1. Field of the Invention
The present invention relates to the field of ophthalmology. More particularly, the invention relates to an improved intraocular irrigating solution for controlling intraocular pressure ("IOP") during intraocular surgical procedures while maintaining the integrity, stability, and function of ocular tissues.
2. Discussion of Related Art
The growth of new surgical techniques and associated products over the past decade has been quite remarkable. For example, cataract surgery, which is a very delicate operation involving replacement of the natural crystallin lens of the human eye with an artificial lens, was previously considered to be a major surgical procedure requiring hospitalization of the patient and a significant recovery period, but today this procedure is routinely performed on an out-patient basis and enables vision to be restored almost immediately. Similar advancements have been achieved in other areas of ophthalmic surgery. These remarkable advancements are attributable to various factors, including improved equipment for performing the surgeries, improved surgical techniques developed by innovative surgeons, and improved pharmaceutical products which facilitate successful surgery by minimizing the risks of damaging sensitive, irreplaceable ocular tissue during surgery. The present invention is directed to a further improvement in one such pharmaceutical product, a solution for irrigating ocular tissue during intraocular surgery. Such solutions are discussed in U.S. Pat. No. 4,550,022; the entire contents of that patent are hereby incorporated in the present specification by reference. The importance of such solutions to ophthalmic medicine is explained in the '022 patent. The relevant portions of that explanation are repeated below.
Any scission into the human body is detrimental to the human body and invariably results in cell loss. The need to keep cell loss to a minimum is particularly crucial during any surgical procedure performed on delicate and irreplaceable tissues, such as the tissues of the eye, nerves, etc.
The cornea of the eye is comprised of five layers: epithelium, Bowman's membrane, stroma, Descemet's membrane, and endothelium. The endothelium layer is particularly vulnerable to trauma as the endothelial cells are infrequently, if ever, replaced as a normal process in the adult life. The endothelium is principally responsible for the maintenance of the proper state of hydration of the stromal layer. The stromal layer has a tendency to imbibe fluid, a tendency which is counter-balanced by outward fluid transport via the endothelium. If the proper fluid balance is not maintained in the stromal layer, the cornea thickens and the characteristic transparency of the cornea is lost. Accordingly, cell loss or damage in the endothelial layer will result in decreased vision. Failure of the endothelium to perform its fluid transport function for short periods of time will result in corneal thickening and visual clouding. Because of the importance of, and the vulnerability of, the endothelial layer, it is necessary during eye surgery, such as cataract and retinal surgery or corneal transplants, to make provisions for the protection of the endothelial cells.
A significant factor causing cell loss during tissue scission is the traumatic change in environment experienced by the internal cells. Exposure to the atmosphere presents a far different environment for the cells than is provided by the natural fluids in which they are bathed. To simulate the natural cellular environment and thereby prevent cell damage, exposed tissue during surgery is frequently irrigated in solutions which attempt to approximate natural body fluids. The value of bathing eye tissue during surgery to prevent cell damage has long been recognized. For internal ocular tissues, such as the endothelium, the aqueous humor is the natural bathing fluid and, hence, an ophthalmic irrigating solution intended to protect the endothelium should as closely as possible resemble the aqueous humor.
Of primary concern in a tissue irrigating solution is that the osmolality of the solution be generally isotonic with cellular fluids so as to maintain equal osmotic pressure within and without the cell membranes. To this end, one of the early ophthalmic irrigating solutions was isotonic (0.9%) saline. However, as has long been recognized, isotonic saline is quite inadequate as an ophthalmic irrigating solution and has been shown to result in endothelial cell swelling, cell damage, and consequent corneal clouding.
Because of the inadequacy of isotonic saline, various alternative electrolyte solutions have been proposed as ophthalmic irrigating solutions in attempts to provide solutions which more closely resemble the aqueous humor and prevent cell damage and corneal clouding. Standard electrolyte solutions primarily intended for injection solutions, such as Ringer's solution and lactated Ringer's solution, have been used as ophthalmic irrigating solutions because of their wide availability as sterile solutions.
A solution intended for ophthalmic irrigation known as "balanced salt solution" has also been developed. Balanced salt solution contains the essential ions, calcium, sodium, potassium, magnesium and chloride in generally optimal concentrations for ocular tissue, and has an acetate-citrate buffer system which is compatible with divalent calcium and magnesium ions.
The various electrolyte solutions used for ophthalmic irrigation have been improvements over normal saline by providing necessary ions in addition to Na.sup.+ and Cl.sup.- as provided by isotonic saline. Mg.sup.++ is an important cofactor for adenosine triphosphatase, an enzyme which plays an important role in mediating the fluid transport pump in the eye. Ca.sup.++ is necessary to maintain the endothelial junction. K.sup.+ is an important factor in many biochemical processes, and the fluid transport pump of the endothelium requires a proper Na.sup.+ /K.sup.+ ratio.
During eye surgery and particularly during surgery which requires extended periods of time, proper electrolytic balance alone is insufficient to retain normal corneal thickness. To maintain proper corneal thickness and prevent cell damage, an irrigating solution in addition to electrolytic balance must provide metabolic support and must particularly provide factors needed for the enzyme-mediated Na.sup.+ /K.sup.+ pump system through which excess fluid is removed from the stroma.
To incorporate factors necessary for sustained metabolism by endothelial cells, glutathione-bicarbonate-Ringers solution ("GBR") was developed in which NaHCO.sub.3, glutathione, dextrose and adenosine (an optional ingredient) are added to Ringer's solution. Bicarbonate, dextrose and glutathione have been shown to be important factors in maintaining structural integrity of endothelial cells. Bicarbonate is included because the aqueous humor has a bicarbonate buffer system; dextrose (d-glucose) provides a substrate for various metabolic pathways; and glutathione has been shown to aid the metabolic pump mechanism by maintaining proper Na.sup.+ /K.sup.+ adenosine-triphosphatase. GBR has been shown effective in maintaining corneal thickness and endothelial cell integrity for up to three hours.
While the effectiveness of a GBR ocular irrigating solution has been known for many years, prior to the early 1980's its use in surgery was quite limited due to stability and sterility problems. It is to be appreciated that sterility of an ophthalmic irrigating solution is absolutely essential. To insure sterility, it is desirable that an irrigating solution be prepackaged so that the quality and sterility may be closely monitored and tested as contrasted with an extemporaneously mixed solution as might be prepared in a hospital pharmacy. The solution will perfuse the eye in essentially a closed system where even a small number of organisms, such as pseudomonas aeruginosa, can produce an overwhelming endophthalmitis.
GBR may not be prepackaged due to the long term incompatibility and/or instability of its various moieties. Of the moieties added to Ringer's solution to formulate GBR, bicarbonate is perhaps the most important. The bicarbonate as well as the phosphate in a bicarbonate-phosphate buffer system may form insoluble precipitates with Mg.sup.++ and Ca.sup.++. While at the ionic concentrations useful in ophthalmic irrigation, precipitation is not a problem in freshly prepared solution, long-term storage is proscribed. As insoluble crystals introduced into the eye will cloud vision, the importance of keeping a tissue irrigating solution free of insoluble precipitates may be readily appreciated.
Complicating the maintenance of GBR's stability is the fact that the pH of GBR will gradually increase due to the inadequacy of the bicarbonate-phosphate buffer. To provide proper pit, i.e., about 7.4, the pH of the original GBR solutions prepared in the hospital pharmacy had to be monitored and adjusted with CO.sub.2 immediately prior to use and even during use. The chances for contamination during pH adjustment was great.
A further factor which proscribes long-term storage of GBR is the unavailability of a proper pH at which all of the moieties are stable. Several moieties of GBR are unstable at the physiological pH of about 7.4. Below a pH of about 8, bicarbonate generally decomposes to CO.sub.2, resulting both in a loss of bicarbonate concentration and increased pH. On the other hand, glucose stability requires a much lower pH. Glutathione, while biologically effective either in reduced or oxidized form, is preferred in the oxidized form because the reduced form quickly oxidizes in aqueous solutions, preventing proper labeling of the irrigating solution. Oxidized glutathione (glutathione disulfide) is unstable over extended periods of time at a pH of above about 5. The concentration of glutathione may also decrease to an unacceptable concentration when stored over long periods of time in admixture with all other components. Because of the demonstrated efficacy of GBR as an ocular irrigating solution, it was highly desirable to provide a formulation which contains the essential factors found in GBR and which could be stored in a sterilized form for use in eye surgery. The invention described in U.S. Pat. No. 4,550,022 provided such a product. An embodiment of the two-part irrigating solution described in U.S. Pat. No. 4,550,022 known as "BSS Plus.RTM. Intraocular Irrigating Solution" was introduced by Alcon Laboratories, Inc., Fort Worth, Tex., in the early 1980s.
Ophthalmic irrigating solutions such as BSS Plus.RTM. Intraocular Irrigating Solution serve to maintain the physical integrity and function of ophthalmic tissues. The chemical composition of such solutions mimics that of the fluid naturally present within the eye (i.e., "aqueous humor"). Although such solutions are well-suited to maintain the normal function of ophthalmic tissues, these solutions are not directly useful in treating or preventing abnormalities such as acute elevations of intraocular pressure associated with intraocular surgical procedures. Since elevations of intraocular pressure during ophthalmic surgical procedures is a potentially serious problem, there has been a need for an improved ocular irrigating solution which not only maintains the physical integrity and function of ophthalmic tissues, but also controls the intraocular pressure of the patient. The present invention is directed to satisfying this need.
U.S. Pat. No. 5,212,196 (House, et al.) describes the topical use of clonidine derivatives to control IOP in connection with surgical procedures, particularly procedures involving the use of a laser. A product based on the invention described in that patent has been marketed by Alcon Surgical, Inc., Fort Worth, Tex., as IOPIDINE.RTM. (apraclonidine hydrochloride) Sterile Ophthalmic Solution. The '196 patent does not disclose the intraocular use of clonidine derivatives for purposes of controlling IOP, nor does it disclose the use of an irrigating solution of the type described herein as a vehicle for intraocular administration of such compounds.
USPTO Backgrounds
USPTO Backgrounds