United States Patent 19 11 4,146,634 Brown et al. 45) Mar. 27, 1979

(54) COMPOSITION (56) References Cited U.S. PATENT DOCUMENTS (75) Inventors: Kenneth Brown; David J. Robinson; 3,686,412 8/1972 Fitzmaurice et al...... 424/283 James E. Taylor, all of 3,705,945 12/1972 Fitzmaurice et al...... 424/283 Loughborough, England 3,777,033 12/1973 Fitzmaurice et al...... 424/283 3,792,063 2/1974 Cairns et al...... 424/283 73) Assignee: Fisons Limited, London, England 3,948,954 4/1976 Cairns et al...... 424/283 OTHER PUBLICATIONS (21) Appl. No.: 810,361 Easty et al., Clinical Allergy, 1972, vol. 2, pp. 99-107. Merck Manual, 12th Ed., 1972, pp. 972-976. (22 Filed: Jun. 27, 1977 Stedman's Medical Dictionary, 1966, p. 1520. Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Merriam, Marshall & Bicknell Related U.S. Application Data 63 Continuation-in-part of Ser. No. 626,786, Oct. 29, 1975, 57 ABSTRACT abandoned, and a continuation-in-part of Ser. No. A pharmaceutical composition in the form of a lozenge, 626,789, Oct. 29, 1975, abandoned. chewable tablet, chewing gum, pastille, gel, paint or paste comprises from 0.01 to 20% by weight of 1,3-bis(- carboxychromon-5-yloxy)-2-hydroxypropane or a (30) Foreign Application Priority Data pharmaceutically acceptable salt thereof in association Nov. 9, 1971 GB United Kingdom ...... 48595/71 with a suitable pharmaceutically acceptable adjuvant, diluent or carrier. The composition is useful for the 51) int. C.’...... A61K 31/35 treatment of mouth ulcers in man. 52 U.S. C...... 424/283 58) Field of Search ...... 424/283 1 Claim, No Drawings 4,146,634 1. 2 hardness as measured by Monsanto Hardness Tester of COMPOSTION greater than 5 kg, and more preferably of greater than 7 kg. The hardness is desirably not greater than 11 kg. This application is a continuation-in-part of our co The carrier for the lozenges is conveniently a sugar, pending applications Ser. No. 626,786, filed Oct. 29, 5 such as glucose, lactose or sucrose, or a substantially 1975, and Ser. No. 626,789, filed Oct. 29, 1975, both non-cariogenic material, for example mannitol, xylitol now abandoned. r or polyethylene glycol. This invention concerns pharmaceutical composi In addition to the active ingredient and the carrier, tions. the lozenges preferably contain one or more binders, 1,3-Bis(2-carboxychromon-5-yloxy)-2-hydroxypro O such as gelatin or liquid glucose BPC 1963, which in pane and the pharmaceutically acceptable salts thereof total may conveniently be present in an amount of from are known compounds which are described and claimed 0.5 to 10% weight of the lozenge. A preferred range is in British Pat. No. 1,144,905. The compounds are from 1 to 5% by weight. known to be of use in the treatment of medical disorders The lozenges may additionally contain a lubricant, caused or exacerbated by products which arise from the 15 such as stearic acid or a stearate such as magnesium combination of certain types of antibody with specific stearate to facilitate manufacture of the lozenge. When antigen. In man, it has been found that the disodium salt one or more lubricants are present, the total content of 1,3-bis-(2-carboxychromon-5-yloxy)-2-hydroxypro thereof in the lozenge is preferably from 0.1 to 5% by pane is of exceptional merit when administered by inha weight. lation in the treatment of asthma. 20 The lozenges may be prepared by conventional loz We have now found that 1,3-bis(2-carboxychromon enge making procedures, for example by admixing the 5-yloxy)-2-hydroxypropane and the pharmaceutically 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane acceptable salts thereof are surprisingly of use in the or salt thereof with the adjuvant, diluent or carrier and treatment in man of aphthous stomatitis (mouth ulcers). compressing the mixture. In a preferred procedure, the Accordingly, this invention provides a pharmaceuti 25 bis-chromone and the adjuvant, diluent or carrier are cal composition in the form of a lozenge, chewable desirably first granulated together before being com tablet, chewing gum, pastille, gel, paint or paste com pressed into the lozenge. The granulation step is prefer prising from 0.01 to 20% by weight of 1,3-bis(2-carbox ably a wet granulation step, and a lubricant is desirably ychromon-5-yloxy)-2-hydroxypropane or a pharmaceu added immediately before the compression step. tically acceptable salt thereof in association with a suit 30 The chewable tablets preferably have a disintegration able pharmaceutically acceptable adjuvant, diluent or time in the British Pharmacopocia Disintegration Test carrier. of greater than 10 minutes and more preferably of Pharmaceutically acceptable salts of the bis-chro greater than 15 minutes. mone include the alkali-metal, for example sodium or The carrier for the chewable tablets is desirably one potassium, salts and the alkaline earth metal, for exam 35 or more of mannitol, polyethylene glycol or cellulose. ple calcium or magnesium, salts. An especially pre The carrier is preferably present in an amount of greater ferred salt is the disodium salt. than 50% by weight of the chewable tablet, and is more Those compositions which are gels, paints or pastes preferably present in an amount of from 60 to 85% by will naturally be applied directly to the afflicted site, weight thereof. whereas those compositions which are lozenges, chew In addition, a binding agent, for example gelatin or a able tablets, chewing gums or pastilles will be dissolved cellulose derivative, such as methyl cellulose or methyl or dispersed in the mouth to give a significant concen hydroxyethyl cellulose, is preferably present, desirably tration of the active ingredient over the afflicted site. in an amount of from 0.5 to 20%, more especially from The compositions which are to be applied directly to 0.5 to 4%, by weight of the chewable tablet. the afflicted site are desirably so formulated that they 45 The chewable tablets may be prepared by conven are not easily washed from the site, and those which are tional tabletting procedures. For example, the dry in to be dissolved or dispersed in the mouth are desirably gredients may simply be admixed and compressed to an so formulated as to give a significant concentration of appropriate hardness. the active ingredient in the mouth over as long a period The chewing gum formulations comprise the active as possible. 50 ingredient dispersed homogeneously throughout a la The lozenge, chewable tablet, chewing gum and pas tex. Most preferably, the active ingredient is made first tille compositions of the present invention preferably into a concentrated aqueous solution thereof, which is contain from 0.2 to 5%, more preferably from 1 to 4%, then dispersed in the latex by a conventional blending for example from 1.5 to 2.5%, by weight of the bis-chro procedure. The latex employed is preferably chicle gum mone. On the other hand, the gel, paint and paste com 55 or jelutong gum or a mixture of both. positions of the present invention preferably contain The lozenge and chewable tablet formulations prefer from 0.5 to 15%, more preferably from 1 to 5%, for ably contain the bis-chromone in finely-divided form example from 1.5 to 2.5%, by weight of the bis-chro having a mass median diameter of less than 10 microns. Ole. The carrier in the lozenge and chewable tablet formula In general, it is believed that a skilled formulation tions is also preferably employed in finely-divided form, chemist would be able to produce a satisfactory compo having a mass median diameter of less than 150 microns. sition having the desired parameters. However, the The pastilles contain from 8 to 30% by weight of a following details are given for further guidance as to the pharmaceutically acceptable gelling agent, and more preferred compositions. preferably from 15 to 25% thereof. Desirably, the gel The lozenges desirably have a disintegration time in 65 ling agent is gelatin. The pastilles preferably also con the British Pharmacopoeia Disintegration Test of tain from 10 to 60% by weight, more preferably from 30 greater than 10 minutes, and more preferably of greater to 50% by weight of a softening agent, for example than 15 minutes. The lozenges also desirably have a glycerol. 4,146,634 3 4. The carrier is preferably water. ite or a cellulose derivative such as carboxymethyl cel The pastilles may be prepared by conventional proce lulose, in an amount in total of from 2 to 30% by weight dures. For example, the gelling agent may be dissolved of the paste, and an aqueous or liquid paraffin base. in the carrier at elevated temperature, the other compo The paste composition may be prepared by conven nents then added, and the solution poured into moulds tional paste-forming procedures. Thus, for example, the and allowed to cool. ingredients may simply be admixed, with heating if The lozenges, chewable tablets, chewing gums and necessary to give a homogeneous product followed by pastilles of the present invention may also contain an cooling, to give the desired paste. Any insoluble materi adherant, which may be a cellulose derivative such as als in the paste should desirably have a mass median methyl cellulose, ethyl cellulose or hydroxypropyl 10 diameter of less than 150 microns. methyl cellulose which enables the composition, when The dosage to be administered will depend to some dissolved in the mouth, to adhere slightly to the af extent on the severity of the affliction to be treated. flicted surfaces of the mough, and thereby increase the However, a dosage of from 0.5 mg to 30.0 mg, prefera contact time between the active ingredient and the bly 1.5 mg to 20.0 mg of the bis-chromone, administered afflicted site. The adherent may be present in an amount 15 in a gel, paint or paste directly on the afflicted site 1 to of from 0.1 to 5% by weight. 4 times a day (i.e. a preferred daily dosage of from 1.5 The dosage of active ingredient to be administered mg to 80.0 mg) is generally found to be satisfactory. will of course depend upon the severity of the affliction. Naturally, the compositions of the present invention However, a dosage of from 0.1 mg to 200 mg, prefera may also contain flavouring or colouring agents, preser bly 2 to 200 mg, of the bis-chromone administered in 20 lozenges, chewable tablets, chewing gum or pastilles 1 vatives, or other medicaments as desired. to 4 times a day (i.e. a preferred daily dosage of from 0.1 All the components of the compositions of the pres mg to 800 mg) is generally found to be satisfactory. ent invention are desirably sterile. The gel compositions of the present invention contain This invention is further described, though only by from 0.5 to 20%, preferably from 0.5 to 10%, for exam 25. way of illustration, in the following Examples. ple from 1 to 5% by weight of a pharmaceutically ac EXAMPLE 1. ceptable gelling agent. The gelling agent employed, which may be any phar The following ingredients were formulated into a 1 maceutically acceptable gelling agent, is preferably gm lozenge as described below: present in the composition in such an amount that the 30 composition is neither so mobile that it runs off the site % w/w to which it is applied nor so stiff that it cannot easily be 1,3-bis(2-carboxychromon-5-yloxy)-2- dispensed or applied. Although the amount to be incor hyroxy-pyropane, disodium salt (mass median diameter < 10 microns) 20 porated for best results will vary with the particular Sucrose (mass median diameter gelling agent employed, it is believed to be within the 35 <150 microns) 95.83 Gelatin 0.64 competence of any skilled formulation chemist to pro Liquid glucose BPC 1963 0.64 duce a composition having the desired characteristics. Stearic acid (powdered) 0.64 Typical gelling agents which may be employed in Peppermint oil 0.25 clude hydroxypropylmethyl cellulose, sodium carboxy 100.00 methyl cellulose, carboxypolymethylene or PVM/MA (a copolymer of methyl vinyl ether and maleic anhy The gelatin and liquid glucose were dissolved in dride). water to give a 10% w/v solution with respect to each. The carrier employed is preferably water, although The sucrose, disodium salt and stearic acid were inde other carriers may be employed if desired, for example pendently mixed intimately and added to the solution. glycerol, propylene glycol or a paraffin base. 45 The gels of the present invention preferably contain a This mixture, after stirring to mix the components, was complexing agent, for example the disodium salt of then passed through a coarse sieve to give coarse parti ethylenediamine tetraacetic acid (EDTA), since this cles, which were dried. Finally the peppermint oil was prevents the formation of insoluble heavy metal salts of added, further mixing was effected, and a lozenge was the bis-chromone. The complexing agent is preferably 50 produced by compressing the mix in a die to a Mon present in an amount of from 0.01 to 0.1% by weight of santo hardness of 7 kg in a conventional manner. the gel. The lozenge which resulted was of pleasant, accept The gels may be prepared by conventional gel-form able taste, had good mouth feel, and dissolved in the ing procedures, for example by dissolving the 1,3-bis(2- mouth over a period of about 10 minutes. carboxychromon-5-yloxy)-2-hydroxypropane or salt 55 EXAMPLE 2 thereof at an elevated temperature in the carrier, and cooling the solution to form the desired gel. The following ingredients were formulated into a The paints of the present invention contain a liquid chewable tablet as described below: carrier, for example water, and a thickening agent, for example glycerol, soldium carboxymethylcellulose or ng pothyethylene glycol in an amount of from 0.5 to 2.0% 1,3-bis(2-carboxychromon-5-yloxy)-2- by weight of the paint. hydroxypropane, disodium salt (mass median diameter < 10 microns) 20.0 The paints may be prepared by conventional paint Milled mannitol 4800 forming procedures. For example, the ingredients may Methyl cellulose 20 cp 7.5 be mixed and blended to the desired consistency. 65 Polyethylene glycol 6000 (micronised) 50.75 The paste compositions of the present invention con Flavouring 1.95 tain one or more thickening agent, for example gelatin, 560.20 pectin, zinc oxide, polyethylene glycol, starch, benton 4,146,634 5 6 The ingredients were admixed and blended to homo this solution, and the mixture was cooled with stirring geneity, and the mixture was then compressed to a in such a way as to avoid the incorporation of air. The Monsanto hardness of 5 kg in a conventional die. A remainder of the water was then added, and the mixture chewable tablet resulted of good acceptability. cooled to 4' C. overnight, with stirring to avoid the incorporation of air, to allow the hydroxypropyl methyl EXAMPLE 3 cellulose to dissolve. A gel resulted of appropriate phys The following ingredients were formulated into a ical characteristics to render it suitable for application in chewing gum as described below: the mouth. 10 EXAMPLE 6 g 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, The following ingredients were formulated into a disodium salt (mass median diameter < 10 microns) 0.4 Chicle gum 0.0 paint as described below: Water 2.0 12.4 15 % 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, The disodium salt was dissolved in the water by heat disodium salt 2.0 Ethyl alcohol (90%) 200 ing, and the solution was added to the melted Chicle Glycerol 20.0 gum. The mixture was then blended to homogeneity Purified water 58.0 and was cast into sticks. On cooling a chewing gum 20 1000 resulted of acceptable quality. EXAMPLE 4 The disodium salt was dissolved in part of the water, and the ethyl alcohol and glycerol were then added to The following ingredients were formulated into pas the solution. Finally, the remainder of the water was tilles as described below: 25 added to give a paint of acceptable characteristics.

% w/w EXAMPLE 7 1,3-bis(2-carboxychromon-5-yloxy)- The following ingredients were formulated into a 2-hydroxypropane, disodium salt 4.0 Gelatin 16.0 30 paste as described below: Glycerol 400 Water 400 Flavouring 9.S. % w/w 100.0 1,3-bis-(2-carboxychromon-5-yloxy)- 2-hydroxypropane, disodium salt 35 (mass median diameter <0 microns) 5.0 The gelatin, glycerol and water were heated together Bentonite 10.0 on a water bath to give a clear solution. The disodium Glycerol 10.0 salt was then dissolved in the solution, and the resultant Distilled water 750 solution was poured into a pastille mould. On cooling, 1000 pastilles were formed of good acceptability. The bentonite was heated at 150 C. for 1 hour to EXAMPLES sterilise it, and was then mixed with the disodium salt. The following ingredients were formulated into a gel The glycerol was then added with trituration, followed as described below: by the water. A paste resulted of acceptable quality. We claim: 45 % ww 1. A method of treating mouth ulcers in man, which 1,3-bis(2-carboxychromon-5-yloxy)-2- method comprises applying to the afflicted site an effec hydroxypropane, disodium salt 2.00 tive amount of 1,3-bis(2-carboxychromon-5-yloxy)-2- Disodium salt of ethylenediamine hydroxypropane or a pharmaceutically acceptable salt tetraacetic acid 0.01 Hydroxypropylmethyl cellulose (5000 cp) 2.00 50 thereof, by means of a pharmaceutical composition in Water 95.99 the form of a lozenge, chewable tablet, chewing gum, 100.00 pastille, gel, paint or paste comprising from 0.01 to 20% by weight of 1,3-bis(2-carboxychromon-5-yloxy)-2- The bis-chromone and the disodium salt of ethylene hydroxypropane or a pharmaceutically acceptable salt diamine tetraacetic acid were dissolved in part of the 55 thereof in association with a suitable pharmaceutically water, and the solution was heated to 95 C. The hy acceptable adjuvant, diluent or carrier. droxypropyl methyl cellulose was then dispersed into s

65

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 4,146, 634 DATED March 27, 1979 NVENTOR(S) : Kenneth Brown et al. It is Certified that error appears in the above-identified patent and that said Letters Patent are hereby Corrected as shown below:

Under "Foreign Application Priority Data", - "Nov. 9, 1971 (GB) United Kingdom . . . . 48595/7l" should be -- Nov. 9, 1974 (GB) United Kingdom..... 48591/74 Nov. 9, 1974 GBJ United Kingdom. . . . . 48595/74-- signed and escaled this Twenty-fifth Day of December 1979 SEAL - Attest:

SIDNEY A. DIAMOND Attesting Officer Commissioner of Patents and Trademarks