Influence of particle design on oral absorption of poorly water-soluble drug in a silica particle-supercritical fluid system.

The physicochemical characteristics and oral absorption of a poorly water-soluble drug, K-832, adsorbed onto porous silica (Sylysia 350), were compared with those of K-832 adsorbed onto non-porous silica (Aerosil 200). K-832 and silica were treated with supercritical CO(2) (scCO(2)) to produce K-832-Sylysia 350 and K-832-Aerosil 200 formulations. Scanning electron microscopy, polarizing microscopy, powder X-ray diffraction, and differential scanning calorimetry results suggested that K-832 mainly existed in an amorphous state in both formulations. The specific surface area of both formulations was much larger than that of pure K-832 crystals. The dissolution rate of K-832 from both formulations was considerably greater than that from corresponding physical mixtures due to rapid wetting of the hydrophilic carrier surfaces and amorphous state, the dissolution from the K-832-Sylysia 350 formulation being the fastest. In vivo absorption tests on the two formulations indicated no significant differences in their peak concentration (C(max)) and the area under their plasma concentration-time curve (AUC), while the concentrations of K-832 in the K-832-Sylysia 350 formulation were significantly higher than those in the K-832-Aerosil 200 formulation 1 h and 1.5 h after administration of these formulations (p<0.05). This could be attributed to the different dispersion states of K-832 in the formulations due to their different three-dimensional structures (porous and non-porous). In physical stability tests, the amorphous drugs in both formulations were stable at room temperature for at least 14 months. Thus, the absorption of poorly water-soluble drugs could be greatly improved by adsorption onto porous silica using scCO(2).

Novel iontophoretic administration method for local therapy of breast cancer.

Ductal drug therapy is a novel therapeutic approach for primary breast cancers, particularly those involving ductal carcinoma in situ lesions. Total or partial mastectomy with or without radiotherapy is the standard local therapy for primary breast cancer. Here, we propose a novel drug administration method for ductal drug therapy based on a drug delivery system (DDS) for primary breast cancer. This DDS was designed to deliver miproxifen phosphate (TAT-59), an antiestrogen drug, to ductal lesions via the milk duct, where carcinomas originate, more efficiently than systemic administration, using an iontophoretic technique applied to the nipple (IP administration). Autoradiography imaging confirmed that TAT-59 was directly delivered to the milk duct using IP administration. The plasma concentrations of TAT-59 and its active metabolite DP-TAT-59 were quite low with IP administration. The area under the curve value of DP-TAT-59 in the mammary tissue was approximately 3 times higher with IP administration than with oral administration, at a 6-fold lower dose, indicating higher availability of the drug delivered via DDS than via systemic administration. The low plasma concentrations would limit adverse effects to minor ones. These characteristics show that this DDS is suitable for the delivery of active DP-TAT-59 to ductal lesions.

Stability of amorphous drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one, in silica mesopores and measurement of its molecular mobility by solid-state (13)C NMR spectroscopy.

This study evaluated the physical stability and molecular mobility of a poorly water-soluble amorphous drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (K-832), adsorbed onto silica mesopores. K-832-Sylysia 740 and K-832-Sylysia 350 formulations, prepared by adsorbing K-832 onto porous silica Sylysia 740 (2.5-nm-diameter pores) and Sylysia 350 (21-nm-diameter pores) and stored at 60°C/80%RH (open and closed conditions), were investigated. Differential scanning calorimetry revealed that crystallization of K-832 in the K-832-Sylysia 350 formulation stored at 60°C/80%RH (open and closed conditions) was faster than that of the other formulation stored under identical conditions. Raman spectroscopy revealed shifts to higher wavenumbers in the K-832-Sylysia 350 and K-832-Sylysia 740 formulations (1497 and 1493 cm(-1), respectively) in comparison to amorphous K-832 (1481 cm(-1)); however, no distinct differences were observed in the spectra of the two formulations. Solid-state (13)C NMR spectroscopy revealed a difference in spin-lattice relaxation time in the rotating frame (T(1ρ)) between the two formulations, suggesting the lower molecular mobility of K-832 in the 2.5-nm-diameter pores than in the 21-nm-diameter pores. Thus, the crystallization rate of amorphous K-832 in the K-832-Sylysia 740 formulation was much slower. These results will be useful in estimating the physical stability of amorphous drugs in mesopores.

Enhancement of dissolution rate and oral absorption of a poorly water-soluble drug, K-832, by adsorption onto porous silica using supercritical carbon dioxide.

The aim of this study was to enhance the dissolution rate and oral absorption of a poorly water-soluble drug, 2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (K-832) by adsorbing it onto the porous silica Sylysia 350 using supercritical CO(2) (scCO(2)) as a solvent. K-832-silica formulations were prepared using scCO(2) or dichloromethane (DCM) as the solvent (K-832-silica scCO(2) and K-832-silica DCM). Scanning electron microscopy, polarizing microscopy, differential scanning calorimetry, and powder X-ray diffraction observations revealed that in both formulations, K-832 existed mainly in an amorphous state. In a dissolution test, 70.2% and 13.3% of K-832 were released from K-832-silica scCO(2) and K-832-silica DCM, respectively, within 5min, whereas only 2.3% of K-832 was released from a physical mixture within 120min. Results of an in vivo absorption test showed that the area under the plasma concentration-time curve and peak concentration of K-832-silica scCO(2) were 8.3- and 13.3-fold greater than those of K-832 crystal, whereas the corresponding values of K-832-silica DCM were 5.0- and 8.3-fold greater than those of K-832 crystal. These results suggest that the method of using scCO(2) as the solvent is effective in enhancing the dissolution rate and oral absorption of poorly water-soluble drugs because it does not require a toxic solvent and surfactant.

Preparation and properties of carrageenan microspheres containing allopurinol and local anesthetic agents for the treatment of oral mucositis.

For the treatment of oral mucositis, carrageenan microspheres containing allopurinol and local anesthetic agents, such as lidocaine hydrochloride, dibucaine hydrochloride and tetracaine hydrochloride were prepared using a spray-drying method. As base materials, kappa-carrageenan and iota-carrageenan were evaluated, since carrageenan mitigates bitter taste of lidocaine hydrochloride, dibucaine hydrochloride and tetracaine hydrochloride. The microspheres were spherical and their average diameters were about 10 microm. The drug loading efficiency was more than 70%. Allopurinol and local anesthetic agents became amorphous by the spray drying. Allopurinol and the local anesthetic agents were released from the microspheres for at least 400 min when iota-carrageenan was used as a base material. On the other hand, the release was prolonged to 600 min when kappa-carrageenan was used. The microspheres were spread and made membranes at the air/water interfaces immediately after dropped on the water surfaces. The properties of the microspheres such as dispersing efficacy and membrane production on the water surfaces suggest that the microspheres can uniformly cover inner surfaces of oral cavity to prevent and treat oral mucositis.

Transdermal delivery of indomethacin by iontophoresis.

The objective of this study was to construct a modified equation for the delivery of a drug by iontophoresis. Indomethacin was selected as a model since it has been widely used as a non-steroidal anti-inflammatory drug (NSAID) for external pharmaceutical preparations. The experiments were performed under a constant current in vivo using rat abdominal skin, and the plasma concentration was monitored by HPLC. Pharmacokinetic parameters were obtained from the plasma concentration profiles after intravenous injection. A theoretical value of the transdermal delivery of drug by iontophoresis was calculated from the plasma concentration and pharmacokinetic parameters. The experimental value was evidently higher than the theoretical one, suggesting the enhancement of passive diffusion with an increase of applied current. The modified equation was proposed for the delivery of a drug by iontophoresis incorporating enhanced passive diffusion.

Evaluation of skin barrier function using direct current III: effects of electrode distance, boundary length and shape.

The objective of this study was to propose a suitable electrode disposition and shape for iontophoretic drug delivery systems in consideration of a reduction in skin barrier function and a distribution of current density. The reduction in barrier function was evaluated with our proposed method, which measured the resistance in the short term. The distribution was estimated using an electromagnetic waves analysis program. Using rectangular electrodes, effects of distance between electrodes and boundary length of the electrode on the barrier function were examined. A distance of 2 mm decreased the barrier function effectively. The barrier function was reduced with increasing electrode boundary length. Furthermore, a surrounded square type electrode was more effective in the reduction of barrier function than a paired square type. With respect to the surrounded type electrodes, both square and circle types decreased the barrier function. However, percutaneous absorption using the circle type electrode was greater than with the square type. These phenomena are attributed to not only the electrode boundary length but also the homogeneous distribution of current density. Therefore, the surrounded circle type electrode was suitable for iontophoretic transdermal drug delivery systems.

Evaluation of skin barrier function using direct current II: effects of duty cycle, waveform, frequency and mode.

The aim of this study was to evaluate the reduction in skin barrier function caused by pulsed iontophoresis by measuring resistance in the short term. Experiments under direct current (DC) and pulsed direct current (PDC) conditions were carried out using rat abdominal skin in vivo. The resistance was measured every 62.5 micros and analyzed using a two-compartment model consisting of surface and skin resistance. Moreover, the initial value and the rate constant of surface resistance were calculated with the non-linear approximation program. Using this method, effects of duty cycle, waveform, frequency and mode on the skin barrier function were examined. The barrier function decreased with increasing duty cycle. With regard to waveforms, the influence on the skin barrier function was greatest in the order of sine, rectangular, saw and triangular waveforms. A frequency of less than 100 Hz reduced the barrier function. Considering the reduction in barrier function and skin polarization, the PDC of a rectangular waveform (around 75% as duty cycle and less than 100 Hz as frequency) or sine waveform was most suitable. In addition, the difference in the amount of drug delivered by DC and by PDC was discussed.

Evaluation of skin barrier function using direct current I: effects of conductivity, voltage, distance between electrodes and electrode area.

The objective of this study was to evaluate the reduction in skin barrier function caused by direct current iontophoresis by measuring resistance in the short term. The experiments were carried out using rat abdominal skin in vivo. The resistance was measured every 125 ms and analyzed using a two-compartment model consisting of surface and skin resistance. Moreover, the initial value and the rate constant of each resistance were calculated with the non-linear approximation program. The proposed method could evaluate the reduction in barrier function from the initial value and the rate constant of surface resistance with high sensitivity and accuracy. Using this proposed method, the effects of the conductivity of an adhesive pad, voltage, the distance between electrodes and the area of electrode were examined. The increase in conductivity of the adhesive pad decreased the initial value since the rate constant increased. The reduction in barrier function depends on voltage. Although the barrier function decreased up until an electrode distance of 1 cm, it increased beyond 1 cm. These phenomena contributed to the current pass portion in the skin because the resistance was in the order of the stratum corneum, epidermis and dermis. The initial value decreased with increasing electrode area. However, the rate constant was little affected since the current density of a topical electrode adjacent to the other electrode was high.