CA2004571A1 - Transdermal and intranasal administration of renin inhibitory peptides - Google Patents
Transdermal and intranasal administration of renin inhibitory peptidesInfo
- Publication number
- CA2004571A1 CA2004571A1 CA002004571A CA2004571A CA2004571A1 CA 2004571 A1 CA2004571 A1 CA 2004571A1 CA 002004571 A CA002004571 A CA 002004571A CA 2004571 A CA2004571 A CA 2004571A CA 2004571 A1 CA2004571 A1 CA 2004571A1
- Authority
- CA
- Canada
- Prior art keywords
- ile
- phe
- pro
- mehis
- lva
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/553—Renin inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Otolaryngology (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
ABSTRACT
The present invention provides transdermal and intranasal means to administer renin inhibitory peptides and compositions adapted therefor.
The present invention provides transdermal and intranasal means to administer renin inhibitory peptides and compositions adapted therefor.
Description
TRANSDE~AL AND INTRANASAL ADMINISTRATION
BACKCROUND OF~ Y~TI~
The present invention provides a new route of ad~inistration and novel compositions containing known pharmaceutical compounds. In partic~lar, 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
lar~e 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 1~ 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 2~ 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:
2~ (1) a ~ethod 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 re.nin inhibitory 3~ 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 comprisiny, an amount effective to treat or prevent hypertension of a renin inhibitory peptide and a vehicle adapted for intranasal delivery.
Surprisiny,ly and unexpectedly, it has been found that the renin ,` ' ~
~0~7~
-2~
inhibitory peptides retain their activlty through these routes of adm~nis~ration despite conven~lonal knowledg~ in ehe art suggesting otherwise.
By "ren~n inhibitory peptidesn ~s meant a compound capable of S lnhibiting the renin enzyme in mammalian metabolism and h~ving three or more amlno aclds resldues linked by peptidic or pseudo-peptidic bonds. Examples of suc~ 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-~55 (Sankyo); and U.S. Patent 4,548,926 (Sankyo); and U.S. Ratent 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. Spaltenstein, P. Carpinc" F. Miyake and P.B. Hyskin~, Tetrahedron Letters, 27:2095 (1986); D.H. Rich and M.S. Be~natowicz, J. Med. Chem., 25:791 (1982); Roger, J. Med. Chem., 28:1062 (1985);
D.M. Glick et al., Biochsmistry, 21:3746 ~1982); D.H. Rich, B~ochemi-stry, 24:3165 (1985); R.L. Johnson, J. Med. Chem., 25:605 (1982);
R.L. Johnsc,n 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 Sym., Pierce Chemical Company, Rockford, Ill., 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 Jan~ary 1988 incorporated by reference herein); N-[[[2-hydroxy-1,1-bis (hydroxy-methyl))ethyl]amino]carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-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 any ~Of~57~.
pharmacologically ac¢eptable solvent used for transdermal drug delivery. As is apparent to one of ordinary skill in the ~rt, the compounds ~re dissolved ln a suitable trAnsdermal vehicle such as a cream, gel, paste or liquld which are ~enerally know~ in the art for transdermal use. Typical transderm~l vehicles are polyethylene glycol, propylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate. The compounds can also be applied to porous or other material sultable 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 vehlcles 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 co~positions 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 psr 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 treat~ent 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. 5 Example l 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-o ~r~-4-thetized, n~phrectomlzed, ~angllon blocked, recombinant human rsnlnl~fused rats at concentrati.ons of 15, S0 ~nd 150 mg/kg. Th~ blood pressure of these rats is reduced ln a dose dependent manner.
Similarly, the citrate salt of Boc-Pro~Phe-~-MeHls-LVA-Ile-Amp, is applled t~ the shaved skin of an anesthetized, nephrecto~ized, ganglion blocked, recombinant hu~an renin infused rat at a concentra-tion of 150 mg/kg in dlstilled ~ater. The hypotencive resporse is approximately equ$valent to that ellcited by Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp at 150 mg/k~ in dimethylsulfoxide.
Thus, the administratlon of renin inhibitory peptides onto shaved skin in two widely different for~ulations 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. 5 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 dos2 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-~eHis-LVA-Ile-Amp at 3 mg/kg in water evokes pronounced hypert2nsive responses.
A further experiment demonstrates that a 3 ml/kg dose o_ Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp is ~.1 molar citric acid admini,tered intranasally to an anesthetized rat leads to a ?eak plasma 12:21 of 500 ng/ml at 5 min which decreas2s to 300 ng/ml at 30 min follo-~ed by a gradual decline to 150 ng/ml a. 4 hr. The peaX level at 248 ~in is 48~ of the level for intravenous delivery.
Administration of Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp at 3 mg,~g in 0.5 M hydrochloric acid intranasally to anesthetized rats resuits in initial blood levels approximately 50~ as high as those obtain2d with the citric acid formulation administered intranasally. Howeve~, the plasma levels decreases so that at 240 min they are roughly equivalent to the citric acid formulation.
BACKCROUND OF~ Y~TI~
The present invention provides a new route of ad~inistration and novel compositions containing known pharmaceutical compounds. In partic~lar, 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
lar~e 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 1~ 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 2~ 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:
2~ (1) a ~ethod 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 re.nin inhibitory 3~ 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 comprisiny, an amount effective to treat or prevent hypertension of a renin inhibitory peptide and a vehicle adapted for intranasal delivery.
Surprisiny,ly and unexpectedly, it has been found that the renin ,` ' ~
~0~7~
-2~
inhibitory peptides retain their activlty through these routes of adm~nis~ration despite conven~lonal knowledg~ in ehe art suggesting otherwise.
By "ren~n inhibitory peptidesn ~s meant a compound capable of S lnhibiting the renin enzyme in mammalian metabolism and h~ving three or more amlno aclds resldues linked by peptidic or pseudo-peptidic bonds. Examples of suc~ 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-~55 (Sankyo); and U.S. Patent 4,548,926 (Sankyo); and U.S. Ratent 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. Spaltenstein, P. Carpinc" F. Miyake and P.B. Hyskin~, Tetrahedron Letters, 27:2095 (1986); D.H. Rich and M.S. Be~natowicz, J. Med. Chem., 25:791 (1982); Roger, J. Med. Chem., 28:1062 (1985);
D.M. Glick et al., Biochsmistry, 21:3746 ~1982); D.H. Rich, B~ochemi-stry, 24:3165 (1985); R.L. Johnson, J. Med. Chem., 25:605 (1982);
R.L. Johnsc,n 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 Sym., Pierce Chemical Company, Rockford, Ill., 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 Jan~ary 1988 incorporated by reference herein); N-[[[2-hydroxy-1,1-bis (hydroxy-methyl))ethyl]amino]carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-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 any ~Of~57~.
pharmacologically ac¢eptable solvent used for transdermal drug delivery. As is apparent to one of ordinary skill in the ~rt, the compounds ~re dissolved ln a suitable trAnsdermal vehicle such as a cream, gel, paste or liquld which are ~enerally know~ in the art for transdermal use. Typical transderm~l vehicles are polyethylene glycol, propylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate. The compounds can also be applied to porous or other material sultable 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 vehlcles 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 co~positions 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 psr 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 treat~ent 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. 5 Example l 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-o ~r~-4-thetized, n~phrectomlzed, ~angllon blocked, recombinant human rsnlnl~fused rats at concentrati.ons of 15, S0 ~nd 150 mg/kg. Th~ blood pressure of these rats is reduced ln a dose dependent manner.
Similarly, the citrate salt of Boc-Pro~Phe-~-MeHls-LVA-Ile-Amp, is applled t~ the shaved skin of an anesthetized, nephrecto~ized, ganglion blocked, recombinant hu~an renin infused rat at a concentra-tion of 150 mg/kg in dlstilled ~ater. The hypotencive resporse is approximately equ$valent to that ellcited by Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp at 150 mg/k~ in dimethylsulfoxide.
Thus, the administratlon of renin inhibitory peptides onto shaved skin in two widely different for~ulations 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. 5 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 dos2 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-~eHis-LVA-Ile-Amp at 3 mg/kg in water evokes pronounced hypert2nsive responses.
A further experiment demonstrates that a 3 ml/kg dose o_ Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp is ~.1 molar citric acid admini,tered intranasally to an anesthetized rat leads to a ?eak plasma 12:21 of 500 ng/ml at 5 min which decreas2s to 300 ng/ml at 30 min follo-~ed by a gradual decline to 150 ng/ml a. 4 hr. The peaX level at 248 ~in is 48~ of the level for intravenous delivery.
Administration of Boc-Pro-Phe-N-MeHis-LVA-Ile-Amp at 3 mg,~g in 0.5 M hydrochloric acid intranasally to anesthetized rats resuits in initial blood levels approximately 50~ as high as those obtain2d with the citric acid formulation administered intranasally. Howeve~, the plasma levels decreases so that at 240 min they are roughly equivalent to the citric acid formulation.
Claims (10)
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 rein 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 in 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-Ile-Amp; N-[[[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]amino]-carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-AMP, pyricine 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(hydroxylmethyl)ethyl]amino]-carbonyl]-Pro-Phe-N-MeHis-LVA-Ile-AMP, pyridir 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 hydroxylmethyl)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]carbonyll-Pro-Phe-N-MeHis-LYA-Ile-AMP, pyridine N-oxide; or (glucosaminocarbonyl)-Pro-Phe-N-MeHis-LVA-Ile-AMP, N-oxide.
ll. A composition of Claim 5, wherein the vehicle and the peptide are absorbed into a transdermal patch.
ll. A composition of Claim 5, wherein the vehicle and the peptide are absorbed into a transdermal patch.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US28853188A | 1988-12-22 | 1988-12-22 | |
| US07/288,531 | 1988-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2004571A1 true CA2004571A1 (en) | 1990-06-22 |
Family
ID=23107533
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002004571A Abandoned CA2004571A1 (en) | 1988-12-22 | 1989-12-05 | Transdermal and intranasal administration of renin inhibitory peptides |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0449943A1 (en) |
| JP (1) | JPH04502458A (en) |
| AU (1) | AU4664089A (en) |
| CA (1) | CA2004571A1 (en) |
| WO (1) | WO1990006761A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19819652A1 (en) * | 1998-05-02 | 1999-11-11 | Lohmann Therapie Syst Lts | Therapeutic system for topical or transmucosal application of at least one care or active ingredient to or through the nasal mucosa, as well as method for application of the system |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0173481A3 (en) * | 1984-08-06 | 1988-12-21 | The Upjohn Company | Peptides |
| US4906613A (en) * | 1985-11-05 | 1990-03-06 | Schering Corporation | Antiglaucoma compositions and methods |
| US4758584A (en) * | 1987-02-05 | 1988-07-19 | Ciba-Geigy Corporation | Antihypertensive 5-amino-4-hydroxyvaleryl derivatives substituted by sulphur-containing groups |
-
1989
- 1989-12-01 AU AU46640/89A patent/AU4664089A/en not_active Abandoned
- 1989-12-01 EP EP90901256A patent/EP0449943A1/en not_active Withdrawn
- 1989-12-01 WO PCT/US1989/005343 patent/WO1990006761A1/en not_active Application Discontinuation
- 1989-12-01 JP JP2501323A patent/JPH04502458A/en active Pending
- 1989-12-05 CA CA002004571A patent/CA2004571A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU4664089A (en) | 1990-07-10 |
| JPH04502458A (en) | 1992-05-07 |
| WO1990006761A1 (en) | 1990-06-28 |
| EP0449943A1 (en) | 1991-10-09 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |