CA1068608A - Pharmaceutical composition containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane - Google Patents

Abstract

ABSTRACT

There are provided pharmaceutical compositions for the treatment of mouth ulcers in man, the compositions being in the form of a lozenge, chewable tablet, chewing gum or pastille, and comprising from 0.01 to 20% by weight of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt thereof in association with a suitable pharmaceutically acceptable adjuvant, diluent or carrier.

Description

~6~601~3 ~ 2 -~lis invention concerns pharmaccutical com~ositions.
1,3-Bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and the pharmaceutically acceptablc salts thereof are kno~Yn compounds which are described and claimed in ~ritish Patent No 1,144,905.
~le compounds are known to be of use in the treatment o medical disorders caused or exacerbated by products ~hich arise from the combination of certain types of antibody with specific antigen.
In man, it has been found that the disodium salt of 1~3-b;s-t2~carboxychromon-5-yloxy)-2-hydroxypropane is of exceptional merit when administered by inhalation in the treatment of asthma.
We have now found that 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and the pharmaceutically acceptable sal-ts thereoî
are surprisingly of use in the treatment in man of aphthous stomatitis ~mouth ulcers).
Accordingly, this invention provides a pharmaceutical `l -composition in the form of a lo~enge, chewable tablet, chewing gum ~r pastille comprising from 0.01 to 20 I by weight of 1,3-bis~2-carboxychromon-5-yloxy)-2-hydroxypropane l~ 20 or a pharmaceutically acceptable salt thereof in association with a suitable pharmaceutically acceptable adj wantS diluent o~ -.. I carrier.
¦ P}larmaceutically acceptable salts of the bis-chromone include the alkali-metal, for e~ample sodium or potassium, salts and the al~aline ear~h metal, for example calcium or magnesium,

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The compositions, which are to be dissolved in the mouth, are desirably so formulated as to give a significant concentration of the active ingredient in the mouth over as long a period as possible.
The lozenge, che~able tablet, chewing gum and pastille compositions of the present invention preferably contain from 0.2 bo 5~, more preferably from 1 to 4~, for example from 1.5 to 2.5~, by weight of the bis-chromone.
In gen~ral, it is believed that a skilled formulation chemist would be able to produce a satisfactory composition having the desircd parameters. ~lawever, the following details are given for further guidance as to the preferred compositions.
The lo~enges desirably have a disintegration time in the British Phalmacopoeia Disintegr~tion Test of greater than 10 minutes, `'', , ., ~ ... . .. .
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The carrier for the lozenges is conveniently a sugar, such as glucose, lactose or sucrose, or a substantially non-cariogenic material, ¦ for example mannitol, xylitol or polylthylene glycol.
In addition to the acti~-e ingredient and the carrier, the lozenges preferably contain one or more binders, such as gelatin or liquid glucose BPC 1963, which in total may conveniently be present in an amount of from 0.5 to lO~o weight of the lozenge.
A preferred range is from 1 to 5~ by weight.
1 The lozenges may additionally contain a lubricant, such as stearic acid or a stearate such as magnesium stearate to facilitate manufacture of the lozenge. lYhen one or more lubricants are present, the total content thereof in the lozenge is preferably from 0.1 to 5~ by weight.
The 102erges may be pre~ared by conventional lozenge making procedures, for example by admixing the 193-bis~2-carboxychromon-Sylax~--Z~
- 20 hydroxypropane or salt thereof with the adjuvant, diluent or carrier and co~npressing the mixture. In a preferred procedure, the bis-c~romone and the adj w ant, diluent or carrier are desirably firs~ granuIated together before being compressed into the lozenge. ~he granulation step is preferably a wet granulation step, and a lubricant is desirably added immediately be~ore the compression step.
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5 _ ¦ The chewable tablets preferably have a disintegration time' in the British Pharmacopoeia Disintegration Test of ~reater than j 10 minutes and more preferably of greater than 15 minutes.
The carrier for the chewable tablets is desirably one or 5 more of mannitol, polyethylene glycol or cellulose. The carrier is preferably present in an a unt of greater than 50~0 by weight of the chewable tablet, and is more preferably present in an am~unt of from 60 to 85~ by wcight thereof.
In addition, a binding agent, for example gelatin or a 10 cellulose derivative, such as methyl cellulose or methyl hydroxyethyl cellulose, is preferably presen~, desirably in an amount of fro~ 0.5 to 20Q, more especially from 0.5 to 4~0, by ~eight of the chewable tablet.
The chewable tablets may be prepared by conventional table*ting procedures. For example, the dry ingredients may simply be admixed and compressed to an appropriate hardness.
The chewing gum formulations comprise the active ingredient dispersed hom~geneously throughout a latex. ,~lost preferably, the active ingredient is made first into a concentrated a~ueous solutian - ~ thereof, which is then dispersed in the latex by a con~entional blending procedure. The latex employed is preferably c~icle gum ar jelutong gum or a mixture of both.

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The lozenge and chewable tablet formulations preferably contain the bis-chromone in finely-divided form having ; a mass median diameter of less than lO microns. The carrier in the lozenge and chewable tablet fo~mulations is also preferably employed in finely-divided form, having a mass median diameter o less than 150 microns.
I The pastilles contain from 8 to 30 ~ by weight of a phar~aceutically acceptable gellin~ agent, and more preferably from 15 to 25 ~ thereof. Desirably, the gelling agent is gelatin.
The pastilles preferably also contain from 10 to 60~ by weight, more ; preferably from 30 to 50% by weight of a softening agent, for exam~le glycerol.
The carrier is preferably water.
The pastilles may be prepared by conventional procedures.
For example, the gelling agent may be dissolved in the carrier at elevated temperature, the other componenrs then added, and the solution poured into n~ulds and allowed to cool.
The lozenges, chewable tablets, chewing gums and pastilles -¦ of the present in~ention may also contain an adherant, which m~y be a cellulose derivative such as methyl cellulose, ethyl cellulose o~ hydroxypropylmethyl cellulose which enables the composition, when dissolved in the mouth, to adhere slightly to the afflicted surfaces of the ugh, and thereby increase the contact time bekween the active ingredient and the afflicted site. The aaherant may be present in an a~ount of from 0.1 to 53 by weight, The dosage of activc ingredient to be administered will Gf ~
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course depend upon the severity of the affliction. However, a dosage of from 0.1 mg to 2C0 mg, preferably 2 to 200 mg, of the bis-chrone administered in lozenges, chewable tablets, chewing ~ or pastilles 1 to 4 times a day (i.e. a preferred daily dosage of from 0.1 mg to 800 mg) is generally found to be satisfactory.
Naturally, the compositions of the present invention may also contain flavouring or c~louring agents, preseTvatives, or other j medicaments as desired.
;l 15 All the components of the compositions of the present i i~vention are desirably sterile.
This invention is further described, though only by way of illustration, in the following Examples.
Example 1 .
The follo~ing ingredients were formulated into a 1 gm lozenge I as described below:
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1,3-bis(2-carboxychromon-5-yloxy)-2-I hydroxy-propane, disodium salt ~mass I median dicLmeter ~ lO microns) 2.0 Sucrose (mass median diameter C l50 microns) 95.83 Gelatin 0.64 Liquid glucose BPC 19630.64 Stearic acid ~powdered)0064 Peppermint oil 0.25 . 10 lOOoOO' The gelatin and liquid glucose were dissolved in water to give a lOQ W/V solution with respect to each. The sucrose, disodium salt and stearic acid were independently mixed intimately and i added to the solution. This mixture, after sti~ring to mix the components~was then passed through a coarse sieve to give coarse particles~ which were dried. Finally the peppermint oil was added, further mixing was effected, and a lozenge was produced by ¦ compressing the mix in a die to a ~lonsanto hardness of 7 kg in ¦ a conventional manner.
~ lhe lozenge which resulted was of pleasant, acceptable taste, had good 'mouth feel', and dissol~ed in the mouth over a period of .
about 10 minutes.
Exa~ple 2 :
;~ The following ingredients were formllated into a chewable tablet as described below:
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6 8t~ 3 _ 9 -mg 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane, disodium salt (mass , median diameter ~ 10 microns)20.0 j Milled l~nnitol 480.0 ~¦ S Methyl cellulose 20 cp 7.5 ¦ Polyethylene glycol 6000 (micronised) 50.75 Flavouring 1.95 560.20 . . ', lhe ingredients were admixed and blended to ho geneity, and ; the mixture was then compressed to a Monsanto hardness of kg in a conventional die. A chewable tablet resulted of good acceptability.
ample 3 The following ingredients were formulated into a chewing gum as described below:
1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxyprop~ne, disodium salt (mass median diameter ~ 10 microns~ Q~4 Chicle gum - ~G
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The disodium salt was dissOlved in ~le wzte~ by heating, and the solution was added to the melted Chicle gum. The mixture ~as t~en ~lended to homogeneity and was cast into sticks. On cooling a chewing gum resulted ` of acceptable quality.
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Example 4 m e following ingredients were formulated into pastilles as describcd below:
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The gelatin, glycerol and water were heated together on a ¦ water bath to give a clear solution. The disodium salt was then ¦ dissolved in the solution, and the resultant solution was poured¦ 15 into a pastille mould. On cooling, pastilles were formed of gOoa ¦ acceptability.
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Claims (11)

Claims

1. A pharmaceutical composition in the form of a lozenge, chewable tablet, chewing gum or pastille, comprising from 0.01 to 20% by weight of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt thereof in association with a suitable pharmaceutically acceptable adjuvant, diluent or carrier.

2. A composition according to claim 1 which contains a pharmaceutically acceptable alkali-metal or alkaline earth metal salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane.

3. A composition according to claim 2, wherein the alkali-metal salt is the disodium salt.

4. A composition according to claim 1 which contains from 0.2 to 5% by weight of the 1,3-bis(2-carboxy-chromon-5-yloxy)-2-hydroxypropane or pharmaceutically acceptable salt thereof.

5. A composition according to claim 1 in the form of a lozenge having a hardness as measured by Monsanto Hardness Tester of greater than 5 kg.

6. A composition according to claim 5 in which the carrier is selected from the group consisting of glucose, lactose, sucrose, mannitol, xylitol and polyethylene glycol.

7. A composition according to claim 1 in the form of a chewable tablet wherein the carrier comprises greater than 50% by weight of the chewable tablet, and is selected from the group consisting of mannitol, polyethylene glycol and cellulose.

8. A composition according to claim 1 in the form of a chewing gum wherein the active ingredient is homogenously dispersed in a latex.

9. A composition according to claim 8 wherein the latex is chicle gum or jelutong gum.

10. A composition according to claim 1 in the form of a pastille containing from 8 to 30% by weight of a pharmaceutically acceptable gelling agent.

11. A composition according to claim 1 in unit dose form eon-taining from 2 to 200 mg of active ingredient.