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Enhanced Bioavailability of Subcutaneously Injected Insulin by Pretreatment with Ointment Containing Protease Inhibitors

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Abstract

The present study was undertaken to develop an ointment preparation containing a protease inhibitor for stabilizing subcutaneously injected insulin. The ointment containing the protease inhibitor, gabexate mesilate or nafamostat mesilate, was applied to the skin around the insulin injection site. Three results were obtained. First, gabexate and nafamostat inhibited insulin degradation in subcutaneous tissue homogenates in vitro. Second, after application of gabexate or nafamostat ointment, an appreciable amount of gabexate or nafamostat appeared in the subcutaneous tissue of rats or hairless mice and their concentrations were comparable to those seen in the in vitro experiment. Third, insulin degradation at the subcutaneous injection site in the rat was depressed after pretreatment with gabexate or nafamostat ointment. Pretreatment with gabexate or nafamostat ointment increased the plasma immunoreactive insulin (IRI) levels and the hypoglycemic effect of insulin in healthy volunteers. These results indicate that gabexate or nafamostat ointments stabilize subcutaneously injected insulin.

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REFERENCES

  1. W. Sadée. Pharm. Res. 3:3–6 (1986).

    Google Scholar 

  2. R. E. Startford and V. H. L. Lee. Int. J. Pharm. 30:73–82 (1986).

    Google Scholar 

  3. M. Berger, P. A. Halban, W. A. Müller, R. E. Offord, A. E. Renold, and M. Vranic. Diabetologia 15:133–140 (1978).

    Google Scholar 

  4. P. A. Halban, M. Berger, L. Girardier, J. Seydoux, R. E. Offord, and A. E. Renold. Diabetes 27:439 (1978).

    Google Scholar 

  5. M. Berger, P. A. Halban, L. Girardier, J. Seydoux, R. E. Offord, and A. E. Renold. Diabetologia 17:97–99 (1979).

    Google Scholar 

  6. R. W. Stevenson, T. I. Tsakok, and J. A. Parsons. Diabetologia 18:423–426 (1980).

    Google Scholar 

  7. R. W. Stevenson. Diabetologia 22:221–222 (1982).

    Google Scholar 

  8. S. M. O. Guerra and A. E. Kitabchi. J. Clin. Endrocrinol. Metab. 42:869–874 (1976).

    Google Scholar 

  9. J. A. Parsons, B. Rafferty, R. W. Stevenson, and J. M. Zanelli. Br. J. Pharmacol. 66:25–32 (1979).

    Google Scholar 

  10. G. R. Freidenberg, N. White, S. Cataland, T. M. O'Dorisio, J. F. Sotos, and J. V. Santiago. N. Engl. J. Med. 305:363–368 (1981).

    Google Scholar 

  11. T. Kobayashi, S. Sawano, T. Itoh, K. Kosaka, H. Hirayama, and Y. Kasuya. Diabetes 32:331–336 (1983).

    Google Scholar 

  12. W. A. Müller, M. Berger, J. Philippe, P. A. Halban, and R. E. Offord. Lancet 7:1245–1246 (1980).

    Google Scholar 

  13. R. Hori, F. Komada, and K. Okumura. J. Pharm. Sci. 72:435–439 (1983).

    Google Scholar 

  14. K. Okumura, F. Komada, and R. Hori. J. Pharmacobio-Dyn. 8:25–32 (1985).

    Google Scholar 

  15. F. Komada, K. Okumura, and R. Hori. J. Pharmacobio-Dyn. 8:33–40 (1985).

    Google Scholar 

  16. R. Hori, F. Komada, S. Iwakawa, Y. Seino, and K. Okumura. Pharm. Res. 6:813–816 (1989).

    Google Scholar 

  17. M. Marea-Guia and E. Shaw. J. Biol. Chem. 242:5782–5788 (1967).

    Google Scholar 

  18. M. Muramatu and S. Fujii. Biochim. Biophys. Acta 268:221–224 (1972).

    Google Scholar 

  19. S. Fujii and Y. Hitomi. Biochim. Biophys. Acta 661:342–345 (1981).

    Google Scholar 

  20. N. Ikari, Y. Sakai, Y. Hitomi, and S. Fujii. Immunology 49:685–691 (1983).

    Google Scholar 

  21. T. Aoyama, Y. Ino, M. Ozeki, M. Oda, T. Sato, Y. Koshiyama, S. Suzuki, and M. Fujita. Jpn. J. Pharmacol. 35:203–227 (1984).

    Google Scholar 

  22. M. Iwaki, Y. Ino, A. Motoyoshi, M. Ozeki, T. Sato, M. Kurumi, and T. Aoyama. Jpn. J. Pharmacol. 41:155–162 (1986).

    Google Scholar 

  23. P. Freychet, J. Roth, and D. M. Neville. Biochem. Biophys. Res. Commun. 43:869–874 (1971).

    Google Scholar 

  24. A. Junod, A. E. Lambert, W. Stauffacher, and A. E. Renold. J. Clin. Invest. 48:2129–2139 (1969).

    Google Scholar 

  25. J. M. Hammond and L. Jerett. Diabetes 24:1011–1019 (1975).

    Google Scholar 

  26. E. Menegatti, S. Scalia, F. Bortolotti, P. Ascenzi, A. D. Marci, and M. Guarneri. Pharm. Acta Helv. 60:170–174 (1985).

    Google Scholar 

  27. K. Arakawa, M. Kubotori, S. Sugiyama, M. Kurumi, and T. Aoyama. Yakugaku Zasshi 105:512–516 (1985).

    Google Scholar 

  28. A. Hyvarinen and E. A. Nikkilä. Clin. Chim. Acta 7:140–143 (1962).

    Google Scholar 

  29. K. Yamamura, J. Yamada, and T. Yotsuyanagi. J. Chromatogr. 331:383–388 (1985).

    Google Scholar 

  30. N. Ohta, T. Yotsuyanagi, and K. Ikeda. Int. J. Pharm. 29:137–146 (1986).

    Google Scholar 

  31. C. R. Behl, G. L. Flynn, T. Kurihara, N. Harper, W. Smith, W. I. Higuchi, N. F. H. Ho, and C. L. Pierson. J. Invest. Dermatol. 75:346–352 (1980).

    Google Scholar 

  32. H. Durrheim, G. L. Flynn, W. I. Higuchi, and C. R. Behl. J. Pharm. Sci. 69:781–786 (1980).

    Google Scholar 

  33. G. L. Flynn, H. Dürrheim, and W. I. Higuchi. J. Pharm. Sci. 70:52–56 (1981).

    Google Scholar 

  34. C. R. Behl, A. A. El-Sayed, and G. L. Flynn. J. Pharm. Sci. 72:79–82 (1983).

    Google Scholar 

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Author notes

  1. Masaharu Takeyama

    Present address: Department of Hospital Pharmacy, Medical College of Oita, Hasama-cho, Oita, 879-57, Japan

  2. Noriko Kokubu

    Present address: Nippon Wellcome, Yodogawa-ku, Osaka, 532, Japan

Authors and Affiliations

  1. Department of Pharmacy, Kagawa Medical School, Miki-cho, Kita-gun, Kagawa, 761-07, Japan

    Masaharu Takeyama

  2. Department of Medicine, Kagawa Medical School, Miki-cho, Kita-gun, Kagawa, 761-07, Japan

    Toshihiko Ishida

  3. Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606, Japan

    Noriko Kokubu & Ryohei Hori

  4. Department of Hospital Pharmacy, School of Medicine, Kobe University, Chuou-ku, Kobe, 650, Japan

    Fusao Komada, Seigo Iwakawa & Katsuhiko Okumura

Authors
  1. Masaharu Takeyama
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  2. Toshihiko Ishida
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  3. Noriko Kokubu
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  4. Fusao Komada
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  5. Seigo Iwakawa
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  6. Katsuhiko Okumura
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  7. Ryohei Hori
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Takeyama, M., Ishida, T., Kokubu, N. et al. Enhanced Bioavailability of Subcutaneously Injected Insulin by Pretreatment with Ointment Containing Protease Inhibitors. Pharm Res 8, 60–64 (1991). https://doi.org/10.1023/A:1015878222769

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  • DOI: https://doi.org/10.1023/A:1015878222769

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