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Cisplatin was encapsulated into multivesicular liposomes (MVLs) and the entrapment efficiency, size distribution, and in vitro drug release characteristics of the cisplatin-MVLs were studied. Pharmacokinetics, tissue distribution, and therapeutic efficacy of cisplatin-MVLs were compared against injection of cisplatin solution into mice inoculated with the murine carcinoma 180 (S180) tumor. The results showed that the cisplatin-MVLs were capable of high drug loading (0.148:1 mg cisplatin/mg lipid) and high encapsulation efficiency (>80%). The mean diameter of cisplatin-MVLs was 17 microm. In vitro studies of cisplatin-MVLs in saline solution showed that they sustained release of encapsulated drug for >7 days. Cisplatin-MVLs showed higher drug accumulation in the liver, spleen, and tumor regions than cisplatin solution, as well as higher plasma concentrations and a longer circulation time. The therapeutic efficacy of the cisplatin-MVL preparation against S180 tumor-bearing mice is significantly higher than that of cisplatin solution., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1718-1724, 2004)

Nanoparticles (NP) are potential carriers for drug delivery to the targeted intestine. NP based on beta-sitosterol beta-D-glucoside (Sit-G) enhanced the colon-specific absorption of FITC-dextran 4,400 (FD-4), because the concentration-dependent increase of bioavailability appeared in only the colon. In a permeation study, the absorption enhancement in the colon was suppressed in the following conditions: (1) the addition of Sit-G NP to serosa; (2) a permeation study at 4 degrees C; (3) the addition of endocytosis inhibitor, cytochalasin B. NP based on sitosterol, the aglycon of Sit-G, did not increase the FD-4 colonic permeation. The addition of Sit-G NP to the mucosal side induced a decrease of transepithelial resistance (TEER), but this phenomenon was suppressed by an inhibitor of Na(+)-dependent specific glucose transporter, phrolidzin, which did not affect FD-4 permeation. These findings suggested that absorption enhancement by Sit-G NP may not be due to opening of a tight junction, but might be related to endocytosis via glucose residue of Sit-G., (Copyright 2003 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 92:311-318, 2003)

The aim of this study was to prepare injectable emulsions of aclacinomycin A (E-ACM) and evaluate its acute toxicity, antitumor effects, and pharmacokinetics. In E-ACM, the surfactants were polyethylene glycol-lipid and cholesterol, and the oil phase was a vitamin E solution of ACM. The particle size distribution and the zeta potential of E-ACM were measured by the laser light dynamic scattering method. The ACM-loading efficiency was measured by using Sephadex G50 column chromatography. The acute toxicity, antitumor effects, and pharmacokinetics of E-ACM were studied in C57BL/6 mice bearing mouse murine histiocytoma M5076 tumors. The average diameter, zeta potential, and ACM-loading efficiency of E-ACM were 123.0 +/- 1.2 nm, - 12.67 +/- 1.35 mv, and 96.3 +/- 0.3% (n = 3), respectively. When stored at 7 degrees C in the dark for 1 year, the average diameter and ACM-loading efficiency of E-ACM changed into 126.3 +/- 2.3 nm and 97.4 +/- 0.8%, respectively, whereas 6.5 +/- 0.2% ACM decomposition was observed (n = 3). The plasma areas under the biodistribution curves (AUC)(0.03-48h) of E-ACM was significantly greater than that of free ACM (F-ACM). The heart, lung, and kidney AUC(0.03-48h) of E-ACM were significantly smaller than those of F-ACM whereas the liver and spleen AUC(0.03-48h) of E-ACM were not significantly different from those of F-ACM. The tumor AUC(0.03-48h) of E-ACM was significantly greater than that of F-ACM. E-ACM had lower acute toxicity and greater potential antitumor effects than F-ACM in M5076 tumor-bearing C57BL/6 mice. E-ACM is a useful tumor-targeting drug delivery system., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:1128-1134, 2002)

Previously, we reported that dipalmitoylphosphatidylcholine liposomes (DPPC-liposomes) containing soybean-derived steryl glucoside mixtures (SG) (DPPC/SG-liposomes) accumulated in the liver, especially in parenchymal cells. DPPC/SG-liposomes and a mixture of DPPC and SG (DPPC/SG mixture) were compared by means of differential scanning calorimetry, Fourier transform infrared (FT-IR), and enzymatic assays. The results suggested that the maximum molar mixing ratios of DPPC and SG in a powder was DPPC:SG = 7:2.2. Enzymatic assays indicated that the glucose group of SG projected outward from the liposomal surface and that the amount of SG on the liposomal surface was limited, the maximum mole fraction of SG in DPPC/SG-liposomes being 0.27 (DPPC: SG = 7:2.6). FT-IR spectra indicated that the glucose group of SG interacts with the phosphate group of DPPC on the surface of liposomes, since the phosphate symmetric and asymmetric stretching bands of DPPC/ SG-liposomes were shifted to lower frequencies with increasing SG. These results suggested that the glucose group of SG projecting outward from the liposomal membrane contributes to the hepatic cellular distribution of DPPC/SG-liposomes.

Intestinal absorption of recombinant human erythropoietin (Epo) encapsulated in liposomes (Epo/liposomes) was examined by measuring the pharmacological effects of Epo after oral administration in rats. Circulating reticulocyte counts after oral administration of Epo/liposomes showed a profile different from that after intravenous administration. Epo/liposomes 0.1 micron in diameter were absorbed more effectively than those 0.2 micron in diameter. In the 0.1 micron Epo/liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterols (SS), cholesterol (Ch), or soybean-derived sterylglucosides (SG), DPPC/SS (in molar ratio 7/2) and DPPC/Ch (7/2) showed higher efficiency in intestinal absorption than DPPC/Ch (7/4) and DPPC/SG (7/2) at a low dose by the sysmex method. Pharmacological availabilities for oral administration of Epo/liposomes were 0.74-31% and 3.3-30% as evaluated by circulating reticulocyte counts and percentage circulating reticulocytes of erythrocytes, respectively, in comparison to those for intravenous administration of the same dose.

The objectives of this study were to evaluate the size of the diclofenac ion and the electrical behavior of diclofenac salts (DM; M = Li, Na, or K) in ethanol/water mixtures. The molar conductance of DM in aqueous solution was measured in a dilute concentration range of < 10 mol.m-3 at 25 degrees C. The Fuoss-Onsager conductance equation for unassociated electrolytes was used to determine the limiting molar conductance (lambda degrees) of DM. The molar conductivity of DM at a finite concentration was, however, larger than the value calculated by the Fuoss-Onsager limiting law. To correct the difference in the experimental data, two equations were employed to fit the experimental molar conductance of DM. The size of the diclofenac ion was calculated from the limiting molar conductance and compared with the values obtained by the Fedors method and the apparent ionization constant (pKa) of sodium diclofenac in ethanol/water mixture. The Walden products of DM increased up to 20% (w/w) ethanol, but above this concentration of ethanol they decreased. Specific interactions between the ions and solvent are discussed.

The cohesion parameters of diclofenac and propranolol were determined experimentally. The theoretical partition coefficient (Ps,v) was calculated from the activity coefficient (gamma) and the cohesion parameters of the solvent (delta 1 = delta v), solute (delta 2), and skin (delta s). By using the extended Hildebrand solubility equation, the potential energy of solute-solvent interaction in a given solution was considered to have the gamma value derived from solubility data of diclofenac and propranolol in ethanol-aqueous buffer. Values for experimental permeability coefficients (Kp), which were determined from flux and solubility, were compared with values for the respective Ps,v. For a solvent that consists of ethanol-aqueous buffer exhibiting cohesion parameters in the range of delta v = 18-24 (cal/cm3)1/2, the fluxes increased and the Kp decreased because of the similarity in cohesion parameters of these solvents to the solute. The difference between Ps,v and experimental Kp suggests that ethanol in the solvent affects the membrane and diclofenac and propranolol penetrate through the membrane, possibly solvated by ethanol.