Dispersible macromolecule compositions and methods for their preparation and use

• US 6,592,904 B2
• Filed: 11/09/2001
• Issued: 07/15/2003
• Est. Priority Date: 03/07/1994
• Status: Expired due to Fees

• Current Assignee: Novartis Pharma AG (Novartis Ag)
• Original Assignee: Inhale Therapeutic Systems, Inc.
• Inventors: Brewer, Thomas K., Boardman, Terence D., Platz, Robert M.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): DI NOLA BARON, LILIANA
• Application Number:
  US10/007,868
• Publication Number:
  US 20020122827A1
• Time in Patent Office: 613 Days
• Field of Search: 424/489, 424/499, 424/497, 424/400, 424/491, 424/422, 514/2, 514/3, 264/5, 264/12
• US Class Current: 424/491
• CPC Class Codes: A61K 38/28 Insulins
• 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 9/145 with organic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• 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 15/0086 Inhalation chambers

Abstract

A process for preparing ultrafine powders of biological macromolecules comprises atomizing liquid solutions of the macromolecules, drying the droplets formed in the atomization step, and collecting the particles which result from drying. By properly controlling each of the atomization, drying, and collection steps, ultrafine dry powder compositions having characteristics particularly suitable for pulmonary delivery for therapeutic and other purposes may be prepared.

Claims

1. A method for preparing dispersible dry powders of biological macromolecules, said method comprising:

providing an evaporable liquid medium containing a predetermined concentration of a biological macromolecule having a molecular weight of greater than 2 kD;

atomizing the liquid medium;

drying the droplets in a heated gas stream to produce particles comprising a rugosity of at least 2.0 as measured by air permeametry, a moisture content below 10% by weight and a particle size of less than 10 microns.

2. A method as in claim 1 wherein the concentration of total solids in the liquid medium is less than 10% by weight.

3. A method as in claim 2 wherein the solids content is less than 5% by weight.

4. A method as in claim 1 wherein the atomizing conditions are selected to form droplets having an average size below 11 microns.

5. A method as in claim 1 further comprising collecting said particles.

6. A method as in claim 1 wherein 90% of the mass of the dispersible powder consists of particles having a diameter within the range of 0.1 microns-7 microns.

7. A method as in claim 1 wherein 95% of the mass of the dispersible powder consists of particles having a diameter within the range of 0.4 microns-5 microns.

8. As method as in claim 1 wherein the droplets are flowed co-currently with the heated gas stream and wherein the gas stream has an inlet temperature above 90°

C.

9. A method as in claim 8 wherein the inlet temperature is within 120-200°

C.

10. A method as in claim 8 wherein the gas stream has an inlet temperature above 110°

C. and an outlet temperature above 50°

C.

11. A method as in claim 10 wherein the outlet temperature is within 60-80°

C.

12. A method as in claim 5 further comprising packaging at least some of the particles in a container after the collecting step, wherein the particles have not been size classified prior to packaging.

13. A method as in claim 12 wherein the particles are packaged in a unit dosage container.

14. A method as in claim 1 wherein the macromolecule is selected from the group consisting of calcitonin, erythropoietin, factor IX, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, growth hormone, insulin, interferon alpha, interferon beta, interferon gamma, interleukin-2, luteinizing hormone releasing hormone (LHRH), somatostatin, vasopresin analog, follicle stimulating hormone (FSH), amylin, ciliary neurotrophic factor, growth releasing factor, insulin-like growth factor, insulinotropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor, nerve growth factor, parathyroid hormone, thymosin alpha-1, factor IIb/IIIa inhibitor, alpha-1 antitrypsin, anti-RSV antibody, deoxyribonuclease (DNase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, interleukin-1 receptor, and interleukin-1 receptor antagonist.

15. A method as in claim 1 wherein the particles comprise a rugosity measured by air permeametry in the range of 3 to 6.

16. A method as in claim 1 wherein the liquid medium further comprises an excipient.

17. A method as in claim 1 wherein the liquid medium comprises a solution or suspension.

18. A method according to claim 17 wherein the liquid medium comprises an aqueous solution.

19. A method according to claim 1 wherein the liquid medium comprises ethanol.

20. A macromolecule composition prepared by the method of any of claims 1-4 and 6-15, and 17-19.

21. A macromolecule composition according to claim 20 wherein the macromolecule is insulin.

22. A macromolecule composition according to claim 21 in a unit dosage form containing 0.5 mg-15 mg of the composition.

23. A macromolecule composition according to claim 21 further comprising an excipient selected from the group consisting of carbohydrates, amino acids, buffers, and salts.

24. A macromolecule composition according to claim 23 wherein the excipient is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and hydrophobic amino acids.

25. A macromolecule composition according to claim 23 wherein the excipient is selected from the group consisting of mannitol, trehalose, sodium chloride, sodium citrate, leucine, lactose, raffinose, alanine, and glycine.