Phospholipid-based powders for drug delivery

• US 9,439,862 B2
• Filed: 04/02/2014
• Issued: 09/13/2016
• Est. Priority Date: 05/10/2000
• Status: Expired due to Term

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Riess, Jean G, Weers, Jeffry G, Tarara, Thomas E, Dellamary, Luis A, Schutt, Ernest G
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US14/243,639
• Publication Number:
  US 20140212504A1
• Time in Patent Office: 895 Days
• US Class Current: 1/1
• 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

Phospholipid based powders for drug delivery applications are disclosed. The powders comprise a polyvalent cation in an amount effective to increase the gel-to-liquid crystal transition temperature of the particle compared to particles without the polyvalent cation. The powders are hollow and porous and are preferably administered via inhalation.

Claims

1. A particulate composition for delivery to the pulmonary system, the particulate composition comprising:

dry particles, wherein each particle comprises an active agent, a phospholipid, and a polyvalent cation, wherein the particles have a mass median diameter of 0.5 to 5 microns, and wherein the particulate composition is characterized by being deliverable at an emitted dose in a dry powder inhaler of at least 54.55%.

2. A composition according to claim 1 wherein the particles comprise a mass median aerodynamic diameter of less than 10 microns.

3. A composition according to claim 2 wherein the aerodynamic diameter is 0.5 to 5 microns.

4. A composition according to claim 1 wherein the particles are spray dried particles.

5. A composition according to claim 1 wherein the polyvalent cation is present at a molar ratio of cation:

phospholipid of 0.25 to 1.0.

6. A composition according to claim 1 wherein the polyvalent cation is present at a molar ratio of cation:

phospholipid of about 0.5.

7. A composition according to claim 1 wherein the polyvalent cation is present in the form of calcium chloride.

8. A composition according to claim 1 wherein the active agent is selected from the group consisting of an antibiotic, antibody, antiviral agent, anti-epileptic, analgesic, anti-inflammatory agent and bronchodilator.

9. A composition according to claim 1 wherein the active agent comprises one or more of insulin, calcitonin, erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (hGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), leuprolide, somatostatin, somatostatin analogs including octreotide, vasopressin analog, follicle stimulating hormone (FSH), immunoglobulin, insulin-like growth factor, insulintropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor (M-CSF), nerve growth factor, parathyroid hormone (PTH), thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, interleukin-1 receptor, 13-cis retinoic acid, nicotine, nicotine bitartrate, gentamicin, ciprofloxacin, amphotericin, amikacin, tobramycin, pentamidine isethionate, albuterol sulfate, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, ipratropium bromide, flunisolide, fluticasone, fluticasone propionate, salmeterol xinofoate, formeterol fumarate, cromolyn sodium, ergotamine tartrate and analogues, agonists and antagonists thereof.

10. A composition according to claim 1 wherein the active agent comprises tobramycin.

11. A composition according to claim 1 wherein the active agent comprises ciproflaxcin.

12. A composition according to claim 1 wherein the active agent comprises amphotericin.

13. A composition according to claim 1 wherein a particulate composition bulk density is less than 0.05 g/cm³.

14. A composition according to claim 1 wherein the phospholipid is a zwitterionic phospholipid.

15. A composition according to claim 1 wherein the phospholipid comprises one or more of dipalmitoylphosphatidylcholine, disteroylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenolyphosphatidylcholine, diphosphatidyl glycerol, short-chain phosphatidylcholines, long-chain saturated phosphatidylethanolamines, long-chain saturated phosphatidylserines, long-chain saturated phosphatidylglycerols, and long-chain saturated phosphatidylinositols.

16. A composition according to claim 1 wherein the particles further comprise an additional excipient.

17. A composition according to claim 1 wherein the particles further comprise an additional active agent.

18. A unit dose package comprising a reservoir containing a unit dose of a particulate composition according to claim 1.

19. A unit dose package according to claim 18 wherein the unit dose package is insertable into a dry powder inhaler.