壳聚糖作为药物缓释载体的应用及进展

壳聚糖是一种天然聚氨基葡萄糖，也是一种安全无毒、可生物降解的天然高分子，不但具有生物相容性，而且具有抗茵、止血、抑制癌细胞转移等作用，具有优良的生物降解性能和生物亲和性。简单介绍了壳聚糖的性能及作为药物缓释载体的生物学特点，并简要综述了其作为缓释载体的类型及研究应用。     

壳聚糖水凝胶的制备及其在药物释放中的应用

水凝胶作为性能良好的载体,在药物的控释、组织工程等领域有着广泛的应用。壳聚糖是一类天然的带正电荷的碱性多糖,由其形成的水凝胶具有较好的生物相容性、生物降解性、抗菌和低细胞毒性,因此,壳聚糖水凝胶有着良好的生物应用前景。本文综述了壳聚糖水凝胶的制备方法(包括物理交联法和化学交联法),在物理交联法部分着重介绍了离子化合物及聚电解质分子与壳聚糖通过离子交联形成水凝胶,以及利用分子链间的疏水作用形成壳聚糖水凝胶的方法;而在化学交联法部分介绍了合成壳聚糖水凝胶的化学手段,包括交联剂、光照辐射和酶的使用。继而概述了壳聚糖水凝胶在药物缓释应用方面的研究进展,包括温度、pH值和电场响应的药物控释体系。最后展望了壳聚糖水凝胶未来的发展前景。     

壳聚糖微球的制备及其在药物载体中的应用

壳聚糖因其具有良好的生物学特性而成为药物载体研究的热点。药物经壳聚糖负载后,不仅能够达到缓释控释的目的,还能够改变药物的给药方式,降低药物不良反应,提高药物生物利用度。本文就壳聚糖微球的制备及其在药物载体中的应用作一综述。     

壳聚糖作为药物缓释载体的应用及进展

壳聚糖是一种天然聚氨基葡萄糖,也是一种安全无毒、可生物降解的天然高分子,不但具有生物相容性,而且具有抗菌、止血、抑制癌细胞转移等作用,具有优良的生物降解性能和生物亲和性。简单介绍了壳聚糖的性能及作为药物缓释载体的生物学特点,并简要综述了其作为缓释载体的类型及研究应用。     

共同的选择——通过喷雾干燥来提高药物的生物药效率及实现可控制的释放

近来，对于许多定量给药的药物来说，将药效好但溶解性差的药物制成可控释放药物及提高药物的生物药效率变得极其重要。本文着重介绍使用喷雾干燥技术来生产可控释放及／或高药物生物药效率的产品。     

静电喷雾法制备羧甲基纤维素/壳聚糖液芯微胶囊

以羧甲基纤维素(CMC)和壳聚糖(CS)聚合物为原料,采用静电喷雾技术制备了CMC/CS液芯微胶囊。研究了制备条件对微胶囊成型和尺寸的影响,并用激光扫描共聚焦显微镜、扫描电子显微镜和倒置显微镜进行了表征。将四环素与CMC溶液共混,以Al3+-CS作为凝固浴,在电压10 kV、液面距离20 mm、流速10 mL/h的条件下,制备了载药微胶囊。微胶囊的药物包封率随壳聚糖浓度增大而提高,在1.5%时达到99.5%。药物释放实验结果表明CMC/CS液芯微胶囊的释放率与pH有关,控释性能良好。     

自组装囊泡的结构与单分子膜的性质

研究了具有不同主链分子量和侧链长度的N，N-双烷基化壳聚糖单分子膜的性质．结果表明，主链分子量越大，所形成的N，N-双烷基壳聚糖单分子膜的结构越紧密．在主链分子量相同的条件下，N，N-双烷基壳聚糖单分子膜的致密度随着侧链长度的增大而增大，表明N，N-双烷基化壳聚糖分子间的缠结嵌套和疏水相互作用力的增大．比较N，N-双烷基化壳聚糖单分子膜与相应自组装囊泡的性质发现，囊泡的药物平衡释放率随着其相应材料单分子膜压缩模量的增大而减小，呈现出一定的线性关系．单分子膜压缩模量的大小反映囊泡膜结构的紧密程度．     

聚氨基酸复合微胶囊对Hb的控制释放

以生物相容性好、价格低廉的海藻酸钠(ALG)为聚阴离子芯材,通过静电液滴装置制备了平均粒径在290 μm左右、球形度好、表面光洁的海藻酸钙胶珠;再将生物可降解、具有介入治疗作用的聚精氨酸(PLA)与聚组氨酸(PLH)的混合物作为聚阳离子壁材,在海藻酸钙胶珠表面覆上一层高分子聚合膜以制备聚氨基酸复合微胶囊;并以牛血红蛋白Hb为药物模型,对微胶囊的控制释放性能进行了考察并将其初步应用于体外模拟口服给药。结果表明:聚氨基酸复合微胶囊在前0.5 h的累积释放量均低于40％,溶出结束时累积释放量均达到80%以上;ALG/(PLA-PLH)复合微胶囊和ALG/PLH微胶囊的药物释放速率均低于ALG/PLA微胶囊;于10 min成膜时间内制备的微胶囊具有较高的载药量、包封率和缓释性能;以pH 4.6 HAc-NaAc缓冲液为成膜溶媒制备的微胶囊,Hb持续释放时间和残留量均高于蒸馏水组;前2 h在模拟胃液的pH 1.2 HCl溶媒中累计释放的Hb不超过10％且绝大部分是在模拟肠液环境即pH 6.8 PBS 溶媒中释放的;壳聚糖的引入能在一定程度上延长药物释放时间。聚氨基酸复合微胶囊具备一定的缓释性、pH响应性和生理黏附性,有望成为一种口服给药系统用药物载体。      

不同材料包裹的肝素缓释微囊生物相容性评价

制备了三种包覆材料不同的肝素微胶囊，研究了它们的缓释速度。然后把三种肝素微量与聚乳酸制成复合材料，研究其生物相容性，结果表明，胶囊中壳聚糖的加入使微量的释放速度变慢。三种微囊与PLA的复合材料经皮肤刺激试验、皮内刺激试验、热原试验、全身急性毒性试验和细胞培养试验，结果表明，所制备的复合材料在生物学评价试验中均星阴性反应，材料无明显毒性，材料中不存在潜在致敏性物质，所合热原含量符合生物体的要求。肝素缓释微胶囊／PLA复合材料符合三维多孔材料的要求，又具有优良的生物相容性。     

生物相容壳聚糖/蒙脱土复合微球的溶胀与药物缓释性能研究

利用反相乳液聚合法制备出具有良好生物相容性的壳聚糖/蒙脱土复合微球,其中改性蒙脱土作为插层改性剂引入。用X射线衍射和红外光谱分析了改性蒙脱土的结构,以阿司匹林为模型药物,以药物包埋法制备出了壳聚糖/蒙脱土载药微球,并对其缓释性能进行探讨。结果表明,改性蒙脱土的层间距变大,随着蒙脱土含量的增大,复合微球的溶胀率降低,释药率逐渐减小,pH值为1.2下的壳聚糖/蒙脱土载药微球的释药模式为Fickian扩散类型,pH值为7.4下的释药模式为non-Fickian扩散,壳聚糖/蒙脱土复合微球作为药物载体很有潜力。     

Spray-Dried Chitosan as a Direct Compression Tableting Excipient

The objective of this study was to prepare and evaluate a novel spray-dried tableting excipient using a mixture of chitosan and lactose. Three different grades of chitosan (low-, medium-, and high-molecular-weight) were used for this study. Propranolol hydrochloride was used as a model drug. A specific amount of chitosan (1, 1.9, and 2.5 g, respectively) was dissolved in 50 mL of an aqueous solution of citric acid (1%) and later mixed with 50 mL of an aqueous solution containing lactose (20, 19.1, and 18.5 g, respectively) and propanolol (2.2 g). The resultant solution was sprayed through a laboratory spray drier at 1.4 mL/min. The granules were evaluated for bulk density, tap density, Carr index, particle size distribution, surface morphology, thermal properties, and tableting properties. Bulk density of the granules decreased from 0.16 to 0.13 g/mL when the granules were prepared using medium- or high-molecular-weight chitosan compared with the low-molecular-weight chitosan. The relative proportion of chitosan also showed a significant effect on the bulk density. The granules prepared with 1 g of low-molecular-weight chitosan showed the minimum Carr index (11.1%) indicating the best flow properties among all five formulations. All three granules prepared with 1 g chitosan, irrespective of their molecular weight, showed excellent flow properties. Floating tablets prepared by direct compression of these granules with sodium bicarbonate showed 50% drug release between 30 and 35 min. In conclusion, the spray-dried granules prepared with chitosan and lactose showed excellent flow properties and were suitable for tableting.     

Spray-dried chitosan as a direct compression tableting excipient

The objective of this study was to prepare and evaluate a novel spray-dried tableting excipient using a mixture of chitosan and lactose. Three different grades of chitosan (low-, medium-, and high-molecular-weight) were used for this study. Propranolol hydrochloride was used as a model drug. A specific amount of chitosan (1, 1.9, and 2.5 g, respectively) was dissolved in 50 mL of an aqueous solution of citric acid (1%) and later mixed with 50 mL of an aqueous solution containing lactose (20, 19.1, and 18.5 g, respectively) and propanolol (2.2 g). The resultant solution was sprayed through a laboratory spray drier at 1.4 mL/min. The granules were evaluated for bulk density, tap density, Carr index, particle size distribution, surface morphology, thermal properties, and tableting properties. Bulk density of the granules decreased from 0.16 to 0.13 g/mL when the granules were prepared using medium- or high-molecular-weight chitosan compared with the low-molecular-weight chitosan. The relative proportion of chitosan also showed a significant effect on the bulk density. The granules prepared with 1 g of low-molecular-weight chitosan showed the minimum Carr index (11.1%) indicating the best flow properties among all five formulations. All three granules prepared with 1 g chitosan, irrespective of their molecular weight, showed excellent flow properties. Floating tablets prepared by direct compression of these granules with sodium bicarbonate showed 50% drug release between 30 and 35 min. In conclusion, the spray-dried granules prepared with chitosan and lactose showed excellent flow properties and were suitable for tableting.     

The Effect of Chitosan Molecular Weight on the Characteristics of Spray-Dried Methotrexate-Loaded Chitosan Microspheres for Nasal Administration

In this article, the effect of the chitosan molecular weight (MW) on the characteristics of methotrexate (MTX)-encapsulated non-cross-linked chitosan microspheres was studied. Microspheres composed of low-molecular-weight (LMW, 40,000 Da), medium-molecular-weight (MMW, 480,000 Da) and high-molecular-weight (HMW, 850,000 Da) chitosan with the same degree of deacetylation (96%) were obtained by a simple spray-drying method. The MW of chitosan had a noticeable influence on the size distribution, encapsulation efficiency, micromeritic properties (angle of repose and bulk density), controlled release behavior, and mucoadhesive properties. The entrapment efficiencies were in the range of 90–99%. Spray-dried microspheres had a D₅₀ value of 3.3–4.9 μm, which was suitable for nasal insufflations. The microspheres with LMW chitosan have the best flowability and highest bulk density but were found to be poor in terms of adhesion and in controlling the release behavior of MTX. The MMW chitosan microspheres exhibited the strongest adhesion to the mucosal surface, and the angle of repose values were between 34 and 47 degrees. They could control the release rate by modifying the drug/polymer ratios. Microspheres with HMW chitosan exhibited a lower adhesion than MMW chitosan and a lower release rate of MTX. The physical state of MTX in the chitosan matrix was studied by differential scanning calorimetry, which indicated the presence of a solid dispersion of the amorphous drug in the chitosan matrix. Nasal ciliotoxity showed only minor cilia irritation due to the microspheres, and consequently, they are suitable for nasal drug delivery.     

The effect of chitosan molecular weight on the characteristics of spray-dried methotrexate-loaded chitosan microspheres for nasal administration

In this article, the effect of the chitosan molecular weight (MW) on the characteristics of methotrexate (MTX)-encapsulated non-cross-linked chitosan microspheres was studied. Microspheres composed of low-molecular-weight (LMW, 40,000 Da), medium-molecular-weight (MMW, 480,000 Da) and high-molecular-weight (HMW, 850,000 Da) chitosan with the same degree of deacetylation (96%) were obtained by a simple spray-drying method. The MW of chitosan had a noticeable influence on the size distribution, encapsulation efficiency, micromeritic properties (angle of repose and bulk density), controlled release behavior, and mucoadhesive properties. The entrapment efficiencies were in the range of 90-99%. Spray-dried microspheres had a D(50) value of 3.3-4.9 microm, which was suitable for nasal insufflations. The microspheres with LMW chitosan have the best flowability and highest bulk density but were found to be poor in terms of adhesion and in controlling the release behavior of MTX. The MMW chitosan microspheres exhibited the strongest adhesion to the mucosal surface, and the angle of repose values were between 34 and 47 degrees. They could control the release rate by modifying the drug/polymer ratios. Microspheres with HMW chitosan exhibited a lower adhesion than MMW chitosan and a lower release rate of MTX. The physical state of MTX in the chitosan matrix was studied by differential scanning calorimetry, which indicated the presence of a solid dispersion of the amorphous drug in the chitosan matrix. Nasal ciliotoxity showed only minor cilia irritation due to the microspheres, and consequently, they are suitable for nasal drug delivery.     

Chitosan and alginate polyelectrolyte complex membranes and their properties for wound dressing application

This study investigated the characteristics and drug release properties of membranes of chitosan and alginate prepared via a casting/solvent evaporation technique. Membranes of chitosan and alginate with silver sulfadiazine as model drug incorporated in different concentrations and different membrane compositions were obtained. The polyblend solution viscosity reached to the highest at the composition polyblends of (1:1). This chitosan/alginate membranes showed pH- and ionic strength-dependent water uptake properties and had the WVTR rang from 442 to 618 g/m²/day. The maximum value of the dry membrane of breaking strength was 52.16 MPa and the maximum value of the wet membrane breaking elongation was 46.28%. The results of controlled release studies showed that the silver sulfadiazine release rate was the fastest when the alginate content was 50%. On the basis of the requisite physical properties, the chitosan–alginate PEC membrane can be considered for potential wound dressing or controlled release application.     

Alginate-crosslinked chitosan scaffolds as pentoxifylline delivery carriers

To prevent fibrous encapsulation of implants, measures are taken to suppress inflammatory reactions around them. Sustained anti-inflammatory drug release from the scaffolds can potentially be a way to reduce inflammation around these implants. Alginate-crosslinked chitosan is often used to make biocompatible tissue engineered scaffolds. However, there is a lack of quantitative studies on the drug delivery properties of alginate-crosslinked chitosan scaffolds. For this study, chitosan, crosslinked with different concentrations of alginate, was made into porous scaffolds. Infrared and thermal gravimetric analyses showed polyelectrolyte complex formation between chitosan and alginate units. The alginate-crosslinked chitosan scaffolds were more hydrophilic, showed less swelling, had lower pentoxifylline (PTX) release efficacies, were more favorable for initial cell attachment, and were mechanically stronger and more resistant to enzymatic degradation when compared to non-crosslinked chitosan scaffolds. The differences became more significant as the concentrations of chitosan and alginate increased. Furthermore, in vitro tests showed that when PTX was slowly released from the scaffolds, it became more effective in suppressing the production of TNF-α and IL-6 by stimulated macrophage cells.     

Controlled release of drug from folate-decorated and graphene mediated drug delivery system: Synthesis,loading efficiency,and drug release response

A novel folate-decorated and graphene mediated drug delivery system was prepared that involves uniquely combining graphene oxide (GO) with anticancer drug for controlled drug release. The nanocarrier system was synthesized by attaching doxorubicin (DOX) to graphene oxide via strong π–π stacking interaction, followed by encapsulation of graphene oxide with folic acid conjugated chitosan. The π–π stacking interaction, simplified as a non-covalent type of functionalization, enables high drug loading and subsequent controlled release of the drug. The encapsulated graphene oxide enhanced the stability of the nanocarrier system in aqueous medium because of the hydrophilicity and cationic nature of chitosan. The loading and release of DOX indicated strong pH dependence and imply hydrogen-bonding interaction between graphene oxide and DOX. The proposed strategy is advantageous in terms of targeted drug delivery and has high potential to address the current challenges in drug delivery. Thus, the prepared nanohybrid system offers a novel formulation that combines the unique properties of a biodegradable material, chitosan, and graphene oxide for biomedical applications.     

Implantable biodegradable sponges: effect of interpolymer complex formation of chitosan with gelatin on the release behavior of tramadol hydrochloride

The effect of interpolymer complex formation between positively charged chitosan and negatively charged gelatin (Type B) on the release behavior of tramadol hydrochloride from biodegradable chitosan-gelatin sponges was studied. Mixed sponges were prepared by freeze-drying the cross-linked homogenous stable foams produced from chitosan and gelatin solutions where gelatin acts as a foam builder. Generation of stable foams was optimized where concentration, pH of gelatin solution, temperature, speed and duration of whipping process, and, chitosan-gelatin ratio drastically affect the properties and the stability of the produced foams. The prepared sponges were evaluated for their morphology, drug content, and microstructure using scanning electron microscopy, mechanical properties, uptake capacity, drug release profile, and their pharmacodynamic activity in terms of the analgesic effect after implantation in Wistar rats.

It was revealed that whipping 7% (w/w) gelatin solution, of pH 5.5, for 15 min at 25°C with a stirring speed of 1000 rpm was the optimum conditions for stable gelatin foam generation. Moreover, homogenous, uniform chitosan-gelatin foam with small air bubbles were produced by mixing 2.5% w/w chitosan solution with 7% w/w gelatinsolution in 1:5 ratio. Indeed, polyionic complexation between chitosan and gelatin overcame the drawbacks of chitosan sponge mechanical properties where, pliable, soft, and compressible sponge with high fluid uptake capacity was produced at 25°Cand 65% relative humidity without any added plasticizer. Drugreleasestudies showed a successful retardation of the incorporated drug where the t_50% values of the dissolution profiles were 0.55, 3.03, and 4.73 hr for cross-linked gelatin, un-cross-linked chitosan-gelatin, and cross-linked chitosan-gelatin sponges, respectively. All the release experiments followed Higuchi's diffusion mechanism over 12 hr. The achieved drug prolongation was a result of a combined effect of both cross-linking and polyelectrolyte complexation between chitosan and gelatin. The analgesic activity of the implanted tramadol hydrochloride mixed chitosan-gelatin sponge showed reasonable analgesic effect that was maintained for more than 8 hr. Therefore, the use of chitosan and gelatin together appears to allow the formulator to manipulate both the drug release profiles and the mechanical properties of the sponge that could be effectively implanted.