Biocompatible hydrogels for the controlled delivery of anti-hypertensive agent: development,characterization and in vitro evaluation

The aim of the present exploration was to develop novel pH-sensitive cross-linked Gelatin/Polyvinyl pyrrolidone hydrogels using different ratios of both the polymers and to investigate the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and invitro release pattern of the model drug (captopril). Grafting polymerization technique was used for the preparation of these hydrogels using glutaraldehyde as crosslinking agent. These polymeric materials were then used as model systems to envisage various important characterizations like FTIR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction) and scanning electron microscopy (SEM). Phosphate buffers of pH 1.2, 6.5 and 7.5 were used for swelling and invitro drug release profile investigation. Different parameters like swelling analysis, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), solvent interaction parameter (χ), volume fraction of polymer (V_2,s) and diffusion coefficient that affects the drug release behavior were also determined. Higher swelling and release was observed at lower pH values. FTIR spectra showed interaction between gelatin and polyvinyl pyrrolidone and successful formation of cross-linked structure. Pulsatile drug release study showed the controlled delivery of model drug. The release of drug occurred through non-fickian diffusion or anomalous mechanism. Aforementioned characterizations reveal successful formation of copolymer. pH sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable which also predicts their possible use for site specific captopril delivery.     

Analysis of burst release of proxyphylline from poly(vinyl alcohol) hydrogels

The initial high-rate drug release observed at the beginning of many controlled-release processes can be caused by a number of mechanisms, including surface desorption, pore diffusion, or the lack of a diffusion front barrier to regulate the diffusive process. This initial nonsteady-state period is usually referred to as "burst release." A small molecular size drug, proxyphylline, was used as a model solute to study the burst release of a drug from swellable hydrogels based on cross-linked poly(vinyl alcohol) (PVA). The influences of several factors, including drug loading concentration, initial cross-linking ratio of the polymer, initial swollen state of the hydrogel samples, pore diffusion of the drug versus swelling of the hydrogel at the beginning of the release, and osmotic pressure, were investigated to understand the burst behavior. Results show that high drug loading and low cross-linking ratio of the polymer led to more pronounced bursts. Compared to release experiments starting with relaxed samples, samples in dry states had magnified burst effects, but prolonged the release process. Pore diffusion of the drug at the initial stage and the osmotic pressure were shown not to be effective factors leading to burst release within the range of the experimental conditions of this study.     

Surface Cross-Linked Poly (Vinyl Alcohol) Hydrogel for Colon Targeted Drug Release

A series of surface cross-linked PVA hydrogels (previously bulk cross-linked with maleic anhydride) were prepared for different cross-linker (glutaraldehyde) concentration. FTIR-ATR study revealed the cross-linking reaction. Surface cross-linking results in contraction of pores and increase in hydrophobicity, pore tortuosity around the surface of the membrane. As a result swelling, drug release decreases with increasing glutaraldehyde concentration. After surface cross-linking swelling of the hydrogels in simulated gastric fluid (SGF) further decreased to attain half of the value as observed for only bulk cross-linked membranes. Surface cross-linking has improved the colon-targeted release characteristics of the drugs from the PVA hydrogels.     

Nafcillin release from poly(acrylic acid–co–methyl methacrylate) hydrogels

Summary Copolymeric poly(acrylic acid-co-methyl methacrylate) hydrogels for three different compositions: (90/10), (80/20) and (60/40), have been studied. Drug release has been examined as a function of the hydrogel composition by HPLC (High Pressure Liquid Cromatography). The release experiments were carried out at 37 °C. The fraction of available drug release was linear in t^1/2. The values of the diffusional coefficient (0.50<n<1.0) indicate that the nafcillin release mechanism from the hydrogels in study is non-Fickian. The diffusion coefficients for this drug release have been calculated. The molecular diffusion of nafcillin through hydrogels is controlled by the swelling.     

On physical and antibacterial properties and drug release behavior of poly(vinyl alcohol) hydrogels: effect of drug loaded chitosan nanoparticles

This paper deals with influence of chitosan nanoparticles (CNPs) loaded by tetracycline, as a drug, on the physico-mechanical and antibacterial properties as well as drug release behavior of poly(vinyl alcohol), PVA, hydrogels prepared by electron beam irradiation. The formation of spherical chitosan particles in nanoscale size prepared by an ionic gelation method was confirmed by FTIR and UV spectroscopy, and scanning electron microscopy analyses. The drug release kinetic studies from drug loaded chitosan nanoparticles (DLCNPs) at pH = 7.4 revealed a linear and steady release behavior over long period of time. The theoretical analysis of the swelling kinetic data, using Peppas’s model showed that the swelling kinetic is governed by Fickian diffusion for all the prepared hydrogels, however, the water diffusion coefficient, and therefore, the swelling content were lower for the hydrogels loaded with DLCNPs as compared to the ones with the neat drug. In agreement with these results, the hydrogels containing DLCNPs exhibited a more controlled drug release behavior with significantly stronger antibacterial activity. The tensile mechanical properties of the hydrogels not affected by the DLCNPs were found to be suitable for wound dressing applications.     

Synthesis of biodegradable thermo- and pH-responsive hydrogels for controlled drug release

Novel intelligent hydrogels composed of biodegradable and pH-sensitive poly(l-glutamic acid) (PGA) and temperature sensitive poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate) (PNH) were synthesized and characterized for controlled release of hydrophilic drug. The influence of pH on the equilibrium swelling ratios of the hydrogels was investigated. A higher PNH content resulted in lower equilibrium swelling ratios. Although temperature had little influence on the swelling behaviors of the hydrogels, the changes of optical transmittance of hydrogels as a function of temperature were marked, which showed that the PNH part of hydrogel exhibited hydrophobic property at temperature above the lower critical solution temperature (LCST). The biodegradation rate of the stimuli-sensitive hydrogels in the presence of enzyme was directly proportional to the PGA content. Lysozyme was chosen as a model drug and loaded into the hydrogels. The in vitro drug release experiment was carried out at different pH values and the release data suggested that both the pH and PNH content played important roles in the drug release behaviors of the hydrogels.     

京尼平交联大豆蛋白/壳聚糖复合凝胶的控释

利用天然无毒的京尼平交联大豆蛋白(SB)和壳聚糖(CS)制备复合水凝胶(HD)并用作茶碱的控释载体。同时对其在模拟胃肠液和pH7.4缓冲液（PBS）中的控释特性进行了研究。结合扫描电镜和红外光谱以及核磁共振表征了复合凝胶的表观形态和结构。结果表明,复合水凝胶中大豆蛋白和壳聚糖通过京尼平发生了明显的交联作用,并呈现致密的片层结构。复合凝胶在模拟胃肠液和pH7.4PBS中均呈现溶胀现象,在模拟胃液中的溶胀度较低。而且凝胶在pH1.2模拟胃液中的释放量比模拟肠液和pH7.4PBS液中的低,并发现该凝胶具有pH响应,在120 h内可实现对茶碱的可控释放。因此,这种京尼平交联的复合凝胶具有作为药物在胃肠道中定向运送载体的潜力。     

ANALYSIS OF BURST RELEASE OF PROXYPHYLLINE FROM POLY(VINYL ALCOHOL) HYDROGELS

The initial high-rate drug release observed at the beginning of many controlled-release processes can be caused by a number of mechanisms, including surface desorption, pore diffusion, or the lack of a diffusion front barrier to regulate the diffusive process. This initial nonsteady-state period is usually referred to as "burst release." A small molecular size drug, proxyphylline, was used as a model solute to study the burst release of a drug from swellable hydrogels based on cross-linked poly(vinyl alcohol) (PVA). The influences of several factors, including drug loading concentration, initial cross-linking ratio of the polymer, initial swollen state of the hydrogel samples, pore diffusion of the drug versus swelling of the hydrogel at the beginning of the release, and osmotic pressure, were investigated to understand the burst behavior. Results show that high drug loading and low cross-linking ratio of the polymer led to more pronounced bursts. Compared to release experiments starting with relaxed samples, samples in dry states had magnified burst effects, but prolonged the release process. Pore diffusion of the drug at the initial stage and the osmotic pressure were shown not to be effective factors leading to burst release within the range of the experimental conditions of this study.     

Influence of Unmodified and β-Glycerophosphate Cross-Linked Chitosan on Anti-Candida Activity of Clotrimazole in Semi-Solid Delivery Systems

The combination of an antifungal agent and drug carrier with adjunctive antimicrobial properties represents novel strategy of complex therapy in pharmaceutical technology. The goal of this study was to investigate the unmodified and ion cross-linked chitosan’s influence on anti-Candida activity of clotrimazole used as a model drug in hydrogels. It was particularly crucial to explore whether the chitosans’ structure modification by β-glycerophosphate altered its antifungal properties. Antifungal studies (performed by plate diffusion method according to CLSI reference protocol) revealed that hydrogels obtained with chitosan/β-glycerophosphate displayed lower anti-Candida effect, probably as a result of weakened polycationic properties of chitosan in the presence of ion cross-linker. Designed chitosan hydrogels with clotrimazole were found to be more efficient against tested Candida strains and showed more favorable drug release profile compared to commercially available product. These observations indicate that novel chitosan formulations may be considered as promising semi-solid delivery system of clotrimazole.     

静电喷射技术制备可酸致突释给药的壳聚糖微颗粒

利用静电喷射技术,以西咪替丁作为模型药物,混有药物的壳聚糖水溶液作为喷射液,甲苯/正己醇的混合溶液作为接收液,成功制备得到可在酸性条件下溶解并突释给药的壳聚糖载药微颗粒。系统考察了交联剂含量对壳聚糖微颗粒的药物包封率以及载药量的影响,并研究了壳聚糖微颗粒在酸性条件下的溶解特性以及在体外的突释给药效果。结果表明,当交联剂质量分数为2%时,壳聚糖微颗粒的包封率及载药量最大,分别为80%和3.8%。由于对苯二甲醛与壳聚糖交联形成的Schiff-base结构,使得壳聚糖微颗粒能够在中性条件下保持结构完整,而在酸性条件下由于Schiff-base结构的不稳定性致使微颗粒迅速溶解。因此,体外释药实验结果显示,在pH = 2、37℃的模拟胃酸溶液中,1min内壳聚糖微颗粒即可达到最大释药效果,而在pH = 6.4、37℃的水溶液中,壳聚糖微颗粒可以较长时间保持稳定,药物释放缓慢。这种具有酸致突释释药性能的壳聚糖微粒载体在胃部给药系统方面有良好的应用前景。     

Swelling behaviour and paracetamol release from poly(<Emphasis Type="Italic">N</Emphasis>-isopropylacrylamide-itaconic acid) hydrogels

Copolymer hydrogels of N-isopropylacrylamide and itaconic acid (IA), crosslinked with N,N′-methylenebisacrylamide, were prepared by radical copolymerization. These hydrogels were investigated with regard to their composition to find materials with satisfactory swelling and drug release properties. A paracetamol is used as a model drug to investigate drug release profile of the hydrogels. It was found that the investigated hydrogels exhibited pH- and temperature-dependent swelling behaviour with restricted swelling and lower equilibrium degree of swelling at lower pH values and temperatures above the LCST value of PNIPAM (around 34 °C). The diffusion exponent for paracetamol release indicate that the mechanism of paracetamol release are governed by Fickian diffusion, while in all release media initial diffusion coefficient was lower than late time diffusion coefficient. Furthermore, the paracetamol release rate depends on the hydrogel degree of swelling and it increased in the first stage of diffusion process, whereas was no significant difference thereafter. The presence of the IA moieties incorporated into the network weakened the shear resistance of the hydrogels. In order to calculate the pore size the characteristic ratio for PNIPAM, C _n  = 11.7, was calculated. Based on the pore size, the investigated hydrogels can be regarded as microporous. According to the obtained results swelling behaviour, mechanical properties, drug-loading capacity and the drug release rate could be controlled by hydrogel composition and crosslinking density, which is important for application of the investigated hydrogels as drug delivery systems.     

Interpenetrating polymeric network hydrogels for potential gastrointestinal drug release

New interpenetrating polymeric network (IPN) hydrogels based on chitosan (C), poly(N‐vinyl pyrrolidone) (PVP) and poly(acrylic acid) (PAAc), crosslinked with glutaraldehyde (G) and N,N‘‐methylenebisacrylamide (MBA), were prepared and investigated for potential gastrointestinal drug delivery vehicles utilizing a model drug, amoxicillin. IPN hydrogels were synthesized by simultaneous polymerization/crosslinking of acrylic acid monomer in the presence of another polymer (C) and crosslinker (G, MBA). Three different concentrations of glutaraldehyde were used (0.5, 1.0 and 2.0 w/w) to control the overall porosity of the hydrogels, named C‐P‐AAc/0.5, C‐P‐AAc/1.0 and C‐P‐AAc/2.0, respectively. Spectroscopic and thermal analyses such as Fourier transform infrared spectroscopy, thermogravimetric analysis and thermomechanical analysis were performed for IPN characterization. Equilibrium swelling studies were conducted for pH and temperature response behavior. Swelling studies were also carried out in simulated gastric fluid of pH = 1.1 and simulated intestinal fluid of pH = 7.4 to investigate possible site‐specific drug delivery. It was found that the release behavior of the drug from these IPN hydrogels was dependent on the pH of the medium and the proportion of crosslinker in the IPN. It was observed that amoxicillin release at pH = 7.4 was higher than at pH = 1.1. The analysis of the drug release showed that amoxicillin was released from these hydrogels through a non‐Fickian diffusion mechanism. Copyright © 2007 Society of Chemical Industry     

Development of polyampholyte hydrogels based on laponite for electrically stimulated drug release

Polyampholyte hydrogels (PAHs) composed of laponite, polyacrylamide and poly(3‐acrylamidopropyl)trimethylammonium chloride crosslinked with ethylene glycol dimethacrylate were synthesized and characterized for their sensitivity to external conditions and their ability to control the release of the active drug agent paracetamol. Three PAHs were synthesized by taking the weight ratio of laponite to total monomer as 7, 15 and 29%. PAHs were characterized using Fourier transform infrared spectroscopy, thermogravimetric analysis and swelling measurements carried out in various media. Equilibrium and pulsatile swelling studies were performed on all hydrogels to determine to what extent the hydrogels would respond to changes in environmental pH, ionic strength and electric field, and how fast that response would be. Paracetamol was loaded into the hydrogels, and was released into buffered solutions as a function of pulsatile changes in pH and electric field. © 2014 Society of Chemical Industry     

l-Ascorbic acid release from phema hydrogels

Controlled release of L-ascorbic acid from poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels is reported. PHEMA hydrogels were synthesized from 2-hydroxyethyl methacrylate (HEMA) monomer in an oven. We studied the swelling of PHEMA discs in water as a fuction of temperature and thickness of xerogel discs. The fractional swelling was linear in (time)^1/2 at short times. Drug release has been examined as a fuction of temperature, initial drug load and thickness of the PHEMA discs. The fraction of avaible drug release was linear in (time)^1/2 during the initial stage too. The release experiments were carried out at 308 K. These studies allow to determinate a diffusion coefficient for transport of water into the hydrogels and a diffusion coefficient for L-ascorbic acid release from the hydrogel.     

Reinforcement and chemical cross-linking in collagen-based scaffolds in cartilage tissue engineering: a comparative study

Mechanical strength and biocompatibility are issues of most concern for scaffolds in cartilage tissue engineering. Collagen modification is always used to strengthen scaffolds. There are mainly two ways for collagen modification: inclusion of reinforcing phase to form composites and chemical cross-linking. To explore an alternative approach, the collagen hydrogel modified by a reinforcement phase was compared with cross-linking. Collagen-alginate hydrogel (CAH) and collagen hydrogel cross-linked by genipin (CGH), which were different in modification methods, were chosen candidates. A comprehensive study was carried out on mechanical, structural and biological properties including swelling ratio measurement, in vitro degradation, AFM, mechanical test, thermogravimetric analysis, and in vitro cartilage tissue engineering. The results showed that mechanical strength of collagen was more enhanced for CGH than CAH, as evidenced by analysis of swelling ratio, in vitro degradation, AFM, mechanical test and thermostability. MTT and histological results showed that CGH was superior to CAH with less cytotoxicity and more chondrocytes distributed as well as more aggrecan secreted. With the increase in culture time, the cytotoxicity of cross-linker may be alleviated. CGH may provide a more favorable biomimetic environment for cartilage growth. All these indicated that selecting a cross-linker with a minimal cytotoxicity could be more promising for collagen modification, with improvements observed in both physical and biological properties. For reinforcement, it was required that the incorporated component should be equipped with better or equivalent properties compared with collagen. This study provided important implications to engineering collagen-based hydrogels for cartilage graft applications.     

Enzyme-based green approach for the synthesis of gum tragacanth and acrylic acid cross-linked hydrogel: its utilization in controlled fertilizer release and enhancement of water-holding capacity of soil

Enzyme lipase catalyzed graft copolymerization of acrylic acid onto gum tragacanth was carried out in an aqueous medium using glutaraldehyde as a cross-linker, one more step towards green chemistry. Various reaction variables such as time, amount of solvent, temperature, pH, lipase concentration, and monomer and cross-linker concentrations were optimized to achieve a cross-linked candidate polymer with maximum fluid absorbance capacity. The structure and morphology were confirmed by Fourier transform infrared spectroscopy and scanning electron microscopy. The synthesized hydrogel held a large amount of water and was used as a device for controlled release of urea. A 10 % (w/w) of swelled hydrogel was found to enhance the water-holding capacity of the soil. The synthesized device could increase the moisture content up to 52 % in sandy loam soil and 72 % in clay soil and was found to enhance the water-holding capability of the soil. Further, the candidate polymer was studied for the controlled release of urea under eco-friendly conditions and showed case-II type urea release. The initial diffusion coefficient was found to be higher than the later diffusion coefficient indicating a higher urea release rate during the early stage. Thus, the synthesized polymer is important from technological point of view.     

Controlled release of diltiazem hydrochloride

A new type of complex reservoir–matrix system for the controlled delivery of diltiazen hydrochloride was developed. This capsule-type device was designed for oral administration to humans and/or animals. It contained (i) an appropriate amount of the drug in a compartment; (ii) a swelling-controlled membrane which was prepared by mixing polymeric materials with another appropriate amount of the drug; and (iii) a water-soluble gelatin capsule as container. The swelling-controlled membranes were prepared from poly(2-hydroxyethyl methacrylate) hydrogels. The effect of pH on the swelling of the hydrogels was studied. In-vitro dissolution testing was carried out to evaluate the release of the drug using a continuous-flow method. Zero-order release kinetics was obtained over a period of 12 h.     

A computational and experimental approach to develop minocycline-imprinted hydrogels and determination of their drug delivery performances

In this study, minocycline-imprinted hydrogels are developed for controlled drug delivery in ocular disease treatments. An integrated computational and experimental study are conducted for investigating the relationship between design parameters and the drug loading/release performance of hydrogels. First, suitable functional monomers are determined for successful drug-imprinting by studying pre-polymerization conditions with full-atom molecular dynamics (MD) simulations. MD simulations suggest that acrylic acid and itaconic acid are suitable monomers for imprinting minocycline. Then, minocycline-imprinted hydrogels are synthesized with acrylic acid, commonly used in hydrogels, and three different amounts of cross-linker ethylene glycol dimethacrylate, 1, 2 and 3 mol%. All hydrogels are characterized and their drug loading and release performances are determined. Our computational and experimental calculations indicate an optimum cross-linker amount of 2 mol% for controlled minocycline release from imprinted hydrogels with an imprinting factor of almost 3. Finally, the drug release kinetics are determined by Korsmeyer-Peppas model.     

Evaluation of the influence of spirulina microalgae on the drug delivery characteristics of genipin cross-linked chitosan hydrogels

Abstract

Chitosan-spirulina hydrogels were prepared by crosslinking of chitosan with genipin, in presence of spirulina microalgae. The swelling ratios and kinetic parameters of the hydrogels in distilled water, pH:2 and pH:7.4 solutions and the drug 5-Fluorouracil delivery capacities of the hydrogels were determined by gravimetric and spectrophotometric analyses, respectively and the results were statistically evaluated. The morphological structures, thermal and mechanical properties of the hydrogels were investigated using related techniques. Furthermore, cytotoxicity test was performed for assessment of biocompability of the hydrogels.The all results indicate that spirulina significantly improves the drug delivery properties of the genipine cross-linked hydrogels.     

Controlled release of urea from chitosan microspheres prepared by emulsification and cross-linking method

Encapsulation of urea was performed in chitosan microspheres via emulsification followed by cross-linking with genipin, a natural cross-linker. The microspheres were prepared by varying different parameters, e.g., concentrations of chitosan, urea and cross-linker. The effect of these parameters on urea loading (%), urea content (%), entrapment efficiency (%) and release rate was studied. Higher amount of chitosan (1.0?g) and cross-linker concentration (0.75?mmol/g of chitosan) produced entrapment efficiencies of 99.0 and 78.5?%, respectively. Release rate was found to be dependent on the concentrations of urea, chitosan, cross-linker and temperature of the release medium. Higher concentration of loaded urea enhanced the release rate, whereas higher concentrations of chitosan and cross-linker reduced it. Higher temperature of the release medium improved the release rate. It was found that water uptake (%) increased through the increase of concentrations of urea and chitosan and decrease of that of cross-linker. Fourier transform infrared (FTIR) spectroscopy indicated the incorporation of urea in the chitosan microspheres. There was no significant interaction between chitosan and urea as evidenced by FTIR study. Surface of the urea-loaded microspheres appeared coarser and rough compared to that of unloaded microspheres as revealed by scanning electron microscopy.