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(12) United States Patent (10) Patent No.: US 8,026,285 B2 Bezwada (45) Date of Patent: Sep

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US008O26285B2 (12) United States Patent (10) Patent No.: US 8,026,285 B2 BeZWada (45) Date of Patent: Sep. 27, 2011 (54) CONTROL RELEASE OF BIOLOGICALLY 6,955,827 B2 10/2005 Barabolak ACTIVE COMPOUNDS FROM 2002/0028229 A1 3/2002 Lezdey 2002fO169275 A1 11/2002 Matsuda MULT-ARMED OLGOMERS 2003/O158598 A1 8, 2003 Ashton et al. 2003/0216307 A1 11/2003 Kohn (75) Inventor: Rao S. Bezwada, Hillsborough, NJ (US) 2003/0232091 A1 12/2003 Shefer 2004/0096476 A1 5, 2004 Uhrich (73) Assignee: Bezwada Biomedical, LLC, 2004/01 17007 A1 6/2004 Whitbourne 2004/O185250 A1 9, 2004 John Hillsborough, NJ (US) 2005/0048121 A1 3, 2005 East 2005/OO74493 A1 4/2005 Mehta (*) Notice: Subject to any disclaimer, the term of this 2005/OO953OO A1 5/2005 Wynn patent is extended or adjusted under 35 2005, 0112171 A1 5/2005 Tang U.S.C. 154(b) by 423 days. 2005/O152958 A1 7/2005 Cordes 2005/0238689 A1 10/2005 Carpenter 2006, OO13851 A1 1/2006 Giroux (21) Appl. No.: 12/203,761 2006/0091034 A1 5, 2006 Scalzo 2006/0172983 A1 8, 2006 Bezwada (22) Filed: Sep. 3, 2008 2006,0188547 A1 8, 2006 Bezwada 2007,025 1831 A1 11/2007 Kaczur (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2009/0076174 A1 Mar. 19, 2009 EP OO99.177 1, 1984 EP 146.0089 9, 2004 Related U.S. Application Data WO WO9638528 12/1996 WO WO 2004/008101 1, 2004 (60) Provisional application No. 60/969,787, filed on Sep. WO WO 2006/052790 5, 2006 4, 2007. OTHER PUBLICATIONS (51) Int. Cl. J. Org. Chem, 1959, 24, 523-526. A6 IK 47/48 (2006.01) Gutowska et al. J. Biomater, Res., 29, 811-21 (1995). Hoffman, J. Controlled Release, 6, 297-305 (1987). (52) U.S. Cl. ..................................... 514/772.3; 424/426 Mikos et al. Biomaterials, 14, 323-329 (1993). (58) Field of Classification Search ........................ None Shugens et al. J. Biomed. Mater. Res., 30, 449-462 (1996). Bulletin of the Material Research Society, Special Issue on Tissue See application file for complete search history. Engineering (Guest Editor: Joachim Kohn), 21 (11), 22-26 (1996). Remington's Pharmaceutical Sciences, 18' ed., Mack Publishing (56) References Cited Company, Eason, PA, 1990, p. 1445. van Dijk-Wolthuis, W.N.W.; Hoogeboom, J.; van Steenbergen, M.; U.S. PATENT DOCUMENTS Tsang, S.; and Hennick, W. "Degradation and Release Behavior of Dextran-Based Hydrogels', Macromolecules, 30; (1997) 4639 3,903,007 A 9, 1975 Ernst 4645. 3,987,797 A 10/1976 Stephenson van Dijk-Wolthuis, W.N.E., Tsang, S.; Kettenes-van den Bosch, J.; 4,020, 100 A 4, 1977 Evans and Hennick, W. "A new class of polymerizable dextrans with 4,024,871 A 5/1977 Stephenson hydrolysable groups: hydroxyethyl methacrylated dextran with and 4,130,639 A 12/1978 Shalaby without oligolactate spacer', Polymer, 38 (25); (1997) 6235-6242. 4,532,928 A 8, 1985 Bezwada Kurisawa et al. Macromol. Chem. Phys. 199,705-709 (1998). 4,605,730 A 8/1986 Shalaby Heller, J.; Helwing, R.F.; Baker, R.W.; and Tuttle, M.E. "Controlled 4,653,497 A 3, 1987 Bezwada release of water-soluble macromolecules from bioerodible 4,689,424 A 8/1987 Shalaby hydrogels' Biomaterials, 4; (1983) 262-266. 4,829,099 A 5, 1989 Fuller Brondsted (Brondsted, H.; and Kopccek, J. “Hydrogels for site 4,886,870 A 12/1989 D'Amore specific oral drug deliver: Synthesis and characterization' Biomateri 5,082,925 A 1/1992 Shalaby als, 12; (1991) 584-592. 5,378,540 A 1, 1995 Olson Ulbrich, K.; Subr, V.; Seymour, L.W.; and Duncan, R. “Novel biode 5,521,431 A 5, 1996 Tahara gradable hydrogels prepared using the divinylic crosslinking agent 5,759,830 A 6, 1998 Vacanti N, O-dimethacryloylhydroxylamine 1. Synthesis and characteriza 5,801,033. A 9, 1998 Hubbell tion of rates of gel degradation, and rate of release of model drugs, in 5,834,274 A 11, 1998 Hubbell vitro and in vivo” Journal of Controlled Release, 24; (1993) 181-190. 5,834,513 A 11/1998 Ptchelintsev 5,843,743 A 12, 1998 Hubbell Primary Examiner — Robert A Wax 5,895,150 A 4, 1999 Watabe Assistant Examiner — Danah Al-Awadi 5,932,229 A 8, 1999 Ptchelintsev (74) Attorney, Agent, or Firm — Vance Intellectual Property, 5,951,997 A 9, 1999 Bezwada PC 6,045,813 A 4/2000 Ferguson 6,083,208 A 7, 2000 Modak (57) ABSTRACT 6,106,505 A 8, 2000 Modak The present invention relates to the discovery of biodegrad 6,207,139 B1 3, 2001 Lee 6,224,579 B1 5, 2001 Modak able multi-armed oligomers wherein the end groups of these 6,468,519 B1 10/2002 Uhrich oligomers have been functionalized with biologically active 6,596,657 B1 7/2003 Shalaby molecules. The resultant multi-armed oligomers end-func 6,689,350 B2 2/2004 Uhrich tionalized with biologically active molecules have a control 6,773,721 B1 8/2004 Wong lable degradation profile. The hydrolytic degradation of oli 6,780,799 B2 8/2004 Shalaby gomers of the present invention releases the biologically 6,861,068 B2 3/2005 Ng active compound as such with no change in native chemical 6,869,615 B2 3, 2005 Chen Structure. 6,887,974 B2 5, 2005 Pathak 6,890,561 B1 5, 2005 Blatt 38 Claims, No Drawings US 8,026,285 B2 1. 2 CONTROL RELEASE OF BIOLOGICALLY DETAILED DESCRIPTION OF THE PRESENT ACTIVE COMPOUNDS FROM INVENTION MULT-ARMED OLIGOMERS The present invention relates to the discovery of biodegrad CROSS REFERENCE TO RELATED 5 able multi-armed (two armed, three armed, four armed, six APPLICATIONS armed) oligomers wherein the end groups of these oligomers have been functionalized with biologically active molecules. This application claims the benefit of U.S. Application No. The resultant multi-armed oligomers end-functionalized with 60/969,787, filed Sep. 4, 2007, the entirety of which is incor biologically active molecules have a controllable degradation 10 profile. The hydrolytic degradation of oligomers of the porated herein by reference. present invention releases the biologically active compound as such with no change in native chemical structure. FIELD OF THE INVENTION As used herein, the term “biologically active compound The present invention relates to the discovery of biodegrad refers to a naturally occurring, semi-synthetic, or synthetic 15 therapeutic agent that provides a therapeutically desirable able multi-armed oligomers wherein the end groups of these effect when administered to a mammal (e.g., human). Bio oligomers have been functionalized with biologically active logically active compounds capable of incorporation into molecules. The resultant multi-armed oligomers end-func polymers of the present invention possess at least two func tionalized with biologically active molecules have a control tional groups that can each be incorporated into an ester or lable degradation profile. The hydrolytic degradation of oli amide linkage of a polymer of the present invention, such that, gomers of the present invention releases the biologically upon hydrolysis of the polymer, the therapeutic agent is active compound as Such with no change in native chemical obtained. The biologically active compounds useful in the Structure. present invention have at least one aryl or heteroaryl ring and at least one hydroxyl (OH), substituted or unsubstituted BACKGROUND OF THE INVENTION 25 amino, or carboxylic acid substituent on the aromatic or het eroaromatic ring, or functional derivatives of Such substitu Biologically active compounds are well known (e.g., aspi ents, such as esters, amides, methyl ethers, and/or glycosides, rin and capsaicin) and have been beneficially administered to or other derivatives that would be apparent to those skilled in patients in need thereof for more than a century. One problem the art. Additional examples of the number of aromatic that has been associated with many biologically active com 30 groups present in the phenolic include (a) 1, 2, and 3 and (b) pounds is that they can be difficult to dissolve in water or the 1 and 2. Additional examples of the number of functional human body and can also be very difficult to polymerize. Due (e.g., hydroxyl) groups present on the phenolic include (a) 1, to the availability and numerous uses of biologically active 2, 3, 4, and 5 and (b) 1 and 2. compounds, it is desirable to enhance their native value by, for The biologically active compounds can also comprise example, providing compounds or combinations of com 35 other functional groups (e.g., hydroxyl groups, amine groups, pounds with a specific controlled degradation profile or range and carboxylic acids) that can be used to modify the proper ties of the polymer (e.g. for branching, for cross linking, for enabling controlled release of the biologically active com appending other molecules (e.g. another biologically active pound over an extended, controllable time range. The present compound) to the polymer, for changing the solubility of the invention is directed to these and other important ends. 40 polymer, or for effecting the biodistribution of the polymer. Lists of therapeutic agents can be found, for example, in: SUMMARY OF INVENTION Physicians’ Desk Reference, 61 Ed., 2007, Thomson Healthcare Company: USPN Dictionary of USAN and Inter The present invention relates to biodegradable multi national Drug Names, 2000, The United States Pharmaco armed (e.g., 2, 3, 4, 5, or 6 arms) oligomers wherein the end 45 poeia Convention, Inc., Rockville, Md.; and The Merck groups of these oligomers have been functionalized with bio Index, 14" Ed., 2007, John Wiley & Sons. One skilled in the logically active molecules.
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    Prediction of Premature Termination Codon Suppressing Compounds for Treatment of Duchenne Muscular Dystrophy using Machine Learning Kate Wang et al. Supplemental Table S1. Drugs selected by Pharmacophore-based, ML-based and DL- based search in the FDA-approved drugs database Pharmacophore WEKA TF 1-Palmitoyl-2-oleoyl-sn-glycero-3- 5-O-phosphono-alpha-D- (phospho-rac-(1-glycerol)) ribofuranosyl diphosphate Acarbose Amikacin Acetylcarnitine Acetarsol Arbutamine Acetylcholine Adenosine Aldehydo-N-Acetyl-D- Benserazide Acyclovir Glucosamine Bisoprolol Adefovir dipivoxil Alendronic acid Brivudine Alfentanil Alginic acid Cefamandole Alitretinoin alpha-Arbutin Cefdinir Azithromycin Amikacin Cefixime Balsalazide Amiloride Cefonicid Bethanechol Arbutin Ceforanide Bicalutamide Ascorbic acid calcium salt Cefotetan Calcium glubionate Auranofin Ceftibuten Cangrelor Azacitidine Ceftolozane Capecitabine Benserazide Cerivastatin Carbamoylcholine Besifloxacin Chlortetracycline Carisoprodol beta-L-fructofuranose Cilastatin Chlorobutanol Bictegravir Citicoline Cidofovir Bismuth subgallate Cladribine Clodronic acid Bleomycin Clarithromycin Colistimethate Bortezomib Clindamycin Cyclandelate Bromotheophylline Clofarabine Dexpanthenol Calcium threonate Cromoglicic acid Edoxudine Capecitabine Demeclocycline Elbasvir Capreomycin Diaminopropanol tetraacetic acid Erdosteine Carbidopa Diazolidinylurea Ethchlorvynol Carbocisteine Dibekacin Ethinamate Carboplatin Dinoprostone Famotidine Cefotetan Dipyridamole Fidaxomicin Chlormerodrin Doripenem Flavin adenine dinucleotide