Particulate drug-containing products and method of manufacture

• US 7,125,566 B2
• Filed: 11/19/2003
• Issued: 10/24/2006
• Est. Priority Date: 12/21/1999
• Status: Expired due to Term

• Current Assignee: Endo Pharmaceuticals Colorado, Inc.
• Original Assignee: Rxkinetix, Inc. (Endo International PLC)
• Inventors: Etter, Jeffrey B.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US10/717,429
• Publication Number:
  US 20040161467A1
• Time in Patent Office: 1,070 Days
• Field of Search: 424/489, 424/499, 424/43, 424/45
• US Class Current: 424/489
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• 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 9/14 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 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Abstract

Provided is a compressed anti-solvent technique for manufacture of drug-containing powders for pulmonary delivery. The drug is processed in a cosolvent system including two or more mutually soluble organic solvents. Also provided are powders manufacturable by the manufacture method, including powders of substantially pure drug and powders including a biocompatible polymer for pulmonary sustained drug release applications. Also provided are packaged products including drug-containing powder in a container that is receivable by and operable with a dry powder inhaler to produce an aerosol including dispersed drug-containing particles when the inhaler is actuated.

Claims

1. A method for making a drug-containing particulate product, the method comprising:

contacting a drug-containing feed solution with a compressed anti-solvent fluid to precipitate drug-containing particles, the feed solution including the drug in a cosolvent system including at least a first organic solvent and a second organic solvent that are mutually soluble; and

separating the drug-containing particles from the anti-solvent fluid;

wherein the feed solution comprises a biocompatible polymer and the particles are multi-component particles comprising at least a portion of the biocompatible polymer.

2. The method of claim 1, wherein the drug is more soluble in the first organic solvent than is the biocompatible polymer, and the biocompatible polymer is more soluble in the second organic solvent than is the drug.

3. The method of claim 1, wherein the biocompatible polymer is hydrophobic, the first organic solvent being a polar solvent for the drug and the second organic solvent being a nonpolar solvent for the biocompatible polymer.

4. The method of claim 1, wherein the first organic solvent is substantially miscible with water and the second organic solvent is substantially immiscible with water.

5. The method of claim 1, wherein the second organic solvent comprises at least one of methylene chloride, formaldehyde, dioxolane, chloroform, benzene, ethyl ether, toluene, xylene, 1,3-dioxane and THF.

6. The method of claim 5, wherein the first organic solvent comprises an alcohol.

7. The method of claim 6, wherein the first organic solvent comprises a C₁–

C₅ alkanol.

8. The method of claim 7, wherein the second organic solvent comprises methylene chloride.

9. The method of claim 1, wherein the method comprises, prior to the contacting step, preparing the feed solution, the preparing comprising mixing a first solution having the drug dissolved therein with a second solution having the biocompatible polymer dissolved therein, the first solution including the first organic solvent and the second solution including the second organic solvent.

10. The method of claim 9, wherein during the mixing step, the second solution is added to the first solution.

11. The method of claim 1, wherein the weight ratio of the drug to the biocompatible polymer in the feed solution is larger than 5:

95.

12. The method of claim 1, wherein the weight ratio of the drug to the polymer in the feed solution is in a range of from 5:

95 to 50;

50.

13. The method of claim 1, wherein the contacting step is conducted under conditions so that the multi-component particles have a degree of encapsulation of the drug by the polymer of greater than 50 percent.

14. The method of claim 1, wherein the contacting step is conducted under conditions so that the multi-component particles have a degree of encapsulation of the drug by the polymer of greater than 70 percent.

15. The method of claim 1, wherein the biocompatible polymer comprises repeating units from polymerization of at least one monomer selected from the group consisting of an alphahydroxycarboxylic acid, a cyclic diester of an alphahydroxycarboxylic acid, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, an epoxide, and a glycol.

16. The method of claim 1, wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first organic solvent of from 10:

90 to 99;

1.

17. The method of claim 1, wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first organic solvent of larger than 30:

70.

18. The method of claim 1, wherein the first organic solvent and the second organic solvent are present in the cosolvent system at a volume ratio of the second organic solvent to the first organic solvent of from 50:

50 to 90;

10.

19. The method of claim 1, wherein the compressed anti-solvent fluid, during the contacting, is at a reduced pressure of larger than 0.8 and a reduced temperature of larger than 0.95, the reduced pressure being a ratio of pressure expressed in atmospheres of the compressed anti-solvent fluid during the contacting to the critical pressure expressed in atmospheres of the compressed anti-solvent fluid, and the reduced temperature being a ratio of temperature expressed in K of the compressed anti-solvent fluid during the contacting to the critical temperature expressed in K of the compressed anti-solvent fluid.

20. The method of claim 19, wherein the compressed anti-solvent fluid, during the contacting, is at a reduced pressure of larger than 0.9.

21. The method of claim 1, wherein the compressed anti-solvent fluid, during the contacting, is in a supercritical state.

22. The method of claim 1, wherein the compressed anti-solvent fluid comprises compressed carbon dioxide.

23. The method of claim 1, wherein the drug is selected from the group consisting of a protein, a peptide and a genetic material.

24. The method of claim 1, wherein the concentration of the drug in the feed solution is smaller than 3 mg of the drug per milliliter of the feed solution.

25. The method of claim 1, wherein the feed solution comprises the biocompatible polymer dissolved in the cosolvent system.

26. The method of claim 1, wherein the feed solution comprises both the biocompatible polymer and the drug dissolved in the cosolvent system.

27. The method of claim 1, wherein the contacting comprises extracting the first organic solvent and the second organic solvent into the anti-solvent fluid.

28. The method of claim 1, wherein the feed solution is substantially free of amphiphillic materials that improve solubility of the drug in the feed solution through hydrophobic ion pairing with the drug.

29. The method of claim 1, wherein the biocompatible polymer is selected from the group consisting of poloxamers, polyanhydrides, phosphatriazenes and combinations thereof.

30. The method of claim 1, wherein the biocompatible polymer comprises a poly(lactic acid).

31. The method of claim 1, wherein the drug is insulin.