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The in vivo elimination and tissue distribution (2 h after administration) of various types of formulations of alpha-tocopherol as a model drug were examined in rats. An organic cosolvents formulation of alpha-tocopherol (alpha-tocopherol/EtOH/polyethylene glycol 400) was rapidly removed from the blood circulation, the ratio of the distributed alpha-tocopherol was 20% in the lungs, about 70% in the liver and about 10% in the spleen. The main reason for this was considered to be the appearance of droplets more than 10 microns in diameter in the blood. Elimination of the micelle formulation using Brij58 from the blood was the most rapid, followed by Tween80 and HCO60. This order is thought to be due to the difference in the polyoxyethylene group among these surfactants. In liposome formulations, liposomes having a diameter of about 80 nm were the most stable in the blood circulation, and alpha-tocopherol was distributed in the reticuloendothelial system (RES) in the smallest ratio. The uptake of liposomes by the spleen and lungs depended on the liposome size. The uptake by the liver was in the decreasing order of 28 nm >> 42 nm, 151 nm, 195 nm, 3656 nm > 106 nm > 75 nm. The 100 nm lipid emulsion was eliminated from the blood more rapidly than the 100 nm liposome formulation.

Administration of liposomes loaded with active drugs can result in enhanced therapeutic activity 1,2) and reduced toxic side effects. [3][4][5] For example, liposomes are widely used to improve the delivery of many anticancer, antibiotic and antifungal drugs, such as doxorubicin, epirubicin, vincristine and ciprofloxacin. [6][7][8][9][10] The effectiveness of this formulation approach is dependent on the rate of drug release from the liposomes. Liposomes that rapidly release their contents in vivo will not improve delivery of drugs to target sites 2); for therapeutic value, it is important that drugs are retained in liposomes in vivo for an appropriate time.11,12) Weakly basic drugs can be actively concentrated inside liposomes using a transmembrane pH gradient [13][14][15] or an ammonium sulfate gradient.16) However, the retention of drugs in liposomes is drug-dependent and can vary dramatically. For example, the anticancer drugs doxorubicin and epirubicin are well retained inside liposomes, [17][18][19] whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. 14,19,20) In order to obtain homogenous preparations, liposomes are often extruded through polycarbonate filters of 0.4, 0.2 and 0.1 mm pore size. A high proportion of liposomes that are passed through 0.2 mm filters remain as multilamellar vesicles. On the other hand, extrusion of liposomes through 0.1 mm filters produces mainly unilamellar vesicles.21) Zhang et al. 22) reported that the release of the amphiphilic drug 5-carboxyfluorescein (CF) was greater from unilamellar liposomes than from multilamellar liposomes of similar particle size. The curvature of small unilamellar vesicles (SUVs) is greater, and packing between lipids in the membranes is looser, compared with large unilamellar vesicles. For this reason, SUVs are believed to release drugs more readily. 23,24) The aim of the present study was to identify the causes of the rapid release of drugs, such as vincristine, from liposomes and then to apply this knowledge to the development of more stable formulations. Initially, we investigated the effect of particle size on the leakage of drugs from liposomes incubated in fetal bovine serum (FBS); for these studies, doxorubicin and vincristine were used as examples of wellretained and readily released drugs, respectively. MATERIALS AND METHODS MaterialsEgg yolk phosphatidylcholine (EPC) was purchased from Nippon oil and fat (Tokyo, Japan). Vincristine and doxorubicin were acquired from Sigma-Aldrich (St. Louis, MO, U.S.A.) and Kyowa Hakko (Tokyo, Japan), respectively. FBS was obtained from GIBCO BRL (Grand Island, NY, U.S.A.). Nuclepore polycarbonate filters and Sepharose CL-6B were purchased from Corning (Acton, MA, U.S.A.) and Amersham Pharmacia Biotech (Uppsala, Sweden), respectively. All other chemicals were of analytical grade quality.Preparation of Liposomes EPC liposomes were formed by hydrating the lipid with the following buffers: (i) 100 mmol/l citric acid (pH 4.0), (ii) 10 mmol/l Tris-HCl (pH 7.3...

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Novel wrapped liposomes comprised of polyanion drug and cationic lipid complexes wrapped with neutral lipids were prepared using an efficient, innovative procedure. In this study, dextran fluorescein anionic (DFA) was used as an example of a polyanionic compound. During the process, neutral lipids accumulated around the complexes and eventually covered the complexes. The resulting liposomes were 120-140 nm in diameter and the encapsulation efficiency was up to 90%. In fetal bovine serum, DFA/cationic lipid complexes degraded rapidly but the wrapped liposomes were considerably more stable. Following intravenous administration to rats, DFA/cationic lipid complexes were rapidly eliminated whereas the wrapped liposomes exhibited a much longer blood half-life. These data suggest that DFA is located on the surface of the complexes, but DFA is present inside the wrapped liposomes. The drug-delivery properties of the wrapped liposomes established in the present study suggests that formulations based on this technology could offer important advantages for the administration of many types of drug including antisense oligonucleotides, plasmids and siRNAs which may therefore lead to improved therapeutic effectiveness of this range of drugs. The method of preparation of the wrapped liposomes is so simple that it should be straightforward to adapt to a manufacturing scale.

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