Controlled release of dexamethasone from poly(vinyl alcohol) hydrogel

This study investigated a chemically crosslinked poly(vinyl alcohol) (PVA) hydrogel controlled drug delivery system to deliver the anti-inflammatory drug dexamethasone (DEX). The PVA hydrogels, with different crosslinking densities, were characterized by swelling studies, electron scanning microscopy, viscosity, Fourier transform infrared spectroscopy (FTIR) and in vitro release assessment. Increasing crosslinking density slowed and decreased swelling and water absorption. FTIR analysis suggested DEX has possible interactions with the crosslinker and the PVA polymer. In vitro release of DEX from PVA hydrogels was sustained for 33 days and appeared to fit the Higuchi and Korsmeyer–Peppas models. This work indicates the likelihood of PVA hydrogel as a controlled drug release system for DEX for anti-inflammatory uses.     

Solid films of blended poly(vinyl alcohol)/poly(vinyl pyrrolidone) for topical S-nitrosoglutathione and nitric oxide release

Nitric oxide (NO) is responsible for biological actions in mammals, ranging from the control of arterial pressure to immunological responses. In this study, S-nitrosoglutathione (GSNO), a spontaneous NO donor, was incorporated in solid films of blended poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) comprising a biomaterial with potential for the local delivery of NO. In dry conditions, the extinction of the absorption bands of GSNO was correlated with the increase of the absorption band of its dimmer, GS-SG, implying NO release through the homolytic cleavage of the S-N bond. Mass spectrometry was used to confirm and to monitor the release of free NO from solid PVA/PVP-GSNO films to the gas phase. Kinetic measurement based on the Griess reaction was used to show that solid PVA/PVP-GSNO films are also capable of releasing both NO and GSNO to aqueous solution trough diffusion. Storage experiments have shown that GSNO is highly stabilized in the dry PVA/PVP matrix. The results indicate that GSNO-containing PVA/PVP films may be used for delivering free NO and/or GSNO topically and controllably.     

Pharmacokinetics and biodisposition of poly(vinyl alcohol) in rats and mice

Poly(vinyl alcohol) (PVA) of various molecular weight (MW=10,560-116,600) was successfully labeled with fluorescein isothiocyanate isomer I (FITC) according to the method of de Belder and Granath. A high-performance size-exclusion chromatographic procedure was developed for the quantitative analysis of FITC-labeled poly(vinyl alcohol) (F-PVA) in biological samples. F-PVA (80 K) disappeared slowly from the blood circulation according to the first-order kinetics (t1/2=7 h) after intravenous injection to rats. A dose-independent behavior of F-PVA (80 K) was observed in the blood circulation, in the tissue distribution and in the urinary and fecal excretions. This suggested that PVAs are eliminated exclusively by the mechanisms that do not involve saturable transport processes. Furthermore, it was found that PVAs are very stable in the body because no degradation product was detected in the urine and feces. 125I-labeled poly(vinyl alcohol) (125I-PVA) was prepared by introducing tyramine residues to the hydroxyl groups of PVA molecules by the 1,1'-cabonyldiimidazole (CDI) activation method. 125I-PVA (80 K) was retained in the blood circulation for several days after intravenous injection to mice. Although the tissue distribution of PVAs was small, a significant accumulation into the liver and the spleen was observed. Fluorescence microscopic examination of paraffin section of the liver revealed that F-PVA (80 K) was endocytosed by the liver parenchymal cells. 125I-PVA (80 K) captured by liver was slowly transported via the bile canaliculi and gall bladder to the intestine and excreted in the feces. It was suggested, therefore, a long time is necessary for 125I-PVA (80 K) to be excreted perfectly from the body.     

The effects of plasticizers and titanium dioxide on the properties of poly(vinyl alcohol) coatings.

Poly(vinyl alcohol) has not previously been examined in much detail as a controlled release polymer for use in pharmaceutical formulations. However, this food grade polymer has barrier and tensile properties which make it attractive for such applications. The effects of several diluents and fillers on Poly(vinyl alcohol) (PVAL) coatings have been determined using both mechanical property and water vapor permeability measurements. It has been found that the alcohol ethoxylate Neodol 23-6.5 (CH3(CH2)11-O-(CH2-CH2-O)6-H) acts as a plasticizer for PVAL only up to 15-20 wt% in contrast to 600 molecular weight Polyethylene Glycol (PEG 600), which continuously plasticizes PVAL. The effects of Neodol on PVAL mechanical properties and water vapor permeability at higher concentrations can be explained in terms of Neodol phase separation and has been confirmed with DSC. The inert filler and whitener titanium dioxide (TiO2) monotonically degrades film mechanical properties and increases water vapor permeability of the coating. Attempts to correlate coating dust generated during particle attrition tests with mechanical property measurements were unsuccessful. A correlation between accelerated granule stability and water vapor permeability of the PVAL coating was established.     

Preparation, characterization and controlled release investigation of interpenetrating polymer networks of poly(acrylic acid)/triazole modified poly(vinyl alcohol)

A series of interpenetrating polymer networks of poly(acrylic acid) (PAA)/triazole modified poly(vinyl alcohol) (TMIPNs) were synthesized by radical polymerization in methanol at room temperature with l-ascorbic acid (Vc) and peroxide hydrogen (H2O2) as initiators and trihydroxymethyl propane glycidol ether (6360) as a crosslinker. The structures of the gels were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The swelling/deswelling behavior of hydrogels was studied in different pH and different concentrations of NaCl aqueous solutions. The results showed that the TMIPNs hydrogels had excellent pH- and salt-sensitivity in the range of the investigation. The mechanism of the swelling and the deswelling was discussed and the results were confirmed further by scanning electron microscope (SEM). In addition, the controlled release behavior of TMIPNs in vitro was also studied. The effects of physical stimulus (ultraviolet ray and ultrasonic wave), salt concentration, pH value and the swelling/deswelling on the controlled released behavior were also explored.     

Release characteristics of diclofenac sodium from poly(vinyl alcohol)/sodium alginate and poly(vinyl alcohol)-grafted-poly(acrylamide)/sodium alginate blend beads.

In this study, acrylamide (AAm) was grafted onto poly(vinyl alcohol) (PVA) with UV radiation at ambient temperature. The graft copolymer (PVA-g-PAAm) was characterized by using Fourier transform infrared spectroscopy (FTIR), elemental analysis and differential scanning calorimetry (DSC). Polymeric blend beads of PVA-g-PAAm and PVA with sodium alginate (NaAlg) were prepared by cross-linking with glutaraldehyde (GA) and used to deliver a model anti-inflammatory drug, diclofenac sodium (DS). Preparation condition of the beads was optimized by considering the percentage entrapment efficiency, particle size, swelling capacity of beads and their release data. Effects of variables such as PVA/NaAlg ratio, acrylamide content, exposure time to GA and drug/polymer ratio on the release of DS were discussed at three different pH values (1.2, 6.8, 7.4). It was observed that, DS release from the beads decreased with increasing PVA/NaAlg (m/m) ratio, drug/polymer ratio (d/p) and extent of cross-linking. However, DS release increased with increasing acrylamide content of the PVA-g-PAAm polymer. The highest DS release was obtained to be 92% for 1/1 PVA-g-PAAm/NaAlg ratio beads. It was also observed from release results that DS release from the beads through the external medium is much higher at high pH (6.8 and 7.4) than that at low pH (1.2). The drug release from the beads mostly followed Case II transport.     

Preparation and study of poly(vinyl acetate) and poly(styrene) nanosized latex with indometacin

During the last decade the number of investigations on the preparation and application of more effective drug release systems on the basis of nanocarriers from biocompatible and biodegradable polymers are considerably increasing. This is notably in force for practically water insoluble drugs to be applied in liquid forms (eye solutions for an example). The aim of the work presented was the preparation of model poly(vinyl acetate) and poly(styrene) nanosupports for indometacin and their potential inclusion in eye drops. The polymers are synthesized as nanosized latex by a radical polymerization of the monomers in the presence of indometacin. It is proved that the low polymerization temperature and initiator used do not influence indometacin structure and properties. The nanoparticles were characterized by attenuated total reflection Fourier transform infrared spectroscopic analyses, atomic force microscopy, scanning electron microscopy and transmission electron microscopy. The size of the latex particles was around 200 nm, determined by the scan electron microscopy. The indometacin delivery rate from the supports discussed in aqueous solutions was determined at pH 7.4. The change of this rate, in comparison with that for a pure drug substance, was established also as well as its dependence on the nature of the carrier.     

米诺地尔醇脂质体的制备

目的制备米诺地尔醇脂质体并评价其质量。方法采用乙醇注入法制备米诺地尔醇脂质体,以包封率为评价指标进行正交试验筛选出最佳的处方和工艺。采用HPLC测定主药含量、透析袋法测定醇脂质体的包封率。并对其粒径、电位、包封率等理化性质进行研究。结果各因素最佳的水平组合：药脂重量比为1∶10、胆固醇与大豆磷脂的重量比为1∶2、无水乙醇为处方量的30%。所制醇脂质体为乳黄色,平均粒径为1.103μm,Zeta电位为-3.69 mV,平均包封率为66.7%。结论米诺地尔醇脂质体的制备工艺简便可行,质量稳定可控,为开发新剂型奠定了实验基础。     

Preparation of a novel freeze thawed poly(vinyl alcohol) composite hydrogel for drug delivery applications.

We describe a drug delivery system based on a physically cross-linked poly(vinyl alcohol) (PVA) hydrogel for the release of Theophylline (TH). A composite was created by freezing an aqueous solution of PVA/NaOH onto a PVA/poly(acrylic acid) substrate. This formed a strong interface and demonstrated greater physical strength than the hydrogel alone. Such systems have potential for a variety of localised controlled drug delivery applications, for example, as coatings for implantable devices. Importantly, the results suggest that a versatile synthetic platform is possible that may provide different functional materials or combination of such. The resultant samples were characterised using optical microscopy, modulated differential scanning calorimetry (MDSC) and dissolution testing. The microstructure of the gels was examined using micro-thermal analysis (microTA) which is a combination of atomic force microscopy and thermal analysis. TH was found to have an effect on the crystalline structure and dissolution showed a Fickian release, suggesting that swelling and crystallinity were the controlling mechanisms.     

Deamidation of a model hexapeptide in poly(vinyl alcohol) hydrogels and xerogels

Abstract: Polymeric controlled release systems have been proposed to prolong the half‐lives of protein and peptide drugs in vivo and to deliver active drug at a controlled rate. These systems are ineffective, however, if the drug is not stable during storage and release. This study addresses the effect of poly(vinyl alcohol) on the stability and release of an incorporated hexapeptide, VYPNGA, which undergoes deamidation. Two types of peptide‐loaded poly(vinyl alcohol) matrices were formed, a semisolid hydrogel and a lower water content ‘xerogel’, and stored at 50°C for up to 122 days. The hexapeptide was less stable in both poly(vinyl alcohol) matrices than in aqueous buffer or lyophilized polymer‐free powders. The type of poly(vinyl alcohol) matrix appeared to influence the degradation mechanism, since the product distributions differ in the hydrogel and the xerogel. The results suggest that, rather than stabilizing this peptide, incorporation in poly(vinyl alcohol) matrices reduces stability relative to solution and lyophilized controls.     

Pegylated enzyme entrapped in poly(vinyl alcohol) hydrogel for biocatalytic application

A procedure for enzyme entrapment into matrices suitable for biocatalytic applications is reported. The method, which takes advantage of the stable formation of polyvinyl alcohol (PVA) hydrogels by freezing and thawing PVA aqueous solutions, was assayed using lipase as model enzyme. The leakage of lipase was minimised by using high molecular weight PVA and by previous conjugation of the enzyme to PEG. The immobilised PEG enzyme maintained its catalytic activity in organic solvents also, thus allowing enzymatic activity towards water insoluble substrates. The activity was largely increased reducing the diffusional constrain by cutting the matrices into slices of micron size. Matrix-entrapped lipase-PEG, when used in the hydrolysis of acetoxycoumarins, showed a conversion rate of about 10 times lower than the enzyme-PEG in the free form, and maintained regioselectivity when a diacetylated product was used as substrate.     

Electrically controlled release of sulfosalicylic acid from crosslinked poly(vinyl alcohol) hydrogel

Electrically controlled drug delivery using poly(vinyl alcohol) (PVA) hydrogels as the matrix/carriers for a model drug was investigated. The drug-loaded PVA hydrogels were prepared by solution-casting using sulfosalicylic acid as the model drug and glutaraldehyde as the crosslinking agent. The average molecular weight between crosslinks, the crosslinking density, and the mesh size of the PVA hydrogels were determined from the equilibrium swelling theory as developed by Peppas and Merril, and the latter data were compared with those obtained from scanning electron microscopy. The release mechanisms and the diffusion coefficients of the hydrogels were studied using modified Franz-Diffusion cells in an acetate buffer with pH 5.5 and temperature 37 degrees C during a period of 48 h, in order to determine the effects of crosslinking ratio, electric field strength, and electrode polarity. The amounts of drug released were analyzed by UV-vis spectrophotometry. The amounts of drug released vary linearly with square root of time. The diffusion coefficients of drug-loaded PVA hydrogels decrease with increasing crosslink ratio. Moreover, the diffusion coefficients of the charged drug in the PVA hydrogels depend critically on the electric field strength between 0 and 5 V as well as on the electrode polarity. Thus, the release rate of sulfosalicylic acid can be altered and controlled precisely through electric field stimulation.     

A poly(vinyl alcohol) nanoparticle platform for kinetic studies of inhaled particles

The lack of a well defined nanosystem that retains its physicochemical properties and can be tracked in complex biological environments is one reason why the study of NP transport across biological barriers is currently so difficult. As a result, surprisingly little is known about the fate of sub-micron particles once they deposit in the airways of the lung. The aim of this study was to design and manufacture a novel nanoparticle (NP) core that would be physically stable, i.e., not aggregate in biological fluids, and act as a tracking system to investigate NP distribution in the lung. Accordingly, covalent fluorescent labeling (to allow particle tracking) of 40% hydrolyzed poly(vinyl alcohol) was undertaken by inducing dissociation of the carboxylic acid group (ArCOO^?) of 5(6)-carboxyfluorescein (CF) which then reacted with the hydroxyl group of poly(vinyl alcohol) (PVA) to produce a covalently linked PVA-CF ester. Polymer purification was followed by NP manufacture and characterization in biological media. In contrast to commercial latex particles which aggregated in both cell culture medium and Hank’s balanced salt solution (HBSS), the PVA nanoparticles retained their original size (ca. 220 nm), maintained a neutral surface charge in cell culture medium for 24 h and were not acutely toxic to respiratory cells in vitro.     

Microparticulated systems based on chitosan and poly(vinyl alcohol) with potential ophthalmic applications

Abstract

Spherical microparticles for encapsulation of drugs for the treatment of diseases, with a diameter ranging between 2 and 4?µm, were obtained by double crosslinking (ionic and covalent) of chitosan and poly(vinyl alcohol) blend in a water-in-oil emulsion. Microparticles characterisation was carried out in terms of structural, morphological and swelling properties in aqueous media. The presence of chitosan in particles composition confers them a pH-sensitive character. Toxicity and hemocompatibility tests prove the biocompatible character of microparticles. The pilocarpine loading capacity is high as well as the release efficiency which increases up to 72 and 82% after 6?h. The obtained results recommend the microparticles as sustained release drug carriers for the treatment of eye diseases.     

Preparation and characterisation of poly(vinyl alcohol)/cyclodextrin microspheres as matrix for inclusion and separation of drugs

Poly(vinyl alcohol) (PVA) microspheres containing cyclodextrin (CD) were obtained by chemical cross-linking with glutaraldehyde of an acidified mixture solution of PVA and alpha-, beta- or gamma-CD. The amount of linked CD in microspheres, estimated by tetrazolium blue method, decreases in the order beta- > gamma- > alpha-CD. The dimensions of PVA/gamma-CD microspheres are much higher than those of PVA/alpha- and beta-CD. The cross-linking density of microspheres was estimated by the amount of iodine retained by the polymer matrix. The pore size as well as the porous volume of PVA/CD microspheres decrease significantly on increasing the amount of glutaraldehyde, but are enough large to permit the access of drugs to the CD cavity. In order to test the PVA/CD microsphere inclusion ability, the microspheres were packed in a glass column and the liquid chromatographic behaviour by isocratic elution of different drugs or typical organic compounds, taken as model drugs, was investigated.     

Chemical stability of peptides in polymers. 1. Effect of water on peptide deamidation in poly(vinyl alcohol) and poly(vinyl pyrrolidone) matrixes.

This paper examines the effect of water content, water activity, and glass transition temperature (T(g)) on the deamidation of an asparagine-containing hexapeptide (VYPNGA; Asn-hexapeptide) in lyophilized poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) at 50 degrees C. The rate of Asn-hexapeptide deamidation increases with increasing water content or water activity and, hence, decreasing T(g). The rate of deamidation is more sensitive to changes in these parameters in PVA than in PVP. Deamidation is clearly evident in the glassy state in both formulations. In the glassy state, the peptide is more stable in PVA than in PVP formulations but is less stable in the rubbery state. No single variable (water content, water activity, or T(g)) could account for the variation in deamidation rates in PVA and PVP formulations. Deamidation rates were correlated with the degree of plasticization by water (distance of T(g) from the dry intrinsic glass transition temperature); coincident curves for the two polymers were obtained with this correlation. Deamidation in PVA and PVP was closely correlated with the extent of water-induced plasticization experienced by the formulation relative to its glass transition at 50 degrees C, suggesting that the physical state of formulations could be used to predict chemical stability.     

Hydrogels formed by crosslinked poly(vinyl alcohol) as sustained drug delivery systems

Poly(vinyl alcohol) was crosslinked with ethylene glycol diglycidyl ether to obtain hydrogel-forming polymers. The polymers were also substituted with oleoyl chloride, providing hydrogels with weak solubility. These new polymeric materials were evaluated for the formulation of sustained drug delivery systems. Vancomycin hydrochloride was used as a peptidic model drug whose sustained release should minimize its inactivation in the upper part of the gastrointestinal tract. Spray-dried mixtures of the drug and the polymer [at 1:4 and 1:8 (w:w) ratios] were prepared and the release of the drugs from the mixtures was evaluated in vitro at pH 2.0, 5.5, 7.4, and 8.0. The results indicated that the crosslinked polymers slowed down the release of the drugs with respect to the pure drug at each pH. The degree of crosslinking of ethylene glycol diglycidyl ether and the extent of substitution with oleoyl chloride were found to influence drug release.