Pragmatic Approaches to Delivery of Peptides and Proteins as Drugs

  • Deborah A. Eppstein
Part of the NATO ASI Series book series (NSSA, volume 155)


In the past decade, the explosion of recombinant DNA technology has led to cloning, and ultimately production of, a multitude of proteins previously unavailable for study as therapeutic agents. Also, there have been significant advances in biological and structural knowledge of peptide/polypeptide hormones which has led to an increase in research on and production of peptide drugs by synthetic methods. Although the increased knowledge and availability of peptide/protein therapeutic agents has opened an exciting and challenging new chapter in development of therapeutic entities, at the same time it is also forcing development of novel delivery methods. Simply put, peptides and proteins cannot readily be administered by the conventional oral route, due to their degradation by proteases of the digestive tract as well as lack of efficient absorption. Parenteral administration by intramuscular, subcutaneous, or intravenous injection can be utilized effectively for some protein and peptide drugs for treatment of acute disease situations for which only a limited number of injections are required. However, such repeated injections are undesirable for chronic administration. Unfortunately the nature of many of the diseases which are targets for treatment by these peptide/protein drugs is chronic rather than acute.


Adenosine Deaminase Protein Drug Peptide Drug Absorption Enhancer Muramyl Dipeptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abuchowski, A., van Es. T., Palczuk, N. C., and Davis, F. F., 1977a. Alteration of immunological properties of bovine serum albumin by covalent attachment of polyethylene glycol. J.Biol.Chem.., 252:3578.Google Scholar
  2. Abuchowski, A., McCoy, J. R., Palczuk, N. C., van Es, T., and Davis, F. F. 1977b, Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase, J.Biol.Chem., 252:3582.Google Scholar
  3. Allison, A. C., 1978, Mode of action of immunological adjuvants, J.Reticuloendothel.Soc., 26:619.Google Scholar
  4. Allison, A. C., and Byars, N. E., 1986a, An adjuvant formulation that selectively elicits the formation of antibodies of protective isotypes and of cell-mediated immunity, J.Immunol.Meth., 95:157.Google Scholar
  5. Allison, A. C., and Gregoriadis, G., 1974, Liposomes as immunological adjuvants, Nature 252:252.PubMedGoogle Scholar
  6. Alving, C. R., Banerji, B., Clements, J. D., and Richards, R. L., 1980, Adjuvanticity of lipid A and lipid A fractions in liposomes, in: “Liposomes and Immunobiology,” B.H. Tom, and H.R. Six, eds., Elsevier, pp. 67–68, New York.Google Scholar
  7. Alving, C. R., Richards, R. L., Moss, J., Alving, L. I., Clements, J. D., Shiba, T., Kotani, S., Wirtz, R. A., and Hockmeyer, W. T., 1986, Effectiveness of liposomes as potential carriers of vaccines: Applications to cholera toxin and human malaria sporozoite antigen, Vaccine, 4:166.PubMedGoogle Scholar
  8. Amkraut, A. A., and Martins, A. B., 1984, Method for administering immuno-potentiator, U. S. Patent 4,484,923.Google Scholar
  9. Berman, B., Davis-Reed, L., Silverstein, L., Jaliman, D., France, D., and Lebwohl, M., 1986, Treatment of Verrucae vulgaris with α 2 interferon, J.Infect.Pis., 154:328.Google Scholar
  10. Brown, L., Siemer, L., Munoz, C., and Langer, R., 1986a, Controlled release of insulin from polymer matrices: In vitro kinetics, Diabetes, 35:684.Google Scholar
  11. Brown, L., Munoz, C., Siemer, L., Edelman, E., and Langer, R., 1986b, Controlled release of insulin from polymer matrices: Control of diabetes in rats, Diabetes, 35:692.Google Scholar
  12. Byars, N. E., and Allison, A. C., 1987, An adjuvant formulation for use in vaccines to elicit both cell-mediated and humoral immunity, Vaccine, 5:223.PubMedGoogle Scholar
  13. Caldwell, L., Nishihata, T., Rytting, J. H., and Higuchi, T., 1982, Lymphatic uptake of water-soluble drugs after rectal administration, J.Pharm.Pharmacol., 34:520.PubMedGoogle Scholar
  14. Chen, R. H.-L., Abuchowski, A., van Es, T., Palczuk, N. C., and Davis, F. F. 1982, Properties of two v rate oxidases modified by the covalent attachment of poly (ethylene glycol), BJochim.Biophys.Acta., 660:293.Google Scholar
  15. Clark, R. G., and Robinson, I. C., 1985, Growth induced by pulsatile infusion of an ansidated fragment of human growth hormone releasing factor in normal and GHRF-deficient rats, Nature, 314:281.PubMedGoogle Scholar
  16. Clark, R. G., Jansson, J. O., Isaksson, O., and Robinson, I. C. A. F., Intravenous growth hormone: Growth response to patterned infusions in hypophysectomized rats, J.Endocr., 104:53.Google Scholar
  17. Clayton, R. N., 1982, Gonadrotropin-releasing hormone modulation of its own pituitary receptors: Evidence for biphasic regulation, Endocrinol., 111:152.Google Scholar
  18. Davis, D., and Gregoriadis, G., 1987, Liposomes as adjuvants with immuno-purified toxoid: influence of liposomal characteristics, Immunology, 61:229.PubMedGoogle Scholar
  19. Davis, D., Davies, A., and Gregoriadis, G., 1987, Liposomes as adjuvants with immunopurified tetanus toxoid: The immune response, Immunol.Lett., 14:341.PubMedGoogle Scholar
  20. Davis, S., Abuchowski, A., Park, Y. K., and Davis, F. F., 1981, Alteration of the circulating life and antigenic properties of bovine adenosine deaminase in mice by attachment of polyethylene glycol, Clin.Exp. Immunol., 46:649.PubMedGoogle Scholar
  21. Douglas, R. M., Moore, B. W., Miles, H. B., Davis, L. M., Graham, N. M. H., Ryan, P., Worswick, D. A., and Albrecht, J. K., 1986, Prophylactic efficacy of intranasal alpha2-interferon against rhinovirus infections in the family setting, N.Eng.J.Med., 314:65.Google Scholar
  22. Edelman, E. R., Kost, J., Bobeck, H., and Langer, R., 1985, Regulation of drug release from polymer matrices by oscillating magnetic fields, J.Biomed.Mater.Res., 19:67.PubMedGoogle Scholar
  23. Edelman, E. R., Brown, L., Taylor, J., and Langer, R., 1987, In vitro and in vivo kinetics of regulated drug release from polymer matrices by oscillating magnetic fields, J.Biomed.Mater.Res., 21:339.PubMedGoogle Scholar
  24. Eppstein, D. A., 1982, Altered pharmacologic properties of liposome-assoc-iated human interferon-alpha, J.IFN Res., 2:117.Google Scholar
  25. Eppstein, D. A., 1986a, Medical utility of interferons: approaches to increasing therapeutic efficacy, Pharm.Intl., August:195.Google Scholar
  26. Eppstein, D. A., 1986b, Alternative delivery of interferons, in: “Targeting of Drugs with Synthetic Systems,” G. Gregoriadis, J. Senior, and G. Poste, eds., Plenum Pub.Co., pp. 207. New York.Google Scholar
  27. Eppstein, D. A., and Feigner, P. L., 1987, Applications of liposome formulations for antimicrobial/antiviral therapy, in: “Liposomes as Drug Carriers: Trends and Progress,” G. Gregoriadis, eds., Wiley and Sons, Inc. (In press).Google Scholar
  28. Eppstein, D. A., and Longenecker, J. P., 1988, Alternative delivery systems for peptides and proteins ad drugs, in: “Critical Reviews in Therapeutic Drug Carriers, CRC Press,” in press.Google Scholar
  29. Eppstein, D. A., and Stewart II W. E., 1981, Binding and capture of human interferon-alpha by reverse evaporation vesicles, multilamellar vesicles and small unilamellar vesicles, J.Ifn Res., 1:495.Google Scholar
  30. Eppstein, D. A., and Stewart, II W. E., 1981, Altered pharmacological properties of liposome-associated human interferon-alpha, J.Virol., 41:575.Google Scholar
  31. Eppstein, D. A., van der Pas, M. A., Fraser-Smith, E. B., Kurahara, C. G., Feigner, P. L., Matthews, T. R., Waters, R. v., Venuti, M. C., Jones, G. H., Metha, R., and Lopez-Berestein, G., 1986, Liposome-encapsulated muramyl dipeptide analogue enhances non-specific host immunity, Int.J.Immunotherapy, 11(2):115.Google Scholar
  32. Eppstein, D. A., van der Pas, M. A., Schryver, B. B., Feigner, P. L., Gloff, C. A., and Soike, K. F., 1986a, Controlled-release and localized targeting of interferons, in: “Delivery Systems for Peptide Drugs,” S. S. Davis, L. Ilium, E. Tomlinson, eds., Plenum Press, pp. 227, New York,Google Scholar
  33. Eppstein, D. A., Kurahara, C. G., Bruno, N. A., van der Pas, M. A., Marsh, Y. V., and Schryver, B. B., 1986b, Pathways to increasing efficacy of interferons: Drug synergy and sustained-release, in: “Biology of the Interferon System, 1985,” Elsevier Sci.Publ. pp. 401, New York.Google Scholar
  34. Epstein, M. A., Morgan, A. J., Finerty, S., Randle, B. J., and Kirkwood, J. K., 1985, Protection of cottontop tamarins against Epstein-Barr virus-induced malignant lymphoma by a prototype subunit vaccine, Nature 318:287.PubMedGoogle Scholar
  35. Eron, L. J., Judson, F., Tucker, S., Prawer, S., Mills, J., Murphy, K., Hickey, M., Rogers, M., Flannigan, S., Hien, N., Katz, H. I., Goldman, S., Gottlieb, A., Adams, K., Burton, P., Tanner, D., Taylor, E., and Peets, E., 1986, Interferon therapy for condylomata acuminata, N.Eng.J.Med., 315:1059.Google Scholar
  36. Fara, J. W., 1985, Osmotic delivery systems for research, Meth.Enzymol., 112:470.PubMedGoogle Scholar
  37. Farr, B. M., Gwaltney, Jr., J. M., Adams, K. F., and Hayden, F. G., 1984, Intranasal interferon-α2 for prevention of natural rhinovirus colds, Antimicrob.Agents Chemotherap., 26:31.Google Scholar
  38. Fidler, I. J., Sone, S., Fogler, W. E., and Barnes, Z. L., 1981, Eradication of spontaneous metastases and activation of alveolar macrophages by intravenous injection of liposomes containing muramyl dipeptide, Proc.Natl.Acad.Sci.USA., 78:1650.Google Scholar
  39. Fidler, I. J., Sone, S., Fogler, W. E., Smith, D., Braun, D. G., Tarcsay, L., Gisler, R. H., and Schroit, A. J., 1982, Efficacy of liposomes containing a lipophilic muramyl dipeptide derivative for activating the tumoricidal properties of alveolar macrophages in vivo, J.Biol.Resp.Modif., 1:43.Google Scholar
  40. Francis, M. J., Fry, C. M., Rowlands, D. J., Brown, F., Bittle, J. L., Houghten, R. A., and Lerner, R. A., 1985, Immunological priming with synthetic peptides of foot and mouth disease virus, J.Gen.Virol., 66:2347.PubMedGoogle Scholar
  41. Fraser-Smith, E. B., Eppstein, D. A., Larsen, M. A., and Matthews, T. R., 1983, Protective effect of a muramyl dipeptide analog encapsulated in or mixed with liposomes against Candida albicans infection, Infect.Immun., 39:172.PubMedGoogle Scholar
  42. Furr, B. J. A., and Hutchinson, F. G., 1985, Biodegradable sustained release formulation of the LH-RH analogue ‘Zoladex’ for the treatment of hormone-responsive tumors, in: “EORTC Genitourinary Group Monograph 2, Part A: Therapeutic Principles in Metastatic Prostatic Cancer,” Alan R. Liss, Inc., pp. 143.Google Scholar
  43. Gall, S. A., Hughes, C. E., and Trofatter, K., 1985, Interferon for the therapy of condyloma acuminatum, Am.J.Obstet.Gynecol., 153:157.PubMedGoogle Scholar
  44. Gregoriadis, G., 1980, The liposome-drug carrier concept: Its development and future, in: “Liposomes in Biological Systems,” G. Gregoriadis and A. C. Allison, eds., John Wiley and Sons, Ltd., pp. 25. New York.Google Scholar
  45. Gregoriadis, G., Davies, A., and Davis, D., 1987, Liposomes as immunological adjuvants: antigen incorporation studies, Vaccine 5:145.PubMedGoogle Scholar
  46. Hayden, F. G., Gwaltney Jr., J. M., and Johns, M. E. 1985, Prophylactic efficacy and tolerance of low dose intranasal interferon-alpha2 in natural respiratory viral infections, Antiviral Res., 5:111.PubMedGoogle Scholar
  47. Hayden, F. G., Albrecht, J. K., Kaiser, D. L., and Gwaltney, Jr., J. M., 1986, Prevention of natural colds by contact prophylaxis with intranasal alpha2-interferon, N.Eng.J.Med., 314:71.Google Scholar
  48. Heller, J. 1984, Biodegradable polymers in controlled drug delivery, Crit.Rev.Ther.Drug Carrier Syst., 1:39.PubMedGoogle Scholar
  49. Heller, J., Sanders, L. M., Mishky, P., and Ng, S. Y., Release of an LHRH analogue from crosslinked poly(ortho ester), Proc. 13th Int. Symp. on Controlled Release of Bioactive Materials, Norfolk, VA.Google Scholar
  50. Hershfield, M. S., Buckley, R. H., Greenberg, M. L., Melton, A. L., Schiff, R., Hatem, C., Kurtzberg, J., Markert, M.L., Kobayashi, R. H., Kobayushi, A. L., and Abuchowski, A., 1987, Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase, New Eng.J.Med., 316:589.PubMedGoogle Scholar
  51. Herzog, C., Just, M., Berger, R., Havas, L., and Fernex, M., 1983, Intranasal interferon for contact prophylaxis against common cold in families, Lancet 2.Google Scholar
  52. Herzog, C., Berger, R., Fernex, M., Friesecke, K., Havas, L., Just, M., and Dubach, U. C., 1986, Intranasal interferon (rlFN-αtA, Ro 22–8181) for contact prophylaxis against common cold: a randomized, double-blind and placebo-controlled field study, Antiviral Res., 6:171.PubMedGoogle Scholar
  53. Hoffman, P. G., Henzl, M. R., Chaplin, M. D., and Nerenberg, C. A., 1987, Phase I and II Studies: Clinical development of Nafarelin acetate, J.Androl., 8:517.Google Scholar
  54. Hsu, T. T-P., and Langer, R., 1985, Polymers for the controlled release of macromolecules: Effect of molecular weight of ethylene-vinyl acetate copolymer, J.Biomed.Mater.Res., 19:445.PubMedGoogle Scholar
  55. Hunter, R., Strickland, F., and Kézdy, 1981, The adjuvant activity of nonionic block polymer surfactants, 1. The role of hydrophile-lipophile balance, J.Immunol., 127:1244.PubMedGoogle Scholar
  56. Ikic, D., Kirhmajer, V., Maricic, Z., Jusic, D., Krusic, J., Knezevic, M., Rode, B., and Soos, E., 1981, Application of human leucocyte interferon in patients with carcinoma of the uterine cervix, Lancet, 1:1027.PubMedGoogle Scholar
  57. Juliano, R. L., and McCullough, H. W., 1980, Controlled delivery of an anti-tumor drug: localized action of liposome encapsulated cytosine arabinoside administered via the respiratory system, J.Pharmacol. Exp.Ther., 214:381.PubMedGoogle Scholar
  58. Katre, N. V., Knauf, M. J., and Laird, W. F., 1987, Chemical modifications of recombinant interleukin-2 by polyethylene glycol increases its potency in the murine meth A sarcoma model, Proc.Natl.Acad.Sci.USA, 84:1487.PubMedGoogle Scholar
  59. Kohn, J., Niemi, S. M., ALbert, E. C., Murphy, J. C., Langer, R., and Fox, J. G., 1986, Single-step immunization using a controlled release biodegradable polymer with sustained adjuvant activity, J.Immunol. Methods, 95:31.PubMedGoogle Scholar
  60. Kost, J., Noecker, R., Kunica, E., and Langer, R., 1985, Magnetically controlled release systems: Effect of polymer composition, J.Biomed. Mater.Res., 19:935.PubMedGoogle Scholar
  61. Kotani, S., Kinoshita, F., Morisuki, I., Shimono, T., Okunaga, T., Takada, H., Tsujimoto, M., Watanabe, Y., and Kato, K., 1977, Immunoadjuvant activities of synthetic 6–0-acyl-N-acetylmuramyl-L-alanyl-D-isoglu-tamine with special reference to the effect of its administration with liposomes, Biken J 20:05.Google Scholar
  62. Kramp, W. J., Six, H. R., Drake, S., and Kasel, J. A., 1979, Liposomal enhancement of the immunogenicity of adenovirus type 5 hexon and fiber vaccines, Infect.Immun., 25:771.PubMedGoogle Scholar
  63. Langer, R., 1982, controlled release of macromolecules, Chemtech, Feb:98.Google Scholar
  64. Langer, R., Hsieh, D. S. T., Rhine, W., and Folkman, J., 1980, Control of release kinetics of macromolecules from polymers, J.Membr.Sci., 7:333.Google Scholar
  65. Langer, R., Brem, H., and Tapper, D., 1981, Biocompatibility of polymeric delivery systems for macromolecules, J.Biomed.Mater.Res., 15:267.PubMedGoogle Scholar
  66. Langer, R., Siegel, R., Brown, L., Leong, K., Kost, J., and Edelman, E., 1986, Controlled release, Three mechanisms, Chem.Tech., 16:108.Google Scholar
  67. Lau, A. S., Hannigan, G. E., Freedman, M. H., and Williams, B. R. G., 1986, Regulation of interferon receptor expression in human blood lymphocytes in vitro and during the interferon therapy, J.Clin.Invest., 77:1632.PubMedGoogle Scholar
  68. Leong, K. W., Brott, B. C., and Langer, R., 1985, Bioerodible polyan-hydrides as drug-carrier matrices: I. Characterization, degradation, and release characteristics, J.Biomed.Mat.Res., 19:941.Google Scholar
  69. Leong, K. W., D’Amore, P., Marietta, M., and Langer, R., 1986, Bioerodible polyanhydrides as drug-carrier matrices. II. Biocompatibility and chemical reactivity, J.Biomed.Mat.Res., 20:51.Google Scholar
  70. Longenecker, J. P., Moses, A. C., Flier, J. S., Silver, R. D., Carey, M. C., and Dubovi, E. J., 1987, Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep, J.Pharm.Sci., 76:351.PubMedGoogle Scholar
  71. Lopez-Berestein, G., Milas, L., Hunter, N., Mehta, K., and Hersh, E. M., Kurahara, C. G., van der Pas, M., and Eppstein, D. A., 1984, Prophylaxis and treatment of experimental lung metastases in mice after treatment with liposome-encapsulated 6–0-stearoyl-N-acetyl-muramyl-L-α-aminobutyryl-D-isoglutamine, Clin.Expl.Metastasis, 2:127.Google Scholar
  72. Manesis, E. k., Cameron, C. H., and Gregoriadis, G., 1978, Incorporation of Hepatitis-B surface antigen (HB5Ag) into liposomes, Biochem.Soc. Transact., 6:925.Google Scholar
  73. Mark, D., Lin, L., and Lu, S., 1985, 1986, U.S. Patent # 4,518,584, and #4,588,585, Human recombinant cysteine depleted interferon-3 muteins.Google Scholar
  74. Marx, P. A., Pedersen, N. C., Lerche, N. W., Osborn, K. G., Lowenstine, L. J., Lackner, A. A., Maul, D. H., Kwang, H-S., Kluge, J. D., Zaiss, C. P., Sharpe, V., Spinner, A. P., Allison, A. C., and Gardner, M. B., 1986, Prevention of simian acquired immune deficiency syndrome with a formalin-inactivated type D retrovirus vaccine, J.Virol., 60:431.PubMedGoogle Scholar
  75. Mathiowitz, E., and Langer, R., 1987, Polyanhydride microspheres as drug carriers, J.Cntrl.Rel., 5:13.Google Scholar
  76. Maxwell, B. L., Talpaz, M., and Gutterman, J. U., 1985, Down-regulation of peripheral blood cell interferon receptors in chronic myelogenous leukemia patients undergoing human interferon (HuIFN-α) therapy, Int.J.Cancer, 36:23.PubMedGoogle Scholar
  77. Monto, A. S., Shope, T. C., Schwartz, S. A., and Albrecht, J. K. 1986, Intranasal interferon-α2b for seasonal prophylaxis of respiratory infection, J.Infect.Pis., 154:128.Google Scholar
  78. Moore, J. A., Wilking, H., and Daugherty, A. L., Delivery systems for recombitant methionyl human growth hormone, in: “Delivery Systems for Peptide Drugs,” S. S. Davis, L. Ilium, and E. Tomlinson, eds., Plenum Press, 317, New York.Google Scholar
  79. Muranishi, S., 1984, Characteristics of drug absorption via the rectal route, Meth. and Find.Exptl.Clin.Pharmacol., 6:763.Google Scholar
  80. Naylor, P. T., Larsen, H. S., Huang, L., and Rouse, B. T., 1982, In vivo induction of anti-herpes simplex virus immune response by type 1 antigens and lipid incorporated into liposomes, Infect.Immun. 36:1209.PubMedGoogle Scholar
  81. Niimura, M., 1983, Intralesional human fibroblast interferon in common warts, J.Dermatol., 10:217.PubMedGoogle Scholar
  82. Nishihata, T., Rytting, J. H. Caldwell, L., Yoshioka, S., and Higuchi, T., Adjuvant effects on rectal absorption, in: “Optimization of Drug Delivery,” H. Bundgaard, A. B. Hansen, and H. Kofod, eds., Munksgaard, Copenhagen, 17, 1982.Google Scholar
  83. North, J. R., Morgan, A. J., Thompson, J. L., and Epstein, M. A., 1982, Purified Epstein-Barr mr 340,000 glycoprotein induces potent virus-neutralizing antibodies when incorporated in liposomes, Proc.Natl. Acad.Sci.USA., 79:7504.PubMedGoogle Scholar
  84. Pazin, G. J., 1985, Interferons in papilloma virus infections, Antiviral Res.Suppl., 1:251.Google Scholar
  85. Pitt, C. G., 1987, The controlled delivery of polypeptides including LHRH analogs, in: “Contraceptive and Therapeutic Applications, Part 2,” B.H. Vickery and Nestor Jr., J.J., eds., MTP Press, pp. 557. Boston.Google Scholar
  86. Preis, I., and Langer, R. S., 1979, A single step immunization by sustained antigen release, J.Immunol.Methods, 28:193.PubMedGoogle Scholar
  87. Rhine, W. D., Hsieh, D. S. T., and Langer, R., 1980, Polymers for sustained macromolecule release: Procedures to fabricate reproducible delivery systems and control release kinetics, J.Pharmaceut Sci., 69:265.Google Scholar
  88. Robey, W. G., Authur, L. O., Matthews, T. J., Langlois, A., Copeland, T. D., Lerche, N. W., Oroszlan, S., Bolognesi, D. P., Gilden, R. V., and Fischinger, P. J., 1986, Prospect for prevention of human immunodeficiency virus infection: Purified 120-kDa envelope glycoprotein induces neutralizing antibody, Proc.Natl.Acad.Sci.USA., 83:7023.PubMedGoogle Scholar
  89. Robinson, M. R. G., Denis, L., Mahler, C., Walker, K., Stitch, R., and Lunglmayr, G., 1985, An LH-RH analogue (Zoladex) in the management of carcinoma of the prostate: A preliminary report comparing daily subcutaneous injections with monthly depot injections, Eur.J.Surg. Oncology., 11:159.Google Scholar
  90. van Rooijen, N., and van Nieuwmegen, R., 1980, Liposomes in immunology: Evidence that their adjuvant effect results form surface exposition of the antigens, Cell.Immunol., 49:402.PubMedGoogle Scholar
  91. van Rooijen, N., and van Nieuwmegen, R., 1981, Immunoadjuvant properties of liposomes, in: “Targeting of Drugs,” G. Gregoriadis, ed., Plenum, pp 310–326, New York.Google Scholar
  92. Samo, T. C., Greenberg, S. B., Palmer, J. M., Couch, R. B., Harmon, M. W., and Johnson, P. E., 1984, Intranasally applied recombinant leukocyte A interferon in normal volunteers. II. Determination of minimal effective and tolerable dose, J.Infect.Dis., 150:181.PubMedGoogle Scholar
  93. Sanchez, Y., Ionescu-Matiu, I., Dreesman, G. R., Kramp, W., Six, H. R., Hollinger, F. B., and Melnick, J. L., 1980, Humoral and cellular immunity to hepatitis B virus-derived antigens: comparative activity of Freund complete adjuvant, alum, and liposomes, Infect.Immun., 30:728.PubMedGoogle Scholar
  94. Sanders, L. M., Kent, J. S., McRae, G. I., Vickery, B. H., Tice, T. R., and Lewis, D. H., 1984, Controlled release of a luteinizing hormone-releasing hormone analogue from poly(d, 1-lactide-co-glycolide) microspheres, J.Pharm.Sci., 73:1294.PubMedGoogle Scholar
  95. Sanders, L. M., McRae, G. I., Vitale, K. M., and Kell, B. A., 1985, Controlled delivery of an LHRH analogue from biodegradable injectable microspheres, J.Cntrl.Rel., 2:187.Google Scholar
  96. Sanders, L. M., Kell, B. A., McRae, G. I., and Whitehead, G. W., 1986a, Prolonged controlled-release of nafarelin, a luteinizing hormone-releasing hormone analogue, from biodegradable polymeric implants: Influence of composition and molecular weight of polymer, J.Pharm.Sci., 75:356.Google Scholar
  97. Sanders, L. M., Vitale, K. M., McRae, G. I., and Mishky, P. B., 1986b, Controlled delivery of nafarelin, an agonistic analogue of LHRH, from microspheres of poly (d, 1 lactic-co-glycolic) acid, in: “Delivery Systems for Peptide Drugs,” S. S. Davis, L. Ilium, and E. Tomlinson, eds., Plenum Press, pp 125. New York.Google Scholar
  98. Schally, A. V., Kook, A. I., Monje, E., Redding, T. W., and Paz-Bouza, J. I., 1986, Combination of a long-acting delivery system for luteinizing hormone-releasing hormone agonist with Novantrone chemotherapy: increased efficacy in the rat prostate cancer mode, Proc.Nat1.Acad. Sci.USA, 83:8764.Google Scholar
  99. Schneider, A. I., 1972, Polylactide systems, U. S. Patent #3, 636, 956.Google Scholar
  100. Schonfeld, A., Schattner, A., Crespi, M., Levavi, H., Shoham, J., Nitke, S., Wallach, D., Hahn, T., Yarden, O., Doerner, T., and Revel, M., 1984, Intramuscular human interferon-3 injection sin treatment of condylomata acuminata, Lancet, 1:1039.Google Scholar
  101. Siddiqui, W. A., Taylor, D. W., Kan, S-C, Kramer, K., and Richmond-Crum, S. M. 1978, Vaccination of experimental monkeys against Plasmodium falciparum: A possible safe adjuvant, Science, 201:1237.PubMedGoogle Scholar
  102. Theakston, R. D. G., Zumbuehl, O., and New, R. R. C., 1985, Use of liposomes for protective immunization in sheep against Echis carinatus snake venom, Toxicon., 23:921.PubMedGoogle Scholar
  103. Urquhart, J., Fara, J. W., and Willis, K. L., 1984, Rate-controlled delivery systems in drug and hormone research, Ann.Rev.Pharmacol. Toxicol., 24:199.Google Scholar
  104. Vance, J. C., Bart, B. J., Hansen, R. C., Reichman, R. C., McEwen, C., Hatch, K. D., Berman, B., and Tanner, D. J., 1986, Intralesional recombinant alpha-2 interferon for the treatment of patients with condyloma acuminatum or verruca plantaris, Arch.Dermatol., 122:272.PubMedGoogle Scholar
  105. Vesterinen, E., Meyer, B., Purola, E., and Cantell, K., 1984a, Treatment of Vaginal flat condyloma with interferon cream, Lancet, 1:157.Google Scholar
  106. Vesterinen, E., Meyer, B., Cantell, K., and Purola, E., 1984b, Topical treatment of flat vaginal condyloma with human leukocyte interferon, Obstet.Gynecol., 64:535.Google Scholar
  107. Wachsmann, D., Klein, J. P., Scholler, M., and Frank, R. M., 1985, Local and systemic immune response to orally administered liposome-assoc-iated soluble S. mutants. cell wall antigens, Immunology 54:189.PubMedGoogle Scholar
  108. Yoshikawa, H., Takada, K., Muranishi, S., Satoh, Y., and Naruse, N., 1984, A method to potentiate enteral absorption of interferon and selective delivery into lymphatics, J.Pharm.Dyn., 7:59.Google Scholar
  109. Ysohikawa, H., Takada, K., Satoh, Y., Naruse, N., and Muranishi, S., 1985, Potentiation of enteral absorption of human interferon alpha and selective transfer into lymphatics in rats, Pharm.Res., 2:249.Google Scholar
  110. Yau-Young, A., Lau, M., Chow, J., and Ling, J-P., 1987, Sustained release of a peptide from liposome formulations, J.Cell.Biochem.Suppl., 11B:118.Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Deborah A. Eppstein
    • 1
  1. 1.Syntex ResearchPalo AltoUSA

Personalised recommendations