Vitamin A aerosol-inhalate preparations

• US 5,112,598 A
• Filed: 05/02/1989
• Issued: 05/12/1992
• Est. Priority Date: 05/04/1988
• Status: Expired due to Term

• Current Assignee: Hermes Fabrik Pharmazeutischer Preparate Franz Gradinger GmbH & Company KG
• Original Assignee: Hermes Fabrik Pharmazeutischer Preparate Franz Gradinger GmbH & Company KG
• Inventors: Biesalski, Hans K.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): AZPURU, CARLOS A
• Application Number:
  US07/346,439
• Time in Patent Office: 1,106 Days
• Field of Search: 424/45, 424/46, 424/78, 514/725
• US Class Current: 424/46
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/07 Retinol compounds, e.g. vitamin A retinoic acids A61K31/203
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/23 of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A pharmaceutical preparation consisting of retinoic acid and/or an ester ofetinoic acid and/or an ester of retinol as active substances, which are present in the preparation form of an aerosol, is advantageously suitable for topical treatment of mucosal diseases in man and animal.

Claims

1. An aerosol-inhalate pharmaceutical preparation comprising 0.01-50% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, and, in the case of dust aerosols, the balance of the composition 50-99.99% by weight carrier gas, and in the case of mist aerosols, the balance of the composition selected from the group consisting of:

(a) 0-49.99% by weight non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 50-99.99% by weight propellant gas; and

(b) 50-99.99% by weight water or water plus a water-miscible, physiologically compatible liquid and carrier gas.

4. A pharmaceutical preparation according to claim 1 in which said fatty acids are selected from the group consisting of palmitic acid, stearic acid, oleic acid, linoleic acid and linolenic acid.

8. A pharmaceutical preparation according to claim 1 in which said active substance is present as solid particles in the carrier gas.

9. A pharmaceutical preparation according to claim 1 in which active substance is present in the form of an active-substance-containing liquid in the carrier gas.

10. A pharmaceutical preparation according to claim 1 in which said active substance is dispersed in the carrier gas comprised of a propellant gas or propellant gas mixture.

11. A pharmaceutical preparation according to claim 1 in which said active substance is dissolved in said non-aqueous lipophilic readily volatile and physiologically compatible solvent.

12. A pharmaceutical preparation according to claim 1 in which said active substance is dissolved in said carrier gas selected from the group consisting of a liquified propellant gas or propellant gas mixture.

13. A pharmaceutical preparation according to claim 1 in which said active substance is dissolved in said solvent selected from the group consisting of 1,1,2-trichloro-1,2,2-trifluoroethane or trichlorofluoromethane.

14. A pharmaceutical preparation according to claim 1 in which said aerosol-inhalate is a dust aerosol and said active substance is dispersed in said carrier gas selected from the group consisting of low-boiling fluorohydrocarbons, low-boiling fluorochlorohydrocarbons, and liquified compounds which are gaseous at room temperature and atmospheric pressure.

15. A pharmaceutical preparation according to claim 1 in which said aerosol-inhalate is a dust aerosol and said active substance is dispersed in said carrier gas selected from the group consisting of dichlorodifluoromethane, 1,2-dichloro-1,1,2,2-tetrafluoroethane, 1,2-dichloro-1,2,2,2-tetrafluoroethane, chlorotrifluoroethalene, dichlorofluoromethane, 1,1-difluoroethane, 1-chloro-1,1-difluoroethane, tetrafluoromethane, mixtures thereof, liquified propane, liquified butane, and liquified dimethylether.

16. A pharmaceutical preparation according to claim 1 in which said aerosol-inhalate is a dust aerosol and said active substance is dispersed in said carrier gas selected from the group consisting of compressed nitrogen, compressed carbon dioxide, compressed dinitrogenoxide, and compressed air.

2. A pharmaceutical preparation according to claim 2 in which said active substance is a member selected form the group consisting of esters of retinol with physiologically compatible carboxylic acids and esters of retinoic acid with alcohols.

3. A pharmaceutical preparation according to claim 2 in which said active substance is selected from the group consisting of retinol esters of saturated and unsaturated fatty acids.

5. A pharmaceutical preparation according to claim 2 in which said active substance is a retinoic acid ester prepared from an alcohol which is either monovalent or multivalent;

primary, secondary or tertiary; and

aliphatic alicyclic or aromatic.

6. A pharmaceutical preparation according to claim 2 in which said active substance is a retinoic acid ester prepared from an aliphatic, monovalent, primary alcohol.

7. A pharmaceutical preparation according to claim 2 in which said active substance is a retinoic acid ester prepared from a member selected from the group consisting of methanol, ethanol, and fatty alcohols.

17. An aerosol-inhalate pharmaceutical preparation comprising 0.01% to 50% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, the aerosol-inhalate in the form of a mist aerosol, said preparation further comprising 0% to 49.99% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent and 50% to 99.99% by weight of a propellant gas.

18. An aerosol-inhalate pharmaceutical preparation comprising 0.01% to 30% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, the aerosol-inhalate being a mist aerosol, said preparation further comprising 0% to 30% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 40% to 99.99% by weight of a propellant gas.

19. An aerosol-inhalate pharmaceutical preparation comprising 0.05% to 25% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist aerosol, said preparation further comprising 0% to 30% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 45% to 99.99% by weight of a propellant gas.

20. An aerosol-inhalate pharmaceutical preparation comprising 0.1% to 15% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, the aerosol-inhalate in the form of a mist aerosol, said preparation further comprising 0% to 25% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent and 60% to 99.99% by weight of a propellant gas.

21. An aerosol-inhalate pharmaceutical preparation comprising 0.1% to 10% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist aerosol, said preparation further comprising 0% to 25% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 65% to 99.99% by weight of a propellant gas.

22. An aerosol-inhalate pharmaceutical preparation comprising 0.1% to 7% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist aerosol, said preparation further comprising 5% to 23% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 70% to 94.9% by weight of a propellant gas.

23. An aerosol-inhalate pharmaceutical preparation comprising 0.1% to 5% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist aerosol, said preparation further comprising 10% to 20% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 75% to 89.9% by weight of a propellant gas.

24. An aerosol-inhalate pharmaceutical preparation comprising 0.17% by weight retinol palmitate, said preparation in the form of a mist-aerosol, said preparation further comprising 19.83% by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 80% by weight of a propellant gas.

25. An aerosol-inhalate pharmaceutical preparation comprising 3.9% by weight retinol palmitate, said aerosol-inhalate in the form of a mist-aerosol, said preparation further comprising 20 by weight of a non-aqueous lipophilic readily volatile and physiologically compatible solvent, and 76.1% by weight of a propellant gas.

26. An aerosol-inhalate pharmaceutical preparation comprising 0.01% to 50% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist-aerosol, said preparation further comprising 1% to 30% by weight of an emulsifier and/or water-miscible, physiologically compatible liquid, the balance comprised of water and carrier gas.

27. An aerosol-inhalate pharmaceutical preparation comprising 0.05% to 20% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist-aerosol, said preparation further comprising 5% to 30% by weight of an emulsifier and/or water-miscible, physiologically compatible solvent, the balance comprised of water and carrier gas.

28. An aerosol-inhalate pharmaceutical preparation comprising 0.01% to 10% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist-aerosol, said preparation further comprising 5% to 25% by weight of an emulsifier and/or water-miscible, physiologically compatible liquid, the balance comprised of water and carrier gas.

29. An aerosol-inhalate pharmaceutical preparation comprising 0.05% to 5% by weight of at least one active substance selected from the group consisting of an ester of retinol and an ester of retinoic acid, said aerosol-inhalate in the form of a mist-aerosol, said preparation further comprising 10% to 25% by weight of an emulsifier and/or water-miscible, physiologically compatible liquid, the balance comprised of water and carrier gas.

30. An aerosol-inhalate pharmaceutical preparation comprising retinol palmitate oil (1 million Iu/g) at 1.0% by weight stabilized with BHA/BHT, said preparation further comprising 22.0% by weight of an emulsifier, 2.0% by weight 1,2-propylene glycol, the balance comprised of water and carrier gas.