The aerosol solvent extraction system (ASES) process was applied to prepare miconazole (MCZ) liposomes in a dry and reconstitutable form, the optimized temperature and pressure of which were 35 degrees C and 8.0 MPa, respectively. The influence of compositions of phosphatidylcholine (PC), cholesterol (CHOL), and poloxamer 407 (POLOX) as well as the pH of hydration medium on physical and chemical stability of both dry microparticles and liposomes hydrated from them were examined following storage at 4 degrees C and 25 degrees C for 3 months. MCZ microparticles in dry powder were stable on storage at 4 degrees C but degraded considerably after storage at 25 degrees C. MCZ liposomes hydrated from dry ASES-prepared microparticles at pH 4.0 tended to aggregate, whereas those hydrated at pH 7.2 tended to reduce in size on storage, especially with the addition of CHOL. Liposomes with high MCZ content stored at 4 degrees C degraded faster than when stored at 25 degrees C. Addition of POLOX tended to retard the degradation of MCZ liposomes, whereas CHOL appeared to enhance the degradation on storage under both conditions. The chemical degradation of MCZ liposomes appeared to follow the acid-catalyzed hydrolysis. The MCZ liposomes prepared by the ASES process in this study were substantially internalized after being incubated with human lymphocytes.
Zanamivir is currently used for the treatment of H1N1 and H5N1 influenza viruses. Due to its highly hydrophilic property, zanamivir has poor oral bioavailability. Liposomal formulations are known to improve oral absorption of hydrophilic drugs. The present study investigates the effect of liposomes encapsulating zanamivir on the permeation of zanamivir across Caco-2 monolayers. Among the formulations studied, neutral liposomes composed of Phospholipon(®) 90 G and cholesterol at molar ratio of 7:3 gave the highest entrapment efficiency of zanamivir. The extrusion of liposomes loading zanamivir (LZV) resulted in the reduced-size liposomal zanamivir (RLZV), which had mean diameter at 283±42 nm and gave higher encapsulation efficiency of zanamivir at 34.69±6.37% compared to 28.32±5.25%. Transport studies across Caco-2 cell monolayers showed that the apparent permeation coefficients (P(app)) of LZV and RLZV were respectively 2.2- and 3.0-fold greater than that of zanamivir solution. The P(app) of RLZV was 1.4-fold higher than that of LZV. On the basis of these results, liposomes are able to improve permeability of zanamivir across the Caco-2 monolayers, thereby possibly enhancing oral bioavailability of zanamivir.
The solubility of various drugs in a constant ratio of phosphatidylcholine-cholesterol carrier were studied to investigate their influence on drug recovery in drug-lipid microparticles produced by the aerosol solvent extraction system (ASES) process. Solubility of the drugs in such lipid carrier were determined by using differential scanning calorimetry and confirmed by X-ray powder diffraction study. The results showed that drug possessing relatively high solubility in the lipid carrier used could lead to a higher amount of drug recovered in the drug-lipid microparticles produced. However, too high amount of dissolved drug imposed an adverse effect on the solidification of the lipid carrier during ASES processing, which led to partial film formation in the production column and hence a lower yield of microparticles. Such adverse effect was not the case for the drugs with low solubility in the carrier but there was an incomplete recovery of drug in the produced microparticles due to the partial extraction by the supercritical gas instead. The maximum amount of drug recovered in the ASES-prepared microparticles was found to correlate to the solubility of drug in the lipid carrier so that it might be utilized as a predictive parameter for determining the amount of drug to be incorporated into the microparticles.
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