Patent 6,455,073

This invention provides reagents and methods for specifically delivering antibiotic, antimicrobial and antiviral compounds, drugs and agents to phagocytic mammalian cells. The invention also relates to specific delivery to and uptake of such compounds by phagocytic cells. The invention specifically relates to reagents and methods for facilitating the entry of antibiotic, antimicrobial and antiviral compounds, drugs and agents into phagocytic cells. The invention specifically provides compositions of matter and pharmaceutical embodiments of such compositions comprising such antibiotic, antimicrobial or antiviral compounds, drugs and agents conjugated to, impregnated with or coated onto particulate carriers generally termed microparticles. In particular embodiments, the antibiotic, antimicrobial and antiviral compounds, drugs and agents are covalently linked to a microparticle via a specifically-degradable linker molecule which is the target of a microorganism-specific protein having enzymatic activity. Also provided are porous microparticles impregnated with antibiotic, antimicrobial or antiviral compounds, drugs and agents wherein the surface or outside extent of the microparticle is covered with a degradable coating that is specifically degraded within an infected phagocytic mammalian cell. Also provided are nonporous microparticles coated with antibiotic, antimicrobial or antiviral compounds, drugs and agents and further coated wherein the surface or outside extent of the microparticle is covered with a degradable coating that is specifically degraded within an infected phagocytic mammalian cell. Thus, the invention provides cell targeting of drugs wherein the targeted drug is only released in cells infected with a particular microorganism. Methods of inhibiting, attenuating, arresting, combating and overcoming microbial infection of phagocytic mammalian cells in vivo and in vitro, especially cells infected with tuberculosis-causing and other Mycobacterium species microorganisms, are also provided.

SUMMARY OF THE INVENTION

The present invention is directed to improved reagents and methods for delivering antibiotic, antimicrobial or antiviral compounds, drugs or agents to phagocytic cells in vivo and in vitro. In particular, the invention is directed towards delivery of antimicrobial compounds, drugs and agents specific for treatment of tuberculosis and other Mycobacterium-caused diseases in humans.

The invention provides drug delivery vehicles that are microparticles conjugated to, coated with, or impregnated with one or a multiplicity of antimicrobial compounds, drugs or agents specific for the treatment of tuberculosis and other Mycobacterium-caused diseases in animals, most preferably humans. In one preferred embodiment, the antibiotic, antimicrobial or antiviral compound, drug or agent is a prodrug of an activated form of the anti-tuberculosis drug isoniazid. In a second preferred embodiment, the antibiotic, antimicrobial or antiviral compound, drug or agent is a competitive inhibitor of long chain enol-acyl carrier protein reductase (termed InhA), an M. tuberculosis-encoded enzyme required for production of an essential bacterial cell wall component, mycolic acid. In a third preferred embodiment, the antibiotic, antimicrobial or antiviral compound, drug or agent is an irreversible inhibitor of InhA, otherwise termed a "suicide substrate" herein.

In one aspect, this delivery system achieves specific delivery of antibiotic, antimicrobial or antiviral compounds, drugs or agents to phagocytic cells through conjugating the antibiotic, antimicrobial or antiviral compound, drug or agent with a particular microparticle via a cleavable linker moiety that is specifically cleaved in an infected cell. Alternatively, specific delivery is achieved by impregnating the antibiotic, antimicrobial or antiviral compound, drug or agent into a porous microparticle, which is then coated with a specifically-degraded coating material that is specifically degraded in an infected cell. In yet another alternative embodiment, the delivery system comprises a nonporous microparticle wherein an antibiotic, antiviral and antimicrobial compound, drug or agent is prepared as a coating on the particle surface, and the particle is then further coated by a specifically-degradable coating material that is specifically degraded in an infected cell. In another embodiment, a porous or non-porous microparticle is impregnated or coated with a first antibiotic, antimicrobial or antiviral compound, drug or agent, then coated with a specifically-degradable or non-specifically degradable coating material, then further coated with a second coating of a antibiotic, antimicrobial or antiviral compound, drug or agent that can be the same or different than the first coating of antibiotic, antimicrobial or antiviral compound, drug or agent, then further coated with a second coating of a specifically-degradable or non-specifically degradable coating material that may be the same or different than the first specifically-degradable or non-specifically degradable coating, wherein the microparticle can comprise a multiplicity of such alternating coatings of antibiotic, antimicrobial or antiviral compounds, drugs and agents and specifically-degradable or non-specifically degradable coatings, provided that the final coating of the microparticle is a specifically-degradable coating that is specifically degraded only in a cell infected with a pathological or disease-causing microorganism, most preferably a Mycobacterium species. In each embodiment of the microparticles of the invention, specific release of the antibiotic, antimicrobial or antiviral compounds, drugs and agents from the microparticle is achieved by enzymatic or chemical release of the compound, drug or agent from the microparticle by cleavage of the cleavable linker moiety or the specifically-degradable coating material in infected phagocytic cells. Such microparticles can be produced to provide sequential, delayed, sustained or controlled release of the antibiotic, antimicrobial or antiviral compounds, drugs or agents of the invention.

In a first aspect, the specific delivery of antibiotic, antimicrobial or antiviral compounds, drugs or agents achieved by the present invention results from conjugating, impregnating or coating such compounds, drugs or agents to microparticles. Specific intracellular accumulation and facilitated cell entry is mediated by the phagocytic uptake of microparticle-conjugated antibiotic, antimicrobial or antiviral compounds, drugs or agents by such cells. Preferred embodiments of phagocytic cellular targets include phagocytic hematopoietic cells, preferably macrophages and phagocytic neutrophiles, most preferably macrophages, mononuclear cells and phagocytic neutrophiles from lung tissue.

Particularly preferred targets of the microparticle-conjugated antibiotic, antimicrobial or antiviral compounds, drugs or agents of the invention are phagocytic cells, including phagocytic hematopoietic cells, preferably macrophages and phagocytic neutrophiles and most preferably macrophages, mononuclear cells and phagocytic neutrophiles from lung tissue that are infected with M. tuberculosis, M. africanum, M. bovis or any other microorganism that causes tuberculosis in an animal, most preferably a human. Also preferred targets are cells infected with M. leprae, M. avium, M. intracellulare, M. scrofulaceum, M. kansasii, M. xenopi, M. marinum, M. ulcerans, M. fortuitum and M. chelonae. For such cells, the embodiments of the microparticle-conjugated antibiotic, antimicrobial or antiviral compounds, drugs or agents of the invention are comprised of cleavable linker moieties or specifically-degradable coatings whereby chemical or enzymatic cleavage of said linker moieties or coatings is specific for tuberculosis- or other disease-causing Mycobacterium-infected phagocytic cells. Such microparticles provide for infected cell-specific release of antibiotic, antimicrobial or antiviral compounds, drugs or agents, such as isoniazid, activated isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide, and competitive, non-competitive and "suicide substrate" InhA inhibitors or any other anti-tuberculosis or anti-Mycobacterium drug or agent, in such infected cells. It is understood that all phagocytic cells are expected to take up such microparticle-conjugated or coated antibiotic, antimicrobial or antiviral embodiments of the invention. However, it is an advantageous feature of the microparticle-conjugated antibiotic, antimicrobial or antiviral compounds of the invention that specific release of biologically-active forms of such antibiotic, antimicrobial or antiviral drugs or agents is dependent on the presence of the infectious microorganism in the phagocytic cell.

The invention provides compositions of matter and pharmaceutical compositions thereof comprising a porous microparticle into which is impregnated with an antibiotic, antimicrobial or antiviral compound, the impregnated porous microparticle being further coated with a specifically-degradable coating material. In this aspect of the invention, the specifically-degradable coating material is specifically degraded inside a phagocytic mammalian cell infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism, allowing the specific release of the antibiotic, antimicrobial or antiviral compound within the infected cell. In preferred embodiments, the specifically-degradable coating material is a substrate for a protein having an enzymatic activity found specifically in phagocytic cells infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism. In additional preferred embodiments, the specifically-degraded coating material is chemically cleaved under physiological conditions that are specific for phagocytic cells infected with a tuberculosis-causing microorganism. In preferred embodiments, the antibiotic, antimicrobial or antiviral compound, drug or agent impregnating the microparticle is an activated embodiment of said compound, drug or agent, as defined herein. In alternative embodiments, the microparticle is impregnated with a multiplicity of antibiotic, antimicrobial or antiviral compounds, drugs or agents.

In alternative aspects, the coating material is nonspecifically cleaved chemically or enzymatically inside a phagocytic cell, wherein the antibiotic, antimicrobial or antiviral compound, drug or agent is in a form that is only specifically activated in the cell when the cell is infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism (wherein said antibiotic, antimicrobial or antiviral compounds, drugs or agents are termed "prodrugs" as defined herein when provided in this form). In alternative embodiments, the microparticle is impregnated with a multiplicity of antibiotic, antimicrobial or antiviral compounds, drugs or agents or prodrug embodiments thereof. In preferred embodiments of the invention, the antibiotic compound is a specifically bactericidal or bacteriostatic against a microorganism that causes tuberculosis in an animal, most preferably a human, most preferably M. tuberculosis, M. africanum, M. bovis. Preferred antibiotic compounds used to impregnate such porous microparticles include activated isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide, and competitive, uncompetitive, non-competitive and "suicide substrate" InhA inhibitors or any other anti-tuberculosis or anti-Mycobacterium compound, drug or agent. Activated and prodrug embodiments of these or other antibiotic, antimicrobial or antiviral compounds, drugs or agents are also preferred, and activated embodiments of said drugs are particularly preferred.

In preferred embodiments, the antimycobacterial drugs used in the practice of the invention are "activated" embodiments (as defined herein) of competitive, uncompetitive, non-competitive and "suicide substrate" inhibitors of long chain enol-acyl carrier protein reductase (InhA), a Mycobacterium-specific enzyme necessary for the production of mycolic acid, which an essential component of the mycobacterial cell wall. Inhibition of this enzyme by isoniazid is the basis of current anti-tuberculosis treatment modalities, and resistance to isoniazid is the principle form of drug resistance exhibited by mycobacteria. The compounds of the invention overcome resistance by being "pre-activated", i.e., these compounds do not rely on activation in the mycobacterium-infected cell for activity (unlike compounds do not rely on activation in the mycobacterium-infected cell for activity (unlike isoniazid itself). Thus, it is expected that resistance is less likely to be developed against these drugs.

The invention also provides compositions of matter and pharmaceutical compositions thereof comprising a nonporous microparticle onto which is coated an antibiotic, antimicrobial or antiviral compound, the coated nonporous microparticle being further coated with a specifically-degradable coating material. In this aspect of the invention, the specifically-degradable coating material is specifically degraded inside a phagocytic mammalian cell infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism, allowing the specific release of the antibiotic, antimicrobial or antiviral compound within the infected cell. In preferred embodiments, the specifically-degradable coating material is a substrate for a protein having an enzymatic activity found specifically in phagocytic cells infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism. In additional preferred embodiments, the specifically-degraded coating material is chemically cleaved under physiological conditions that are specific for phagocytic cells infected with a tuberculosis-causing microorganism. In preferred embodiments, the antibiotic, antimicrobial or antiviral compound, drug or agent coating the microparticle is an activated embodiment of said compound, drug or agent, as defined herein. In alternative aspects, the coating material is nonspecifically cleaved chemically or enzymatically inside a phagocytic cell, wherein the antibiotic, antimicrobial or antiviral compound, drug or agent is in a form that is only specifically activated in the cell when the cell is infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism (wherein said antibiotic, antimicrobial or antiviral compound, drug or agent is termed a "prodrug" as defined herein when provided in this form). In alternative embodiments, the microparticle is coated with a multiplicity of antibiotic, antimicrobial or antiviral compounds, drugs or agents or prodrug embodiments thereof.

In preferred embodiments of the invention, the antibiotic compound is a specifically bactericidal or bacteriostatic against a microorganism that causes tuberculosis in an animal, most preferably a human, most preferably M. tuberculosis, M africanum, M bovis. Preferred antibiotic compounds used to coat such porous microparticles include activated isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide, and competitive, uncompetitive, non-competitive and "suicide substrate" InhA inhibitors or any other anti-tuberculosis or anti-Mycobacterium compound, drug or agent. Activated and prodrug embodiments of these or other antibiotic, antimicrobial or antiviral compounds, drugs or agents are also preferred, and activated embodiments are particularly preferred. Most preferred embodiments have the generic structure disclosed above

Additional embodiments of the compositions of matter and pharmaceutical compositions thereof comprising the porous and non-porous, impregnated or coated microparticles of the invention are provided wherein the porous or non-porous microparticle is impregnated or coated with a first antibiotic, antimicrobial or antiviral compound, drug or agent, then coated with a specifically-degradable or non-specifically degradable coating material, then further coated with a second coating of a antibiotic, antimicrobial or antiviral compound, drug or agent that can be the same or different than the first coating of antibiotic, antimicrobial or antiviral compound, drug or agent, then further coated with a second coating of a specifically-degradable or non-specifically degradable coating material that may be the same or different than the first specifically-degradable or non-specifically degradable coating, wherein the microparticle can comprise a multiplicity of such alternating coatings of antibiotic, antimicrobial or antiviral compounds, drugs or agents and specifically-degradable or non-specifically degradable coatings, provided that the final coating of the microparticle is a specifically-degradable coating that is specifically degraded in a cell infected with a pathological or disease-causing microorganism, most preferably a Mycobacterium species. Such microparticles can be produced to provide sequential, delayed, sustained or controlled release of the antibiotic, antimicrobial or antiviral compounds, drugs or agents of the invention. In each embodiment of the microparticles of the invention, specific release of the antibiotic, antimicrobial or antiviral compound, drug or agent from the microparticle is achieved by enzymatic or chemical release of the compound, drug or agent from the microparticle by cleavage of the specifically-degradable coating material in infected phagocytic cells. Antibiotic, antimicrobial and antiviral compounds, drugs or agents released by non-specific chemical or enzymatic degradation are advantageously provided in inactive, prodrug forms that are specifically activated in cells infected with pathological or disease-causing microorganism, most preferably a Mycobacterium species. In one alternative embodiment of this aspect of the invention, the "gatekeeper" for release of the antibiotic, antimicrobial or antiviral drug, compound or agent coating the microparticle is the ultimate, specifically-degraded coating material, which is only removed from the microparticle in a phagocytic cell infected with a pathological or disease-causing microorganism, most preferably a Mycobacterium species. In preferred embodiments, the antibiotic, antimicrobial or antiviral agent is provided in an activated form as defined herein. In said preferred embodiments, the "gatekeeper" specifically-degraded coating material prevents release of physiologically-significant amounts of the activated compound, drug or agent anywhere other than inside an infected phagocytic cell, most preferably a phagocytic cell infected with a pathological or disease-causing microorganism, most preferably a Mycobacterium species.

In an alternative embodiment, each antimicrobial, antibiotic or antiviral drug, compound or agent is provided in the form of a prodrug that is activated only in a phagocytic cell infected with said pathological or disease-causing microorganism, most preferably a Mycobacterium species. In this alternative embodiment, delivery of the antibacterial, antibiotic or antiviral drug, compound or agent in an active form to a phagocytic cell will only occur in such a cell that is infected with a pathological or disease-causing microorganism, most preferably a Mycobacterium species wherein both the specifically-degradable coating and the prodrug are degraded and activated, respectively, by an enzymatic or chemical reaction specific for the infected cell.

In these aspects of the invention, the antibiotic, antimicrobial or antiviral compound, drug or agent will be understood to dissolve from the surface of the microparticle upon enzymatic or chemical degradation of the organic coating material. Release of the antibiotic, antimicrobial or antiviral compound, drug or agent can be accomplished simply be mass action, i.e., whereby the compound dissolves from the surface of the nonporous microparticle into the surrounding cytoplasm within the cell, or leaches or is released from the porous microparticle.

The invention also provides compositions of matter and pharmaceutical compositions thereof comprising an antibiotic, antimicrobial or antiviral compound, drug or agent linked to a microparticle via a cleavable linker moiety. The cleavable linker moieties of the invention comprise two linker functional groups, wherein the cleavable linker moiety has a first end and a second end. The microparticle is attached to the first end of the cleavable linker moiety through a first linker functional group and the antibiotic, antimicrobial or antiviral compound, drug or agent is attached to the second end of the cleavable linker moiety through a second linker functional group. The cleavable linker moieties of the invention are specifically cleaved inside an infected phagocytic mammalian cell, for example, a phagocytic cell infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism. In preferred embodiments, the cleavable linker moieties of the invention comprise a substrate for a protein having an enzymatic activity found specifically in phagocytic cells infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism. In a particular embodiment of this aspect of the invention, the cleavable linker moiety is a peptide of formula (amino acid)_n, wherein n is an integer between 2 and 100, preferably wherein the peptide comprises a polymer of one or more amino acids. In additional preferred embodiments, the cleavable linker moieties of the invention are moieties that are chemically cleaved under physiological conditions that are specific for phagocytic cells infected with a tuberculosis-causing microorganism. In preferred embodiments, the antibiotic, antimicrobial or antiviral compound, drug or agent impregnating the microparticle is an activated embodiment of said compound, drug or agent, as defined herein. In alternative embodiments, the microparticles of the invention are provided comprising either a multiplicity of antimicrobial, antibiotic or antiviral compounds, drugs, or agents or a multiplicity of cleavable linker moieties, or both.

In alternative aspects, the cleavable linker moieties are nonspecifically cleaved chemically or enzymatically inside a phagocytic cell, wherein the antibiotic, antimicrobial or antiviral compound, drug or agent is in a form that is only specifically activated in the cell when the cell is infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism (wherein said antibiotic, antimicrobial or antiviral compounds, drugs or agents are termed "prodrugs" as defined herein when provided in this form).

In preferred embodiments of the invention, the antibiotic compound is a specifically bactericidal or bacteriostatic against a microorganism that causes tuberculosis in an animal, most preferably a human, most preferably M. tuberculosis, M. africanum, M. bovis. In preferred embodiments, the antibiotic compound is isoniazid, activated isoniazid, rifampin, streptomycin, ethambutol and pyrazinamide, and competitive, uncompetitive, non-competitive and "suicide substrate" InhA inhibitors or any other anti-tuberculosis or anti-Mycobacterium compound, drug or agent. Activated and prodrug embodiments of these or other antibiotic, antimicrobial or antiviral compounds, drugs or agents are also preferred.

The most preferred embodiments of the microparticles of the invention comprise prodrugs forms of activated isoniazid conjugates with NAD (termed isoniazid-NAD analogues, of INA, herein) that are inactivated by covalent modification of the activated drug to block binding of the drug to NAD-requiring enzymes, including InhA and mammalian cell, most preferably human cell-derived, NAD requiring enzymes. In the most preferred embodiments of this aspect of the invention, the inactivated prodrug form is specifically activated only in Mycobacterium-infected cells. In one aspect, such specific cleavage is due to a chemical linkage in the derivative that is labile within the infected cell due to conditions caused by or that result from infection of the cell with the mycobacteria. In another preferred aspect, such specific cleavage is due to an enzymatic activity which is produced either by the mycobacteria itself or by the cell as the result of infection with said mycobacteria, wherein the linkage is enzymatically cleaved by the enzymatic activity. In particularly preferred embodiments, the derivatizing group is a urea moiety that is specifically cleaved in Mycobacteria-infected cells by a mycobacteria-encoded urease.

The microparticle-drug conjugates of this invention have numerous advantages. First, the drug-microparticle conjugates are specifically taken up by phagocytic mammalian cells. Second, antibiotic, antimicrobial or antiviral compound, drugs or agents, most preferably anti-tuberculosis and anti-Mycobacterium compounds, drugs or agents comprising the drug-microparticle conjugates of the invention, are linked to the microparticle or covered by a coating comprising a specifically degradable moiety or material that is specifically cleaved upon entry into appropriate phagocytic cells, i.e., phagocytic cells infected with a tuberculosis-causing or other Mycobacterium-associated disease-causing microorganism. Third, the conjugates of the invention can be combined with other drug delivery approaches to further increase specificity and to take advantage of useful advances in the art. Fourth, the specificity of microparticle delivery to phagocytic cells and the specificity of conjugated antibiotic, antimicrobial or antiviral compound, drug or agent release in infected phagocytic cells permits the use and administration of efficacious antibiotic, antimicrobial or antiviral compounds, drugs or agents that are otherwise too toxic to be administered directly to an animal. Fifth, the specific delivery of the microparticles of the invention to phagocytic cells, and the specific release of antibiotic, antimicrobial or antiviral compounds, drugs or agents, and particularly activated embodiments thereof, permits direct administration of forms of said compounds, drugs and agents as they are activated by infectious organism-specific enzymatic or chemical modification, thereby providing a way of overcoming common forms of resistance to otherwise or previously efficacious antibiotic, antimicrobial or antiviral compounds, drugs or agents.

Thus, the invention also provides a method of killing a microorganism infecting a mammalian cell, preferably a phagocytic mammalian cell. This method comprises contacting an infected phagocytic mammalian cell with the compositions of matter or pharmaceutical compositions of the invention in vivo or in vitro. The invention also provides methods for treating microbial infections in an animal, most preferably a human wherein the infecting microbe is present inside a phagocytic cell in the human, the method comprising administering a therapeutically effective amount of the compositions of matter or pharmaceutical compositions of the invention to the human in a pharmaceutically acceptable carrier. Thus, the invention also provides pharmaceutical compositions comprising the compositions of matter of the invention in a pharmaceutically acceptable carrier. In most preferred embodiments, the infecting microorganism is a tuberculosis-causing microorganism such as M. tuberculosis, M. africanum or M. bovis.

Thus, in a first aspect the invention provides compositions of matter, pharmaceutical compositions and methods for targeting antibiotic, antimicrobial or antiviral compounds, drugs and agents to phagocytic cells. In a second aspect, the invention provides compositions of matter, pharmaceutical compositions and methods for the specific release of antibiotic, antimicrobial or antiviral compounds, drugs and agents inside phagocytic cells. The invention in yet a third aspect provides compositions of matter, pharmaceutical compositions and methods for intracellular delivery of targeted antibiotic, antimicrobial or antiviral compounds, drugs and agents to phagocytic cells. In each of these aspects is provided compositions of matter, pharmaceutical compositions and methods for introducing antibiotic, antimicrobial or antiviral compounds, drugs and agents into phagocytic mammalian cells wherein the unconjugated compound, drug or agent would not otherwise enter said phagocytic cell, the compound, drug or agent would not be specifically targeted to said phagocytic cell or the compound, drug or agent would have deleterious or toxic effects on non-infected cells. In this aspect is included the introduction of said compounds, drugs or agents in antibiotic, antimicrobial or antiviral embodiments that would not otherwise enter the cell, for example, as charged embodiments or salts, or wherein the compound, drug or agent is unstable or has a short half-life. In addition, the antibiotic, antimicrobial or antiviral compounds, drugs and agents useful in this invention are provided in activated forms in which they are toxic to normal cells, or which are activated by infectious agent-specific enzymatic or chemical modifications, but which are conjugated to or coated within a microparticle of the invention and released only in phagocytic cells infected with a tuberculosis or other Mycobacterium-associated disease-causing microorganism. In yet another aspect is provided compositions of matter, pharmaceutical compositions and methods for the specific coordinated targeting of more than one antibiotic, antimicrobial or antiviral compound to infected phagocytic mammalian cells. In another aspect, the invention provides compositions of matter, pharmaceutical compositions and methods for the introduction and specific release of antibiotic, antimicrobial or antiviral compounds, drugs or agents, preferably anti-tuberculosis and anti-Mycobacterium compounds, drugs or agents, and other compounds into cells infected by a tuberculosis-causing or other Mycobacterium-associated disease-causing pathological microorganism. In a final aspect, the invention provides compositions of matter, pharmaceutical compositions and methods for sequential, delayed, sustained or controlled intracellular release of antibiotic, antimicrobial, or antiviral compounds, drugs or agents impregnated within a coated, porous microparticle, or coated onto a nonporous microparticle, wherein the degradation of either a layer of the coating or the microparticle or both provides said sequential, delayed, sustained or controlled intracellular release of the antibiotic, antimicrobial or antiviral compounds, drugs or agents of the invention.

Claim 1 of 12 Claims

What is claimed is:

1. A composition of matter comprising an activated antibiotic, antimicrobial or antiviral compound, a nonporous microparticle, and a coating material, wherein the antibiotic, antimicrobial or antiviral activity of the compound requires modification in vivo by an enzymatic or chemical activity specific for infected cells and resistance to said compound is mediated by inactivation of said enzymatic or chemical activity, whereby the compound is activated in vitro by chemically modifying the compound to overcome resistance thereto, wherein the nonporous microparticle is coated with the compound and said coated microparticle is further coated with the coating material, and wherein the coating material is specifically degraded inside a phagocytic mammalian cell infected with a microorganism to allow release of the compound within the infected cell.

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