Comparative pharmacokinetic and pharmacodynamic studies on erythropoietin administered alone or in combination with sodium hyaluronate were performed in rats to demonstrate the potential application of sodium hyaluronate to a sustained release formulation of erythropoietin (SRE). Following subcutaneonus administration, serum erythropoietin levels in the rats treated with SRE persisted longer than those in the rats treated with an erythropoietin solution. Administration of a bulk erythropoietin solution once a week yielded a remarkable effect on erythropoiesis. The time-course profiles of hematocrit and hemoglobin level, however, were rather fluctuating, indicating that adverse effects, such as hypertension, might be incurred. In contrast, weekly administration of SRE comprising sodium hyaluronate, erythropoietin, and serum albumin gave smoother time-course profiles of erythropoiesis. Serum albumin was found to play an important role in SRE. Since preparation of SRE requires neither organic solvent nor heating, possibility of losing biological activity of erythropoietin would be minizized. The viscous property of SRE would lead to the stabilization of erythropoietin against physical disturbance, which would be beneficial especially for self-administration dosage form. In addition, the fluidity of SRE allowed subcutaneous injection with a small gauge needle (e. g., 26 G). Considering that sodium hyaluronate is biocompatible and biodegradable, the SRE proposed in this study would be a promising candidate for weekly formulation of erythropoietin.

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In this investigation, we classified the site and mechanism of action of three penetration enhancers based on a two-layer diffusion model with the polar and nonpolar routes in the stratum corneum. 1-geranylazacycloheptan-2-one(GACH)increases the drug partitioning between the nonpolar route and aqueous vehicle, while d-limonene increases drug diffusivity in the nonpolar route. Oleic acid increases both partitioning and diffusivity of drugs in the nonpolar route. The simulation based on the analytical results revealed that the enhancement ratio has a bell-shaped relationship against the lipophilicities of drugs when an enhancer increases the diffusivity or partitioning of drugs in the nonpolar route. It was also shown that the amount of a drug in the skin increases with an increase in drug partitioning, while it dose not change so much with an increase in drug diffusivity. Further, a simulation revealed the effect of an enhancer on skin penetration of drugs is dependent on polarity of vehicles in the finite dose system.

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Biodegradable microspheres containing cisplatin were prepared by a solvent-evaporation method and release profiles were evaluated in vitro. Cisplatin was entrapped in the microspheres prepared by poly (L-lactic acid) (L-PLA)with high encapsulation efficiency of about 80%. The microspheres containing cisplatin were spherical with diameters of about 60 μm. About 20% of the loaded cisplatin was released during the initial hours and release rates of cisplatin were very small thereafter. Attempts were made to enhance the release rate by incorporating fatty acid esters or gelatin as additives in the microspheres. The release patterns of cisplatin from the microspheres were different depending on the kinds of esters. In order to clarify the causes of its difference, appearances of the microspheres were observed with a scanning electron microscope. There was difference in their appearances in their surface and crosssection. The release rates of cisplatin from the microspheres were increased by incorporating gelatin in them.

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Antisense oligonucleotide hold great promise as potential therapeutic agents for inhibiting the expression of undesirable genes specifically. Whereas, interleukin-1β(IL-1β) play a key role in the inflammation and the developing of rheumatoid arthritis(RA). To block the IL-1β production by antisense DNA method, we synthesized antisense oligonucleot ides (20mers)with ph osphoroth ioate linkages targeting the human IL-1β mRNA. These antisense oligonucleotides were tested for inhibition of IL-1β production in LPS-stimulated human peripheral blood mononuclear cells from healthy volunteer and primary synobiocytes from patients with RA. These cells were cultured with each oligonucleotide and total IL-1β contents were measured by using ELISA system. Antisense oligonucleotides inhibited the production of IL-1β in both cells in a dose-dependent manner.

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Oxidized carboxymethyl-D-manno-n-glucan-DXR conjugates (MG-CM-AD-DXR) prepared via Schiff's base formation possesses not only higher concentration in plasma and tumor but also lower in heart than DXR. In the present investigation, antitumor effects and toxicities of the conjugates were compared with those of DXR. MG-CM [0.5]-AD-DXR (DS of CM groups : 0.5) and MG-CM [1.0] -AD-DXR (DS of CM groups : 1.0)exhibited a growth inhibition similar to DXR against mouse leukemia P388 cells in vitro, but were found to be 2.3-and 1.7-fold more potent than DXR after the intravenous injection in rats bearing Walker 256, respectively. MG-CM[0.5]-AD-DXR conjugate also showed 1.7-fold more effective than DXR in rats bearing Yoshida sar coma. On the other hand, toxicities of MG-CM[0.5]-AD-DXR in rats, reduction of peripheral white blood cells and platelets counts on day 4 and body weight loss, were less than those of DXR after the intravenous injection at a dose of 10 mg/kg as DXR. These toxicities induced by MG-CM[1.0]-AD-DXR were similar to those by DXR, and MG-CM[0.5]-AD-DXR conjugate had less lethal toxicity than DXR in mice.

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Peplomicin-containing poly (lactic acid)microspheres(PEP-MS)were prepared, and its long retention and lymphtropic delivery were studied. PEP-MS released 70% of PEP in saline within 24 hours. PEP and PEP-MS were injected into the esophageal wall of rabbits, and PEP concentration of peripheral venous blood and lymph of thoracic duct were measured from 5 minutes to 6 hours after injection. In group “PEP”, PEP concentration of peripheral venous blood and lymph of thoracic duct were same level, but in group “PEP-MS”, PEP concentration of lymph of thoracic duct was higher than of peripheral venous blood. One day after administration of PEP, PEP was not found in esophagus, lymph nodes, lung and kidney, But one day after administration of PEP-MS, PEP was found to still remain 3.0 μg/g in esophagus.

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For we aimed at establishing enteral administration route of cytokine recombinant interleukin-2 (rIL-2)to enhance its effects, absorption of rIL-2 through the large intestine was investigated in the rats. rIL-2 (5 × 10⁵ units/rat) dissolved in distilled water and lipid-surfactant mixed micelles(MM), which is composed of linoleic acid and sodium-taurocholate, as an absorption promoter was administered into the large intestine from rectum. During 5 hours after administration of rIL-2, the blood and the lymph were periodically taken from the jugular vein and the thoracic duct, respectively, The serum and lymphatic concentrations of rIL-2 were both undetectable in rats receiving rIL-2 dissolved in distilled water. By contrast, in rats receiving rIL-2 dissolved in MM, the lymphatic concentration showed a high level, 52 units/ml, whereas the serum concentration remained under the detectable level. Thus, the increase in the lymphatic selectivity of rIL-2 is considered due to its macromolecular weight ranging about 15000. Based on these results, it may be concluded that rIL-2 with MM can be remarkably absorbed from the large intestine and specifically transferred into the lymphatic system.

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Directly injective chemotherapy combined with transcatheter arterial embolization (TAE) was achieved in 50 nodules with hepatocellular carcinoma. Four to thirty-five days after TAE, the anticancer agents dissolved in contrast media were directly injected into the tumor tissue using the ultrasonically-guided puncture needle. The dynamics of the anticancer drugs marked with non-ionic and water-soluble contrast media was explored by the sequential CT studies. The accumulation of the contrast media was obserbed in 27 out of 50 tumor nodules during 2 weekes or more after the injection. In one case, who was autopsied 6 months after the injection, the higher concentration of anticancer drugs and iodine in the tumor tissues was detected than in surrounding liver parenchyma. In conclusion, this procedure was considered to be an effective drug delivery method to achieve a targeting chemotherapy in the tumor nodules.

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The skin permeability of nine steroidal drugs with a different lipophilicity across excised hairless mouse skin was evaluated by the use of an ethanol/panasate 800 (tricaprylin) (40/60) system as a lipophilic vehicle and an ethanol/water (60/40) system as a hydrophilic vehicle. Two different correlations were shown between the skin permeability and n-octanol/water partition coefficient (log P) of the steroidal drugs in the two binary vehicles, respectively : The skin permeability of the drugs was increased with an increase in the hydrophilicity of the drugs by the use of the ethanol/panasate 800 (40/60) binary vehicle, however, the ethanol/water (60/40) binary vehicle showed the contrary tendency in the skin permeability of the drugs. The above results could be explained from the concept of thermodynamic activity of the drug in the vehicle and in the skin by the use of solubility parameter. It was suggested that the solubility parameter of the skin is higher for the ethanol/panasate 800(40/60) vehicle and is lower for the ethanol/water (60/40) vehicle than those of the vehicles, since the skin may be affected by the vehicles. Therefore, it could be considered that the above tendencies are due to an increase of partition of the hydrophilic drug for the ethanol/panasate 800 (40/60) lipophilic binary vehicle and of the lipophilic drug for the ethanol/water (60/40) hydrophilic binary vehicle, to the skin.

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The effects of ethanol and polyethylene glycol 400 (PEG400) solution, additives or enhancers in the transdermal drug delivery systems, upon the skin metabolism of a prednisolone ester have been investigated in the hairless mouse skin in vitro. PEG400 was found to inhibit the bioconversion of the prednisolone ester in a dose-dependent manner. The water content in the skin (viable skin)decreased gradually when the content of PEG400 increased. The appearance rate of the metabolite, prednisolone, was approximately proportional to the water content in the viable skin contacting with the PEG400 solution. While ethanol was found to exhibit the penetration enhancement as well as the inhibition of the skin metabolism, As a result of this counterbalance of ethanol effect, the appearance rate of the metabolite following the skin bioconversion reached an maximum value at a certain concentration of ethanol. The present study suggests that the effects of additives or enhances on the skin metabolism should be carefully examined for optimizing the transdermal drug delivery systems.

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