US005723281A United States Patent (19) 11 Patent Number: 5,723,281 Segall et al. 45 Date of Patent: Mar. 3, 1998 54 PLASMA-LIKE SUBSTANCE Fischer et al. "Flush Solution 2. A New Concept for One -to-Three Day Hypothermic Renal Storage Preservation” 75) Inventors: Paul E. Segall; Harold D. Waitz: Hal Transplantation (1985) 39(2):122-126. Sternberg; Judith M. Segall, all of Kallerhoff et al., "Effects of Preservation Conditions and Berkeley, Calif. Temperature on Tissue Acidification in Canine Kidneys" Transplantation (1985) 39(5):485-489. 73) Assignee: BioTime, Inc., Berkeley, Calif. Ross et al. "72-HR Canine Kidney Preservation Without Continuous Perfusion' Transplantation (1976) (21) Appl. No.: 471,396 21(6):498-501. (22 Filed: Jun. 6, 1995 Sprung et al., "Effects of Acute Hypothermia and b-Adren ergic Receptor Blockade on Serum Potassium Concentration Related U.S. Application Data in Rats' Critical Care Medicine (1991), 19(12):1545-51. Wall et al., "Simple Hypothermic Preservation for Trans 60 Division of Ser. No. 133,527, Oct. 7, 1993, abandoned, which is a continuation-in-part of Ser. No. 71533, Jun, 4, porting Human Livers Long Distances for Transplantation” 1993, Pat. No. 5,407,428. Transplantation (1977) 23(3):210-216. (51) Int. Cl. ................. A01N 1/00; A61K 31/715; Primary Examiner-Leon B. Lankford, Jr. A61K 31/72: A61K 47/36 Assistant Examiner-Francisco C. Prats 52 U.S. Cl. ............................ 435/12; 435/1.1; 435/1.3; Attorney, Agent, or Firm-Karl Bozicevic; Bozicevic & 514/54; 514/59; 514/60; 424/717 Reed, LLP; Bret Field 58) Field of Search ............................... 435/1.1, 1.2, 1.3: 514/54, 59, 60; 424/717 57 ABSTRACT An artificial plasma-like substance having at least one water (56) References Cited soluble polysaccharide oncotic agent selected from the U.S. PATENT DOCUMENTS group consisting of high molecular weight hydroxyethyl starch, low molecular weight hydroxyethyl starch, dextran 3.356,570 12/1967 Butcher. 3,758,382 9/1973 Knorpp. 40 and dextran 70, and albumin which is buffered by lactate 4,663,166 5/1987 Veech. and has a pre-administration pH of between 5 and 6.5 is 4,923,442 5/1990 Segall et al. .............................. 604/52 disclosed. Also disclosed is an artificial plasma-like solution 5,130.230 7/1992 Segall et al. having at least two water soluble polysaccharide oncotic agents one of which is eliminated from the circulation OTHER PUBLICATIONS slowly and the other of which is eliminated from the Belzer et al., "Combination Perfusion-Cold Storage for circulation quickly. Supplimentation of the plasma-like solu Optimum Cadaver Kidney Function and Utilization" Trans tion with certain ions is described. A system for adminis plantation (1985) 39(2):118-121. tration of the plasma-like solution to a subject wherein the Bishop et al., "Evaluation of Hypertonic Citrate Flushing system comprises a first and second solution each having Solution for Kidney Preservation Using the Isolated Per particular buffers is described. The plasma-like solution fused Rat Kidney" Transplantation (1978) 25(5):235-239. including cryoprotective adducts is also disclosed. The use Carpenter et al., J. Dairy Sci. (1990) 73:3627-3636. of the plasma-like solution in organ transplant, novel che Clinical Diagnosis by Laboratory Methods, 15th Ed., motherapy procedures, and tissue, organ and organism cryo (1974), Davidsohn et al (eds.) Appendix 3, pp. 1376-1382. preservation are also disclosed. Collins, "Hypothermic Kidney Storage" Transplant Proc. (1977) 9(3):1529-1534. 11 Claims, No Drawings 5,723,281 1 2 PLASMA-LKE SUBSTANCE those of the solutions of the present invention. In addition, the electrolyte and ion concentrations differ markedly from CROSS-REFERENCES those disclosed for the present invention. Segall et al. Federation Proceedings 44(3):623. (1985) This application is a divisional of our application Ser. No. 5 disclose that a Ringer's lactate-based heparinized blood 08/133,527, filed Oct. 7, 1993, now abandoned, which is a substitute containing 6% dextran 40 was used to lower the continuation-in-part application Ser. No. 08/071.533, filed body temperature of hamsters prior to the circulation of Jun. 4, 1993, now U.S. Pat. No. 5407,428 to which we cold-protective solutions, which are not disclosed, for 1 to claim priority under 35 USC S 120 and which are incorpo 1.5 hours. rated herein by reference in their entirety. Segall et al. (1987) Federation Proceedings, page 1338, FIELD OF THE INVENTION disclose that a blood substitute, which included dextrose (180 mg/dl) and 25 mM HEPES, was used to perfuse a dog The invention relates to the field of plasma-like solutions to 3 degrees C. when perfusion was stopped entirely. There which may be used to treat hypovolemic subjects or to is no disclosure of the complete composition of the blood substitute for the blood or plasma of a subject. 15 substitute. Segall et al. U.S. Pat. No. 4,923.442 and the reissue BACKGROUND thereof disclose a number of solutions used in blood sub Perfusion solutions and blood substitutes are known. The stitution of living subjects all of which include at least some blood substitutes of Collins et al. Kidney preservation for concentration of a cardioplegia agent, usually potassium ion. transplantation. Lancet 1219-1222 (1969); Collins G. M., 20 Segall et al., U.S. Pat. No. 4.923.442 also discloses surgical Hypothermic kidney storage. Transplant. Proc. I:1529 methods, particularly in respect to instrument placement and (1977); Filcher et al. Flush solution 2. a new concept for one the control of pulmonary wedge pressure generally appli to three day hypothermic renal storage preservation. Trans cable to perfusion of subjects. U.S. Pat. No. 4,923.442 and plantation 39:2, 122-126 (1985); Robs et al. 72-hour canine 25 its reissue are incorporated herein by reference. kidney preservation without continuous perfusion. Trans Segall et al., U.S. Pat. No. 5,130.230 discloses a blood plantation 21:498 (1976); Sacks et al. Transplantation substitute which may be used as a system of solutions in 19:283 (1974) and Kallerhoff et al. Effects of the preserva which a number of solutions, in some embodiments two tion conditions and temperature on tissue acidification in solutions and in other embodiments four solutions, are used canine kidneys. Transplantation 39:5, 485-489 (1985) all 30 sequentially to completely replace the blood of living sub consist only of low molecular weight molecules that readily jects. In one of the embodiments, one of the solutions, traverse the capillary bed of the subject and thus are gen identified as the recovery solution, of a four solution system erally incapable of maintaining proper ionic or fluid balance is disclosed as having, in addition to several dissolved salts or plasma volume when used in an intact mammalian and other constituents, dissolved potassium chloride in a subject. 35 concentration range of 0 to 10 mM. In describing the blood Klebanoff and Phillips. Cryobiology6:121-125 (1969) substitute, the specification of U.S. Pat. No. 5,130.230 disclosed hypothermic asanguinous perfusion of dogs with discloses that the blood substitute comprises "an aqueous 11 of 15 subjects surviving up to 95 minutes when perfused solution of electrolytes at physiological concentration, a with buffered Ringer's lactate at 7.1 to 16 degrees C. macromolecular oncotic agent, a biological buffer having a (44.8-60.8 degrees F). Those blood substitutes that have an buffering capacity in the range of physiological pH. simple impermeable substance to maintain volume use human nutritive sugar or sugars, magnesium ion in a concentration serum albumin or a mixture of plasma proteins, as the sufficient to substitute for the flux of calcium across cell impermeate molecule to maintain blood volume. These are membranes. The blood substitute also includes the forgoing disclosed in Wallet al. Simple hypothermic preservation for solution and a cardioplegia agent such as potassium ion in a transporting human livers long distances for transplantation, 45 concentration sufficient to prevent or arrest cardiac fibrilla Transplantation, 23:210 (1977); Belzer et al., Combination tion.” Thus potassium ion at physiological concentration is perfusion-cold storage for optimum cadaver kidney function part of the base solution of the disclosed blood substitute. and utilization, Transplantation 39:2, 118-121, (1985). The specification also discloses that concentration of cations Haff et al. Journal of Surgical Research 19:1, 13-19 including MgH, Ca++ and K+ in excess of that normally (1975) describe the asanguineous hypothermic perfusion of 50 found in mammalian blood are suitable for exerting a dogs using two solutions: the first, a flush solution com cardioplegia effect. Lastly the specification discloses that the prised of pooled delipidated homologous plasma and blood substitute may be used as a blood volume expander electrolytes, and the second comprised of pooled delipidated and that "(f)urthermore if the blood substitute according to homologous plasma, electrolytes and additional potassium the invention is used as a blood volume expander in a subject chloride at a concentration of 10 milliBquivalents/liter 55 at non-hypothermic temperatures, the cardioplegia agent (mEq/1). Haffetal also disclose the use of a pulsatile pump described . will generally be omitted so that normal oxygenator and hypothermic perfusion with their solutions cardiac function can be maintained." From the forgoing it is and suggest that the procedures could be used for long clear that the blood substitute when used as a blood volume distance transport of cadaver organ donors and as an alter expander at normal body temperatures contains K+ at physi native to hypothermic circulatory arrest for blood-free intri ological concentrations but not in concentrations sufficient cate Surgery. to cause cardioplegia.