Oral administration of recombinant human erythropoietin in liposomes in rats: influence of lipid composition and size of liposomes on bioavailability.

Intestinal absorption of recombinant human erythropoietin (Epo) encapsulated in liposomes (Epo/liposomes) was examined by measuring the pharmacological effects of Epo after oral administration in rats. Circulating reticulocyte counts after oral administration of Epo/liposomes showed a profile different from that after intravenous administration. Epo/liposomes 0.1 micron in diameter were absorbed more effectively than those 0.2 micron in diameter. In the 0.1 micron Epo/liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and soybean-derived sterols (SS), cholesterol (Ch), or soybean-derived sterylglucosides (SG), DPPC/SS (in molar ratio 7/2) and DPPC/Ch (7/2) showed higher efficiency in intestinal absorption than DPPC/Ch (7/4) and DPPC/SG (7/2) at a low dose by the sysmex method. Pharmacological availabilities for oral administration of Epo/liposomes were 0.74-31% and 3.3-30% as evaluated by circulating reticulocyte counts and percentage circulating reticulocytes of erythrocytes, respectively, in comparison to those for intravenous administration of the same dose.

[1]  M. R. Mauk,et al.  Stability of lipid vesicles in tissues of the mouse: a gamma-ray perturbed angular correlation study. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[2]  C. H. Lin,et al.  Cloning and expression of the human erythropoietin gene. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Lowe,et al.  Calcitonin and Insulin in Isobutylcyanoacrylate Nanocapsules: Protection Against Proteases and Effect on Intestinal Absorption in Rats , 1994, The Journal of pharmacy and pharmacology.

[4]  M. Higuchi,et al.  Physicochemical and biological comparison of recombinant human erythropoietin with human urinary erythropoietin. , 1990, Journal of biochemistry.

[5]  J. Kawada,et al.  Effects of oral administration of positively charged insulin liposomes on alloxan diabetic rats: preliminary study. , 1979, Endocrinologia japonica.

[6]  G. Brecher,et al.  A time-saving device for the counting of reticulocytes. , 1950, American journal of clinical pathology.

[7]  S. Davis,et al.  Microparticulate absorption from the rat intestine , 1994 .

[8]  D. McCarthy,et al.  Nanosphere and microsphere uptake via Peyer's patches: observation of the rate of uptake in the rat after a single oral dose , 1992 .

[9]  M. Bar‐eli,et al.  Delivery of interferon to intracellular pathways by encapsulation of interferon into multilamellar liposomes is independent of the status of interferon receptors. , 1994, Cytokine.

[10]  F. Szoka,et al.  Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Y. Barenholz,et al.  Delivery of cytokines by liposomes. I. Preparation and characterization of interleukin-2 encapsulated in long-circulating sterically stabilized liposomes. , 1994, Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy.

[12]  E. Fritsch,et al.  Isolation and characterization of genomic and cDNA clones of human erythropoietin , 1985, Nature.

[13]  C. Winearls,et al.  EFFECT OF HUMAN ERYTHROPOIETIN DERIVED FROM RECOMBINANT DNA ON THE ANAEMIA OF PATIENTS MAINTAINED BY CHRONIC HAEMODIALYSIS , 1986, The Lancet.

[14]  G. Durand,et al.  Oral ingestion of insulin liposomes: effects of the administration route. , 1981, Life sciences.

[15]  D. Barrow,et al.  Cholesterol-phosphatidylcholine interactions in multilamellar vesicles. , 1980, Biochemistry.

[16]  T. Nagai,et al.  Effects of dose, pH and osmolarity on intranasal absorption of recombinant human erythropoietin in rats. , 1995, Biological & pharmaceutical bulletin.

[17]  J. Adamson,et al.  Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. , 1987, The New England journal of medicine.

[18]  T. Nagai,et al.  Effect of soybean-derived sterol and its glucoside mixtures on the stability of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylcholine/cholesterol liposomes , 1994 .

[19]  E. Goldwasser,et al.  PROGRESS IN THE PURIFICATION OF ERYTHROPOIETIN , 1968 .

[20]  E. Goldwasser,et al.  Purification of human erythropoietin. , 1977, The Journal of biological chemistry.

[21]  T. Hayakawa,et al.  Simple in vivo bioassay for erythropoietin , 1991, British journal of haematology.

[22]  J. Wiessner,et al.  Binding of insulin to the external surface of liposomes. Effect of surface curvature, temperature, and lipid composition. , 1982, Biochimica et biophysica acta.

[23]  H. Patel,et al.  Intracellular digestion of saturated and unsaturated phospholipid liposomes by mucosal cells. Possible mechanism of transport of liposomally entrapped macromolecules across the isolated vascularly perfused rabbit ileum. , 1985, Biochimica et biophysica acta.

[24]  P. Couvreur,et al.  Protection of insulin from enzymatic degradation by its association to liposomes , 1985 .

[25]  V. Labhasetwar,et al.  Liposomes as a carrier for oral administration of insulin: effect of formulation factors. , 1994, Journal of microencapsulation.