Dispersible macromolecule compositions and methods for their preparation and use

• US 7,138,141 B2
• Filed: 03/31/2003
• Issued: 11/21/2006
• Est. Priority Date: 03/07/1994
• Status: Expired due to Fees

• Current Assignee: Novartis Ag
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Brewer, Thomas, Boardman, Terrence, Platz, Robert
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US10/403,482
• Publication Number:
  US 20030215514A1
• Time in Patent Office: 1,331 Days
• Field of Search: 424/491, 424/489, 424/497, 424/499, 514/2, 514/3, 514/5, 514/12
• US Class Current: 424/489
• 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 macromolecule selected from the group consisting of proteins, polypetides, oligopeptides, nucleic acids, and polysaccharides, wherein the concentration of total solids in the liquid medium is less than 10% by weight;

atomizing the liquid medium consisiting of said marcomolecule to form droplets by flowing the liquid medium and an atomization gas stream at a gas;

liquid mass flow ratio above 5 under conditions selected to form droplets having an average size of between 5 μ

m and 11 μ

m; and

drying the droplets in a single drying step, in a heated gas stream, wherein the heated gas stream has an outlet temperature of at least 70°

C., to produce particles having a rugosity of at least 2.0 as measured by air permeametry, wherein 90% of the mass of the powder comprises particles having a diameter in the range of between about 0.1 microns and about 7 microns, and wherein the particles have a final moisture content of below 5% by weight.

2. A method of claim 1 further comprising collecting said particles.

3. A method as in claim 1 wherein 90% of the mass of the powder comprises particles having a diameter within the range of 0.4 microns–

5 microns.

4. A method as in claim 1 further comprising packaging at least some of the particles in a container, wherein the particles have not been size classified prior to packaging.

5. A method as in claim 4 wherein the particles are packaged in a unit dosage container.

6. A method as in claim 1 wherein the macromolecule is selected from the group consisting of calcitonin, reythropoietin, factor IX, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, growth hormone, insulin, interferon alpha, interferon beta, interferon gamma, interleukin-2, leutenizing hormone releasing hormone (LHRH), somatostatin, vasopressin analog, follicle stimulating hormone (FSH), amylin, ciliaryneurotrophic factor, growth hormone releasing factor (GRE), insulin-like growth factor, insulinotropin, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, macrophage colony stimulating factor(M-CSF), 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.

7. A method as in claim 1 wherein the particles comprise a rugosity measured by air permeability in the range from 3 to 6.

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

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

10. A method as in claim 9 wherein the liquid medium comprises an aqueous solution.

11. A method as in claim 1 wherein the liquid medium comprises ethanol.

12. A composition prepared by the method of claim 1.

13. A composition as in claim 12 wherein the macromolecule is insulin.

14. A composition as in claim 12 in a unit dosage form containing 0.5 mg–

15 mg of the composition.

15. A composition as in claim 12 comprising an excipient selected from the group consisting of carbohydrates, amino acids, buffers and salts.

16. A composition as in claim 14 wherein the excipient is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, and hydrophobic amino acids.

17. A composition as in claim 15 wherein the excipient is selected from the group consisting of manitol, trehalose, sodium chloride, sodium citrate, leucine, lactose, raffinose, alanine, and glycine.

18. A method as in claim 1 wherein 95% of the mass of the powder comprises particles having a diameter within the range of 0.4 microns–

5 microns.