Yasuko Obata

Neural network based optimization of drug formulations.

A pharmaceutical formulation is composed of several formulation factors and process variables. Several responses relating to the effectiveness, usefulness, stability, as well as safety must be optimized simultaneously. Consequently, expertise and experience are required to design acceptable pharmaceutical formulations. A response surface method (RSM) has widely been used for selecting acceptable pharmaceutical formulations. However, prediction of pharmaceutical responses based on the second-order polynomial equation commonly used in an RSM, is often limited to low levels, resulting in poor estimations of optimal formulations. The purpose of this review is to describe the basic concept of the multi-objective simultaneous optimization technique, in which an artificial neural network (ANN) is incorporated. ANNs are being increasingly used in pharmaceutical research to predict the nonlinear relationship between causal factors and response variables. Superior function of the ANN approach was demonstrated by the optimization for typical numerical examples.

Formula optimization of theophylline controlled-release tablet based on artificial neural networks.

Formulation of the controlled-release tablet containing theophylline was optimized based on the simultaneous optimization technique in which an artificial neural network (ANN) was incorporated. As model formulations, 16 kinds of theophylline tablets were prepared. The amounts of Controse, the mixture of hydroxypropylmethyl cellulose with lactose, cornstarch and compression pressure were selected as causal factors. The release profiles of theophylline were characterized as the sum of the fast and slow release fractions. The initial weight, the rate constant in the fast release fraction and the rate constant in the slow release fraction were estimated as release parameters. A set of release parameters and causal factors were used as tutorial data for ANN and analyzed using a computer. Based on the plasma concentration profiles of theophylline predicted by the pharmacokinetic analysis in humans, a desirable set of release parameters was provided. The simultaneous optimization was performed by minimizing the generalized distance between the predicted values of each response and the desirable one that was optimized individually. The optimization technique incorporating ANN showed a fairly good agreement between the observed values of release parameters and the predicted results.

Effect of ethanol on skin permeation of nonionized and ionized diclofenac

Abstract The effect of ethanol on the skin permeation of diclofenac (DF) was investigated using excised hairless rat abdominal skin in vitro. The steady-state flux of DF increased with increase in the pH of DF-suspended donor solution; this phenomenon demonstrated a close correspondence with enhancement in the solubility of DF in the donor solution. In constrast, the steady-state permeability coefficient ( P ) of DF was inversely proportional to the change in pH of the donor solution, suggesting that the pattern of skin permeation of DF apparently obeyed the pH-partition theory, although the contribution of the ionized form of DF cannot be taken as being negligible. In order to determine the contribution of either the nonionized or ionized form on the skin permeation of DF, the permeability coefficients for each form (nonionized and ionized molecules) were calculated using the P values and the degree of ionization of DF in the donor solution. Addition of ethanol in the donor solution led to a marked decrease in the P value of nonionized DF, whereas the P value of ionized DF was not greatly affected by ethanol. A large amount of ethanol might increase the extent of permeation of DF through the lipid pathway by affecting the dense barrier structure of the skin. The flux of the ionized form of DF was particularly enhanced due to the increase in solubility as a result of the addition of ethanol, since the partition coefficient (skin/donor solution) of the ionized form was not greatly decreased compared with that of the nonionized form.

Infrared spectroscopic study of lipid interaction in stratum corneum treated with transdermal absorption enhancers.

To develop a transdermal drug delivery system, it is necessary to search for effective modulators to act as permeation enhancers and evaluate its mechanisms of action. It has been suggested that attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) is a useful tool for evaluating the functional group interaction of the intercellular lipids in the stratum corneum. The purpose of this study is elucidation of the effect of the transdermal permeation enhancers on the intercellular lipid in hairless rat stratum corneum using the ATR-FTIR. Firstly, to confirm the frequencies related to the intercellular lipid in stratum corneum, CH(2) asymmetric and symmetric vibrations were clearly related to the intercellular lipids. In intact stratum corneum, the blue shift of CH(2) asymmetric and symmetric stretching vibrations begins at about 40 degrees C and remarkable change is induced at 50 degrees C. The administration of l-menthol causes disorder of the intercellular lipids in stratum corneum similar to that of heat application. The disordering of intercellular lipid lattices in stratum corneum induced by the l-menthol might be related to the enhancing effect of l-menthol. The results provide information for the development of novel transdermal drug delivery systems.

Buccal absorption of ergotamine tartrate using the bioadhesive tablet system in guinea-pigs

The buccal administration of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea-pigs. T(max) of ET in plasma of buccal administration was significantly smaller than that of oral administration. For the buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W-35 was most effective. It is likely that the high lipophilic property of Witepsol W-35 in which ET was dissolved facilitated the drug release by its relatively low melting point (around 35 degrees C), consequently a rapid absorption. In addition, the enhancing activity of the cod-liver oil extract (CLOE) in hydrophilic ointment on the in vivo buccal ET absorption was clarified to be comparable to that in the in vitro study utilizing the keratinized epithelial-free membrane (KEF-membrane) of the hamster cheek pouch.

Role of the charge, carbon chain length, and content of surfactant on the skin penetration of meloxicam-loaded liposomes

The objective of this study was to investigate the influence of surfactant charge, surfactant carbon chain length, and surfactant content on the physicochemical characteristics (ie, vesicle size, zeta potential, elasticity, and entrapment efficiency), morphology, stability, and in vitro skin permeability of meloxicam (MX)-loaded liposome. Moreover, the mechanism for the liposome-enhanced skin permeation of MX was determined by Fourier transform infrared spectroscopy and differential scanning calorimetry. The model formulation used in this study was obtained using a response surface method incorporating multivariate spline interpolation (RSM-S). Liposome formulations with varying surfactant charge (anionic, neutral, and cationic), surfactant carbon chain length (C4, C12, and C16), and surfactant content (10%, 20%, and 29%) were prepared. The formulation comprising 29% cationic surfactant with a C16 chain length was found to be the optimal liposome for the transdermal delivery of MX. The skin permeation flux of the optimal formulation was 2.69-fold higher than that of a conventional liposome formulation. Our study revealed that surfactants affected the physicochemical characteristics, stability, and skin permeability of MX-loaded liposomes. These findings provide important fundamental information for the development of liposomes as transdermal drug delivery systems.

Effect of Cod-Liver Oil Extract on the Buccal Permeation of Ergotamine Tartrate

Ergotamine tartrate (ET) is used clinically in the treatment of migraines. However, the bioavailability of ET is rather poor following oral administration. Therefore, we tried to improve ET delivery using buccal administration. The purpose of this study was to investigate the characteristics of the permeation of ET through the hamster cheek pouch in vitro using a two-chamber diffusion cell, and to evaluate the effect of permeation enhancers on the transbuccal delivery of ET. Cod-liver oil extract (CLOE), polyoxyethylene hydrogenated castor oil (HCO 60), sodium glycocholate (GC), and sodium caprate (CA) were selected as premeation enhancers considering their low irritancy of the mucosa. When the enhancers were added to the donor cell at a 5% concentration each, the ET permeation rate markedly increased compared with that in a control not containing enhancer. Among these enhancers, CLOE exhibited the greatest effect. Because CLOE is composed of 16 kinds of fatty acids, the enhancement action of each of the major components was separately determined. As major fatty acids, palmitic acid, oleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were selected and their enhancing effects were studied. The enhancing effect of each fatty acid was significantly lower than that of CLOE.

Novel method to observe subtle structural modulation of stratum corneum on applying chemical agents.

In the development of functional chemicals such as percutaneous penetration enhancers and cosmetics, the structural evidence at the molecular level in stratum corneum (SC) is highly desirable. We developed a method to observe a minute structural change of intercellular lipid matrix and corneocytes on applying the chemicals to the SC using synchrotron X-ray diffraction technique. The performance of the present method was demonstrated by applying typical chemicals, chloroform/methanol mixture, hydrophilic ethanol and hydrophobic d-limonene. From the small- and wide-angle X-ray diffraction we obtained the following results: on applying chloroform/methanol mixture the intercellular lipids were extracted markedly, on applying ethanol the intercellular lipid structure was slightly disrupted, ethanol molecules were taken into the corneocytes and in addition the pools of ethanol seem to be formed in the hydrophilic region of the intercellular lipid matrix in the SC, and on applying d-limonene the repeat distance of the long lamellar structure increased by incorporating d-limonene molecules, the intercellular lipid structure was slightly disrupted, and the pools of d-limonene were formed in the hydrophobic region of the intercellular lipid matrix in the SC.

A statistical approach to the development of a transdermal delivery system for ondansetron.

Transdermal delivery of drugs has gained attention as an alternative to intravenous and oral methods of delivery. However, the skin permeation of drugs is generally poor. To overcome this problem, many permeation enhancers have been developed. In this study, ondansetron hydrogels were prepared, and their skin permeation and pharmacological effects were evaluated in mice. To prepare the hydrogels, a Box-Behnken design was introduced. Fifteen formulations of ondansetron hydrogels composed of hydroxyethylcellulose and hydroxypropylcellulose as gel bases, l-menthol as a penetration enhancer and isopropanol (IPA), N-methyl-2-pyrrolidone (NMP) and water as a solvent were prepared. The quantities of IPA (X(1)), l-menthol (X(2)) and NMP (X(3)) were selected as causal factors. We performed an in vitro skin permeation study and an in vivo skin irritation study with the test hydrogels. The flux and the total irritation score were selected as response variables. The optimal formulation, one that has an appropriate penetration and an acceptable skin irritation score, was estimated using a nonlinear response surface method incorporating thin-plate spline interpolation. The optimal formulation also delivered the desired pharmacological activity. These results indicated the feasibility of delivering ondansetron transdermally.

Altered sphingoid base profiles predict compromised membrane structure and permeability in atopic dermatitis

BACKGROUND Ceramide hydrolysis by ceramidase in the stratum corneum (SC) yields both sphingoid bases and free fatty acids (FFA). While FFA are key constituents of the lamellar bilayers that mediate the epidermal permeability barrier, whether sphingoid bases influence permeability barrier homeostasis remains unknown. Pertinently, alterations of lipid profile, including ceramide and ceramidase activities occur in atopic dermatitis (AD). OBJECT We investigated alterations in sphingoid base levels and/or profiles (sphingosine to sphinganine ratio) in the SC of normal vs. AD mice, a model that faithfully replicates human AD, and then whether altered sphingoid base levels and/or profiles influence(s) membrane stability and/or structures. METHODS Unilamellar vesicles (LV), incorporating the three major SC lipids (ceramides/FFA/cholesterol) and different ratios of sphingosine/sphinganine, encapsulating carboxyfluorescein, were used as the model of SC lipids. Membrane stability was measured as release of carboxyfluorescein. Thermal analysis of LV was conducted by differential scanning calorimetry (DSC). RESULTS LV containing AD levels of sphingosine/sphinganine (AD-LV) displayed altered membrane permeability vs. normal-LV. DSC analyses revealed decreases in orthorhombic structures that form tightly packed lamellar structures in AD-LV. CONCLUSION Sphingoid base composition influences lamellar membrane architecture in SC, suggesting that altered sphingoid base profiles could contribute to the barrier abnormality in AD.