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(12) United States Patent (10) Patent No.: US 7,790,141 B2 Pathak Et Al

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(12) United States Patent (10) Patent No.: US 7,790,141 B2 Pathak Et Al US007790141B2 (12) United States Patent (10) Patent No.: US 7,790,141 B2 Pathak et al. (45) Date of Patent: Sep. 7, 2010 (54) RADIO-OPAQUE COMPOUNDS, (56) References Cited COMPOSITIONS CONTAINING SAME AND U.S. PATENT DOCUMENTS METHODS OF THEIR SYNTHESIS AND USE M 5,384.333 A 1, 1995 Davis (75) Inventors: Chandrashekhar P. Pathak, Phoenix, 5,410,016 A 4/1995 Hubbell et al. AZ (US); Sanjay M. Thigle, Kalyan 5,514,379 A 5/1996 Weissleder et al. (IN) 5,565,215 A * 10/1996 Grefet al. ................... 424,501 5,567,410 A 10, 1996 Torchilin et al. (73) Assignee: Pathak Holdings, LLC, Phoenix, AZ 5,824.333 A 10/1998 Scopelianos (US) 6,174,330 B1 1/2001 Stinson 6,475.477 B1 1 1/2002 Kohn et al. (*) Notice: Subject to any disclaimer, the term of this 6,599,448 B1* 7/2003 Ehrhard et al. .............. 252/582 patent is extended or adjusted under 35 U.S.C. 154(b) by 1147 days. * cited by examiner (21) Appl. No.: 10/914,701 Primaryy Examiner D L. Jones (22) Filed: Aug. 9, 2004 (74) Attorney, Agent, or Firm Dardi & Herbert, PLLC (65) Prior Publication Data (57) ABSTRACT US 2005/OO36946A1 Feb. 17, 2005 O O Radio-opaque biodegradable compositions are formed by Related U.S. Application Data modifying terminal groups of synthetic and natural biode (60) Provisional application No. 60/494.340, filed on Aug. gradable polymers such as polylactones with iodinated moi 11, 2003. eties. The biodegradable property of the compositions ren s ders them suitable for use in medical field such as drug (51) Int. Cl. delivery, imaging. Compounds disclosed in this invention A6 IK 5L/00 (2006.01) exist as neat liquid. Certain compositions disclosed in this A6M 36/14 (200 6. 01) invention form hydrophobic iodine rich domains when dis Solved in water, Such domains provide better contrasting (52) U.S. Cl. .................... 424/1.89: 424/1.11; 424/1.65; properties as well as ability to dissolve hydrophobic bioactive 424/1.81; 424/1.85: 424/9.4 drugs. Certain iodinated moieties disclosed in the invention (58) Field of Classification Search ................ 424/1.11, are capable of cross linking natural proteins in situ in presence 424/1.29, 1.41, 1.49, 1.65, 1.73, 1.81, 1.85, of suitable catalysts and co-catalysts. 424/9.1, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 1.89 See application file for complete search history. 15 Claims, 14 Drawing Sheets U.S. Patent Sep. 7, 2010 Sheet 1 of 14 US 7,790,141 B2 s S U.S. Patent Sep. 7, 2010 Sheet 2 of 14 US 7,790,141 B2 cN O V / w S O y C V ÞOL,O— l U.S. Patent Sep. 7, 2010 Sheet 5 of 14 US 7,790,141 B2 OH COOH NH NH OH OH SH O - NH NH Natural polyner conta in in g N function a reactive groups OH OH lop a mid to or is ovue Prote is such as Zero length cross linker, preferably water soluble Colla gen of album in , Cross inker such as: PBS pH 6 to 7.5 1-Ethy -3-(3-dim ethylam in op ropyl)carbodiim ide N -hydroxy Hydroch to ride (E D C) succi i r ide as co-cataly st M old the reaction mixture to a desired shape such as micro s p the re. -NH NK HN -OH HN O O 2 -SH HO HS HN O Prote in cross linked using iodinated compound, The preferred shape of cross linked polymer is micro sphere FIG.5 U.S. Patent Sep. 7, 2010 Sheet 6 of 14 US 7,790,141 B2 O COOH HCOCHN O NH2 1. N OH O -SH O -- Natural polymer Containingr HCCOHN functional reactive groups Ditriozoate n-hydroxysucCninide ester PBS, pH 7.2 With or without solubilizing sovent such as dimethyl sulfoxide cooH 5 NHCOCH 3. NHOCCH Water soluble iodinated protein useful for medical x-ray based imaging applications FIG.6 U.S. Patent Sep. 7, 2010 Sheet 7 of 14 US 7,790,141 B2 U.S. Patent Sep. 7, 2010 Sheet 8 of 14 US 7,790,141 B2 O OHHO /// !!!!!!!! 8’5)|–| U.S. Patent Sep. 7, 2010 Sheet 9 of 14 US 7,790,141 B2 U.S. Patent Sep. 7, 2010 Sheet 10 of 14 US 7,790,141 B2 O t g/n O E. Z 2. / o \stp U.S. Patent Sep. 7, 2010 Sheet 11 of 14 US 7,790,141 B2 cy 3 OF D-O U.S. Patent Sep. 7, 2010 Sheet 12 of 14 US 7,790,141 B2 5 O <—HO U.S. Patent Sep. 7, 2010 Sheet 13 of 14 US 7,790,141 B2 d U.S. Patent Sep. 7, 2010 Sheet 14 of 14 US 7,790,141 B2 -Sess CC O O N O O 1 O US 7,790,141 B2 1. 2 RADIO-OPAQUE COMPOUNDS, “Injectable composition” means any polymeric or non COMPOSITIONS CONTAINING SAME AND polymeric composition that can be injected as a liquid and METHODS OF THEIR SYNTHESIS AND USE converted into Solid inside a human body using minimally invasive Surgical devices. RELATED APPLICATIONS Polyethylene glycol (PEG) or polyethylene oxide (PEO) refers to the same polymer which is made by polymerization of ethylene oxide. This application claims priority of U.S. Provisional Appli Polymeric nomenclature used in this patent application cation No. 60/494,340 filed Aug. 11, 2003 Such as poly (lactic acid) or polylactic acid or polylacticacid 10 refer to the same polymer, unless otherwise stated clearly. BACKGROUND This is also true for all others polymers referred in this patent application. This present invention relates to biodegradable radio The radio-opaque nature of many compounds allows them opaque compounds that can be used as contrast agents in to be traced within a human or an animal body and therefore medical imaging, Surgical markers and for localized drug 15 Such compounds find application in medical diagnostics and delivery. The invention also relates to radio-opaque com pharmaceutical field. Some of the applications of such radio pounds, compositions containing such compounds and meth opaque compounds include medical imaging applications ods of their synthesis and use. Such as X-rays, angiography, urography, phlebography and drug delivery at a localized site. Definitions: In medical imaging techniques such as X-ray imaging, All scientific and technical terms used herein have the same attenuation of soft tissue by X-ray radiation can be improved meaning as is commonly understood by one skilled in the by exogenously administering a radio-opaque compound, synthetic polymer chemistry, polyethylene glycol modifica which gets distributed in the tissue to be imaged. The infused tion chemistry, controlled drug delivery and synthetic biode compound preferentially absorbs X-ray radiation in the tissue gradable chemistry art, and to which this invention belongs; 25 and therefore improves quality of the image. Such improved unless it is defined specifically for this invention. image results in better diagnosis of the medical condition. “Oligomers are defined as low molecular weight poly It is desired that such compounds should mix with the body meric compounds. In this invention, oligomers may be fluids without causing significant change in the local chemi defined as polymeric compounds with molecular weight cal environment such as osmolarity, which is concentration of between 400-20000 Daltons. 30 the solute per unit of total volume of solution and pH, should “Cross-linked material' is meant to denote the conversion be economically feasible, chemically stable, highly water of a soluble material to an insoluble state. The crosslinked soluble, readily injectable with low viscosity and a ready to material may still be in a highly hydrated State. inject solution, biologically inert and should be removable “In situ' is meant to denote at a local site, especially within safely and completely by the body. or in contact with living organisms, tissue, organs, or the 35 The radio opaque compounds reported in the prior art body. generally fall into two categories: ionic and non-ionic. The ionic monomeric compounds used as contrast media for intra “Bioactive' as used herein, refers to one or all of the activi vascular use have an osmolarity seven to eight times that of ties of a compound that show pharmacological or biological normal human blood. This hyper-osmolarity is partly activity in human or animal body. Such biological activity is 40 believed to be responsible for several subjective and objective preferred to have therapeutic effect. The bioactive com adverse effects such as pain, endothelial damage, thrombosis pounds that can be used include, but not limited to: antiviral and thrombophlebitis, disturbance of the blood-brain barrier, agents; antiinfectives such as antibiotics; antipruritics; antip bradycardia in cardioangiography and increased pressure in sychotics; cholesterol or lipid reducing agents, cell cycle the pulmonary circulation. On the other hand, non-ionic com inhibitors, anticancer agents, antiparkinsonism drugs, HMG 45 pounds such as lohexol, lopamidol, metrizamide are formu CoA inhibitors, antirestenosis agents, antiinflammatory lated as less hyperosmolar solutions. However, the current agents; antiasthmatic agents; antihelmintics; immunosup non-ionic radio opaque compounds are much more expensive pressives; muscle relaxants; antidiuretic agents; vasodilators; nitric oxide, nitric oxide releasing compounds, beta-blockers; and exhibit relatively high rate of adverse events. In a recent hormones; antidepressants; decongestants; calcium channel Small clinical study, two non-ionic media containing lohexol blockers; growth factors such as bone growth factors, wound 50 and loversol were compared. More than 10% patients, receiv healing agents, analgesics and analgesic combinations; local ing either lohexol or loversol reported adverse events, which anesthetics agents, antihistamines; sedatives; angiogenesis were categorized from mild to moderate to severe.
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