Note: Descriptions are shown in the official language in which they were submitted.
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BA 11390/77
This invention relates to new comPounds, mixtures and methods
for their preparation and use, .
A variety of anti-histamines have been known for many years
for use in the palliative treatment of allergic conditions.
However the anti-histamines have, in the vast majority of cases
been administered systemically, e.g. as elixirs, tablets,
capsules etc. Furthermore most of the anti-histamines have
un~Yanted side effects, e.g. have a sedative action, which causes
their use in high dosage not to be recommended when activities,
such as driving a motor car, are to be under~aken.
Disodium cromoglycate has also been recommended for use in
the treatment of allergic conditions and in particular of asthma
ant allergic rhinitis. By way of contrast to the anti-histamines
disodium cromoglycate has been used prophylactically and has not
in general been recommended ~or use in a curative sense~ i.e.
during an attack of the allergy.
We have now ount that mixtures o disodium cromoglycate
with certain anti-histamines, and salts of l,3-bis(2-carboxychromon-
5-yl-oxy)propan-2-ol with those antihistamines, possess the
advantage that they are both palliative and prophylactic, are
more effective, produce less side effects, can be used at lower
doses, can be administered directly to the site of the allergy,
are longer acting, are more stable, or possess other desirable
p~operties as compared to antihistamines l~hen used on their o~n,
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disodium cromoglycate when used on its ~n, or certain other
; mixtures when tested in certain pharmacological mcdels relevant
to the nasal or ocular manifestations of allergy.
According to the invention we provide a salt of 1,3-bis(2-
S carboxychromon-5-ylaxy)propan-2-ol with a basic compound which
has anti-histamine ~ receptor antagonist properties, and which
contains a 6 membered nitrogen heterocyclic ring.
The basic compound which has anti-histamine Hl receptor
antagonist properties may be, for example, trimeprazine,
10 cyproheptadine, pheniramine, mepyramine, chlorpheniramine,
brompheniramine, dimethindene, carbinoxamine, tripelennamine or
preferably triprolidine. We prefer the salt to be at least 1~,
! - and preferably at least 4~, w/v soluble in water.
The salt may be made by a metathetical process, e.g. by
15 reacting a suitable salt, such as the sodium salt, o 1,3-bis(2-
carboxychromon-5-yloxy)propan-2-ol with an appropriate salt,
e.g. the hydrochloride, of the an~ihistamine, However the salt
is preerably produced by reacting the ree acid, 1,3-bis~2-
carboxychromon-5-yloxy)propan-2-ol with the ree antihistamine
20 base, as such a process does not produce a bi-product inorganic
salt. The reaction may be carried out in a solvent which is
inert under the reaction conditions. The solvent is preferably
one in which the desired salt is soluble, e.g. water or an
alkanol such as ethanol. The desired salt may be isolated and
25 purified, for example by crystallisation or by freeze drying.
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According to the invention we therefore provide the salt
when not in solution, e.g. the salt t~hen in a substantially dry
fonm, or when in admixture with insufficient liquid, e.g. water, -~
to dissolve it all.
The salt may, if desired, be used in conjunction with one or
more other salts of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol,
notably the disodium salt thereo.
According to our invention therefore we also provide a
pharmaceutical mixture comprising
(a) one or more d 1,3-bis~2-carboxychromon-5-yloxy)propan-2-ol,
or a pharmaceutically acceptable salt thereo~, (herein referred
to collectively as 'active ingredient') in combination with
(b) one or more anti-histamines havinba ~ receptor antagonist
proPerties and which contains a 6 membered nitrogen heterocyclic
15 ring. - -We prefer to use the di-sodium salt of 1,3-bis~2-carboxy-
chromon-5-yloxy)propan-2-ol, which is commonly known as disodium
cromoglycate or cromolyn sodium, or a salt with a basic compound
; which has antihistamine Hl receptor antagonist properties and
~hich contains a 6 membered nitrogen heterocyclic ring, as
active ingredient.
The anti-histamine may be any of those described above or a
pharmaceutically acceptable salt thereof, e.g. the hydrochloride?
tartrate or maleate thereof.
The ratio of active ingredient and antihistamine in the
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composition l~ill vary with the particular active ingredient and
antihistamine used and the specific purpose for which the
composition is intended. When the active ingredient is itself
a salt of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol with an
antihistamine it may be necessary to use, none, or only a very
small proportion of 'ree' antihista~ine ti.e. of the basic
antihistamine itself or of a salt of the antihistamine other
than with 1,3-bis~2-carboxychromon-5-yloxy)propan-2-ol).
We prefer the composition to contain only one active
ingredient and only one antihistamine.
A suitable daily dose o active inbredient for most
purposes is in the range 1 to 100 mg and preferably 1 to 20 mg,
! (measured as disodium cromoglycate).
A suitable daily dosage of antihistamine will vary with the
antihistamine and is in the following ranges:-
Cyproheptadine (as the hydrochloride) 0.1-40 mg
Trimeprazine (as the tartrate) 0.1-40 mg
Pheniramine (as the maleate) 0.1~50 mg
Mepyramine (as the maleate) 0.1-lOOmg
Chlorpheniramine (as the maleate) 0.1-20 mg
Brompheniramine (as the maleate) 0.1-8 mg
Dimethindine taS the maleate) 0.1-6 mg
Carbinoxamine (as the maleate) 0.1-8 mg
Tripelenna~ine (as the hydrochloride) 0.1-lOCmg
Triprolidine (as the hydrochloride) 0.1-7.5mg
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A preferred daily dosage of the antihistamine is from 0.1
to S mg, and more preferably from O.S to 2 mg.
The composition may be administered as divided doses from ~ -
1 to 6, and preferably from 2 to 4, times per day, Each dose may
con~rise one or more unit doses.
The specific ratios of particular active ingredients and
particular antihistamines in any composition according to the
invention can be calculated from the above daily dosages. We
prefer a composition containing from 1,000 to 0.2 parts by ~Yeight,
and more preferably from 40 to 0.5 parts by weight of active
ingredient (measured as disodium cromoglyca~e) for each part by
weight of antihistamine. ~e particularly prefer a composition
, containing disodium cromoglycate and triprolidine in a weight
ratio of about 20:1.
According to our invention we also provide a method for the
treatment of a condition of the eye, nose or skin which condition
has an allergic component, e.g. allergic rhinitis, which com~rises
adm~nistration of a salt and/or ~ixture according to the
invention to an individual mammal, e.g. human, suffering from
such a condition. The administration is preferably to the nose.
According to the invention we also provide a method for
the treatment o a condition of the eye, nose or skin which
condition has an allergic component, e.g. allergic rhinitis,
which comprises sequential or si~ultaneous administration of
active ingredient and an antihistamine having ~ receptor
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antagonist properties and which contain a 6 membered nitrogen
heterocyclic ring, to an individual mammal, e.g. human, suffering
from such a condition. ;-
Conditions of the outer eye in which the method of the
invention may be used include vernal catarrh (vernal kerato-
conjunctivitis) and marginal corneal ulceration or infiltration.
Other conditions which may be treated by the method of the
invention include the ocular 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 summer where an external
allergen plays a part in the disorder. Further conditions of the
! eye which may be mentioned are 'irritable eye' or ~non-speciic
conjunctivitis', herpes simplex keratitis and conjunctivitis,
herpes zoster keratitis and conjunctivitis, adenovirus
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infections, phlyctenular conjunctivitis, corneal homograft
rejection, trachoma, anterior uvetis and drug sensitivity.
Conditions of the nose which may be mentioned include
season 1 rhinitis, e.g. hay ever; perennial rhinitis, nasal
polyps and allergic mani~estations of the nasopharynx.
Dermatoses which may be treated include those involving
skin mast cells and/or antibody/antigen reactions and include
eczemas and especially atopic eczema, drug eruptions, psoriasis~
dermatitis herpetiformis, pemphigus and chronic skin ulcers,
notably those affecting man in tropical climates.
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When sequential or simultaneous ad~inistration of active
ingredient and antihistamine is used the ratios and dosa~es of
the active ingredient and antihistamine are as described above -
with respect to the mixtures. ~e prefer the administration of
the active ingredient and the antihistamine to be within about
10 minutes of one another.
The invention therefore also provides a pharmaceutical
package comprising at least one dose of active ingredient and
at least one dose of the antihistamine. The doses are preferably
unit doses and are preferably arranged in the package in a
particular order together with written or pr mted 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 dose of active ingredient and a
lS dose of the antihistamine in a particular order, e,g. a dose
of the former before a dose of the latter. The package is
preferably a sealed package and may comprise a tube, box or
chart in or on which the doses are packed. The doses are
preferably suitable for nasal administration, e.g. spray
~ formulations for spraying into the nose, and preferably contain
the doses of active ingredient and the antihistamine in the
ratios set out above for the compositions.
In order to produce suitable coT~ositions the salt, the
active ingredient and the antihistamine, either separately or
as a mixture thereof, are worked~up with an organic or inorganic
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pharmaceutically acceptable adjuvant or excipient.
We-prefer compositions which are designed to be administered
to the eye or nose, e.g. aqueous solutions containing, for
example up to 10~ by weight of the salt or mixture according to
the invention. The compositions may also contain one or more
preservatives, e.g. benzylkonium chloride and/or phenylethyl
alcohol. The preservative may be present in up to about 2.0~ w~v
and may, for example,comprise from about 0.002~ w/v to 0.05~ w/v
of benzylkonium chloride and/or from about 0.1~ to 1.0~ w/v of
phenylethyl alcohol, or from about O.OOOS~ to 0.005~ of phenyl
mercuric nitrate, or from about 0.005 to 0.05~ of thiomersal,
or fjrom about 0.2 to 1.0~ of chlorbutol. The composition may
, also contain a sequestering agent, e.g. disodium edetate. The
sequestering agent may be present in from about 0.005~ to 0.2~ w/v.
The pH of the composition may be controlled by inclusion of one
or re buffers~ e.g. monosQ'dium phosphate or di-sodium phosphate.
The pH of the composition may be adjusted to be compatible with
physiological solutions and/or to improve the solubility of the
ingredients or the stability of the composition. The composition
may also include an agent which increases its viscosity, e.g.
certain cellulose derivatives or a polyvinyl alcohol.
Compositions to be administered to the eye or nose are
preferably isotonic.
Alternatively we provide powder compositions for administration
to the nose and pre~erably comprising fine particles of the
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antihistamine and/or of the salt of 1,3-bis(2-carboxychromon-5-
yloxy)propan-2-ol.
The active ingredient and the antihistamine may, if desired,
be used in a specific form, e.g. having a mass median diameter
of less than 10 microns.
The invention is illustrated, but in no way limited by the
following Examples.
Yample 1 :'
~ heniramine salt of 1,3-bis~2-carboxychromon-5-yloxyj-
propan-2-ol
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l-(~-Chlorophenyl)-1-(2-pyridyl)-3-N,N-dimethylpropylamine
maleate ~3~7 parts) was dissolved in water, basified using 10
NaOH, extracted into ether and drie~ CNa2S04). The drying agent
and ether l~ere removed, water was added followed by 1,3-bis~2-
carboxychromon-5-yloxy)propan-2-ol (2.3 parts). This mixture
was stirred for 2 hours, washed with ether, and traces of ether
were removed before the product was isolated from the aqueous
solution by freeze drying.
Analysis:
Pound: C, 60.0 H, 5.9 N, 4.9
Calc for C23Hl6oll-~cl6Hl9clN2)-8l~2o '
a~ple 2
Triprolidine salt of 1,3-bis(2-carboxyc_romon-5-yloxy)propan-2-ol
1.2g o trans-2-~3-(1-pyrrolidinyl)-1-~tolypropenyl J-
pyridine hydrochloride were dissolved in 50 ml of water and
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basified with 10~ NaOH. The free base was extracted into ether
and dried over magnesium sulphate. Filtration and evaporation
of the ether left the residual free base. To this was added a
slight excess of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol
(0.9g) and water (20 ml). After stirring for - hour insolubles
were removed by filtration and the salt was isolated from the
filtrate by freeze drying. The salt crystallised from acetone;
m.p. indefinite - darkening and decomposing above 200C.
Analysis:
Found C,69.1; H, 6.2; N, 5.3;
or C23Hl6ll~(ClgH22N2)2~l2H20 C,69.1, H,6.1; N
Exam~le 3
Triprolidine ~ydrochloride BP l.Og
Disodium Cromoglycate BP 20.0g
Benzalkonium Chloride Solution USP (50~ w/v) 0.31 ~1
Disodium edetate 0~2~ ,
Distilled water,i to lOOO~ ml
lg of triprolidine hydrochloride was dissolved in 500 ml of
an aqueous solution containing 20g o~ disodium cromoglycate and
0.2g of disodium edetate. The benzalkonium chloride was dissolved
in a further 300 ml of water and this solution was added to the
disodium cromoglycate solution. The bulk solution was made up
to l,OCO ml with further water and sterile filtered. The
composition was fille~ into 15 ml coloured bottles fitted with
a device to administer me*ered doses o~ the liquid in spray form.
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Example 4
The composition of Example 3 was compared in blind crossover
trials with a 2% aqueous solution of disodium cromoglycate and a
placebo in 16 humans suffering from allergic rhinitisO The patients
kept diary cards on which they expressed preferences for the
; compositions used. Analysis of the preferences showed a higher ~
preference for the composition of Example 3 as compared to the 2~ -
aqueous solution of disodium cromoglycate, and a highly significant
preference for the composition of Example 3 as compared to placebo.
Example 5
Triprolidine Hydrochloride BoPo lO0g
Disodium Cromoglycate BoPo 2000g
Disodium Edetate BoPo 002g
Benzoalkonium Chloride Solution USP, 50~ w/r 004ml
Phenylethyl Alcohol BPC (1963) 402g
~' Distilled water to lOOOO0ml
The Benzoalkonium Chloride Sol~tion was dissolved with ~tirring
in 300 ml of di~tilled water, and the Phenylethyl Alcohol was then
added and di~solved with stirringO The Disodium Edetate and
Tr~iprolidine H~drochloride were dissolved in a further 500 ml of
distilled water9 and then the Disodium Cromoglycate added and dis-
~olved. The two solutions were mixed together and made up to volume
with distilled water. This final solution was sterile filtered and
aseptically filled into 10 ml sterile polythene dropper bottlesO
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