Kakuji Tojo

Concentration profiles of solids suspended in a stirred tank

The solids concentration profiles in a slurry mixing tank with mechanical agitation have been measured by using a photo-electric method. The concentration profile has been explained by the sedimentation-dispersion model in which the slurry flow in a stirred tank with a flat-disk turbine or a marine propeller is assumed to be dominated mainly by the upflow. The model parameters, modified Peclet numbers, Pes in terms of the falling velocity of the solid particles and Pef in terms of the liquid flow velocity, have been markedly influenced by the amount of the solids suspended. The Peclet number Pes is proportional to the solids concentration in the stirred tank under the present experimental conditions, while the parameter ratio Pef/Pes, which coincides with the ratio of the liquid flow velocity to the falling velocity of the solid particles, approaches a constant value as the concentration of solid particles is increased to 20vol.% or more.

Effect of Ultrasound Application on Skin Metabolism of Prednisolone 21-Acetate

AbstractPurpose. The effect of ultrasound on skin penetration and metabolism of prednisolone (PN) and prednisolone 21-acetate (PNA) was investigated in the hairless mouse skin in vitro. Methods. The abdominal skin excised freshly was pretreated under different ultrasound intensities (4.32, 2.88, and 1.50 W/cm2) for 10, 30, and 60 min. The penetration/metabolism rate of PNA and its metabolite (PN) was then measured using a side-by-side diffusion cell. Results. The skin penetration of PN was enhanced by the ultrasound pretreatment. This enhancement was attributed to the decrease in the stratum corneum barrier capacity by ultrasound energy. The steady-state appearance rate of PN following the skin bioconversion of PNA decreased appreciably with increasing the product of the duration of pretreatment (Dp, min) and the intensity of ultrasound applied (Iu W/cm2). When the product value was less than 40 W/cm2 ⋅ min, the steady-state appearance rate of the PN hardly increased in spite of the penetration enhancement of PNA. Conclusions. These findings indicated a possible deactivation of the skin enzymes by ultrasound energy.

Evaluation of methodology for assessing release characteristics of thermosoftening vehicles

Abstract— Methodology has been devised for the testing and evaluation of the mechanistic release of drug or markers from thermosoftening materials, as represented by the Gelucire class of excipients, which could be predictive. Release of a drug (anhydrous theophylline) and a marker (D&C yellow No. 10) was determined using a calibrated stationary disc/rotating fluid system. Of the fourteen commercially available Gelucire excipients, six were investigated in detail (G46/07, G48/09, G50/02, G50/13, G53/10, G62/05) and found to have biphasic release profiles. Lipid soluble materials demonstrated predominantly diffusion‐controlled release, while water‐dispersible materials absorbed water and showed signs of swelling which led to erosion as an additional component of the release characteristics.

Long-Term Permeation Kinetics of Estradiol: (III) Kinetic Analyses of the Simultaneous Skin Permeation and Bioconversion of Estradiol Esters

AbstractThe skin permeation system developed earlier in this laboratory was utilized to study the kinetics of the simultaneous skin permeation and bioconversion of 5 estradiol esters. The equilibrium solubility of estradiol esters in the lipophilic silicone fluid and in hydrophilic PEG 400/saline solution was found to be dependent upon the alkyl chain length of the esters. Estradiol-3,17-diacetate had a greater solubility in silicone fluid and a lower solubility in PEG 400/saline solution than estradiol-17-acetate. The (skin/silicone fluid) partition coefficients were observed to decrease as the alkyl chain increased in length. During the course of skin permeation, the estradiol esters were metabolized by esterase to regenerate estradiol. The rate of appearance of estradiol from the estradiol esters was observed to be dependent upon the ester concentration on stratum corneum surface and to follow the order of: diacetate > valerate > heptanoate > cypionate > acetate. From the dermal uptake and metabolism s...

Pharmacokinetic model of intravitreal drug injection

A dynamic mathematical model is developed to describe the distribution and elimination behavior of a drug in the vitreous body following intravitreal injection. The effects of three elimination pathways--the annular gap between the lens and the ciliary body (the posterior chamber), the lens, and the retina-choroid-sclera membrane--upon the concentration distribution in the vitreous body and the time course of the rate of elimination have been quantitatively demonstrated. The effects of metabolism in the vitreous body and the site of injection are also simulated. The annular gap between the lens and the ciliary body (the posterior chamber) is found to be a main route of elimination for large molecules injected into the vitreous body. For small or highly lipophilic molecules, however, both the posterior chamber and the retina-choroid-sclera membrane act as major routes of elimination. The lens pathway may contribute negligibly to the escape of drugs from the vitreous body. The concentration on the surface of the retina is appreciably affected by the site of injection or the initial distribution profiles, while the concentration gradient on the lens surface remains almost independent of the site of injection. To maintain the therapeutic concentration in the vitreous body or in the retina for a prolonged period of time, the drug must be injected into the posterior area of the vitreous body. When the drug is injected into the anterior segment of the vitreous body, the drug molecules quickly escape into the posterior chamber from the annular gap between the lens and the ciliary body. The present mathematical model describes well in vivo elimination profile of lomefloxacin following intravitreal injection.

In vitro apparatus for controlled release studies and intrinsic rate of permeation

Abstract The hydrodynamic characteristics of an in vitro apparatus for membrane moderated controlled drug release studies were investigated by measuring a dissolution rate from benzoic acid disk. An empirical correlation was developed for estimating the mass transfer coefficient. A simple method for correcting the effect of diffusion boundary layer on the rate of drug permeation was also described. The intrinsic rates of progesterone, testosterone and hydrocortisone through the silicone membrane were then evaluated by the correction method described.

Kinetics and Thermodynamics of Drug Permeation Through Silicone Elastomers (I) Effect of Penetrant Hydrophilicity

AbstractThe hydrophilicity of progesterone, a lipophilic penetrant, was progres sively increased by addition of one or more hydroxy substituents at different positions on the steroid skeleton. Effects of these hydrophilic substituents on the kinetics and thermodynamics of permeation of progesterone molecules through polydimethylsiloxane and polytrifluoropropylmethylsiloxane membranes were studied. The addition of OH groups was found to reduce substantially the apparent and intrinsic permeation rates of progesterone. The magnitude of this reduction was observed to be dependent upon the number and the position of hydroxy groups and could be attributed to the decrease in the polymer solubility and the increase in the aqueous solubility of progesterone molecules. A remarkable difference was observed between the intrinsic and apparent rates of permeation for progesterone, while no significant difference for the hydroxyl derivatives of progesterone. The rate of permeation increased with temperature as expected ...

Diffusion and Metabolism of Prednisolone Farnesylate in Viable Skin of the Hairless Mouse

The diffusion and metabolism of prednisolone 21-farnesylate were investigated in viable skin of the hairless mouse in vitro. The pro-drug ester was extensively metabolized in viable skin, while it was stable in the donor and receptor solutions. The rate of appearance of the prodrug and its metabolite prednisolone was markedly influenced by the direction of the skin placed between the in vitro diffusion half-cells. The rate of bioconversion of the prodrug was determined as a function of the distance from the surface of the skin. The prodrug was increasingly metabolized with the distance from the surface of the skin, indicating that the responsible enzymes are enriched in the lower layers of the viable skin. A model with linearly increasing enzyme activity in the viable skin accounts for the in vitro profiles of the diffusion/metabolism of the prodrug in the viable skin of hairless mouse.

Concentration profile in plasma after transdermal drug delivery

Abstract The plasma profile of the drug concentration after transdermal delivery was stimulated on the basis of a dynamic mathematical model. The skin was assumed to be a bilayer membrane which consists of the stratum corneum and the viable epidermis. A conventional multi-compartment model was also assumed to describe the drug elimination/distribution in the body. The effects of the skin permeation kinetics as well as the body elimination/distribution on the plasma profile of the drug concentration were analyzed under various modes of application for the drug delivery system.

Skin Irritation in Transdermal Drug Delivery Systems: A Strategy for its Reduction

PurposeActive pharmaceutical ingredients (API) in transdermal drug delivery systems (TDS) often causes skin irritation such as erythema and edema. We have studied a possible approach for the reduction of skin irritation by patch formulations that control the rates of skin permeation and elimination of API.MethodsLoxoprofen (LX-base) was used to induce the skin irritation. The redness value (Δa) was evaluated as a measure of erythema by Chroma Meter. The in vitro skin permeation and release profiles were also investigated by using a side-by-side diffusion cell.ResultsThe redness values were not correlated either with the cumulative amount of API permeated or the concentration of LX-base in the skin, but well correlated with the elimination rate of LX-base from the skin after the removal of the formulation. The formulation with gradual decrease of permeation rate during application accelerated the elimination rate after application, and resulted in the reduction of the skin irritation.ConclusionsThe skin pharmacokinetics of API, not only permeation during application but also release after the patch removal, was found to be a significant factor for skin irritation. To minimize the skin irritation, it’s also important to eliminate the residual API in the skin promptly after application.