Solubilization of pharmaceutical substances in an organic solvent and preparation of pharmaceutical powders using the same

• US 5,770,559 A
• Filed: 06/06/1995
• Issued: 06/23/1998
• Est. Priority Date: 10/14/1992
• Status: Expired due to Term

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Randolph, Theodore W., Manning, Mark C., Shefter, Eli, Falk, Richard F. III
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): Mohamed, Abdel A.
• Application Number:
  US08/473,008
• Time in Patent Office: 1,113 Days
• Field of Search: 514/2, 514/21, 530/412, 530/418, 530/419, 530/427, 424/450, 424/489
• US Class Current: 424/489
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 38/09 Luteinising hormone-releasing hormone [LHRH] , i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/57 from animals; from humans A61K38/553, A61K38/556 take precedence
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/6905 the form being a colloid or an emulsion
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0078 for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/145 with organic compounds
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5153 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: B01F 23/043 Mixing fluids or with fluids in a supercritical state, in supercritical conditions or variable density fluids
• CPC Class Codes: B01F 23/09 Mixing systems, i.e. flow charts or diagrams for components having more than two different of undetermined agglomeration states, e.g. supercritical states
• CPC Class Codes: C07K 1/30 by precipitation
• CPC Class Codes: Y02P 20/54 using solvents, e.g. supercritical solvents or ionic liquids

Abstract

Provided is a method for preparing a true, homogeneous solution of a pharmaceutical substance dissolved in an organic solvent in which the pharmaceutical substance is not normally soluble. Solubilization is obtained by forming a hydrophobic ion pair complex involving the pharmaceutical substance and an amphiphilic material. The resulting organic solution may be further processed to prepare pharmaceutical powders. A biodegradable polymer may be co-dissolved with the pharmaceutical substance and the amphiphilic material and may be incorporated into a pharmaceutical powder. A preferred method for preparing pharmaceutical powders is to subject the organic solution to gas antisolvent precipitation using a supercritical gas antisolvent such as carbon dioxide. Also provided is a method for making hollow particles having a fiber-like shape which would provide enhanced retention time in the stomach if ingested by a human or animal host.

Claims

1. A method for making particles including a pharmaceutical material, which particles may be recovered in a powder form desirable for use in some pharmaceutical delivery methods such as inhalation for direct pulmonary delivery and injection in a slurry form, the method comprising the steps of:

forming solid particles comprising a pharmaceutical substance from a liquid solution, which particles could be recovered in powder form;

said liquid solution comprising said pharmaceutical substance and an amphiphilic material in solution in a carrier liquid

wherein, said pharmaceutical substance, alone, is substantially not soluble in said carrier liquid and said amphiphilic material is capable of interacting with said pharmaceutical substance such that said pharmaceutical substance, in combination with said amphiphilic material as a hydrophobic ion pair complex, is present in a true, homogeneous solution in said carrier liquid prior to said step of forming said solid particles.

2. The method of claim 1, wherein

said pharmaceutical substance and said amphiphilic material, in said liquid solution, are associated in the form of a hydrophobic ion pair complex, which complex is soluble in said carrier liquid and is dissolved in said carrier liquid in the form of a true homogeneous solution.

3. The method of claim 1, wherein

said amphiphilic material, in said liquid solution, is present at a concentration at which substantially no micelles involving said amphiphilic material and substantially no reverse micelles involving said amphiphilic material are present in said liquid solution.

4. The method of claim 1, wherein

said amphiphilic material is selected from the group consisting of bis(2-ethylhexyl) sodium sulfosuccinate, sodium dodecyl sulfate, cholesterol sulfate, sodium laurate, and ionic forms and dissociation products of the foregoing.

5. The method of claim 1, wherein greater than 90 weight percent of said solid particles are smaller about 10 microns in size.

6. The method of claim 1, wherein greater than 90 weight percent of said solid particles are smaller than 6 microns in size.

7. The method of claim 1, wherein greater than 90 weight percent of said solid particles are in a size range of from 1 micron to 6 microns.

8. The method of claim 1, wherein greater than 90 weight percent of said solid particles are smaller than 1 micron in size.

9. The method of claim 1, wherein the method further comprises recovering said solid particles as a substantially dry powder.

10. The method of claim 1, wherein

said solid particles comprise said amphiphilic material, in addition to said pharmaceutical substance.

11. The method of claim 10, wherein

said solid particles comprise said pharmaceutical substance and said amphiphilic material in the form of a hydrophobic ion pair complex involving said pharmaceutical substance and said amphiphilic material.

12. The method of claim 1, wherein

an antisolvent fluid is provided under conditions at which said antisolvent fluid and said carrier liquid are at least partially miscible and at which said pharmaceutical substance is substantially not soluble in said antisolvent fluid;

and

said step of forming said solid particles comprises contacting said liquid solution with said antisolvent fluid to cause said solid particles to form.

13. The method of claim 12 wherein

said step of forming said solid particles comprises contacting said liquid solution with said antisolvent fluid under conditions which are supercritical or near critical relative to said antisolvent fluid.

14. The method of claim 12, wherein

during said step of forming said solid particles, said liquid solution is contacted with said antisolvent fluid under thermodynamic conditions at which said antisolvent fluid is at a reduced pressure of greater than 0.5, relative to the critical pressure of said antisolvent fluid.

15. The method of claim 1, wherein

said liquid solution further comprises a biodegradable polymer which is dissolved in said carrier liquid;

and

said solid particles comprise said biodegradable polymer, in addition to said pharmaceutical substance.

16. The method of claim 15, wherein

said biodegradable polymer comprises at least some repeating units representative of polymerizing at least one of the following:

an alpha-hydroxycarboxylic acid, a cyclic diester of an alpha-hydroxycarboxylic acid, dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, an epoxide, a glycol and an anhydride.

17. The method of claim 15, wherein

said biodegradable polymer comprises at least some repeating units representative of polymerizing at least one of the following:

lactic acid, glycolic acid, lactide, glycolide, ethylene glycol and ethylene oxide.

18. The method of claim 1, wherein

said solid particles have an elongated, fiber-like shape.

19. The method of claim 18, wherein

said solid particles have a hollow interior extending longitudinally within said solid particles.

20. The method of claim 18, wherein

said particles have a diameter of smaller than 50 microns.

21. The method of claim 18, wherein

said solid particles have a length of 0.5 millimeters to 1 centimeter.

22. The method of claim 1, wherein

said amphiphilic material comprises a molecular structure having a hydrophilic portion and a hydrophobic portion, and wherein said hydrophilic portion is ionic.

23. The method of claim 22 wherein

said hydrophilic portion is anionic.

24. The method of claim 22, wherein

said amphiphilic material is selected from the group consisting of a sulfonate, a sulfate, a phosphate, a carboxylate, a sulfosuccinate and ionic forms and dissociation products of the foregoing.

25. The method of claim 22, wherein

said hydrophilic portion is cationic.

26. The method of claim 22, wherein

said amphiphilic material comprises at least one of an ammonium group, a guadininium group and substituted variations of the foregoing groups.

27. The method of claim 1, wherein

said pharmaceutical substance is directly soluble in an aqueous liquid at a physiological pH and exhibits a charged character when dissolved in an aqueous liquid at a physiological pH.

28. The method of claim 27, wherein

said pharmaceutical substance comprises a protein.

29. The method of claim 27, wherein

said pharmaceutical substance comprises a polypeptide.

30. The method of claim 27, wherein

said pharmaceutical substance comprises at least one of:

(α

-chymotrypsin, ribonuclease, DNase, cytochrome, lypopressin, vasopressin, oxytocin, insulin, calcitonin gene-related peptide, LHRH agonists, ACTH, Gly-Phe-NH₂ dipeptide, bovine pancreatic trypsin inhibitor, human serum albumin, leuprolide, neurotensin, bradykinin, and human growth hormone.

31. The method of claim 27, wherein

said pharmaceutical substance comprises an analgesic.