The appearance of propylene glycol (PG) in rat dermis and subsequent protein structural alteration were examined by measurement of PG spectra from the dermis and the spectra for amide regions from the dermal protein molecules. Spectra were obtained using attenuated total reflectance infrared spectroscopy following treatment of the rat skin with a high-purity oleic acid (HP-OA)/PG vehicle. HP-OA enhanced the PG flux in the dermis. The higher the concentration of HP-OA, the more quickly PG molecules distributed to the dermis and reached the maximal level (steady-state level). Determination of the Amide II frequency in the dermis indicated that the structure of dermal proteins was altered by HP-OA, which implied that HP-OA entered into the dermis. The extent of such alteration was time-dependent and independent of HP-OA concentration. The water content in the dermis did not change with time for at least 4 h after HP-OA treatment, indicating that the dermal tissue did not swell during the course of the experiment and that the spectral absorbance of water did not influence the spectra of Amide II regions. The results of this study suggest that changes in the structure of dermal proteins must be considered as an important determinant for solute penetration through whole skin. In addition, determination of the appearance of a solute, such as PG, in the dermis may be of value for characterizing the action of HP-OA, a skin penetration enhancer.

Long-circulating thermosensitive liposomes with hyperosmotic internal aqueous phase intended for the delivery of macromolecules were prepared and characterized in vitro. Higher osmotic pressure markedly increased the release of macromolecules such as dextran. This effect was pronounced with liposome containing amphipathic polyethyleneglycol. The release of dextran was also influenced by the concentration of amphipathic polyethyleneglycol added to the liposomes. These results indicate that higher internal osmotic pressure and amphipathic polyethyleneglycol content contributes to the in vitro temperature-dependent release of the macromolecule dextran.

The ground or lyophilized mixtures of amphotericin B (AMB) with various polymers were examined in terms of dissolution and bioavailability in oral and rectal administration. The grinding of AMB with polyvinylpyrrolidone (PVP) or sodium caseinate (Na-CSN) decreased the potency of the drug, and the loss of potency in the mixture was greater than that of the drug ground alone. However, some improvement in dissolution by grinding with PVP and Na-CSN was observed. Lyophilization of AMB with PVP or Na-CSN resulted in the highest level of dissolution of the drug. X-ray diffraction patterns indicated that AMB lyophilized with PVP was present in the amorphous state, forming a solid dispersion. The lyophilized mixture of AMB with PVP (1:9, w/w) was administered to rabbits orally or rectally. When administered orally, bioavailability of the lyophilized mixture increased significantly, showing 3.7-fold greater AUC_0-24h than that of AMB alone. The extent of bioavailability of suppositories markedly varied in the kind of vehicle. Lyophilization of AMB with PVP was found to be useful for improving the bioavailability of AMB.

Drugs for oral ingestion are taken with water although package inserts often do not state this expectation explicity. It is, however, not uncommon that water is not available when oral drugs are to be administered to children who have developed acute fever or that patients refuse to take drugs because of their bitter taste, and hence cannot be treated appropriately. Bearing this in mind, we have recently developed, on a test scale, a preparation (named “Gummi Drug”) of acetaminophen (AAP) mixed in Gummi (a soft gel-type candy) as an orally administered medicine which can be taken without water and does not taste bitter. A Gummi Drug was manufactured under different conditions to explore the optimum conditions for preparing that which should be uniformaly distributed in the vehicle. We found that a suspension-type Gummi Drug (mixed AAP powder, named “SUS-Gummi”) of AAP can be manufactured with high distribution uniformity when the active ingredient is added at a temperature of 50°C and the drug is subjected to 24-h aging at 10°C using a plastic plate. In the case of a dissolution-type Gummi Drug (mixed after dissolving AAP in ethanol, named “DIS-Gummi”) of AAP, we also found that a method of manufacturing with high distribution uniformity was additional heating of 60°C and the same aging condition with SUS-Gummi. We suggest that DIS-Gummi was superior to SUS-Gummi in terms of uniform distribution, although about 0.5% ethanol remained in the former preparation.

We investigated the effect of a 3-component solid dispersion system on the gastrointestinal absorption of the poorly water-soluble drug (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-3-(3-methylphenyl) urea (YM022) in beagle dogs. Absorption of YM022 from the 3-component system was markedly improved compared to that when administered using the β-form crystal, amorphous form and 2-component solid dispersion. The concentration of dissolved YM022 at 20°C was determined in purified water, JP 13 1st disintegration test fluid, and 0.05, 0.1 and 0.5% solutions of either polyoxyethylene hydrogenated caster oil 60 (HCO-60) or hydroxypropylmethylcellulose 2910 (TC-5E), both of which are components of the YM022 solid dispersion system. In HCO-60 aqueous solution, YM022 concentration in the amorphous form and 2- and 3-component solid dispersion systems was markedly higher than that in stable crystalline form. On succesive dispersion of the 3-component system in purified water with the replacement of solution with fresh purified water at each dispersion, the initial high level of YM022 concentration was maintained. These findings indicate that interaction among YM022, TC-5E and HCO-60 in solid and solution states may result in the improvement of YM022 bioavailability.

In order to develop the intravenous injection of water-insoluble drugs, compatibility tests with infusion fluids, especially the occurrence of drug precipitate, were studied using the solubility product. A quinolone derivative (AT) was used as the water-insoluble drug. A lactic acid was selected for the optimal salt form. When the AT solution containing 0.006 _M lactic acid was admixed with a typical infusion fluid having a chloride ion, a hydrochloride salt was precipitated. The limit of precipitation yielded between 1.4 and 1.7×10^-5 Eq²/ι² as the ion product ([AT⁺][Cl^-]). This value agreed with the solubility product of the drug (Ksp), 1.62×10^-5 Eq²/ι². These results suggest that the limit of salt precipitate when a drug solution is admixed with infusion fluids can be estimated by the solubility product.

In our previous paper, we explored the optimum conditions for manufacturing a Gummi Drug of acetaminophen (AAP) with uniform distribution and manufactured, on a test scale, a Gummi Drug of AAP (mixed AAP and Gummi base after dissolving AAP in ethyl alcohol). In this study, we examined the release of AAp from this Gummi Drug in comparison to that of a powder preparation of the drug. At the same time, the AAP dissolution test was conducted at various pH levels, and it was found that AAP release from Gummi Drug was scarcely affected by pH levels. Furthermore, considering that the Gummi Drug is expected to be masticated within the oral cavity, we examined the release of AAP from Gummi Drugs divided into different sized morsels to investigate the effects of mastication on release. The results indicated that the release of AAP from the Gummi Drug is affected greatly by the degree of mastication. AAP release of the Gummi Drug when divided into 8 or more pieces was comparable to that of a powder AAP preparation. Adequate mastication is therefore an important factor when using a Gummi Drug of AAP.