ABSTRACT
For the preparation of microcapsules using the W/O/W (water in oil in water) emulsion system, it is essential to control various factors such as the dispersed state of the organic phase in the W/O/W emulsion, the difference in the solute concentration between the inner and outer aqueous phases and the volume fraction of the dispersed phase. In this study, cross-linked microcapsules were prepared by the in-situ polymerization of styrene and divinylbenzene and biodegradable microcapsules were prepared by the solvent evaporation method. The effects of the preparation conditions on the capsule morphology and entrapment efficiency of water-soluble materials were investigated. The average diameter of the surface pores and internal hollows were controlled on a sub-micron order by changing the preparation conditions such as diluent concentration, volume fraction of the dispersed droplets in the W/O (water in oil) emulsion, surfactant concentration monomer ratio and salt concentration in the outer aqueous phase. Furthermore, the water-soluble materials were completely entrapped in the biodegradable microcapsule by changing the preparation conditions such as volume fraction of the dispersed droplets in the W/O emulsion, salt concentration in the inner and outer aqueous phases, polymer concentration and supersonic irradiation of the W/O droplets.
Subject(s)
Capsules/chemistry , Drug Compounding/methods , Biocompatible Materials , Drug Carriers/chemistry , Drug Delivery Systems , Emulsions , Humans , Microscopy, Electron, Scanning , Microspheres , Particle Size , Polymers/chemistry , SolubilityABSTRACT
Microspheres containing cisplatin (CDDP) embedded in poly-d,l-lactic acid (PLA) and polyethylene glycol acid (CDDP-PPMS) were developed to improve treatment of malignant effusions. In vitro studies demonstrated that CDDP was released continuously for more than 4 weeks from CDDP-PPMS without initial burst. CDDP-PPMS was compared with CDDP aqueous solution (CDDP-SOL) by i.p. administration in rats for 1) tissue distribution, 2) toxicity and 3) therapeutic effects against Yoshida sarcoma. We found that the CDDP concentration in the omentum was maintained at a higher level than in the CDDP-SOL group, while the particles of CDDP-PPMS were observed in the stomata of the omentum by electron microscopy. Concentrations of CDDP in the lung, liver, kidney and blood were lower in the CDDP-PPMS group than in the CDDP-SOL group. All rats given CDDP-PPMS containing < or = 28 mg/kg were alive, whereas in the CDDP-SOL group, all rats given > or = 16 mg/kg died from side effects. The LD50 of CDDP-PPMS and CDDP-SOL were 32.8 and 14.8 mg/kg, respectively. The survival of rats with peritoneal metastasis was better in the CDDP-PPMS group than in the CDDP-SOL group.
Subject(s)
Cisplatin/administration & dosage , Lactic Acid/administration & dosage , Peritoneal Neoplasms/drug therapy , Pharmaceutical Vehicles/administration & dosage , Polyethylene Glycols/administration & dosage , Polymers/administration & dosage , Sarcoma, Yoshida/drug therapy , Animals , Chemistry, Pharmaceutical , Cisplatin/pharmacokinetics , Cisplatin/toxicity , Injections, Intraperitoneal , Lactic Acid/chemistry , Lactic Acid/pharmacokinetics , Male , Microspheres , Neoplasm Transplantation , Peritoneal Neoplasms/metabolism , Peritoneal Neoplasms/secondary , Pharmaceutical Vehicles/chemistry , Pharmaceutical Vehicles/pharmacokinetics , Polyesters , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Polymers/chemistry , Polymers/pharmacokinetics , Rats , Sarcoma, Yoshida/metabolism , Sarcoma, Yoshida/secondary , Tissue DistributionABSTRACT
Cisplatin incorporated into polylactic acid/polyethylene glycol acid blend polymeric microspheres was prepared as a dosage (CDDP-MS) by solvent evaporation method in oil-in-oil emulsion system. CDDP-MS and CDDP aqueous solutions (CDDP-SOL) were intraperitoneally administered to compare the tissue distribution of CDDP in 72 rats each. On 0.5, 1, 7, 14, 21 and 30 days, the omentum, lung, liver and kidney were removed, and the CDDP concentration was measured. The CDDP concentration of CDDP-MS group was maintained at a high level in the omentum for a long time. On the other hand, the CDDP level of the CDDP-MS group was low in the lung, liver and kidney, compared with the CDDP-SOL group. Additionally, acute toxicity of anticancer drug in CDDP-MS group was reduced, compared with CDDP-SOL. The effects of CDDP-MS, CDDP-SOL, empty-MS and non-therapy group on survival time were compared using intraperitoneally administered Yoshida sarcoma. The survival time in CDDP-MS, CDDP-SOL, non-therapy and empty-MS group were 43 +/- 24, 11.7 +/- 4.7, 9.8 +/- 1.1, and 7.8 +/- 1.1 days each. Consequently, it was suggested that CDDP-MS is useful as a tool in loco-regional chemotherapy using drug delivery system.
Subject(s)
Cisplatin/administration & dosage , Peritoneal Neoplasms/drug therapy , Animals , Cisplatin/pharmacokinetics , Delayed-Action Preparations , Drug Delivery Systems , Emulsions , Lactic Acid , Microspheres , Polyesters , Polyethylene Glycols , Polymers , Rats , Sarcoma, Yoshida/drug therapyABSTRACT
Cisplatin incorporated into polylactic acid/polyethylene glycol acid blend polymeric microspheres was prepared as a dosage (CDDP-MS) by the solvent evaporation method in an oil-in-oil emulsion system. When CDDP-MS was preserved in phosphate-buffer saline, the dissolution rate of cisplatin from CDDP-MS was 14% after one day, 25% after 5 days, 33% after 7 days, 66% after 21 days and 85% after 30 days. CDDP-MS and CDDP aqueous solution (CDDP-SOL) were intraperitoneally administered to compare the tissue distribution of cisplatin in 42 rats each. On days 0.5, 1, 5, 7, 14 and 21, omentum, lung, liver and kidney were removed, and the CDDP concentration was measured. The CDDP concentration of the CDDP-MS group was maintained at a high level in the omentum for a long time. On the other hand, the CDDP level of CDDP-MS group was low in the lung, liver and kidney, compared with the CDDP-SOL group. Consequently, it was suggested that CDDP-MS is useful as a carrier in a drug delivery system, since it improves the burst effect and releases CDDP for a long time without serious side effects.
