No abstract

The present study was undertaken to prepare proliposomes of Cyclosporine A (CsA) to increase its oral bioavailability. The proliposomes were prepared by spraying a solution of CsA, egg lecithin and cremophor EL in methanol-chloroform mixture onto directly compressible lactose (carrier) in a rotary evaporator. A dry free flowing powder of proliposomes was obtained. The dry proliposomal powder was characterized for surface morphology by scanning electron microscopy (SEM). Then the proliposomes were hydrated with distilled water to produce liposomes, which were characterized for particle size distribution, % drug entrapment, and morphological characteristics by transmission electron microscopy (TEM). The liposomes exhibited good entrapment of about 99%. The entrapment of CsA in liposomes was found to be dependent mainly on the drug:lipid ratio. Bioavailability studies were carried out for three different formulations of CsA i.e., free drug suspension; proliposomes derived liposomes and marketed formulation (Pannimun Bioral, Microemulsion) on male SD rats. The results of bioavailability studies indicated that the difference in the mean drug concentration of the free drug and the liposomes was found to be statistically significant (p < 0.05, p value is 0.032). The absorption constant for liposomal product was much greater (10.26 h(-1)) than for free drug solution (1.2 h(-1)) or the marketed sample of microemulsion (2.51 h(-1)) and the volume of distribution was found to be less for liposomes (7629.88 ml/kg) than that of the free drug solution (10971.92 ml/kg) and marketed microemulsion (9012.07 ml/kg). The results of these studies have shown that a stable proliposomal formulation of CsA for oral administration can be prepared which can be easily hydrated into liposomes from which CsA can exert its clinical effects with a better oral bioavailability.

Low entrapment of drugs into liposomes is a serious challenge in their commercial application. 6-Mercaptopurine (6-MP), an antineoplastic agent, is such a drug with low entrapment efficiency (EE). We devised their lipophilic derivatization as a means of enhancing EE by covalently coupling 6-MP with glyceryl monostearate (GMS) via a succinic anhydride spacer. This prodrug had an improved partition coefficient value of 25.16 compared to 1.22 for free drug, confirming higher lipophilicity. A hydrolysis rate study of prodrug indicated 2.90%, 12.5%, 24.1%, and 25.1% hydrolysis in phosphate buffered saline (PBS) (pH 7.4) and 10%, 20%, and 30% serum, respectively. Liposomes of phosphatidylcholine (PC)/sphingomyelin, cholesterol, and dicetyl phosphate bearing drug or prodrug were prepared by shaking by hand and sonication methods. The EE was found to increase from 1.92% for free drug to 91.8% for drug-conjugate. An in vitro cell line toxicity study on L1210 leukemia cells showed improved performance of liposome-encapsulated drug-conjugate compared to free drug. The plasma drug level profile following administration of free drug and the liposomal formulation containing prodrug (HE liposome) manifested a higher sustained level of the latter, which was further improved in case of sphingomyelin-containing liposomes (STHE liposome). The pharmacokinetic parameters revealed an increase in half-life, from 61 min to 120 min for the HE liposomes and 296 min for the STHE liposomes. Therefore, increased entrapment was made possible through lipophilic derivatization, and it was subsequently tested in vivo.

Non-ionic surfactant vesicles (niosomes) have shown promise as cheap, chemically stable alternatives to liposomes. Niosomes of spans (Sorbitan monoesters) have shown promise of commercial exploitation. Hence, niosomes were prepared of 5-fluorouracil (FU) using different spans. Niomsomes were prepared by the hand shaking method (HSM), reverse phase evaporation (REV) and ether injection method (EIM) using a series of Spans, i.e. Span 20, 40, 60 and 80. HSM giving least permeable vesicles were used to study the effect of variables like type of Span, composition of lipid and total lipid concentration on entrapment efficiency (EE) and release rate. Span 40 and 60 released 40.9 and 37.1% drug in 6 h while Span 20 and 80 displayed 52.2 and 57.1% release, respectively in the same time. Niosomes of Span 40 showed a mean vesicle size of 8.1 microns, EE of 15.3 +/- 1.3% and released 78.6% drug in 6 h; inclusion of cholesterol reduced the vesicle size to 4.8 microns, EE to 12.3 +/- 0.9% and the release to 50.5% (in 6 h), while incorporation of dicetyphosphate further reduced the vesicle size to 3.87 microns, EE to 10.9 +/- 1.1% and reduced release to 40.9% (in 6 h). Increase in the amount of lipid used translated into an almost linear increase in EE. Biodistribution of drug in rats was modified on encapsulation. The concentration of niosomal drug in liver, lung and kidney was increased while it decreased in intestine compared to free drug solution following intravenous administration. The niosomal formulation displayed higher and sustained plasma drug level profile compared to free drug solution. Pharmacokinetic calculations revealed an increase in half-life, area under the curve and decrease in volume of distribution of the drug on encapsulation. Thus, the study suggests that niosomes can act as promising carriers for 5-Fluorouracil.