Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – From carboxylic acid or derivative thereof
Reexamination Certificate
2000-05-03
2002-10-22
Hampton-Hightower, P. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
From carboxylic acid or derivative thereof
C528S355000
Reexamination Certificate
active
06469132
ABSTRACT:
BACKGROUND OF THE INVENTION
(a) Field of the Invention
The present invention relates to diblock copolymers and more particularly to polycaprolactone-b-polyethylene oxide (PCL-b-PEO) diblock copolymers used in micellar systems.
(b) Description of Prior Art
Colloidal drug delivery vehicles such as liposomes, microspheres, nanospheres and block copolymer micelles increase the therapeutic index and improve the selectivity of various potent drugs (Gregoriadis G., (1995)
TIBS,
13:527-537; Muller R. H., (1991)
Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization and In vivo Distribution,
CRC Press Inc., Florida; Kabanov A. V., Alakhov V. Y. (1997) “Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery” In
Amphiphilic Block Copolymers: Self
-
Assembly and Applications
edited by Alexamdris P., Lindman B., Elsevier, Netherlands; Kwon G. et al. (1997)
J. Controlled Release,
48:195-201; La S. B. et al. (1996)
Journal of Pharmaceutical Sciences,
85:85-90; Kataoka K. et al. (1992)
J. Control. Release,
24:119-132). These vehicles optimize the therapeutic efficacy of drugs by preventing their rapid elimination from the body, reducing their systemic toxicity, delaying their degradation and optimizing their metabolism (Muller R. H., (1991)
Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization and In vivo Distribution,
CRC Press Inc., Florida; Kabanov A. V., Alakhov V. Y. (1997) “Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery” In
Amphiphilic Block Copolymers: Self
-
Assembly and Applications
edited by Alexamdris P., Lindman B., Elsevier, Netherlands). In addition, they also provide for effective delivery of drugs to specific target sites (Muller R. H., (1991)
Colloidal Carriers for Controlled Drug Delivery and Targeting: Modification, Characterization and In vivo Distribution,
CRC Press Inc., Florida) and aid in overcoming both transport limitations and defense mechanisms associated with the multi-drug resistance phenotype.
It is known to use micellar systems formed from block copolymers in drug delivery (Kabanov A. V., Alakhov V. Y. (1997) “Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery” In
Amphiphilic Block Copolymers: Self
-
Assembly and Applications
edited by Alexamdris P., Lindman B., Elsevier, Netherlands; Kwon G. et al. (1997)
J. Controlled Release,
48:195-201; La S. B. et al. (1996)
Journal of Pharmaceutical Sciences,
85:85-90; Kataoka K. et al. (1992)
J. Control. Release,
24:119-132; Bader H., Ringsdorf H., Schmidt B., (1984)
Angewandte Makromolekulare Chemie,
123:457-485). Copolymers are formed from two or more monomeric units which, following polymerization, are arranged in a specific manner depending on the type of copolymer desired. Block copolymers consist of a block or sequence of one repeat unit coupled to a block of another repeat unit.
Micelles are formed from individual block copolymer molecules, each of which contains a hydrophobic block and a hydrophilic block. The amphiphilic nature of the block copolymers enables them to self-assemble to form nanosized aggregates of various morphologies in aqueous solution such that the hydrophobic blocks form the core of the micelle, which is surrounded by the hydrophilic blocks, which form the outer shell (Zhang L. Eisenberg A. (1995)
Science,
268:1728-1731; Zhang L, Yu K., Eisenberg A. (1996)
Science,
272:1777-1779). The inner core of the micelle creates a hydrophobic microenvironment for the non-polar drug, while the hydrophilic shell provides a stabilizing interface between the micelle core and the aqueous medium. The properties of the hydrophilic shell can be adjusted to both maximize biocompatibility and avoid reticuloendothelial system uptake.
The size of the micelles is usually between 10 nm and 100 nm (Kabanov A. V., Alakhov V. Y. (1997) “Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery” In
Amphiphilic Block Copolymers: Self
-
Assembly and Applications
edited by Alexamdris P., Lindman B., Elsevier, Netherlands). This size is small enough to allow access to small capillaries while avoiding reticuloendothelial system uptake (Kabanov A. V., Alakhov V. Y. (1997) “Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery” In
Amphiphilic Block Copolymers: Self
-
Assembly and Applications
edited by Alexamdris P., Lindman B., Elsevier, Netherlands). Micelles in this size range are also large enough to escape renal filtration, which increases their blood circulation time.
Existing block copolymer micelle systems are based on polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide triblock copolymer or on block copolymers which have a polypeptide or polylactic acid core-forming block and a polyethylene oxide block which forms the hydrophilic corona (Kabanov A. V., Alakhov V. Y. (1997) “Micelles of Amphiphilic Block Copolymers as Vehicles for Drug Delivery” In
Amphiphilic Block Copolymers: Self
-
Assembly and Applications
edited by Alexamdris P., Lindman B., Elsevier, Netherlands; Kwon G. et al. (1997)
J. Controlled Release,
48:195-201; La S. B. et al. (1996)
Journal of Pharmaceutical Sciences,
85:85-90; Kataoka K. et al. (1992)
J. Control. Release,
24:119-132).
Polycaprolactone and polyethylene oxide are used in a variety of biomedical applications (Elbert D. L., Hubbell J. A., (1996)
Annu. Rev. of Mater. Sci.,
26:365-394; Lee J. H. et al. (1995) Prog.
Polym. Sci.,
20:1043-1079). Polycaprolactone is a synthetic semicrystalline biodegradable polymer that, due to its biodegradability, has been tried both as a structural material in the production of medical devices such as implants, sutures, stents and prosthetics, and as a carrier for a variety of drugs. Polycaprolactone pastes have been developed as a drug delivery system for the anti-cancer agent taxol and the anti-neoplastic agent bis(maltolato)oxovanadium. Nanoparticle, nanocapsule and microparticle drug carriers made of polycaprolactone have been assayed for the ocular delivery of indomethacin. Polyethylene oxide is commonly used to impart blood compatibility to a material surface (Elbert D. L., Hubbell J. A., (1996)
Annu. Rev. of Mater. Sci.,
26:365-394; Lee J. H. et al. (1995) Prog.
Polym. Sci.,
20:1043-1079).
Triblocks of polycaprolactone-b-polyethylene oxide-b-polycaprolactone (PCL-b-PEO-b-PCL) have been used to form tablets. Matrices to be used as implants for drug delivery systems have been formed from PCL
6
-b-PEO
90
-b-PCL
6
.
The use of diblock copolymer micelles of methoxy poly(ethylene glycol) and &Sgr;-caprolactone as a drug delivery system is known.
The transport of a biologically active agent to a specific site requires a vehicle which is properly armed to confront the many obstacles or barriers it will face within the body. For this, the drug carrier must be tailor-made to suit a particular application. For example, drug accessibility to the central nervous system (CNS) is limited by the blood-brain barrier and major obstacles to delivering drugs to the CNS include the biocompatibility of the materials used and a control of the release kinetics of the drug delivery system used. There lacks an adequate means of long-term delivery to the CNS.
The FK506 drug, otherwise known as tacrolimus or Prograf™, has been effectively used to achieve immunosuppression in organ transplant recipients. FK506 binds to the immunophilin FKBP12 to form a complex which binds to and inhibits calcineurin; this, in turn, results in immunosuppression. FK506 promotes neuronal outgrowth in terms of the enhancement of neurite extension in PC 12 (rat pheochromocytoma) cell cultures and explant cultures of rat sensory ganglia. However, the use of FK506 for the treatment of neurodegenerative diseases is limited by its immunosuppressant activity.
At present, FK506 is administered either orally, in a capsule, or by injection as a sterile solution. A microemulsion formulation of FK506 has also been developed.
L-685,818 is a structural analogue to FK506. L-685,818 has reta
Allen Christine
Eisenberg Adi
Maysinger Dusica
Côté France
Hampton-Hightower P.
McGill University
Quinn Jennifer
Swabey Ogilvy Renault
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