Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-12-02
2003-01-21
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S103000, C536S105000, C536S106000, C536S124000
Reexamination Certificate
active
06509323
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to linear cyclodextrin copolymers and linear oxidized cyclodextrin copolymers. These copolymers, respectively, contain a cyclodextrin moiety, unoxidized or oxidized, as a monomer unit integrated into the copolymer backbone. The invention also relates methods of preparing linear cyclodextrin copolymers and linear oxidized cyclodextrin copolymers. Such cyclodextrin copolymers may be used as a delivery vehicle of various therapeutic agents.
2. Background of the Invention
Cyclodextrins are cyclic polysacchaides containing naturally occurring D(+)-glucopyranose units in an &agr;-(1,4) linkage. The most common cyclodextrins are alpha (&agr;)-cyclodextrins, beta (&bgr;)-cyclodextrins and gamma (&ggr;)-cyclodextrins which contain, respectively. six, seven or eight glucopyranose units. Structurally, the cyclic nature of a cyclodextrin forms a torus or donut-like shape having an inner apolar or hydrophobic cavity, the secondary hydroxyl groups situated on one side of the cyclodextrin torus and the primary hydroxyl groups situated on the other. Thus, using (&bgr;)-cyclodextrin as an example, a cyclodextrin is often represented schematically as follows:
The side on which the secondary hydroxyl groups are located has a wider diameter than the side on which the primary hydroxyl groups are located. The hydrophobic nature of the cyclodextrin inner cavity allows for the inclusion of a variety of compounds. (
Comprehensive Supramolecular Chemistry,
Volume 3, J. L. Atwood et al., eds., Pergamon Press (1996); T. Cserhati,
Analytical Biochemistry,
225:328-332 (1995); Husain et al.,
Applied Spectroscopy,
46:652-658 (1992); FR 2 665 169).
Cyclodextrins have been used as a delivery vehicle of various therapeutic compounds by forming inclusion complexes with various drugs that can fit into the hydrophobic cavity of the cyclodextrin or by forming non-covalent association complexes with other biologically active molecules such as oligonucleotides and derivatives thereof. For example, U.S. Pat. No. 4,727,064 describes pharmaceutical preparations consisting of a drug with substantially low water solubility and an amorphous, water-soluble cyclodextrin-based mixture. The drug forms an inclusion complex with the cyclodextrins of the mixture. In U.S. Pat. No. 5,691,316, a cyclodextrin cellular delivery system for oligonucleotides is described. In such a system, an oligonucleotide is noncovalently complexed with a cyclodextrin or, alternatively, the oligonucleotide may be covalently bound to adamantine which in turn is non-covalently associated with a cyclodextrin.
Various cyclodextrin containing polymers and methods of their preparation are also known in the art. (
Comprehensive Supramolecular Chemistry,
Volume 3, J. L. Atwood et al., eds., Pergamon Press (1996)). A process for producing a polymer containing immobilized cyclodextrin is described in U.S. Pat. No. 5,608,015. According to the process, a cyclodextrin derivative is reacted with either an acid halide monomer of an &agr;,&bgr;-unsaturated acid or derivative thereof or with an &agr;,&bgr;-unsaturated acid or derivative thereof having a terminal isocyanate group or a derivative thereof. The cyclodextrin derivative is obtained by reacting cyclodextrin with such compounds as carbonyl halides and acid anhydrides. The resulting polymer contains cyclodextrin units as side chains off a linear polymer main chain.
U.S. Pat. No. 5,276,088 describes a method of synthesizing cyclodextrin polymers by either reacting polyvinyl alcohol or cellulose or derivatives thereof with cyclodextrin derivatives or by copolymerization of a cyclodextrin derivative with vinyl acetate or methyl methacrylate. Again, the resulting cyclodextrin polymer contains a cyclodextrin moiety as a pendant moiety off the main chain of the polymer.
A biodegradable medicinal polymer assembly with supermolecular structure is described in WO 96/09073 A1. The assembly comprises a number of drug-carrying cyclic compounds prepared by binding a drug to an &agr;, &bgr;, or &ggr;-cyclodextrin and then stringing the drug/cyclodextrin compounds along a linear polymer with the biodegradable moieties bound to both ends of the polymer. Such an assembly is reportably capable of releasing a drug in response to a specific biodegradation occurring in a disease. These assemblies are commonly referred to as “necklace-type” cyclodextrin polymers.
However, there still exists a need in the art for linear cyclodextrin polymers in which the cyclodextrin moiety is part of the main chain and not a pendant moiety off the main chain and a method for their preparation.
SUMMARY OF THE INVENTION
This invention answers this need by providing a linear cyclodextrin copolymer. Such a linear cyclodextrin copolymer has a repeating unit of formula Ia, Ib, or a combination thereof:
The invention also provides methods of preparing a linear cyclodextrin copolymer. One method copolymerizes a cyclodextrin monomer precursor disubstituted with the same or different leaving group and a comonomer A precursor capable of displacing the leaving group. Another such method involves iodinating a cyclodextrin monomer precursor to form a diiodinated cyclodextrin monomer precursor and then copolymerizing the diiodinated cyclodextrin monomer precursor with a comonomer A precursor to produce the linear cyclodextrin copolymer. Another method involves iodinating a cyclodextrin monomer precursor to form a diiodinated cyclodextrin monomer precursor, aminating the diiodinated cyclodextrin monomer precursor to form a diaminated cyclodextrin monomer precursor and then copolymerizing the diaminated cyclodextrin monomer precursor with a comonomer A precursor to produce the linear cyclodextrin copolymer. Yet another method involves the reduction of a linear oxidized cyclodextrin copolymer to the linear cyclodextrin copolymer.
The invention further provides a linear oxidized cyclodextrin copolymer. A linear oxidized cyclodextrin copolymer is a linear cyclodextrin copolymer which contains at least one oxidized cyclodextrin moiety of formula VIa or VIb:
Each cyclodextrin copolymer of the invention may be oxidized so as to form a linear oxidized cyclodextrin copolymer having a repeating unit of formula VIa, VIb, or a combination thereof.
The invention also provides a method of preparing a linear oxidized cyclodextrin copolymer. One method involves oxidizing a linear cyclodextrin copolymer such that at least one cyclodextrin monomer is oxidized. Other methods involve copolymerizing an oxidized cyclodextrin monomer precurser with a comonomer A precursor.
The invention still further provides a linear cyclodextrin copolymer or linear oxidized cyclodextrin copolymer grafted onto a substrate and a method of their preparation. The invention also provides a linear cyclodextrin copolymer or linear oxidized cyclodextrin copolymer crosslinked to another polymer and a method of their preparation. A method of preparing crosslinked cyclodextrin polymers involves reacting a linear or linear oxidized cyclodextrin copolymer with a polymer in the presence of a crosslinking agent.
The invention provides a linear cyclodextrin copolymer or linear oxidized cyclodextrin copolymer having at least one ligand bound to the cyclodextrin copolymer. The ligand may be bound to either the cyclodextrin moiety or the comonomer A moiety of the copolymer.
The invention also provides a cyclodextrin composition containing at least one linear cyclodextrin copolymer of the invention and at least one linear oxidized cyclodextrin copolymer of the invention. The invention also provides therapeutic compositions containing a therapeutic agent and a linear cyclodextrin copolymer and/or a linear oxidized cyclodextrin copolymer of the invention. A method of treatment by administering a therapeutically effective amount of a therapeutic composition of the invention is also described.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1
depicts Transfection Studies with Plasmids Encoding Luciferase Reporter Gene:
FIG. 1A
, Transfection w
Davis Mark E.
Gonzalez Hector
Hwang Suzie (Sue Jean)
California Institute of Technology
Crane L. E.
Morgan & Lewis & Bockius, LLP
Richter Johann
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