METHODS FOR FINE PARTICLE
CROSS REFERENCE TO RELATED
This application is a continuation-in-part of U.S. Ser. No. 07/846331 filed Mar. 6,1992, now U.S. Pat. No. 5301,664 which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to methods and apparatuses using supercritical fluid mixtures for forming fine particles for drug delivery, mass spectrometry, powder and film formation and other applications.
BACKGROUND OF THE INVENTION
Aerosols and vapors have a variety of medicinal and industrial uses. An aerosol is a two-phase system consisting of a gaseous continuous phase and a discontinuous phase of individual particles. Vapors are molecularly dispersed and are a single gaseous phase. The individual particles in an aerosol can be solids or liquids (Swift, D. L. (1985), "Aerosol characterization and generation," in Aerosols in Medicine Principles. Diagnosis and Therapy (Moren, F. et al. eds) 53-75).
Liquids under pressure have been used to purify and mix products to a desired final form. U.S. Pat. No. 5,056,511 to Ronge for "Method and Apparatus for Compressing, Atomizing and Spraying Liquid Substances," issued Oct. 15, 1991, discloses atomizers for creating small droplets of liquids, such as peanut oil in which vitamins A and E are solubilized, involving compression of the liquid at a pressure of300 to 800x10s Pa and the sudden release of pressure to cause an explosive spray. U.S. Pat. No. 5,169,433 to Lindsay et al. issued Dec. 8,1992 for "Method of Preparing Mixtures of Active Ingredients and Excipients Using Liquid Carbon Dioxide" discloses the use of liquid (not supercritical) carbon dioxide under pressure to solubilize active ingredients and excipients, and slow conversion of the liquid carbon dioxide to the gaseous phase to form a product which can be easily solubilized or dispersed in water.
Supercritical fluids have been used in the production of aerosols for precipitation of fine solid particles. The phenomenon was observed and documented as early as 1879 by Hannay, J. B. and Hogarth. J., "On the Solubility of Solids in Gases," Proc. Roy. Soc. London 1879 A29, 324, who described the precipitation of solids from supercritical fluids: "When the solid is precipitated by suddenly reducing the pressure, it is crystalline, and may be brought down as a 'snow' in the gas, or on the glass as a 'frost'..."
This phenomenon has been exploited in processes for producing fine particles, however, its use has been limited to substances which are soluble in the supercritical fluid.
Mohamed, R. S., et al. (1988), "Solids Formation After the Expansion of Supercritical Mixtures," in Supercritical Fluid Science and Technology, Johnston, K. P. and Penninger, J. M. L., eds., describes the solution of the solids naphthalene and lovastatin in supercritical carbon dioxide and sudden reduction of pressure to achieve fine particles of the solute. The sudden reduction in pressure reduces the solvent power of the supercritical fluid, causing precipitation of the solute as fine particles.
Tom, J. W. and Debenedetti, P. B. (1991), "Particle Formation with Supercritical Fluids—a Review," J. Aerosol. Sci. 22:555- 584, discusses rapid expansion of supercritical
solutions (RESS) techniques and their applications to inorganic, organic, pharmaceutical and polymeric materials. The RESS technique is useful to comminute shock-sensitive solids, to produce intimate mixtures of amorphous materials, 5 to form polymeric microspheres and deposit thin films. Critical properties of common RESS solvents are provided. The solvents include carbon dioxide, propane, n-pentane, propylene, ethanol, and water. In all cases the RESS process requires dissolving of at least one solid in the supercritical
Smith U.S. Pat. No. 4,582,731 for "Supercritical Fluid Molecular Spray Film Deposition and Powder Formation," issued Apr. 15,1986, and Smith U.S. Pat. No. 4,734,451 for "Supercritical Fluid Molecular Spray Thin Films and Fine Powders," both of which are incorporated herein by
15 reference, describes a typical RESS process involving rapidly releasing the pressure of a supercritical solution of a solid solute to form a film of the solute on a substrate, or to form a fine powder of the solute.
Sievers et al. U.S. Pat. No. 4,970,093 for "Chemical
20 Deposition Methods Using Supercritical Fluid Solutions," issued Nov. 13, 1990, incorporated herein by reference, discloses a process similar to the RESS process for depositing a film on a substrate by rapidly releasing the pressure of a supercritical reaction mixture to form a vapor or aerosol
25 which deposits a film of the desired material on a substrate. Alternatively, the supercritical fluid contains a dissolved first reagent which is contacted with a gas containing a second reagent which reacts with the first reagent to form particles of the desired material deposited as a film on the substrate.
30 Sievers, et al. PCT Publication WO 9317665 published Sep. 16, 1993, corresponding to the parent application hereof, discloses the use of nebulizers utilizing medicaments dissolved in supercritical fluids to deliver physiologically active substances to a patient, preferably to lung tissues of
35 the patient The supercritical fluid process provides particles of the desired size range for administration to the patient's lungs (less than about 6.5 um). The process is limited to solutes which will dissolve in the supercritical fluid or the supercritical fluid and cosolvents.
40 The use of supercritical co-solvents, e.g., carbon dioxide and nitrous oxide, to dissolve poorly soluble active principles is described in Donsi, G. and Reverchon, E. (1991), "Micronization by Means of Supercritical Fluids: Possibility of Application to Pharmaceutical Field," Pharm. Acta Helv.
A modification of the RESS process is described in PCT Publication WO 90/03782 of The Upjohn Company for "Finely Divided Solid Crystalline Powders via Precipitation Into an Anti-Solvent" which involves dissolving a desired
50 solid in a supercritical fluid and adding an anti-solvent which is miscible with the supercritical fluid but not with the solute in order to precipitate the solute. Such an anti-solvent process, referred to as the "gas anti-solvent (GAS) precipitation process is also discussed in Debenedetti, P. G., et al.
55 (1993), "Application of supercritical fluids for the production of sustained delivery devices," J. Controlled Release 24:27-44. The GAS process is also discussed with respect to production of insulin powder in Yeo, S-D, et al. (1993), "Formation of Microparticulate Protein Powders Using a
60 Supercritical Fluid Antisolvent," Biotechnology and Bioengineering 41:341-346. Again, the usefulness of the process is limited to the precipitation of solutes which may be dissolved in the supercritical fluid. None of the foregoing literature discloses or suggests the
65 use of mixtures of supercritical fluids with immiscible liquids to process desired substances or form aerosols or vapors.