基于β-环糊精接枝聚L-谷氨酸星型聚合物的可注射水凝胶的制备与表征

采用Gadelle-Defaye法制备了全-6-氨基-β-环糊精[β-CD-(NH2)7],并用"Grafting-from"接枝法得到不同分子量的星型结构β-环糊精-g-聚L-谷氨酸(β-CD-g-PLGA).对β-CD-g-PLGA进行酰肼化改性后与醛基化海藻酸钠(ALG-CHO)通过席夫碱交联反应制备β-CD-g-PLGA/ALG水凝胶.研究了前驱体浓度以及β-CD-gPLGA分子量对β-CD-g-PLGA/ALG水凝胶性能的影响,并以疏水性辛伐他汀(SIM)为模型药物,研究了水凝胶对SIM的控制释放行为.     

β-环糊精交联聚丙烯酸水凝胶的合成及其药物控制释放研究

采用1,3-二环己基碳化二亚胺(DCC)为缩合剂,通过β环糊精与丙烯酸的酯化反应合成了不同取代度的丙烯酸β环糊精酯(βCD6A),以此为单体与丙烯酸通过氧化还原自由基引发聚合,合成出了不同交联密度和不同环糊精含量的新型水凝胶(AAβCD6A).溶胀实验表明,该类水凝胶均具有pH敏感性,溶胀动力学实验进一步对其机理进行了探讨.选择苯丁酸氮芥(CHL)作为模型药物,考察了不同pH下AAβCD6A水凝胶对药物释放行为的影响.结果表明,pH=6.8时药物释放率均大于pH=2.0时药物释放率,环糊精的存在表现出促释作用.     

The screening and evaluating of chitosan/β-cyclodextrin nanoparticles for effective delivery mitoxantrone hydrochloride

The complex of chitosan and β-cyclodextrin (CS-CMβ-CD) has been widely used as drug carrier because it binds the advantages of GCH and β-CDs. But further investigation is still needed to improve their delivery performance before CS-β-CD derivatives can be used as clinical cancer-drug carriers. The aim of the study is to screen suitable carriers of the deviants of chitosan and β-cyclodextrin by evaluating the delivery performance of several carriers towards anticancer drugs. Three kinds of GCS _n -CM _m β-CD polymers made of different amount of glycol chitosan (GCS) and carboxymethyl-β-cyclodextrin (CMβ-CD) were synthesized and GCS_7.5-CM_3-7β-CD was chosen to deliver the drugs due to its better properties. GCS_7.5-CM_3-7β-CD polymers have better cell adhesion performance than GCS, help to directional drug delivery. Then, mitoxantrone hydrochloride (MAH) was used as a model drug to evaluate the loading and releasing properties of GCS_7.5-CM_3-7β-CD polymers. GCS_7.5-CM_3-7β-CD polymers could encapsulate MAH with higher loading efficiency and provide pH sensitive MAH release. The amount of MAH released in acidic medium (pH 5.0) was greater than that in weakly basic medium (pH 7.4). The MAH-loaded nanoparticles shows similar inhibition ability as free MAH to HCT116 cell lines, indicate that MAH can be release from the carrier and kill the cancer cells. In addition, the blank GCS_7.5-CM_3-7β-CD nanoparticles show good biocompatibility to the cell. That is to say, GCS_7.5-CM_3-7β-CD polymers not only have the ability to targeting drug delivery but also can realize pH sensitive release, which make them perspective in cancer pharmaceutical application.     

Formulation and evaluation of gel containing nanostructured lipid carriers of tretinoin–Epi-β-CD binary complex for topical delivery

The objective of present research work was to formulate and evaluate topical gel containing tretinoin–cyclodextrin (CD) binary complex loaded into nanostructured lipid carriers (NLCs). Use of cyclodextrin and nanolipid carrier together in a system produced a synergistic effect by increasing the drug release and skin permeation, thus improving the overall therapeutic effect. Two different cyclodextrins i.e. β-CD and its water soluble polymeric derivative epichlorohydrin-β-cyclodextrin (EPI-β-CD) were used to obtain binary inclusion complex of drug-cyclodextrin (D-CD) systems by two different techniques (kneading and co-evaporation). The prepared solid complexes were characterized by FTIR, DSC, XRD etc. and the best system was selected for loading into nanolipid carriers. NLC comprising glyceryl mono stearate (GMS) and oleic acid were obtained by slightly modified emulsification evaporation method. Four different formulations of NLCs were suitability characterized for particle size, zeta potential, entrapment efficiency, drug loading and drug release. EPI-β-CD was found to be more effective than β-CD in enhancing solubility and dissolution properties of tretinoin. The most effective NLC formulation was incorporated into carbopol hydrogel which showed better permeation properties than that of the reference gel (0.1%).     

Synthesis and Characterization of Chitosan-Albumin Conjugates as pH-Sensitive Biodegradable Hydrogels

A new kind of biodegradable pH-sensitive drug delivery system was developed via chitosan-albumin conjugate hydrogel. Through changing the feeding modes of reactants, two types of hydrogels(comb-type and reticular-type) were synthesized by amidation reactions between 6-O-succinoylated N-phthaloyl chitosan and albumin. The structures and morphologies of the hydrogels were characterized by SEM. And their water swelling capacity, drug loading and releasing properties at different pH values were also investigate...     

Synthesis and characterization of a novel hydroxypropyl chitosan-graft-β-Cyclodextrin copolymer as potential drug carrier

Abstract

One of the most attractive fields in drug delivery is the design of nanoparticles that could be used to transport drugs into the target place at appropriate time. This paper describes the preparation of a novel hydroxypropyl chitosan-graft-β-cyclodextrin (HPCS-g-β-CD) copolymer using the 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) promoted condensation reaction. Structural characterization was finished with FTIR and ¹H NMR spectra, which confirmed the grafting of β-cyclodextrin (β-CD) onto hydroxypropyl chitosan (HPCS). The thermal properties were studied based on DSC and TGA analyses, which revealed the fact that grafting of β-CD onto HPCS resulted in obvious enhancement of the decomposition temperature of the copolymer. Aqueous solution of HPCS-g-β-CD copolymer was stable at pH 7-8 based on the Zeta potential test. The morphological characteristics were investigated by SEM, TEM and AFM analysis, and the results indicated that this copolymer had three-dimensional structure which was suitable for loading drugs.     

Thermodynamic Studies of Insulin Loading into a Glucose Responsive Hydrogel Based on Chitosan‐polyacrylamide‐polyethylene Glycol

The insulin therapy constitutes the preferred treatment for Diabetes Mellitus (DM). The traditional insulin therapy, which consists of daily subcutaneous insulin injections to control blood glucose level, is not able to regulate the blood glucose level precisely. In this research, to facilitate the diabetic patient life, an intelligent drug delivery system based on a biodegrable biopolymer to control the insulin release, was designed. In this system, chitosan‐polyethylene glycol hydrogel and glucose oxidize play the role of drug carrier and glucose biosensor, respectively. To increase the hydrogel drug loading capacity, hydrogels with different PEG content were synthesized and insulin was loaded by swelling‐diffusion method into them. The loaded hydrogels were characterized by Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), High performance liquid chromatography (HPLC), and Thermogravimetric analysis (TGA). Finally, the thermodynamic study for insulin loading process was performed to investigate the stability of the drug in the system.     

Chitosan-Based Surface Molecularly Imprinted Polymer Microspheres for Sustained Release of Sinomenine Hydrochloride in Aqueous Media

The surface molecular imprinting technique has been proposed as a prospective strategy for template molecule recognition and separation by devising the recognition sites on the surface of imprinted materials. The purpose of this study was to establish a novel drug delivery system which was developed by surface molecular imprinting method using β-cyclodextrin (β-CD)-grafted chitosan (CS) (CS-g-β-CD) microspheres as matrix and sinomenine hydrochloride (SM) as the template molecule. By adjusting the amount of functional monomer and cross-linking agent, we got the more excellent adsorption of CS-g-β-CD molecularly imprinted polymers (MIPs-CS-g-β-CD). When the amount of functional monomer was 6 mmol and cross-linking agent was 20 mmol, the maximum binding capacity of MIPs and non-imprinted polymers (NIPs) was 55.9 mg/g and 37.2 mg/g, respectively. The results indicated that the recognition of SM with MIPs was superior to NIPs. The adsorption isotherms of MIPs-CS-g-β-CD indicated that the adsorption behavior fitted better to the Langmuir model, which showed that the adsorption process of polymer was monomolecular layer. In in vitro drug release studies, the accumulative release amount of MIPs-CS-g-β-CD was up to 78% within 24 h. MIPs exhibited an excellent controlled SM release profile without burst release and the mechanism of SM release was shown to conform to non-Fick diffusion. Therefore, MIPs-CS-g-β-CD were successfully applied to extraction of SM and used as the materials for drug delivery system.     

Design and synthesis of novel polyglycerol hybrid nanomaterials for potential applications in drug delivery systems

The synthesis of a new drug delivery system based on hybrid nanomaterials containing a β-CD core and hyperbranched PG is described. Conjugating PG branches onto β-CD not only increases its water solubility but also affects its host/guest properties deeply. It can form molecular inclusion complexes with small hydrophobic guest molecules such as ferrocene or FITC with reasonable release. In addition, the achievable payloads are significantly higher as for carriers such as hyperbranched PGs. Short-term in vitro cytotoxicity and hemocompatibility tests on L929 cell lines show that the hybrid nanomaterial is highly biocompatible. Due to their outstanding properties, β-CD-g-PG hybrid nanomaterials are introduced as promising materials for nanomedicine, e.g., for drug delivery issues.     

Preparation and Characterization of a Novel Drug Delivery System: Biodegradable Nanoparticles in Thermosensitive Chitosan/Gelatin Blend Hydrogels

A novel injectable in situ gelling drug delivery system (DDS) consisting of biodegradable N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanoparticles and thermosensitive chitosan/gelatin blend hydrogels was developed for prolonged and sustained controlled drug release. Four different HTCC nanoparticles, prepared based on ionic process of HTCC and oppositely charged molecules such as sodium tripolyphosphate, sodium alginate and carboxymethyl chitosan, were incorporated physically into thermosensitive chitosan/gelatin blend solutions to form the novel DDSs. Resulting DDSs interior morphology was evaluated by scanning electron microscopy. The effect of nanoparticles composition on both the gel process and the gel strength was investigated from which possible hydrogel formation mechanisms were inferred. Finally, bovine serum albumin (BSA), used as a model protein drug, was loaded into four different HTCC nanoparticles to examine and compare the effects of controlled release of these novel DDSs. The results showed that BSA could be sustained and released from these novel DDSs and the release rate was affected by the properties of nanoparticle: the slower BSA release rate was observed from DDS containing nanoparticles with a positive charge than with a negative charge. The described injectable drug delivery systems might have great potential application for local and sustained delivery of protein drugs.     

Novel nanoparticles composed of chitosan and β-cyclodextrin derivatives as potential insoluble drug carrier

This research was aim to develop novel cyclodextrin/chitosan(CD/CS) nanocarriers for insoluble drug delivery through the mild ionic gelation method previously developed by our lab. A series of different bcyclodextrin(β-CD) derivatives were incorporated into CS nanoparticles including hydroxypropyl-bcyclodextrin(HP-β-CD), sulphobutylether-β-cyclodextrin(SB-β-CD), and 2,6-di-O-methy-β-cyclodextrin(DM-β-CD). Various process parameters for nanoparticle preparation and their effects on physicochemical properties of CD/CS nanoparticles were investigated, such as the type of CD derivatives,CD and CS concentrations, the mass ratio of CS to TPP(CS/TPP), and p H values. In the optimal condition,CD/CS nanoparticles were obtained in the size range of 215–276 nm and with the zeta potential from30.22 m V to 35.79 m V. Moreover, the stability study showed that the incorporation of CD rendered the CD/CS nanocarriers more stable than CS nanoparticles in PBS buffer at p H 6.8. For their easy preparation and adjustable parameters in nanoparticle formation as well as the diversified hydrophobic core of CD derivatives, the novel CD/CS nanoparticles developed herein might represent an interesting and versatile drug delivery platform for a variety of poorly water-soluble drugs with different physicochemical properties.     

甲基丙烯酸N,N-二甲氨基乙酯与丙烯酰β-环糊精共聚水凝胶的合成及其性能研究

用不同的方法合成了两种结构不同的丙烯酰 β 环糊精酯 (β CD 3 A和 β CD 6 A) ,以此为单体与甲基丙烯酸N ,N 二甲氨基乙酯 (DMAEMA)通过氧化还原自由基引发聚合 ,合成出两类含 β 环糊精结构单元的新型水凝胶 .用核磁共振 ,红外光谱及元素分析对两种单体及共聚物的结构和组成进行了表征 .溶胀实验结果表明 ,两类水凝胶均具有较好的pH、温度及离子强度敏感性 ,且因其交联网络结构不同 ,其溶胀性能有所差异     

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.     

亲核取代法制备壳聚糖6-OH固载环糊精衍生物

通过苯甲醛对壳聚糖2-NH2希夫碱化保护后,将壳聚糖C6位—OH与对甲苯磺酰氯反应形成对甲苯磺酰酯;然后用β-环糊精(-βCD)的单—NH2取代衍生物与之发生亲核取代反应,将环糊精固载到壳聚糖分子链上;最后,将得到的固载产物中的希夫碱脱保护后得到壳聚糖6-OH定位固载环糊精衍生物.采用FTIR,13C-NMR,元素分析,UV等表征手段对各步产物的结构进行了表征.紫外光谱法测定表明,-βCD在壳聚糖分子链C6位上的固载率达到了170.81μmol.g-1,远高于文献报道的其它方法制得的固载产物.采用XRD对各步产物的结晶性能进行了研究.     

Biocompatible hydrogel for cartilage repair with adjustable properties

Synthesis of hydrogel at mild conditions is considered one most important challenge, especially if the hydrogel will be used for hosting bioactive materials or drugs. The procedure of hydrogel preparation should have no effect on the properties of the hosted materials. Hyaluronic acid (HA) was modified by adding dialdehyde groups to its structure to facilitate formation of hydrogel at very mild conditions. Dialdehyde HA (DHA) was prepared through oxidation of HA using sodium metaperiodate as oxidizing agent. The prepared DHA was characterized by Fourier‐transform infrared (FTIR) spectroscopy and X‐ray diffraction (XRD) and aldehyde content. A hydrogel was prepared using different chitosan/DHA molar ratio and fixed amount of glutaraldehyde at 25°C. The prepared hydrogel has tunable properties and pores size depending on the chitosan/DHA molar ratio. Sodium diclofenac was loaded on the hydrogel as a model drug. The hydrogel was characterized by FTIR spectroscopy, swelling rate, gel fraction, drug release profile, and cytotoxicity. The results obtained indicated that the properties of the prepared hydrogel, including gelling time, gel fraction, swelling, pores size, and drug release profile are highly tuned depending on the chitosan/DHA molar ratio. The drug loading efficiency was in the range of 70% to 85%. The cytotoxicity results reveal that the prepared hydrogel has a very low toxicity in presence and absence of sodium diclofenac.     

Oxidized Xanthan Gum Crosslinked NOCC: Hydrogel System and Their Biological Stability from Oxidation Levels of the Polymer

Dynamic hydrogel systems from N,O-carboxymethyl chitosan (NOCC) are investigated in the past years, which has facilitated their widespread use in many biomedical engineering applications. However, the influence of the polymer's oxidation levels on the hydrogel biological properties is not fully investigated. In this study, chitosan is converted into NOCC and introduced to react spontaneously with oxidized xanthan gum (OXG) to form several injectable hydrogels with controlled degradability. Different oxidation levels of xanthan gum, as well as NOCC/OXG volume ratios, are trialed. The infrared spectroscopy spectra verify chemical modification on OXG and successful crosslinking. With increasing oxidation levels, more dialdehyde groups are introduced into the OXG, resulting in changes in physical properties including gelation, swelling, and self-healing efficiency. Under different volume ratios, the hydrogel shows a stable structure and rigidity with higher mechanical properties, and a slower degradation rate. The shear-thinning and self-healing properties of the hydrogels are confirmed. In vitro assays with L929 cells show the biocompatibility of all formulations although the use of a high amount of OXG15 and OXG25 limited the cell proliferation capacity. Findings in this study suggested a suitable amount of OXG at different oxidation levels in NOCC hydrogel systems for tissue engineering applications.     

Biodegradable and antibacterial poly(azomethine‐urethane)‐chitosan hydrogels for potential drug delivery application

In this study, biodegradable and antibacterial poly(azomethine‐urethane) (PAMU)‐ and chitosan (CS)‐based hydrogels have been prepared for controlled drug delivery applications. Structural and morphological characterizations of the hydrogels were performed via Fourier transform‐infrared and scanning electron microscopy analyses. Thermal stability, hydrophilicity, swelling, mechanical, biodegradation, protein absorption properties, and drug delivery application of PAMU‐ and CS‐based hydrogels were also investigated. The swelling performance of the hydrogels was studied in acidic, neutral, and alkaline media. Swelling results showed that the hydrogels have higher swelling capacity in acidic and alkaline media than neutral medium. Biodegradation experiments of the hydrogels were also studied via hydrolytic and enzymatic experiments. The drug release property of the hydrogel was carried out using 5‐fluoro uracil (5‐FU), and 5‐FU release capacity of the hydrogels was found in the range from 40.10% to 58.40% after 3 days.     

Radiation synthesis of poly[(dimethylaminoethyl methacrylate)-co-(ethyleneglycol dimethacrylate)] hydrogels and its application as a carrier for anticancer delivery

The use of hydrogels as carriers for anticancer delivery has been a subject of significant recent research. In our recent work, we have shown that diffusion-controlled delivery of flutamide from hydrogels containing poly (dimethylaminoethyl methacrylate (DMAEMA)/ethyleneglycol dimethacrylate (EGDMA)) can be possible and controlled by the three-dimensional structure. Hydrogels based essentially on dimethylaminoethyl methacrylate and different ratios of ethyleneglycol dimethacrylate monomers were synthesized using gamma radiation copolymerization. The influence of copolymer composition and pH value of the surrounding medium on swelling behavior into the glassy polymer were discussed. The results showed that the ratio of EGDMA in the comonomer feeding solution has a great effect on the gel fraction and water content in the final hydrogel. In this regard, it was observed that the increase of EGDMA ratio decreased these properties. The ability of the prepared copolymer to be used as drug carrier for anticancer drug-delivery system was estimated using flutamide as a model drug. 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 DMAEMA content of hydrogel.     

A green chemistry approach towards synthesizing hydrogel for sustained ocular delivery of brinzolamide: In vitro and ex vivo evaluation

Brinzolamide is a carbonic anhydrase inhibitor used in the eye drop form for the treatment of glaucoma. It requires frequent dosing to attain therapeutic concentration. Therefore, this study aimed to prepare sustained ocular drug delivery of brinzolamide. The objective of the study was to prepare a hydrogel loaded with a nanostructured lipid carrier (NLC) of brinzolamide. The hydrogel was prepared by a green synthesis approach using genipin as a natural crosslinking agent and polymers such as carboxymethyl chitosan and poloxamer 407. The melt emulsification-ultra sonication method was used to prepare a nanostructured lipid carrier of brinzolamide, which was loaded into a hydrogel using a swelling and loading method. The NLC formulation has shown small particle sizes of 111.20 ?± ?2.15 ?nm, polydispersity index of 0.280 ?± ?0.005 and % entrapment efficiency of 82.16% ?± ?0.14%. The NLC-loaded hydrogels of brinzolamide formulations were studied for swelling properties and showed temperature and pH-responsive swelling behavior. The optimized hydrogel formulation has been studied for in vitro drug release and showed drug release for a longer duration (24 ?h) than marketed eye drops (8 ?h). In an ex vivo study, hydrogel formulations showed transcorneal permeability 4.54 times greater than marketed eye drops. The hydrogel formulation of brinzolamide produced by the green synthesis method has shown sustained-release properties with no sign of ocular irritation. Hence, the hydrogel of brinzolamide-loaded NLC would be the potential drug delivery approach in the near future for sustained ocular drug delivery in glaucoma management.     

Synthesis and characterization of copolymers of β-cyclodextrin derivatives

Cyclodextrins (CDs) are cyclic oligosaccharides made up of d-glucose units connected by 1,4-glucosidic linkages. β-CD is a cyclical starch derivative containing seven glucopyranose units. β-CD derivatives have characteristic property of larger surface area, robust mechanical strength, high surface to volume ratio, electrical and optical properties for analyte determination, good dispersion, easy removal of the template, surface modification, functionalization and handling capacity. In this work, an attempt is made to prepare succinyl-β-CD-acrylamide (S-β-CD-AA) copolymer and β-CD-malic anhydride (β-CD-MAH) copolymer. For the synthesis of S-β-CD-AA, S-β-CD derivative is prepared and further, acrylamide (AA) along with cross-linker undergoes free radical copolymerization for the formation of gel like product. The degree of succinylation (DS) of β-CD derivative is estimated. S-β-CD-AA copolymer showed potential swelling, and deswelling characteristic. Another copolymer is prepared from β-CD malic anhydride derivative. Further, the derivative is treated with cellulose and ethylene diamine tetra acetate (EDTA) to form β-CD-MAH copolymer. The two derivatives are characterized by several techniques. Thermal stability of these copolymers is estimated with the help of thermogravimetric analysis. The basic characterization of the presence of functional groups is done using UV–visible spectroscopy, and infrared spectroscopy. The elemental analysis helped to estimate C, H, N, S in the synthesized compounds. The surface morphology characterization is done with the help of scanning electron microscopy. X-ray diffraction analysis helped in determination of crystal structure of β-CD-MAH. β-CD derivatives prepared may be potential candidate to prepare inclusion complex, in drug delivery, drug loading and several similar applications.