Sugibayashi Kenji

Swelling and mechanical properties of poly(vinyl alcohol) hydrogels

Abstract Poly(vinyl alcohol) (PVA) aqueous solutions (of high water content) were repeatedly frozen and thawed to obtain PVA hydrogels. Both the degree of cross-linking and the viscoelastic behavior of the network structure in the PVA hydrogels varied directly as a function of the number of freeze-thaw cycles, as well as the thawing temperature. Swelling kinetics of these PVA hydrogels in water were studied by weighing hydrogels swollen with water at various temperatures and time points. The rate of swelling of PVA hydrogels linearly increased with the square root of immersion time in water. A comparison of the amount of water in the swollen PVA matrix with the variation in the storage modulus of PVA hydrogels demonstrated a tendency for decrease in water absorption, as well as an increase in elasticity, with increasing cross-link density and network structure formation in these PVA hydrogels. The rate coefficients of swelling, defined as the change in the absorbed amount of water in the hydrogel vs. the square root of immersion time, increased with increasing temperature of the swelling procedure.

Penetration enhancing effect of Azone on the transport of 5-fluorouracil across the hairless rat skin

Abstract The effect of the penetration enhancer, Azone, on drug transport across skin was investigated using an in vitro permeation technique involving diffusion cells, hairless rat skin and 5-fluorouracil. The permeability of 5-fluorouracil across full-thickness skin (stratum corneum to dermis transport) was enhanced by Azone about 100-fold although a lag time of approximately 10 h was observed. This long lag time was not found after in vitro and in vivo pretreatments with Azone. Azone had no effect on the epidermis-to-dermis transport (across stripped skin) or dermis-to-stratum corneum transport (across reversed full-thickness skin). These results suggest that the amount of Azone in the skin, especially in the stratum corneum, may be related to its penetration enhancing effect. The results also suggest that incorporation of Azone into transdermal dosage forms could be useful in enhancing the transport of drugs for which the rate-limiting step for percutaneous absorption is penetration of the stratum corneum.

Diffusion of drugs in acrylic-type pressure-sensitive adhesive matrix. II. Influence of interaction

Abstract The release of 16 drugs of different molar volumes and functional groups from acrylic-type pressuresensitive adhesive (PSA) matrices was measured. 2-Ethylhexylacrylate (2-EHA) and acrylic acid (AA) copolymer were used to make the PSA matrix. The diffusion coefficient of drugs in the PSA matrix was calculated from the release data using a nonlinear regression analysis. The relationship between the diffusion coefficient of drugs in the PSA matrix and their physicochemical properties such as molar volume and chemical structure was examined. The diffusion coefficient of drugs in the PSA matrix was affected by their molar volume and by the type of functional group present. The observed diffusion behavior was interpreted by the free-volume theory, following classification by functional group and the interaction evaluated between the drug and PSA carboxyl group. The rank order confirmed from the logarithm of diffusion coefficient vs the drugs molar volume profiles (LogD- Mv profile) could not, however, be sufficiently explained by the electrostatic interaction between the PSA component (carboxyl group ) and the drug with various degrees of dipole moment values. Influence of a drug on the polymer-polymer interaction can be estimated by measuring the effect of the drugs loading on its diffusivity in the PSA matrix. A modified WLF equation was used to obtain the interaction parameter, β. The rank order of intensity of the interaction by the model drugs lidocaine, ketoprofen, aminopyrine and dipropylphthalate was evaluated by measuring the β value, and was consistent with that obtained from the LogD- Mv profiles. The absorbance of OH stretching arising from the carboxyl group at 4000 to 2000 cm −1 of the PSA without drugs on Fourier transform infrared spectroscopy ( FT-IR ) was increased with an increase in the acrylic acid content in the PSA, while the absorbance was decreased by the addition of dipropylphthalate, ketoprofen and lidocaine. The extent of the decrease was dependent on the drugs. The results obtained from FT-IR measurement also supported the rank order observed in the diffusion study. A series of these results appeared to indicate that detailed evaluation of interactions such as polymerpolymer, polymer-drug and drug-drug were required for the exact analysis of a drugs diffusion behavior through the polymer matrix (PSA).

Diffusion of drug in acrylic-type pressure-sensitive adhesive matrices. I. Influence of physical property of the matrices on the drug diffusion

Abstract Pressure-sensitive adhesive (PSA) matrices of varying ratio of 2-ethylhexylacrylate/acrylic acid co-polymers were prepared. The diffusion coefficients of prostaglandin El (PGE1) from the PSA matrices at 37 °C were calculated from release profiles. The apparent viscosity of the PSA matrices, as measured by a shear creep method, increased with increasing acrylic acid content, average molecular weight of copolymer and crosslinking agent in the PSA matrices. Generally, the PGE1 diffusion coefficient was inversely proportional to the viscosity of the PSA matrices with varying acrylic acid content. In contrast, the diffusion coefficient was virtually independent of the apparent viscosity with varying copolymer MW and crosslinking density. To further understand the relationship between the diffusion coefficient and viscosity, the microscopic viscosity of the migration routes of PGE1 in the PSA matrix was evaluated from the glass transition temperatures (Tg) to determine whether the microscopic and macroscopic (apparent) viscosities are similar. The results suggest that PGE1 diffusion coefficients from the PSA matrices can be predicted from the Tgs and microscopic viscosities.

Prediction of skin permeability of drugs. II. Development of composite membrane as a skin alternative

Abstract Artificial composite membranes composed of silicone and pHEMA (poly(2-hydroxyethyl methacrylate)) were developed as an alternative for skin membranes. The structure of the composite membranes was designed based on a model simulation of drug permeation properties. Composite membrane permeabilities for a wide range of drugs with diverse physicochemical properties were measured and compared with those of excised hairless rat skin. A reasonable correlation was found between the calculated and observed permeability coefficients, and between the observed values for the composite and excised skin membranes. It is suggested that human skin permeability of drugs may be predicted by using slightly modified composite membranes.

Mathematical models describing the drug release kinetics from pressure sensitive adhesive matrix

Abstract Several mathematical models for facilitating the interpretation of the release data cf lipophilic drugs from highly lipophilic matrices were proposed. Aminopyrine (AMP), ethinylestradiol (EE) and dipropylphthalate (DPP) were used as model drugs, and acrylic type pressure sensitive adhesive (PSA) was used as a model lipophilic matrix. Release experiments were performed using a diffusion cell at 37°C. AMP was completely released from the PSA, whereas only a fraction of EE and DPP loaded was released. There are usually several resistances involved in the diffusion of a drug through the matrix, such as interfacial transfer resistance (R) and transport resistance across the stagnant layer (H) during the drug release process; several equations containing above resistances were therefore developed in the Laplace dimension and used to interpret the obtained release data for the three drugs. Analysis of the results suggested that the stagrant layer could be neglected when using our type of diffusion cell and that the release data of the drugs from the PSA matrix could be interpreted by introducing the interfacial migration resistance and partition coefficient between the matrix and receiver solution into a Ficks diffusion equation.

Preparation and evaluation of biodegradable albumin microspheres containing mitomycin C

Abstract Albumin microspheres containing the antitumor agent, mitomycin C (MMC), were prepared by glutaraldehyde cross-Unking and heat solidification in order to administer MMC to the tumor site and to maintain prolonged MMC release by a chemoembolization technique. Various emulsification conditions were utilized in order to ameliorate the drug release curve, the mean particle size and the yield of albumin microspheres. Drug release experiments revealed that entrapped drugs were released slowly from microspheres except for the initial burst effect. The digestion of albumin microspheres, when incubated in the pH 7.4 phosphate buffer containing various proteases, was indicated by determination of weight loss and by scanning electron microscopic observation. An in vivo biocompatibility test was carried out to assess the irritability of the microspheres prepared by the various methods. Microspheres prepared were found to cause acute inflammation, but elicited no severe inflammatory responses.

Application of a thermo-responsive membrane to the transdermal delivery of non-steroidal anti-inflammatory drugs and antipyretic drugs

Abstract A thermo-responsive membrane was incorporated into a transdermal therapeutic system (TTS) which responds to thermal stimuli associated with skin temperature changes. The thermo-responsive membrane was prepared by pouring monooxyethylene trimethylolpropane tristearate (MTTS) between two porous polypropylene films. The TTS with this thermoresponsive membrane as a rate controlling membrane released non-steroidal anti-inflammatory drugs (indomethacin, ketoprofen) and antipyretic drugs (acetoaminophen, ethenzamide) in response to temperature changes between 32 and 38°C in the in vitro experiments. It was then shown that the temperature-activated TTS was operative in vivo in a rabbit model .

Effect of styrene-butadiene-styrene copolymer membrane on controlling skin permeation of drugs and solvents

Abstract The usefulness of styrene-butadiene-styrene copolymer (SBS) as a membrane to maintain a constant reservoir for skin permeation of drugs that was not altered by the vehicle applied was evaluated in in vitro experiments using diffusion cells and excised hairless rat skin. Flurbiprofen and various ratios of water-ethanol mixed solvents were selected as model drug and vehicle, and the influx of the drug, ethanol and water and efflux of water through the skin were observed. The influx of ethanol from neat cthanol was about twice that of water from neat water, A decrease in the vehicle volume was observed in an in vivo experiment. Solvent transport markedly affected permeation of the drug itself. Application of an SBS membrane suppressed skin permeation of ethanol and water from the formulations and endogenous water from the body, thus keeping fluctuations of solvent (vehicle) compositions of topical formulations to a low level and resulting in an almost constant flux of flurbiprofen. Loading of positive pressure from the formulation side allowed even further control of the solvent composition. These results suggest the usefulness of SBS membrane as a rate-limiting membrane for multi-component enhancer formulations.

Effect of chemoembolization of albumin microspheres containing mitomycin C on AH 272 liver metastasis in rats

Abstract The utility of synthesized albumin microspheres containing mitomycin C (MMC), as a chemoembolization material against liver tumors in rats was evaluated. By observing angiograms of tumorous and normal rat livers with a soft X-ray apparatus, it was found that the blood flow in target site (tumor site) could be obstructed by infusion of albumin microspheres into the blood vessels of the liver. Furthermore, histological observations demonstrated that the blood vessels of target sites in the liver were embolized by albumin microspheres containing MMC and that parenchymal cells of the liver around the interlobular connective tissue were necrosed by MMC released from the infused albumin microspheres. The antitumor effects of albumin microspheres containing MMC on AH 272 liver metastasis were noticeably increased by intra-arterial administration compared to control (saline infusion) and free MMC. These results suggest that albumin microspheres containing MMC may be very useful as a material for chemoembolization.