Solid molecular dispersions of poorly water-soluble drugs in poly(2-hydroxyethyl methacrylate) hydrogels.

The applicability of cross-linked hydrogels in forming solid molecular dispersions to enhance the delivery of poorly soluble drugs has not been fully explored. The purpose of this study is to characterize physicochemical parameters affecting the formation of solid molecular dispersions of poorly water-soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels and to investigate the effect of storage humidity levels on their physical stability. Samples were prepared by an equilibrium solvent loading process, using diclofenac sodium, piroxicam and naproxen as model drugs. These were characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), as well as changes in the physical state during storage under different humidity conditions. The results show that a threshold drug loading level of about 30% exists in these solid molecular dispersions, above which amorphous to crystalline transition may occur. At any given drug loading, the onset of such change in physical state is accelerated at higher relative humidity levels during storage. The presence of hydrogen bonding between the polymer and the drug, as reflected in the observed FTIR band shifts, improves the compatibility between the drug and the polymer. This, together with a decreased mobility in the glassy polymer, helps to retard the crystallization event below the loading threshold. An increase in dissolution rate is also observed from the polymeric solid molecular dispersion as compared with that of the crystalline pure drug. These physicochemical results indicate that solid molecular dispersions based on PHEMA hydrogels can effectively enhance the dissolution and therefore should be potentially useful in improving the oral bioavailability of poorly water-soluble drugs.     

Enhanced kinetic solubility profiles of indomethacin amorphous solid dispersions in poly(2-hydroxyethyl methacrylate) hydrogels

The feasibility of forming solid molecular dispersions of poorly water-soluble drugs in crosslinked poly(2-hydroethyl methacrylate) (PHEMA) hydrogel has recently been reported by our group. The purpose of the present study is to investigate the extent of enhancement of kinetic solubility of amorphous solid dispersions (ASDs) of indomethacin (IND) in crosslinked PHEMA hydrogels as compared with those based on conventional water-soluble polymer carriers. Our results show that under non-sink conditions, the initial solubility enhancement is higher for ASDs based on polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose acetate succinate (HMPCAS), but the ability to maintain this solubility enhancement at longer times is better for ASDs based on PHEMA over a period of 24h with the extent of solubility enhancement of IND ASDs in PHEMA falling between those in PVP and HPMCAS at 10.0% IND loading after 6h and outperforming those in PVP and HPMCAS at 32.9% IND loading after 8h. The observed kinetic solubility profiles reflect the fact that the amorphous IND is released from PHEMA by a different mechanism than those from water-soluble polymer carriers. In this case, the dissolution of IND ASD from water-soluble PVP and HPMCAS is almost instantaneous, resulting in an initial surge of IND concentration followed by a sharp decline due to the nucleation and crystallization events triggered by the rapid build-up of drug supersaturation. On the other hand, the dissolution of IND ASD from insoluble crosslinked PHEMA hydrogel beads is less rapid as it is regulated by a feedback-controlled diffusion mechanism, thus avoiding a sudden surge of supersaturation in the dissolution medium. The absence of an apparent decline in drug concentration during dissolution from IND-PHEMA ASD further reflects the diminished nucleation and crystallization events during IND dissolution from hydrogel-based solid molecular dispersions. Based on the XRD analyses, a threshold IND loading level of about 34% in PHEMA has been identified, above which amorphous to crystalline transition tends to occur. Also, by selecting the appropriate particle sizes, immediate to controlled release of IND from IND-PHEMA ASD can be readily achieved as the release rate increases with decreasing PHEMA bead size. Furthermore, a robust physical stability has been demonstrated in IND-PHEMA ASD with no drug precipitation for up to 8 months at IND loadings below 16.7% under direct open cup exposure to accelerated stability conditions (40°C/75% RH).     

The mechanism of interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate)

The extent of the interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate), (PHEMA), is independent of temperature between 22-50 degrees C which is consistent with an ion-ion interaction mechanism. Different contact lens materials exhibit different affinities for chlorhexidine digluconate, the extent of uptake correlating in rank order with the number of free carboxylic acid sites in the polymers. Esterification of the carboxyl groups with diazomethane, resulted in a reduction in the affinity of the treated polymers for chlorhexidine to a near basal level. The uptake of chlorhexidine in soaking solution experiments involving lenses made from PHEMA and the more ionic material, poly(2-hydroxyethyl methacrylate-co-isobutyl methacrylate-co-methacrylic acid), was consistent with their carboxylate content. However, the fraction of bound disinfectant released was lower from the terpolymer, suggesting there are differences in bonding strengths between chlorhexidine and different contact lens hydrogels.     

The mechanism of interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate)

The extent of the interaction between chlorhexidine digluconate and poly(2-hydroxyethyl methacrylate), (PHEMA), is independent of temperature between 22–50 °C which is consistent with an ion-ion interaction mechanism. Different contact lens materials exhibit different affinities for chlorhexidine digluconate, the extent of uptake correlating in rank order with the number of free carboxylic acid sites in the polymers. Esterification of the carboxyl groups with diazomethane, resulted in a reduction in the affinity of the treated polymers for chlorhexidine to a near basal level. The uptake of chlorhexidine in soaking solution experiments involving lenses made from PHEMA and the more ionic material, poly(2-hydroxyethyl methacrylate - co-isobutyl methacrylate - co - methacrylic acid), was consistent with their carboxylate content. However, the fraction of bound disinfectant released was lower from the terpolymer, suggesting there are differences in bonding strengths between chlorhexidine and different contact lens hydrogels.     

In-vivo drug delivery of 5-fluorouracil using poly(2-hydroxyethyl methacrylate-co-acrylamide) hydrogels

Poly(2-hydroxyethyl methacrylate-co-acrylamide) hydrogels crosslinked with ethylen glycol dimethacrylate were used as devices for the in-vivo drug release of 5-fluorouracil (5-FU). Drug-loaded hydrogels were subcutaneously implanted in the back of Wistar rats. All hydrogel discs reached an equilibrium swelling degree, which was slightly larger than that determined in-vitro. After 30 days of implantation, the hydrogel discs were transparent, and without fracture or apparent degradation. In addition, a fibrous capsule was not detected around the hydrogels that had greater hydration degrees. Release of 5-FU from these hydrogels allows the drug to remain in the plasma from 1 to 5 days, in spite of its short plasma half-life (15 min). This was an improvement of up to 98-times compared with the intraperitoneal drug administration. Administration of 5-FU by implantation of 2-hydroxyethylmethacrylate-co-acrylamide copolymeric hydrogels seems to be a good candidate for 5-FU therapy, since the drug released results in a therapeutically suitable plasma concentration of 5-FU for an extended period of time, despite the short half-life of the drug.     

On the anomalous sorption behaviour of chlorhexidine with poly(2-hydroxyethyl methacrylate)

General observations of solute: plastic interactions would suggest that the sorption of the cationic preservative, chlorhexidine, with poly (2-hydroxyethyl methacrylate) (PHEMA) is not only unexpected but also atypical in its properties. The polymer and preservative were investigated independently and the sorption of PHEMA with simple solutes, namely benzoic acid, benzocaine and aniline found to exhibit conventional properties. The single exception was the uptake of small amounts of benzocaine and aniline cations at acidic pH's. In order to elucidate the sorption characteristics of chlorhexidine a series of N¹-(p-chlorophenyl)-N⁵-alkylbiguanide acetates were synthesized. The anomalous sorption behaviour observed between PHEMA and the bis biguanide, chlorhexidine, was also found to be characteristic of these monofunctional biguanide derivatives. The extent of the interactions increased with increasing alkyl chain length (R = methyl to n-octyl), this being interpreted in terms of an interaction binding mechanism via the biguanide functional group stabilized by van der Waal's forces between the alkyl chain and the polymer backbone. Atypical sorption behaviour was observed for simple organic cations, biguanide and N¹-phenylbiguanide acetate with PHEMA, a possible inference being that this is a general characteristic of all cationic sorption with PHEMA.     

Evaluation of poly(2-hydroxyethyl methacrylate) gels as drug delivery systems at different pH values

Studies of dynamic and equilibrium swelling, structural characterisation and solute transport in swollen poly(2-hydroxyethyl methacrylate) gels (pHEMA) cross-linked with tripropyleneglycol diacrylate (TPGDA) were done for a wide range of TPGDA concentrations. The influence of the pH on these pHEMA properties was evaluated. In swelling studies it was found that in changing the pH from 6.5 to 12.0, a large increase in swelling occurred, from approximately 48 to 55%, for the lowest concentration of TPGDA (1 mol%), and from 40 to 80% for the highest concentration (10 mol%). Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) measurements were made after the equilibrium swelling of the gels at different pH values, to explain these results. The advantage of using these gels as controlled drug delivery systems is illustrated using salicylic acid (SA) as a model drug. The loading and the release of the SA were made at different pH values and the results obtained showed that it is possible to modulate the hydrogel performance by controlling an external factor, the pH at which the drug loading and release were performed.     

Chitosan-functionalised poly(2-hydroxyethyl methacrylate) core-shell microgels as drug delivery carriers: salicylic acid loading and release

This work presents the evaluation of chitosan-functionalised poly(2-hydroxyethyl methacrylate) (CS/PHEMA) core-shell microgels as drug delivery carriers. CS/PHEMA microgels were prepared by emulsifier-free emulsion polymerisation with N,N?′-methylenebisacrylamide (MBA) as a crosslinker. The study on drug loading, using salicylic acid (SA) as a model drug, was performed. The results showed that the encapsulation efficiency (EE) increased as drug-to-microgel ratio was increased. Higher EE can be achieved with the increase in degree of crosslinking, by increasing the amount of MBA from 0.01?g to 0.03?g. In addition, the highest EE (61.1%) was observed at pH 3. The highest release of SA (60%) was noticed at pH 2.4, while the lowest one (49.4%) was obtained at pH 7.4. Moreover, the highest release of SA was enhanced by the presence of 0.2 M NaCl. The pH- and ionic-sensitivity of CS/PHEMA could be useful as a sustained release delivery device, especially for oral delivery.     

Release dynamics of ciprofloxacin from swellable nanocarriers of poly(2-hydroxyethyl methacrylate): an in vitro study

Swellable polymeric nanosystems have emerged as promising materials in drug release technologies. Such systems have shown potential in releasing antibiotic drugs and to do so controllably. In the present investigation poly(2-hydroxyethyl methacrylate) nanoparticles were synthesized by suspension polymerization of 2-hydroxyethyl methacrylate and characterized by various techniques such as Fourier transform–infrared spectrometry, scanning electron microscopy, particle size analysis, and surface charge measurements. The synthesized nanoparticles were swellable in water and showed promise to function as a swelling controlled-release system. The release kinetics of drug-loaded particles was studied in phosphate-buffered saline (PBS) using ciprofloxacin as a model antibacterial drug. The chemical stability of the pure and released drug was also assessed in PBS (pH 7.4), acidic (pH 1.8), and alkaline (pH 8.6) solutions. The in vitro blood compatibility of nanoparticles was also investigated in terms of hemolysis tests. The drug-loaded nanoparticles were also examined for their antibacterial and blood-compatible behaviors.From the Clinical EditorSwellable polymeric nanosystems have emerged as promising materials in drug release technologies. In this paper, the release kinetics, antimicrobial properties and in vitro “blood compatibility” is reported for a specific swellable polymeric nanosystem.     

Dynamic swelling behavior of gamma-radiation induced polyelectrolyte poly(AAm-co-CA) hydrogels in urea solutions

The aim of this study was to investigate the equilibrium swelling properties in urea solutions of gamma-radiation induced polyelectrolyte copolymeric hydrogels consisting of acrylamide (AAm) and crotonic acid (CA). Poly(acrylamide-co-crotonic acid), poly(AAm-co-CA) hydrogels containing different amounts of CA were obtained in the form of rods after radiation. Swelling experiments were performed in aqueous urea solutions at 25 degrees C, gravimetrically. The hydrogels showed large extents of swelling in aqueous (urea/water) media the swelling being highly dependent on the chemical composition of the hydrogels and irradiation dose. The percentage swelling of poly(AAm-co-CA) hydrogels was between 1160 and 4250%, while that of the AAm hydrogels was between 670 and 900%. The diffusional exponent values (n) are between 0.51 and 0.66, hence the diffusion of urea/water into the hydrogels is non-Fickian. Equilibrium urea/water contents of the hydrogel systems were changed between 0.870 and 0.977.     

Bioadhesive properties and rheology of polyether-modified poly(acrylic acid) hydrogels

Transient rheological properties and mucoadhesion of hydrogels composed of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO, or Pluronic) block copolymers and poly(acrylic acid) were explored. Nine Pluronic copolymers ranging in nominal molecular weight and PPO/PEO content were grafted to PAA through C-C bonds, with or without the use of divinyl cross-linker, ethylene glycol dimethacrylate (EGDMA). The hydrogel elasticity increased with the PPO content in the copolymers, as well as in the presence of EGDMA. Tensile tests were conducted to measure the fracture strength and the work of adhesion between the hydrogels and rat intestinal tissue. The fracture strength was proportional to the gel pseudoequilibrium modulus and depended on the nominal length of the PPO segments in the parent Pluronic copolymer. The work of mucoadhesion and gel cohesion declined with the loss angle measured in oscillatory shear experiments. The length of the PEO segments in Pluronic affected the work of adhesion. Applications of the Pluronic-PAA gels as vehicles in oral drug delivery are discussed. The longest Pluronic copolymers bonded to PAA resulted in copolymeric gels with strongest mucoadhesive properties.     

In vitro and in vivo behaviour of narciclasine released from matrices based on poly (2-hydroxyethyl methacrylate).

Narciclasine (1,2,3,7-tetrahydroxy-8,9-methylendioxy-1,2,3,4-tetrahydrophena ntridone) is a natural substance with strong antimitotic effects on cells and potential antitumor activity. Its release form a hydrogel matrix was studied with the purpose of avoiding the concentration spikes of the parenteral administration. The matrix prepared by gamma ray polymerization of a mixture of 2-hydroxyethyl methacrylate (85%) and trimethylolpropane trimethacrylate (15%) was found to release narciclasine for several days, according to a diffusion controlled mechanism. In agreement with its antimitotic effect, narciclasine inhibited the growth rate of healthy mice, when the drug-loaded matrix was introduced subcutaneously. Antitumor effect was observed in an experimental model of Erlich ascitic tumor when low amounts of tumor cells were inoculated. No effect was observed at high concentrations of inoculum or towards solid tumors (Sarcoma 180). This behaviour was related to the rapid clearance of narciclasine from the body which prevented the reaching of sufficient therapeutical concentrations. A pharmacokinetic investigation carried out by an original method of assay demonstrated that narciclasine was accumulated in significant amounts in the kidney only and eliminated in urine with a half time of less than 20 min.     

The influence of gamma-irradiation upon the chemical and biological properties of insulin

Partially purified insulin preparations of bovine and porcine origin, were subjected to gamma-irradiation with doses ranging from 1.0 up to 25 kGy (0.1–2.5 Mrad) at 0C or ambient temperature. The susceptibility of insulin to the irradiation was determined by chromatography, electrophoresis and assay of the biological activity. The sterilizing effect of the gamma-irradiation was investigated forBacillus pumilus as well as for artificial mixtures of lactose and several bacilli. It is concluded that the sterilizing dose for the investigated insulins was 2.2 kGy. At doses up to 25 kGy at 0C no specific radiolytic products were detectable, whereas the biological activity was fully retained. The content of dimers and the content of related peptides appeared to increase gradually with the irradiation dose absorbed. No effects of long-term storage could be demonstrated on biological and chemical properties of insulin after 2.2, 4.5 and 7.5 kGy.     

聚甲基丙烯酸-2-羟乙酯软骨膜的制备及性能研究

目的制备缓、控释性能优异的依诺沙星-聚甲基丙烯酸-2-羟乙酯水凝胶膜,在体外研究其性能。方法以过硫酸铵（〔（NH4）2S2O8〕）作为引发剂,KH570（γ-甲基丙稀酰氧基丙基三甲基硅烷）为交联剂,2-甲基丙烯酸-2-羟乙酯（HEMA）为原料聚合成水凝胶膜。选用依诺沙星为模型药物水相聚合,通过分步法和同步法导入药物,并测定其体外释药情况。结果水凝胶膜表面形态理想,导入药物后的载药膜具有良好的膨胀性能和更优秀的缓、控释特征。结论以甲基丙烯酸-2-羟乙酯（25%）为单体、KH570（γ-甲基丙稀酰氧基丙基三甲基硅烷）为交联剂通过溶液聚合开发出一类性能优异的载药水凝胶膜。     

Effect of thermal cycling on the properties of thermoresponsive poly(N-isopropylacrylamide) hydrogels

Crosslinked poly(N-isopropylacrylamide) hydrogels have been widely studied for a variety of thermoresponsive applications, including chromatography, affinity precipitation, controlled biocatalysis, viable cell immobilisation, biomimetic actuators and, in particular, modulated drug delivery. The exploitation of crosslinked poly(N-isopropylacrylamide) hydrogels in all these applications relies on the well-known temperature-sensitive swelling properties of these hydrogels. The purpose of the current study was to determine the effects of repeated thermal cycling on the thermoresponsive swelling behaviour of crosslinked poly(N-isopropylacrylamide) hydrogels. The results show that repeated thermal cycling leads to the formation of cracks on the surface of the hydrogels. Repeated thermal cycling also results in a decreased degree of swelling in the crosslinked poly(N-isopropylacrylamide) hydrogels at temperatures below the volume phase transition temperature (VPTT).     

The influence of various counter ions on the interaction of chlorhexidine with the hydrophilic contact lens polymer,poly(2-hydroxyethyl methacrylate)*

The commercially available salts of chlorhexidine were found to interact with the hydrogel poly (2-hydroxyethyl methacrylate) to different extents, the affinity for the polymer decreasing in the order acetate, gluconate, chloride. The uptakes of the acetate and gluconate salts were almost entirely irreversible over the concentration range studied. The influence of some alternative counter ions, namely amino acids and dicarboxylic acid salts, was examined and found to generate a three-fold variation in the extent of the chlorhexidine interaction. Uptakes were greatest for counter ions that were either hydrophobic in character or bore a net negative charge. Only two compounds, glycine and monosodium oxalate, were successful in reducing the extent of sorption below that observed for chlorhexidine hydrochloride.     

Intravenous fate of poly(2-(dimethylamino)ethyl methacrylate)-based polyplexes

The objective of this study was to assess the in vivo fate of poly(2-(dimethylamino)ethyl methacrylate) (pDMAEMA)-based polyplexes after intravenous administration into mice. Circulation kinetics and tissue distribution in terms of plasmid localization and transfection efficiency were assessed. To gain more insight into the observed biodistribution and gene expression profile, the interaction of pDMAEMA-based polyplexes with blood components (erythrocytes and albumin) was investigated in vitro. In the case of i.v. injection of positively charged polyplexes at a dose of 30 microg DNA most of the radioactivity was found in the lungs and the liver 60 min after injection. In the case of pDMAEMA/DNA polyplexes with a negative charge, uptake occurred mainly by the liver. Administration of positively charged complexes at a 30 microg DNA dose resulted in reporter gene expression primarily in the lungs. Injection of negatively charged complexes and naked plasmid did not result in luciferase expression in any of the organs examined. In vitro turbidity experiments showed the induction of a charge dependent aggregation process upon addition of albumin to the polyplexes pointing out to the involvement of aggregate formation in the dominant lung uptake of the positively charged polyplexes. Also, incubations of polyplexes after pre-incubation with a physiological concentration of albumin with washed erythrocytes confirmed that polyplexes induce the formation of extremely large structures. This paper underlines the need for the design of systems with reduced interaction with blood components to promote the delivery of DNA to target tissues outside the lungs.