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(12) Patent Application Publication (10) Pub. No.: US 2017/0072023 A1 ABUCHOWSKI Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0072023 A1 ABUCHOWSKI Et Al US 20170072023A1. (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0072023 A1 ABUCHOWSKI et al. (43) Pub. Date: Mar. 16, 2017 (54) HEMOGLOBIN COMPOSITIONS A6IR 9/08 (2006.01) A61R 4I/00 (2006.01) (71) Applicant: Prolong Pharmaceuticals, LLC, South (52) U.S. Cl. Plainfield, NJ (US) CPC .......... A61K 38/42 (2013.01); A61K 41/0009 (2013.01); A61K 47/48215 (2013.01); A61 K (72) Inventors: Abraham ABUCHOWSKI, Califon, 9/08 (2013.01) NJ (US); Steven SLOSHBERG, Union, NJ (US); Keith O'HARE, East (57) ABSTRACT Windsor, NJ (US) The invention provides compositions containing hemoglo (21) Appl. No.: 15/358,447 bin, particularly PEGylated hemoglobin. The PEGylated hemoglobin molecule is capable of transferring oxygen or 1-1. carbon monoxide bound thereto to a tissue with which it is (22) Filed: Nov. 22, 2016 in proximity. Exemplary PEGylated hemoglobin formula Related U.S. Application Data tions of the invention are virally inactivated. Various com positions of the invention include deoxygenated hemoglo (62) Division of application No. 12/797,582, filed on Jun. bin, which may be conjugated with one or more water 9, 2010. soluble polymer. PEGylated hemoglobin includes those (60) Provisional application No. 61/185.547, filed on Jun. species in which the iron atom of the hemoglobin molecule 9, 2009. is not bound to oxygen or any other species, and hemoglobin s molecules in which a species other than oxygen, e.g., carbon Publication Classification monoxide, is bound to the iron atom. The compositions of the invention are formulated as hypo-, iso- or hypertonic (51) Int. Cl. solutions of the PEGylated hemoglobin. The compositions A6 IK 38/42 (2006.01) are of use to treat and/or ameliorate disease, injury and insult A6 IK 47/48 (2006.01) by providing for the oxygenation of tissues and/organs. Patent Application Publication Mar. 16, 2017. Sheet 1 of 7 US 2017/0072023 A1 Freshoe rified Biod errogobin Extract hieroglobin 50kD Dialysis 50kD Dialysis Cosiversier Degxygentation C CO For 3OOk trafiltration Ok. Concentration Aseptic Fi Aseptic.rea Fi Deoxygentation Vira inactivatier Fitrio Pirified enogobiri FIGURE 1 Patent Application Publication Mar. 16, 2017. Sheet 2 of 7 US 2017/0072023 A1 Oxygen Debt as a Resuit of hypovolenic Shock, Post-Adrainistration of Hetastarch, Packed Red Bood Celis, Oxyglobin, and PEGohib 8&Seiite ReS,Sitatics Heinoff age Kiss&flation 60.0 - , , O. O. ES 3. t 8. i. ty e 8O. O. es. as as 2. is or iOC FIGURE 2 Patent Application Publication Mar. 16, 2017. Sheet 3 of 7 US 2017/0072023 A1 FIGURE 3A CS S S 60 -{0- No Transfusion Sh -- PEG-Albumin s 40 -A-PEG-COHb O 30 60 90 120 150 140 O) 120 100 o 8O S FIGURE 3B X 60 aO 40 O 5 2O :: O - O 3O 60 90 120 150 Time (min) A. MCAO Transfusion Reperfusion Patent Application Publication Mar. 16, 2017. Sheet 4 of 7 US 2017/0072023 A1 4 D. No Transfusion PEG-Albumin PEG-COH 1 hour 24 hour Duration of Reperfusion FIGURE 4 Patent Application Publication Mar. 16, 2017. Sheet 5 of 7 US 2017/0072023 A1 FIGURE 5A FIGURE 5B FIGURE 5C -()- No Transfusion Cortex -()- No Transfusion Striatum D. No Transfusion -(9- PEG-Albumin Cortex -- PEG-Albumin Striatum PEG-Albumin -A-PEG-COHb Cortex -A-PEG-COHb Striatum PEG-COH 100 1 O O -- 1 O O 8O 8O 8 O 6O 60 40 40 2O 20 1 2 3 4 5 6 7 1 2 3 4 5 6 7 Cortex Striatum Coronal Section Number Coronal Section Number Anterior Posterior Anterior Posterior Patent Application Publication Mar. 16, 2017. Sheet 6 of 7 US 2017/0072023 A1 FIGURE 6 Patent Application Publication Mar. 16, 2017. Sheet 7 of 7 US 2017/0072023 A1 ^ . { { -----Yssessssssssssssssssssssss-s Nx&YR& - . st ---------------- sSyas 80.0 ic NSN'it is Stability of PEG-Hb at 37°C FIGURE 7 US 2017/0072023 A1 Mar. 16, 2017 HEMOGLOBIN COMPOSITIONS (Biopure, Cambridge, Mass.). However none of these prod ucts have been established to produce significant increases CROSS-REFERENCE TO RELATED in tissue oxygenation and none have received FDA approval, APPLICATIONS either because they are ineffective or produce significant toxicity. 0001. This application claims priority to U.S. Provisional Patent Application Ser. No. 61/185.547, filed Jun. 9, 2010, 0006 Lack of suitable HBOCs has greatly hindered basic which is incorporated herein by reference in its entirety for research into the physiology of tissue oxygenation and our all purposes. understanding of the critical mechanisms involved in shock and its ensuing tissue damage. With regards to the HBOCs FIELD OF THE INVENTION that have undergone clinical testing and produced significant toxicity, Scarce information is available on the cause of these 0002 The present invention resides in the field of blood toxicities. Substitutes and resuscitation fluids, including polymer-modi fied protein, e.g., hemoglobin, formulations capable deliv 0007 Thus, the methods for treating trauma induced hemorrhage are presently insufficient. While blood transfu ering oxygen or carbon monoxide to tissues. sion can restore oxygen to tissue and replenish lost circu BACKGROUND OF THE INVENTION lating Volume, use of blood as a means to treat hemorrhaging outside of medical facilities has significant practical prob 0003 Trauma is one of the leading causes of death in the lems. First of all there are generally limited quantities of United States. The primary reason for the high mortality rate blood available and for each person treated typing is nec is the inability to maintain tissue oxygenation of the patient essary to prevent killing the patient through an immune between the time of injury and time of Surgery at a medical reaction. However the most important problem in using facility. The lack of oxygenation results in tissue damage, blood to treat trauma patients outside of medical facilities is organ failure and death. Therefore, a major focus in treating the storage and packaging constraints inherent in using this traumatic shock is administering therapeutics providing as tissue. Thus, blood transfusions are not normally employed much oxygen as possible to internal tissues and organs of the in point of care treatment of trauma patients. patients. 0008. In fact, the standard approaches to treat trauma 0004 An obvious approach to maintain oxygenation is primarily involve maintenance of intravascular circulating blood transfusion. However, there are significant practical Volume through administration of either isotonic, hyper problems using blood in point of care treatment which make tonic, or hyperoncotic Solutions. These approaches are the routine use of stored human blood for use outside the intended to provide short term replenishment of circulatory medical facility impractical on a wide spread basis. Standard Volume and can also increase blood flow and hence oxygen approaches to treat trauma primarily involve maintenance of delivery to tissues. However, when hemorrhage is severe, intravascular circulating volume through administration of these treatments cannot uniformly increase oxygenation of either isotonic, hypertonic, or hyperoncotic Solutions. These internal tissues and organs enough to effectively prevent treatments cannot uniformly increase oxygenation of inter ischemia and organ failure. As a consequence, we have a nal tissues and organs enough to effectively prevent isch high death rate from those individuals subject to severe emia and organ failure. trauma. 0005. As a consequence there is a major effort to develop hemoglobin based oxygen carriers (HBOCs) which are 0009 For years attempts have been made to develop capable of restoring oxygen carrying capacity of trauma hemoglobin based oxygen carriers (HBOCs) which are patients. HBOCs have a number of advantages over the use capable of providing oxygen to trauma patients. HBOCs stored human blood, including a decreased chance of disease have a number of advantages over the use stored human transmission, no immune reactivity, lack of a need for blood without many of the problems associated with using typing, and most importantly improved availability with blood to treat trauma. These advantages include a decreased decreased storage demands. A number of groups have devel chance of disease transmission, no immune reactivity, lack oped HBOCs and several companies have conducted clinical of a need for typing, and most importantly improved avail trials to develop their hemoglobin based products as blood ability with decreased storage demands. Ideally HBOCs substitutes. Hemoglobin (HGB) isolated from human or should be able to bind oxygen and release it to needed animal blood, or a synthetically produced oxygen carrier, tissues. It should be in a ready to use Solution that is in a such as perfluorocarbon, are two types of blood substitutes form that is stable for months under most environmental that have been in clinical trials. Other red blood cell sub conditions especially those commonly encountered in point stitutes, have also been developed and characterized for use of care conditions in which trauma patients need treatment. in patients. (See, for example, Red Blood Cell Substitutes, 0010. Over the years a number of attempts have been 1998, (Eds.) A. S. Rudolph, R. Rabinovici, and G. Z. made to develop HBOCs as oxygen therapeutics using either Feuerstein, Dekker, New York, N.Y.). Such red blood cell native or recombinant human hemoglobin, modified forms Substitutes may be used in conjunction with standard medi of human hemoglobin or modified forms of hemoglobin cal therapies, such as transfused blood or blood products. As from other species. Unmodified hemoglobin can be used as a specific example, Enzon, Inc. (Piscataway, N.J.), has an oxygen therapeutic however it binds NO, and causes developed a polyethylene glycol (PEG)-modified bovine severe vasoconstriction and hypertension. As a consequence hemoglobin, abbreviated PEG-HGB. PEG-HGB is produced of its molecular weight, hemoglobin can cause significant by a process in which strands of PEG are crosslinked to the toxicities, especially to the kidney where it clogs the glom surfaces of HGB molecules, for example, as disclosed in erular apparatus.
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