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

• US 8,349,294 B2
• Filed: 12/14/2010
• Issued: 01/08/2013
• Est. Priority Date: 05/10/2000
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Riess, Jean, Dellamary, Luis A, Schutt, Ernest G, Weers, Jeffry G, Tarara, Thomas E
• Primary Examiner(s): HUI, SAN MING R
• Application Number:
  US12/967,482
• Publication Number:
  US 20110082076A1
• Time in Patent Office: 756 Days
• Field of Search: 424/450, 424/502, 424/489, 424/9.32, 424/405
• 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_g) of at least 20° C. above the recommended storage temperature (Tst) for drug delivery.

Claims

1. A microparticle for drug delivery wherein the microparticle comprises an active agent and an excipient, wherein the active agent comprises an antibiotic, wherein the excipient comprises a metal ion-lipid complex, wherein the metal ion is chosen from the group consisting of lanthanide metals, actinide metals, group IIa and IIIb metals, transition metals or mixtures thereof, wherein the lipid comprises a phospholipid, and wherein the complex results in a glass transition temperature increase of the microparticle.

2. The microparticle of claim 1 wherein the microparticle has a glass transition temperature of at least 20°

C. above a storage temperature for the drug or active agent.

3. The microparticle of claim 1 wherein the phospholipid is chosen from the group consisting of DPPC, DSPC, DMPC, dioctylphosphatidycholine, soy phosphatidylcholine, egg phosphatidylcholine and partially hydrogenated phosphatides and polymerizable phospholipids.

4. The microparticle of claim 1 wherein the presence of the metal ion raises the glass transition temperature of the microparticle at least 2°

C. above that of the same microparticle without the metal ion.

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

6. The microparticle of claim 1 wherein the lipid component is comprised of a mixture of at least two lipids.

7. The microparticle of claim 1 wherein the microparticle has a mean volume aerodynamic particle size of about 0.5 μ

m to 7 μ

m.

8. A composition comprising a plurality of microparticles of claim 7.

9. The microparticle composition of claim 8 wherein the microparticles are substantially non-hollow and non-porous.

10. The microparticle composition of claim 9 further comprising a powder modifying agent.

11. The microparticle composition of claim 10 wherein the powder modifying agent is a carbohydrate.

12. The microparticle composition of claim 11 wherein the carbohydrate is selected from the group consisting of lactose, sucrose, hydroxyl ethyl starch;

hetastarch, trehalose, mannose and mannitol.

20. The microparticle of claim 1 wherein the active agent comprises a plurality of active agents.

21. The microparticle of claim 1 wherein the excipient comprises a plurality of excipients.

22. The microparticle of claim 1 wherein the complex results in a glass transition temperature increase sufficient to stabilitize against water sorption.

23. The microparticle of claim 1 wherein the antibiotic comprises tobramycin.

13. A stable microparticle composition for drug delivery wherein the microparticle is comprised of a metal ion-lipid complex formed by the following process:

dispersing a phospholipid in water to create a first preparation;

suspending a metal compound or salt in water to create a second preparation;

adding an antibiotic;

combining the first and second preparations; and

spray drying the combined preparations to create a stable metal ion-lipid microparticle composition.

14. The microparticle composition of claim 13 wherein the phospholipid is selected from the group consisting of soy phosphatidylcholine, egg phosphatidylcholine, DPPC, DSPC, DMPC, dioctylphosphatidylcholine, and partially and fully hydrogenated phosphatides.

15. The microparticle composition of claim 13 wherein the metal ion is added in the form of calcium salt.

16. The microparticle composition of claim 13 wherein the combined preparation is spray dried with an inlet temperature within the range of 40-100°

C. and an outlet temperature within the range of 30-85°

C.

17. The microparticle composition of claim 13 wherein the antibiotic is added to one of the preparations selected from the group consisting of the first preparation, the second preparation and the combination of the first and second preparation.

18. The microparticle composition of claim 13 wherein the drug or active agent is added to the formed metal ion-lipid complex.

19. The microparticle composition of claim 13 wherein the antibiotic comprises tobramycin.