Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-12-18
2003-08-26
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S025330, C536S025340, C536S025500, C536S025600, C536S026260, C536S026600, C536S026700, C536S026710, C536S026800, C514S045000, C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000, C435S006120, C435S091100
Reexamination Certificate
active
06610841
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to the treatment of diseases using nucleotide-based prodrugs. More particularly, the present invention relates to nucleotide-based prodrugs and their drug-delivery applications. The nucleotide-based prodrugs of the present invention comprise a drug component covalently attached via junctional ester bond(s) to one or more nucleotide components. Release and activation of the drug component of a nucleotide-based prodrug arises from hydrolysis of the junctional ester bond joining the nucleotide component to the drug component. The active drug component may be a nucleoside analog, a nucleic acid ligand, or a non-nucleoside drug. The nucleotide component provides a means of targeting and/or anchoring the nucleotide-based prodrug to the desired tissue compartment and/or a mechanism of sustained release of the active drug, thereby providing for a more effective drug delivery system with reduced toxicity. The targeting and/or anchoring of the nucleotide-based prodrugs to the desired tissue can be achieved through several methods, including employing a nucleic acid ligand as the nucleotide component, and/or by incorporating photocrosslinkable bases into the nucleotide component, and/or by covalently bonding the nucleotide component to a macromolecular support. The invention further includes lipid constructs comprising a nucleotide-based prodrug.
BACKGROUND OF THE INVENTION
Current Methods of Sustained Release Drug Delivery
Many controlled release, tissue-targeted drug delivery systems have been developed and investigated in the laboratory, but few have reached the pharmaceutical marketplace. For reviews of this area of drug delivery research. (See Tomlinson, E. (1987)
Adv. Drug Delivery Rev.
1:87-198 and Chein Y. W. 1992. Novel Drug Delivery Systems, New York, N.Y. Marcel Dekker, Inc. Many of the obstacles confronting scientists in this area of drug delivery research are illustrated by the examples provided below.
Insoluble Drug Depots
The most widely used slow release drug depots are contraceptive progestins implanted subcutaneously (e.g., Depo-Provera®). Some progestin formulations are encapsulated in permeable silicone chambers (e.g., Norplant®). Corticosteroid depots are also available (e.g., Depo-Medrol®). The deposition and sustained release of these drugs relies upon their relatively low solubilities in aqueous fluids. The steroids slowly dissolve at the surface of the implant, and diffuse into surrounding interstitium and capillaries. This sustained release technology is based entirely upon the drugs' physicochemical properties, the geometry of the implant and its location in the tissue. The contraceptive's target tissues (hypothalamus and adenohypophysis) are far removed from the depot, but low systemic drug levels are effective. The situation is different in the case of corticosteroid suspensions, which are used to treat locally inflamed tissues. A suspension of insoluble corticosteroid (DepoMedrol®) is injected directly into the tissue, so the targeting of the drug is crude. The drug's absorption into local capillaries can lead to relatively high systemic levels and toxicity. Thus, only a few DepoMedrol® injections can be given to a patient each year.
Polymers Impregnated with Drugs
Drugs generally diffuse relatively rapidly from hydrated polymers. More avid drug sequestration is required to prolong drug release, but solving this engineering problem is very difficult. Each drug must be empirically matched to a polymer with a specific set of physicochemical properties. The polymer must not induce a macrophage-mediated foreign body reaction, and it must be non-immunogenic and chemically inert. Despite these constraints, a few products have been created (Dang, et al. (1996)
Pharm. Res.
13:683-691). Gliadel® wafers (Guilford Pharmaceuticals) are used to deliver the alkylating agent bichloronitrosourea (BCNU) to brain tumors. After surgical resection of aggressive glioblastoma multiforme tumors, wafers are inserted into the cavity as a local adjuvant chemotherapy. Gliadel® wafers are comprised of a proprietary polymer impregnated with BCNU, which is released locally into peritumoral cerebral tissues for months after surgery. This method of dosing is crude, and unfortunately, Gliadel® doesn't prolong survival more than a few months.
Hydrogels and other Polymers that Retard Drug Diffusion
Another strategy to localize drugs is to inject tissues with a polymer, such as a gel, soaked in a solution of the drug (Samuelov Y. et al. (1979)
J. Pharm. Sci.
68:325-329; Graham, N. B. (1984)
Biomaterials
5:27-36; Roorda, W. E. et al. (1986)
Pharm Week [Sci]
8:165-189; Kaleta-Michaels, S. J. et al. (1994)
Proc. Ann. Meet. Am. Assoc. Cancer Res.
35:A2473; Hnatyszyn, H. J. (1994)
PDA J Pharm Sci Technol.
48:247-254; Nunes, G. L. et al. (1994)
J. Am. Coll. Cardiol.
23:1578-83). Release of the drug into the surrounding tissue is limited by the viscosity of the gel, which isolates the drug from the interstitial fluid and local capillaries and thus retards diffusion. The rate of drug diffusion out of the gel is largely determined by the physical and biological properties of the gel, for example its hydrophobicity, tensile strength and biodegradability (Park, K. et al. (1993)
Biodegradable Hydrogels for Drug Deliver.
Technomic Publishing Co., Inc. Lancaster, Pa.). Several biological and non-biological gels are in various stages of development, including chimeric recombinant elastin-silk protein (Protein Polymers, Inc), collagen (Matrix Pharmaceuticals, Inc), poly-lactic acid (PLA), poly-glycolic acid, poly(&egr;-caprolactone), poly(&bgr;-hydroxybutyrate), poly(&bgr;-hydroxyvalerate), polydioxanone, poly(ethylene terephthalate), poly(malic acid), poly(tartronic acid), poly(ortho esters), polyanhydrides, polycyanoacrylates, poly(phosphoesters), polyphosphazenes, hyaluronidate, polysulfones, polyacrylamides, polymethacrylate, CarboPol and hydroxyapaptite (Park, K. et al. (1993) In most cases, the rate of drug release can be controlled by altering the gel's water swelling capacity, tensile strength and rate of biodegradation—properties that can be adjusted by various chemical manipulations.
Biodegradable Hydrogels with Pendant Chains Covalently Coupled to Drugs
Controlled release from the above mentioned drug delivery systems is achieved by manipulating the physicochemical and biological properties of a polymer that is separate from the pharmacologically active drug molecule. Small drug molecules diffuse relatively rapidly through such hydrated polymers, thereby markedly limiting the duration of drug release. To address this shortcoming, investigators have sought to produce controlled release bioactive polymer systems comprised of biodegradable polymers covalently coupled to pharmacologically active drug molecules (reviewed in Bioactive Polymeric Systems (1985) Gebelein, G. C. and Carraher, C. E. Editors. Plenum Press, New York, N.Y.). Bioactive polymers have been synthesized by coupling pharmacologically active drugs to pendant chains via amide bonds or via more labile carbonyl ester linkages. Activation and release of the drugs requires hydrolysis of the amide or carbonyl ester bonds, and such hydrolytic reactions must occur at a rate that is slower than the rate of degradation of the biocompatible macromolecular support (i.e., the “backbone”). Drugs have been attached to a variety of polymeric “backbones”, including starch microparticles (Laakso, T. et al. (1987)
J. Pharm. Sci.
76: 134-140; Stjarnkvist, P. et al. (1991)
J. Pharm. Sci.
80:436-440); poly(2-hydroxypropyl) methacrylamide copolymers (Duncan, R. et al. (1990)
Biochem. Biophys. Res. Comm.
94: 284-290); poly-D-lysine (Shen, W-C et al. (1985)
J. Biol. Chem.
260:10905-10908); and poly-N-(3-hydroxypropyl)-L-glutamine/leucine copolymers (Negishi, N. et al. (1987)
Pharmaceutical Res.
4:305-310). Bioactive polymers wherein amide bonds link the drug to the pendant chain hydrolyze very slowly and they are relatively stable in serum an
Gilead Sciences, Inc.
Swanson & Bratschun L.L.C.
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