Oregon Health & Science University

Enzrel Inc.

State of Oregon

Oradel Medical Ltd.

Milton Yatvin

Michael J Meredith

Michael H Stowell

Vincent S Gallicchio

Richard L Pederson

Guru V Betageri

Michael H B Stowell

Michael Stowell

Miroslav Malkovsky

John F Witte

Ronald W McClard

David W Parks

This invention provides novel methods and reagents for specifically delivering biologically active compounds to phagocytic mammalian cells. The invention also relates to specific uptake of such biologically active compounds by phagocytic cells and delivery of such compounds to specific sites intracellularly. The invention specifically relates to methods of facilitating the entry of antiviral and antimicrobial drugs and other agents into phagocytic cells and for targeting such compounds to specific organelles within the cell. The invention specifically provides compositions of matter and pharmaceutical embodiments of such compositions comprising conjugates of such antimicrobial drugs and agents covalently linked to particulate carriers generally termed microparticles. In particular embodiments, the antimicrobial drug is covalently linked to a microparticle via a cleavable linker moiety that is non-specifically cleaved in a phagocytic cell. In additional embodiments, the biologically-active compound is provided in an inactive, prodrug form that is activated by a chemical or enzymatic activity specific for cells infected by a microorganism, particularly a pathological or disease-causing microorganism. Thus, the invention provides cell targeting of drugs wherein the targeted drug is only activated in cells infected with a particular microorganism. Alternative embodiments of such specific drug delivery compositions also contain polar lipid carrier molecules effective in achieving intracellular organelle targeting in infected phagocytic mammalian cells. Particular embodiments of such conjugates comprise antimicrobial drugs covalently linked both to a microparticle via a cleavable linker molecule and to a polar lipid compound, to facilitate targeting of such drugs to particular subcellular organelles within the cell. Also provided are porous microparticles impregnated with antiviral and antimicrobial drugs and agents wherein the surface or outside extent of the microparticle is covered with a degradable coating that is degraded within a phagocytic mammalian cell. Also provided are nonporous microparticles coated with an antiviral or antimicrobial drug and further coated wherein the surface or outside extent of the microparticle is covered with a degradable coating that is degraded within a phagocytic mammalian cell. Methods of inhibiting, attenuating, arresting, combating and overcoming microbial infection of phagocytic mammalian cells in vivo and in vitro are also provided.

Nonporous microparticle-prodrug conjugates for treatment of infection

This invention comprises pharmaceutical compositions for administering a biologically active compound to an animal. Particularly provided are proliposomal compositions that are advantageously used to deliver biologically active compounds to the gastrointestinal tract after oral administration.

Liposome drug delivery

This invention comprises pharmaceutical compositions for administering a polycyclic, aromatic, antioxidant or anti-inflammatory compound to an animal. Particularly provided are proliposomal compositions that are advantageously used to deliver polycyclic, aromatic, antioxidant or anti-inflammatory compounds to the gastrointestinal tract after oral administration.

Liposome drug delivery of polycyclic, aromatic, antioxidant or anti-inflammatory compounds

This invention herein describes a method of facilitating the entry of drugs into cells and tissues at physiologically protected sites at pharmacokinetically useful levels and also a method of targeting drugs to physiologically protected sites in vivo. Also provided are drug conjugates with an amino acid or derivative thereof for facilitating such targeted drug delivery. The conjugates and methods of this invention provide an advance over other drug targeting methods known in the prior art, because the invention provides drug concentrations in such physiologically protected sites that can reach therapeutically-effective levels after administration of systemic levels much lower than are currently administered to achieve a therapeutic dose. This technology is appropriate for use with psychotropic, neurotropic, neurological, antibiotic, antibacterial, antimycotic, antiviral, antiproliferative or antineoplastic drugs, agents and conjugates, for rapid and efficient introduction of such agents across, e.g., the blood-brain barrier. Further, the invention provides means for retention and prolonged enzymatic release of such drugs, agents and conjugates comprising the conjugates of the invention, in the brain and central nervous system and other physiologically-protected sites.

Covalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites

Methods and reagents are provided for specifically targeting biologically active compounds such as antiviral and antimicrobial drugs, or prodrugs containing the biologically active compound to specific sites such as specific organelles in phagocytic mammalian cells. The biologically active compound or prodrug is linked to a microparticle with a linker that is non-specifically or specifically cleaved inside a phagocytic mammalian cell. Alternatively, the biologically active compound or prodrug is impregnated into a porous microparticle or coated on a nonporous microparticle, and then coated with a coating material that is non-specifically or specifically degraded inside a phagocytic mammalian cell. The prodrug contains the biologically active compound linked to a polar lipid such as ceramide with a specific linker such as a peptide that is specifically cleaved to activate the prodrug in a phagocytic mammalian cell infected with a microorganism. A microparticle linked antimicrobial drug or prodrug may be used for killing a microorganism infecting a phagocytic mammalian cell in vivo or in vitro.

Composition containing porous microparticle impregnated with biologically-active compound for treatment of infection

This invention provides compositions of matter, pharmaceutical compounds, methods of synthesizing such compounds and methods for using such compounds to treat animals infected with a pathogenic mycobacterium. The invention specifically provides compositions and pharmaceutical compositions thereof for the treatment of tuberculosis and other Mycobacterium-caused diseases.

Anti-mycobacterial compositions

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.

Covalent microparticle-drug conjugates for biological targeting

Anti-mycobacterial compounds

This invention herein describes a method of facilitating the entry of drugs into cells and tissues at physiologically protected sites at pharmicokinetically useful levels and also a method of targeting drugs to specific organelles within the cell. This polar lipid/drug conjugate targeting invention embodies an advance over other drug targeting methods known in the prior art, because the invention provides drug concentrations in such physiologically protected sites that can reach therapeutically-effective levels after administration of systemic levels much lower than are currently administered to achieve a therapeutic dose. This technology is appropriate for use with psychotropic, neurotropic and neurological drugs, agents and compounds, for rapid and efficient introduction of such agents across the blood-brain barrier. Further, the invention provides means for retention and prolonged enzymatic release of psychotropic, neurotropic and neurological drugs, agents and compounds comprising the conjugates of the invention, in the brain and central nervous system.

Covalent polar lipid conjugates with neurologically active compounds for targeting

This invention herein describes a method of facilitating the entry of drugs into cells and tissues at pharmokinetically useful levels and also a method of targeting drugs to specific organelles within the cell. This polar lipid/drug conjugate targeting invention embodies an advance over other drug targeting methods because through this method, intracellular drug concentrations may reach levels which are orders of magnitude higher than those achieved otherwise. Furthermore, it refines the drug delivery process by allowing therapeutic agents to be directed to certain intracellular structures. This technology is appropriate for use with antiproliferative, antibiotic, antimycotic, antiviral and antineoplastic drugs, in particular in combination with a multiplicity of other emollients and agents to make up topically-active substances such as salves, for rapid and efficient introduction of such agents through the epidermis for treatment of skin diseases and other disorders.

Growing community of inventors

Portland, OR, United States of America

Milton Yatvin