Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Aftertreated polymer
Reexamination Certificate
2000-07-21
2002-10-22
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Aftertreated polymer
C424S078270, C424S486000, C424S181100, C424SDIG001
Reexamination Certificate
active
06468522
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to disulfide-linked conjugates of therapeutic agents containing at least one thioamide group with thiol-containing polymers, so as to provide a controlled release pharmaceutical composition for administration to animals for the prophylaxis or treatment of various conditions or diseases.
BACKGROUND OF THE INVENTION
Derivatives of polymers such as polyethylene glycol (PEG) containing thiol (—SH) groups may be used as a controlled release carrier for therapeutic agents with thiol groups, by administering the polymer to which the therapeutic agent is linked by a disulfide bridge. Reduction of the disulfide group by endogenous reducing agents results in the release of the therapeutic agent (Huang et al.[10]; Woghiren et al.[19]). Furthermore, the therapeutic agent linked to the polymer may be in an inactive, or prodrug form, which when released becomes active. The inclusion of various targeting agents which also have been conjugated to the same polymer to target the therapeutic agent to particular sites within the body or to enhance cellular uptake have been described.
Appended PEG chains may provide the favorable pharmacologic properties of protection of the underlying protein from immune surveillance and proteolytic enzymes, in addition to a lower rate of clearance from the bloodstream (Davis et al., 1981). Furthermore, based on the properties provided by the PEG portion of the conjugate (Davis et al., 1981), conjugates of therapeutic agents as prodrugs with polymers provides certain advantages such as reduction in possible toxicity, since biological activity of a large bolus of that drug would not appear immediately upon administration to the patient. Thus, the biological activity might be present at a relatively constant, therapeutic level in the bloodstream over an extended time period due to two opposing actions, the conversion of inactive prodrug to active drug and the clearance of active drug from the body.
While therapeutic agents which have a thiol group, or may be derivatized to have one without loss of activity, are suitable for the above process, numerous other compounds without such groups cannot be bound to thiol-containing polymers following standard procedures to produce a controlled release composition. This is particularly true for compounds with a thioamide group. It is toward the development of a controlled release delivery system for therapeutic agents with thioamide groups that the present application is directed.
The citation of any reference herein should not be construed as an admission that such reference is available as “Prior Art” to the instant application.
SUMMARY OF THE INVENTION
In its broadest aspect, the present invention is directed to a pharmaceutical composition which is a disulfide-linked conjugate between at least one therapeutic agent comprising prior to conjugation a thioamide moiety, and at least one polymer comprising prior to conjugation at least one thiol group. The polymeric portion of the polymer which comprises prior to conjugation at least one thiol group may be a homopolymer or a copolymer, and may be by way of non-limiting example, polyethylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, N-(2-hydroxypropyl)methacrylamide, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, polypropylene oxide, copolymers of ethylene/maleic anhydride copolymer, polylactide/polyglycolide copolymers, polyaminoacids, copolymer of polyethylene glycol and an amino acid, or polypropylene oxide/ethylene oxide copolymers. The polymer may also be a branched polymer or a dendrimer, i.e., a multi-branched polymer.
In a preferred embodiment, the polymer is a polyethylene glycol polymer (PEG), for example, of a molecular weight of from about 300 to about 30,000 Da, and preferably, from about 600 to about 5,000 Da. The PEG has functional groups or may be derivatized to bear functional groups to which a compound providing a free thiol group may be attached. The polymer comprising at least one thiol group may have from one to about ten thiol groups per polymer; preferably from one to about three thiol groups per polymer. The thiol group on the polymer may be sterically hindered.
The polymer comprising at least one thiol group may be prepared from, for example, &agr;,&ohgr;-diamino-polyethylene glycol and thiomalic acid; &agr;,&ohgr;-dihydroxy-polyethylene glycol and thiomalic acid; &agr;,&ohgr;-dicarboxy-polyethylene glycol and cysteamine; &agr;,&ohgr;-dicarboxy-poly(ethylene glycol) and 1-amino-2-methyl-2-propanethiol; or &agr;,&ohgr;-dicarboxy-PEG subunits and lysine, wherein carboxy groups on the lysines are derivatized to form thiol groups. The selection of the thiol compound providing the disulfide link to the thioamide-containing compounds and the covalent link to the polymer may be selected from a number of compounds containing a thiol group and a reactive group which may be attached to a polymer.
The therapeutic agent comprising prior to conjugation a thioamide moiety may be an agent that contains such a thioamide group in its active form, or a therapeutic agent which is modified to contain a thioamide group. For example, therapeutic agents with thioamide groups include UC781; R82150; HBY097; troviridine; S2720; UC38and 2′,3′-dideoxy-3′-fluoro-4-thiothymidine. However, the invention is not so limiting. Furthermore, other compounds with thioamide-like groups of similar reactivity to thioamide-containing compounds as described herein are likewise suitable as compositions as described herein. Such compounds include but are not limited to thioureas and thiourethans.
In a further aspect of the invention, the polymer may additionally have a functional group, which may be derivatized with a compound such as but not limited to a cell uptake enhancer or a tissue targeting agent.
The composition of the present invention may include a second therapeutic agent, or a second and a third therapeutic agent. This may be achieved by preparing polymers conjugated to each therapeutic agent separately, and then mixing these polymers to provide a composition with more than one therapeutic agent. In another embodiment, a single polymer to which at least two thiol groups is attached may be derivatized with a mixture of therapeutic agents. The relative amounts of the different agents conjugated to the polymer may be selected to correspond with the therapeutic effectiveness of each compound. The therapeutic agents conjugated to the polymer of the invention are released in vivo under reducing conditions. The in-vivo half life of the therapeutic agent in the composition may be increased compared with that of the therapeutic agent alone in vivo. Furthermore, the therapeutic agent may be therapeutically inactive or weakly active in the composition. The water solubility of the therapeutic agent may be increased in said composition compared to its inherent water solubility.
In another broad aspect, the invention is directed to a pharmaceutical composition which is a disulfide-linked conjugate between at least one therapeutic agent comprising prior to conjugation a thioamide moiety, a bifunctional compound comprising prior to conjugation at least one thiol group, and at least one polymer attached to one or more of the bifunctional compounds. The polymer may be a homopolymer or a copolymer, and may be by way of non-limiting example, poly(ethylene glycol), carboxymethylcellulose, dextran, polyvinyl alcohol, N-(2-hydroxypropyl)methacrylamide, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, polypropylene oxide, copolymers of ethylene/maleic anhydride copolymer, polylactide/polyglycolide copolymers, polyaminoacids, copolymer of polyethylene glycol and an amino acid, or polypropylene oxide/ethylene oxide copolymers. The polymer may also be a branched polymer or a dendrimer, i.e., a multi-branched polymer. For linkage to the bifunctional compound, the polymer may have one or more similar or different functional groups such as an amino or carboxy group, which may be cr
Qiu Bo
Stein Stanley
Zhang Guobao
Fubara Blessing
Klauber & Jackson
University of Medicine and Dentistry of New Jersey
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