Engineered particles and methods of use

• US 7,306,787 B2
• Filed: 03/12/2002
• Issued: 12/11/2007
• Est. Priority Date: 09/29/1997
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Nektar Therapeutics
• Inventors: Tarara, Thomas E., Weers, Jeffry G., Kabalnov, Alexey, Schutt, Ernest G., Dellamary, Luis A.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Haghighatian, Mina
• Application Number:
  US10/096,780
• Publication Number:
  US 20030064029A1
• Time in Patent Office: 2,100 Days
• Field of Search: 424/45, 424/43, 424/489, 424/450, 424/46, 424/487, 424/499, 424/459, 424/434, 128/203.15, 514/3, 514/4
• US Class Current: 424/45
• 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: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• 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

Engineered particles are provided may be used for the delivery of a bioactive agent to the respiratory tract of a patient. The particles may be used in the form of dry powders or in the form of stabilized dispersions comprising a nonaqueous continuous phase. In particularly preferred embodiments the particles may be used in conjunction with an inhalation device such as a dry powder inhaler, metered dose inhaler or a nebulizer.

Claims

1. A method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages in a single breath, the method comprising:

providing a receptacle containing a mass of particles, the particles comprising a bioactive agent and having perforated microstructures with a bulk density of less than 0.5 g/cm³; and

administering the particles as an aerosol from the receptacle to a subject'"'"'s respiratory tract;

wherein the particles are sized and shaped so that at least 50% of the mass of the particles are delivered to the subject'"'"'s respiratory tract and wherein the fine particle fraction of particles of the aerosol is greater than 60% w/w.

2. A method according to claim 1 wherein the particles comprise an aerodynamic diameter of less than 5 microns.

3. A method according to claim 2 wherein the particles comprise a geometric diameter of 1–

30 microns.

4. A method according to claim 3 wherein the particles comprise a phospholipid.

5. A method according to claim 4 wherein the particles further comprise calcium.

6. A method according to claim 3 wherein the particles that deposit in the lung provide an emitted dose that is at least 60% w/w.

7. A method according to claim 3 wherein the particles that deposit in the lung provide an emitted dose that is at least 70% w/w.

8. A method according to claim 4 wherein the particles comprise a geometric diameter of less than 5 microns.

9. A method according to claim 8 wherein the bulk density is less than 0.1 g/cm³.

40. A method according to claim 1 wherein the bioactive agent is at least one of anti-allergics, bronchodilators, bronchoconstrictors, hydrophilic and lipophilic respiratory agents, pulmonary lung surfactants, analgesics, antitussives, diuretics, antibiotics, antivirals, vaccines, antifungals, immunosuppressive agents, immunoacitve agents, anesthetics, anginal preparations, antifectives, lekotriene inhibitors, antagonists, anticholinergics, mast cell inhibitors, antihistamines, anti-inflammatories, antineoplastics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antigens agents, proteins, peptides, poly-nucleotides and combinations thereof.

41. A method according to claim 4 where the phospholipid comprises at least one of disteroylphospyatidylcholine, dipalmitoylphosphatidylcholine, diarachidoylhosphatidylcholine, or dibehenoylphosphatidylcholine.

42. A method according to claim 4 where the phospholipid comprises at least one of phosphatidyloholines, phosphatidylethanolamines, phosphatidylserines, phosphatidyiglycerols, phosphatidylinositols, glycolipids, ganglioside, sphingomyelin, phosphatidic acid, cariolipin, polyethylene glycol, chum, hyaluronic acid, polyvinylpyrrolidone, monosaccharides, disaccharides, disaccharides, palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol esters, cholesterol hemisuccinate and combinations thereof.

10. A method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages, the method comprising:

providing a suspension of particles in a hydrofluoroalkane propellant, the particles comprising a bioactive agent, perforated microstructures and a bulk density of less than 0.5 g/cm³; and

administering the particles to a subject'"'"'s respiratory tract as an aerosol,

wherein the particles are sized and shaped so that the mass of particles impacting the throat is less than 40% w/w.

11. A method according to claim 10 wherein the mass of particles impacting the throat is less than 30% w/w.

12. A method according to claim 10 wherein the mass of particles impacting the throat is less than 20% w/w.

13. A method according to claim 10 wherein said particles are administered via a metered dose inhaler.

14. A method according to claim 10 wherein said particles comprise a geometric diameter of 1–

30 microns and an aerodynamic diameter of less than 5 microns.

15. A method according to claim 14 wherein said particles comprise a phospholipid.

16. A method according to claim 15 wherein said particles further comprise calcium.

43. A method according to claim 10 wherein the bioactive agent is at least one of anti-allergics, bronchodilators, bronchoconstrictors, hydrophilic and lipophilic respiratory agents, pulmonary lung surfactants, analgesics, antitussives, diuretics, antibiotics, antivirals, vaccines, antifungals, immunosuppressive agents, immunoacitve agents, anesthetics, anginal preparations, antifectives, lekotriene inhibitors, antagonists, anticholinergics, mast cell inhibitors, antihistamines, anti-inflammatories, antineoplastics, anesthetics, anti.4uberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antigens agents, proteins, peptides, poly-nucleotides and combinations thereof.

44. A method according to claim 15 where the phospholipid comprises at least one of disteroylphospyatidylcholine, dipalmitayiphosphatidyicholine, diarachidoylhosphatidylcholine, or dibehenoylphosphatidylcholine.

45. A method according to claim 15 where the phosphofipid comprises at least one of phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidyiglycerols, phosphatidylinositols, glycolipids, ganglioside, sphingomyelin, phosphatidic acid, cariolipin, polyethylene glycol, chitin, hyaluronic acid, polyvinylpyrrolidone, monosaccharides, disaccharides, disaccharides, palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol esters, cholesterol hemisuccinate and combinations thereof.

17. A method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages, the method comprising:

providing particles comprising a bioactive agent and having perforated microstructures with a bulk density of less than 0.5 g/cm³; and

administering the particles to a subject'"'"'s respiratory tract in a single breath,

wherein the particles are sized and shaped so that the deposition of the particles in the deep lung is independent of inhalation flow rate and wherein said administration results in a fine particle fraction of at least 60% w/w.

18. A method according to claim 17 wherein said particles comprise a geometric diameter of 1–

30 microns and an aerodynamic diameter of less than 5 microns.

19. A method according to claim 18 wherein said particles comprise a phospholipid.

20. A method according to claim 19 wherein said particles further comprise calcium.

46. A method according to claim 17 wherein the bioactive agent is at least one of anti-all ergics, bronchodilators, bronchoconstrictors, hydrophilic and lipophilic respiratory agents, pulmonary rung surtactants, analgesics, antitussives, diuretics, antibiotics, antivirals, vaccines, antifungals, immunosuppressive agents, immunoacitve agents, anesthetics, anginal preparations antifectives, lekotriene inhibitors, antagonists, anticholinergics, mast cell inhibitors, antihistamines, anti-inflammatories, antineoplastics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antigens agents, proteins, peptides, poly-nucleotides and combinations thereof.

47. A method according to claim 19 where the phospholipid comprises at least one of disteroylphospyatidylcholine, dipalmitoylphosphatidylcholine, diarachidoylhosphatidytcholine or dibehenoylphosphatidylcholine.

48. A method according to claim 19 where the phospholipid comprises at least one of phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, glycolipids, gangl ioside, sphingomyelin, phosphatidic acid, cariolipin, polyethylene glycol, chitin, hyalu ronic acid, polyvinylpyrrolidone, monosaccharides, disaccharides, disaccharides, palmitic acid, stea rio acid, oleic acid, cholesterol, cholesterol esters, cholesterol hemisuccinate and combinations thereof.

21. A method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages in a single breath, the method comprising:

providing a receptacle containing a mass of porous particles, the porous particles comprising a bioactive agent and having a bulk density of less than 0.5 g/cm³; and

administering the porous particles as an aerosol from the receptacle to a subject'"'"'s respiratory tract;

wherein the porous particles are sized and shaped so that at least 50% of the mass of the porous particles are delivered to the subject'"'"'s respiratory tract and wherein the fine particle fraction of porous particles of the aerosol is greater than 60% w/w.

22. A method according to claim 21 wherein the porous particles comprise an aerodynamic diameter of less than 5 microns.

23. A method according to claim 22 wherein the porous particles comprise a geometric diameter of 1–

30 microns.

24. A method according to claim 23 wherein the porous particles comprise a phospholipid.

25. A method according to claim 24 wherein the porous particles further comprise calcium.

26. A method according to claim 21 wherein porous the particles that deposit in the lung provide an emitted dose that is at least 60% w/w.

27. A method according to claim 21 wherein the porous particles comprise a geometric diameter of less than 5 microns.

28. A method according to claim 21 wherein the bulk density is less than 0.1 g/cm³.

49. A method according to claim 21 wherein the bioactive agent is at least one of anti-allergics, bronchodilators, bronchoconstrictors, hydrophilic and lipophilic respiratory agents, pulmonary lung surfactants, analgesics, antitussives, diuretics, antibiotics, antivirals, vaccines, antifungals, immunosuppressive agents, immunoacitve agents, anesthetics, anginal preparations, antifectives, lekotriene inhibitors, antagonists, anticholinergics, mast cell inhibitors, antihistamines, anti-inflammatories, antineoplastics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antigens agents, proteins, peptides, poly-nucleotides and combinations thereof.

50. A method according to claim 24 where the phospholipid comprises at least one of disteroylphospyatidylcholine, dipalmitoylphosphatidylcholine, diarachidoylhosphatidylcholine, or dibehenoylphosphatidylcholine.

51. A method according to claim 27 where the phospholipid comprises at least one of phosphatidylcholines, phosphatidylethanolamines, phosphatidylserines, phosphahdyiglycerols, phosphatidylinositols, glycolipids, ganglioside, sphingomyelin, phosphatidic acid, cariolipin, polyethylene glycol, chitin, hyaluronic acid, polyvinylpyrrolidone, monosaccharides, disaccharides, disaccharides, palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol esters, cholesterol hemisuccinate and combinations thereof.

29. A method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages, the method comprising:

providing a suspension of porous particles comprising a bioactive agent and a bulk density of less than 0.5 g/cm³ in a hydrofluoroalkane propellant; and

administering the porous particles to a subject'"'"'s respiratory tract as an aerosol,

wherein the porous particles are sized and shaped so that the mass of porous particles impacting the throat is less than 40% w/w.

30. A method according to claim 29 wherein the mass of porous particles impacting the throat is less than 30% w/w.

31. A method according to claim 29 wherein the mass of porous particles impacting the throat is less than 20% w/w.

32. A method according to claim 29 wherein said porous particles are administered via a metered dose inhaler.

33. A method according to claim 29 wherein said porous particles comprise a geometric diameter of 1–

30 microns and an aerodynamic diameter of less than 5 microns.

34. A method according to claim 33 wherein said porous particles comprise a phospholipid.

35. A method according to claim 34 wherein said porous particles further comprise calcium.

52. A method according to claim 29 wherein the bioactive agent is at least one of anti-ailergics, bronchodilators, bronchoconstrictors, hydrophilic and lipophilic respiratory agents, pulmonary lung surfactants, analgesics, antitussives, diuretics, antibiotics, antivirals, vaccines, antifungals, immunosuppressive agents, immu noacitve agents, anesthetics, anginal preparations, antifectives, lekotriene inhibitors, antagonists, anticholinergics, mast cell inhibitors, antihistamines, anti-inflammatories, antineoplastics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antigens agents, proteins, peptides, poly-nucleotides and combinations thereof.

53. A method according to claim 31 where the phospholipid comprises at least one of disteroylphospyatidylcholine, dipalmitoylphosphatidylcholine, diarachidoylhosphatidylcholine, or dibehenoylphosphatidylcholine.

54. A method according to claim 34 where the phospholipid comprises at least one of phosphatidyicholines, phosphatidylethanolamines, phosphatidylserines, phosphatidylglycerols, phosphatidylinositols, glycolipids, ganglioside, sphingomyelin, phosphatidic acid, cariohpin, polyethylene glycol, chitin, hyaluronic acid, polyinylpyrrolidone, monosaccharides, disaccharides, disaccharides, palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol esters, cholesterol hemisuccinate and combinations thereof.

36. A method of delivering a therapeutic dose of a bioactive agent to the pulmonary air passages, the method comprising:

providing porous particles comprising a bioactive agent and having a bulk density of less than 0.5 g/cm³; and

administering the porous particles to a subject'"'"'s respiratory tract in a single breath,

wherein the porous particles are sized and shaped so that the deposition of the porous particles in the deep lung is independent of inhalation flow rate and wherein said administration results in a fine particle fraction of at least 60% w/w.

37. A method according to claim 36 wherein said porous particles comprise a geometric diameter of 1–

30 microns and an aerodynamic diameter of less than 5 microns.

38. A method according to claim 37 wherein said porous particles comprise a phospholipid.

39. A method according to claim 38 wherein said porous particles further comprise calcium.

55. A method according to claim 36 wherein the bioactive agent is at least one of anti-allergics, bronchodilators, bronchoconstrictors, hydrophilic and lipophilic respiratory agents, pulmonary lung surfactants, analgesics, antitussives, diuretics, antibiotics, antivirals, vaccines, antifungals, immunosuppressive agents, immunoacitve agents, anesthetics, anginal preparations, antifectives, lekotriene inhibitors, antagonists, anticholinergics, mast cell inhibitors, antihistamines, anti-inflammatories, antineoplastics, anesthetics, anti-tuberculars, imaging agents, cardiovascular agents, enzymes, steroids, genetic material, viral vectors, antigens agents, proteins, peptides, poly-nucleotides and combinations thereof.

56. A method according to claim 38 where the phospholipid comprises at least one of disteroylphospyatidylcholine, dipalmitoylphosphatidylcholine, diarachidoylhosphatidylcholine, or dibehenoylphosphatidylcholine.

57. A method according to claim 38 where the phospholipid comprisesat least one of phosphatidyloholines, phosphatidylethanolamines, phosphatidylserines, phosphatidyiglycerols, phosphatidylinositols, glycolipids, ganglioside, sphingomyelin, phosphatidic acid, cariolipin, polyethylene glycol, chitin, hyaluronic acid, polyvinylpyrrolidone, monosaccharides, disaccharides, disaccharides, palmitic acid, stearic acid, oleic acid, cholesterol, cholesterol esters, cholesterol hemisuccinate and combinations thereof.