Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2002-07-19
2004-12-07
Hightower, P. Hampton (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S322000, C528S327000, C528S328000, C528S341000, C528S342000, C528S345000, C528S354000, C528S360000, C528S363000, C528S364000, C528S373000, C525S054100, C525S054200, C525S408000, C525S411000, C525S415000, C424S078080, C424S078170, C424S078190, C424S078220, C424S484000, C424S486000
Reexamination Certificate
active
06828412
ABSTRACT:
The present invention is concerned with degradable polymers and the production of materials therefrom. These polymers and materials find utility in polymer therapeutics and pharmaceutical compositions for the treatment of disease.
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 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 can form aggregates such as polymeric micelles and complexes. Another important set of medical applications include those 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 an active therapeutic drug.
Covalent conjugation of a drug to a soluble, biocompatible polymer can result in improved efficacy of the drug. Compared to the free, unconjugated drug, polymer-drug conjugates exhibit this improvement for the following main reasons: (1) altered biodistribution, (2) prolonged circulation, (3) release of the drug 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).
For the treatment of cancer there are marked improvements in therapeutic efficacy and site specific passive capture through the enhanced permeability and retention (EPR) effect. The EPR effect results from enhanced permeability of macromolecules or small particles within the tumour neovasculature due to leakiness of its discontinuous endothelium. In addition to the tumour angiogenesis (hypervasculature) and irregular and incompleteness of vascular networks, the attendant lack of lymphatic drainage promotes accumulation of macromolecules that extravasate. This effect is observed in many solid tumours for macromolecular agents and lipids. The enhanced vascular permeability will support the great demand of nutrients and oxygen for the rapid growth of the tumour. Unless specifically addressed for tumour cell uptake by receptor-medicated endocytosis, polymers entering the intratumoural environment are taken up relatively slowly by fluid-phase pinocytosis.
An increasing number of physiologically soluble polymers have been used as macromolecular partners for the conjugation of bioactive molecules. Many polymers have the disadvantage of being non-degradable in the polymer mainchain. For example, PEG (Monfardini C, Veronese F: Stabilization of substances in circulation.
Bioconjugate Chem
., 1998, 9, 418-450. Zalipsky S: Chemistry of polyethylene glycol conjugates with biologically active molecules.
Adv. Drug Delivery Rev
., 1995, 16, 157-182. Delgado C, Francis G, Fisher D: The uses and properties of PEG-liked proteins.
Crit. Rev. Ther. Drug Carrier Syst
., 1992, 9, 249-304. Nucci M L, Shorr D, Abuchowski A: The therapeutic values of poly(ethylene glycol)-modified proteins.
Adv. Drug Delivery Rev
., 1991, 6, 133-151. Nathan A, Zalipsky S, Ertel S, Agathos S, Yarmush M, Kohn J: Copolymers of lysine and polyethylene glycol: A new family of functionalized drug carriers.
Bioconjugate Chem
., 1993, 4, 54-62) and HPMA (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) copolymers have been extensively studied for conjugation. PEG is also generally used in the pharmaceutical industry as a formulation excipient. These hydrophilic polymers are soluble in physiological media, but their main disadvantage is that the polymer mainchain does not degrade in vivo. Thus it is not possible to prohibit accumulation of these polymers in the body. Only polymers with a molecular weight lower than the renal threshold can be used for systemic administration. It is imperative that for the systemic use of non-degradable polymers such as HPMA and PEG only molecules of a molecular weight which are readily cleared be administered or else long-term deleterious accumulation in healthy tissue will invariably result (Seymour L, Duncan R, Strohalm J, Kopecek J: Effect of molecular weight (Mw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distributions and rate of excretion after subcutaneous, intraperitoneal and intravenous administration to rats.
J. Biomed. Mater. Res
., 1987, 21, 1341-1358. Schneider P, Korolenko T, Busch U: A review of drug-induced lysosomal disorders of the liver in man and laboratory animals.
Microscopy Res. Tech
., 1997, 36, 253-275. Hall C, Hall O: Experimental hypertension elicited by injections of methyl cellulose.
Experientia
, 1961, 17, 544-454. Hall C, Hall O: Macromolecular hypertension: hypertensive cardiovascular disease from subcutaneously administered polyvinyl alcohol.
Experientia
, 1962, 18, 38-40).
Although some natural polymers such as polysaccharides have the advantage of being degradable in vivo, e.g. dextran, they typically lack a strict structural uniformity and have the propensity upon chemical modification (i.e. conjugation of a bioactive molecule) to become immunogenic or non-degradable (Vercauteren J, Bruneel D, Schacht E, Duncan R: Effect of the chemical modification of dextran on the degradation by dextranases.
J. Bio. Comp. Polymers
, 1990, 5, 4-15. Shalaby W, Park K: Chemical modification of proteins and polysaccharides and its effect on enzyme-catalysed degradation. In: Shalaby S, ed. Biomedical Polymers. Designed-to-degrade systems. New York: Hanser Publishers, 1994). Other polysaccharides which have been investigated for biomedical conjugation applications include chitosan (Ohya Y, Huang T, Ouchi T, Hasegawa K, Tamura J, Kadowaki K, Matsumoto T, Suzuki S: a-1,4-Polygalactosamine immobilised 5-fluorouracils through hexamethylene spacer groups via urea bonds.
J. Cont. Rel
., 19
Brocchini Stephen James
Clochard Marie-Claude Dubois
Dickstein Shapiro Morin & Oshinsky LLP.
Hampton Hightower P.
School of Pharmacy, University of London
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