、胰岛素的分泌、日均胰岛素用量、低血糖发生率及日均费用。探讨3种不同胰岛素治疗方法对2型糖尿病的降糖作用。结果A、B两组患者治疗2周后血糖控制水平、胰岛素的分泌、血糖达到良好控制的时间，日均胰岛素用量，低血糖的发生均优于C组（P〈0．01）。A、B两组血糖控制水平，胰岛素的分泌无差异，而血糖达到良好控制的时间及日均胰岛素用量，A组优于B两组。日均费用B组则明显低于A组。结论 胰岛素泵强化治疗和胰岛素多点注射强化治疗都可以使初诊2型糖尿病患者的胰岛细胞功能和血糖得到同样程度的改善，胰岛素泵具有更加快速、稳定、安全性好的作用，胰岛素多点注射则具有治疗费用相对较低的优点。     

The influence of arrangement sequence on the glucose-responsive controlled release profiles of insulin-incorporated LbL films

Insulin, glucose oxidase and positively charged star polymers were incorporated into multilayer films by the layer-by-layer (LbL) assembly method. It is interesting to find that the arrangement sequence of the three components could significantly affect the glucose-responsive controlled release behaviors. The insulin release in vitro could be tuned to linear release and obtain desired “on–off” sensitivity in response to stepwise glucose challenge, just by rearranging the assembly sequence of LbL building blocks. Further, the controlled release of insulin in vivo, as well as the hypoglycemic effect, could be obviously prolonged from 17 days to 36 days by this simple strategy without changing the dosage of all the LbL components. In addition to provide a potential glucose-responsive delivery system for insulin, the strategy described in this paper could be valuable for various drug-incorporated LbL systems with three or more components.     

The effect of degree of acrylic derivatisation on dextran and concanavalin A glucose-responsive materials for closed-loop insulin delivery

Formulations of dextran methacrylate (dex-MA) and concanavalin A methacrylamide (con A-MA) were photo-polymerized to produce covalently cross-linked glucose-responsive materials for the basis of a closed-loop insulin delivery device. The viscoelastic properties of these polymerised materials were tested rheologically in the non-destructive oscillatory mode within the linear viscoelastic range at glucose concentrations between 0% and 5% w/w. The degree of acrylic substitution was varied for the dex-MA and con A-MA, and as the formulation glucose concentration was raised, a graded decrease in storage modulus, loss modulus and complex viscosity when compared at 1 Hz was observed for each cross-linked material. Increasing the degree of substitution (DS) of the derivatised dextran produced viscosity profiles at higher values throughout the glucose concentration range. A comparison with non-polymerised mixtures shows similar rheological properties but at much lower values across the chosen glucose concentration range. High-pressure liquid chromatography analyses and in vitro diffusion experiments showed that there were optimum degrees of derivatisation to minimise dex-MA and con A-MA component leach from the material. The in vitro diffusion experiments also showed that differential delivery of insulin in response to glucose was possible with candidate polymerised glucose-responsive formulations, thus highlighting the potential of such a novel glucose-sensitive material to be used as part of implantable closed-loop insulin delivery device.     

Glucose-responsive UV polymerised dextran-concanavalin A acrylic derivatised mixtures for closed-loop insulin delivery

A novel UV polymerised glucose-responsive mixture containing concanavalin A (con A) and dextran was synthesised and characterised as a "smart" biomaterial to form the basis of a closed-loop delivery device. Dextran and con A precursors were modified with acrylic side groups and then UV polymerised to produce covalently bonded mixtures which were examined by FTIR. The viscoelastic properties of these polymerised mixtures containing glucose concentrations between 0% and 5% w/w were also examined using oscillatory rheometry within the linear viscoelastic range across a frequency range of 0.01-50 Hz. As the formulation glucose concentration was raised, a graded decrease in storage modulus, loss modulus and complex viscosity when compared at 1 Hz was observed. Increasing the mixture irradiation time produced viscosity profiles at higher values throughout the glucose concentration range. The subsequent testing of such formulations in in vitro diffusion experiments revealed that the leaching of the mixture components is formulation dependent and is restricted significantly in the covalently bonded mixtures. Insulin delivery in response to glucose in the physiologically relevant glucose concentration range was demonstrated using the novel polymerised mixture at 37 degrees C. The performance of this covalently cross-linked glucose-responsive biomaterial has been improved in terms of increased mixture stability with reduced component leaching. This could, therefore be used as the basis of the design of a closed-loop drug delivery device for therapeutic agents used for the management of diabetes mellitus.     

A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery

Success in the oral delivery of therapeutic insulin can significantly improve the quality of life of diabetic patients who must routinely receive injections of this drug. However, oral absorption of insulin is limited by various physiological barriers and remains a major scientific challenge. Various technological solutions have been developed to increase the oral bioavailability of insulin. Having received considerable attention, nano-sized polymeric particles are highly promising for oral insulin delivery. This review article describes the gastrointestinal barriers to oral insulin delivery, including chemical, enzymatic and absorption barriers. The potential transport mechanisms of insulin delivered by nanoparticles across the intestinal epithelium are also discussed. Finally, recent advances in using polymeric nanoparticles for oral insulin delivery and their effects on insulin transport are reviewed, along with their future.     

Self-assembled molecular structures as ultrasonically-responsive barrier membranes for pulsatile drug delivery

Noninvasive ultrasound has been shown to increase the release rate on demand from drug delivery systems; however, such systems generally suffer from background drug leaching. To address this issue, a drug-containing polymeric monolith coated with a novel ultrasound-responsive coating was developed. A self-assembled molecular structure coating based on relatively impermeable, ordered methylene chains forms an ultrasound-activated on-off switch in controlling drug release on demand, while keeping the drug inside the polymer carrier in the absence of ultrasound. The orderly structure and molecular orientation of these C12 n-alkyl methylene chains on polymeric surfaces resemble self-assembled monolayers on gold. Their preparation and characterization have been published recently (Kwok et al. [Biomacromolecules 2000;1(1):139-148]). Ultrasound release studies showed that a copolymer of 2-hydroxyethyl methacrylate and ethylene glycol dimethacrylate (MW 400) coated with such an ultrasound-responsive membrane maintained sufficient insulin for multiple insulin delivery, compared with a substantial burst release during the first 2 h from uncoated samples. With appropriate surface coating coverage, the background leach rate can be precisely controlled. The biological activity of the insulin releasate was tested by assessing its ability to regulate [C14]-deoxyglucose uptake in 3T3-L1 adipocyte cells in a controlled cell culture environment. Uptake triggered by released insulin was comparable to that of the positive insulin control. The data demonstrate that the released insulin remains active even after the insulin had been exposed to matrix synthesis and the methylene chain coating process.     

纳米粒子作为药物输送和药物控释体系的应用前景

纳米粒子作为药物和基因的载体显现出极大的潜力并被广泛研究。纳米粒子的超微小体积可使药物输送智能化,例如靶向定位地将药物投递到病灶局部或专一性地作用于靶细胞。纳米粒子的载体材料可屏蔽药物不良气味、维持药物长期缓慢释放、延长药物半衰期和减小毒副作用等。本文将从纳米药物输送、控释制剂的制备和应用前景等方面进行综述。     

Optimization of pharmaceutical formulations for therapy

A pharmaceutical formulation is aimed at ensuring drug delivery at the site of action in order to produce the desired therapeutic effect. The design of a pharmaceutical formulation must reflect the chemical reactivity of the drug substance as well as those of any other substances that are used in the formulation. Standardized manufacturing procedures that conform to accepted codes of Good Manufacturing Practices are prerequisites for the preparation of pharmaceutical formulations for optimal drug delivery. Drug formulations produced by such methods are expected to have the desired bioavailability characteristics for pharmacotherapy. The different types of pharmaceutical formulations usually prepared for administration by various routes are aimed at achieving the most appropriate drug delivery system for each drug. When necessary, special drug delivery systems are designed to achieve this objective. Advances in biotechnology has led to production of labile substances for use as drugs in therapy and this has created new challenges in the development of novel drug delivery systems. The sublingual, buccal, nasal and oropharyngeal routes of drug delivery have become of great interest in the delivery of bioactive peptides like insulin and interferons and pharmaceutical formulations have to be designed to meet such challenges. Of no less importance are the traditional herbal preparations whose formulation strategies have been much less understood and their therapeutic significance underestimated. Greater interest in, and investment on research on these herbal preparations will open new avenues for pharmacotherapy.     

Characterization of glucose-sensitive insulin release systems in simulated in vivo conditions

We studied the glucose-responsive insulin controlled release system based on the hydrogel poly(2-hydroxyethyl methacrylate-co-N,N-dimethylaminoethyl methacrylate), also called poly(HEMA-co-DMAEMA), with entrapped glucose oxidase, catalase and insulin. When exposed to physiological fluids, glucose diffuses into the hydrogel, glucose oxidase catalyzes the glucose conversion to gluconic acid, causing swelling of the pH-sensitive hydrogel and subsequently increased insulin release. The higher the glucose concentration in the medium, the higher and faster the swelling and release rates. The effects of polymer morphology and oxygen availability on hydrogel swelling and on insulin release kinetics were tested. Polymer morphology was modified by changing the crosslinking agent (tetraethylene glycol dimethacrylate) concentration (0-0.95 vol%). Oxygen availability was modified by changing the immobilized catalase concentration (0-15 units catalase per unit glucose oxidase) and by bubbling oxygen through the medium. The results indicated that: (i) Hydrogels without crosslinking agent were found to be stable in water, and their sensitivity to pH and glucose was higher than the chemically crosslinked hydrogels. (ii) Immobilization of catalase in addition to glucose oxidase in hydrogels prepared without crosslinking agent, resulted in enhanced swelling kinetic. In addition, we carried out primary in vivo experiments on rats, which demonstrated that at least some of the entrapped insulin retains its active form and is effective in reducing blood glucose levels. Moreover, no tissue encapsulation was observed around matrices implanted in the peritoneum. In conclusion, the pH-sensitive hydrogel poly(HEMA-co-DMAEMA) can be manipulated to produce glucose-responsive insulin release system that is effective in reducing blood glucose levels.