CA2179147A1 - Improved intraocular irrigating solution containing non-steroidal antiinflammatory agent - Google Patents

Abstract

Pharmaceutical compositions useful in ophthalmic surgery are described. The compositions include one or more non-steroidal antiinflammatory drugs, and are useful for preventing or treating ophthalamic inflammation and other conditions associated with ophthalmic surgery. Methods of using the compositions in connection with ophthalmic surgical procedures are also described.

Description

.' ' ' 217qt47 ,1 .
o 95116435 PcTrUss4~l4ls6 IMPROVED INTRAOCULAR IRRIGATING SOLUTION CONTAINING NON-STEROIDAL ANTIINFLAMMATORY AGENT
Back~round of Invention:
1. Fi~ of ~h,- Tnv~nrinn The present invention relates to the field of orhth~lmQlngy~ Morc particulady, tbe invendon relates to an improved solution for rn~inr~inin~ the integnty, shbility~ and function of ocular tissues during invasive surgical procedures.

2. Dic~c~inn of R-' ' Art The grovJth of new surgical techniques and associated products over the past decade has been quite remarkable. For examplc, cataract surgery, which is a very delicate operauon involving ~ G~ .. of the natural crystallin lens of the human eye with an artificia] lens, was prGviously considercd to be a major surgical procedure requiring hn5pit~1i70tinn 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 ' '~. Similar ~ ,--b have been achieved in other areas of ophthalmic surgery. The3e remarkable ad~ are attributable to various factors, including improved equipment for performing the surgerics, improYed surgical tGchniques developed by innovative surgeons, and improved ~ I products which facilitate successful surgery by minimizing the risks of damaging sensitive, irreplaceable ocular ti3sue during surget~. The present invention is directed to a further i~ u,~ o~lL in one such ~ 1 product. a soludon for irrigating ocular tissue during intraocular surgery. Such solutions are discussed in United ShteGs Patent No. 4,55û,û~2; the entire contents of that patent are hereby i-l-,oluu-dl~d in the present ~ ;r;, ~ ", by referencc . - 2 ~

Thc imponanee of such solutions to ophthalmie medieine is explained in the '0~ patent.
The relevant ponions of that explanation are repeated below.
Any scission into the human hody is d~trimenlal to the human hody and invarinblyresults in eell loss. The need to keep eell loss tn a minimum is partieularly erucial dunng any surgical proeedure petformed on delicate and ulcpla"~"iblc tissues, such as the tissues of the eye, nerves, ete.
The comea of the eye is eomprised of f~ve layers: epithelium, Bowman's membrane, sttoma, Deseemet's membrane, and ~n~oth~ nn The ~n~h,~ m layer is panieularly vulnerable to trauma as the endothelial eeLs are inftequently, if ever, teplaced as a normal ptocess in the adult life. The ~n~h~thf-~ nn is principally responsible for the of the proper state of hydration of the sttomal layer. The stromal layer has a tendeney to imbibe fluid, a tendeney whieh is eounter-balaneed by outwatd fluid transpor~ via the rn~ th~ nn If the proper fluid balanee is not maintained in the stromal layer, the eornea thiekens and the chatacteristic t~ tJ~cll~y of the eornea is lost.
Aeeordingly, eell loss or damage in the endothelial layer will result in decreased vision.
Failure of the ~ to perform its fluid transpon function for shon periods of timewill result in comeal thickening and visual elouding. Because of the importanee of, and the vulnerability of, the endothelial layer, it is necessary during eye surgery, such as cataract and retinal surgery or eomeal transplants, to make provisions for the protection of the endothelial eells.
A significant factor causing cell loss dunng tissue scission is the traumatic change in U~V~IUII~ c.;~ d by the internal eells. Exposure to the atmosphere prescnts afat different ~.,vi. u,,,~,~l,l for the eells than is provided by the natural fluids in whieh they are bathed. To simulate the natural eeLular .", v;-u~ and thereby prevent eel I damage, exposed tissue during surgery is frequently irrigated in solutions which attempt to approximate natural body fluids. The value of bathing eye tissue duting surgery to prevent eell datnage has long been tecognized. For intemal oeular tissues, sueh as thc ~,,luLh~LI~..,, the aqueous humor is the natural bathing fluid and, hence, an ophthalmic irrigating so~ution intended to protect the r~ t~ should as closely as possible resemble the aqueous humor.

. ~179147 Of primary concem in a tissue irrigating solution is that the osmolality of the solution he generally isotonic with cellular fluids so as to maintain equal osmotic pressure within and without the cell ml~mhr~n~ To this end, one of the early ophthalmic irrigating solutions was isotonic (0.9%) saline However, as has long been recognized, s isotonic saline is quite inadequate as an ophthalmic irrigating solution and has been shown to result in endotflelial cell swelling, cell damage, and consequent comeal clouding.
Because of the inadequacy of isotonic saline, Yarious altemative electrolyte soluhons have been proposed as ophthalmic irrigating solutions in attempts to provide solutions which more closely resemble the aqueous humor and prevent cell damage and comeal clouding. Standard electrolyte soluhons primarily intended for injection solutions, such as Ringer's solution and lactated Ringer's solution, haYe been used as ophthalmic irrigating solutions because of their wide availability as sterile solucions.
A solution intended for ophthalmic irrigation known as ''balanced salt solution" has also been deYeloped. Balanced salt solution contains tbe essential ions, calcium, sodium, potassium, magnesium and chloridG in generally optimal cnn~r.nfrAtinnc 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 over normal saline by providing necessary ions in addition to Na~ and Cl asprovidedbyisotonicsaline. Mg+tisanimportantcofactorforadenosinefrirhn~r~ cf~
an enzyme which plays an important role in mediating the fluid ttansport pump in the eye.
Ca~ is necessar,Y to maintain fhe endothelial junction. K' is an important factor in many l.;n. 1....,;. ,.1 processes, and the fluid transport pump of the r~ h~ requires a proper Nal/K+ ratio.
During eye surger,Y and particularly during surgery which requires extended periOd.c of time, proper electrolytic balance alone is insufficient to retain nommal comeal tbickness.
To maintain proper comeal tbickness 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~lK' pump system through which e~cess fluid is re~oved from the stroma.

~1 ~9 1 47 Wl~ 95/16 Z35 PCTn~S9 Z/1.1196 To incorp~ra~e factors necessary for sust~ined melabolism by endo~heli~l cells.
glu~athione-bicarc~na~e-Ringers solution ("GBR") was developed in which NaHCO;, glutathione, dextrose and adenosinc (an optional ingredient) are added ~o Ringer's solution.
Bicarbonate, dextrose and glutathione have been shown to be importan~ fac~ors inmAinlAinin~ structural integrity of endothelial cells. Bicarbonate is included because ~he aqueous humor has a bicarbonate buffer system; dextrose (d-glucose) provides a substr. te for various metabolic pathways; and glutathione has been shown to aid the metabulic pumr mechanism by mAin~Ainin~ proper Nat/K' adenosine-lrirhn~rh~tA~e. GBR has been shown effective in mAin~^:Ain,, corneal thickness and endothelial cell integnty for up to lo three hours.
While the effectiveness of a GBR ocular img~ting solution has been known for many years, prior to t}te early l9~0's its use in surgery was quite limited due to stability and sterility problems. It is to be appreciated that sterility of an ophthalmic irrigatin~
solu~ion is absolutely essential. To insure sterility, it is desirable that an irrigating solution be prepackaged so that the quality and steriZi~y may be closely monitored and tesled as contrasted with an extemporaneously mixed solution as might be prepared in a hospital pharmacy. The solution will perfuse the eye in essentiarZy a closed system where even a small number of organisms, such as ~ rl, AA,A~A aerZ gmosa, can produce an U~ g ,-nrlrJph~h^l~niti~
A~O GBR may not be l"~ r~ i due to the long term ;llr~ y 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 b,icarbonate as well as the phosphate in a bicarbonate-phosphate buffer system may form insoluble precipita~es with Mg~ and Ca~. While at the ionic f~ useful in ophthalmic imgation, ~5 ~lC~ iUll is not a problem in freshly prepared solution, long-term storage is proscribed.
As insoluble crystaZs introduced into the eye will doud vision, the importance of keeping a tissue irrigating solution free of insoluble precipitates may be readily Arrr~AAiAtPrl.
~'rmrlir~lin~ the rnAinlAnAAnr~ of GBR's stability is the fact that the pH of GBR
will graduaily increase due to the inadequacy of the bicarbonate-phosphate buffer. To 3û provide proper pH, i.e., about 7.4, the pH of the original GBR solutions prepared in the . 21791~7 ~ W095/lG435 PCT/TJS94114196 hospital pharmac~ had to be monitored and adjusted with CO, immediately prior to use and even during use. The chances for ronl~min~tinn during pH adjustment was great.
A further factor which proscribes long-term storage of GBR is the unavailabilityof a proper pH a~ which all of the moieties are stable. Severai moieties of GBR are unstable at the physiological pH of about ~.4. Below a rH of about 8, bicarbonate generally lr~ n~> to CO~, resulting both in a loss of bicarbonate cnn~Pntr~tinn and increased pH. On the other hand, glucose stability requires a pH of less than about 6.
G1 ~ ' , while biologically effective either in reduced or oxidized form, is preferred in the oxidized form because the reduced form quickly oxidiæs in aqueous solutions, preventing proper labeling of the irrigating solution. Oxidized glutathione (glutatbione disulfide) is unstable over extended penods of time at a pH of above about 5. The concentration of glutathione may also decrease to an, hiP cnnrPntrAtinn when stored over long periods of time in admixture with all otber rnmrnnPn~ Because of the rlt~nnnnc r~tt~d efficacv 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 describe~ in U.S
Patent No. 4,550,022 provided such a product. An ~ ~ hr~ 1 of the two-part irrigating solution described in U.S. Patent No, 4.550,022 Icnown as "BSS Plusa~ Intraocular Irrigating Solution" was introduced by Alcon r,~hnr~tnri~s, Inc., Fort Worth, Texas, in the early 1980s.
Ophthalmic irrigating solutions such as BSS Plus(f) Intraocular Irrigating Solution serve to maintain the physical integrity and function of ophthalmic tissues. The chemical cnn~rn~itinn of such solutions mimics that of the nuid naturally present within the eye (i.e., "aqueous humor"). Although such solutions are well-suited to maintain the norrnal function of ophthalmic tissues, these solutions are not directly usefol in treating or preventing abnormalities such as ;"ri~ Since ;"n~ ;.,., of ophthalmic tissues is a problem frequently associated with ophthalmic surgical procedures, there has been a need for an improved ocular irrigatiAg solution which not only maintaiAs the physical integrity and function of ophthalmic tissues, but also prevents or alleviates jnfi~nnln~tinn of those tissues. The present invention is directed to satisfying this need.

21791~7 o 95116435 Pcr~594/14196 Both steroidal and non-steroidal agents have bccn uùlized ~o treat ophthdlmic infl~mm~tinn The use of non-steroidal ~ntiinnAmm~tnry agents is believed to h~vecertain advantages relative to tht use of steroids. Amnng other things, the nnn-slernidal agents are relatively snluble in water, while sternids having potent ~ l;;"rlA",-~tnry 5 activity (e g., 11r ` .. If Lh ``. ' -- ) are generally not soluble in water. Moreover, s~eroids have a propensiy to elevate intraocular pressure in some patients. Since intraocular irrigatin~
soluùons are generally ao,ueous, the solubility of an An,iinfl~mm1tnr~ drug in water is an important consideration.
The use of non-steroidal ~ lry agents in conjunction with an intraocular 0 irrigating solution is descnbed in a series of articles by Shimada, et al. See, e.g., Shimada, et al., "Effects of ll...l,i~,-u-,,., on F~ , Cataract Extraction", Atarashii ~'lar~ca (Jo-m~l of th.- Eye~. volume 4, number ~, pages 719-722 (1987). The experiments conducted by Shimada, et al., focused on the ability of llu~ vrt", to mainLain dila[ion of the pupil during inLraocular surgical pmcedures~ A balanced salt solution was used as the vehicle for the nu-bi"ur~ Similar r ~ involving the use of flurbiprofen and in~inmPthqr;n in buffered saline solutions are descnbed in Gimbel, "The Erîect of Treatment with Topical Nv-,~t~.vi,ldl Anti-;..n~ ..y Drugs with and withou~
Intraoperative Fl.;,.. ~,h ;. on the MAintPn~nre of Mydriasis during Cataract Surgery", OohthAlmn~ v. volume 96, number 5, pages 585-588 (1989) The use of ;.. l,.. Il ~ ;"
to reduce swel~ing and other trauma associated with ophthalmic surgery is described by Alvarez, et al., "Role of the intraocular irrigating solutions in the r~thngPn~cic of the iLlt;~,LUllly retinal edema". Curren~ye Research. volume 6. number 12, pages 1369-1379 (1987). The use of non-steroidal anti- '' y agents to trea~ corneal endothelial tissues is described in U.S. Patent No. 5,051,443 issued to Neufeld, el al, on September 24, 1991 None of the above-cited F~hlirAtinnc discloses or suggests the combined use of a nonsteroidal Antiir~ ry drug and an ophthalmic imgating solution of tbe type described and claimed herein~
S~mm~ry of lhP ~nvention:
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 Wo 95/16435 PCT/US94/14196 is particularly useful in prevenLing or treating inflammation associated with ophthalmic surgery. More specificalJy. the invention is directed to imgatlng solutions compnsing:
one or more nonsteroidal ~ tory agents, a free radical scavenger ~o protecl comeal endothelial cells, electrolytes to maintain the stability of ophthalmic tissues, an energy source to satisfy the metabolic l~u~uiuulm~ of corneal endothelial cells and other ophthalmic tissues during surgical procedures. bicarbonale to maintain the fluid pum~
system of corneal endothelial cells and other ophthalmic tissues, and a buffer.
The invention has a number of advantages relative to prior f nmrn~i~innc and methods for treating ophthalmic i,,ll- ,,,,~l;,,,. A principal advantage is that the irrigating solutions of the invention perform multiple functions. The solutions prevent cell necrosis and maintain norfnal cel~ular functions during ocular surgical procedures, as discussed above, but also modulaoe intraocular pressure, prevent surgically induced miosis, and suppress post-surgical intl~mnl~-inn and allergic reactions. The solutions are also useful for treating ;, n~ ", of ocular tissue associated with ocular surgery or other conditions, such as iritis and ,UlljUll~LiViLi~, and preventing cystoid macular edema.
The ~AU,IUuOlf~ _uu~ addition of A":;;~n~ y agents at the time of surgery presents several significant risks, such as the risk of an improper rnn~Pntr~tinn of the ~"I;;"nA~ ry agent The present invention eliminaoes these risk by providing an ophthalmic r~ f nmrn~itinn containing one or more nonsteroidal ~n~iin,f~ ry agents which is specifically forrnulated and adapted for use as an rntraocular irrigant. Specific advantages of the ~ f,~ of the prcsent invention therefore include: (i) delivery of a controlled dose of one or more ,~ y agent to the patient; (ii) assurance that the f ullly~.~iLiul, is soerile at the time of use, and (iii) adaptation of the pH, osmolality and buffering capacity of the ~ -- so that it is ideally suited for intraocular use DP~rrirtinn nf Preferred l~...I,n,l;,... :~:
Tlle non-steroidal ~ y drugs ("NS AIDs ") used in the present in vention may be generally categorized as cyclooxygenase and llyoJ~f~lla5f antagonists NSAlI)s suppress infl~mm~tnry responses by disrupting the synthesis of prnct~el~nf~inc More specifically, this class of compounds inhibit cyclooxygenase, and cyclooxygenase converts 2~79~7 WO 95/16~35 PCT/U594/14196 arachidonic acids to proc~ n~linc~ NSAlDs have generally diverse chemical structurcs.
but al~ lack a steroid nucleus. This class of compounds includes various subclasses, based on chemical structure: salicylates, such as aspirin and salicylic ~cid; fenamic acids, such as flufenamic acid, niflumic acid and mefenamic acid; indoles, such as in~inmPth~rin sulindac and tolmetitn; phenylalkanoic acids, such as suprofen, ketorolac, flurbiprofen and ibuprofen; phenylacetic acids, such as diclofenac: and enolic acids (also referred to as pyrazolones), such as u~y~ and phenylbutazone. Further examples of NSAIDs are listed below.
Nimesulide Amfenac Indoprofen û Bromfenac Fenoprofen Fcnclozic acid Acecloferac Carprofen Orpanixin Flosulide Flurofenoc Fenbufen Mefezoloc Fenclorac Benoxaprofen .nmn~ m Felbinac Naproxen 5 Ketoprofen Pirprofen Isofezolac Trapsufenic acid Clidanac Etodolic acid Proquazine Loxoprofen FnfPn~miC~rir Lornoxicam BW 7556 For further background concerning NSA~Ds, see J. P. Famaey, et al., Therareutic ~rlh-~-innc of NSATr~s. published by Marccl Dekker, Inc., New York, New York, USA
(1992). For a specific discussion of the use of NSAlDs in the field of ophthalmology, see Chapter 16 of that text and the following article: Allan J. Flach, "Cyclo-oxygenase Inhibitors in Ophthalmology", Survev of Ol~hth~lmnlocv volume 36, number 4, pages 259-283 (1992). The entire contents of both of the above-cited ~ bl;c ~ are hereby h.~UllJUldL~d in the present crl.~ifir1tinn by reference.
The preferred subclasses of NSAIDS for purposes of the present invention are p~._..yldlk~loic 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 NSAlDs in an amount of from about I to about 20Q millimoles/liter ("mM/I").

Wo 95/16435 PCTNS94/14196 The irrigating solutions of ~he present invention also include an amoun~ of a ~`ree radical scavenger effective ~o ~rotect the comeal endothelial cells and mainlain normal function of those cells. The preferred free radical scavengers include ascorbate, glutathione and cysOEine, as well as esOErs, and analogues and other equivalents of these -nmro~md~ The most preferred free radical scavenger is glutathione. Thc solutions wil~
contain one or more free radical scavengers in a rnnr,-ntr~inn of from about 0.01 to ahout 3 mM/I.
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 lGuuur~lr~ of corneal endothelial cells and other ophthalmic tissues dunng the surgical procedure; an amount of hicarbonaOE effective to maintain the f uid pump sysOEm of corneal Pn~nthPthi~l cells and other ophthalmic tissues; and a buffer in an amount sufîîcient to maintain the pH of the cnmrn~irinn in the range of 6.8 to 8Ø
The present invention may be embodied in various types of ophthalmic irrigating form~ tinn~, but will generally be provided in the form of r,n aqueous solution. As will be appreciated by those skilled in the art, some of the components of the formulations may need to be segregated prior to the time of use, due to ~nn~i~iPr~tinn~ involving tbe chemical stability of certain ~ . the potential for adverse chemical interactions between cert~in ~ . and the methods of sterilization suitable for certain ~,OlU,UUIIC,III~, aS discussed above under the heading "Background of the Invention'`.
The most preferred PmhodimPnt of the present invention is a two-part product similar to BSS Plus~ Intraocular Irrigating Solution. The ~ ,n~ of thc two partsare such that each is individually stable and may be separately stored for long periods.

. . ~17~4;~
Wo 95/16435 Pcrlu594/14196 When mixed ~ogether the two parts form 3 tissue im~ating solution that m~y he used for surgery during the next 24 hours. The mixed solution is useful for ocular surgery as it contains the necessary factors to maintain endothelial cel] inregrity and corneal thickness during ocular surgery. The combined imgating solution contains the necessary ions for s tissue stability, Catt, Mgt', Nat, K+ and Cl in a bicarbonate-phosphate buffer as well as reduced glutathione and dextrose. The electrolytes are provided in proportions conducivc to m~inr~;ning the physical integrity and metabolism of corneal endothelial cells and other ocular tissues. For this purpose, the irrigating solution will typically contain from about 50 to about 500 millimoles per liter ("mM/I") Nat, from about I to about 10 mM/I K', 0 f}om about 0.1 to about 5 mM/I Cat~, from about 0.1 to about 10 mM/I Mgtt and from about 50 to about 500 mMA Cl. To maintain the osmohc stability of the cells, theosmolality 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.Z-7.8. To maintain the fluid pump system, the bicarbonate ~ in the combined irrigating solution is between about 10 and about 50 mM/I. To stabilize the pH, an additional buffering agent is proYided. Preferably the buffering agent is phosphate which is provided in sufficient quantity so that final phosphate ~ -t;-l ~ of the irrigating solution is between about 0.1 and ahout 5 mM/I. The final irrigating solution contains between about I and about zo 25 mM/I dextrose and between 0.01 and about 3 mMA 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 217~1~7 wo sstl6~3s PCrlUS9411~196 7.2 and about 7.8. As hereinbefnre mentioned, the pH of a bicarbonate-containingsolution is preferably above about 8.0 to preven~ rnmrn~ition of the bicarbonate. 1~ h~ls been found, however, that the bicarbonate may be stabi~ized if it is added to a solution with a pH of above about 8 and thereafter adjusted to a pH between 7 and 8.
Accordingly, when the neutral solution is prepared, Na~HPO~ is added pr~or to the addition of NaHCO3, so that NaHCO3 is dissolved in a solution with a pH of between ab()ut 8 and 9. The solution is thereafter adjusted with dilute acid, such as H3SO~, H3PO~ or HCI, to the desired fmal pH of the neutral solution. Alternatively, carbon dioxide may be added to adjust the pH.
o Potassium and additional sodium are provided in the basic solution in the form or sodium and potassium salts, such as sodium or potassium chlorides, sulfates. acetates, citra~es, ~actates, and gluconates. Tbe sodium and potassium are compatible with all of the moieties pnesent in the finished issue irrigating solution, and sodium chloride and potassium chloride may be added ~o either solution or divided between the solutions.
However, in view of the fact that the neutral solution provides thc buffer system, thc pH
of the final irrigation solution may be added to adjust the pH.
The æidic solution provides the Ca~ in the form of calcium chlonde, 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 ~u,u;.~ L that the acidic solution haYe 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 adjusted below a pH of about 5 with a relatively small amount of HCI. Because the - - . 2179~7 WO 95116435 PCT/lJS94114t96 acidic solution is unbuffered. its pH is a reflection of the ~cid COnCenlralion and ~ess icid is needed to adjust Lhe pH of a small volume. The large volume of buffered neutr~]
solution may be adjusted very close to the final pH of the irrigating solution and will bc relatively unaffected by the addition of tbe ~mall volume of the acidic solutionPreferably, Lhe ratio of the neutral solution volume to the acidic solution volume is about 10 to I to about 40 to 1.
The neutral solution and Lhe acidic solution are stenlized and separately bottled or contained under sterile conditions by sLandard oechniques, such as autoclaving, or use of soerilizing filters, but preferably by heat st~rili7.-i()n Typically, the neutral solution, 0 which preferably contains only inorganic moieties, is autoclaved, wheneas tbe acidic solution, which preferably contains the organic ~ is microfiltered. To avoid the need for measuring volumes in the hospital which may introduce possible error andlor cnn~min~tinn~ it is highly preferred tbat particular volumes of the neutral and acidic solutions be boLt~ed so that adding the entire content of a conLainer of the acidic solution to the enhre conoent of a container of Lhe neutral solution nesulLs in the correctly formulaoed 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 Lhe formation of detectable pnecipitateS and without rit~er~tinn Precautions to maintain sterility of the soluLons and to insure correct mixing of the zo acidic and neutral solutions cannot be overdone. While Lhe rnanufacturer may takc all due precauLons Lo mainLain quality control. ~ ' by a oechnician may render all such precauLons for naughL Any opening of a container, no matter how carefully performed, increases Lhe likelihood of rnn~min~inn in the contenLs. ~s one meLhod of substantially 21 ~9~7 WO 95/16435 PCT/~59.t/1~1196 eliminating the possibility of improper mixin~ and to reduce the likelihood or r nn-~mir~ n, the solutions may be shipped in a con~aaner having a firsL chamher tol the neutral solution, an isolated second charnber for the acidic solution and mean~ to u~ te. the chambers without opening the cont~iner. Various types of con~ainer~
S for the shipment of multi-part medical solutions may be utilized. As one example, 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 Iyophilized powder formed from that solution. The container cap may include a plunger means which, when depressed, causes a sharp point of blade depending thcrefrom to break the membrane. The container is thereafter agit~ted, as by shaking, to complete the sterile mixing in proper volume of the acidic and neutral soluhons.The proper mixing of the acidic and neutral solutions may also be carried out byaseptically 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. Alternately, a sterile double-ended needle can be ased 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 nedle 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 ~0 ~,ulllp~uL~ lt syringe can also be utilized, with the Iyophilized powder of the acidic solution in one ~ ll, and a diluent for the powder in the second compartment.
The u~lilpolLI~lLs are separated by a movable stopper or membrane which can be displaced by depressing the plunger of the synnge, thereby allowing the diluent to be WO 95116435 PCTIUS94/]4196 combined with the powder. Once the powder is dissolved, the resulting solution is thcn added to the bottle containing the ncutral buffered solution by inserting a cannula attached to the front of tbe syringe through a stopper in the top of the bottle.
The two-part solution of the present invention also provides an advantage as ~o safety if a lechnician 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 solu[ion were used with thc acidic solution being mixed therewith.
The pnesent invention may be embodied in various types of forrn~ ti~nc R~lc~c",~~ r -"~ c are described in the following examples.
F.~t~MPl.Tr, I
The following two-part formulation is similar to the BSS Plus6~ Tntraocular Irrigating Solution available from Alcon T ~ r~t~ri~c, Inc., Fort Worth, Texas, USA. That product, which is described in United States Patent No. 4.sso,0æ (Garabedian, et al.), consists of two solutions referred to as "Part 1" and "Part II", respectively. The following description illustratcs how that product or similar products could be modirled Lo incorporate the present invention.
Part I (neutral solution) is made by dissolving sodium chloride, potassium chloride, and anhydrous dibaslc sodium phosphate in water for injection at about 20' C. Then sodium bicarbonate is added and dissolved. Additional water for injection is addcd to make the desired volume and IN HCI is added to adjust thc pH to about 7.4. The solution is then passed through a 0.45 micron Millipore filter and placed in a bot~le. The filled bottle is then stoppered. vacuumed and sealed. The sealed bottle is sterilized hy autoclaving at 121' C for about 23 minutes.

21 ~9 ~
Wo 95/16~35 PCT~Sg4/14196 Part n (acidic solution) is made by dissolYing 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 l"' ~ bottle and sealed with a rreslPrili7~ rubber stopper.
For many free radicals tbat are sensitive to oxygen, tbe container is flushcd with nitrogen gas. Also, a nitrogen blar~et is maintained over the solution to displace air and protect the solution from oxidation. Immediately after flushing the filled container with nitrogen gas, it is sealed by means of a rr~.~t~rili7Pd rubber stopper.
One or more NSAIDS may be added to either tbe neutral solution or the acidic 0 so~ution, depending on the PKA of the NSAlDs selected.
When Parts I and 11 are combined, the ~ of the resulting formulation is as follows:
Troredients ~n~ ' '' (rM/I) Reduced Glutathione 0.01-3.0 Bi-.~ 1-50 Calcium 0. 1-5 M~rlr~ m 0.1-10 Potassium 1-10 2~ Sodium 50-500 Phosphate 0. 1-5 Glucose 1-25 Chloride 50 500 Sodium Hydroxide Adjust pH
' 25 and/or Hydrochloric Acid Adjust pH
Water for Injection q 5 2 1 i7~ ~ ~.7 wo 95/16435 Pcr~594/14196 The following formulation is a more specific example of the Part I solution described in Example I above:
In,predients C~ - Cnnrl~n~ration G clpart I ~480ml) Suprofen 0 4800 1.00 Sodium Chloride, USP 3.5712 7 440 Potassium Chloride, USP .1896 .395 Dibasic Sodium Phosphate .2078 433 Sodium Bicarbonate .1261 263*
Purge with CO2 to Adjust pH
Water for Injection q.s. 480 ml * Includes 20% excess The invention may also be embodied in products formulated or configured differently from the two-part product described above. For example, one or more ~;~ r of the formulation, such as the above-described acidic solution containing nr can be Iyophilized (i.e., freeze-dried) following preparation and then as a solution prior to use. A formulation of this type is described in ~Inited States Patent No. 4,975,419.

Claims (24)

What is Claimed is:

1. A pharmaceutical composition for irrigating ophthalmic tissue during an intraocular surgical procedure comprising:

an antiinflammatory effective amount of a nonsteroidal antiinflammatory drug;

an amount of a free radical scavenger effective to maintain normal function of corneal endothelial cells;

electrolytes in an amount effective to maintain tissue stability;

an energy source 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 8Ø

2. A composition according to Claim 1, wherein the nonsteroidal antiinflammatory drug comprises a phenylalkanoic acid.

3. A composition according to Claim 1, wherein the nonsteroidal antiinflammatory drug comprises a phenylacetic acid.

4. A composition according to Claim 1, wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of suprofen, bromfenac, diclofenac, ketorolac, flurbiprofen and ibuprofen.

5. A composition according to Claim 1, wherein the composition comprises a first part and a second part, said first part comprising a neutral solution containing the bicarbonate and the buffer, and said second part comprising an acidic solution containing the free radical scavenger, the energy source and the divalent electrolytes, and wherein the nonsteroidal antiinflammatory drug and monovalent electrolytes are contained in either said first part or said second part.

6. A composition according to Claim 5, wherein the free radical scavenger is selected from the group consisting of ascorbate, glutathione and cysteine.

7. A composition according to Claim 5, wherein the free radical scavenger comprises glutathione.

8. A composition according to Claim 5, wherein the composition comprises:
0.1 to 5 mM/l of the free radical scavenger;
1 to 25 mM/l of dextrose;
1 to 200 mM/l of the nonsteroidal antiinflammatory drug;
50 to 500 mM/l Na+;
1 to 10 mM/l K+;
0.1 to 5 mM/l Ca++;
50 to 500 mM/l Cl;
10 to 50 mM/l bicarbonate; and 0.1 to 5 mM/l phosphate.

9. A composition according to Claim 8, wherein the nonsteroidal antiinflammatory drug comprises a phenylalkanoic acid.

10. A composition according to Claim 8, wherein the nonsteroidal antiinflammatory drug comprises a phenylacetic acid.

11. A composition according to Claim 8, wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of suprofen, bromfenac, diclofenac, ketorolac, flurbiprofen and ibuprofen.

12. A composition according to Claim 8, wherein the free radical scavenger is selected from the group consisting of ascorbate, glutathione and cysteine.

13. An improved method of irrigating ophthalmic tissue during intraocular surgical procedures which comprises applying to the affected ocular tissue a composition comprising:

an antiinflammatory effective amount of a nonsteroidal antiinflammatory drug;

an amount of a free radical scavenger effective to maintain normal function of corneal endothelial cells;

electrolytes in an amount effective to maintain tissue stability;

an energy source 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 8Ø

14. A method according to Claim 13, wherein the nonsteroidal antiinflammatory drug comprises a phenylalkanoic acid.

15. A method according to Claim 13, wherein the nonsteroidal antiinflammatory drug comprises a phenylacetic acid.

16. A method according to Claim 13, wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of suprofen, bromfenac, diclofenac. ketorolac, flurbiprofen and ibuprofen.

17. A method according to Claim 13, wherein the composition comprises a first part and a second part, said first part comprising a neutral solution containing the bicarbonate and the buffer, and said second part comprising an acidic solution containing the free radical scavenger, the energy source and the divalent electrolyoes. and wherein the nonsteroidal antiiflammatory drug and monovalent electrolytes are contained in either said first part or said second part.

18. A method according to Claim 17, wherein the free radical scavenger is selected from the group consisting of ascorbate, glutathione and cysteine.

19. A method according to Claim 17, wherein the free radical scavenger comprises glutathione.

20. A method according to Claim 17, wherein the composition comprises:
0.1 to 5 mM/l of the free radical scavenger;
1 to 25 mM/l of dextrose;
1 to 200 mM/l of the nonsteroidal antiinflammatory drug;
50 to 500 mM/l Na+;
1 to 10 mM/l K+;
0.1 to 5 mM/l Ca++;
50 to 500 mM/l Cl;
10 to 50 mM/l bicarbonate; and 0.1 to 5 mM/l phosphate.

21. A method according to claim 20, wherein the nonsteroidal antiinflammatory drug comprises a phenylalkanoic acid.

22. A method according to claim 20, wherein the nonsteroidal antiinflammatory drug comprises a phenylacetic acid.

23. A method according to Claim 20, wherein the nonsteroidal antiinflammatory drug is selected from the group consisting of suprofen, bromfenac, diclofenac, ketorolac, flurbiprofen and ibuprofen.

24. A method according to Claim 20, wherein the free radical scavenger is selected from the group consisting of ascorbate, glutathione and cysteine.