Long-Circulating Emulsions (Oil-in-Water) as Carriers for Lipophilic Drugs

AbstractPurpose. Rapid clearance of parenterally administered oil-in-water emulsions from blood by the reticuloendothelial system (RES), mainly macrophages of the liver and spleen, has been one of the major obstacles for delivering lipophilic drugs to cells other than those in the RES. The purpose of this study therefore is to overcome this problem and develop emulsions that will have prolonged blood circulation time. Methods. A series of amphipathic polyethylene-glycol (PEG) derivatives have been included as co-emulsifier into emulsions composed of Castor oil and phosphatidylcholine. The effect of amphipathic PEG on reducing the RES uptake and prolonging the blood circulation of the emulsion particles has been tested in vivo using mice as an animal model. Results. Inclusion of PEG derivatives such as Tween-80 or dioleoyl N-(monomethoxy-polyethyleneglycol succinyl)phosphotidylethanolamine (PEG-PE) into emulsions composed of Castor oil and phosphatidylcholine decreases the RES uptake and increases blood residence time of the emulsions. The activity of PEG derivatives in prolonging the circulation time of emulsions depends on the PEG chain length (PEG2000≥PEG5000>PEG1000, Tween-80) and the PEG density on emulsion surface. Conclusions. Inclusion of amphipathic PEG as emulsifier into oil-in-water emulsions is a very effective method to prolong the blood half life of the emulsions. Emulsions with long circulating half life in blood should be very useful as a delivery vehicle for lipophilic drugs.

[1]  Davis Ss,et al.  The preparation and properties of sterile intravenous emulsions. , 1983 .

[2]  Martyn C. Davies,et al.  Polystyrene-Poly (Ethylene Glycol) (PS-PEG2000) Particles as Model Systems for Site Specific Drug Delivery. 2. The Effect of PEG Surface Density on the in Vitro Cell Interaction and in VivoBiodistribution , 1994, Pharmaceutical Research.

[3]  L. Huang,et al.  pH-sensitive immunoliposomes as an efficient and target-specific carrier for antitumor drugs. , 1986, Cancer research.

[4]  K. Hubner,et al.  Gadolinium-labeled liposomes: targeted MR contrast agents for the liver and spleen. , 1987, Radiology.

[5]  M. Bally,et al.  Polyethylene glycol modified phospholipids stabilize emulsions prepared from triacylglycerol. , 1994, Journal of pharmaceutical sciences.

[6]  V. Torchilin,et al.  Biodegradable long-circulating polymeric nanospheres. , 1994, Science.

[7]  A A Bogdanov,et al.  Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity. , 1994, Biochimica et biophysica acta.

[8]  M. Woodle,et al.  Sterically stabilized liposomes. , 1992, Biochimica et biophysica acta.

[9]  D. Papahadjopoulos.  A new Perspective on Liposomes , 1992 .

[10]  C. Bucana,et al.  Analysis of the fate of systemically administered liposomes and implications for their use in drug delivery. , 1982, Cancer research.

[11]  G. Weissmann,et al.  Enzyme replacement via liposomes. Variations in lipid compositions determine liposomal integrity in biological fluids. , 1979, Biochimica et biophysica acta.

[12]  P. Artursson,et al.  Biopharmaceutics of Microparticulate Drug Carriers , 1987, Annals of the New York Academy of Sciences.

[13]  A. Gabizon,et al.  Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Singh,et al.  Parenteral emulsions as drug carrier systems. , 1986, Journal of parenteral science and technology : a publication of the Parenteral Drug Association.

[15]  L. Huang,et al.  Role of liposome size and RES blockade in controlling biodistribution and tumor uptake of GM1-containing liposomes. , 1992, Biochimica et biophysica acta.

[16]  K. Matthay,et al.  Specific enhancement of drug delivery to AKR lymphoma by antibody-targeted small unilamellar vesicles. , 1984, Cancer research.

[17]  B. Lundberg,et al.  Preparation of drug-carrier emulsions stabilized with phosphatidylcholine-surfactant mixtures. , 1994, Journal of pharmaceutical sciences.

[18]  L. Huang,et al.  Cytotoxicity of diphtheria toxin A fragment to toxin-resistant murine cells delivered by pH-sensitive immunoliposomes. , 1987, Cancer research.

[19]  B. Lebleu,et al.  Antibody-targeted liposomes containing oligodeoxyribonucleotides complementary to viral RNA selectively inhibit viral replication. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Legendre,et al.  Delivery of Plasmid DNA into Mammalian Cell Lines Using pH-Sensitive Liposomes: Comparison with Cationic Liposomes , 1992, Pharmaceutical Research.

[21]  L. Huang,et al.  Large liposomes containing ganglioside GM1 accumulate effectively in spleen. , 1991, Biochimica et biophysica acta.

[22]  G. Gregoriadis.  Liposomes as drug carriers : recent trends and progress , 1988 .

[23]  L. Huang,et al.  pH-sensitive immunoliposomes mediate target-cell-specific delivery and controlled expression of a foreign gene in mouse. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[24]  L. Leserman,et al.  Differential endocytosis of T and B lymphocyte surface molecules evaluated with antibody-bearing fluorescent liposomes containing methotrexate. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[25]  T M Allen,et al.  Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. , 1991, Biochimica et biophysica acta.

[26]  J. C. Robbins,et al.  Modified in vivo behavior of liposomes containing synthetic glycolipids. , 1981, Biochimica et biophysica acta.

[27]  Kazuo Maruyama,et al.  Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes , 1990, FEBS letters.