Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2002-09-09
2004-01-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S491000
Reexamination Certificate
active
06676972
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to reagents and methods for facilitating the entry of biologically-active compounds into phagocytic cells. The invention specifically provides particulate carriers generally termed microparticles comprising antimicrobial compounds, both per se as compositions of matter and as pharmaceutical compositions thereof. Alternative embodiments of said microparticle carriers are provided wherein one or a multiplicity of antimicrobial compounds are linked to a microparticle via a specifically-cleaved linker moiety, or wherein a porous microparticle is impregnated with one or a multiplicity of antimicrobial compounds, or wherein the microparticle is coated with one or a multiplicity of antimicrobial compounds, wherein the impregnated or coated microparticle is further coated with a specifically-degradable coating material, wherein in their respective embodiments the specifically-cleaved linker moiety and the specifically-degradable coating material are the targets of a microorganism-specific protein having an enzymatic activity not otherwise expressed in the phagocytic cell, or that is specifically expressed by the phagocytic cell only when infected with said microorganism. Thus, the invention provides cell targeting of drugs to phagocytic cells wherein the targeted drug is only released in phagocytic cells that infected with a particular microorganism. Methods of treating diseases having an intracellular microbial etiology are also provided, particularly for the treatment of tuberculosis and other Mycobacterium-caused diseases.
2. Background of the Related Art
A major goal in the pharmacological arts has been the development of reagents and methods for facilitating specific delivery of therapeutic compounds, drugs and other agents to the appropriate cells and tissues that would benefit from such treatment, and the avoidance of the general physiological effects of systemic or otherwise inappropriate delivery of such compounds, drugs or agents to other cells or tissues of the body. The most common example of the need for such specificity is in the field of antibiotic therapy, in which the amount of a variety of antibiotic, antimicrobial and antiviral compounds, drugs and agents that can be safely administered to a patient is limited by their cytotoxic and immunogenic effects.
It is also recognized in the medical arts that certain cells are the sites of pharmacological action of certain compounds, drugs or agents or are involved in the biological response to certain stimuli. In particular, it is now recognized that certain cell types are reservoirs for occult infection that evades normal immune surveillance and permits the persistence of a chronically infected disease state. Specific delivery of diagnostic or therapeutic compounds, drugs or agents to such cells is thus desirable to increase the specificity and effectiveness of clinical diagnostic or therapeutic techniques.
A. Drug Targeting
It is desirable to increase the efficiency and specificity of administration of a therapeutic compound, drug or agent to the cells of the relevant tissues in a variety of pathological states. This is particularly important as relates to antibiotic, antimicrobial and antiviral compounds, drugs or agents. These compounds, drugs or agents typically have pleiotropic antibiotic, immunogenic, cytopathic and cytotoxic effects that damage or destroy uninfected cells as well as infected cells. In addition, certain compounds, drugs or agents are “activated” or chemically modified by an enzymatic or chemical activity specific for infected cells, in which activated form the compounds, drugs or agents are particularly toxic. Resistance to these types of compounds, drugs or agents can arise by attenuation, mutation or ablation of the chemical or enzymatic activity in the infected cell. Thus, an efficient delivery system which would enable the delivery of such compounds, drugs or agents, particularly said “activated” forms thereof, specifically to infected cells would increase the efficacy of treatment, overcome drug resistance, reduce the associated “side effects” of such drug treatments, and also serve to reduce morbidity and mortality associated with clinical administration of such compounds, drugs or agents.
Numerous methods for enhancing the cytotoxic activity and the specificity of antibiotic drug action have been proposed. One method, receptor targeting, involves linking the therapeutic agent to a ligand which has an affinity for a receptor expressed on the desired target cell surface. Using this approach, antibiotic, antimicrobial and antiviral compounds, drugs and agents are intended to adhere to the target cell following formation of a ligand-receptor complex on the cell surface. Entry into the cell could then follow as the result of internalization of ligand-receptor complexes. Following internalization, the antibiotic, antimicrobial and antiviral compounds, drugs and agents may then exert therapeutic effects directly on the cell.
The ligand-receptor approach is plagued by a number of biological limitations. Receptor-mediated uptake does not specifically target infected cells; all cells that happen to express the receptor take up the drug. A further limitation of the receptor targeting approach lies in the fact that there are only a finite number of receptors on the surface of target cells. It has been estimated that the maximum number of receptors on a cell is approximately one million (Darnell et al., 1990,
Molecular Cell Biology,
2d ed., W. H. Freeman: N.Y.). This estimate predicts that there may be a maximum one million drug-conjugated ligand-receptor complexes on any particular cell. Since not all of the ligand-receptor complexes may be internalized, and any given ligand-receptor system may express many-fold fewer receptors on any particular cell surface, the efficacy of intracellular drug delivery using this approach is uncertain. Other known intracellular ligand-receptor complexes (such as the steroid hormone receptor) express as few as ten thousand hormone molecules per cell, and thus are even less suitable for mediating cell-specific targeting of antibiotic, antibiotic or antiviral compounds, drugs and agents. Id. Finally, once the bound drug entered a cell, it would not be expected to be differentially released in infected cells.
Other methods of delivering therapeutic agents at concentrations higher than those achievable through the receptor targeting process include the use of lipid conjugates that have selective affinities for specific biological membranes. These methods have met with little success (see, for example, Remy et al., 1962,
J. Org. Chem.
27: 2491-2500; Mukhergee & Heidelberger, 1962,
Cancer Res.
22: 815-22; Brewster et al., 1985,
J. Pharm. Sci.
77: 981-985).
Liposomes have been used to attempt cell targeting
U.S. Pat. No. 5,223,263, issued Jun. 29, 1993 to Hostetler et al. disclose conjugates between antiviral nucleoside analogues and polar lipids.
U.S. Pat. No. 5,484,809, issued Jan. 16, 1996 to Hostetler et al. disclose taxol and taxol derivatives conjugated to phospholipids.
U.S. Pat. No. 5,580,571, issued Dec. 3, 1996 to Hostetler et al. disclose nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,744,461, issued Apr. 28, 1998 to Hostetler et al. disclose nucleoside analogues conjugated to phosphonoacetic acid lipid derivatives.
U.S. Pat. No. 5,744,592, issued Apr. 28, 1998 to Hostetler et al. disclose nucleoside analogues conjugated to phospholipids.
U.S. Pat. No. 5,756,116, issued May 26, 1998 to Hostetler et al. disclose nucleoside analogues conjugated to phospholipids.
International Patent Application Publication Number WO89/02733, published April 1989 to Vical disclose conjugates between antiviral nucleoside analogues and polar lipids.
European Patent Application Publication Number 0350287A2 to Vical disclose conjugates between antiviral nucleoside analogues and polar lipids.
International Patent Application Publication Number WO93/00910 to Vical disclose conjugates between
Meredith Michael J.
Pederson Richard L.
Yatvin Milton B.
Bennett Rachel M.
McDonell Boehnen Hulbert & Berghoff
Oregon Health and Science University
Page Thurman K.
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