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

Definitions

• the present invention provides a new route of administration and novel compositions containing known pharmaceutical compounds.
• 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.
• 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;
• 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.
• 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
• 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) .
• a vehicle adapted for transdermal delivery is meant an pharmacologically acceptable solvent used for transdermal drug delivery.
• 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.
• 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.
• 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.
• they are useful for the same purposes described in the refer ⁇ ences described above, which are hereby incorporated by reference.
• renin inhibitory peptides are administered in dosages equipotent to the dosages from the other routes of administration described in the references cited above.
• 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
• 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.
• DMSO dimethylsulfoxide
• 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.
• 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.
• 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.

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• 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)
• Dermatology (AREA)
• Otolaryngology (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)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicinal Preparation (AREA)

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• 1989
  • 1989-12-01 WO PCT/US1989/005343 patent/WO1990006761A1/en not_active Ceased
  • 1989-12-01 AU AU46640/89A patent/AU4664089A/en not_active Abandoned
  • 1989-12-01 JP JP2501323A patent/JPH04502458A/ja active Pending
  • 1989-12-01 EP EP90901256A patent/EP0449943A1/de not_active Withdrawn
  • 1989-12-05 CA CA002004571A patent/CA2004571A1/en not_active Abandoned

Non-Patent Citations (1)

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