United States Patent [19]
`Desai et al.
`
`[54] PRESERVED OPHTHALMIC DRUG
`COMPOSITIONS CONTAINING POLYMERIC
`QUATERNARY AMMONIUM COMPOUNDS
`
`[75]
`
`Inventors: Suketu D. Desai; Diane S. Nelms, both
`of Fort Worth, Tex.
`
`[73] Assignee: Alcon Laboratories, Inc., Fort Worth,
`Tex.
`
`[21] Appl. No.: 340,763
`
`Nov. 16, 1994
`
`[22] Filed:
`Int. Cl.6
`............................ A61K 6/00; A61K 31174;
`[51]
`A61K 47/00
`[52] u.s. ci . ....................... 424n8.04; 424/401; 5141912;
`5141913; 514/914; 514/954
`[58] Field of Search ................................. 424/401, 78.04,
`424/657, 658, 659, 660; 5141912, 913,
`914, 954
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`US005603929A
`5,603,929
`[11] Patent Number:
`[45] Date of Patent:
`Feb. 18, 1997
`
`4,407,791 10/1983 Stark ......................................... 424/80
`4,525,346
`6/1985 Stark ......................................... 424/80
`4,822,819
`4/1989 DeSantis et al ........................ 514/530
`4,822,820
`4/1989 DeSantis et al ........................ 514/530
`4,836,986
`6/1989 Ogunbiyi et al .......................... 422/28
`8/1989 Mazuel et al ............................. 514/54
`4,861,760
`4,960,799 10/1990 Nagy ....................................... 514/567
`5,037,647
`8/1991 Chowhan et al ......................... 424n8
`5,110,493
`5/1992 Cherng-Chyi et al .................. 514/413
`5,149,693
`9/1992 Cagle et al ............................... 514/40
`5,149,694
`9/1992 Cagle et al ............................... 514/40
`5,173,507 12/1992 DeSantis et al ........................ 514/530
`5,188,826
`2/1993 Chandrasekaran et al .......... 424n8.04
`5,300,287
`4/1994 Park ..................................... 424n8.04
`5,342,620
`8/1994 Chowhan ................................ 424/422
`
`FOREIGN PATENT DOCUMENTS
`
`89/06964
`91/09523
`94/15597
`
`8/1989 WIPO .
`7/1991 WIPO .
`7/1994 WIPO .
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner--Sharon Howard
`Attorney, Agent, or Firm-Patrick M. Ryan
`ABSTRACT
`
`[57]
`
`3,931,319
`4,027,020
`4,136,173
`4,136,177
`4,136,178
`
`111976 Green et al. . ........................ 260/567.6
`5/1977 Green et al. ....................... 424/248.56
`111979 Pramoda et al ......................... 424/177
`111979 Lin et al. ................................ 424/211
`111979 Lin et al. ................................ 424/211
`
`Disclosed are storage-stable preserved ophthalmic compo(cid:173)
`sitions containing acidic drugs in combination with poly(cid:173)
`meric quaternary ammonium compounds and boric acid.
`
`20 Claims, No Drawings
`
`LUPIN EX1005, Page 1
`
`

`
`5,603,929
`
`1
`PRESERVED OPHTHALMIC DRUG.
`COMPOSITIONS CONTAINING POLYMERIC
`QUATERNARY AMMONIUM COMPOUNDS
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates generally to ophthalmic
`compositions. In particular, the present invention relates to
`the use of a polymeric quaternary ammonium compound and
`boric acid to provide preserved, storage-stable ophthalmic
`compositions of acidic drugs.
`Ophthalmic formulations generally contain one or more
`active compounds along with excipients such as surfactants,
`comforting agents, complexing agents, stabilizers, buffering
`systems, chelating agents, viscosity agents or gelling poly- 15
`mers and anti-oxidants. Ophthalmic formulations which are
`intended for multidose use require a preservative.
`Organo-mercurials have been used as preservatives in
`ophthalmic formulations including ophthalmic solutions of
`acidic drugs. These organo-mercurials include thimerosal, 20
`phenylmercuric acetate and phenylmercuric nitrate. Organo(cid:173)
`mercurials, however, have limitations due to potential mer(cid:173)
`cury toxicity and poor chemical stability.
`Sorbic acid, has also been used to preserve ophthalmic
`formulations, but it too possesses poor chemical stability as 25
`well as poor antimicrobial activity.
`Benzalkonium chloride is a widely used preservative in
`ophthalmic solutions. However, benzalkonium chloride and
`other quaternary ammonium compounds are generally con(cid:173)
`sidered to be incompatible with ophthalmic compositions of
`drugs with acidic groups, such as nonsteroidal antiinflam(cid:173)
`matory drugs ("NSAIDS"). These preservative lose their
`ability to function as they form complexes with the charged
`drug compounds.
`U.S. Pat. No. 5,110,493 discloses stable ophthalmic 35
`NSAID formulations which do not contain organo-mercurial
`preservatives. Instead, the reference NSAID formulations
`use quaternary ammonium compounds, such as cetyltrim(cid:173)
`ethylammonium bromide, cetylpyridinium chloride and
`preferably, benzalkonium chloride, and a stabilizing amount 40
`of a nonionic surfactant.
`PCf application WO 94/15597 discloses the use of lau(cid:173)
`ralkonium chloride, the c12 homolog of benzalkonium chlo(cid:173)
`ride, in ophthalmic formulations of drugs which are incom- 45
`patible with benzalkonium chloride. Unlike the mixture of
`alkyldimethylbenzylammonium chloride known as benza(cid:173)
`lkonium chloride, this PCT application discloses that lau(cid:173)
`ralkonium chloride is compatible with acidic drug entities;
`apparently it does not form insoluble ion complexes with the 50
`charged drug compounds.
`In some cases, the present lack of a single preservative
`which is safe, stable, and able to meet both the United States
`Pharmacopoeia (USP) and European Pharmacopoeia (Ph.
`Eur.) preservative effectiveness requirements for ophthalmic
`formulations of acidic drugs has forced pharmaceutical
`companies to develop more than one formulation of the
`same drug, with each formulation containing a different
`preservative.
`U.S. Pat. No. 4,960,799 discloses storage stable aqueous
`ophthalmic compositions containing diclofenac, a nonste(cid:173)
`roidal antiinflammatory drug, and/or its pharmaceutically
`acceptable salts. The reference compositions include EDTA
`as a stabilizing agent, a solubilizer such as polyethoxylated
`castor oil, and a bacteriostat. The preferred bacteriostats are 65
`thimerosal and sorbic acid. No mention is made of any
`polymeric quaternary ammonium preservative.
`
`2
`The use of POLYQUAD® and other polymeric quater(cid:173)
`nary ammonium compounds as a disinfectant and preserva(cid:173)
`tive in contact lens care and artificial tear solutions is known.
`See, for example, U.S. Pat. Nos. 5,037,647; 4,525,346; and
`5 4,407,791.
`U.S. Pat. No. 4,525,346, in addition to disclosing appli(cid:173)
`cations in contact lens and artificial tear solutions, also
`discloses the use of certain polymeric quaternary ammonium
`compounds in formulations containing certain ophthalmic
`10 drugs. However, neither this reference nor any of the other
`references mentioned above discloses the use of a polymeric
`quaternary ammonium compound as a preservative in for(cid:173)
`mulations of acidic ophthalmic drugs, that is, drugs which
`may be incompatible with positively charged preservatives.
`
`SUMMARY OF THE INVENTION
`
`It has now been discovered that the use of a combination
`of a polymeric quaternary ammonium compound such as
`POLYQUAD® and boric acid in ophthalmic compositions
`of acidic drugs provides a storage-stable composition which
`has surprisingly good preservative efficacy. This preserva(cid:173)
`tive combination of a polymeric quaternary ammonium
`compound and boric acid is useful in ophthalmic composi(cid:173)
`tions of acidic drugs such as prostaglandins, antifungals,
`antibactedals, and diagnostic agents. This preservative com(cid:173)
`bination is especially useful in ophthalmic solutions of drugs
`containing either a carboxyl group such as non-steroidal
`anti-inflammatory drugs (NSAIDS) or a sulfonamide group
`30 such as antibacterial drugs.
`The present invention also relates to a method for treating
`or controlling ocular inflammation which comprises topi(cid:173)
`cally administering to the affected eye a composition com(cid:173)
`prising a NSAID, a polymeric quaternary ammonium com(cid:173)
`pound and boric acid.
`Among other factors, the present invention is based on the
`discovery that ophthalmic compositions containing a poly(cid:173)
`meric quaternary ammonium compound and boric acid may
`be effectively preserved by the USP and Ph. Eur. preserva(cid:173)
`tive effectiveness requirements despite the absence of
`EDTA, a conventional chelating agent known to potentiate
`the antimicrobial activity of preservatives such as benzalko(cid:173)
`nium chloride and sorbic acid.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The polymeric quaternary ammonium compounds useful
`in the compositions of the present invention are those which
`have an antimicrobial effect and which are ophthalmically
`acceptable. Preferred compounds of this type are described
`in U.S. Pat. Nos. 3,931,319; 4,027,020; 4,407,791; 4,525,
`346; 4,836,986; 5,037,647 and 5,300,287; and PCT appli-
`55 cation WO 91/09523 (Dziabo et a!.). The most preferred
`polymeric ammonium compound is polyquaternium 1, oth(cid:173)
`erwise known as POLYQUAD® or ONAMERM® with a
`number average molecular weight between 2,000 to 30,000.
`Preferably, the number average molecular weight is between
`60 3,000 to 14,000.
`The polymeric quaternary ammonium compounds are
`generally used in the compositions of the present invention
`in an amount from about 0.00001 to about 3 wt %, prefer(cid:173)
`ably from about 0.001 to about 0.1 wt %. Most preferably,
`the compositions of the present invention contain from about
`0.001 to about 0.05 wt% of polymeric quaternary ammo(cid:173)
`nium compounds.
`
`LUPIN EX1005, Page 2
`
`

`
`15
`
`20
`
`30
`
`EXAMPLE 1
`
`The following formulations are representative of pre(cid:173)
`ferred compositions of the present invention.
`
`Ingredient
`
`Sodium Diclofenac
`Sulfacetamide
`Sodium
`Suprofen
`HPMC*
`Tromethamine
`Boric Acid
`Vitamin E TPGS**
`Mannitol
`POLYQUAD®
`HCl!NaOH
`Purified Water
`
`A
`
`0.1
`
`Formulation (wt %)
`c
`
`B
`
`10
`
`0.1
`2.0
`1.2
`3.0
`3.5
`4
`q.s. to pH 7.4
`q.s. to 100%
`
`0.1
`2.0
`1.2
`3.0
`1.6
`0.005
`q.s. to pH 7.4
`q.s. to 100%
`
`0.25
`0.1
`2.0
`1.2
`3.0
`3.6
`0.005
`q.s. to pH 7.4
`q.s. to 100%
`
`*Hydroxypropyl Methyl Cellulose
`**Vitamin E Tocopheryl Polyethylene Glycol 1000 Succinate
`
`3
`The boric acid used in the compositions of the present
`invention includes not only boric acid, but also its oph(cid:173)
`thalmically acceptable acid addition salts, as well as borate(cid:173)
`polyol complexes of the type described in U.S. Pat. No.
`5,342,620 (Chowhan). In general, an amount from about 0.3
`to about 5.0 wt % is used in the compositions of the present
`invention. It is preferred to use from about 0.3 to about 3.0
`wt %, and it most preferred to use from about 0.5 to about
`2.0 wt %. The water soluble borate-polyol complexes useful
`in the compositions of the present invention preferably
`comprise borate and polyol in a molar ratio between about
`1:1 and about 1:10.
`Suitable ophthalmic agents which may be included in the
`compositions of the present invention and administered via
`the method of the present invention include, but are not
`limited to, the racemic and enantiomeric forms and oph(cid:173)
`thalmically acceptable salts, amides, esters and prodrugs of
`the following types of drugs containing an acidic function(cid:173)
`ality such as --COOH, -S02NH2 , or S02NHR groups:
`anti-glaucoma agents, such as carbonic anhydrase inhibitors,
`prostaglandins and prostaglandin derivatives; non-steroidal
`anti-inflammatory agents, including but not limited to those
`classified as ary 1- or heteroary 1- alkanoic acids, such as
`diclofenac, bromfenac, flurbiprofen, suprofen, ketorolac,
`indomethacin and ketoprofen; anti-bacterials and anti-infec(cid:173)
`tives, including sulfa drugs, such as sulfacetamide sodium, 25
`and beta-lactams such as penicillins and cephalosporins; and
`diagnostic agents such as sodium fluorescein. Combinations
`of ophthalmic agents may also be used in the compositions
`of the present invention.
`The compositions of the present invention may addition-
`ally include other ophthalmically acceptable components
`such as comfort enhancing agents, buffers (e.g., phosphate,
`acetate, carbonate, and citrate), other preservatives (e.g.,
`benzalkonium chloride and individual homologs of benza- 35
`lkonium chloride, parabens, chlorobutanol, and biguanides
`such as chlorhexidine and hydroxypropyl methyl bigu(cid:173)
`anide), surfactants (e.g. poloxamers such as Pluronics®;
`polysorbates such as Tweens®; tyloxapol; sarcosinates such
`as Hamposyl®; and polyethoxylated castor oils such as 40
`Cremophor®), and tonicity agents (e.g., sodium chloride,
`mannitol, dextrose and xylitol). In addition, other excipients,
`such as antioxidants, chelating agents and complexing
`agents may be added to the compositions of the present
`invention as desired or as necessary.
`The compositions of the present invention may also
`include viscosity modifying agents such as: cellulosic
`ethers, such as, hydroxypropyl methyl cellulose (HPMC),
`hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose,
`hydroxypropyl cellulose, methyl cellulose, and carboxym- 50
`ethyl cellulose; carbomers (e.g. Carbopol®); polyvinyl alco(cid:173)
`hol; polyvinyl pyrrolidone; alginates; carrageenans; and
`guar, karaya, agarose, locust bean, tragacanth and xanthan
`gums. The concentration of such viscosity modifiers will
`vary between about 0.1 to about 5 wt %, but such formu- 55
`lations will generally have a viscosity between about 10 and
`about 5000 centipoise.
`The ophthalmic compositions of the present invention
`may additionally contain polymers which will undergo
`sol-to-gel transition upon exposure to physical or chemical 60
`stimuli, such as changes in pH, ion concentration, and/or
`temperature. Examples of such polymers include but are not
`limited to: certain carrageenans, and gellan, locust and
`xanthan gums, such as those described in U.S. Ser. No.
`08/108,824 (Lang et al.), U.S. Pat. No. 4,861,760 (Mazuel et 65
`al), U.S. Pat. No. 4,136,173 (Pramoda et al), U.S. Pat. No.
`4,136,177 (Linet al.), and U.S. Pat. No. 4,136,178 (Linet al).
`
`5,603,929
`
`5
`
`4
`The contents of these patent applications and patents relating
`to the polymers cited above are hereby incorporated by
`reference herein.
`The acidic drugs in the compositions of the present
`invention may also be encapsulated in microparticles such as
`microcapsules, microspheres, nanocapsule, nanospheres,
`and liposomes to improve comfort, and/or provide for sus(cid:173)
`tained release. The following examples are presented to
`illustrate further various aspects of the present invention, but
`10 are not intended to limit the scope of the invention in any
`respect.
`
`Preparation
`The preparation of Formulation A is detailed below.
`Formulations B and C can be prepared in similar fashion.
`Initially, a 10% stock solution of TPGS and a 2% stock
`solution of HPMC were prepared in water under constant
`stirring. Heat was applied if necessary to ensure complete
`dissolution.
`To a tared glass vessel containing approximately 40%
`final weight of purified water was added diclofenac-sodium.
`This mixture was stirred until the diclofenac was completely
`45 dissolved. The following ingredients were then added with
`stirring in the order given below, and each ingredient was
`completely dissolved before addition of the next ingredient:
`stock solution of vitamin E TPGS; tromethamine; boric acid;
`Polyquad®; mannitol; and stock solution of HPMC.
`Water was then added to bring the formulation to 95% of
`its final weight, and the pH of the formulation adjusted to
`between 7 and 7.4 using NaOH and/or HCl. Water was then
`added to bring the final weight to 100%. The resulting
`formulations were approximately isotonic (above 300 mil(cid:173)
`liOsmoles per kilogram (mOsrnlkg)).
`
`EXAMPLE2
`
`The antimicrobial preservative effectiveness of the poly(cid:173)
`meric quaternary ammonium compound/boric acid combi(cid:173)
`nation of the present invention was determined using an
`organism challenge test according to the methods described
`in the United States Pharmacopeia XXII (USP) and Euro(cid:173)
`pean Pharmacopoeia (1994(Ph. Eur.). Samples were inocu(cid:173)
`lated with known levels of gram-positive (Staphylococcus
`aureus ATCC 6538) and gram-negative (Pseudomonas
`aeruginosa ATCC 9027 and Escherichia coil ATCC 8739)
`
`LUPIN EX1005, Page 3
`
`

`
`5,603,929
`
`5
`vegetative bacteria, yeast (Candida albicans ATCC 10231)
`and mold (Aspergillus niger ATCC 16404) and sampled at
`specified intervals to determine if the antimicrobial preser(cid:173)
`vative system was capable of killing or inhibiting the
`propagation of organisms purposely introduced into the
`formulation. The rate or level of antimicrobial activity
`determined compliance with the USP and/or Ph. Eur. pre(cid:173)
`servative efficacy standards for ophthalmic preparations.
`The compendia! preservative standards for ophthalmic
`preparations are presented below:
`
`Log Reduction of Organism Population
`
`Time Pull
`
`USP
`
`Ph. Eur.
`A
`(Target)
`
`Ph. Eur.
`B
`(Min)
`
`6 hours
`24 hours
`7 days
`14 days
`28 days
`
`7 days
`14 days
`28 days
`
`For Bacteria:
`
`2
`3
`
`NR
`For Fungi:
`
`2
`
`NI
`
`3
`NI
`
`NI
`NI
`
`1
`3
`
`NI
`
`1
`NI
`
`NR = No organisms recovered
`NI = No increase at this or any following time pulls
`- = No requirement at this time pull
`
`5
`
`10
`
`25
`
`6
`preservative effectiveness requirements, and an ophthalmi(cid:173)
`cally acceptable vehicle; wherein the acidic ophthalmic
`agent is selected from the group consisting of anti-glaucoma
`and non-steroidal anti-inflammatory agents; provided that
`the composition does not contain a viscosity-enhancing
`amount of polyvinyl alcohol.
`2. The composition of claim 1 wherein the ophthalmic
`agent is a non-steroidal anti-inflammatory agent.
`3. The composition of claim 2 wherein the non-steroidal
`anti-inflammatory agent comprises an aryl- or heteroaryl(cid:173)
`alkanoic acid, or an ophthalmically acceptable salt, ester,
`amide, or prodrug thereof.
`4. The composition of claim 3 wherein the non-steroidal
`anti-inflammatory agent is selected from the group consist(cid:173)
`ing of: diclofenac, flurbiprofen, suprofen, bromfenac, ket-
`15 erolac,
`indomethacin, ketaprofen, and ophthalmically
`acceptable salts, esters, amides or prodrugs thereof.
`5. The composition of claim 4 wherein the non-steroidal
`anti-inflammatory agent is selected from the group consist(cid:173)
`ing of diclofenac and its ophthalmically acceptable salts,
`20 esters, amides, or prodrugs thereof.
`6. The composition of claim 4 wherein the non-steroidal
`anti-inflammatory agent is selected from the group consist(cid:173)
`ing of suprofen and its ophthalmically acceptable salts,
`esters, amides, or prodrugs thereof.
`7. The composition of claim 4 wherein the non-steroidal
`anti-inflammatory agent is selected from the group consist(cid:173)
`ing of bromfenac and its ophthalmically acceptable salts,
`esters, amides, or prodrugs thereof.
`8. The composition of claim 7 wherein the antimicrobial
`30 polymeric quaternary ammonium compound is polyquater(cid:173)
`nium 1.
`9. The composition of claim 8 wherein the polyquater(cid:173)
`nium 1 has a number average molecular weight from 2,000
`to 30,000.
`10. The composition of claim 9 wherein the polyquater(cid:173)
`nium 1 has a number average molecular weight from 3,000
`to 14,000.
`
`The results of the preservative challenge study conducted
`on Formulation A are shown below in Table 1. These results
`illustrate that an ophthalmic formulation of ail acidic drug
`can be globally preserved, that is, can comply with the USP
`and Ph. Eur. A preservative effectiveness requirements for 35
`ophthalmic preparations, using a combination of a poly(cid:173)
`meric quaternary ammonium compound and boric acid.
`
`TABLE 1
`
`Preservative Challenge Results for Formulation A
`
`TEST
`
`INITIAL
`
`Number of Microorganisms Per Milliliter*
`
`ORGANISM
`
`COUNT
`
`6Hr
`
`24Hr
`
`Day 7
`
`Day 14
`
`Day 21 Day 28
`
`S. aureus
`P. aeruginosa
`E. coli
`C. albicans
`A. niger
`
`1.5 X 106
`1.0 X 106
`1.1 X 106
`1.2 X 106
`1.3 X 106
`
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<10
`<0
`<10
`6.3 X 10' 4.1 X 104 4.4 X 102
`<10
`<10
`1.4 X 106 3.9 X 10' 2.5 X 10' 8.0 X 101 6.5 X 101
`
`<10
`<10
`<10
`<10
`<10
`
`*Limit of detection: <10 CFU/mL
`
`The invention has been described by reference to certain
`preferred embodiments; however, it should be understood
`that it may be embodied in other specific forms or variations
`thereof without departing from its spirit or essential char(cid:173)
`acteristics. The embodiments described above are therefore
`considered to be illustrative in all respects and not restric(cid:173)
`tive, the scope of the invention being indicated by the
`appended claims rather than by the foregoing description.
`What is claimed is:
`1. A storage stable ophthalmic composition comprising a
`therapeutically effective amount of one or more acidic
`ophthalmic agents, a combination of an antimicrobial poly(cid:173)
`meric quaternary ammonium compound and boric acid in an
`amount effective to meet at least the minimum United States
`Pharmacopeia XXII and European Pharmacopeia (1994)
`
`11. The composition of claim 1 wherein the concentration
`of the antimicrobial polymeric quaternary ammonium com-
`55 pound is between about 0.00001 and about 3 percent by
`weight.
`12. The composition of claim 11 wherein the concentra(cid:173)
`tion of the antimicrobial polymeric quaternary ammonium
`compound is between about 0.001 and about 0.1 percent by
`weight.
`13. The composition of claim 12 wherein the concentra(cid:173)
`tion of the antimicrobial polymeric quaternary ammonium
`compound is between about 0.001 and about 0.05 percent by
`65 weight.
`14. The composition of claim 1 wherein the ophthalmi(cid:173)
`cally active forms of boric acid are selected from the group
`
`60
`
`LUPIN EX1005, Page 4
`
`

`
`5,603,929
`
`7
`cons1stmg of boric acid, ophthalmically acceptable acid
`addition salts of boric acid and borate-polyol complexes.
`15. The composition of claim 1 wherein the concentration
`of boric acid is between about 0.3 and about 5.0 percent by
`weight.
`16. The composition of claim 15 wherein tbe concentra(cid:173)
`tion of boric acid or ophthalmically active forms thereof is
`between about 0.3 and about 3 percent by weight.
`17. The composition of claim 16 wherein the concentra(cid:173)
`tion of boric acid or ophthalmically active forms thereof is
`between about 0.5 and about 2 percent by weight.
`18. The composition of claim 14 wherein the ophthalmi(cid:173)
`cally active forms of boric acid are water soluble borate(cid:173)
`polyol complexes having a molar ratio of borate to polyol
`from 1:1 to 1:10.
`
`8
`19. An ophthalmic formulation comprising diclofenac or
`an ophthalmically acceptable salt, ester, amide or prodrug
`thereof, and a combination of an antimicrobial polymeric
`quaternary ammonium compound and boric acid in an
`amount effective to meet at least tbe minimum United States
`Pharmacopeia XXII and European Pharmacopeia (1994)
`preservative effectiveness requirements; provided, that the
`formulation does not contain a viscosity-enhancing amount
`10 of polyvinyl alcohol.
`20. The formulation of claim 19 wherein tbe formulation
`comprises sodium diclofenac, boric acid, mannitol,
`polyquatemium 1 and a comfort-enhancing agent.
`
`* * * * *
`
`LUPIN EX1005, Page 5