Yutaka Higashi

Chitosan Dispersed System for Colon-specific Drug Delivery

A chitosan dispersed system (CDS), which was composed of active ingredient reservoir and the outer drug release-regulating layer dispersing chitosan powder in hydrophobic polymer, was newly developed for colon-specific drug delivery. An aminoalkyl methacrylate copolymer RS (Eudragit) RS) was selected as a hydrophobic polymer because it is hardly dissolved in acidic medium in which easily dissolves chitosan. In order to obtain the bi-functional releasing characteristics, i.e. time dependent and site specific, capsules containing the active ingredient (Drug Capsules) were coated by the chitosan dispersed hydrophobic polymer, resulting in CDS Capsules. The release rate could be controlled by changing the thickness of the layer. Furthermore, for colon-specific drug delivery, an additional outer enteric coating was necessary to prevent the drug release from CDS Capsules in the stomach, since chitosan dispersed in the layer dissolves easily under acidic conditions. Resultant enteric-coated CDS Capsules reached the large intestine within 1-3 h after oral administration and they were degraded at the colon in beagle dogs.

Phosphatidylserine as a determinant for the tissue distribution of weakly basic drugs in rats

Interorgan variation in tissue distribution of weakly basic drugs such as quinidine, propranolol, and imipramine was investigated as a function of binding to phosphatidylserine (PhS) in tissues. Tissue distributions of these drugs were determined using 10 different tissues at a steady-state plasma concentration and were expressed as tissue-to-plasma partition coefficients (Kp values). The concentration of PhS in the tissue was determined by two-dimensional thin-layer chromatography. Plotting of Kp values, except for brain, against the tissue PhS concentrations showed a linear relationship, indicating that PhS is a determinant in the interorgan variation of these tissue distributions. Further, differences in tissue distribution among the drugs was considered to be due to the difference in binding potency to PhS. Drug binding parameters to individual standard phospholipid were determined using a hexane-pH 4.0 buffer partition system. Binding was highest to PhS, and a linear relationship was found between the log nK [product of the number of binding sites (n) and the association constant (K) for PhS binding] obtained in vitro and Kp values of drugs in tissues in vivo. The empirically derived equation, Kp = 14.3 × (log nK) × (PhS cone.) − 8.09, was found to predict Kp values in vivo of weakly basic drugs. Thus, a determinant of interorgan variation in the tissue distribution of the weakly basic drugs studied was the tissue concentration of PhS and the drug binding affinity to PhS.

In-vitro Permeability to Salicylic Acid of Human, Rodent, and Shed Snake Skin

Abstract— In‐vitro permeability to salicylic acid of human, rodent, and shed snake skin has been examined for the purpose of selecting model membranes for human skin corresponding to different anatomic sites, since a marked regional variation is suggested among the different sites. The greatest permeability to salicylic acid was observed in the scrotum, that of the sole was negligible. The cheek, neck, and inguinal skin seemed more permeable than the breast, back, thigh, lower leg, or foot skin. Shed snake and skin of hairless rat were found to show similar permeability to human breast and thigh skin. Wistar rat and nude mouse skin showed similar permeability to human cheek, neck, and inguinal skin.

Pharmacokinetic Analysis of the Absorption Enhancing Action of Decanoic Acid and Its Derivatives in Rats

The enhancing action of decanoic acid (C1O) and its derivatives on mucosal absorption of phenolsulfonphthalein (PSP) in the jejunum or colon was analyzed using pharmacokinetics in rats. After administration of a solution containing PSP and an enhancer [C10, 2-hydroxydecanoic acid (2-OHC10), or 3-hydroxydecanoic acid (3-OHC10)] into the jejunal or colonic loop, the amounts of PSP and enhancer remaining in the loop and/or plasma PSP concentration were determined periodically. 2-OHC10 exhibited a greater absorption enhancing potency than C10, while 3-OHC10 was less effective. Disappearance of residual PSP from the loop ceased after complete absorption of the enhancer. The enhancer-induced disappearance rate constant of PSP correlated well with the product of the enhancer disappearance rate and its capacity to sequester calcium ions. In conclusion, the enhancement of PSP mucosal absorption by C10 and its derivatives is consistent with a pharmacokinetic model, assuming that the enhanced membrane permeability of PSP depends on the enhancer disappearance kinetics from the loop and its calcium ion sequestration capacity.

Role of Phosphatidylserine in the Cellular and Subcellular Lung Distribution of Quinidine in Rats

The role of phosphatidylserine in the cellular and subcellular lung distribution of quinidine was investigated in rats, since quinidine was found to bind preferentially to phosphatidylserine. The concentration of phosphatidylserine in the cellular and subcellular fractions was determined after separation by two-dimensional thin-layer chromatography. Selective accumulation of quinidine in vivo was observed in the alveolar macrophage at the cellular level and in the plasma membrane at the subcellular level. Both alveolar macrophages and plasma membranes were rich in phosphatidylserine compared to other fractions. When plasma levels were kept at steady state by i.v. infusion, the distribution of quinidine in the lung cellular and subcellular fractions was linearly correlated with the concentration of phosphatidylserine (r = 0.906). These results suggest that the concentration of phosphatidylserine is a dominant determinant of the cellular and subcellular lung distribution of quinidine.

Effects of low-dose phenytoin administered to newborn mice on developing cerebellum

To examine correlations between dose levels of phenytoin (PHT) and neurotoxic effects on cerebellar development, we administered 10, 17.5, 25, and 35 mg/kg PHT suspended in sesame oil orally to newborn Jcl:ICR mice once a day during postnatal days 2-4 and determined plasma PHT concentrations during the administration period. Mortality rates were 12.5% and 35.2% in males and 15.3% and 33.3% in females for the 25 and 35 mg/kg PHT-treated groups during the PHT treatment, respectively. In the 25 and 35 mg/kg PHT-treated groups, total brain weight, the size of the cerebellum, and cerebellar weight were significantly reduced on postnatal day 21. However, in the 10 and 17.5 mg/kg PHT-treated groups, total brain weight and the size and weight of the cerebellum did not differ from those of the control group. Histologically, the number of pyknotic cells in the external granular layer (EGL) in the 25 and 35 mg/kg PHT-treated groups was increased on postnatal day 5, and the EGL was thicker than in the control group on postnatal day 14. Some of the Purkinje cells in the 35 mg/kg PHT-treated group showed degeneration. Plasma PHT levels were 10.7 +/- 2.2 and 24.6 +/- 2.6 micrograms/ml in the 25 and 35 mg/kg PHT groups on the third day of PHT treatment, respectively. In the 25 mg/kg PHT group, plasma PHT level was found to be in the therapeutic range for humans, 10-20 micrograms/ml. Accordingly, during pregnancy, epileptic women should be carefully given PHT at the lowest effective dose while plasma PHT levels are monitored properly. These findings emphasize the importance of pharmacokinetics in evaluating of phenytoin-induced developmental neurotoxicity.

Biopharmaceutics: Effect of Ointment Bases on Topical and Transdermal Delivery of Salicylic Acid in Rats: Evaluation by Skin Microdialysis

Microdialysis has been used to determine the concentration of salicylic acid in skin tissue and plasma periodically for 4 h to evaluate the effect of ointment bases on topical and transdermal delivery of salicylic acid. The ointment bases examined were solbase (water‐soluble), poloid and white petrolatum (oleaginous), hydrophilic poloid (water in oil (w/o) type emulsion lacking water) and absorptive ointment (w/o‐type emulsion containing water). The ointments (0.1 g) containing 25 μmol salicylic acid were applied for 2 h to the surface of rat skin (1 cm2) with (intact) or without the stratum corneum.

Decanoic acid induced enhancement of rectal absorption of hydrophilic compounds in rats.

The enhancing effect of decanoic acid (CIO) on the rectal absorption of phenolsulfonphtalein (PSP) was analyzed with a pharmacokinetic model. The transfer index of PSP from the rectal lumen to the epithelial layer in the presence of C10 was proportional to the product of the C10 disappearance rate from the rectal lumen and its calcium ion sequestration capacity. The enhancement of rectal PSP absorption by different doses of C10 was also predictable by using a permeability index, Pa, of PSP, which was defined as a proportionality constant relating transfer index and the product value described above. The Pa values of various hydrophilic compounds with different molecular weights were also estimated from their rectal bioavailability in the presence of C10. A linear relationship was observed between Pa values and reciprocal values of the square root of individual molecular weight. These findings suggest that the Pa index is related to the permeant’s diffusion coefficient through paracellular aqueous openings formed by C10.

In-vivo Calibration of Microdialysis Probe by Use of Endogenous Glucose as an Internal Recovery Marker: Measurement of Skin Distribution of Tranilast in Rats

To estimate the absolute concentration of substrates surrounding a microdialysis probe in‐vivo, we developed a simple calibration method using endogenous glucose as an internal recovery marker and determined the skin distribution of tranilast (N‐(3,4‐dimethoxycinnamoyl)anthranic acid), an anti‐allergic agent, in rats.

Gastrointestinal absorption of griseofulvin from liquid organic acids and esters in rats

Abstract Griseofulvin was administered to rats in the dosage form of an aqueous suspension, a corn oil-in-water emulsion, or a solution of liquid organic acids and esters and the absorption characteristics of griseofulvin following its oral, intraduodenal or intragastric administration were compared. The extent of absorption of griseofulvin was markedly enhanced when administered orally as either a solution of ethyl acetoacetate, methyl propionate, or methyl caproate. Greatest absorption was observed in the methyl propionate solution. The absorption result of the methyl propionate solution was higher than that of an aqueous suspension when evaluated by AUC and C max . It was also found that ethyl acetoacetate enhanced mainly the gastric absorption of griseofulvin and methyl propionate and methyl caproate enhanced the intestinal absorption of griseofulvin. The effect of the vehicles on the gastric emptying process of griseofulvin and gastrointestinal mucosal damage was also investigated. A strong inhibitory effect on the gastric emptying process of griseofulvin was observed following oral administration of emulsion, methyl propionate or methyl caproate solution. Gastrointestinal mucosal damage was not observed in any of the cases. Some discussions are also presented.