Therapeutic compositions of 1,3-bis(2-carboxychromon-5-yloxyl)propan-2-ol and aspirin or indomethacin

There is described a pharmaceutical mixture comprising 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, and aspirin or indomethacin. The mixture causes less gastrointestinal adverse effects than aspirin or indomethacin on their own.

This invention relates to a mixture and a method for its preparation. 
Aspirin, indomethacin and a number of other anti-inflammatory agents are 
widely used in the treatment of inflammatory conditions, but suffer from 
the disadvantage that they can cause gastro-intestinal irritation, pain, 
nausea, indigestion and in particular gastro-intestinal micro bleeding. We 
have now surprisingly found that the gastro-intestinal side effects of the 
anti-inflammatory agents indomethacin and aspirin can be inhibited by the 
application of di-sodium cromoglycate in combination with the 
anti-inflammatory. 
According to our invention therefore we provide a pharmaceutical 
composition comprising 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a 
pharmaceutically acceptable salt thereof, (herein referred to collectively 
as `active ingredient`) in combination with aspirin or indomethacin. 
We prefer to use the di-sodium salt of 
1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, which is commonly known as 
disodium cromoglycate (DSCG) or cromolyn sodium. 
When aspirin is used a suitable ratio of the compounds in the combination 
is from about 6,000 to 0.12 parts, preferably from 600 to 0.3 parts, and 
more preferably 600 to 1.2 parts by weight of aspirin to each part by 
weight of active ingredient. When indomethacin is used a suitable ratio of 
the compounds in the combination is from 0.02 to 1,000, preferably from 
0.05 to 100, and more preferably from 0.3 to 100 parts by weight of 
indomethacin to each part by weight of active ingredient. 
When aspirin is used a suitable daily dosage for most anti-inflammatory 
purposes is in the range 3 to 80 mg per kg, and preferably 3 to 40 mg per 
kg, of the subject to be treated's body weight. Thus for an adult human 
the normal dosage is in the range of from about 180 mg to 4.8g per day, 
and preferably from 180 mg to 2.4g per day, preferably given in divided 
doses 3 to 8, and preferably 3 to 4 times per day. When indomethacin is 
used a suitable daily dosage for most anti-inflammatory purposes is in the 
range 0.33 to 8.33 mg, and preferably from 0.83 to 8.33 mg, per kg of the 
subject to be treated's body weight. Thus for an adult human the normal 
dosage is in the range of from about 20 to 500 mg per day, preferably 
given in divided doses 2 to 5, and preferably 2 to 3 times per day. In 
the case of both aspirin and indomethacin each dose may comprise one or 
more unit doses, e.g. tablets or capsules. 
For human use therefore we provide compositions in unit dosage form 
comprising from 60 to 600 mg of aspirin and from 0.1 to 500 mg, preferably 
from 1 to 200 mg, and more preferably from 1 to 50 mg of active 
ingredient. Also for human use we provide compositions in unit dosage form 
comprising from 10 to 100 mg, and preferably from 25 to 100 mg, of 
indomethacin and from 0.1 to 500 mg, preferably from 1 to 200 mg, and more 
preferably from 1 to 50 mg, of active ingredient in unit dosage form. We 
particularly prefer compositions in unit dosage form comprising up to 100 
mg of active ingredient as higher unit doses of active ingredient may tend 
to cause an increase in gastrointestinal irritation. 
According to our invention we also provide a method for the treatment of an 
inflammatory and/or painfull condition, e.g. arthritis such as rheumatoid 
arthritis, rheumatism and other disorders, e.g. inflammatory disorders or 
platelet aggregation, normally treated with aspirin or indomethacin, which 
comprises administration of a composition according to the invention to an 
individual mammal, e.g. human, suffering from such a condition. The 
administration is preferably per os, and is most preferably administration 
by mouth (oesphagaeal administration). 
According to the invention we also provide a method for the treatment of an 
inflammatory and/or painfull condition, e.g. arthritis such as rheumatoid 
arthritis, rheumatism, and other disorders, e.g. inflammatory disorders or 
platelet aggregation, normally treated with aspirin or indomethacin, which 
comprises sequential or simultaneous administration of active ingredient 
and indomethacin or aspirin to an individual mammal, e.g. human, suffering 
from such a condition or disorder. 
The active ingredient is preferably administered in such a way that it is 
available in the gastrointestinal tract-before the aspirin or the 
indomethacin, e.g. the active ingredient may be administered before the 
aspirin or indomethacin. Alternatively the active ingredient may be 
administered together with or after the aspirin or indomethacin, but in 
such circumstances the aspirin or indomethacin are preferably used in 
delayed or sustained release form. 
When sequential or simultaneous administration of active ingredient and 
aspirin or indomethacin is used the ratios and dosages of the active 
ingredient and aspirin or indomethacin are as described above with respect 
to the mixtures. 
The invention therefore also provides a pharmaceutical package comprising 
at least one unit dose of active ingredient and at least one unit dose of 
indomethacin or aspirin. The unit doses are preferably arranged in the 
package in a particular order together with written or printed indications 
or directions, the indications or directions and the manner of packing 
being such as to provide guidance in relation to and to facilitate the 
taking of a unit dose of active ingredient and a unit dose of aspirin or 
indomethacin in a particular order, e.g. a unit dose of the former before 
a unit dose of the latter. The package is preferably a sealed package and 
may comprise a tube, box or chart in or on which the unit doses are 
packed. The unit doses are preferably suitable for oesophagaeal 
administration and preferably contain the doses of active ingredient and 
indomethacin or aspirin in the ratios set out above for the combinations. 
The suppression of the side effects of the aspirin or the indomethacin may 
be further enhanced by the post -- or preferably pre-dosing of the subject 
with additional active ingredient. 
In order to produce suitable compositions the active ingredient and the 
aspirin or indomethacin, either separately or as a mixture thereof, are 
worked up with organic or inorganic pharmaceutically acceptable adjuvants 
or excipients. Examples of such adjuvants are: 
For tablets and dragees: Binders, for example, cellulosic materials, e.g. 
microcrystalline cellulose and methyl cellulose; disintegrating agents, 
for example starches, e.g. maize starch; stabilisers, e.g. against 
hydrolysis of the active ingredients; flavouring agents, for example 
sugars such as lactose; fillers; stearates and inorganic diluents, e.g. 
talc. 
For syrups, suspensions or dispersions: A liquid vehicle in which the 
active ingredients may be dissolved or suspended, e.g. water; and 
suspending agents, e.g. cellulose derivatives, gums etc. 
For hard or soft capsules: Diluents, e.g. lactose; glidants, e.g. 
stearates; inorganic materials, e.g. silica or talc; stabilizers and 
dispersing agents. 
For suppositories: Natural or hardened oils, waxes etc. A large number of 
proprietary emulsifying bases are available and are suitable for use in 
suppositories. These include `Witepsol` bases, consisting of hydrogenated 
triglycerides of lauric acid with added monoglycerides; and `Massupol` 
bases, which consist of glyceryl esters of lauric acid with a very small 
amount of glyceryl monostearate. 
For enemas: Water, sodium chloride, buffers etc. 
We prefer compositions which are designed to be administered by mouth 
(oesophagaeally). 
The composition may also contain further adjuvants, for example a 
composition for use in tablets may contain lubricants and glidants to 
assist in tabletting, e.g. magnesium stearate, or wetting agents to assist 
in granulation, e.g. dioctyl sodium sulphosuccinate. The compositon may 
also if desired contain a pharmaceutically acceptable dye or colourant, 
and may, if desired, be coated using conventional film or sugar coating 
techniques. 
If desired the composition, or one or more components thereof, may be 
formulated in sustained release form, e.g. by coating some or all of the 
drug particles themselves or granules thereof made with, for example, 
sucrose and of a size up to 2 mm in diameter with a layer of, e.g. 
beeswax, Carnuba wax, stearic or palmitic acids, cetyl alcohol or similar 
substances which could be expected to be slowly dissolved or digested or 
to act as semi-permeable membranes through which the active ingredients 
can diffuse when the preparations are ingested. The composition may 
contain drug particles or granules which are uncoated in admixture with 
particles or granules having one or more coats of the coating medium, and 
may be in the form of a capsule containing the particles or granules or 
alternatively a tablet, for which other adjuvants may be required, such as 
glidants or lubricants. The mixture may be administered as an enteric 
coated composition to make the active ingredients available at the 
appropriate part of the gastro-intestinal tract. This may be achieved by 
coating the tablet with a continuous film of material which is resistant 
and impermeable to gastric secretions, but which is susceptible to 
intestinal secretions. Typical film materials are shellac and its 
derivatives and cellulose acetate phthalate. 
We prefer compositions which are adapted to release some or all of the 
active ingredient first and to release the aspirin or indomethacin later. 
Thus a solid composition may comprise a core of aspirin or indomethacin 
surrounded in part or in whole by an outer layer containing the active 
ingredient. The core may, if desired or necessary, be coated with a 
material which is relatively slowly dissolved or degraded by the gastric 
juices, e.g. shellac, beeswax, Carnuba wax, stearic or palmitic acids, or 
cetyl alcohol or the like and this coating may in turn be coated with a 
material containing the active ingredient which is relatively quickly 
dissolved or degraded by the gastric juices, e.g. sugar or a cellulose 
ether such as hydroxypropylmethylcellulose. Alternatively the composition 
may comprise discrete particles of the active ingredient, which may be 
coated or uncoated, but which are adapted to dissolve or disperse quickly 
in the gastrointestinal tract, in admixture with discrete particles of 
aspirin or indomethacin which are preferably coated or treated so that 
they dissolve or disperse the aspirin or indomethacin slowly in the 
gastrointestinal tract. We prefer the composition to be such that the 
aspirin or indomethacin begin to be available in the gastrointestinal 
tract from about 5 to 15 minutes after the active ingredient commences to 
be available in the gastrointestinal tract. 
The active ingredient and the indomethacin or aspirin may, if desired, be 
used in a specific form, e.g. having a mass medium diameter of less than 
10 microns. 
The active ingredient and the indomethacin or aspirin may also be 
formulated as an aqueous, e.g. a water chloroform (400:1), solution 
containing from 0.001 to 10.0% by weight of the active ingredient plus the 
indomethacin or aspirin. 
We prefer compositions containing aspirin.

The invention is illustrated, but in no way limited by the following 
Examples in which DSCG means di-sodium cromoglycate. 
EXAMPLE 1 
Male Charles River CD rats (150-250 g) receive 5 uCi .sup.59 Feferric 
citrate B.P. (radiochemical Centre) intravenously and are maintained on 
normal diet for at least one week. Two to three days before dosing the 
animals are housed singly in wire bottomed cages and put on a restricted 
diet of 15 g diet/day. 
A blood sample is taken from a tail vein at this time. The animals are not 
fed on the morning of dosing. They are dosed twice at a 4-5 hour interval 
with anti-inflammatory agent (5 ml/kg in 0.1% `Tween 80`) as suspensions 
of the free acid. Where DSCG is administered it is given jointly with the 
anti-inflammatory drug. In some experiments an additional dose of DSCG 
alone is given 2 hours before the first joint dose. Sawdust trays under 
the cages are changed on the day of dosing and the faecal samples from 
each rat collected during the 4 days post-dose. 
Radioactivity of blood and faeces is estimated in a .gamma.-counter. Blood 
loss in the stools is calculated for each rat and results are expressed as 
the group mean ml/kg blood loss. Statistical treatment of the results is 
by a Mann-Whitney U-test. Indomethacin plasma levels were estimated 
spectrofluorimetrically by the method of Holt & Hawkins Brit. Med. J. 1, 
1354 (1965). 
The results are shown in Tables 1 and 2. 
Table 1 
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The effect of DSCG upon aspirin-induced faecal blood loss 
No of rats 
ml/kg blood 
Dose (mg/kg b.i.d.) 
in group loss P.sub.1 
P.sub.2 
______________________________________ 
(a) Control 6 0.41 
Aspirin 300 7 0.55 0.07 
0.08 
Aspirin 300 
+ DSCG 100 7 0.48 0.13 
(b) Control 5 0.64 
Aspirin 300 5 1.80 &lt;0.01 
Aspirin 300 
+ DSCG 100 5 1.73 &lt;0.01 
Aspirin 300 + 
DSCG 100 + 
*DSCG 100 
pre-dose 5 0.91 0.03 &lt;0.01 
______________________________________ 
*An additional dose of DSCG alone was administered 2 h before the first 
combined dose. 
P.sub.1 and P.sub.2 are probability values derived from a Mann-Whitney 
U-test. The probability P.sub.1 is associated with a difference between 
control and aspirin-treated groups. The P.sub.2 value is associated with 
difference between the aspirin and aspirin + DSCG groups. 
Table 2 
______________________________________ 
The effect of DSCG upon indomethacin-induced faecal blood loss 
Faecal blood loss 
No. of rats 
ml/kg increase 
Dose (mg/kg b.i.d.) 
in group after treatment 
P 
______________________________________ 
(a) Indomethacin 5 
6 2.72 
Indomethacin 5 + 
DSCG 100 7 0.75 0.03 
(b) Indomethacin 5 
5 32.2 
Indomethacin 5 + 
DSCG 100 6 14.8 0.06 
(c) Indomethacin 5 
5 18.5 
Indomethacin 5 + 
DSCG 100 5 4.0 0.02 
Indomethacin 5 + 
DSCG 50 5 3.7 0.02 
(d) Indomethacin 5 
5 5.0 
Indomethacin 5 + 
DSCG 50 4 1.07 0.14 
Indomethacin 5 + 
DSCG 20 5 2.45 &gt;0.2 
Indomethacin 5 + 
DSCG 10 5 1.86 &lt;0.2 
(e) Indomethacin 5 
5 3.23 
Indomethacin 5+ 
DSCG 20 5 1.01 0.08 
(f) Indomethacin 5 
5 7.86 
Indomethacin 5 + 
DSCG 100 5 4.63 &lt;0.2 
______________________________________ 
*In expts 2c, d, e and f and additional dose of 100 mg DSCG alone was 
given 2 h before the first combined dose. 
P value is the probability associated with a difference between the 
indomethacin and indomethacin + DSCG groups. 
In some further experiments aspirin and DSCG were administered on a 
subacute basis. Animals were given one single dose of aspirin with or 
without DSCG by mouth each day for 5 consecutive days. Drugs were given 
one hour before feeding. Faeces were collected during the dosing period 
and for 3 days after administration of compound had ceased. The results of 
these experiments are shown in Table 3. 
Table 3 
______________________________________ 
The effect of DSCG upon faecal blood loss induced by subacute 
administration of aspirin 
No of ml/kg 
Dose mg/kg daily 
rats blood loss 
P.sub.1 
P.sub.2 
______________________________________ 
(a) Aspirin 100 7 1.79 
Aspirin 100 + 
DSCG 100 7 1.16 -- 0.08 
(b)* Control 10 0.99 
Aspirin 100 9 1.97 &lt;0.001 
Aspirin 100 + 
DSCG 25 10 1.74 &lt;0.001 
&gt;0.1 
Aspirin 100 + 
DSCG 50 10 1.59 &lt;0.001 
&gt;0.1 
Aspirin 100 + 
DSCG 100 10 1.29 &lt;0.05 0.05&lt;p 
&gt;0.1 
______________________________________ 
* In this experiment DSCG was given as a suspension of the free acid. 
P.sub.1 and P.sub.2 are probability values derived from a Mann-Whitney U 
test. The probability P.sub.1 is associated with a difference between 
control and aspirin treated groups. The P.sub.2 value is associated with 
difference between the aspirin and aspirin + DSCG groups. 
Example 2 
______________________________________ 
mg/tablet 
______________________________________ 
Aspirin 300 
DSCG 100 
Maize starch BP as binder 
15 
Maize starch as disintegrant 
45 
Microcrystalline cellulose BPC 
80 
Talc 10 
550 
______________________________________ 
Example 3 
______________________________________ 
mg/tablet 
______________________________________ 
Indomethacin 25 
DSCG 100 
Maize starch BP as binding 
7 
Maize starch as disintegrant 
25 
Lactose BP 100 
Magnesium Stearate BP 5 
262 
______________________________________ 
EXAMPLE 4 
Example 4 
______________________________________ 
1. Central Core Formulation 
Aspirin BP 300 mg 
Maize Starch BP 45 mg 
______________________________________ 
Sieve the aspirin through a 20 mesh sieve and the maize starch through a 40 
mesh sieve. Mix these ingredients and compress into `slugs`. Granulate the 
`slugs` using a 12 mesh screen. 
______________________________________ 
2. Formulation of Outer Layer 
mg % By weight 
______________________________________ 
1,3-Bis(2-carboxychromon-5-yloxy)-2- 
hydroxypropane, disodium salt 
100 49.8 
Sodium bicarbonate BP 75 37.3 
Maize starch BP 17.8 8.9 
Talc BP (sterilised) 8.0 4.0 
Purified water BP QS QS 
200.8 100.0 
______________________________________ 
The sodium bicarbonate, after being passed through a 100 mesh screen, was 
mixed in a drum roller with the bis-chromone, which had been passed 
through a 60 mesh screen. Half the starch was then added, and the drum was 
rolled for about 20 minutes. The mixed powder was then transferred to a 
mixing bowl and damped down with the water (approximately 120 ml per kg of 
dry powder). The damped powder was then passed through an 8 mesh screen 
and was dried at 50.degree. C for 2 hours, the dry product then being 
passed through a 16 mesh screen and blended with the talc and the 
remaining starch. 
3. Intermediate Layer 
An inert intermediate layer may, if desired, be used between the core and 
outer layer to delay the onset of disintegration and dissolution of the 
aspirin containing core. This intermediate layer may consist of fillers, 
e.g. lactose, dicalcium phosphate, a polymeric binder e.g. gelatin, 
polyvinylpyrrolidone, and a lubricant e.g. metallic stearates, talc etc. A 
suitable formulation comprises: 
Lactose BP 120 mg 
Dicalcium phosphate USP XVII 30 mg 
Gelatin BP 3 mg 
Magnesium stearate BP 1 mg 
The lactose and dicalcium phosphate, after being passed through a 40 mesh 
sieve, were mixed in a planetary mixer for 10 minutes and damped down with 
a 12% w/w aqueous solution of the gelatin (approx 150 ml solution per kg 
of dry powder). The damped down mixture was then passed through an 8 mesh 
screen and dried at 60.degree. C for 2 hours, the dry product then being 
passed through a 20 mesh screen and blended with the magnesium stearate. 
Compression 
The core formulation may be compressed into a solid core and the 
intermediate and outer layers may be compressed around this core using a 
suitable rotary compression coating machine, e.g. a `Manesty,` `Drycota` 
or `Bicota` machine.