SSE Real Procedures That Requirrigation. the Additive
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United States Patent 19 11 Patent Number: 4,886,786 Lindstrom et al. (45) Date of Patent: Dec. 12, 1989 54 ADDITIVE FORIRRIGATION SOLUTION (56) References Cited OR SURGICAL SOLUTION U.S. PATENT DOCUMENTS 76 Inventors: Richard L. Lindstrom, 20050 4,024,237 5/1977 Eichel et al. ................. r 514/54 Lakeview Ave., Excelsior, Minn. 4,725,586 2/1988 Lindstrom et al. ................... 514/59 55331; Debra L. Skelnik, P.O. Box 344, Rt.s 5, Cambridge, Minn.w 55008 AssistantPrimary Examiner-JohnnieExaminer-Elli Peselev R. Brown 21 Appl. No.: 151,480 Attorney, Agent, or Firm-Hugh D. Jaeger 22 Filed: Feb. 2, 1988 57 ABSTRACT An additive for intraocular irrigation solution or surgi Related U.S. Application Data cal solution which provides the anterior chamber and . posterior chamber of the eye with protection during SSEser. No. 836i56, Mar, 1986, Pat No. 4725,586 forreal the solutions procedures is composed that requirrigation. of a balanced The salt additivesolution a wwe way was a wy weak a ty suso wwa aws wwa containing dextrose supplemented with chondroitin 51) Int. Cl'............................................. A61K 31/70 sulfate. Other chemical compositions can supplement 52 U.S. C. ........................................ 514/54; 514/23; the additive. 514/21; 514/2 58 Field of Search .......................... 514/54, 23, 21, 2 6 Claims, No Drawings 4,886,786 1. 2 in intracellular fluid, helps maintain intercellular pH, ADDTVE FOR RRGATION SOLUTION OR fluid movement, corneal deturgesence, and membrane SURGICAL SOLUTION potential difference across the corneal endothelium. The base medium of the irrigation solution or surgical CROSS REFERENCES TO CO-PENDING 5 solution with the additive consists of a Balanced Salt APPLICATIONS Solution or Lactated Ringers Solution containing five This application is a continuation-in-part of Ser. No. essential ions. 761,407, filed Aug. 1, 1985, entitled Irrigation Solution, One significant aspect and feature of the additive of now U.S. Pat. No. 4,696,917, which is a continuation-in the present invention is to protect the anterior and pos part of Ser. No. 836,156, filed Mar. 4, 1986, entitled terior segments of the cornea during surgical proce Surgical Solution, now U.S. Pat. No. 4,725,586. dures, to maintain homeostasis after surgical trauma, and to provide necessary metabolic substrates that may BACKGROUND OF THE INVENTION be needed for wound repair. 1. Field of the Invention Another significant aspect and feature of this additive The present invention pertains to an additive for an is use in other applications when added to the irrigation irrigation solution or a surgical solution for the anterior solution, such as: 1. An ophthalmic irrigating and lubri and posterior chamber of the eye. The additive can also cating eye drop; 2. In the solution for burn wounds; 3. be used in other solutions, such as corneal preservation As a general surgical solution for use in surgeries where medium, for other surgical or medical applications. a solution is required; 4. As a vehicle for ophthalmologi 2. Description of the Prior Art 2O cal drugs, such as drops; 5. As an anticataract drug; 6. There are two intraocular irrigation solutions com As an eye drop; 7. As a corneal preservation medium monly being used in ophthalmic surgeries. These two additive; 8. As a general irrigation solution including irrigation solutions are balanced salt solution and BSS orthopedics, such as athroscopy; urology, such as cys Plus. BSS is a balanced salt solution that incorporates a toscopy; neurosurgery; as well as in artificial insemina sodium citrate and sodium acetate buffering system. 25 tion, obstectrics, and gynecology OBGYN); 9. As a BSS Plus consists of a balanced salt solution with a bicarbonate buffering system, with glucose added as an woundhealing solution; or 10. As an anti-ulcer drug. additional osmotic agent and energy source. An addi DESCRIPTION OF THE PREFERRED tional component, oxidized glutathione, is reduced by EMBOOMENTS the ocular cells and serves as an anti-oxidant. In addi-30 The solution additive such as to an irrigation solution tion, Lactated Ringers Solution is used when BSS and or a surgical solution is used at a concentration of 1-100 BSS Plus are not available. parts for each 500 parts of a commercially available SUMMARY OF THE INVENTION balanced salt solution (BSS) base such as that sold by The general purpose of the present invention is an 35 Iolab or Alcon. additive for an irrigation solution or surgical solution Typically, the additive concentrate contains one or which provides the anterior and posterior chamber of more of the components in Table A. the eye protection during surgical procedures that re TABLE A quire irrigation. This additive specifically protects the Preferred corneal endothelium in anterior segment surgery. The 40 Component Range Component corneal endothelium and other anterior and posterior glycosaminoglycan 0.001-550 mg/ml chondroitin sulfate chamber structures are in direct contact with the addi an antioxidant 0-10 nM 2-mercaptoethanol tive in the solution. energy source 0-20 nM dextrose According to one embodiment of the present inven 0-20 nM pyruvate tion, an additive includes: 1. A protective coating agent 45 amino acid 0-10 mM cystine of a highly negatively charged glycosaminoglycan such buffer 0-100 nM sodium bicarbonate as chondroitin sulfate which is a naturally occurring, biodegradable material normally found in the human The formulation is a representative concentration of the cornea; In some cases, 2. An effective antioxidant such additive made up in a total volume of 1-50 ml balanced as 2-mercaptoethanol, that can be utilized in both the 50 salt solution or water. oxidized and reduced forms by human corneal endothe The additive can then be added to 500 ml of balanced lial cells. 2-mercaptoethanol is used as a carrier of cys salt solution as in Table B. This irrigation solution addi tine into the cells. Cystine may well be the limiting tive is therefore defined at proportionate concentrations amino acid for the synthesis of protein as well a glutathi at all other volumes one. The addition of 2-mercaptoethanol increases the 55 intracellular level of glutathione, and aids in membrane TABLE B and maintenance of cell junctional complexes; 3. An Additive of 50 ml made up in energy source, such as dextrose, is the starting molecule Balance Salt Solution (BSS) Base Medium: for glycolysis, a central pathway for recovery of chemi chondroitin sulfate 4400 mg/ml 2-mercaptoethanol S.SOM cal energy as ATP (adenosine triphosphate). 4. An addi- 60 dextrose SS.0 nM tional energy source such as a pyruvate, is provided for pyruvate 1100 nM additional biosynthetic synthesis that may be required cystine 33.00 nM by the ocular cells after surgical trauma. 5. An amino sodium bicarbonate 275.00 nM acid cystine in the presence of 2-mercaptoethanol, is Balance Salt Solution (BSS) Base Medium: sodium chloride .64% provided so that corneal endothelial cells can con- 65 potassium chloride O75% stantly utilize cystine in the additive, and maintain intra calcium chloride 0.48% cellular cystine and glutathione levels during intraocu magnesium chloride O30% lar perfusion. 6. A bicarbonate buffer system, important sodium acetate .39% 4,886,786 3 4. 1. Fibroblastic growth factor (FGF), a single chain TABLE B-continued polypeptide, isolated and purified from the pitui Additive of 50 ml made up in tary, human (hPGF) fibronectin or bovine fibro sodium citrate .17% nectin (bfGF), acidic or basic forms. Molecular weight range of 14K to 16K. This factor has been Or made up in distilled injection grade water. The final demonstrated mitogenic in vitro to a wide variety concentration of the additive after dilution with an of cells comprising mesoderm and neuroectoderm appropriate amount of Balance Salt Solution is de tissue. scribed in Table C. This also includes synthetic formulated FGF basic 10 TABLE C peptides consisting of: (1-24) Final Concentration Approximate Pro-Ala-Leu-Pro-Glu-Asp-Gly-Gly-Ser-Gly Final Ranges of Ala-Phe-Pro-Pro-Gly-His-Phe-Lys-Asp-Pro Component Concentration final concentration 15 Lys-Arg-Leu-Try chondroitin sulfate 4.00 mg/ml (0-100 mg/ml) and synthetic formulated FGF acidic peptides consist 2-mercaptoethanol 0.50 nM (0-2 mM) dextrose 0.92 mg/ml (0-20 mM) ing of: (1-11) pyruvate 100 nM (0-20 mM) Phen-Asn-Leu-Pro-Leu-Gly-Asn-Tyr-Lys-Lys-Pro cystine 100 mM (0-10 mM) Fibroblastic growth factor: 100 ng/ml-100 mg/ml sodium bicarbonate 2S.00 nM (0-100 mM) 2O 2. Endothelial cell growth supplement (ECGS), pre pared from the hypothalamus as a lyophilized ex This additive is therefore defined at proportionate con tract. This growth supplement has demonstrated centrations at all other volumes. mitogenic in vitro to a wide variety of endothelial cells; i.e., human corneal endothelial cells, human GROUPINGS 25 umbilical vein endothelial cells, and mouse Balb/c An additive concentrate comprising one or more of fibroblasts. the following components in Balanced Salt or like solu Endothelial Cell Growth supplement: 200 tion. (lyophilized) ug/ml-500 mg/ml a, a glycosaminoglycan: 1.0-mg/ml to 550 mg/ml. 3. Urogastrone or Epidermal growth factor (EGF), a 1. chondroitin sulfate 30 single chained polypeptide, is composed of 53 2. dermatan sulfate amino acids, containing 3 disulfide bonds and has 3. heparan sulfate been isolated from mouse submaxillary glands 4. heparin sulfate (mEGF) and human urine (hEGF). This growth 5. keratan sulfate factor has been demonstrated to be mitogenic in 6. hyaluronic acid 35 vitro for a wide variety of cells of ectodermal and b. an antioxidant mesodermal origin. 1. ascorbic acid: 1 mM-20 nM This also consists of synthetic mouse EGF: 2.