Phospholipid-based powders for drug delivery

• US 8,709,484 B2
• Filed: 10/24/2008
• Issued: 04/29/2014
• Est. Priority Date: 05/10/2000
• Status: Expired due to Term

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Weers, Jeffry G., Tarara, Thomas E., Dellamary, Luis A., Riess, Jean G., Schutt, Ernest G.
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US12/258,163
• Publication Number:
  US 20090047358A1
• Time in Patent Office: 2,013 Days
• Field of Search: 424/489, 424/46, 424/502
• US Class Current: 424/489
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 9/1611 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Phospholipid based powders for drug delivery applications are disclosed. The powders may include 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 method for producing a phospholipid particulate composition comprising:

adding a polyvalent cation to a formulation comprising a phospholipid wherein a molar ratio of polyvalent cation to phospholipid is sufficient to increase a gel-to-liquid crystal transition temperature of the particles compared to particles without the polyvalent cation such that the particles have a gel-to-liquid crystal transition temperature that is greater than room temperature by at least 20 C; and

drying said formulation to form a dry particulate composition comprising hollow and porous particles,

wherein said dry particulate composition is characterized by being deliverable at an emitted dose of at least 54.55%.

2. A method according to claim 1 wherein the particulate composition comprises particles having a mass median diameter of less than 20 microns.

3. A method according to claim 2 wherein the mass median diameter is 0.5-5 microns.

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

5. A method according to claim 4 wherein the aerodynamic diameter is 0.5-5 microns.

6. A method according to claim 1 wherein the drying step is performed by spray drying.

7. A method according to claim 6 wherein the spray drying process comprises making a feedstock comprising the phospholipid.

8. A method according to claim 7 wherein the feedstock comprises a colloidal solution or suspension.

9. A method according to claim 8 wherein the polyvalent cation is added to the feedstock at a molar ratio of cation:

phospholipid of 0.25-1.0.

10. A method according to claim 9 wherein the polyvalent cation is added to the feedstock as calcium chloride.

11. A method according to claim 1 wherein the formulation further comprises an active agent.

12. A method according to claim 11 wherein the active agent is a therapeutic agent.

13. A method according to claim 12 wherein the therapeutic agent is selected from the group consisting of an antibiotic, antibody, antiviral agent, anti-epileptic, analgesic, anti-inflammatory agent and bronchodilator.

14. A method according to claim 13 wherein the therapeutic agent is 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.

15. A method according to claim 13 wherein the therapeutic agent is tobramycin.

16. A method according to claim 13 wherein the therapeutic agent is ciproflaxcin.

17. A method according to claim 13 wherein a formulation bulk density is less than 0.05 g/cm³.

18. A method according to claim 13 wherein the drying step comprises spray drying, and wherein an inlet temperature is between 60°

C. and 170°

C. and an outlet temperature is about 40°

C. to 120°

C.

19. A method according to claim 13 wherein the therapeutic agent is amphotericin.