United States Patent £191
`Stevenson et al.
`
`[11]
`
`[45]
`
`4,053,628
`Oct. 11, 1977
`
`[54] COMPOSmON
`[75]
`Inventors: Neil Arthur Stevenson; George
`WardeD, both of Loughborough,
`England
`[73] Assignee: Fisons Limited, London, England
`[21] Appl. No.: 677,274
`[22] Filed:
`Apr. 15, 1976
`
`[30]
`
`Related U.S. Application Data
`[60] Division of Ser. No. 471,141, May 17, 1974, Pat. No.
`3,975,536, which is a continuation-in-part of Ser. No.
`443,521, Feb. 19, 1974, abandoned, which is a
`continuation of Ser. No. 251,198, May 8, 1972,
`abandoned.
`Foreign Application Priority Data
`May 12, 1971 United Kingdom ............... 14529/71
`Dec. 9, 1971
`United Kingdom ............... 57169/71
`May 25, 1973 United Kingdom ............... 25237/73
`May 25, 1973 United Kingdom ............... 25238/73
`United Kingdom ............... 26649/73
`June 5, 1973
`July 12, 1973 United Kingdom ............... 33325/73
`Int. CJ,2 .............................................. A61K 31/35
`[51]
`[52] U.S. CI ..................................................... 424/283
`
`[58] Field of Search .............. : .......................... 424/283
`
`[56]
`
`3,671,625
`3,686,412
`3,705,945
`3,720,690
`3,777,033
`3,975,536
`
`References Cited
`U.S. PATENT DOCUMENTS
`Altounyan ............................. 424/83
`6/1972
`Fitzmaurice et al. ................. 424/83
`8/1972
`Fitzmaurice et al. ................. 424/83
`12/1972
`King et al. ............................. 424/83
`3/1973
`Fitzmaurice et al. ................. 424/83
`12/1973
`Stevenson et al. .................... 424/83
`8/1976
`
`Primary Examiner-Donald B. Moyer
`Attorney, Agent, or Firm-Wenderoth, Lind & Ponack
`
`ABSTRACf
`[57]
`There is described a composition comprising a substan(cid:173)
`tially clear, sterile aqueous solution containing as active
`ingredient a therapeutically useful proportion of l,3-
`or
`a
`bis(2-carboxy-chromon-5-yloxy)-propan-2-ol,
`pharmaceutically acceptable (e.g. the di-sodium) salt
`thereof, or of 5,5' -[[5,5' -(2-hydroxytrimethylene)dioxy ](cid:173)
`bis[4-oxo-4H-l-benzopyran-2-yl]]tetrazole, or a phar(cid:173)
`maceutically acceptable (e.g.
`the di-sodium) salt
`thereof. The composition is indicated for the treatment
`of conditions of the eye and the nose.
`
`6 Claims, No Drawings
`
`Page 1 of 5
`
`SENJU EXHIBIT 2006
`MYLAN v. SENJU
`IPR2016-00626
`
`

`
`1
`
`4,053,628
`
`25
`
`35
`
`COMPOSmON
`This application is a division of application Ser. No.
`471,141, filed May 17, 1974 now U.S. Pat. No.
`3,975,536, which application is in turn a continuation-in- 5
`part of application Ser. No. 443,521 filed Feb. 19, 1974
`(now abandoned), which application is a continuation
`of application Ser. No. 251,198, filed May 8, 1972 (now
`abandoned).
`This invention relates to new pharmaceutical compo- 10
`sitions and methods for their preparation.
`Initial attempts to formulate 1,3-bis(2-carboxychro(cid:173)
`mon-5-yloxy)propan-2-ol, 5,5' -[[5,5' -(2-hydroxytrime(cid:173)
`thylene )dioxy ]bis-[ 4-oxo-4H-1-benzopyran-2-yl]]tet-
`razole and their pharmaceutically acceptable salts as 15
`aqueous solutions produced compositions which rap(cid:173)
`idly became cloudy and were entirely unacceptable. A
`further difficulty was that the polar nature of the com(cid:173)
`pounds and their high molecular weight indicated that
`they would combine with most of the known preserva- 20
`tives for aqueous pharmaceutical solutions to form in(cid:173)
`soluble precipitates thus simultaneously removing both
`active ingredient and preservative from the solution and
`further aggravating the problem of cloudiness men-
`tioned above.
`We have now found that it is possible to formulate
`these highly polar compounds in such a way that clear
`solutions are formed.
`According to our invention we provide a composi(cid:173)
`tion comprising a substantially clear, sterile aqueous 30
`solution containing as active ingredient a therapeuti(cid:173)
`cally useful proportion of 1,3-bis(2-carboxy-chromon-5-
`yloxy)-propan-2-ol, or a pharmaceutically acceptable
`(e.g. the di-sodium) salt thereof, or of 5,5'-[[5,5'-(2-
`hydroxytrimethylene)dioxy ]bis[4-oxo-4H-1-benzopy-
`ran-2-yl]]tetrazole, or a pharmaceutically acceptable
`(e.g. the di-sodium) salt thereof.
`Parmaceutically acceptable salts include salts with
`alkali metal cations, e.g. sodium, potassium and lithium
`salts; ammonium salts and salts with organic bases, e.g. 40
`piperidine, triethanolamine or diethylaminoethylamine
`salts.
`The solution may contain from 0.1 to 10%, preferably
`from 0.5 to 5% and more preferably about 1, 2 or 4%
`w/v of the active ingredient.
`In addition to the active ingredient the composition
`may also contain an effective proportion of a pharma(cid:173)
`ceutically acceptable chelating or sequestering agent.
`Suitable sequestering or chelating agents include so(cid:173)
`dium charboxymethyl cellulose, citric, tartaric or phos- 50
`phoric acid, and amino carboxylate compounds, prefer(cid:173)
`ably ethylenediamine tetraacetic acid or its salts, e.g. its
`calcium salt, its calcium-sodium salt, or more preferably
`its di-sodium salt. Further examples of amino carboxyl(cid:173)
`ate compounds are Penna Kleer 80 SO available from 55
`Refined Products Corporation of Lyndhurst N.J., USA
`and glycine derivatives, e.g. N,N-dihydroxy ethyl gly(cid:173)
`cine and its salts, e.g. its sodium salt.
`The concentration of the chelating or sequestering
`agent may vary considerably, but in any case should be 60
`such as to ensure that no precipitate of metal salts of the
`active ingredient occurs. A suitable concentration of
`chelating or sequestering agent may be from 0.005 to
`0.1, and preferably from 0.01 to 0.1% w/v. When a very
`low concentration, i.e. less than about 0.40, preferably 65
`less than 0.32 ppm of 'metal ions' are present, for exam(cid:173)
`ple when the solution contains less than 0.08 ppm of
`ionic iron and less than 0.25 ppm of ionic zinc, the che-
`
`45
`
`2
`lating or sequestering agent may if desired by dispensed
`with. When a chelating or sequestering agent is used the
`concentration of 'metal ions' is preferably less than
`about 20 ppm and more preferably less than 10 ppm.
`By the term 'metal ions' we mean ions of metals in
`groups Ila, lb, lib and IVb (also those of groups Ilia
`and IVa) of the periodic table and of the transition
`metals. Specific 'metal ions' which are detrimental, in
`excessive concentrations, i.e. above about 20 ppm, to
`the compositions of the invention are Pb+ + and Ca + +,
`(also Cu++ and AI+++) and in particular Fe++,
`Fe+++, Zn++ and Mg++ ions. We particularly prefer
`to keep the concentration of Mg+ +ions as low as possi(cid:173)
`ble, e.g. less than about 0.2 ppm and preferably less than
`about 0.12 ppm in the solution (less than about 2 ppm in
`the dry active ingredient and less than about 0.8 ppm in
`the water used to make the solution).
`The composition may if desired contain an effective
`proportion, e.g. from 0.001 to 0.10% w/v, of a pharma(cid:173)
`ceutically acceptable preservative or sterilising agent.
`One example of a suitable preservative is sodium 2-
`(ethyl mercuriothio) benzoate known generically as
`"Thiomersal", which may be present in the composition
`in from 0.001 to 0.05 and preferably from 0.005 to 0.02,
`e.g. about 0.01% w/v. Other suitab)e preservatives
`include pharmaceutically acceptable quaternary ammo(cid:173)
`nium compounds, e.g. cetyl pyridinium chloride, tet(cid:173)
`radecyltrimethyl ammonium bromide known generi(cid:173)
`cally as 'Centrimide', benzyl dimethyl [2-[2-[p-(1,1,3,3-
`tetramethyl butyl)]phenoxy]ethoxy] ammonium chlor(cid:173)
`ide, known generically as 'Benzethonium chloride', and
`myristyl-'Y-picolinium chloride, anyone of which may
`be used at a concentration of from about 0.002 to 0.05,
`e.g. about 0.02% w/v. The preferred presenatives
`amongst the quaternary ammonium compounds are how(cid:173)
`ever the alkyl benzyl dimethyl ammonium chlorides and
`mixtures thereof, e.g. that known generically as 'Benzal·
`konium chloride'. This latter consists of a mixture of
`compounds of formula
`
`in which R is an alkyl group C8H 17to C 18H37• We partic(cid:173)
`ularly prefer to use a mixture of such compounds in
`which R is C10H21 to C 1J129 and especially that specific
`compound in which R is C 12H25• 'Benzalkonium chlor(cid:173)
`ide', and the compounds of the formula given above,
`may be used at a concentration of from 0.005 to 0.10
`preferably 0.005 to 0.05, e.g. about O.ot% w /v and may
`optionally be used in combination with 0.2 to 2.0, e.g.
`0.4% w/v of 2-phenylethanol (BPC 1963). 'Benzalko(cid:173)
`nium chloride' (and the compounds of the formula
`given above) and 2-phenylethanol have been found to
`have a synergistic effect, particularly against Pseudomo(cid:173)
`nas aeruginosa, when used in combination with the di(cid:173)
`sodium salt of ethylenediamine tetra acetic acid.
`The composition may also contain conventional ex(cid:173)
`cipients, e.g. sodium chloride, dextrose or mannitel, and
`buffers, e.g. sodium dihydrogen orthophosphate (so(cid:173)
`dium acid phosphate BP), di-sodium hydrogen phos(cid:173)
`phate (sodium phosphate BP) sodium citrate/citric acid,
`and boric acid/sodium borate. The proportion and con(cid:173)
`centration of excipients and buffers may be varied
`within fairly wide ranges, provided the resulting solu-
`
`Page 2 of 5
`
`

`
`4,053,628
`
`3
`tion is stable and non-irritant when applied to the appro(cid:173)
`priate tissues. For maximum stability the preferred pH is
`from 4 to 7.5, preferably 4 to 7.0, with minimal buffering
`to avoid tissue irritation. The maximum total concentra(cid:173)
`tion of excipients and buffers is preferably less than 5% 5
`w/v and more preferably less than 2% w/v.
`The composition may also contain one or more addi(cid:173)
`tional compounds which are therapeutically useful in
`the eye.
`Examples of such additional therapeutically useful 10
`compounds include other anti-allergic agents, e.g. anti(cid:173)
`histamines and anti-inflammatory agents; deconges(cid:173)
`tants; anti-viral agents and vasoconstrictors.
`As anti-histamine compounds there may be men(cid:173)
`tioned, for example Antazoline or diphenhydramine 15
`hydrochloride.
`As anti-inflammatory agents there may be mentioned
`anti-inflammatory steroids, for example Prednisolone;
`anti-bacterials, for example sulphacetamide and pro(cid:173)
`pamidine isethionate; antibiotics, for example Tetracy- 20
`cline, Chloramphenicol, Neomycin or Framycetin and
`anti-micotic agents, for example nystatin or amphoteri(cid:173)
`cin B.
`As an example of decongestants there may be men-
`tioned Phenylephrine.
`As an example of anti-viral agents there may be men(cid:173)
`tioned Idoxuridine.
`As an example of vasoconstrictors there may be men(cid:173)
`tioned Oxymetazoline.
`The additional therapeutically useful compounds 30
`should, of course, be present in a therapeutically useful
`proportion. In general the additional compoinds, other
`than the anti-biotics, may be present at a concentration
`of from about 0.05 to 0.6% w/v. The anti-bacterials
`may however in certain cases by present in greater 35
`concentrations, for example up to 10, 20 or even 30%
`w/v.
`We also provide a method of treatment of conditions
`of the eye which comprises the use of the additional 40
`therapeutically useful compounds separately from, but
`simultaneously with the compositions described herein
`which do not contain the additional therapeutically
`useful compound, i.e. concurrent therapy rather than
`therapy with a mixture.
`Examples of suitable concentrations (w/v) of addi(cid:173)
`tional therapeutically useful compounds in the composi(cid:173)
`tions of this invention are given below:
`
`4
`The concentration of the additives in the solution may
`be in the range 0.25 to 5% w/v and is preferably in the
`range 0.5 to 1.5% w/v.
`The additives may of course be present in addition to
`any chelelating or sequestering agents, preservatives,
`excipients, buffers, additional therapeutically useful
`compounds etc.
`The composition, when it does not contain a preser(cid:173)
`vative, may be made up using conventional techniques,
`e.g. by dissolving the chelating or sequestering agent (if
`included) in freshly distilled water, adding the excipi-
`ents, buffers etc to the aqueous solution of chelating or
`sequestering agent, adding the active ingredient to the
`resulting solution, stirring, filtering and then sterilising
`the composition by autoclaving, for example at a tem(cid:173)
`perature of about 115• C for about 30 minutes. The
`autoclaving of the product may, if desired, be omitted
`when the composition is produced by sterile filtration
`into a previously sterilised container under aseptic con(cid:173)
`ditions.
`Compositions which contain preservatives may be
`made up by mixing two aqueous solutions of equal vol(cid:173)
`umes one containing twice the desired final concentra(cid:173)
`tion of the active ingredient, chelating or sequestering
`agent, and other additives, and the other containing
`twice the desired final concentration of the preserva-
`tive. The resulting mixture may then be filtered under
`sterile conditions. Surprisingly we find that mixture of a
`solution of the anionic active ingredient with a solution
`of a cationic quaternary ammonium preservative does
`not precipitate all the preservative from the mixed solu-
`tion.
`The components of the composition should be as free
`as possible from 'metal ions' and contact with materials
`yielding such ions should be avoided during manufac(cid:173)
`ture. If desired 'metal ions' may be removed from the
`components of the composition by conventional means,
`e.g. by ion exchange.
`According to the invention there is also provided a
`method of treatment of conditions of the eye or nose, in
`which conditions allergy or immune reactions play a
`contributory part, which method comprises administra(cid:173)
`tion of a composition according to the invention or
`some other form of l,3-bis(2-carboxychromon-5-yloxy)
`propan-2-ol, or a pharmaceutically acceptabtable salt,
`e.g. the di-sodium salt, ester, e.g. a C 1 to 6 alkyl ester,
`or amide (e.g. the amide derived from ammonia) thereof
`topically or by sub-conjunctival injection to a patient
`having such a condition.
`The dosage to be administered will of course vary
`with the condition to be treated, with its severity and
`with its location. However, in general for use in the eye
`a dosage of about 1 or 2 drops (e.g. from 0.66 to 1.32 mg
`of active ingredient) into the affected eye from 2 to 4
`55 times a day is found to be satisfactory. More frequent
`dosage may, of course, be used if desired. For use in the
`nose a dosage of about 0.16 ml (e.g. about 3.2 mg of
`active ingredient) is indicated (0.08 ml per nostril).
`Conditions of the outer eye in which the method of
`the invention has proved successful include vernal ca(cid:173)
`tarrh (vernal kerato-conjunctivitis) and marginal cor(cid:173)
`neal ulceration or infiltration. Other conditions which
`may be treated by the method of the invention include
`the occular effects of hay fever, 'allergic eyes' where
`the allergen is known or unknown and spring/summer
`conjunctivitis. This latter term is used to mean allergic
`disorders of the eyes occurring in the spring and sum(cid:173)
`mer where an external allergen plays a part in the disor-
`
`25
`
`45
`
`50
`
`Idoxuridine
`Oxymetazoline
`Phenylephrine HCl (eye drops)
`Antazoline phosphate
`Diphenhydramine hydrochloride
`Prednisolone sodium phosphate
`Chloramphenicol
`·
`Sulphacetamide sodium
`Tetracycline
`Nystatin
`
`0.1%
`0.05%
`0.10%
`0.5%
`0.2%
`0.518%
`0.5%
`10-30%
`1-3%
`1%
`
`The composition may also contain additives designed
`to increaSe the viscosity and/or to prolong the action of 60
`the active ingredient.
`Suitable additives include cellulosic compounds, e.g.
`methyl cellulose, hydroxypropylmethyl cellulose, hy(cid:173)
`droxypropylethyl cellulose, hydroxyethyl cellulose and
`ethylhydroxyethyl cellulose; polyvinyl alcohols; gela- 65
`tin; polyvinylpyrolidone; polyethylene glycols; propyl(cid:173)
`ene glycol and glycerin.
`Combinations of additives may be used if desired.
`
`Page 3 of 5
`
`

`
`5
`der. Further conditions of the eye _which may be .men(cid:173)
`tioned are 'irritable eye' or 'non-specific conjunctivitis',
`Herpes Simplex Keratitis and Conjunctivitis, . Herpes
`Zoster Keratitis and Conjunctiv~tis, adenovirus infec(cid:173)
`tions,. phlyctenular conjunctivitis, corneal homograft
`rejection, Trachoma, anterior uveitis and drug sensitiv(cid:173)
`ity.
`Conditions of the nose which may be mentioned in(cid:173)
`clude seasonal rhinitis, e.g. hay fever; perennial rhinitis,
`nasal polyps and allergic manifestatio~s of the naso- 10
`pharynx. Preserved solutions are particularly useful in
`the treatment of conditions of the nose, ·e.g. as a nasal
`spray containing 2% of active ingredient.
`The unpreserved compositions may be put up in sin(cid:173)
`gle applications containers containing from 0.3 to Q.7 ml 15
`of solution and the preserved compositions may be put
`up in multi-dose (plastics, e.g. polyethylene, or glass)
`packs containing S to 20, preferably 7.5 or 17.5 ml of
`solution.
`We also provide solutions suitable for injection,.e.g. 20
`sub-conjunctivally, preferably sterile unpreserved solu-
`tions which are substantially free of particulate material.
`Whether a solution is substantially clear will be
`readily determinable by those skilled in the art, and will
`depend on the number, size and type of particles in the 25
`solution. Thus large particles are less acceptable than
`are partiCles of less than 50 microns. in diameter. We
`prefer the solutions of the invention to contain less than
`20, preferably less than 16 and more preferably less than
`12 particles per 8 mls of solution when the solution is 30
`viewed in a particle free container under the magnifyer
`of a polarised light viewer. Desirably the solution con(cid:173)
`tains less than 4 such particles per 8 mls.
`The invention is illustrated but in no way limited by
`the following Examples:
`
`EXAMPLE 1
`
`35
`
`4,053,628
`
`6
`-continued
`Phenylethyl alcohol BPC 1963
`Cetyl pyridinium chloride BP
`Domiphen bromide BP
`s or PhenoxyethanolBPC
`
`0.3-0.6% w/v
`0.02% w/v
`0.01% w/v
`O.S-1.0%w/v
`
`Pharmaceutically acceptable combinations of the
`above preservatives may also be used
`
`e.g. Benzalkonium chloride BP
`+ Phenylethylalcohol
`p-hydroxybenzoates )
`+ phenoxyethanol BPC
`
`0.02% w/v
`0.4% w/v
`
`0.4% ('Phenonip')
`
`The sodium cromoglycate BP may be replaced by
`
`S,S'-[(S,S'-(2-hydroxytrimethylene)-
`dioxy]bis[4-oxo-4H-1-benzopyran-2-
`2.0% w/v
`yl]]tetrazole di-sodium salt
`--=--=---------------------
`
`EXAMPLE3
`
`Preserved Buffered isotonic eye-drop solution
`Sodium cromoglycate BP
`· Di-sodium edetate BP
`Sodium chloride BP
`Sodium phosphate BP (Na2HP04. 12H20)
`Sodium acid phosphate BP (NaH2P04. 2H20)
`Thiomersal BP
`Sterile distilled water
`
`1.0% w/v
`0.01% w/v
`0.42% w/v
`0.12% w/v
`0.47% w/v
`0.01% w/v
`
`Thiomersal BP may be replaced by any of the preser(cid:173)
`vatives listed in Example 2. In some cases, the quantity
`of sodium chloride in the formulation may have to be
`adjusted to maintain isotonicity.
`
`EXAMPLE4
`
`Unpreserved eye drop solution
`Di-sodium salt of 1,3-bis(2-carboxy-
`chromon-S-yloxy)-propan-2-ol
`1.0% w/v
`O.S6% w/v
`Sodium chloride BP
`0.26% w/v
`Sodium acid phosphate BP
`0.59% w/v
`Sodium phosphate BP
`0.01% w/v
`Di-sodium edetate BP
`to 100%
`Distilled water
`--------------------------------------~
`
`40
`
`EXAMPLE2
`
`Preserved Nasal Spray Solution
`Di-sodium salt of 1,3-bis(2-carboxy(cid:173)
`chromon-S-y1oxy)-propan-2-ol
`(Sodium cromoglycate BP)
`2.0% w/v
`Di-sodium edetate BP
`0.01% w/v
`Thiomersal BP
`0.01% w/v
`Sterile distilled water
`to 100%
`---------------------------------------55
`
`so
`
`Sodium cromoglycate BP
`Disodium edetate BP
`Thiomersal BP
`Sterile distilled water
`
`2.0% w/v
`0.01% w/v
`0.002% w/v
`to 100% w/v
`
`200g of sodium cromoglycate, lg of sodium edetate
`and 0.20g ofThiomersal are dissolved with stirring in 10
`litres of sterile distilled water. The resulting solution is
`then sterile ftltered and bottled in 10 or 15 ml bottles.
`
`EXAMPLES
`
`Sodium cromoglycate BP
`Disodium edetate BP
`Benzalkonium chloride solution BP
`Phenylethyl alcohol BPC 1963
`Sterile distilled water
`
`2.0% w/v
`0.01% w/v
`0.04% w/v
`0.4% w/v
`to 100% w/v
`
`Thiomersal BP may be replaced by the following
`preservatives
`
`lg of sodium edetate and 200g of sodium cromogly(cid:173)
`cate are dissolved, in that order, with stirring in 4 litres
`::::Be-nzal---::-ko-n-:-iu_m_c-:hl-:-o-n-:-.d:-e-=u::s=p:-------:0:-::.0,-:1-:::%:-w-/-:-v---- 60 of sterile filtered distilled water to yield a solution A.
`40g of phenylethyl alcohol and 4 ml of Benzalkonium
`Benzalkonium chloride solution BP
`0.02% w/v
`chloride are dissolved, in that order, in 4litres of sterile
`Benzethonium chloride
`0.02% w/v
`Centrimide BP
`0.02% w/v
`filtered distilled water with gentle stirring to yield a
`Myristy1-')'-pico1inium chloride
`0.02% w/v
`solution B. Solution B is then added gradually over a
`Chlorocresol BP
`0.1% w/v
`Th
`Chlorbutol BP
`O.S% w/v
`65 period of S minutes to solution A with stirring.
`e
`Chlorhexidine salts (e.g. acetate,
`resulting solution is then made up to 10 litres with sterile
`glyconate)
`filtered distilled water, stirred for 20 minutes, allowed
`Phenyl mercuric salts (e.g. nitrate,
`acetate)
`to settle and filtered under pressure through a Whatman
`p-hydroxy benzoates
`
`o.oos-0.01% w/v
`
`0.1% w/v
`0.4-0.8% w/v
`
`Page 4 of 5
`
`

`
`7
`gamma 12 filter. The filtered solution is then bottled in
`10 or 1 S ml bottles.
`
`4,053,628
`
`EXAMPLE6
`
`Composition designed to increase the viscosity of solution
`2.0% w/v
`Sodium cromoglycate BP
`Di-sodium edetate BP
`0.01% w/v
`Benzalkonium chloride solution BP
`0.04% v/v
`Phenylethyl alcohol BPC 1963
`0.4% w/v
`Sodium carboxymethyl cellulose
`'Edifas' BSO
`Sterile distilled water
`
`O.S% w/v
`to 100% w/v
`
`8
`3. A method for the treatment of conditions of the eye
`or nose in which conditions allergy or immune reac(cid:173)
`tions play a contributory part which comprises adminis(cid:173)
`tering topically or by sub-conjunctival injection to a
`5 patient suffering from such condition a compostion
`which comprises a sterile aqueous solution containing
`1,3-bis(2-carboxy-chromon-5-yloxy)-propan-2-ol or a
`pharmaceutically acceptable salt thereof as an active
`ingredient, wherein, in said composition, the said active
`10 ingredient is present in an amount of from 0.1 to 10%
`w/v, the composition contains less than about 20ppm of
`ions of metals in Groups Ila, lb, lib and IVb of the
`Periodic Table and of the transition metals, the compo(cid:173)
`sition contains from about 0.05 to 0.1% w /v of a phar-
`We claim:
`1. A method of treatment of conditions of the eye or 15 maceutically acceptable chelating or sequestering
`agent, and the said composition is a substantially clear
`nose, in which conditions allergy or immune reactions
`play a contributory part, which method comprises ad-
`aqueous solution.
`ministration of 1,3-bis(2-carboxychromon-5 -yloxy)pro-
`4. A method according to claim 1 wherein the condi-
`pan-2-ol, or a pharmaceutically acceptable salt thereof,
`tion to be treated is a condition of the eye selected from
`topically or by sub-conjunctival injection to a patient 20 the group of vernal catarrh, marginal corneal ulceration
`having such a condition.
`or infiltration, occular effeets of hay fever, non-specific
`2. A method for the treatment of conditions of the eye
`conjunctivitis, Herpes Simplex Keratitis and Conjuncti-
`or nose in which conditions allergy or immune reac-
`vitis, Herpes Zoster Keratitis and Conjunctivitis, adeno-
`tions play a contributory part which comprises adminis-
`virus. infections, phlyctenular conjunctivitis, corneal
`tering topically or by sub-conjunctival injection to a 25 homograft rejection, Trachoma, anterior uveitis and
`patient suffering from such condition a composition
`drug sensitivity.
`which comprises a sterile aqueous solution containing
`S. A method according to claim 1 wherein the condi-
`1,3-bis(2-carboxy-chromon-5-yloxy)-propan-2-ol or a
`tion to be treated is a condition of the nose selected from
`pharmaceutically acceptable salt thereof as an active
`· the group of seasonal rhinitis, perennial rhinitis, nasal
`ingredient, wherein, in said composition, the said active 30 polyps and allergic manifestations of the nasopharynx.
`ingredient is present in an amount of from 0.1 to 10%
`6. A method according to claim 4 wherein the dosage
`w/v, the said composition containes less than about 0.40
`to be administered is from 0.66 to 1.32 mg. of the 1,3-
`ppm of ions of metals in Groups Ila, lb, lib and IVb of
`bis(2-carboxychromon-5-yloxy)propan-2-ol or pharma-
`the Periodic Table and of the transition metals, the said
`ceutically acceptable salt thereof to the affected eye
`composition being a substantially clear, sterile aqueous 35 from 2 to 4 times per day.
`•
`•
`solution.
`
`•
`
`•
`
`•
`
`40
`
`45
`
`so
`
`55
`
`60
`
`65
`
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