Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use

• US 7,871,598 B1
• Filed: 05/10/2000
• Issued: 01/18/2011
• Est. Priority Date: 05/10/2000
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Schutt, Ernest G., Weers, Jeffry G., Riess, Jean, Dellamary, Luis A., Tarara, Thomas E.
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US09/568,818
• Time in Patent Office: 3,905 Days
• Field of Search: 424/9.32, 424/450, 424/489, 424/502
• US Class Current: 424/9.32
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7036 having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• 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 9/008 comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
• CPC Class Codes: A61K 9/0082 Lung surfactant, artificial mucus
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61M 15/0065 Inhalators with dosage or measuring devices A61M15/0028 takes precedence; dosage devices incorporated in aerosol cans B65D83/52
• CPC Class Codes: A61M 2205/3306 Optical measuring means
• 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

Abstract

Microparticle compositions comprising metal ion-lipid complexes for drug delivery are described including methods of making the microparticle compositions and methods of treating certain conditions and disease states by administering the microparticle compositions. The metal ion-lipid complexes can be combined with various drugs or active agents for therapeutic administration. The microparticle compositions of the present invention have superior stability to other microparticle compositions resulting in a microparticle composition with longer shelf life and improved dispersability. The microparticle compositions of the present invention have a transition temperature T_m of at least 20° C. above the recommended storage temperature (Tst) for drug delivery.

Claims

1. A powder composition comprising a plurality of microparticles, the microparticles comprising an active agent and a metal ion-lipid complex, and the powder composition has a metal ion concentration of greater than 0 and up to and including 25% w/w, and a lipid concentration of 25-90% w/w, and wherein the density of the microparticles as measured by He displacement is 0.5-2.0 g/ml and the T_g of the microparticles is at least 2°

C. greater than that of microparticles without the metal ion.

2. The powder composition of claim 1 wherein the lipid component comprises a mixture of at least two lipids.

3. The powder composition of claim 1 wherein the lipid comprises a phospholipid.

4. The powder composition of claim 1 wherein the metal ions are chosen from the group consisting of lanthanide metals, actinide metals, group IIa and IIIb metals, transition metals or mixtures thereof.

5. The powder composition of claim 4 wherein the metal ion is chosen from the group consisting of calcium, zinc, aluminum, iron and magnesium, their water soluble salts and mixtures thereof.

6. The powder composition of claim 1 wherein the metal ion has more than a one positive charge.

7. The powder composition of claim 3 wherein the phospholipid is selected from the group consisting of dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, and dimyristoylphosphatidylcholine.

8. The powder composition of claim 7 wherein the microparticle has a phospholipid concentration from about 20-90% w/w.

9. The powder composition of claim 1 wherein the active agent is selected from the group consisting of antiallergics, antifungals, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholingerics, anesthetics, antituberculars, imaging agents, cardiovascular agents, enzymes, steroids, DNA, RNA, viral vectors, antisense agents, proteins, peptides, immunoglobulins, and combinations thereof.

10. The powder composition of claim 1 wherein the active agent is selected from the group consisting of albuterol, budesonide, fluticasone, salmeterol, formoterol, nicotine, triamcinolone, dexamethasone, beclomethasone, gentamicin, ciprofloxacin, paclitaxel, amphotericin, amikacin, tobramycin, insulin, human growth hormone, and salts thereof.

11. The powder composition of claim 1 further comprising a surfactant selected from the group consisting of nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof.

12. The powder composition of claim 11 wherein the surfactant is selected from the group consisting of sorbitan esters, ethoxylated sorbitan esters, fatty acid salts, sugar esters, ethylene oxides, and combinations thereof.

13. The powder composition of claim 1 further comprising a polymer selected from the group consisting of polysaccharides, polyvinyl alcohol, polyvinyl pyrrolidone, polylactides, polyglycolides, polyethylene glycol, cyclodextrins, starches, carboxymethylcellulose, hydroxylmethyl cellulose or mixtures thereof.

14. The powder composition of claim 1 wherein the microparticles are administered by inhalation.

15. The powder composition of claim 14 comprising a mean volume aerodynamic particle size of 0.5-7 microns.

16. The powder composition of claim 15 wherein the microparticle is administered via a dry powder inhaler.

17. The powder composition of claim 15 wherein the microparticle is administered via a metered dose inhaler.

18. The powder composition of claim 1 in table or capsule form for oral administration.

32. The powder composition of claim 1 wherein the microparticles are administered by inhalation.

33. The powder composition of claim 32 comprising a mean volume aerodynamic particle size of 0.5-7 microns.

34. The powder composition of claim 32 wherein the microparticle is administered via a dry powder inhaler.

35. The powder composition of claim 32 wherein the microparticle is administered via a metered dose inhaler.

38. The powder composition of claim 1 wherein the lipid is zwitterionic.

40. The powder composition of claim 1 wherein the microparticles are suspended in a fluorocarbon or fluoroalkane containing propellant.

19. A powder composition comprising a plurality of microparticles, the microparticles comprising an active agent, a metal ion, and a phospholipid, wherein the metal ion forms a coordination bond with the phospholipid, and the powder composition has a metal ion concentration of greater than 0 and up to and including 25% w/w, and a phospholipid concentration of 25-90% w/w, and wherein the density of the particle as measured by He displacement is at least 0.5-2.0 g/ml and the transition temperature of the microparticle exceeds its storage temperature by at least 20°

C.

20. The powder composition of claim 19 wherein the lipid component is comprised of a mixture of at least two lipids.

21. The powder composition of claim 19 wherein the lipid comprises a phospholipid.

22. The powder composition of claim 21 wherein the phospholipid is selected from the group consisting of dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, and dimyristoylphosphatidylcholine.

23. The powder composition of claim 22 wherein the microparticle has a phospholipid concentration of from about 20-90% w/w.

24. The powder composition of claim 19 wherein the metal ions are chosen from the group consisting of lanthanide metals, actinide metals, group IIa and IIIb metals, transition metals or mixtures thereof.

25. The powder composition of claim 24 wherein the metal ion is chosen from the group consisting of calcium, zinc, aluminum, iron and magnesium, their water soluble salts and mixtures thereof.

26. The powder composition of claim 19 wherein the metal ion has more than a one positive charge.

27. The powder composition of claim 19 wherein the active agent is selected from the group consisting antiallergics, antifungals, bronchodilators, pulmonary lung surfactants, analgesics, antibiotics, leukotriene inhibitors or antagonists, antihistamines, antiinflammatories, antineoplastics, anticholingerics, anesthetics, antituberculars, imaging agents, cardiovascular agents, enzymes, steroids, DNA, RNA, viral vectors, antisense agents, proteins, peptides, immunoglobulins, and combinations thereof.

28. The powder composition of claim 19 wherein the active agent is selected from the group consisting of albuterol, budesonide, fluticasone, salmeterol, formoterol, nicotine, triamcinolone, dexamethasone, beclomethasone, gentamicin, ciprofloxacin, paclitaxel, amphotericin, amikacin, tobramycin, insulin, human growth hormone, and salts thereof.

29. The powder composition of claim 19 further comprising a surfactant selected from the group consisting of nonionic detergents, nonionic block copolymers, ionic surfactants and combinations thereof.

30. The powder composition of claim 29 wherein the surfactant is selected from the group consisting of sorbitan esters, ethoxylated sorbitan esters, fatty acid salts, sugar esters, ethylene oxides, and combinations thereof.

31. The powder composition of claim 19 further comprising a polymer selected from the group consisting of polysaccharides, polyvinyl alcohol, polyvinyl pyrrolidone, polylactides, polyglycolides, polyethylene glycol, cyclodextrins, starches, carboxymethylcellulose, hydroxymethyl cellulose or mixtures thereof.

36. The powder composition of claim 19 in tablet or capsule form for oral administration.

37. The powder composition of claim 19 wherein the T_g of the microparticle is at least 2°

C. greater than that of particles without the metal ion.

39. The powder composition of claim 19 wherein the lipid is zwitterionic.

41. The powder composition of claim 19 wherein the microparticles are suspended in a fluorocarbon or fluoroalkane containing propellant.

42. A powder composition comprising a plurality of microparticles, the microparticles comprising an active agent and a metal ion-lipid complex, and the powder composition has a metal ion concentration of greater than 0 and up to and including 25% w/w, and a lipid concentration of 25-90% w/w, wherein the T_g of the microparticles is at least 2°

C. greater than that of microparticles without the metal ion, and wherein the active agent is selected from the group consisting of albuterol, budesonide, fluticasone, salmeterol, formoterol, nicotine, triamcinolone, dexamethasone, beclomethasone, gentamicin, ciprofloxacin, paclitaxel, amphotericin, amikacin, tobramycin, insulin, human growth hormone, and salts thereof.

43. The powder composition of claim 42 wherein the microparticles are suspended in a fluorocarbon or fluoroalkane containing propellant.