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.     

Characterization of chitosan microparticles reinforced cellulose biocomposite sponges regenerated from ionic liquid

The chitosan-microparticles reinforced cellulose biocomposite sponges regenerated from ionic liquid were prepared and characterized. Fourier transform infrared (FTIR) spectroscopy confirmed that the cellulose dissolved in 1-allyl-3-methylimidazolium chloride without derivatization. Chitosan particles as reinforcement were incorporated into the cellulose matrix. FTIR spectra indicated hydrogen bonding between hydroxyl groups of cellulose and chitosan. The biocomposite sponges showed uniform three-dimensional interconnected porous structures. The breaking strength of the sponges increased significantly, from 0.09 to 0.32 MPa with the addition of 1.0 wt% chitosan. The sponges also demonstrated excellent antibacterial activity against S. aureus and E. coli with the average inhibition zone diameters >2 mm and the inhibition rate higher than 80 %. Furthermore, the biocomposite sponges exhibited good moisture penetrability and high porosity. The water uptake ability of the sponge was >25 times of its weight in water with a fast swelling. The chitosan/cellulose composite sponge is expected to be a promising material for potential applications as wound dressing.     

Characterisation of DM-β-cyclodextrin:prednisolone complexes and their formulation as eye drops

Several ocular treatment options have been developed to overcome a broad range of ocular infections and corneal pathologies. Even though, commonly used ophthalmic formulations are only able to promote a short therapeutic effect, demanding a frequent dosing regimen. This study took advantage of dimethyl-β-cyclodextrin to overcome prednisolone low water solubility through complexes formation. These complexes were characterized by phase-solubility studies (K_s = 732; CE = 0.864), ¹H-NMR, Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy. Particle size distribution, prednisolone assay, rheology and osmolality were assessed to evaluate dimethyl-β-cyclodextrin and HPMC influence on the eye formulation main physicochemical properties. ¹H-NMR studies showed a 1:1 molar ratio complexes’ stoichiometry; and the other physical characterisation methods (FTIR spectra and DSC thermograms) proved a successful interaction between prednisolone and dimethyl-β-cyclodextrin. Dimethyl-β-cyclodextrin promoted a statistical significative water solubility increase of drug and the particle size of all suspensions prepared presented a d90 lower than 90 μm. The presence of dimethyl-β-cyclodextrin did not change the pseudoplastic behaviour of this HPMC-based suspension, but a lower viscosity was obtained in the presence of the complexes. As the final formulation was hypotonic its osmolality was adjusted with NaCl. Overall, dimethyl-β-cyclodextrin:prednisolone complexation in the presence of hydrophilic polymer HPMC appears to be an advantageous approach for the ocular administration of this drug.     

Cotton‐hydrogel composite for improved wound healing: Antimicrobial activity and anti‐inflammatory evaluation—Part 2

Infection is one of the major risk factors for the development of chronic wounds. Antimicrobial wound dressing has been pointed out as a viable option for the prevention and treatment of wound infections. Thus, we developed a composite material based on cotton textile substrates functionalized with cyclodextrin‐hydroxypropyl methyl cellulose‐based hydrogel. The composites' ability to encapsulate and release gallic acid (antimicrobial phenolic acid) was evaluated, as well as their mechanical properties and antimicrobial and anti‐inflammatory capacity. All composites were able to retain gallic acid in their structure, with similar loading profile. The presence of gallic acid on composites was confirmed by FTIR and TGA. Composites storage moduli was reduced by the presence of gallic acid. The results suggest a straight relation between the swelling ability and gallic acid drug delivery profile. The drug delivery mechanism, of the developed composites, was mainly controlled by Fickian diffusion, based on the experimental data fitting to the Peppas‐Sahlin model. Gallic acid antimicrobial and anti‐inflammatory properties were transferred to the composite materials. According to the results, the developed composites can be applied on the prevention or treatment of chronic wounds.     

Synthesis and characterization of zinc chloride containing poly(acrylic acid) hydrogel by gamma irradiation

In this study, the characterization of zinc chloride incorporated into a poly(acrylic acid) (PAAc) hydrogel prepared by gamma-ray irradiation was investigated. Zinc chloride powder with different concentrations was dissolved in the PAAc solution, and it was crosslinked with gamma-ray irradiation. The effects of various parameters such as zinc ion concentration and irradiation doses on characteristics of the hydrogel formed were investigated in detail for obtaining an antibacterial wound dressing.In addition, the gel content, pH-sensitive (pH 4 or 7) swelling ratio, and UV–vis absorption spectra of the zinc particles in the hydrogels were characterized. Moreover, antibacterial properties of these new materials against Staphylococcus aureus and Escherichia coli strains were observed on solid growth media. The antibacterial tests indicated that the zinc chloride containing PAAc hydrogels have good antibacterial activity.     

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, ¹H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.     

PVA-clay nanocomposite hydrogels for wound dressing

Polymer gels as soft biomaterials have found diverse applications in biomedical field, e.g. in management and care of wound as wound dressing.The recent researches on nanocomposite materials have shown that some properties of polymers and gels significantly improve by adding organoclay into polymeric matrix. In this work, in order to obtain wound dressing with better properties, nanocomposite hydrogel wound dressing was prepared using combination of polyvinyl alcohol hydogel and organoclay, i.e. Na-montmorillonite, via the freezing-thawing method. The effect of organoclay quantity on the structural, swelling, physical and mechanical properties of nanocomposite hydrogel wound dressing was investigated. The results showed that the nanocomposite hydrogels could meet the essential requirements for the reasonable wound dressing with some desirable characteristics such as relatively good swelling, appreciated vapour transmission rate, excellent barrierity against microbe penetration and mechanical properties. The results also indicated that the quantity of the clay added to the nanocomposite hydrogel is the key factor in obtaining such suitable properties required for wound dressing.     

Effect of β-cyclodextrins based nanosponges on the solubility of lipophilic pharmacological active substances (repaglinide)

Cyclodextrin based nanosponges (CD-NS) are nanostructured cross-linked polymers, usually obtained by reacting cyclodextrin with a cross-linker such as carbonyldiimidazole, organic carbonates or (±) epichlorohydrin. They have been used to increase the solubility and stability of poorly soluble pharmacological active substances, as they combine the complex forming properties of CDs and properties of polymers (such as the high molecular weight). The affinity of CDs for certain lipophilic molecules is characteristic to the polymeric nano-structured system and allows the development of specific drug delivery systems. Knowing that cyclodextrin capacity to form inclusion complexes is maintained and enhanced when the CD molecules form aggregates, cross-link together or copolymerize with other compounds, we have synthesized cyclodextrin based nanosponges (from β-cyclodextrin and sulfobutylether-β-cyclodextrin). The complexing properties of the polymers were investigated against repaglinide (a hypoglycemic agent, practically insoluble in water). Solubility studies were performed according to the method reported by Higuchi and Connors and the phase solubility diagrams were plotted. The repaglinide-nanosponges complexes were prepared, lyophilized and the resulted inclusion complexes were characterized by FT-IR and NMR. The solubility profile and the loading capacity of the cyclodextrin based polymers were also determined.     

Synthesis of network poly(N-vinylimidazole) and properties of the related hydrogels

Imidazole-containing network polymers have been prepared via quaternization of linear poly(1-vinylimidazole). Owing to the affinity for water, crosslinked poly(1-vinylimidazole) is capable of limited swelling in water and concomitant formation of polyelectrolyte hydrogels. Imidazole-containing hydrogels can be doped with different metal ions and can serve as matrixes for stabilization of particles obtained via reduction of nanosize metals.     

Chitosan-Placental ECM Composite Thermos-Responsive Hydrogel as a Biomimetic Wound Dressing with Angiogenic Property

Attempts are being made to develop an ideal wound dressing with excellent biomechanical and biological properties. Here, a thermos-responsive hydrogel is fabricated using chitosan (CTS) with various concentrations (1%, 2.5%, and 5% w/v) of solubilized placental extracellular matrix (ECM) and 20% β-glycerophosphate to optimize a smart wound dressing hydrogel with improved biological behavior. The thermo-responsive CTS (TCTS) alone or loaded with ECMs (ECM-TCTS) demonstrate uniform morphology using SEM. TCTS and ECM1%-TCTS and ECM2.5%-TCTS show a gelation time of 5 min at 37 °C, while no gel formation is observed at 4 and 25 °C. ECM5%-TCTS forms gel at both 25 and 37 °C. The degradation and swelling ratios increase as the ECM content of the hydrogel increase. All the constructs show excellent biocompatibility in vitro and in vivo, however, the hydrogels with a higher concentration of ECM demonstrate better cell adhesion for fibroblast cells and induce expression of angiogenic factors (VEGF and VEGFR) from HUVEC. Only the ECM5%-TCTS has antibacterial activity against Acinetobacter baumannii ATCC 19606. The data obtained from the current study suggest the ECM2.5%-TCTS as an optimized smart biomimetic wound dressing with improved angiogenic properties now promises to proceed with pre-clinical and clinical investigations.     

Development of Antibacterial,Degradable and pH-Responsive Chitosan/Guar Gum/Polyvinyl Alcohol Blended Hydrogels for Wound Dressing

The present research is based on the fabrication preparation of CS/PVA/GG blended hydrogel with nontoxic tetra orthosilicate (TEOS) for sustained paracetamol release. Different TEOS percentages were used because of their nontoxic behavior to study newly designed hydrogels’ crosslinking and physicochemical properties. These hydrogels were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and wetting to determine the functional, surface morphology, hydrophilic, or hydrophobic properties. The swelling analysis in different media, degradation in PBS, and drug release kinetics were conducted to observe their response against corresponding media. The FTIR analysis confirmed the components added and crosslinking between them, and surface morphology confirmed different surface and wetting behavior due to different crosslinking. In various solvents, including water, buffer, and electrolyte solutions, the swelling behaviour of hydrogel was investigated and observed that TEOS amount caused less hydrogel swelling. In acidic pH, hydrogels swell the most, while they swell the least at pH 7 or higher. These hydrogels are pH-sensitive and appropriate for controlled drug release. These hydrogels demonstrated that, as the ionic concentration was increased, swelling decreased due to decreased osmotic pressure in various electrolyte solutions. The antimicrobial analysis revealed that these hydrogels are highly antibacterial against Gram-positive (Staphylococcus aureus and Bacillus cereus) and Gram negative (Pseudomonas aeruginosa and Escherichia coli) bacterial strains. The drug release mechanism was 98% in phosphate buffer saline (PBS) media at pH 7.4 in 140 min. To analyze drug release behaviour, the drug release kinetics was assessed against different mathematical models (such as zero and first order, Higuchi, Baker–Lonsdale, Hixson, and Peppas). It was found that hydrogel (CPG2) follows the Peppas model with the highest value of regression (R² = 0.98509). Hence, from the results, these hydrogels could be a potential biomaterial for wound dressing in biomedical applications.     

pH- and temperature-responsive hydrogels of acrylic acid,N-isopropylacrylamide and a non-ionic surfmer: phase behaviour,swelling properties and drug release

Copolymer hydrogels composed of N-isopropylacrylamide (NIPAM), acrylic acid (AA) and the non-ionic surfactant monomer (surfmer) ω-methoxy poly(ethylene oxide)₄₀undecyl-α-methacrylate (PEO-R-MA-40) were prepared and studied with regard to swelling behaviour and drug release behaviour. The gels were prepared upon γ-irradiation of the corresponding aqueous comonomer solution in a one-step reaction. Transparent, stable hydrogels were obtained. Studies of light transmission indicate a dual pH- and T-responsive behaviour, which originates from the AA and NIPAM content of the gels, respectively. Presence of large amounts of surfmer increases the phase transition temperature, but also increases the network density, which lowers the permeability of the gels. Swelling properties and release of ibuprofen (Ibu) were studied in simulated gastric fluid (SGF, pH 1) and phosphate buffer solution (PBS, pH 6.8). It was found that swelling and release are controlled by the nature and quantity of comonomers, pH, temperature and ionic strength of the aqueous phase. Swollen gels shrink in SGF and PBS, whereas dry gels exhibit a strong swelling both in SGF and PBS. Copolymer gels of AA and surfmer exhibit a strong, linear release of Ibu in SGF and PBS. If NIPAM is copolymerized in the gel, the drug release is decelerated in SGF probably due to formation of hydrogen bonds between NIPAM and Ibu at low pH. For example, a gel composed of 10 % (w/w) NIPAM, 1 % (w/w) AA and 1.5 % (w/w) surfmer exhibits a release of 10 % within 2 h in SGF and 58 % within 20 h in PBS.     

One Step Fabrication and Application of Antibacterial Electrospun Zein/Cinnamon Oil Membrane Wound Dressing via In situ Electrospinning Process

Antibacterial wound dressing can benefit the wound healing by preventing bacterial infection, especially for the electrospun ones due to their porous structures and easily loading antibacterial drugs. However, it is challenging to apply the antibacterial electrospun wound dressing to covering the wound conveniently and safely. Here, we presented one step fabrication and application of antibacterial electrospun zein/cinnamon oil wound dressing via a handheld electrospinning setup. The prepared zein/cinnamon oil wound dressing showed gas permeability of (76.1±5.45) mm/s, hydrophilicity with zero body fluid contact angle, swelling stability after 24 h as well as antibacterial zones over 5 cm against both E. coli and S. aureus bacteria. Moreover, in situ electrospinning process can deposit the electrospun zein/cinnamon oil fibers directly onto the wound, meantime forming a wound dressing. The mice cut-wound model experiment demonstrated that the one step in situ fabrication and application of zein/cinnamon oil wound dressing could nearly heal the wound within 11 d.     

Validated HPLC Method for Simultaneous Quantitation of Bergenin,Arbutin, and Gallic Acid in Leaves of Different Bergenia Species

Bergenia species (Saxifragaceae) are important sources of herbal medicines in Asia, mainly in Russia. Various plant parts are valued for their antibacterial, anti-inflammatory, antioxidant sand adaptogenic effect, and used for the dissolution of kidney and bladder stones. In this study a rapid reversed phase liquid chromatography (RP-HPLC) method has been developed for rapid screening and identifying of the main active components in leaf samples of Bergenia accessions. The main goal of this study was to develop an efficient method for the simultaneous identification and detection of arbutin, bergenin and gallic acid from Bergenia leaf samples, which were extracted with a methanolic solvent mixture [methanol:water = 1:1 (v/v)]. Chromatographic separations were performed on a reversed phase Luna C18(2)-HST HPLC column. This chromatographic system provided increased speed and efficiency for separations, without the need for ultra-high pressures. Reversed phase HPLC coupled with diode array detector method was used for the analysis. The method was validated using ICH guidelines. The level of gallic acid was significantly higher in Bergenia crassifolia samples compared to Bergenia cordifolia. However, the samples of the two Bergenia species did not differ substantially regarding the concentrations of arbutin and bergenin. The novel method proved to be fast and allowed sufficient separation and quantification of arbutin, bergenin and gallic acid, the most important bioactive compounds of Bergenia leaves; thus facilitating rapid screening and quality assessment of Bergenia samples of various botanical and geographical origins.     

Novel temperature-sensitive, β-cyclodextrin-incorporated poly(N-isopropylacrylamide) hydrogels for slow release of drug

Novel temperature-sensitive poly(N-isopropylacrylamide) hydrogels containing water-soluble -cyclodextrin polymer were prepared by forming semi-interpenetrating polymeric networks. Compared to the conventional poly(N-isopropylacrylamide) gel, the -cyclodextrin-incorporated hydrogels showed the same lower critical solution temperature due to the independence of the -cyclodextrin polymer in the networks. The release time of ibuprofen from the novel gel was significantly prolonged, which was presumably attributed to the formation of the inclusion complexes between the cyclodextrin groups and the drug molecules.Jian-Tao Zhang and Shi-Wen Huang have contributed equally to this work.     

Preparation and characteristics of hydroxypropyl-β-cyclodextrin polymeric nanocapsules loading nimodipine

Nimodipine loaded hydroxypropyl-β-cyclodextrin polymeric nanocapsules were prepared by interfacial polyaddition of hydroxypropyl-β-cyclodextrin and isophorone diisocyante in a miniemulsion system. The effects of ultrasonicate times on the preparation of miniemulsion, the total amount of hydroxypropyl-β-cyclodextrin and isophorone diisocyante, and the molar ratio of isophorone diisocyante to hydroxypropyl-β-cyclodextrin on the capsule size and drug release behavior from capsule were investigated. The chitosan based polymeric nanocapsules were prepared as a control to study the effect of hydroxypropyl-β-cyclodextrin molecules in capsule matrix on the drug release. The results indicated that the droplet size of miniemulsion and capsule size decreased with increasing sonicate times. When the total amount of hydroxypropyl-β-cyclodextrin and isophorone diisocyante, and the molar ratio of isophorone diisocyante to hydroxypropyl-β-cyclodextrin were increased, the capsule as well, but the drug release rates from capsules became slower. The drug release behaviors from hydroxypropyl-β-cyclodextrin polymeric nanocapsules were affected by the drug diffusion through the polymer matrix and the formation of inclusion complex between drug and hydroxypropyl-β-cyclodextrin.     

UHPLC Determination of Enantiomeric Purity of Sertraline in the Presence of its Production Impurities

A fast and low reagents consuming ultra-high performance liquid chromatography method was developed for the determination of the enantiomeric purity of sertraline in presence of its stereoisomers and four other process-related chiral impurities. The optimum chromatographic conditions were achieved using a commercially available C8 column with sub-2-μm particle size, and a mobile phase of 10 mM tetrabutylammonium hydrogen sulfate buffer pH = 3-acetonitrile (87:13, v/v) and 12 mM 2-hydroxypropyl-β-cyclodextrin as chiral additive, with ultraviolet detection at 220 nm. The method was validated in terms of ruggedness, specificity, linearity, accuracy, precision, and limits of detection and quantification. Different variables affecting the enantioresolution and retention time were optimized, such as pH, buffer concentration and type, chiral additive concentration and type, flow rate, stationary phase, mobile phase, and column temperature. Total analysis time was reduced by 50 % compared with conventional HPLC; also 94 % of acetonitrile and 90 % of 2-hydroxypropyl-β-cyclodextrin were saved.     

Release of theophylline and aminophylline from acrylic acid/n‐alkyl methacrylate hydrogels

The swelling capacity and release rate of two homologous drugs, theophylline and aminophylline, from acrylic acid/n‐alkyl methacrylate hydrogels have been studied. The maximum equilibrium swelling increases as the molar fraction of acrylic acid or the chain length of the methacrylate in the hydrogels increases. Water diffusion to the hydrogels is non‐Fickian. Both drugs are released from the fully swollen hydrogels according to Fick's law. However, the drug release from xerogels deviates from Fick's law, especially for aminophylline. As expected because of its larger size, aminophylline diffuses more slowly than theophylline under similar experimental conditions. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2756–2765, 2004     

Development of implantable hydroxypropyl-β-cyclodextrin coated polycaprolactone nanoparticles for the controlled delivery of docetaxel to solid tumors

Treatment of cancer is one of the most challenging problems and conventional therapies are inadequate for targeted, effective and safe therapy. Development of nanoparticle-based drug delivery systems emerge as promising carriers in this field to ensure delivery of anticancer drug to tumor site. The aim of this study was to design hydroxypropyl-β-cyclodextrin (CD) coated nanoparticles using poly(ε-caprolactone) (PCL) and its derivative poly(ethylene glycol)-block-poly(ε-caprolactone) (mePEG-PCL) to be applied as implants to tumor site following surgical operation in cancer patients. CD coated PCL and mePEG-PCL nanospheres were developed to encapsulate poorly soluble chemotherapeutic agent docetaxel (DOC) to improve solubility of drug and to enhance cellular penetration with longer residence time and higher local drug concentration. Nanospheres were prepared according to the nanoprecipitation method and coated with hydroxypropyl-β-cyclodextrin (Cavasol^® W7HP). Cyclodextrin coating was performed for higher drug encapsulation and controlled but complete drug release from nanoparticles. Nanoparticle diameters varied between 60 and 136 nm depending on polymer used for preparation and coating. All nanoparticles have negative surface charge and zeta potential values varied between ?22 and ?37 mV. Encapsulation efficiency of formulations were found to be between 46 and 73 % and CD coated nanoparticles have significantly higher entrapment efficiency. Drug release profiles of nanoparticles were similar to each other and all formulations released encapsulated drug in approximately 12 h. Especially, CD-PCL nanoparticles were found to have highest entrapment efficiency and anticancer efficacy against MCF-7 human breast adenocarcinoma cell lines. Our study proved that polycaprolactone and its PEGylated derivatives can be suitable for development of implantable nanoparticles as a potential drug delivery system of DOC for cancer treatment and a good candidate for further in vivo studies.     

Antitumoral and MMP-2 inhibition activity of raloxifene or tamoxifen loaded nanoparticles containing dimethyl-β-cyclodextrin

A new nanoparticle formulation has been developed by using dimethyl-β-cyclodextrin (DM-β-CD) with raloxifene HCl or tamoxifene citrate. Both drugs are insoluble in water and represent as low bioavailibilities when given orally. Tamoxifen has an FDA approval for breast cancer prevention and the treatment. Raloxifene is approved for osteoprosis treatment. Both drugs were selected as a model drug antitumoural activity and MMP-2 inhibition studies were evaluated on breast cancer cell lines MCF-7 and MDA-MB 231. MMP-2 is known to be responsible for tumour invasion and initation the of angiogenesis. DM-β-CD and sodium taurocholate (NaTC) have been used as absorption enhancers to increase penetration effect of raloxifene/tamoxifen on the tumour cells and aimed to provide high antitumoral activity and MMP-2 inhibition results by developed nanoparticle formulations. The effects of two absorption enhancers were compared. The highest antitumoral activity was observed for DM-β-CD—raloxifene HCl nanoparticle formulation and also MMP-2 enzyme inhibit effectively.