Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to the field of ophthalmology. More particularly, the invention relates to an improved solution for maintaining the integrity, stability, and function of ocular tissues during invasive surgical procedures.
• 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.
• the present invention is directed to a further improvement in one such pharmaceutical product, a solution for irrigating ocular tissue during intraocular surgery.
• a solution for irrigating ocular tissue during intraocular surgery Such solutions are discussed in United States Patent 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.
• 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.
• 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.
• 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.
• osmolality of the solution be generally isotonic with cellular fluids so as to maintain equal osmotic pressure within and without the cell membranes.
• isotonic 0.8% saline.
• 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.
• 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 + and Cl as provided by isotonic saline.
• Mg ⁇ is an important cofactor for adenosine triphosphatase, an enzyme which plays an important role in mediating the fluid transport pump in the eye.
• Ca "1 ⁇ is necessary to maintain the endothelial junction.
• K + is an important factor in many biochemical processes, and the fluid transport pump of the endothelium requires a proper Na + /K + 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.
• GRR glutathione-bicarbonate-Ringers solution
• 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 Na7K + adenosine-triphosphatase.
• GBR has been shown effective in maintaining corneal thickness and endothelial cell integrity for up to three hours.
• GBR may not be prepackaged due to the long term incompatibility and/or instability of its various moieties.
• 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 " " and Ca "1"1' . While at the ionic concentrations useful in ophthalmic irrigation, precipitation is not a problem in freshly prepared solution, long-term storage is proscribed.
• 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 pH, 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 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 2 , resulting both in a loss of bicarbonate concentration and increased pH.
• glucose stability requires a pH of less than about 6.
• 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. Patent No. 4,550,022 provided such a product.
• An embodiment of the two-part irrigating solution described in U.S. Patent No, 4,550,022 known as "BSS Plus® Intraocular Irrigating Solution" was introduced by Alcon Laboratories, Inc., Fort Worth, Texas, in the early 1980s.
• Ophthalmic irrigating solutions such as BSS Plus® 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").
• aqueous humor aqueous humor
• these solutions are not directly useful in treating or preventing abnormalities such as inflammation. Since inflammation of ophthalmic tissues is a problem frequently associated with ophthalmic surgical procedures, 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 prevents or alleviates inflammation of those tissues.
• the present invention is directed to satisfying this need.
• non-steroidal and non-steroidal agents have been utilized to treat ophthalmic inflammation.
• the use of non-steroidal antunflammatory agents is believed to have certain advantages relative to the use of steroids.
• the non-steroidal agents are relatively soluble in water, while steroids having potent antunflammatory activity (e.g., dexamethasone) are generally not soluble in water.
• steroids have a propensity to elevate intraocular pressure in some patients. Since intraocular irrigating solutions are generally aqueous, the solubility of an antunflammatory drug in water is an important consideration.
• the present invention is directed to the provision of an improved irrigating solution which is generally useful in the prevention or treatment of ophthalmic inflammation, and is particularly useful in preventing or treating inflammation associated with ophthalmic surgery. More specifically, the invention is directed to irrigating solutions comprising: one or more nonsteroidal antunflammatory agents, a free radical scavenger to protect corneal endothelial cells, electrolytes to maintain the stability of ophthalmic tissues, an energy source to satisfy the metabolic requirements of corneal endothelial cells and other ophthalmic tissues during surgical procedures, bicarbonate to maintain the fluid pump system of corneal endothelial cells and other ophthalmic tissues, and a buffer.
• irrigating solutions comprising: one or more nonsteroidal antunflammatory agents, a free radical scavenger to protect corneal endothelial cells, electrolytes to maintain the stability of ophthalmic tissues, an energy source to satisfy the metabolic requirements of corneal endothelial cells and other ophthalmic tissues during
• the invention has a number of advantages relative to prior compositions and methods for treating ophthalmic inflammation.
• a principal advantage is that the irrigating solutions of the invention perform multiple functions.
• the solutions prevent cell necrosis and maintain normal cellular functions during ocular surgical procedures, as discussed above, but also modulate intraocular pressure, prevent surgically induced miosis, and suppress post-surgical inflammation and allergic reactions.
• the solutions are also useful for treating inflammation of ocular tissue associated with ocular surgery or other conditions, such as ulceris and conjunctivitis, and preventing cystoid macular edema.
• the extemporaneous addition of antunflammatory agents at the time of surgery presents several significant risks, such as the risk of an improper concentration of the antunflammatory agent.
• the present invention eliminates these risk by providing an ophthalmic pharmaceutical composition containing one or more nonsteroidal antunflammatory agents which is specifically formulated and adapted for use as an intraocular irrigant.
• Specific advantages of the compositions of the present invention therefore include: (i) delivery of a controlled dose of one or more antunflammatory agent to the patient; (ii) assurance that the composition is sterile at the time of use, and (iii) adaptation of the pH, osmolality and buffering capacity of the composition so that it is ideally suited for intraocular use.
• NSAIDs non-steroidal antunflammatory drugs
• NSAIDs may be generally categorized as cyclooxygenase and lipoxygenase antagonists. NSAIDs suppress inflammatory responses by disrupting the synthesis of prostaglandins. More specifically, this class of compounds inhibit cyclooxygenase, and cyclooxygenase converts arachidonic acids to prostaglandins. NSAIDs have generally diverse chemical structures. but all lack a steroid nucleus.
• This class of compounds includes various subclasses, based on chemical structure: salicylates, such as aspirin and salicylic acid: fenamic acids, such as flufenamic acid, niflumic acid and mefenamic acid; indoles, such as indomethacin, sulindac and tolmetin; phenylalkanoic acids, such as suprofen, ketorolac, flurbiprofen and ibuprofen; phenylacetic acids, such as diclofenac; and enolic acids (also referred to as pyrazolones), such as oxyphenbutazone and phenylbutazone. Further examples of salicylates, such as aspirin and salicylic acid: fenamic acids, such as flufenamic acid, niflumic acid and mefenamic acid; indoles, such as indomethacin, sulindac and tolmetin; phenylalkan
• NSAIDs are listed below.
• NSAIDS for purposes of the present invention are phenylalkanoic acids and phenylacetic acids.
• the most preferred NSAIDS are bromfenac, suprofen and diclofenac.
• the irrigating solutions of the present invention will typically contain one or more NSAIDs in an amount of from about 1 to about 200 millimoles/liter ("mM/1").
• the irrigating solutions of the present invention also include an amount of a free radical scavenger effective to protect the corneal endothelial cells and maintain normal function of those cells.
• the preferred free radical scavengers include ascorbate, glutathione and cysteine, as well as esters, and analogues and other equivalents of these compounds.
• the most preferred free radical scavenger is glutathione.
• the solutions will contain one or more free radical scavengers in a concentration of from about 0.01 to about 3 mM/1.
• the solutions further comprise: electrolytes in an amount effective to maintain
• tissue stability an energy source, such as dextrose, in an amount effective to satisfy the metabolic requirements of corneal endothelial cells and other ophthalmic tissues during the surgical procedure; an amount of bicarbonate effective to maintain the fluid pump system of corneal endothethial cells and other ophthalmic tissues; and a buffer in an amount sufficient to maintain the pH of the composition in the range of 6.8 to 8.0.
• an energy source such as dextrose
• the present invention may be embodied in various types of ophthalmic irrigating formulations, but will generally be provided in the form of an aqueous solution.
• some of the components of the formulations may need to be segregated prior to the time of use, due to considerations involving the chemical stability of certain components, the potential for adverse chemical interactions between certain components, and the methods of sterilization suitable for certain components, as discussed above under the heading "Background of the Invention".
• the most preferred embodiment of the present invention is a two-part product similar to BSS Plus ® Intraocular Irrigating Solution.
• the compositions of the two parts are such that each is individually stable and may be separately stored for long periods. When mixed together the two parts form a tissue irrigating solution that may be used for
• the mixed solution is useful for ocular surgery as it
• the combined irrigating solution contains the necessary factors to maintain endothelial cell integrity and corneal thickness during ocular surgery.
• the combined irrigating solution contains the necessary ions for tissue stability, Ca ⁇ , Mg ++ , Na + , K + and Cl " in a bicarbonate-phosphate buffer as well as reduced glutathione and dextrose.
• the electrolytes are provided in proportions conducive to maintaining the physical integrity and metabolism of corneal endothelial cells and other ocular tissues.
• the irrigating solution will typically contain from about 50 to about 500 millimoles per liter ("mM/1") Na + , from about 1 to about 10 mM/1 K + , from about 0.1 to about 5 mM/1 Ca**, from about 0.1 to about 10 mM/1 Mg "1-1" and from about 50 to about 500 mM/1 Cl " .
• the osmolality is between about 260 and about 330 mOsm and preferably about 290-310 mOsm. So as to closely match the physiological pH of 7.4, the pH of the final irrigating solution is between about 6.8 and about 8.0 and preferably about 7.2-7.8.
• the bicarbonate concentration in the combined irrigating solution is between about 10 and about 50 mM/1.
• an additional buffering agent is provided.
• the buffering agent is phosphate which is provided in sufficient quantity so that final phosphate concentration of the irrigating solution is between about 0.1 and about 5 mM/1.
• the final irrigating solution contains between about 1 and about 25 mM/1 dextrose and between 0.01 and about 3 mM/1 of glutathione.
• the neutral solution provides the phosphate and bicarbonate buffering moieties, preferably in the form of dibasic sodium phosphate and sodium bicarbonate.
• the pH of the solution is adjusted to about the physiological pH, of 7.4, preferably to between about 7.2 and about 7.8.
• the pH of a bicarbonate-containing solution is preferably above about 8.0 to prevent decomposition of the bicarbonate. It has been found, however, that the bicarbonate may be stabilized if it is added to a solution with a pH of above about 8 and thereafter adjusted to a pH between 7 and 8.
• Na 2 HPO 4 is added prior to the addition of NaHCO 3 , so that NaHCO 3 is dissolved in a solution with a pH of between about 8 and 9.
• the solution is thereafter adjusted with dilute acid, such as H 2 SO 4 , H-,PO 4 or HCl, to the desired final pH of the neutral solution.
• dilute acid such as H 2 SO 4 , H-,PO 4 or HCl
• carbon dioxide may be added
• Potassium and additional sodium are provided in the basic solution in the form of sodium and potassium salts, such as sodium or potassium chlorides, sulfates, acetates, citrates, lactates, and gluconates.
• the sodium and potassium are compatible with all of the moieties present in the finished tissue irrigating solution, and sodium chloride and potassium chloride may be added to either solution or divided between the solutions.
• the neutral solution provides the buffer system
• the pH of the final irrigation solution may be added to adjust the pH.
• the acidic solution provides the Ca “1"1" in the form of calcium chloride, the Mg ++ in the form of magnesium chloride, the glutathione and the dextrose.
• the pH is adjusted to about 5 or less to provide long-term stability to the dextrose and glutathione. Because of the requirement that the acidic solution have a low pH, it is preferable that the volume of the neutral solution greatly exceed the volume of the acidic solution and that the acidic solution contain no buffering agents.
• the acidic solution may be
• the ratio of the neutral solution volume to the acidic solution volume is about
• the neutral solution and the acidic solution are sterilized and separately bottled or contained under sterile conditions by standard techniques, such as autoclaving, or use of sterilizing filters, but preferably by heat sterilization.
• the neutral solution which preferably contains only inorganic moieties
• the acidic solution which preferably contains the organic components
• particular volumes of the neutral and acidic solutions be bottled so that adding the entire content of a container of the acidic solution to the entire content of a container of the neutral solution results in the correctly formulated tissue irrigating solution.
• the solutions may be mixed up to 24 hours before a surgical procedure without the occurrence of significant pH change and without the formation of detectable precipitates and without degradation.
• the solutions may be shipped in a container having a first chamber for the neutral solution, an isolated second chamber for the acidic solution and means to communicate the chambers without opening the container.
• a container may have a lower chamber containing a measured volume of the neutral solution separated by a membrane from an upper chamber containing a measured volume of the acidic solution or a lyophilized powder formed from that solution.
• the container cap may
• a plunger means which, when depressed, causes a sharp point of blade depending therefrom to break the membrane.
• the container is thereafter agitated, as by shaking, to complete the sterile mixing in proper volume of the acidic and neutral solutions.
• the proper mixing of the acidic and neutral solutions may also be carried out by aseptically removing the acidic solution from its package with a sterile syringe and needle and aseptically adding the acidic solution to the contents of the neutral solution package through the rubber stopper.
• a sterile double-ended needle can be used to transfer the acidic solution to the neutral solution by aseptically inserting one end of the needle into the vial containing the acidic solution and then aseptically inserting the other end of the needle into the neutral solution package, whereby the vacuum that is maintained therein transfers the acidic solution to the neutral solution and is mixed.
• a two compartment syringe can also be utilized, with the lyophilized powder of the acidic solution in one compartment, and a diluent for the powder in the second compartment.
• the compartments are separated by a movable stopper or membrane which can be displaced by depressing the plunger of the syringe, thereby allowing the diluent to be combined with the powder.
• the resulting solution is then added to the bottle containing the neutral buffered solution by inserting a cannula attached to the front of the syringe through a stopper in the top of the bottle.
• the two-part solution of the present invention also provides an advantage as to safety if a technician should fail to properly mix the two solutions.
• the larger volume neutral solution is physiologic so that there is less chance of toxicity if the basic solution were used with the acidic solution being mixed therewith.
• the present invention may be embodied in various types of formulations. Representative formulations are described in the following examples.
• Part I Intraocular Irrigating Solution available from Alcon Laboratories, Inc., Fort Worth, Texas, USA.
• That product which is described in United States Patent No. 4,550,022 (Garabedian, et al.), consists of two solutions referred to as "Part I” and "Part II", respectively.
• Part II Intraocular Irrigating Solution
• Part I neutral solution
• Part II acid solution
• Part II is made by dissolving calcium chloride dihydrate, magnesium chloride hexahydrate, dextrose, and glutathione in water for injection.
• the solution is then sterile filtered through a 0.22 micron membrane filter and aseptically filled into a presterilized bottle and sealed with a presterilized rubber stopper.
• the container is flushed with nitrogen gas. Also, a nitrogen blanket is maintained over the solution to displace air and protect the solution from oxidation. Immediately after flushing the filled container with
• One or more NSAIDS may be added to either the neutral solution or the acidic solution, depending on the PKA of the NSAIDs selected.
• the invention may also be embodied in products formulated or configured differently from the two-part product described above.
• one or more components of the formulation such as the above-described acidic solution containing glutathione, can be lyophilized (i.e., freeze-dried) following preparation and then reconstituted as a solution prior to use.
• a formulation of this type is described in United States Patent No. 4,975,419.

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• 1994
  • 1994-12-13 AU AU13996/95A patent/AU1399695A/en not_active Abandoned
  • 1994-12-13 WO PCT/US1994/014196 patent/WO1995016435A2/en not_active Application Discontinuation
  • 1994-12-13 CA CA002179147A patent/CA2179147A1/en not_active Abandoned
  • 1994-12-13 EP EP95905340A patent/EP0734248A1/de not_active Withdrawn
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