PULMONARY DELIVERY PARTICLES COMPRISING WATER INSOLUBLE OR CRYSTALLINE ACTIVE AGENTS

• US 20100272823A1
• Filed: 05/05/2010
• Published: 10/28/2010
• Est. Priority Date: 09/29/1997
• Status: Active Grant

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Novartis Pharma AG (Novartis Ag)
• Inventors: TARARA, Thomas E., Kabalnov, Alexey, Weers, Jeffrey G., Schutt, Ernest G., Dellamary, Luis A.
• Granted Patent: US 9,554,993 B2
• Time in Patent Office: Days
• US Class Current: 424/502
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/10 Expectorants
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous 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 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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

A pulmonary delivery medicament comprises a plurality of particulates, the particulates comprising a structural matrix and a water insoluble and/or crystalline active agent. The particulates have a geometric diameter of 0.5 to 50 μm. The water insoluble active agent can be a fungicide, antibiotic, budesonide. A method of making the medicament comprises forming a liquid feedstock, and forming a feedstock suspension by suspending in the liquid feedstock, the active agent and an excipient capable of forming a structural matrix, such as a phospholipid. The feedstock suspension is spray dried to produce the particulates.

Claims

1-30. -30. (canceled)

31. A powder composition comprising a plurality of perforated microstructures, said microstructures comprising an active agent, a mean aerodynamic diameter of less than 5 μ

m, and a bulk density of less than 0.5 g/cm³, wherein, when suspended in a fluid medium, the volume of the medium displaced by the perforated microstructures comprises less than 70% of the average microstructure volume defined by the microstructure boundary if the microstructures were solid.

32. The powder of claim 31, wherein the microstructures have a mean geometric particle size of 1-30 μ

m.

33. The powder of claim 31 further comprising calcium.

34. The powder of claim 31, wherein the microstructures have a mean porosity of 0.5-80%.

35. The powder of claim 34, wherein the microstructures have a mean pore size of 20-200 nm.

36. The powder of claim 31, wherein the bulk density is less than 0.1 g/cm³.

37. The powder of claim 31, wherein said perforated microstructures comprise hollow porous microspheres.

38. The powder of claim 37, wherein a mean aerodynamic diameter of said microstructures is between 0.5 and 5 μ

m, and a mean geometric diameter is less than 5 μ

m.

39. The powder of claim 37, wherein the microstructures comprise a surfactant selected from the group consisting of phospholipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, biocompatible fluorinated surfactants and combinations thereof.

40. The powder of claim 39, wherein said surfactant is a phospholipid selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

41. The powder of claim 40, wherein said phospholipid comprises a gel to liquid crystal transition temperature of greater than 40°

C.

42. The powder of claim 31, wherein the active agent is selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholinergics, anesthetics, antituberculars, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof.

43. The powder of claim 31, wherein a fine particle fraction is from 30-70% by weight.

44. The powder of claim 31 comprising a throat deposition of less than about 40% by weight when administered by an inhalation device.

45. A method for forming a particulate composition comprising perforated microstructures by spray drying, comprising:

providing a feed stock comprising a phospholipid and calcium chloride;

atomizing said feed stock to produce dispersed droplets; and

drying said droplets in order to form perforated microstructures comprising phospholipid and calcium, said particulates comprising a bulk density of less than 0.5 g/cm³.

46. The method of claim 45, wherein the feed stock further comprises a bioactive agent selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholinergics, anesthetics, antituberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof.

47. The method of claim 45, wherein the feed stock comprises a colloidal system selected from the group consisting of emulsions, reverse emulsions, microemulsions, multiple emulsions, particulate dispersions, or slurries.

48. The method of claim 45, wherein the feed stock comprises 2 to 50% v/v of a blowing agent selected from the group consisting of fluorinated compounds, non-fluorinated oils, ammonium salts, alcohols and hydrocarbons having a boiling point below 100°

C., chloroform, ethyl acetate, acetone, nitrogen, carbon dioxide and camphor or latex.

50. The method of claim 45, wherein said phospholipid is selected from the group consisting of dilauroylphosphatidylcholine, dioleylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, dibehenoylphosphatidylcholine, diarachiodylphosphatidylcholine and combinations thereof.

51. The method of claim 45, wherein said feed stock comprises a blowing agent to phospholipid ratio of at least 4.8 w/w.

52. The method of claim 45, wherein the particles are characterized by at least one property of an aerodynamic diameter of between 0.5-5.0 μ

m, and a bulk density of less than 0.1 g/cm³.

53. The method of claim 45, wherein said particulates comprise hollow porous microspheres.

49. The method of 45, wherein the drying is performed in a spray dryer having an outlet temperature operated at a temperature at least 20°

C. less than the boiling point of the blowing agent.

54. A method for forming a powder comprising perforated microstructures by spray drying, comprising the steps of:

providing a feed stock comprising a bioactive agent selected from the group consisting of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholinergics, anesthetics, antituberculars, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antisense agents, proteins, peptides and combinations thereof, surfactant, and 2-50% v/v of a blowing agent selected from the group consisting of fluorinated compounds, non-fluorinated oils, ammonium salts, alcohols having a boiling point below 100°

C., hydrocarbons, chloroform, ethyl acetate, acetone, nitrogen, carbon dioxide, camphor, and latex;

atomising said feed stock to produce dispersed droplets; and

drying said droplets to form perforated microstructures comprising said bioactive agent and surfactant.

55. The method of claim 54, wherein the blowing agent comprises a fluorinated compound selected from the group consisting of perfluorooctyl bromide, perfluorobutyl ethane, and perfluorooctyl iodide.

56. The method of claim 55, wherein said blowing agent/surfactant ratio is within 10-50 w/w.

57. The method of claim 56, characterized in that the particulates comprise at least one of the properties of an aerodynamic diameter of between 0.5 and 5.0 μ

m, a mean geometric diameter less than 5 μ

m, and a bulk density of less than 0.1 g/cm³.

58. The method of claim 54, wherein said perforated microstructures comprise hollow porous microspheres.