Engineered particles and methods of use

• US 8,168,223 B1
• Filed: 06/21/2001
• Issued: 05/01/2012
• Est. Priority Date: 09/29/1997
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Pharma AG (Novartis Ag)
• Inventors: Tarara, Thomas E., Weers, Jeffry G., Kabalnov, Alexey, Schutt, Ernest G., Dellamary, Luis A.
• Primary Examiner(s): Landau, Sharmila G.
• Assistant Examiner(s): Welter, Rachel
• Application Number:
  US09/886,296
• Time in Patent Office: 3,967 Days
• Field of Search: 424/1.13, 424/1.21, 424/400, 424/489, 424/490, 424/450, 424/40, 424/422, 424/434, 424/497, 424/43, 424/46, 424/1.29, 424/DIG.7, 514/951, 514/963, 514/946
• US Class Current: 424/489
• 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. An inhaleable powder composition comprising a plurality of particulate microstructures, the particulate microstructures comprising:

(a) a structural matrix comprising phospholipid and calcium, wherein the particulate microstructures comprise greater than about 50% phospholipid;

(b) an active agent;

(c) a mean geometric diameter of 1-30 microns;

(d) a mean aerodynamic diameter of less than 5 microns; and

(e) a bulk density of less than about 0.5 g/cm³.

2. The composition of claim 1 wherein the particulate microstructures are porous and have a mean porosity of 0.5-80%.

3. The composition of claim 2 wherein the particulate microstructures have a mean porosity of 2-40%.

4. The composition of claim 3 wherein the particulate microstructures have a mean pore size of 20-200 nm.

5. The composition of claim 1 wherein the fine particle fraction of the particulate microstructures in the composition is greater than 20% w/w.

6. The composition of claim 5 wherein the fine particle fraction of the particulate microstructures in the composition is from about 30% to 70% w/w.

7. The composition of claim 1 wherein the particulate microstructures comprise a bulk density of less than 0.1 g/cm³.

8. The composition of claim 7 wherein the particulate microstructures comprise a bulk density of less than 0.05 g/cm³.

9. The composition of claim 1 wherein the particulate microstructures comprise perforated microstructures.

10. The composition of claim 1 wherein said particulate microstructures comprise hollow microspheres.

11. The composition of claim 1 wherein the particulate microspheres comprise a shell with a thickness of 0.1-0.5 μ

m.

12. The composition of claim 1 wherein the particulate microstructures comprise a mean aerodynamic diameter of between 0.5 μ

m and 5 μ

m.

13. The composition of claim 1 wherein the particulate microstructures comprise a mean geometric diameter of less than 10 microns.

14. The composition of claim 13 wherein the particulate microstructures comprise mean geometric diameter is less than 5 microns.

15. The composition of claim 1 wherein the phospholipid comprises a gel to liquid crystal transition temperature of greater than 40°

C.

16. The composition of claim 1 wherein the phospholipid comprises a zwitterionic phospholipid.

17. The composition of claim 1 wherein the phospholipid comprises at least one of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

18. The composition of claim 1 wherein the active agent is a bioactive agent.

19. The composition of claim 18 wherein the bioactive agent comprises at least one of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholinergics, anesthetics. antituberculars, antivirals, fungicides, immunoactive agents, vaccines, immunosuppressive agents, imaging agents, cardiovascular agents, enzymes, steroids, DNA, RNA, viral vectors, antisense agents, proteins, peptides and combinations thereof.

20. The composition of claim 18 wherein the bioactive agent comprises at least one of fentanyl, morphine, lung surfactant, leuprolide, interferon, insulin, budesonide, formoterol, goserelin, and growth hormones.

21. The composition of claim 18 wherein the bioactive agent is an aminoglycoside antibiotic.

22. The composition of claim 18 wherein the bioactive agent is a fungicide.

23. A composition comprising a plurality of particulate microstructures, the particulate microstructures comprising:

(a) a structural matrix comprising phospholipid and calcium, the phospholipid comprising a gel to liquid crystal transition temperature of greater than 40°

C., wherein greater than about 50% of the particulate microstructures comprise phospholipid;

(b) an active agent;

(c) a mean geometric diameter of 1-30 microns;

(d) a mean aerodynamic diameter of less than 5 microns; and

(e) a bulk density of less than about 0.5 g/cm³.

24. The composition of claim 23 wherein the particulate microstructures are porous and have a mean porosity of 0.5-80%.

25. The composition of claim 24 wherein the particulate microstructures have a mean porosity of 2-40%.

26. The composition of claim 24 wherein the particulate microstructures have a mean pore size of 20-200 nm.

27. The composition of claim 23 wherein the fine particle fraction of the particulate microstructures in the composition is greater than 20% w/w.

28. The composition of claim 27 wherein the fine particle fraction of the particulate microstructures in the composition is from about 30% to 70% w/w.

29. The composition of claim 23 wherein the particulate microstructures comprise a bulk density of less than 0.1 g/cm³.

30. The composition of claim 29 wherein the particulate microstructures comprise a bulk density of less than 0.05 g/cm³.

31. The composition of claim 23 wherein the particulate microstructures comprise perforated microstructures.

32. The composition of claim 23 wherein said particulate microstructures comprise hollow microspheres.

33. The composition of claim 23 wherein the particulate microspheres comprise a shell with a thickness of 0.1-0.5 μ

m.

34. The composition of claim 23 wherein the particulate microstructures comprise a mean aerodynamic diameter of between 0.5 μ

m and 5 μ

m.

35. The composition of claim 23 wherein the particulate microstructures comprise a mean geometric diameter of less than 10 microns.

36. The composition of claim 35 wherein the particulate microstructures comprise mean geometric diameter is less than 5 microns.

37. The composition of claim 23 wherein the phospholipid comprises a gel to liquid crystal transition temperature of greater than 40°

C.

38. The composition of claim 23 wherein the phospholipid comprises a zwitterionic phospholipid.

39. The composition of claim 23 wherein the phospholipid comprises at least one of dilauroylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine dibehenoylphosphatidylcholine, diarachidoylphosphatidylcholine and combinations thereof.

40. The composition of claim 23 wherein the active agent is a bioactive agent.

41. The composition of claim 40 wherein the bioactive agent comprises at least one of antiallergics, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, antiinfectives, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholinergics, anesthetics. antituberculars, antivirals, fungicides, immunoactive agents, vaccines, immunosuppressive agents, imaging agents, cardiovascular agents, enzymes, steroids, DNA, RNA, viral vectors, antisense agents, proteins, peptides and combinations thereof.

42. The composition of claim 40 wherein the bioactive agent comprises at least one of fentanyl, morphine, lung surfactant, leuprolide, interferon, insulin, budesonide, formoterol, goserelin, and growth hormones.

43. The composition of claim 40 wherein the bioactive agent is an aminoglycoside antibiotic.

44. The composition of claim 40 wherein the bioactive agent is a fungicide.