Phase separation induced in gelatin-base coacervation systems by addition of water-soluble nonionic polymers I: Microencapsulation

A microencapsulation procedure in which water-soluble nonionic polymers (especially, polyethylene oxide or polyethylene glycol) were added to gelatin-base coacervation systems is described. The advantages of this method are: (a) The addition of a small amount of polyethylene glycol (PEG) or polyethylene oxide (PEO) to a complex coacervation system (e.g., gelatin-acacia) allows microencapsulation to occur over an expanded pH region (pH 2-9 in gelatin-acacia). (b) These polymers induce phase separation in an aqueous solution of gelatin alone and enable the preparation of gelatin-coated microcapsules not only in the vicinity of the isoelectric point (pH 9.0), but over a wide pH range (pH 5.5-9.5). (c) Spherical single-seeded microcapsules can be obtained.     

Gelatin-Acacia Microcapsules for Trapping Micro Oil Droplets Containing Lipophilic Drugs and Ready Disintegration in the Gastrointestinal Tract

Nonhardened gelatin-acacia microcapsules were studied for encapsulation of microdroplets of oil solution containing a lipophilic drug as core material and ready disintegration with release of micro oil droplets in the gastrointestinal tract. Probucol and S-312-d, a Ca-channel blocker, were employed as model lipophilic drugs. Glyceryl tricaprylate and tricaprate mixture solutions containing these drugs were encapsulated according to the complex coacervation method and were recovered as free-flowing powders without any hardening (cross-linking) step. The microcapsules obtained were disintegrated, and the emulsion was reproduced within 3 min at 37°C in the first or second test solution defined in the Japanese Pharmacopeia XII. When the microcapsules were stored as a powder at room temperature in a closed bottle, no significant change in their appearance or disintegration time upon rehydration was observed even after 1 year. Oral bioavailabilities of model drugs from the microcapsules were tested in rats and dogs and compared with those from other conventional formulations. Gastrointestinal absorption of both probucol and S-312-d from the microcapsules was remarkably more efficient than that from other formulations such as powders, granules, or oil solution. The proposed method for microencapsulation could be useful for powdering drug-containing oil solutions or O/W emulsions while maintaining excellent bioavailability.     

A novel and simple type of liposome carrier for recombinant interleukin-2

The strong interaction between recombinant interleukin-2 (IL-2) and liposome was characterized and its possible application to drug-delivery control considered. The liposomes were prepared with egg phosphatidylcholine, distearoyl-phosphatidylglycerol (DSPG), dipalmitoyl-phosphatidylcholine, dipalmitoyl-phosphatidylglycerol or distearoyl-phosphatidylcholine (DSPC). Small and hydrophobic liposomes were selected, which were composed of saturated and long-fatty-acid-chain phospholipids. When the composition and the mixture ratio of IL-2 and the liposomewere optimized, morethan 95% ofthe lyophilized IL-2 (Imunace, 350000 JRU) was adsorbed consistently onto the DSPC-DSPG liposome (molar ratio, 10:1; 25 micromol mL(-1); 30 nm in size). Merely mixing IL-2 lyophilized with liposome suspension is convenient pharmaceutically. After intravenous administration to mice, liposomal IL-2 was eliminated half as slowly from the systemic circulation as free IL-2, with more than 13 and 18 times more IL-2 being delivered to the liver and spleen, respectively. After subcutaneous administration of liposomal IL-2 to mice, the mean residence time of IL-2 in the systemic circulation was 8 times that of free IL-2. These results show that IL-2 consistently adsorbs onto the surface of liposomes after optimization of its composition and mixing ratio. Intravenous and subcutaneous administration to mice demonstrates the gradual release of IL-2. Further trials are warranted using these liposomes.     

Phase separation induced in gelatin-base coacervation systems by addition of water-soluble nonionic polymers II: effect of molecular weight

Phase separation, induced in aqueous solutions of gelatin or gelatin-acacia by adding polyethylene oxide (PEO) or polyethylene glycol (PEG) of different molecular weights, was examined. The minimum concentration (Cp) of PEO or PEG required to cause phase separation decreased with an increase in the molecular weight (M2) of the polymer. The dependence of Cp on M2 for a complex coacervation (gelatin-acacia-water) system was larger than for a simple coacervation (gelatin-water) system, in which Cp was approximately proportional to M2-1/2. Elemental analyses indicated that coacervates induced in gelatin-water systems by the addition of PEO (or PEG) did not contain PEO (or PEG); therefore, phase separation may be due to incompatibility.     

A significant enhancement of therapeutic effect against hepatic metastases of M5076 in mice by a liposomal interleukin-2 (mixture).

Recombinant interleukin-2 (IL-2) was strongly and almost completely adsorbed onto small hydrophobic liposomes under optimal conditions (liposome: DSPC-DSPG; molar ratio, 10:1; 30-50 nm in size, ratio of IL-2 to liposome: 4.0 JRU/nmol lipid). This liposomal IL-2 improved the distribution of IL-2 after intravenous administration as reported, previously. Liposomal IL-2 (300-10000 JRU/mouse per day) was significantly more effective than free IL-2 alone for inhibiting against the experimental metastases of M5076 in mice. The inhibitory effect of liposomal IL-2 was greatest in the liver. The ED(50) of liposomal IL-2 and that of free IL-2 in the liver were 1640 and 12500 JRU/mouse per day, respectively. This simple preparation (mixture) using IL-2 and liposome suspension is expected to have potential for increasing therapeutic efficacy against hepatic metastases.