Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Polymers from only ethylenic monomers or processes of...
Reexamination Certificate
2002-08-09
2004-10-12
Pezzuto, Helen L. (Department: 1713)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Polymers from only ethylenic monomers or processes of...
C526S204000, C526S217000, C526S261000, C526S262000, C526S263000, C526S281000, C526S307200
Reexamination Certificate
active
06803438
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with a class of polymer precursors with narrow molecular weight distribution and the production therefrom of physiologically soluble polymer therapeutics, functionalised polymers, pharmaceutical compositions and materials, all with similar molecular weight characteristics and a narrow molecular weight distribution.
BACKGROUND OF THE INVENTION
Polymer Therapeutics (Duncan R: Polymer therapeutics for tumour specific delivery
Chem
&
Ind
1997, 7, 262-264) are developed for biomedical applications requiring physiologically soluble polymers and include biologically active polymers, polymer-drug conjugates, polymer-protein conjugates, and other covalent constructs of polymer with bioactive molecules. An exemplary class of a polymer-drug conjugate is derived from copolymers of hydroxypropyl methacrylamide (HPMA) which have been extensively studied for the conjugation of cytotoxic drugs for cancer chemotherapy (Duncan R: Drug-polymer conjugates: potential for improved chemotherapy.
Anti
-
Cancer Drugs,
1992, 3, 175-210. Putnam D, Kopecek J: Polymer conjugates with anticancer activity.
Adv.Polym.Sci.,
1995, 122, 55-123. Duncan R, Dimitrijevic S, Evagorou E: The role of polymer conjugates in the diagnosis and treatment of cancer.
STP Pharma,
1996, 6, 237-263). An HPMA copolymer conjugated to doxorubicin known as PK-1, is currently in Phase II evaluation in the UK. PK-1 displayed reduced toxicity compared to free doxorubicin in the Phase I studies (Vasey P, Twelves C, Kaye S, Wilson P, Morrison R, Duncan R, Thomson A, Hilditch T, Murray T, Burtles S, Cassidy J: Phase I clinical and pharmacokinetic study of PKI (HPMA copolymer doxorubicin): first member of a new class of chemotherapeutic agents: drug-polymer conjugates.
Clin. Cancer Res.,
1999, 5, 83-94). The maximum tolerated dose of PK-1 was 320 mg/m
2
which is 4-5 times higher than the usual clinical dose of free doxorubicin.
The polymers used to develop Polymer Therapeutics may also be separately developed for other biomedical applications where the polymer conjugate is developed (e.g. as a block copolymer) to form aggregates such as polymeric micelles and complexes (Kataoka K, Kwon G, Yokoyama M, Okano T. Sakurai Y: Block copolymer micelles as vehicles for drug delivery.
J. Cont.Rel.,
1993, 24, 119-132. Inoue T, Chen G, Nakamae K, Hoffman A: An AB block copolymer of oligo(methyl methacrylate) and poly(acrylic acid) for micellar delivery of hydrophobic drugs.
J Cont. Rel.,
1998, 51, 221-229. Kwon G, Okano T: Polymeric micelles as new drug carriers.
Adv. Drug Del. Rev.,
1996, 21, 107-116.). The polymers used to develop Polymer Therapeutics may also be separately developed for other biomedical applications that require the polymer be used as a material rather than as a physiologically soluble molecule. Thus, drug release matrices (including microspheres and nanoparticles), hydrogels (including injectable gels and viscious solutions) and hybrid systems (e.g. liposomes with conjugated poly(ethylene glycol) (PEG) on the outer surface) and devices (including rods, pellets, capsules, films, gels) can be fabricated for tissue or site specific drug delivery. Polymers are also clinically widely used as excipients in drug formulation. Within these three broad application areas: (1) physiologically soluble molecules, (2) materials and (3) excipients, biomedical polymers provide a broad technology platform for optimising the efficacy of a therapeutic bioactive agent.
Therapeutic bioactive agents which can be covalently conjugated to a polymer include a drug, peptide and protein. Such conjugation to a soluble, biocompatible polymer can result in improved efficacy of the therapeutic agent. Compared to the free, unconjugated bioactive agent, therapeutic polymeric conjugates can exhibit this improvement in efficacy for the following main reasons: (1) altered biodistribution, (2) prolonged circulation, (3) release of the bioactive in the proteolytic and acidic environment of the secondary lysosome after cellular uptake of the conjugate by pinocytosis and (4) more favourable physicochemical properties imparted to the drug due to the characteristics of large molecules (e.g. increased drug solubility in biological fluids) (Note references in Brocchini S and Duncan R: Polymer drug conjugates: drug release from pendent linkers. The Encyclopedia of Controlled Drug Delivery, Wiley, N.Y., 1999, 786-816.).
Additionally, the covalent conjugation of bioactive agents to a polymer can lead to improved efficacy that is derived from the multiple interactions of one or more of the conjugated bioactive agents with one or more biological targets. Such polyvalent interactions between multiple proteins and ligands are prevalent in biological systems (e.g. adhesion of influenza virus) and can involve interactions that occur at cell surfaces (e.g. receptors and receptor clusters) (Mammen M, Choi S, Whitesides GM: Polyvalent interactions in biological systems: Implications for design and use of multivalent ligands and inhibitors. Angew.
Chem. Int. Ed.
1998, 37, 2754-2794. Whitesides G, Tananbaum JB. Griffin J, Mammen M: Molecules presenting a multitude of active moieties. PCT Int. Appl. WO 9846270). Multiple simultaneous interactions of a polymer bioactive conjugate will have unique collective properties that differ from properties displayed by the separate, individual, unconjugated bioactive components of the conjugate interacting monovalently.
Additionally, an appropriately functionalised polymer can interact with mucosal membranes (e.g. in the gastrointestinal, respiratory or vaginal tracts) by polyvalent interactions. Such a property is valuable for prolonged and/or preferential localisation of a functionalised polymeric excipient used for site specific delivery or altering optimally the biodistribution of a bioactive agent.
Additionally polymer bioactive agent conjugates and/or aggregates can be designed to be stimuli responsive (Hoffman A, Stayton PS: Interactive molecular conjugates. U.S. Pat. No. 5,998,588), for example, to be for membranelytic after being taken up by a cell by endocytosis. These polymeric constructs must incorporate the membrane penetration features seen in natural macromolecules (toxins and transport proteins) and viruses. Cytosolic access has been shown to be rate limiting during polymer-mediated transfection (Kichler A, Mechtler A, Mechtler K, Behr JP, Wagner E: Influence of membrane-active peptides on lipospermine/DNA complex mediated gene transfer,
Bioconjugate Chem.,
1997, 8(2), 213-221.). Many of the cationic polymers (e.g. (poly-L-lysine) (PLL) and poly(ethyleneimine) (PEI), chitosan and cationic PAMAM dendrimers) that have been used for in vitro transfection studies are either cytotoxic (IC
50
values <50 &mgr;g/ml) or hepatotropic after i.v. injection. Such molecules are totally unsuitable for in vivo/clinical development. Alternative endosomolytic molecules have been proposed but are either too toxic (i.e. poly(ethylenimine) or potentially immunogenic (e.g. fusogenic peptides, reviewed (Plank C, Zauner W, Wagner E: Application of membrane-active peptides for drug and gene delivery across cellular membranes,
Advanced Drug Delivery Reviews,
1998, 34, 21-35. Wagner E, Effects of membrane-active agents in gene delivery,
J. Cont. Release,
1998, 53, 155-158.). Polymers, some with zwitterionic features, (Richardson S, Kolbe H, Duncan R: Potential of low molecular mass chitosan as a DNA delivery system: Biocompatibility, body distribution and ability to complex and protect DNA
Int. J. Pharm.,
1999 178, 231-243. Richardson S, Ferruti P, Duncan R: Poly(amidoamine)s as potential endosomolytic polymers: Evaluation of body distribution in normal and tumour baring animals,
J. Drug Targeting,
1999) have been shown to have considerable potential for membranelytic activity as a function of pH which could be capable of rupturingthe endosome to gain access to the ctyosolic environment of cells.
For the treatment of cancer there are marked improvements in therapeutic
Brocchini Stephen James
Godwin Antony
Pezzuto Helen L.
Polytherics Limited
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