Dispersion for pulmonary delivery of a bioactive agent

• US 20080233194A1
• Filed: 05/27/2008
• Published: 09/25/2008
• Est. Priority Date: 09/29/1997
• Status: Active Grant

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Schutt, Ernest G., Weers, Jeffry G., Dellamary, Luis A., Tarara, Thomas E., Kabalnov, Alexey
• Granted Patent: US 8,080,263 B2
• Time in Patent Office: Days
• US Class Current: 424/484
• CPC Class Codes: A61K 31/685 one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• 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: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/906 Drug delivery
• CPC Class Codes: Y10S 977/926 Topical chemical, e.g. cosmetic or sunscreen

Abstract

Stabilized dispersions are provided for the delivery of a bioactive agent. The dispersions preferably comprise a plurality of perforated microstructures dispersed in a suspension medium that typically comprises a liquid fluorochemical. As density variations between the suspended particles and suspension medium are minimized and attractive forces between microstructures are attenuated, the disclosed dispersions are particularly resistant to degradation, such as by settling or flocculation. In particularly preferred embodiments the stabilized dispersions may be directly administered to the lung of a patient using an endotracheal tube or bronchoscope.

Claims

1. A stabilized dispersion for the pulmonary delivery of a bioactive agent comprising a nonaqueous suspension medium having dispersed therein a plurality of perforated microstructures comprising at least one bioactive agent wherein said suspension medium substantially permeates said perforated microstructures.

2. A dispersion according to claim 1 wherein the permeable microstructures comprise at least one of a phospholipid, nonionic detergent, nonionic block copolymer, ionic surfactant, biocompatible fluorinated surfactant or combinations thereof.

3. A dispersion according to claim 1 wherein the permeable microstructures comprise a phospholipid.

4. A dispersion according to claim 3 wherein the phospholipid is a saturated phospholipid.

5. A dispersion according to claim 3 wherein the permeable microstructures comprise an inorganic salt.

6. A dispersion according to claim 5 wherein the inorganic salt comprises calcium chloride.

7. A dispersion according to claim 5 wherein the gel to liquid transition temperature of the permeable microstructures is greater than 40°

C.

8. A dispersion according to claim 1 wherein the permeable microstructures and suspension medium have a refractive index differential of less than 0.5.

9. A dispersion according to claim 1 wherein the permeable microstructures have a mean density selected to provide a density differential with that of the suspension medium of less than 0.6 g/cm³.

10. A dispersion according to claim 1 wherein the suspension medium comprises a fluorochemical.

11. A dispersion according to claim 1 wherein the bioactive agent comprises one or more of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, anti-inflammatories, antineoplastics, anticholinergics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides or combinations thereof.

12. A dispersion according to claim 1 wherein the bioactive agent is gentamicin.

13. A dispersion according to claim 1 wherein the permeable microstructures have a mean diameter of 1-30 μ

m.

14. A dispersion according to claim 1, wherein the bioactive agent is gentamicin.

15. A dispersion according to claim 1, wherein the bioactive agent is ampicillin.

16. A dispersion according to claim 1, wherein the bioactive agent is beclamethasone dipropionate.

17. A dispersion according to claim 1, wherein the bioactive agent is triamicinolone acetonide.

18. A dispersion according to claim 1, wherein the bioactive agent is DNAse I.

19. A dispersion according to claim 1, wherein the bioactive agent is albuterol sulfate.

20. A dispersion according to claim 1, wherein the bioactive agent is insulin.