Yoshihiro Tokudome

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.

Preparation and characterization of ceramide-based liposomes with high fusion activity and high membrane fluidity.

Liposomes are useful vesicles that deliver drugs effectively to various organs. For transdermal applications, liposomes with high membrane fluidity, high fusion activity, and comprising stratum corneum lipid have been used for drug delivery. With the aim to increase drug distribution to the skin, we developed new liposomes with three characteristics: high membrane fluidity, high fusion activity to the stratum corneum lipid liposomes (SCLL), and lipid compositions based on stratum corneum lipids. New liposomes were prepared based on SCLL. First, lipid compositions of SCLL were optimized. Second, the alkyl chain length of ceramides and fatty acids, and the saturation degree of fatty acids were altered. As a result, liposomes with the highest membrane fluidity and fusion activity to SCLL were composed of C-8 ceramide/cholesterol/linolenic acid/cholesterol sulfate = 45/5/5/45 (w/w%), and named C8L. C8L had 1.54-times greater membrane fluidity and 6.57-times greater fusion activity to SCLL than SCLL. Transmission electron microscopy revealed that C8L had a spherical structure. The surface charge and the particle size were approximately -47.7 mV and 184 nm, respectively. Thus, in the future, C8L will be used to facilitate drug delivery to the skin.

Non-invasive and rapid analysis for observation of internal structure of press-coated tablet using X-ray computed tomography.

Background: Since the internal structure of a tablet can be measured without destruction of the sample by X‐ray computed tomography (CT), it could be applied to quality control of tablets during the manufacturing process. Aim: A novel, fast, noninvasive tablet observation method was developed to evaluate the internal structure of commercial press-coated tablets by using X-ray CT. Method: Thirty-two CT image slices of four kinds of commercial press-coated tablets (tablets A, B, C, and D) were measured 300 m interval between edges of the tablet by using an X-ray CT. The thinnest layer thickness of the tablets and distance between centers of gravity (DCG) of tables were calculated. Results: The order of the TLT of the tablets was tablet B > tablet C > tablet D > tablet A. The result indicated that the order of DCG was tablet A > tablet D > tablet C > tablet B. Noninvasive observation of the internal structure of commercial, press-coated tablets by X-ray CT has been demonstrated to be useful in quality control of production. Conclusion: The internal structure of press-coated tablets could be observed without pretreatment, without destruction, and very rapidly by X‐ray CT.

Long-term therapeutic effect of novel calcium phosphate-based compounds injected in ovariectomized rats

The specific aim of this study was to evaluate the efficacy of well-characterized Mg/Zn/F-CaP preparations (administered by injection) in preventing bone mineral deficiency in ovariectomized (OVX) rats. Donryu rats (4 weeks old, average weight 70 g) were divided into six experimental groups: GN (normal), GC (control, OVX), and OVX rats injected with suspensions of MZF-CaPs (G2, G3, and G4) or with Zn-containing tricalcium phosphate (ZnTCP, G1). The composition of the preparations was G1: 34.1 wt % Ca; 19.5 wt % P; and 6.17 wt % Zn; G2 (#51): 23.7 wt % Ca; 13.6 wt % P; 1.1 wt % Mg; 2.9 wt % Zn, and 1.1 wt % F; G3 (#68): 22.4 wt % Ca; 14.1 wt % P; 2.6 wt % Mg, 2.6 wt % Zn, and 2.3 wt % F; G4 (#76): 28.5 wt % Ca; 15.5 wt % P; 1.9 wt % Mg, 1.8 wt % Zn, and 3.0 wt % F. The suspensions (10 mg/0.2 mL) were injected into the right thigh once a week for 12 weeks. Bone mineral density (BMD) was measured by X-ray computed tomography and bone mechanical strength (BMS) was measured as femoral three-point bending strength. BMD and BMS were significantly higher in the femurs from groups G1, G2, G3, and G4 than from GC. No significant difference was observed in BMD or BMS between the left and right femurs for any group. The results indicate that the injected Mg/Zn/F-CaP compounds were effective in preventing bone loss induced by ovariectomy in rats and suggest that these compounds have potential use for treating osteoporosis.

Effects of solid-state reaction between paracetamol and cloperastine hydrochloride on the pharmaceutical properties of their preparations

Tablets containing both paracetamol (PM) and cloperastine hydrochloride (CLH) in a combination formulation prepared by standard vertical granulation technology were found to have altered pharmaceutical properties. The hardness and disintegration time of tablets containing both PM and CLH gradually increased during storage, and the cross-screw did not operate smoothly during preparation of the mixed powder. The objective of the present study was to investigate the mechanism of formation of eutectic mixtures consisting of PM and CLH. Binary mixtures of PM and CLH in various proportions were prepared as physical mixtures and analyzed by DSC to study their thermal behavior. Phase diagrams obtained from the endothermic peaks due to melting of physical mixtures of PM and CLH demonstrated the formation of eutectic mixtures with eutectic temperatures of 86.9-110.2 degrees C depending on the ratio of constituents. The formation of the eutectic mixture was studied for a 50:50 mol.% ratio of PM and CLH. PXRD analysis revealed that the eutectic mixture of PM and CLH is structurally different from native PM and CLH. The most probable interaction sites between PM and CLH were demonstrated by DSC analysis of a binary mixture of PM and CLH prepared by melt quenching.

Nano- and macro-geometrical structural change of caffeine and theophylline anhydrate tablets during hydration process by using X-ray computed tomography

The effects of nano- and macro-geometrical factors on the hydration kinetics of caffeine (CA) and theophylline anhydrate (TA) tablets at high humidity were investigated using X-ray high-resolution computed tomography (CT). Hydration profiles of CA and TA tablets obtained at 25 and 50 MPa, 96% relative humidity, and 20 degrees C were measured by weight and X-ray CT. The total tablet volume (G-V) and average tablet density (G-D) calculated based on the volume and weight of tablets, and tablet volume (CT-V) and tablet density (CT-D) were evaluated by X-ray CT. The hydration kinetics of CA and TA tablets followed two-dimensional growth of nuclei (Avrami-Erofee) and three-dimensional phase boundary equations, respectively. The increase in the G-V of TA tablets was initially more than, but later less than, that of CA tablets. The G-D of CA tablets varied extensively and was constant initially, whereas that of TA tablets decreased significantly in the initial stage. The CT-V of CA tablets gradually increased initially, but that of TA tablets increased significantly early on. The inter-granular volume (IG-V) of both tablets decreased initially with large fluctuations, but then increased. The CT-D of CA tablets decreased significantly, but that of TA tablets did not decrease. The hydration kinetics of CA and TA tablets was affected by changes in the geometrical structure of the tablets. X-ray CT is a powerful tool for evaluating dynamic changes inside tablets.