Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-10-12
2002-05-14
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S051000, C514S078000
Reexamination Certificate
active
06387876
ABSTRACT:
BACKGROUND OF THE INVENTION
Field of the Invention
A major goal in the pharmacological arts has been the development of methods and compositions to facilitate the specific delivery of therapeutic and other agents to the appropriate cells and tissues that would benefit from such treatment, and the avoidance of the general physiological effects of the inappropriate delivery of such agents to other cells or tissues of the body. One common example of the need for such specificity is in the field of antiproliferative agent therapy for the treatment of skin diseases and disorders, in which the amount of a variety of antiproliferative agents to be safely administered topically or locally to a patient is limited by their systemic cytotoxic effects.
In addition, it is recognized in the medical arts that certain subcellular organelles are the sites of pharmacological action of certain drugs or are involved in the biological response to certain stimuli. Specific delivery of diagnostic or therapeutic compounds to such intracellular organelles is thus desirable to increase the specificity and effectiveness of such clinical diagnostic or therapeutic techniques. The invention provides polar lipid drug conjugates that target dermal, intradermal and infradermal structures in skin for delivery of therapeutic agents for the treatment of skin diseases and disorders.
Drug Targeting
It is desirable to increase the efficiency and specificity of administration of a therapeutic agent to the cells of the relevant tissues in a variety of pathological states. This is particularly important as relates to antiproliferative agents. Such agents typically have pleiotropic antibiotic and cytotoxic effects that damage or destroy uninvolved cells and tissues as well as cells and tissues comprising the pathological site. Thus, an efficient delivery system which would enable the delivery of such drugs specifically to the diseased or affected tissues cells would increase the efficacy of treatment and reduce the associated “side effects” of such drug treatments, and also serve to reduce morbidity and mortality associated with clinical administration of such drugs.
Numerous methods for enhancing the biological activity and the specificity of drug action have been proposed or attempted. To date, however, efficient or specific drug delivery remains to be predictably achieved.
An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality which could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release.
Medicinal salves and ointments for topical treatment purposes are known in the prior art for the treatment of a variety of pathological conditions. A multitude of pathological and other conditions have been treated by topical application of many classes of compounds in a variety of carriers, such as salves and ointments. However, carriers used in these conventional treatments are in no way specific for deposition of drugs, and suffer from non-specific deposition of the antiproliferative drug into both healthy and affected portions of the skin. Appropriate concentrations of topically-applied antiproliferative drugs, for example, are currently limited by the escape of the active agent(s) into the systemic circulation, with deleterious effects on other tissues and organs. An example of such a situation is the use of the drug methotrexate to treat psoriasis, where the amount of methotrexate that is capable of being topically applied is limited by hepato- and nephrotoxicity caused by systemic escape of the compound from the skin.
There remains a need in the art for an effective means for delivering biologically-active compounds, specifically drugs including antiproliferative drugs, to skin by topical administration of salves, ointments, and the like. Advantageous embodiments of such delivery means are formulated to efficiently deliver the biologically-active compound to the appropriate layer of the skin, while minimizing transit of the compound into the systemic circulation.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to an improved method for delivering biologically-active compounds, particularly drugs including preferably antiproliferative, antibiotic, antimycotic, antiviral and antineoplastic drugs, to cells comprising skin in animals in vivo and in vitro. This delivery system achieves specific delivery of such biologically-active compounds through conjugating the compounds with a polar lipid carrier. This invention has the specific advantage of facilitating the entry of such compounds into cells via a polar lipid carrier, achieving effective intracellular concentration of such compounds more efficiently and with more specificity than conventional delivery systems. The invention particularly provides pharmaceutical composition comprising the drug/polar lipid conjugates of the invention formulated with a medicinal ointment or salve for treatment of a variety of skin disorders.
The invention provides compositions of matter comprising a biologically-active compound covalently linked to a polar lipid carrier molecule. Preferred embodiments also comprise a spacer molecule having two linker functional groups, wherein the spacer has a first end and a second end and wherein the lipid is attached to the first end of the spacer through a first linker functional group and the biologically-active compound is attached to the second end of the spacer through a second linker functional group. In preferred embodiments, the biologically-active compound is a drug, most preferably an antiproliferative drug or agent, an antibiotic drug, an antiviral drug, an antineoplastic drug or a corticosteroid. Preferred polar lipids include but are not limited to acyl- and acylated carnitine, sphingosine, ceramide, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl ethanolamine, phosphatidyl inositol, phosphatidyl serine, cardiolipin and phosphatidic acid. Preferred biologically-active compounds include antineoplastic and antiproliferative agents such as methotrexate, corticosteroids, antimycotics, antibiotics and antiviral compounds. Pharmaceutical compositions comprising the drug/polar lipid conjugates of the invention formulated with a medicinal ointment or salve are also provided.
The invention also provides compositions of matter comprising a biologically-active compound covalently linked to a lipid, most preferably a polar lipid, carrier molecule via a spacer molecule wherein the spacer allows the biologically-active compound to act without being released at an intracellular site. In these embodiments of the invention, the first linker functional group attached to the first end of the spacer is characterized as “strong” and the second linker functional group attached to the second end of the spacer is characterized as “weak”, with reference to the propensity of the covalent bonds between each end of the spacer molecule to be broken.
In other embodiments of the compositions of matter of the invention, the spacer allows the facilitated hydrolytic release of the biologically-active compound at an intracellular site. Other embodiments of the spacer facilitate the enzymatic release of the biologically-active compound at an intracellular site. In particularly preferred embodiments, the spacer functional group is hydrolyzed by an enzymatic activity found in skin, preferably an esterase and most preferably an esterase having a differential expression and activity profile in different skin layers. In additional preferred embodiments, specific release of biologically-active compounds is achieved by enzymatic or chemical release of the biologically-active compound by intracellular cleavage of a cleavable linker moiety in cells infected by a pathogenic organism or otherwise expressing a disease state (for example, hyperplasia associated with a benign or malignant skin condition) via an enzymatic activity specific for such
Stowell Michael HB
Yatvin Milton B.
Davidson Davidson & Kappel LLC
Oregon Health and Science University
Weber Jon P.
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