Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-09-08
2000-11-28
Sayala, Chhaya D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, 530397, 530399, A61K 3823, A61K 3816
Patent
active
061535923
DESCRIPTION:
BRIEF SUMMARY
This invention relates to enhancing the bioavailability of proteolytically labile therapeutic agents by administering the therapeutic agent in combination with a protecting agent comprising a protein, a purified natural protein, a molecular weight fractionated protein, or a partially hydrolyzed protein.
BACKGROUND OF THE INVENTION
Peptide drugs and drugs containing a peptidase labile bond are among the most promising medicinal agents of modern times, but their instability in the presence of proteolytic enzymes in the gastrointestinal tract and other mucosal tissues usually requires that they be administered parenterally. Although patients can be taught to inject parenterally, there has been a long felt need to develop a non-invasive method for self administration of peptide drugs.
Protease inhibitors and penetration enhancers are means often considered to circumvent the enzymatic and penetration barriers to peptide and protein absorption from mucosal routes of administration. Because of such barriers, the bioavailability of peptide and protein drugs from mucosal routes is poor.
Non-parenteral administration of peptide drugs in particular often results in very low bioavailability because of hydrolysis of the peptides by proteolytic enzymes. For leuprolide, this ranges from 0.05% following oral administration to 38% following vaginal administration; for insulin, the corresponding figures are 0.05% and 18%. Lee, Journal of Controlled Release, 13, 213 (1990).
Examples of proteolytic enzymes which inactivate proteolytically-labile therapeutic agents are pepsin, trypsin, chymotrypsin, elastase, and carboxypeptidase in the intestinal lumen, and the aminopeptidases located on the mucosal surfaces of the GI tract, nose, and vagina.
Transport of intact oligopeptides across adult mammalian jejunum has been demonstrated in vitro and in vivo as well as in combination with peptidase inhibitors. Friedman and Amidon, Pharmaceutical Research 8, no. 1, P. 93, (1991).
Fujii et al; U.S. Pat. No. 4,639,435 (1987) claims the use of 1-isopropyl-4-[4-(1,2,3,4-tetrahydronaphthoyloxy)benzoyl] piperazine methanesulfonate as an inhibitor of chymotrypsin to be co-dosed orally or rectally with a chymotrypsin-labile drug (kallikrein or calcitonin). The reference also discloses the use of benzoylpiperazine esters for this purpose. The reference does not describe the mechanism of these inhibitors.
Cho and Flynn; International Patent Application WO-90/03164 (1990) disclose the use of protease inhibitors in oral formulation but do not describe the nature of such inhibitors in detail; the only protease inhibitor which appears in the examples is aprotinin.
Kidron, et al; U.S. Pat. No. 4,579,730 (1986) disclose the use of protease inhibitors in oral formulation of insulin. Soybean flour is disclosed as a source of soybean trypsin inhibitor (Bowman-Birk trypsin/chymotrypsin inhibitor; molecular weight 8000 daltons).
Ziv, et al; Biochem. Pharmacol. 36, 1035-1039 (1987) disclose the use of the protease inhibitor aprotinin to enhance the oral absorption of proteins.
Losse, et al; East German Patent DD 252 539 A1 (1987) disclose the use of epsilon-aminocaproic acid and aprotinin as protease inhibitors in oral formulation of peptides.
Lee; J.; Controlled Release 13, 213-223 (1990) reviews the use of protease inhibitors in formulations of peptides for oral, nasal, buccal, rectal, vaginal, pulmonary, and ocular routes.
Certain small peptides containing up to four amino acids have been shown to enhance the bioavailability of peptide drugs.
Hussain, et al, Biochemical and Biophysical Research Communications, 133, no. 3, 923 (195) suggested that nasal administration of peptides may become an important route provided that peptidases in the nasal mucosa can be transiently inhibited via coadministration of pharmacologically inactive peptidase substrates.
Faraj, et al, Journal of Pharmaceutical Sciences 79, no. 8, 698 (1990) showed that in the presence of the small peptides, L-tyrosyl-L-tyrosine and tri-L-tyrosine methyl ester, the hydrolysis of leucine e
REFERENCES:
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patent: 4579730 (1986-04-01), Kidron et al.
patent: 4639435 (1987-01-01), Fujii et al.
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Parsons et al., Br. J. Pharmocol., vol. 66, pp. 25-32, 1979.
Doron I Friedman and Gordon L. Amidon, "Oral Absorption of Peptides: Influence of pH and Inhibitors on the Intestinal Hydrolysis of Leu-Enkephalin and Analogues", Pharamaceutical Research, vol. 8, No. 1, 93-96, (1991).
Jabar A. Faraj, et al., "Mechanism of Nasal Absorption of Drugs.III: Nasal Absorption of Leucine Enkephalin", Journal of Pharmaceutical Sciences, vol. 79, No. 8, 698-702, (1990).
Vincent H. L. Lee, "Protease Inhibitors and Penetration Enhancers as Approaches to Modify Peptide Absorption", Journal of Controlled Release, 13, 213-223, (1990).
E. Ziv,O. Lior and M. Kidron, "Absorption of Protein Via the Intestinal Wall--A Quantitative Model", Biochemical Pharmacology, vol. 36, No. 7, 1035-1039, (1987).
Anwar Hussain, et al., "Hydrolysis of Leucine Enkephalin in the Nasal Cavity of the Rat--A Possible Factor in the low Bioavailability of Nasally Administered Peptides", Biochemical and Biophysical Research Communications, vol. 133, No. 3, 923-928, (1985).
Ryohei Hori, Fusao Komada and Katsuhiko Okumura, "Pharmaceutical Approach to Subcutaneous Dosage Forms of Insulin", Journal of Pharmaceutical Sciences, vol. 72, No. 4, 435-439, (1983).
Allan K. Smith, Sidney J. Circle and George H. Brother, "Peptization of Soybean Proteins. The Effect of Neutral Salts on the Quality of Nitrogenous Constituents Extracted from Oil-Free Meal", Journal of the American Chemical Society, vol. 60, 1316-1320, (1938).
Rompp Chemie Lexikon, 9th ed., 1989, pp. 232 and 733.
Rompp Chemie Lexikon, 8th ed., 1979, pp. 4382-4383.
Amidon Gordon L.
Leesman Glen D.
Sinko Patrick J.
Port Systems, LLC
Sayala Chhaya D.
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