TRANSDERMAL AND INTRANASAL ADMINISTRATION OF RENIN INHIBITORY PEPTIDES

Abstract: The present invention provides transdermal and intranasal means to administer renin inhibitory peptides and compositions adapted therefor.

Description: TRANSDERMAL AND INTRANASAL ADMINISTRATION OF RENIN INHIBITORY PEPTIDES BACKGROUND OF THE INVENTION The present invention provides a new route of administration and novel compositions containing known pharmaceutical compounds. In particular, the present invention provides transdermal and intranasal administration of renin inhibitory peptides and novel compositions adapted for these routes of administration. Renin cleaves angiotensinogen to produce angiotensinogen I which is converted to the potent pressor angiotensin II. Inhibitors of this enzyme are thus useful in the treatment of hypertension. A large number of renin inhibitory peptides are known. See, e.g., published European Patent Application 173,481 and references cited therein. The present invention thus provides new routes of administration of these known compounds. INFORMATION DISCLOSURE The transdermal delivery of peptide and proteins is discussed in an article "Peptide and Protein Drug Delivery: Opportunities and Challenges" in the Journal Pharmacy International 7:208-212 (August 1986) which notes that the transdermal route appears to be unsatis¬ factory as the skin is relatively impermeable to peptides and proteins. SUMMARY OF THE INVENTION The present invention particularly provides: (1) a method for administering renin inhibitory peptides to a mammal comprising the application of the peptide, in a vehicle adapted for transdermal delivery, to the skin of the mammal; (2) a method for intranasally administering a renin inhibitory peptide to a mammal comprising contacting the renin inhibitory peptides in a vehicle adapted for intranasal delivery into the nasal cavity of a mammal; (3) a transdermal composition comprising a renin inhibitory peptide in an amount effective to treat or prevent hypertension and a vehicle adapted for transdermal delivery; and (4) an intranasal composition comprising an amount effective to treat or prevent hypertension of a renin inhibitory peptide and a vehicle adapted for intranasal delivery. Surprisingly and unexpectedly, it has been found that the renin inhibitory -peptides retain their activity through these routes of administration despite conventional knowledge in the art suggesting otherwise. By "renin inhibitory peptides" is meant a compound capable of inhibiting the renin enzyme in mammalian metabolism and having three or more amino acids residues linked by peptidic or pseudo-peptidic bonds. Examples of such compounds are described in U.S. Patent 4,424,207 (Szelke); European Patent 104041A (Szelke) ; European Patent Application 144.290A (Ciba Geigy AG) ; European Patent 0,156,322 (Merck); European Patent 161-588A (Merck); European Patent 0,172,347 (Abbott); European Patent 172-346-A (Abbott); European Patent 156-318 (Merck); European Patent 157-409 (Merck); European Patent 152-255 (Sankyo); and U.S. Patent 4,548,926 (Sankyo) ; and U.S. patent application, Serial No. 904,149, filed 5 September 1986; U.S. patent application, Serial No. 844,716, filed 27 March 1986; PCT application, Serial No. 000,713, filed 7 April 1986; U.S. patent application, Serial No. 945,340, filed 22 December 1986; and U.S. patent application, Serial No. 825,250, filed 3 February 1986; and A. Spal enstein, P. Carpino, F. Miyake and P.B. Hyskins, Tetrahedron Letters, 27:2095 (1986); D.H. Rich and M.S. Bernatowicz, J. Med. Chem., 25:791 (1982); Roger, J. Med. Chem. , 28:1062 (1985); D.M. Glick et al. , Biochemistry, 21:3746 (1982); D.H.. Rich, Biochemi¬ stry, 24:3165 (1985); R.L. Johnson, J. Med. Chem., 25:605 (1982); R.L. Johnson and K. Verschovor, J. Med. Chem., 26:1457 (1983); R.L. Johnson, J. Med. Chem., 27:1351 (1984); P.A. Bartlett et al. , J. Am. Chem. Soc, 106:4282 (1984); and Peptides: Synthesis, Structure and Function (V.J. Hruby; D.H. Rich, eds.) Proc. 8th American Peptide Sy . , Pierce Chemical Company, Rockford, 111., pp. 511-20; 587-590 (1983). Preferred compounds include: Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp (see copending U.S. application 07/147,073 filed 20 January 1988 incorporated by reference herein); N-[[[2-hydroxy-l,l-bis (hydroxy- methyl))ethyl]amino]carbonyl]-Pro-Phe-N-MeHis-LVA-lie-AMP, pyridine N-oxide, and (glucosaminocarbonyl)-Pro-Phe-N-MeHis-LVA-Ile-AMP, N- oxide (see copending application 07/151,129, filed 1 February 1988, incorporated by reference herein) . By "a vehicle adapted for transdermal delivery" is meant an pharmacologically acceptable solvent used for transdermal drug delivery. As is apparent to one of ordinary skill in the art, the compounds are dissolved in a suitable transdermal vehicle such as a cream, gel, paste or liquid which are generally known in the art for transdermal use. Typical transdermal vehicles are polyethylene glycol, propylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate. The compounds can also be applied to porous or other material suitable for preparing a transdermal patch which can be worn by the patient. Such transdermal vehicles are generally well-known in the pharmaceutical industry. By "a vehicle adapted for intranasal delivery" is meant any pharmacologically acceptable solvent useful for intranasal ad¬ ministration. Such vehicles are well known to those of ordinary skill in the art including, e.g., the citric acid solution described below. Surprisingly and unexpectedly, the methods and compositions of the present invention are useful for the administration of renin inhibitory peptides in the same manner as the oral and parenteral routes of administration previously disclosed for these compounds. Thus, they are useful for the same purposes described in the refer¬ ences described above, which are hereby incorporated by reference. The renin inhibitory peptides are administered in dosages equipotent to the dosages from the other routes of administration described in the references cited above. Typically, dosages from the routes of administration of the instant invention range from 0.1 mg to 1000 mg per kg administered from 1 to 4 times daily. An ordinarily skilled physician or veterinarian can readily determine appropriate dose ranges based on the references cited above and the examples herein. While the present invention is useful for the treatment of hypertension in all mammals, humans are the most preferred. DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is seen more fully by the examples given below. Example 1 Transdermal administration of a renin inhibitory peptide. Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp is dissolved in a solution of dimethylsulfoxide (DMSO) and applied to the shaved skin of anes- thetized, nephrectomized, ganglion blocked, recombinant human renin infused rats at concentrations of 15, 50 and 150 mg/kg. The blood pressure of these rats is reduced in a dose dependent manner. Similarly, the citrate salt of Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp, is applied to the shaved skin of an anesthetized, nephrectomized, ganglion blocked, recombinant human renin infused rat at a concentra¬ tion of 150 mg/kg in distilled water. The hypotensive response is approximately equivalent to that elicited by Boc-Pro-Phe-N-MeHis-LVA- Ile-Amp at 150 mg/kg in dimethylsulfoxide. Thus, the administration of renin inhibitory peptides onto shaved skin in two widely different formulations shows that the compounds retained their hypotensive activity and thus the renin inhibitory peptides are able to be administered transdermally to produce the desired hypotensive effects. Example 2 Intranasal administration of a renin inhibitory peptide. Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp is dissolved in 20 microliters of 0.1 M citric acid is administered to the nasal cavities of anesthetized, ganglion blocked, hog-renin infused rats at a dose of 3 mg/kg. The blood pressure of the rats is reduced. Similarly, anesthetized, nephrectomized, ganglion blocked, rats infused with human recombinant renin also shows that intranasal administration of either Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp at 3 ml/kg and 0.1 molar citric acid or the citrate salt of Boc-Pro-Phe-N-MeHis- LVA-Ile-Amp at 3 mg/kg in water evokes pronounced hypertensive responses. A further experiment demonstrates that a 3 ml/kg dose of Boc- Pro-Phe-N-MeHis-LVA-Ile-Amp is 0.1 molar citric acid administered intranasally to an anesthetized rat leads to a peak plasma level of 500 ng/ml at 5 min which decreases to 300 ng/ml at 30 min followed by a gradual decline to 150 ng/ml at 4 hr. The peak level at 248 min is 48% of the level for intravenous delivery. Administration of Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp at 3 mg/kg in 0.5 M hydrochloric acid intranasally to anesthetized rats results in initial blood levels approximately 50% as high as those obtained with the citric acid formulation administered intranasally. However, the plasma levels decreases so that at 240 min they are roughly equivalent to the citric acid formulation.

Claims: CLAIMS 1. A method for administering a renin inhibitory peptide to a mammal comprising the application of the peptide in a vehicle adapted for transdermal delivery to the skin of the mammal. 2. A method of Claim 1 wherein the mammal is a human. 3. A method for intranasally administering a renin inhibitory peptide to a mammal comprising delivering the renin inhibitory peptides in a vehicle adapted for intranasal delivery into the nasal cavity of a mammal. 4. A method of Claim 3 wherein the mammal is a human. 5. A transdermal composition comprising a renin inhibitory peptide in an amount effective to treat or prevent hypertension and a vehicle adapted for transdermal delivery. 6. An intranasal composition comprising an amount effective to treat or prevent hypertension of a renin inhibitory peptide and a vehicle adapted for intranasal delivery. 7. A method of Claim 2, wherein the peptide is Boc-Pro-Phe-N-MeHis- LVA-lie-Amp; N-[ [ [2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]- carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-AMP, pyridine N-oxide; or (glucosaminocarbonyl)-Pro-Phe-N-MeHis-LVA-Ile-AMP, N-oxide. 8. A method of Claim 4, wherein the peptide is Boc-Pro-Phe-N-MeHis- LVA-Ile-Amp; N- [ [ [2-hydroxy-1,1-bis(hydrox lmethyl)ethyl]amino] - carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-AMP, pyridine N-oxide; or (glucos- aminocarbonyl)-Pro-Phe-N-MeHis-LVA-Ile-AMP, N-oxide. 9. A composition of Claim 5, wherein the peptide is Boc-Pro-Phe-N- MeHis-LVA-Ile-Amp; N-[ [ [2-hydroxy-1,1-bis(hydrox lmethyl)ethyl] - amino]carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-AMP, pyridine N-oxide; or (glucosaminocarbonyl)-Pro-Phe-N-MeHis-LVA-Ile-AMP, N-oxide. 10. A composition of Claim 6, wherein the peptide is Boc-Pro-Phe-N- MeHis-LVA-Ile-Amp; N-[[[2-hydroxy-l,l-bis(hydroxylmethyl)ethyl]- amino]carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-AMP, pyridine N-oxide; or (glucosa inocarbonyl)-Pro-Phe-N-MeHis-LVA-lie-AMP, N-oxide. 11. A composition of Claim 5, wherein the vehicle and the peptide are absorbed into a transdermal patch.

Inventors: GIBSON RICHARD EARLE, LAWSON JUDY ANN, OLANOFF LAWRENCE S, PALS DONALD THEODORE, GIBSON, RICHARD, EARLE, LAWSON, JUDY, ANN, OLANOFF, LAWRENCE, S., PALS, DONALD, THEODORE
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1989
Main classification: A61K37
IPC codes: A61K9, A61K38, A61P9