United States Patent
`
`[19]
`
`5,443,833
`Aug. 22, 1995
`Clark et al.
`[45] Date of Patent:
`
`USO05443833A
`
`[11] Patent Number:
`
`[54] PHARMACEUTICAL COMPOSITIONS
`
`[75]
`
`Inventors:
`
`Andrew R. Clark, Loughborough;
`Paul Wright, Bramcote; Julia H.
`Ratcliffe, Gosport, all of England
`
`[73] Assignee:
`
`Fisons plc, Ipswich, England
`
`[21] App1.No.: 82,804
`
`[22] Filed:
`
`Jun. 25, 1993
`
`Related U.S. Application Data
`
`[63]
`
`Continuation of Ser. No. 742,574, Aug. 7, 1991, aban-
`doned, which is a continuation of Ser. No. 410,020,
`Sep. 20, 1989, abandoned, which is a continuation of
`Ser. No. 133,520, Dec. 16, 1987, abandoned.
`
`Foreign Application Priority Data
`[30]
`Dec. 23, 1986 [GB] United Kingdom ................. 8630767
`Dec. 23, 1986 [GB] United Kingdom ................. 8630769
`Dec. 24, 1986 [GB] United Kingdom ................. 8630904
`Mar. 20, 1987 [GB] United Kingdom ................. 8706684
`
`Int. Cl.5 ................................................ A61K 9/00
`[51]
`[52] U.S. Cl. .................................... 424/400; 424/489;
`424/434
`[58] Field of Search ............. .. 424/489, 400, 450, 434;
`546/97
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
` 4,474,787 10/1984 Cairns
`
`5/1982 Raphael ................................ S46/92
`4,328,341
`4,419,352 12/1983 Cox .........
`..... 424/248.4
`424/258
`514/291
`514/291
`514/291
`514/291
`514/291
`
`4,698,345 10/1987 Dicker
`4,760,072 7/1988 Brown
`4,849,427 7/1989 Nassim
`4,866,072 9/1989 Edwards .
`4,868,192 9/1989 Totton ...........................
`FOREIGN PATENT DOCUMENTS
`
`1/1983 Japan .
`0004722
`2022078 12/1979 United Kingdom .
`215729lA 4/1985 United Kingdom .
`OTHER PUBLICATIONS
`
`Patel, K. R. “Dose—Response Study of Sodium Cro-
`moglycate in Exercise—Induced Asthma,” Thorax, vol.
`37, pp. 663-666.
`
`Br. J. Clin. Phannac, vol. 24, Oct. 1987, pp. 493-501,
`“The Pharmacokinetics of Nedocromil Sodium, 21 New
`Drug for the Treatment of Reversible Obstructive Air-
`ways Disease, in Human Volunteers and Patients With
`Reversible Obstructive Airways Disease”.
`J. Med. Chem, vol. 28, No. 12, 1985, pp. 1832-1842,
`American Chemical Society, H. Cairns et al., “New
`Antiallergic Pyrano(3,2-g)quino1ine-2,8—dicarboxylic
`Acids with Potential for the Topical Treatment of
`Asthma”.
`P. H. List: “Arzneiformenlehre” Chapter Konser—
`vierungmittel pp. 369-373, 1976.
`P. H. List: “Arzneiformenlehre” Chapter Augenarz-
`neien pp. 400-410, 1976.
`R. Voigt: “Lehrbuch der pharmazeutischen Technolo-
`gie”, Chapter 27 Augentropfen, pp. 459-467, 1975.
`Eur. J. Respir. Dis. (Suppl. 147) 1986, pp. 120-131, R.
`M. Auty: “The clinical development of a new agent for
`the treatment of airway inflammation, nedocromil so-
`dium (Tilade)”.
`
`(List continued on next page.)
`
`Primary Examiner—-Thurman K. Page
`Assistant Exarhiner—Wi1liam E. Benston, Jr.
`Attorney, Agent, or Firm——Marsha.l1, O’Too1e, Gerstein,
`Murray & Borun
`
`ABSTRACI‘
`[57]
`A method of treatment of a condition selected from the
`group comprising conjunctivitis, keratitis,
`‘allergic
`eyes’, adenovirus infections, corneal homograft rejec-
`tion, anterior uveitis, nasal polyps, vasomotor rhinitis,
`allergic manifestations of the nasopharynx, reversible
`obstructive airways disease, Crohn’s disease, distal coli-
`tis and proctitis, which method comprises administra-
`tion to a patient suffering from such a condition of a
`therapeutically effective amount of an aqueous solution
`containing, as active ingredient, 9-ethyl-6,9-dihyclro-
`4,6—dioxo-10-propyl-4H-pyrano(3,2-g)quinoline-2,8-
`dicarboxylic acid or a pharmaceutically acceptable salt
`thereof. Also described are novel pharmaceutical com-
`positions suitable for use in such methods of treatment.
`
`3 Claims, No Drawings
`
`   
`


`
`Lannett Holdings, Inc. LAN 1011
`
`

`
`5,443,833
`
`Page 2
`
`OTHER PUBLICATIONS
`
`J. Allergy Clin. Immunol. vol. 79, No. 1, Feb. 19-25,
`1987, p. 186, abstract 247. Schwartz et al. “Efficacy of
`hedocromil sodium .
`. . ragweed seasonal allergic rhimi-
`tis (SAR)”.
`J. Allergy Clin. Immuno. vol. 80, No. 2, Aug. 1987, pp.
`218-222, Corrado et al. “The effect of nedocromil so-
`dium on nasal provocation with allergen”.
`J. Allergy Clin. Immunol., vol. 81, No. 3, Mar. 1988, pp.
`570-574 Ruhno et al. “Intranasal nedocromil sodium in
`the treatment of ragweed—al1ergic rhinitis”.
`Invest. Ophtalmol. Visual Sci._, vol. 29, May 1-6, 1988,
`
`p. 229, Stockwell et al. “Dongle blind group compara-
`tive trial of 2% nedocromil .
`.
`. seasonal allergic con-
`junctivitis”.
`Pharmazie, vol. 37, No. 4, 1982, pp. 261-263 Poh-
`loude1<—Fabini et al. “Zur Stabilitat der Phenylquecksil-
`bersalze”.
`
`Journal of Pharmaceutical Sciences, vol. 65, No. 4, Apr.
`1976, pp. 628-630, Grady et al. “Testing of heat sealing
`by thermal analysis”.
`R. Voight, “Lehrbuch der pharmazeutischen Technolo-
`gie,” 5th edition, 1984, pp. 554-557, Verlag Chemie,
`Weinheim, DE.
`
`

`
`1
`
`PHARMACEUTICAL COMPOSITIONS
`
`5,443,833
`
`This is a Continuation of U.S. application Ser. No.
`07/742,574, filed Aug. 7, 1991, now abandoned; in turn
`a Continuation of Ser. No. 07/410,020 filed Sep. 20,
`1989, now abandoned; in turn a Continuation of Ser.
`No. 07/133,520 filed Dec. 16, 1987, now abandoned.
`
`FIELD OF THE INVENTION
`
`This invention relates to methods of treatment and to
`novel pharmaceutical compositions for use in such
`methods.
`
`DESCRIPTION OF THE PRIOR ARTS
`
`In British Patent No 2022078 there are disclosed a
`number of pyranoquinoline compounds which are indi-
`cated for use in the treatment of reversible airway ob-
`struction. Pharmaceutical
`compositions
`containing
`these compounds are also described, especially compo-
`sitions in which the active ingredient is in powder form
`with a mass median diameter of from 0.1 to 10 microns.
`British Patent Application No 215729lA describes the
`particular utility of the disodium salt of one of these
`compounds,
`9-ethyl-6,9-dihydro-4,6-dioxo-l0-propy1-
`4H-pyrano(3,2-g)quinoline-2,8-dicarboxylic acid, in the
`treatment of reversible airway obstruction. Also de-
`scribed are powdered aerosol compositions of this salt
`for administration to the lung and physical forms of the
`salt which are especially suitable for formulation in this
`way.
`
`BRIEF SUMMARY OF THE INVENTION
`
`We have now surprisingly found that when it is ad-
`ministered in aqueous solution the same compound is
`efficacious in the treatment of a variety of disorders of
`the eye, notably conjunctivitis, as well as in the treat-
`ment of certain disorders associated with other organs.
`Thus, according to the invention there is provided a
`method of treatment of a condition selected from the
`group comprising:
`‘allergic eyes’, adenovirus
`conjunctivitis, keratitis,
`infections, corneal homograft rejection, anterior
`uveitis;
`nasal polyps, vasomotor rhinitis, allergic manifesta-
`tions of the nasopharynx;
`reversible obstructive airways disease;
`Crohn’s disease, distal colitis and proctitis, which
`method comprises administration to a patient suf-
`fering from such a condition of a therapeutically
`effective amount of an aqueous solution of 9-ethyl-
`6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano(3,2-
`g)quinoline-2,8-dicarboxylic acid or a pharmaceuti-
`cally acceptable salt thereof.
`By the term ‘conjunctivitis’ we mean inflammatory
`disorders of the conjunctiva commonly characterised
`by photophobia and irritation. The condition may be
`bacterial or vital and encompasses a number of specific
`types of conjunctivitis; for instance, seasonal allergic
`conjunctivitis, perennial allergic conjunctivitis, vernal
`catarrh (vernal kerato-conjunctivitis) , ‘irritable eye’ or
`‘non-specific conjunctivitis’, Herpes Simplex Conjuncti-
`vitis, Herpes Zoster Conjunctivitis and phlyctenular
`conjunctivitis.
`Similarly, by the term ‘keratitis’ we mean inflamma-
`tion of the cornea which may involve its superficial
`surface (‘superficial keratitis’ including the localised
`form known as ‘corneal ulceration’) or be confined to
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`the deeper layers (‘interstitial keratitis’). Other particu-
`lar forms of keratitis which may be mentioned include
`Herpes Simplex Keratitis and Herpes Zoster Keratitis.
`Proctitis includes chronic (ie ulcerative) and non-
`specific proctitis.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`Pharmaceutically acceptable salts of the active ingre-
`dient include salts with metal cations, such as alkali
`metal cations. We particularly prefer the disodium salt
`which is commonly referred to as nedocromil sodium.
`The solution is administered by a route appropriate to
`the condition being treated. For instance, administra-
`tion may be to the eye, intra-nasally (e.g. as a nasal
`spray), by inhalation as a nebulised cloud or rectally as
`an enema.
`
`We prefer administration of the solution to be by a
`route other than by inhalation. In particular, we prefer
`administration to be to the eye.
`The solution may contain from about 0.1 to 10% w/v
`of the active ingredient. However, we prefer the active
`ingredient to be present at a level of less than 5% and
`more particularly less than 3% w/v, e.g. 0.5%, 1.0% or
`2.0% w/v. The concentration of choice will depend of
`course inter alia on the nature of the condition to be
`treated, its severity and the mode of administration of
`the solution.
`
`In addition to the active ingredient the solution gen-
`erally contains one or more pharmaceutically accept-
`able additives. Examples of classes of additive which
`may be present are:
`a) chelating or sequestering agents,
`b) preservatives, and
`c) viscosity-modifying agents.
`Suitable chelating or sequestering agents include so-
`dium carboxymethyl cellulose, citric, tartaric or phos-
`phoric acid, and amino carboxylate compounds. The
`preferred chelating agent, however, is ethylenediamine
`tetraacetic acid or a salt thereof, especially its di-sodium
`salt.
`
`The concentration of the chelating or sequestering
`agent should be 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 0.5, e.g. 0.01 or 0.1% w/v.
`The choice of preservative, where the solution con-
`tains a preservative, may depend on the route of admin-
`istration. Preservatives suitable for solutions to be ad-
`ministered by one route may possess detrimental prop-
`erties which preclude their administration by another
`route. For nasal and ophthalmic solutions, preferred
`preservatives
`include quaternary ammonium com-
`pounds,
`in particular the mixture of alkyl benzyl di-
`methyl ammonium compounds known generically as
`‘Benzalkonium Chloride’. For solutions to be adminis-
`tered by inhalation, however, the preferred preserva-
`tive is chlorbutol. Other preservatives which may be
`used, especially for solutions to be administered rec-
`tally, include alkyl esters of p-hydroxybenzoic acid and
`mixtures thereof, such as the mixture of the methyl,
`ethyl, propyl and butyl esters which is sold under the
`tradename “Nipastat”.
`The concentration of preservative should be such as
`to ensure effective preservation of the solution ie such
`that bacterial growth in the solution is inhibited. For
`most preservatives the concentration will typically lie
`in the range 0.001 to 0.1% w/v. However, in the case of
`
`

`
`3
`chlorbutol acceptable concentrations are greater than
`0.25% but less than 0.6% w/w ie the concentration of
`chlorbutol is 0.25 to 0.6%, preferably 0.3 to 0.55% e.g.
`0.5% w/w.
`Suitable viscosity enhancing agents which may be
`incorporated into the solution include carbomers ie
`polymers of acrylic acid cross-linked with a polyalkenyl
`polyether, aluminium magnesium silicate, methylcellu-
`lose, hydroxypropyl methylcellulose and other cellu-
`lose derivatives.
`The viscosity of the solution will depend, inter alia,
`on the particular viscosity enhancing agent used and its
`molecular weight and on the target organ. However,
`the solution preferably has a viscosity of at least 100 cps,
`more preferably at least 200 cps and especially more
`than 400 cps, at a shear rate of 50 s‘1. The viscosity of
`the solution is preferably less than 10000 cps, more
`preferably less than 1000 cps and especially less than
`500 cps, at a shear rate of 50 s-"1.
`Viscosities are preferably determined using a rota-
`tional viscometer such as a Rheomat 30 (Rheomat is a
`Trade Mark), at a temperature of from 15° to 25° C. e.g.
`20° C.
`
`For applications which involve the solution being
`administered as a spray e.g. through a nasal pump, we
`prefer the viscosity enhancing agent to have a low, vis-
`cosity at high shear rates, e.g. from about 100 cps to
`about 300 cps at 140 s-1, and a high viscosity at low
`shear fates, e.g. from about 700 cps to about 1200 cps at
`15 s“ .
`Viscosity enhancing agents which we prefer include
`hydroxypropyl methylcellulose and carbomers, in par-
`ticular the carbomer sold as Carbopol 934, the viscosity
`of a neutralised 0.5% w/w aqueous dispersion of which
`lies in the range 29400 to 39400 cps and the heavy metal
`content of which is 0.002% or less. 10 The amount of
`viscosity-modifying agent required to achieve the de-
`sired viscosity will depend on the particular agent used
`and also on its molecular weight. However, we prefer
`to use up to about 2% w/w, e.g. 0.5 to 1.5% w/w of
`viscosity enhancing agent.
`The solution may also contain other conventional
`excipients, e.g. sodium chloride, dextrose or mannitol,
`and buffers, e.g. sodium dihydrogen orthophosphate
`(sodium acid phosphate BP), di-sodium hydrogen phos-
`phate (sodium phosphate BP) sodium citrate/citric acid,
`and boric acid/sodium borate. The proportion and con-
`centration of excipients and buffers may be varied
`within fairly wide ranges, provided the resulting solu-
`tion is stable and non—irritant when applied to the appro-
`priate tissues. The maximum total concentration of ex-
`cipients and buffers is preferably less than 5% w/v and
`more preferably less than 2% W/v. Solutions for rectal
`administration may contain bulking agents, e.g. methyl
`cellulose, to aid retention in the bowel.
`The solution may be made isotonic with physiolog-
`ical fluids by the incorporation of a suitable tonicity
`agent e.g. sodium chloride. The solution typically con-
`tains from about 0.1 to 1.0, more typically 0.5 to 1.0%
`w/v sodium chloride.
`
`5
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Although physiological pH is about 7.4, we prefer the
`pH of the solution to be in the range 3.5 to 6, preferably
`4 to 5.5. In this range of pH, the stability of the solution
`is enhanced, surprisingly with no deleterious effects
`such as undue tissue irritation.
`
`65
`
`The composition of the invention may be made up,
`for example, by dissolving the active ingredient, chelat-
`ing or sequestering agent (if included) and excipients (if
`
`5,443,833
`
`4
`included) in freshly distilled water, adding to this solu-
`tion an aqueous solution containing the preservative (if
`included), adjusting the pH if necessary, making the
`solution up to, the desired volume with distilled water,
`stirring and then sterilising. Alternatively, the active
`ingredient, chelating or sequestering agent (if included)
`and excipients (if included) may be dissolved in a solu-
`tion containing the preservative. Sterilisation is prefera-
`bly performed by sterile filtration into a previously
`sterilised container; Where the preservative used is
`benzalkonium chloride, some complex formation may
`occur when the solutions of active ingredient and pre-
`servative are mixed. It may thus be necessary to use a
`higher concentration of preservative than is desired for
`the final product.
`‘
`Aqueous solutions containing active ingredient, a
`viscosity enhancing agent, e.g. a carbomer, and, option-
`ally, a preservative, e.g. benzalkonium chloride, may be
`prepared by dispersing the viscosity enhancing agent in
`an aqueous solution containing the preservative (if used)
`and the active ingredient, and then, if required, adjust-
`ing the pH, e.g. by addition of sodium hydroxide, and,
`if desired, further diluting the solution with water.
`The solution of the preservative and the active ingre-
`dient may be made simply by dissolving the ingredients
`in water which is low in metal ions.
`The solution is preferably made up at a temperature
`of from about 10° to 50° C., for example at room tem-
`perature.
`The solution may be put up in unit dosage form, in
`which case preservatives may be incorporated, but are
`generally not necessary. Alternatively the solution may
`be put up in multi-dose form. In general it will be neces-
`sary to incorporate one or more preservatives into mul-
`ti-dose solutions to ensure that the solution remains
`sterile after initial use.
`Conventionally, unit doses of aqueous solutions for
`use in nebulisers are packed in glass or plastics ampoules
`which are broken open immediately prior to use. Such
`packaging is both wasteful and expensive to manufac-
`ture. Furthermore, the breaking-open of glass ampoules
`could lead to the formation of glass sherds which can be
`inhaled with the solution.
`We have now found a form of packaging for single-
`dose solutions which overcomes the above-mentioned
`disadvantages. Thus, according to a further aspect of
`the invention, we provide a soft ampoule of plastics
`material sterile-filled with a unit dose of an aqueous
`solution containing, as active ingredient, 9-ethyl-6,9-
`dihydro-4,6-dioxo-l0-propyl-4H-pyrano(3,2—g)quino-
`line-2,8-dicarboxylic acid or a pharmaceutically accept-
`able salt thereof, and sealed.
`We prefer the plastics material to be permeable to
`carbon dioxide. Thus, when the ampoule is stored, car-
`bon dioxide dissolves in the solution and the pH is low-
`ered. Since the stability of the active ingredient
`is
`greater at lower pH,-this has the effect of enhancing the
`stability of the solution.
`Suitable plastics materials from which the ampoule
`may be manufactured include low-density polyethyl-
`ene.
`
`A plurality of ampoules may be connected to, and
`formed integrally with, an anchorage member which
`may be adapted to receive a label or writing, e.g. to
`identify the contents of the ampoules.
`The plastics material may include a pigment or pig-
`ments such that the ampoules correspond in colour to
`the solution contained within them.
`
`

`
`5,443,833
`
`5
`Multi-dose solutions may be packaged in volumes of
`5 to 300 ml. Preferred volumes for inhalation composi-
`tions include 60, 120 and 240 ml. For nasal and ophthal-
`mic compositions multi-dose packs preferably contain
`from 5 to 20 ml of solution.
`We prefer multi-dose solutions to be packaged such
`that unit volumes of the solution to be administered can
`be accurately dispensed. The solution may, for example,
`be packaged in a flexible-walled container provided
`with a cap to receive the unit volume.
`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 about 0.3 to 1.2
`mg of active ingredient depending on the concentration
`of active ingredient) into the affected eye from 2 to 4
`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 0.25 ml (e.g. from about 1.2 mg
`to 5.0 mg of active ingredient) is indicated.
`For rectal administration a total daily dosage of from
`about 50 to 1000 mg of active ingredient, more prefera-
`bly 100 to 400 mg, administered in smaller doses 2 to 4
`times a day is found to be satisfactory. A dosage unit
`may conveniently contain from about 25 to 200 mg of 25
`active ingredient.
`For administration by inhalation a daily dosage of
`from about 10 mg to 100 mg is, in general, found to be
`satisfactory. The daily dosage may be administered in
`divided doses, e.g. from 2 to 4 times a day. More fre-
`quent dosage may of course be used if required.
`The aqueous solutions according to the present in-
`vention are advantageous in that they are longer acting,
`more acceptable to the patient, give rise to higher con-
`centrations of active ingredient in target tissues, give
`rise to effective concentrations of active ingredient in
`target tissues for a longer time or are more stable than
`known similar formulations.
`The invention is illustrated, but in no way limited, by
`the following Examples.
`
`5
`
`10
`
`15
`
`20
`
`30
`
`35
`
`6
`g) were then added to the solution. The pH of the solu-
`tion was adjusted to between 5 and 5.5 by addition of
`sodium hydroxide and the volume made up to 1000 ml
`with purified water.
`The solution was filled into polyethylene bottles of
`120 ml capacity.
`
`Nasal Solution
`
`Example 3
`
`
`Nedocromil Sodium
`1.00% w/v
`Sodium Chloride
`0.715
`Disodium Edetate
`0.01
`Benzalkonium Chloride
`0.02
`
`Purified Water to 100
`
`Nedocromil sodium (100 g), sodium chloride (71.5 g)
`and disodium edetate (1 g) were dissolved in approxi-
`mately 5 liters of purified water. To this solution a dis-
`persion of benzalkonium chloride solution 50% USNF
`(4 g) in approximately 1 liter of purified water was
`added. The solution was made up to 10 liters with puri-
`fied water, stirred for 30 minutes, filtered to remove any
`complex formed and then sterile filtered and filled into
`bottles.
`
`Example 4
`
`Opthalmic Solution
`
`Nedocromil Sodium
`2.00% w/v
`Benzalkonium Chloride
`0.01
`Disodium Edetate
`0.05
`Sodium Chloride
`0.55
`
`Purified Water to 100
`
`Prepared by the method of Example 3 above.
`
`Example 5
`
`Viscous Nasal or Ophthalmic Solution
`
`Nedocromil sodium
`Disodium edetate
`Benzalkonium chloride
`Carbopol 934P
`Sodium hydroxide
`Purified water
`
`1.0% w/w
`0.1
`0.01
`0.73
`q.s.
`to 100
`
`Example 1
`Non-preserved nebuliser solution
`
`0.5% w/v
`Nedocromil Sodium
`0.79
`Sodium Chloride
`q.s.
`Hydrochloric acid
`
`Purified Water to 100
`
`45
`
`Nedocromil sodium (5 g) and sodium chloride (7.9 g) so
`were dissolved in purified water (900 ml). The pH of the
`solution was adjusted to between 5 and 5.5 by addition
`of hydrochloric acid and the volume made up to 1000
`ml with purified water.
`The solution was sterile—filled into low-density poly- 55
`ethylene ampoules which were then sealed.
`
`Example 2
`Preserved nebuliser solution
` 60
`Nedocromil Sodium
`0.5% w/v
`Sodium Chloride
`0.79
`Chlorbutol
`0.5
`Sodium hydroxide
`q.s.
`Purified Water
`to 100
`
`65
`
`Chlorbutol (5 g) was dissolved in purified water (900
`ml) . Nedocromil sodium (5 g) and sodium chloride (7.9
`
`20 g of nedocromil sodium and 2 g of disodium ede-
`tate were dissolved in approximately 600 g of purified
`water. A dispersion of 0.808 g of Benzalkonium Chlo-
`ride Solution 50% USNF in approximately 200 g of
`purified water was added and the resulting dispersion
`made up to 1000 g with purified water and stirred for 30
`minutes.
`-
`
`The dispersion was filtered through a glass fibre pre-
`filter and the first 100 ml discarded. The remainder of
`the filtered solution was filtered through a pre-sterilised
`0.22 um membrane filter and the filtrate collected.
`
`250 g of the filtrate was added to 4.15 g of Carbopol
`934P and stirred until the Carbopol was fully dispersed.
`The pH of the dispersion was adjusted to between pH
`5.5 and 5.8 by addition of 2M sodium hydroxide solu-
`tion. The dispersion was mixed until a homogeneous
`uniform gel was formed. The gel was made up to 500 g
`with purified water, remixed and filtered through a 13
`um stainless steel filter.
`
`

`
`5,443,833
`
`8
`In addition the patients were asked whether the eye-
`drops were an acceptable form of treatment.
`For the 23 patients who completed the trial, the re-
`sults were as follows:
`
`
`No of p¢_:tients
`
`Patients’ assessment
`Clinicians’ assessment
`Rating
`3
`10
`7
`2
`9
`9
`1
`2
`4
`0
`1
`1
`
`
`(One patient failed to record an opinion, and the clini-
`cian failed to record an opinion for two patients).
`18 of the 23 patients recorded that they found the
`treatment acceptable.
`We claim:
`
`1. A method of treating a reversible obstructive air-
`ways disease comprising administering, by inhalation,
`to a patient suffering from, or susceptible to, such a
`condition the nebulized contents of an ampoule of car-
`bon dioxide permeable plastics material filled with a
`unit dose of an aqueous pharmaceutical solution con-
`taining, as active ingredient, from 0.1 to 5% W/V of
`9-ethyl-6,9-di11ydro-4,6-dioxo-10-propyl-4H-
`pyrano(3,2-g)quinoline-2,8-dicarboxylic acid or a phar-
`maceutically acceptable salt thereof, the solution hav-
`ing a pH of 3.5 to 6.0.
`2. The method of treatment according to claim 1,
`wherein the concentration of the active ingredient in
`the solution is from 0.1 to 1.0% W/v.
`3. The method of treatment according to claim 1,
`wherein the active ingredient is nedocromil sodium.
`it
`*
`*
`*
`*
`
`7
`The viscosity of the solution at 20° C. and a shear rate
`of 505*‘ was found to lie in the range 420-480 cps.
`
`Enema Solution
`
`Example 6
`
`
`Nedocromil Sodium
`0.15% w/v
`Nipastat
`0.10
`(Nipastat is a trademark)
`0.812
`Sodium Chloride
`
`Purified Water to 100
`
`10
`
`Methyl cellulose or other agents may be added to aid
`retention of the solution in the bowel.
`
`15
`
`Example 7
`
`Study of 2% Nedocromil Sodium Eye-Drops in the
`Treatment of Seasonal Allergic Conjunctivitis
`'20
`32 patients (11 male, 21 female) with ages in the range
`4 to 69 (average 25.2) participated in an investigation of
`the efficacy of an aqueous solution of nedocromil so-
`dium in the treatment of seasonal allergic conjunctivitis.
`The solution used had the composition given in Exam-
`ple 4. One drop (0.04 ml) was administered per eye four
`times a day for four weeks.
`At the end of the trial, both the patient and the super-
`vising clinician were asked to rate the effectiveness of
`the treatment, using the following 0-3 scale:
`0=no control of symptoms
`1=s1ight control
`2=moderate control
`3 =full control
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`

`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`
`:
`
`5,443,833
`
`DATED
`
`: August 22, 1995
`
`INVENTORISI
`
`:
`
`CLARKETAL.
`
`It is certified that error appears in the above—identified patent and that said Letters Patent is hereby
`corrected as shown below:
`
`Column 3, line 8, "aluminium" should be --aluminum--.
`
`Column 3, line 36, "less. 10 The" should be --less.
`
`1The——.
`
`
`
`
`
`Arrest:
`
`
`Signed and Sealed this
`'
`Second Day ofApril, 1996 :
`@0144 W
`
`BRUCE LEHMAN
`
`
`
` Arresting Oflicer Commissioner of Patemx and Trademarks