Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1987-12-14
1991-10-01
Moezie, F. T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 3, 514866, 530303, A61K 3720
Patent
active
050533894
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to insulin preparations for non-parenteral administration.
BACKGROUND ART
Ever since the discovery of insulin and its successive use for the treatment of Diabetes the only form of administration used in practice has been subcutaneous or intramuscular injection, generally several times a day. In spite of a rapid technical development, this administration still involves a number of disadvantages, such as pain, risk of infection as well as a possibility of chronic tissue injuries. Consequently, there has always been a wish to administer the insulin non-parenterally, and thus in particular oral, rectal, nasal, as well as ophthalmic administrations have been investigated.
The ophthalmic administration of insulin has been disclosed in the specification of Danish Patent No. 135,268, according to which specification an insulin-containing hydrogel is placed under the eyelid. Thereby an absorption of 5-20% of the amount of insulin administered is obtained over a period of several hours.
The oral administration demands that special protective measures are taken in order to prevent the insulin from being decomposed, before absorption can take place through the intestinal mucosa. This can e.g. be done as stated in the specification of Danish patent application No. 1925/83 and Danish patent application No. 2294/84, according to which enzyme inhibitors are added and an encapsulation in a bile-soluble material may be made. Oral administration only gives an absorption of 1-2% of the amount of insulin administered, cf. Galloway et al., Diabetes 21 (1971), pages 640-648.
Rectal insulin administration is disclosed in e.g. German Published Specification No. 2,641,819, U.S. Pat. No. 4,164,573 and U.S. Pat. No. 4,442,090. In this way of administration the insulin is encapsuled in the form of a suppository in which the presence of an enzyme inhibitor is normally not necessary. Hereby an absorption of the amount of insulin administered of about 5% can be obtained.
In the forms of administration mentioned above use is made in almost all cases of a surface-active additive to increase the absorption rate and efficiency of the insulin through the mucosae. An example of such absorption promoting adjuvants are polyoxy ethylene fatty alcohol ethers and in particular bile acids or salts thereof.
Such additives are particularly effective in nasal administration of insulin, vide GB Patent Specifications No. 1,527,605 and No. 1,554,157, and the technique has been further described by S. Hirai et al., Diabetes 27 (1978), pages 296-299, and G. S. Gordon et al., PNAS 82 (1985), pages 7419-7423. In this form of administration the insulin is administered in solution as drops or better in atomized form to the nasal cavity, whereafter the absorption through the nasal mucosa occurs so rapidly, that the maximum insulin concentration is obtained already after 10 to 30 minutes. This rapidly commencing absorption is of particularly therapeutical importance as the maximum insulin concentration in normal subcutaneous injection of dissolved insulin does not commence until after 30-60 minutes, which may cause problems in a much employed Diabetes therapy, in which injections of rapidly acting insulin are given immediately before the principal meals.
However, in the nasal form of administration an adverse effect on the mucosae due to the added absorption promoting adjuvants has been demonstrated after some time, vide S. Hirai et al., Int. J. Pharm. 9 (1981), pages 173-184.
This problem is said to be solved by the use of certain fusidic acid or cephalosporine derivatives as adjuvants, vide the specification of European patent application No. 128,831. The proportion of insulin absorbed by nasal administration in dissolved and atomized form is said to be up to about 20% in the publications mentioned above.
An embodiment of the nasal administration in which the use of surface-active adjuvants can be avoided is known from European patent application No. 122,036. Said embodiment consists in the administration of the
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patent: 4164573 (1979-08-01), Galinsky
patent: 4442090 (1984-04-01), Kakeya et al.
patent: 4534894 (1985-08-01), Cerami et al.
Biol. Chem. Hoppe-Seyler, vol. 366, pp. 521-525 (1985) by Fischer et al., entitled "A Shortened Insulin with Full in Vitro Potency".
Hoppe-Seyler's Z. Physiol. Chem., vol. 356, pp. 1397-1404 (1973) by Hans-Gregor Gattner, entitled "B-Chain Shortening of Matrix-Bound Insulin . . . ".
Eur. j. Biochem, vol. 31, pp. 470-473 (1972) by Massey et al., entitled "The Effect of Acylation on the Molecular Size of Insulin".
Biochemistry, vol. 19, pp. 5926-5931 (1980) by Carpenter et al., entitled "Tetrakis (3-nitrotyrosine) Insulin".
"New Forms of Insulin" by Galloway et al., pp. 640-648.
Diabetes, vol. 27, No. 3, pp. 296-299 by Hirai et al., entitled "Nasal Absorpition of Insulin in Dogs".
Proc. Natl. Acad, Sci. U.S.A., vol. 82, pp. 7419-8423 (11/85) by Gordon et al., entitled "Nasal Adsorpition of Insulin: Enhancement by hydrophobic Bile Salts".
International Journal of Pharmaceutical, pp. 173-184 (1981) by Hirai et al. entitled "Mechanisms for the Enhancement of the Nasal Adsorption of Insulin . . . ".
Method in Enzymology, vol. 61, pp. 125-143 (1981) by Valdes et al., entitled "(9) Study of Protein Subunit Association Equilibria by Elution Gel Chromatography".
Balschmidt Per
Hansen Finn B.
Johansen Bente R.
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