Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
2002-06-26
2004-12-28
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S422000, C424S489000
Reexamination Certificate
active
06835396
ABSTRACT:
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to a process for preparing submicron sized nanoparticles of a poorly water soluble compound by lyophilizing a dispersion of a multiphase system having an organic phase and an aqueous phase, the organic phase having the poorly water soluble compound therein. The method is preferably used to prepare nanoparticles of a poorly water soluble, pharmaceutically active compound suitable for in vivo delivery, particularly by parenteral routes.
2. Background of the Invention
There are an ever increasing number of pharmaceutical drugs being formulated that are poorly soluble or insoluble in aqueous solutions. Such drugs provide challenges to delivering them in an injectable form such as through parenteral administration. Drugs that are insoluble in water can have significant benefits when formulated as a stable suspension of submicron sized particles. Accurate control of particle size is essential for safe and efficacious use of these formulations.
Particles must be less than seven microns in diameter to safely pass through capillaries without causing emboli (Allen et al., 1987; Davis and Taube, 1978; Schroeder et al., 1978; Yokel et al., 1981). One solution to this problem is the production of extremely small particles of the insoluble drug candidate and the creation of a microparticulate or nanoparticulate suspension. In this way, drugs that were previously unable to be formulated in an aqueous based system can be made suitable for parenteral administration. Suitability for parenteral administration includes small particle size (<7 &mgr;m), low toxicity (as from toxic formulation components or residual solvents), and bioavailability of the drug particles after administration.
The parenteral administration of such poorly water soluble pharmaceutical agents has been achieved in the past using emulsions composed of a hydrophobic solvent (e.g., oil) and a stabilized drug dispersed within an aqueous medium, such as a buffer solution or normal saline solution. These liquid/liquid emulsions may be injected intravenously.
One example of this approach utilized the anesthetic, propofol (2,6 diisopropylphenol), in which the pharmacological agent was dissolved within a vegetable oil emulsion to enable intravenous administration. See, e.g., U.S. Pat. Nos. 4,056,635; 4,452,817 and 4,798,846, all to Glen et al. Such emulsions, however, tend to be unstable given the predominance of the oil phase and the absence of antimicrobial agents. In other instances, even where the pharmacological agent is successfully incorporated into an oil-free formulation, particles containing the pharmacological agent may cause irritation at the site of delivery because of their size or form. Furthermore, many insoluble drugs of interest do not show appreciable solubility within traditional oil emulsion systems. One reason for this is that solubility is not strictly defined by polarity, but also includes hydrogen bonding, dipole-dipole interactions, ionic stabilization and atom to atom interactions.
U.S. Pat. No. 4,073,943, issued to Wretlind et al., discloses a method of administering a water-insoluble pharmaceutically active agent by dissolving the agent in oil and emulsifying the solution with water in the presence of surfactants (egg phosphatides, pluronics, polyglycerol oleate, etc.) to form stable lipoid particles of the agent dispersed in the aqueous phase.
U.S. Pat. No. 4,540,602, issued to Motoyama et al., discloses a process for the preparation of an activated pharmaceutical composition containing a water insoluble drug for oral administration. In one procedure of the invention (see Examples 4 to 10), the process is carried out by dissolving the drug in hydrophobic organic solvents, and the resulting solution is emulsified in water. The dispersing medium is then removed rapidly by spray drying, resulting in particles ranging in particle size of from about 0.1 to about 3.0 &mgr;m.
A variety of approaches have been explored for developing stable formulations of a substantially water-insoluble pharmacologically active agent for in vivo delivery. One approach is directed to the production of suspended particles coated with protein. U.S. Pat. No. 5,916,596, issued to Desai et al., discloses the application of high shear to a mixture of an organic phase having a pharmacologically active agent dispersed therein and an aqueous medium containing a biocompatible polymer. The mixture is sheared in a high pressure homogenizer at a pressure in the range of from about 3,000 to 30,000 psi. The '596 patent provides that the mixture must contain substantially no surfactants because the combined use of a surfactant with a protein results in the formation of large, needle-like crystalline particles that increase in size during storage. See columns 17-18, example 4. The biocompatible polymer may be crosslinked as the result of exposure to the high shear conditions in a high pressure homogenizer. In the embodiment in which protein containing sulfhydryl or disulfide groups is used (e.g. albumin), the protein forms a crosslinked shell around droplets of non-aqueous medium. See Column 8, lines 35-48. In Examples 1, 2, 5, 6, 9, 10, 11, and 12, the organic phase is removed rapidly by rotary evaporation at 40° C. and at a reduced pressure of 30 mm Hg, resulting in an aqueous dispersion of particles coated with crosslinked protein. The aqueous dispersion may further be lyophilized to remove the aqueous phase. The '596 patent discloses other alternative methods of removing the solvent, including falling film evaporation, spray drying, and freeze-drying. Example 2 discloses that the crude emulsion may be sonicated to produce nanoparticles ranging from 350-420 nanometers. Example 5 discloses a method to prepare sterile-filterable nanoparticles of less than 200 nm. This method requires that the pharmaceutical agent is initially dissolved in a mixture of substantially water immiscible organic solvent (e.g., chloroform) and a water miscible organic solvent (e.g. ethanol).
U.S. Pat. No. 5,560,933, issued to Soon-Shiong et al., discloses the formation of a polymeric shell around the water-insoluble oil (containing the drug) for in vivo delivery. The method discloses the application of sonication to a mixture comprising a polymer-containing aqueous medium and a dispersing agent (oil) having a substantially water-insoluble drug dispersed therein. In this reference, sonication is used to drive the formation of disulfide bonds in the polymer, causing it to crosslink so as to produce a polymeric shell around the drug. Sonication is conducted for a time sufficient for the disulfide bonds to form.
In U.S. Pat. No. 5,665,383, Grinstaff et al. discloses the application of ultrasound to a single-phase, i.e., an aqueous medium, to encapsulate an immunostimulating agent within a polymeric shell for in vivo delivery. The ultrasound promotes crosslinking of the encapsulating agent by disulfide bonds to form the shell.
Another approach to preparing a water-insoluble drug for in vivo delivery centers on reducing the size of the particles that deliver the drug. In one such series of patents, which include U.S. Pat. Nos. 6,228,399; 6,086,376; 5,922,355; and 5,660,858, Parikh et al. discloses that sonication may be used to prepare microparticles of the water-insoluble compound. Of these patents, U.S. Pat. No. 5,922,355 discloses an improvement to a method that uses sonication for making the smaller particles. The improvement comprises mixing an active pharmacological agent with a phospholipid and surfactants in a single-phase aqueous system and applying energy to the system to produce the smaller particles.
U.S. Pat. No. 5,091,188, issued to Haynes, also discloses reducing the size of particles of a pharmacologically active water-insoluble drug and employing a lipid coating on the particles to confer a solid form. The patent is directed to a pharmaceutical composition of an aqueous suspension of solid particles of the d
Brynjelsen Sean
Doty Mark
Jayswal Nailesh
Kipp James E.
Narayanan Krishnaswamy
Basso Thomas C.
Baxter International Inc.
Fuchs Joseph A.
Mayo Michael C.
Tran S.
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