Toshio Inagi

Enhanced transdermal delivery of indomethacin-loaded PLGA nanoparticles by iontophoresis

Nanoparticles effectively deliver therapeutic agent by penetrating into the skin. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. IM and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis with 3 V/cm was applied, permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents.

Enhanced transdermal delivery of indomethacin using combination of PLGA nanoparticles and iontophoresis in vivo

Nanoparticles effectively deliver therapeutic agent by penetrating into the rat skin in vivo. Indomethacin (IM) and coumarin-6 were loaded in PLGA nanoparticles with an average diameter of 100 nm. Indomethacin (IM) and coumarin-6 were chosen as a model drug and as a fluorescent marker, respectively. The surfaces of the nanoparticles were negatively charged. Permeability of IM-loaded PLGA nanoparticles through rat skin was studied in vivo. Higher amount of IM was delivered through skin when IM was loaded in nanoparticles than IM was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied at 0.05 mA/cm(2), permeability of IM was much higher than that obtained by simple diffusion of nanoparticles through skin. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal systemic delivery of therapeutic agents.

Enhanced transdermal permeability of estradiol using combination of PLGA nanoparticles system and iontophoresis

Estradiol is a therapeutic agent for treatment of perimenopausal symptoms and osteoporosis. Conventional oral or intravenous administration of estradiol has many problems, such as, metabolization in gastrointestinal tract and liver, pain by using an injection needle, rapid increase of drug levels in blood and fast clearance with unwanted side effects including thrombosis, endometriosis and uterus carcinoma. The use of nanocarriers for transdermal delivery has been studied because of their ability to deliver therapeutic agents for long time with a controlled ratio, escaping from the first pass effect by liver. In this study, permeability of estradiol-loaded PLGA nanoparticles through rat skin was studied. Higher amount of estradiol was delivered through skin when estradiol was loaded in nanoparticles than estradiol was free molecules. Also, iontophoresis was applied to enhance the permeability of nanoparticles. When iontophoresis was applied, permeability of estradiol-loaded PLGA nanoparticles was much higher than that obtained by simple diffusion of them through skin, since they have negative surface charges. They were found to penetrate through follicles mainly. Also, enhanced permeability effect of estradiol by using nanoparticle system and iontophoresis were observed in vivo. The combination of charged nanoparticle system with iontophoresis is useful for effective transdermal delivery of therapeutic agents.

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.

Proposed Partition Mechanism of Tetracycline

The partition mechanism of tetracycline in an n-octanol/H2O system was studied by mathematical treatment of the changes in the apparent partition coefficient determined by Colaizzi and Klink (J. Pharm. Sci., 58, 1184 (1969)) and by us, and by measuring the spectral properties of tetracycline in organic solvents. Tetracycline exists in a neutral molecular form in n-octanol, so it could be concluded that transfer of tetracycline from an aqueous to an organic phase is governed not by the amount of the zwitterionic form, but by the amount of the neutral molecular form in the aqueous phase. Results showed that the tetracycline molecule itself is hydrophobic, but that the concentration of the neutral molecular species in the aqueous phase is very small. The relationship between the apparent partition coefficient and the three macroscopic ionization constants of tetracycline at a certain pH was also clarified. From this the macroscopic ionization constants were evaluated. The values agreed very well with those determined by potentiometric titration.

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 13C 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.

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.

An insight into the role of barrier related skin proteins

It is well-known that intercellular lipids in the stratum corneum (SC) of the skin play an important role in maintaining barrier function, and many types of penetration enhancers affecting lipids are used in topical products to improve transdermal drug permeability. Recently, it was reported that functional proteins in tight junctions of the epidermis are important for barrier function. In this study, the effects of penetration enhancers such as fatty esters, amines/amides, and alcohols on the barrier function of the skin were evaluated in rat skin and normal human-derived epidermal keratinocytes (NHEK). All penetration enhancers decreased the electrical impedance (EI), however, the potencies of some penetration enhancers were not equal between rat skin and NHEK. The differences were clarified by immunohistochemical studies: some fatty esters decreased the immunoreactivity of involucrin and keratin 10 in the upper layer of the epidermis, while alcohols decreased the immunoreactivity of desmoglein-1, claudin-1, and E-cadherin located in the lower layer of the epidermis. From these results, it is suggested that penetration enhancers show new action mechanisms disturbing barrier-related proteins in epidermis, which are classified into two categories depending on their action sites.

Effects of nonsteroidal antiinflammatory drugs on the proton exchange reaction between octanol and water: its correlation with their inhibitions of inflammation and prostaglandin synthesis.

Effect of various antiinflammatory drugs on proton exchange between octanol OH and water after partition equilibrium between octanol and water at pH 7.4 was examined. These drugs accelerated the proton exchange reaction to different extents. The rate constant of the proton exchange induced by the drugs was well correlated with their biological potencies in inhibiting Carrageenan-induced edema and prostaglandin synthesis, suggesting that proton or electron movement in an apolar environment is very important for exhibition of these biological effects.