CA1113862A - Mixtures of 1,3-bis(2-carboxy-chromon-5-yloxy) propan- 2-ol or a salt thereof with an antihistamine having h.sub.1 receptor antagonist properties - Google Patents
Mixtures of 1,3-bis(2-carboxy-chromon-5-yloxy) propan- 2-ol or a salt thereof with an antihistamine having h.sub.1 receptor antagonist propertiesInfo
- Publication number
- CA1113862A CA1113862A CA299,237A CA299237A CA1113862A CA 1113862 A CA1113862 A CA 1113862A CA 299237 A CA299237 A CA 299237A CA 1113862 A CA1113862 A CA 1113862A
- Authority
- CA
- Canada
- Prior art keywords
- antihistamine
- propan
- bis
- yloxy
- dose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
Abstract
ABSTRACT
There are described salts id 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol with a basic compound which has anti-histamine H1 receptor antagonist properties and which contains a 6 membered nitrogen heterocyclic ring, and pharmaceutical compositions comprising (a) one or more of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, in combination with (b) one or more anti-histamines having H1 receptor antagonist properties, and which contains a 6 membered nitrogen heterocyclic ring.
There are also described methods of making the salts and composition, packages containing them and methods for their use, e.g. as anti-allergic agents.
There are described salts id 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol with a basic compound which has anti-histamine H1 receptor antagonist properties and which contains a 6 membered nitrogen heterocyclic ring, and pharmaceutical compositions comprising (a) one or more of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, in combination with (b) one or more anti-histamines having H1 receptor antagonist properties, and which contains a 6 membered nitrogen heterocyclic ring.
There are also described methods of making the salts and composition, packages containing them and methods for their use, e.g. as anti-allergic agents.
Description
~11386Z 02/A/135 ~
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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 :,.. ' : ' ' '. . :: '. ~ ; -: : , . . ~ :
, ~ 1113862 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 ., ' ' ~ .:
.
. . , ~ . :
- .
~, ' .
,_ , 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 . . -, .. . . .:
:
.
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 .
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.
' .
. . .
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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,. . . :-, 1~13862 , 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 _ 9 _ ~ `J
:: :
, ~
,_ 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 !
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 ^~ ,. . .
. . . ., .. , , . . . " . .. , .. ..... . . . ... . . . . . . . .. . .. .... .. . . .... . ......... ~ . ., ...... .... ~ .
- , .
ll/A/135 ~`` 1113862 .
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.
~, , 111386~
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
. . .
.
. ~ .
, . ~ -
'~' .
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, .
:
~ ~ ..
, . . .' ~ .' ' ' ' ' ,' ' .
~.', " ~' , . ' ' ~. ' ' . "' , :
03/A/135 l~
--. .
111386~
''; .
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.
,;~;~ . .
,~.,.. . . - , .
- . - ~
: . . . .
-. . .
,__ 4 _ ~L1 1 ~ 2 .
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 :,.. ' : ' ' '. . :: '. ~ ; -: : , . . ~ :
, ~ 1113862 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 ., ' ' ~ .:
.
. . , ~ . :
- .
~, ' .
,_ , 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 . . -, .. . . .:
:
.
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 .
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.
' .
. . .
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 .
.. . ..
, . , , . , ,, - '~ .
. .
-.
- :, .. .
,. . . :-, 1~13862 , 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 _ 9 _ ~ `J
:: :
, ~
,_ 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 !
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 ^~ ,. . .
. . . ., .. , , . . . " . .. , .. ..... . . . ... . . . . . . . .. . .. .... .. . . .... . ......... ~ . ., ...... .... ~ .
- , .
ll/A/135 ~`` 1113862 .
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.
~, , 111386~
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
. . .
.
. ~ .
, . ~ -
Claims (8)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical mixture comprising (a) one or more of l,3-bis (2-carboxychromon-5-yloxy)-propan-2-ol, or a pharmaceutically acceptable salt thereof, and (b) one or more antihistamines having H1 receptor antagonist properties and which contains a 6 membered nitrogen hetero-cyclic ring.
2. A mixture according to Claim 1, which comprises disodium cromoglycate and trimeprazine, cyproheptadine, pheniramine, mepyramine, chlorpheniramine, brompheniramine, dimethindene, carbinoxamine, tripelennamine, triprolidine or a pharmaceut-ically acceptable salt of any one thereof.
3. A mixture according to Claim 1 containing from 1,000 to 0.2 parts by weight of ingredient (a) (measured as disodium cromoglycate) for each part by weight of antihistamine.
4. A mixture according to Claim 3 containing from 40 to 0.5 parts by weight of active ingredient.
5. A mixture according to Claim 4 containing disodium cromoglycate and triprolidine in a weight ratio of 20:1.
6. A pharmaceutical package comprising at least one dose of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharm-aceutically acceptable salt thereof, and at least one dose of an antihistamine having H1 receptor antagonist properties and which contains a 6 membered nitrogen heterocyclic ring.
7. A pharmaceutical package comprising at least one dose of 1,3-bis(2 carboxychrom-5-yloxy) propan-2-ol, or a pharmaceutically acceptable salt thereof, and at least one dose of an antihistamine having H1 receptor antagonist properties and which contains a 6 membered nitrogen heterocyclic ring, wherein said doses are packaged 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 dose of said 1,3-bis(2 carboxychromon-5-yloxy) propan-2-ol, or a pharmaceutically acceptable salt thereof, and a dose of said antihistamine, in, a particular order for the treatment of allergic conditions.
8. A pharmaceutical package according to claim 7 wherein the said unit doses are packaged so as to be suitable for nasal administration to humans.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB11390/77 | 1977-03-17 | ||
| GB11390/77A GB1582362A (en) | 1977-03-17 | 1977-03-17 | Cromoglycic acid salts and compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113862A true CA1113862A (en) | 1981-12-08 |
Family
ID=9985349
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA299,237A Expired CA1113862A (en) | 1977-03-17 | 1978-03-16 | Mixtures of 1,3-bis(2-carboxy-chromon-5-yloxy) propan- 2-ol or a salt thereof with an antihistamine having h.sub.1 receptor antagonist properties |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS53115823A (en) |
| AU (1) | AU516337B2 (en) |
| BE (1) | BE864837A (en) |
| CA (1) | CA1113862A (en) |
| CH (1) | CH628517A5 (en) |
| DE (1) | DE2810974A1 (en) |
| DK (1) | DK113378A (en) |
| FI (1) | FI780782A (en) |
| FR (1) | FR2383937A1 (en) |
| GB (1) | GB1582362A (en) |
| IE (1) | IE46581B1 (en) |
| IL (1) | IL54264A (en) |
| LU (1) | LU79253A1 (en) |
| NL (1) | NL7802869A (en) |
| NO (1) | NO152297C (en) |
| NZ (1) | NZ186712A (en) |
| SE (1) | SE444939B (en) |
| ZA (1) | ZA781520B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA812811B (en) * | 1980-04-30 | 1982-06-30 | Fisons Ltd | Mixtures and salts of beta-2 selective bronchodilators with cromoglycic acid and salts thereof |
| EP0040489A1 (en) * | 1980-05-17 | 1981-11-25 | FISONS plc | Mixtures, salts, packages and pharmaceutical compositions containing 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid or a derivative thereof and an H2 receptor antagonist antihistamine |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL44022A0 (en) * | 1973-01-23 | 1974-05-16 | Fisons Ltd | Novel salts of anti-inflammatory quinoline derivatives,their preparation and pharmaceutical compositions containing them |
| FR2217004A1 (en) * | 1973-02-15 | 1974-09-06 | Aries Robert | Sedatives and bronchodilatories - i.e. salts of 1,3-bis(2-carboxychromon-5-yloxy)propanes with 3-hydroxy-2-hydroxymethyl pyridines |
| FR2230358A2 (en) * | 1973-05-25 | 1974-12-20 | Fisons Ltd | Cromoglycate contg. solns. - contg. a second therapeutically active cpd. e.g. an antihistamine |
| DE2535258C2 (en) * | 1974-08-10 | 1993-06-03 | Fisons Plc, Ipswich, Suffolk | Inhalable drug in pellet form |
-
1977
- 1977-03-17 GB GB11390/77A patent/GB1582362A/en not_active Expired
-
1978
- 1978-03-13 BE BE185891A patent/BE864837A/en not_active IP Right Cessation
- 1978-03-13 FI FI780782A patent/FI780782A/en not_active Application Discontinuation
- 1978-03-13 IL IL54264A patent/IL54264A/en unknown
- 1978-03-14 DK DK113378A patent/DK113378A/en not_active Application Discontinuation
- 1978-03-14 DE DE19782810974 patent/DE2810974A1/en active Granted
- 1978-03-15 ZA ZA00781520A patent/ZA781520B/en unknown
- 1978-03-15 IE IE530/78A patent/IE46581B1/en not_active IP Right Cessation
- 1978-03-16 SE SE7803069A patent/SE444939B/en not_active IP Right Cessation
- 1978-03-16 NZ NZ186712A patent/NZ186712A/en unknown
- 1978-03-16 NO NO780935A patent/NO152297C/en unknown
- 1978-03-16 FR FR7807669A patent/FR2383937A1/en active Granted
- 1978-03-16 NL NL7802869A patent/NL7802869A/en not_active Application Discontinuation
- 1978-03-16 CA CA299,237A patent/CA1113862A/en not_active Expired
- 1978-03-16 CH CH289578A patent/CH628517A5/en not_active IP Right Cessation
- 1978-03-16 LU LU79253A patent/LU79253A1/en unknown
- 1978-03-17 AU AU34272/78A patent/AU516337B2/en not_active Expired
- 1978-03-17 JP JP3002278A patent/JPS53115823A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NO780935L (en) | 1978-09-19 |
| AU3427278A (en) | 1979-09-20 |
| IE46581B1 (en) | 1983-07-27 |
| NO152297B (en) | 1985-05-28 |
| NL7802869A (en) | 1978-09-19 |
| JPS53115823A (en) | 1978-10-09 |
| DE2810974A1 (en) | 1978-09-21 |
| SE444939B (en) | 1986-05-20 |
| CH628517A5 (en) | 1982-03-15 |
| DK113378A (en) | 1978-09-18 |
| LU79253A1 (en) | 1978-10-17 |
| GB1582362A (en) | 1981-01-07 |
| DE2810974C2 (en) | 1988-07-21 |
| ZA781520B (en) | 1979-04-25 |
| FR2383937A1 (en) | 1978-10-13 |
| FR2383937B1 (en) | 1982-07-23 |
| NO152297C (en) | 1985-09-04 |
| IE780530L (en) | 1978-09-17 |
| IL54264A0 (en) | 1978-06-15 |
| NZ186712A (en) | 1979-12-11 |
| SE7803069L (en) | 1978-09-18 |
| BE864837A (en) | 1978-09-13 |
| IL54264A (en) | 1984-01-31 |
| AU516337B2 (en) | 1981-05-28 |
| FI780782A (en) | 1978-09-18 |
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| MKEX | Expiry |