CA1104931A - Pharmaceutical composition containing sulphasalazine - Google Patents

Abstract

Composition Abstract There is described a pharmaceutical composition comprising a compound having sodium cromoglycate like activity, as active ingredient, in combination with sulphasalazine.
There are also described packages containing the separate components of the composition and pharmaceutical formulations containing the composition.

Description

` ~L''3~9~

BA 21975/77 ~SA
Thi.s invention relates to a nixture and a method for its preparation.
Sulphasalazine, i.e. 4-hydroxy-Q'-~pyrid-2-ylsulphamoyl)azo-b~nzene-3-carboxylic acid, has been widely used in the treatment of conditions of the gastro mtestinal tract in mammals, e~g~ man and dogs, but suf~ers from ~he disadvantage tha* it can cause nause~, skin reactions or haematological complicatioDs including neu~ropenia, thrombocytopenia and haemolysis. ~e have now surprisingly found that the side effects of sulphasalazine ~ay be reduced by the use o certain disodium cromoglycate like compounds in combination ~nith the sulphasalazine.. The combinations are also re acti~e in certain mammals than are their individual componentsO
Acsording to our invention there~ore ~e provide a pharmaceutical 'lS composition comprising a compound having sodium cromoglycate like ac~ivity, as active ingredient, in combination with sulphasalazine.
A compound ha~ing sodium cramoglycate like activity is able to inhibit the release of pharmaculogical mediators which result from the in vivo combination of certain types of antibody and speci-fic antigen, for example the combination of reaginic antibody and s~e d:Eic a~tigen ~see Example 27 of British Patent Speci~ica~ion No 1,292,601 - the rat passive cutaneous anaphyl~xis test~.
The active ingredients ~ay be ~haracterised by the ollowing biological tests and results thereof.
The co~pound is ~irst tested in the rat passive cutaneous

- 2 ~

.
.
- . . .;

. ' , ~ ' ' .
.

~l 08/C/87 anaphylaxis test. I-f the compound does not show significant inhibition of allergic manifestations at 20 mg/kg ~Itraperitoneally ~i.p) or intravenously ~i.v3 in this test~ its acti~ity is generally too low. Various other biological tests may be used to show ~hat the compound exhibits its anti-allexgy activity as an inhibitor of the release of mediators of anaphylaxis rather ~han as, -for example an end organ antagonist or an*i-cholin~rgic ~r adenyl cyclase stimulator. There~ore, tests to see if the compound antagonises the e~fect of h~stamine, serotonin9 acetylcholine ~nd slow reacting substance of anaphylaxis (SRSA), that is, that ~he compound is an end organ antagonist o the mediators, nkay be employed. Such tests are ~ell knownO Ac~ive ingredients according to the invention are not end organ antagonis*s.
Specific groups o~ active ingredients are to be found amon~ -the chromone-2-carboxylic acids, and suitable derivatives ~hereo~, e.g. those descrîbed ~n British Patent Speci~ications Nos 1,368,243;
1,144,905; 1,230,087 and West German Patent Specification No 2,553,688.
Other ac~ive ingredients a~e to ~e found among the xanthones, e.g~
o~ Belgian Pa~ent Nos 759J292 and 787,843 and Dutch Patent Speci~ication Nos 72,09622 and 73,06958; among the compounds of Belgian Paten* No 809,93~; among the nltroindanedio~es, e.g. of Belgian Patent ,~o 792,867; among the phenanthrolines7 e~g. o~
Belgian Patent ~o 773,200, among the azapur m es, e.g~ of Belgian Paten~ l~o 776,683; the oxazoles, e.g. of l~rest ~erman OLS 2~459,380;
the 1avones, e~g. o~ Belgian Patent No 8Z3,875; and the oxamic ' ,' . `, ' ' :

.
.,. . ~ , .
:

3~

acids, e.g. of ~Yest German Patent Specification No 2,360,193 ~nd US Patent No 4,038,398.
Particularly preferred are the chromones c~d chromone like con~ounds o British Patent Specificatio~s Nos 1,~44,gO5; and 19230,087 c1nd ~est Genman Patent Specification No 2~553,6~8. ~lore specifically we prefer 1,3-bis~2-carboxychromonL-5~yloxy)propan-2-ol or a pharma~eutically acceptable derivative~ e.g. salt such as the disodium salt, thereof; this la~ter is con~nl~ known as sodium cro~oglycate or cromolyn sodium. As further preferred con~ounds there n~y be ngntioned 6J7~,9-tetrahyd~o-4-oxo-10-propyl-4H-naphthoL~2,3-b~7pyran-2-carboxylic acid; 5~t2-hydroxypropoxy)-8-propyl-chromNne-2-carboxylic acid; 6,7,8,9-tetrahydro-5-hydrox~-4-oxo-10-propyl-4H-naphthoL~2,3-bJ pyran 2-carboxylic acid c~nd pharmaceutically acceptable derivatives of any one thereof.
Phaxmaceutically acceptable derivatives of the above chromone-2-carboxylic acids Include pharmaceutically acceptable sal~s, esters and amides of the 2-carboxylic acid group. suitabIë
salts include ammonium, al~ali metal ~e.g. sodium, potassium and lithium) salts and salts wi~h suitable organic bases, e.g. salts with hydroxylamine, lower alkylamines such as methylamine or ethylamine~ with subs~ituted lower aIkyl~mines, 8.g. hydroxy substituted alkylam m es such as tris~hydroxymethyl)methylamine, or with simple ~onocyclic nitrogen heterocyclic compounds, e.g.
piperidine or morpholine. Suitable esters include simple lower alkyl es~ers, e.g. ~he ethyl ester, esters deriv2d ~rom alco}lols . .

' ' , ' :, ':
: '. . ' ~ "' . ' . :, ~' ''.' ,' ' ' ' '' ' ' ' ~ ' ' ' ' ~
.
,,, ' ' . ' ' ' ' .
'. .
. ..

~ ?33~ lO/C/87 contaLning basic groups~ e,g. di-lower alkyl c~mLno substituted alkanols such as the ~6-~diethylam mo)-ethyl ester7 and acyloxy aIkyl esters, e.g. a lower acyloxy~lower alkyl ester such as ths pivaloyloxyme~hyl ester, or a bis-ester derived -from a dihydroxy compound, e.g. a di(hydroxy-lower alkyl) ~ther, e~g. th~ bis-2-oxapropan-1,3-diyl ester. The ~harmaceutically acceptable salts of the basic esters, e.g. the hydrochloride, may also be used~
WTe preer the composition to contain only one active ingredient.
The ra~io of the sulphasalazine to the active ingredient will o~ course vary with tne particular active ingredîe~t, the speciic conditi~n to be treated and wqth the particular pa*ient. ~owe~er for specific active ingxedients we have Eo-md knat ~he ~oll~ing ratios are appropria~e, ~he parts by weight of the active Ingredient being calculated as the sodium salt:- -Sul~h alazine Active In~redient ~parts by weight) ~one part by weight~
(a) 0.5 to 80,000 ) 1,3-bis~2-carboxy preferably 1 to 40,000 ) chromon-5-ylo~y~
~ore prefeTably 2.5 to 4J000 ) propan-2-ol or a ) phanmaceutically ) acceptabl~ salt ~hereoE
~b) . . :
0.1 ~o 320 ) 5-~2-hydroxypropoxy)-8-preferably 1 to 160 ) propyl-chrom~ne~2~carboxylic acid~ or a pharmaceutically ) acceptable salt thereof :
.. , ., ... , .... , ,, . ,.. , .. , ., .. , .,, .. , ~ ~ .. .. ., .. ~ ,.. . . . .. ........ ..... ....... ....... . . ....
, ~ ~
.

: , ~ L ~? 3 3 L ll/C/87 (c) 1.25 ts 16,000 ) 6,7,8,9-tetrahydro-4-oxo-preferably 5 to 8,0C0 ) 10-propyl-4H-napht~o~ 2,3-b 7-) pyran-2-carboxylic acid, or ) 6,7,8,9-tetrahydro-5-) hydroxy-4-oxo-10-propyl-4H-~ naphtho~2,3-b 7-pyran-2-) carboxylic acid, or a ) pharmaceutically accep~able ) salt of l~ither thereo~
Th~ daily dosage of sulphasalazine -for hun~ns for n~st purposes is up to 12g9 preferably 1 to 8g and m~re preferably 2 to 4g.
The sulphasalaz me may be administered fro~ 1 to 4 times per day.
Each dose of the sulphasalazine may comprise one or more unit doses, e.g. tablets or capsules.
The daily dosage of the active }ngredient will naturally vary with the particular active ingredient. Ho~ever ~or specific active ingredlen~s we have ~ound that the following daily dosages ~calculated as ~he sodium salt) are appropriate:-1,3-bis(2-carboxy up tv 2g, chromon-5-yloxy) preferably 0.5 to propan-2-ol o~ a and mDre preferably pharmaceutically about 0.8g acceptable salt ~hereof 5-(2 hydroxypropoxy)- 25mg to lOg, 8-propyl-chromone-2- preferably ~Smg to 2g carbo~ylic acid, or a pharmaceutically acceptabl~ salt thereo 6~7,8,9-tetrahydro-4- O.5mg to 800mg, oxo-}0-propyl~-4H-naph~ho- pre~erably 0.5mg to 4~0mg Lz93-b3pyran-2-caTbo~ylic acid, or 6,7,8,9-te~ra-hydro-5-hydroxy-4-oxo-10-25 propyl-4H-naphthoL~2~3-b~7- -py~an-2-carboxylic ac~d~
or a pharmaceutically acceptable sal~ of either --thereo ., ,, .:', ` ' ~, .,. .- '' .''' ':, . ' ', ' '...... ' , '' ' . : ' ' .... ., ., .,.. ' ' : ',' ' ' '. . ' "' .. ,' -, , , , , " , , , " , ,. " , , , " , . .. .. . :,. ., .: . ' - ,. .': ' ' ' ' '' ' ' " ' . . : .. .. ., . .. , . , . ' . .. ' . ' . .:. ., ' '.' , ' ' '' . ' .
' .: . ', . : . ' ' ' : ', ", , , ' ' ' ' ' ' . ~ ' ' . , ',, ' ', ', ' , :: .' ' '. ': , , ' .:
: '.. "'. ' ', , - ' ' ' , ' ' '. , , . . . ~, : : ' . ' ' ' ' ., ,: , :, ' :': ' ', ' ' . ":, ., ' " , ' . . : ' , . . .. . .
,,. , ,. ,: . , ' '........ , . ' '' ': . , :

3~

For human use com~ositions in dosage form suitable for administration at one time, e.g. unit dosage foxm, comprise the quantities o~ active ingredient ~calculated as the sddium salt), and of the sulphasalazine specified below:-(a) Up *o 12g, preferably 250 mg to 8g, and more preferably 500 mg to 4g.
~b) 193-Bis-~2-carboxychromo~ 5-~loxy)propan-2-ol 0~1 to 500mg, preferably 1 to 200mg and more preferably 1 to 50mg. ~e particularly prefer co~positions in unit dosage ~orm comprising up to lOOmg, as higher unit doses may tend to cause an increase in gastrointestinal irritation.
~c) ~ 1 chromone-2-carboxylic acid 25mg to 2.5g, pre~erably 25 to SOOmg.
(d~ 6,7,8,9-Tetrahydro-4-oxo-lO-prGpyl-4H~naphthol 2,3 b ~pyran-2-carboxylic acid or 6,7,8,9-Te~rahydro-5-hydroxy-4-oxo-l~propyl-4H-naphtho C2,3-b~ pyran-2-carbo~ylic acid 0.5 to 200 mg, preferably 0.5 to lO0 mg.
Spacific conditions which may be beneficially treated with the compositions of the in~ention include Crohn's disease, atrcphic gastritis, ulcerative colitis, proctitis, distal proctocvli~is, stump proctitis, coeliac disease, regional ileitis, peptic ulceration, gastrointest-inal allergy and irTitable bowel synd~ome.
According to our invention we also provide a method for the treatmen~ o a condition o ~he gastrointestinal tract, which -: . , ~ . .
:...... . , . , .. , . . - : .
. . , ' . . . : , ::: . . ........... ;
- .,.: , . : . . ~ ', .
.. , . . : , , . :
.

~3~

comprises ac~ninistration of a ~omposition according to the in~ention to an inc~vidual mammal, e.g. human, suferLng ~rom such a condition.
The achninistration is preferably ac~n~nistratiorl by mouth (oesophagael administ~ation) or via the rectum.
According to the invention we also provide a mRthoa or the treatme~t of a conditic)n o~ the gastrointestinal ~ract, which co~p~ises sequential or simultaneous administration of acti~e ingredient and sulphasaiazine to an indi~idual mammal, e.g. human, suffering ~rom such a cc~dition or disorder.
The acti~e ingredient is preferably administered in such a way that it is available in the gastrointestinal tract, e.g. the colon~ a~ the same time as the sulphasalazine. Alternatively the active ingredient may be ad~nistered before or after the sulphasalazine.
~ When sequential or simultc~neous administration o~ active ingredie~t and the sulphasalazine is used ~he ra~ios and dosages are as d~scribed above with respect to the mixtures.
The Invention therefore also proviaes a pharmaceutical package comprising a~ least one dose of active ingredient and at least one dose of sulphasalazine. The doses are preferably unît doses and are pre~erably arranged in the package in a particular order toge~her ~lth written or printed indications or di~ections, the indicatlons or directions and the manner of packing bein~ such as to provide guidance in relation *o and to facilitate the t~king o a unit dose o-f ac~ive ingredien~ and a uni~ dose of ~he sulphasalaz ~e ,..

. .
. ~.
., ' '~' " ' " "'' '' ,. ~ '~ ' , . . , :, . .

3~ 14/C/87 !

in a particular order or combination, e.g. a urlit dose of the ormer at the same time as a unit dose o~ the la~er. rne package is pre~erably a sealed package and may comprise a tube, box or chart in or on which the unit doses are packed. The unit doses are S pre~erably suitable for oesophagaeal a~ministration and preferably contain the doses of active ingredient and the sulphasalazine in the ratios set out above for the combinations.
~ n order to produce suitable composi~ions the active ingredien~
and the sulphasalazine, either separately or as a mixture thereof/
are worked up with organic or inorganic pharmaceu~ically acceptable adju~ants or excipients. Examples of such adjuvants are:-For tablets and dragées: Binders, ~or example, celluLosicmaterials, e.g. microcrystalline cellulose ~nd methyl cellulose~
disin~egrating agents, for example starches, e.g. maize starch;
stabilizers, e.g. ag~;nst hydrolysis o~ the active ingredients;
flavour mg agents, ~or example sugars such as lactose; ~illers;
stearates a~d inorganic diluents, e.g. talc.
For syrups~ suspensions or dispersions: A liquid ~ehicle in which ~he acti~e ingredients may be dissol~ed or suspended, e.g.
water; and suspending ag~nts, e.g. cellulose derivatives, gums etc.
Fvr hard or soft capsules: Diluents, e.g. lactose; glidants9 e.g. stearates; ~lorganic materials, e.g. silica or talc;
stabilizers and dispersing agents.
For suppositories: Natural or hardened oils~ waxes etc. A
large number of pr~prietaTy emulsifying bases are available and . ~ :

- . ~ . .
- . .: . .
,. . . :- . :
.. .

f~l~L'rD ~ ~ ~ 15~/87 , are suitable for use in suppositories. These Lnclude 'l~itepsol'*
bases, consisting of hydrogenated triglycerides oE lauric acid ~th added monoglycerides, and '~ssupol' bases, ~ILiCh consist o~
glyceryl esters of lalric acid with a very s~a:Ll amount of glyceryl monostearate.
~or enemas: Water, sodi~n chloride, buffersg etc.
~ e preer compositions ~hich are designed to be adminis*ered by mouth ~oesophageally) or as enen~s, e.g. retention enemas.
The composition may also contain further adjuvants, or 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 composition m~y also if desired contain a pharmaceutically acceptable dye or colourant, and may, if desired, be coa*ed using conventional film or sugar coating techniques.
If desired the composition, or one or more components the~eof, may be formulated in sustained or controlled release ~orm; é.g. by coating some ~r all of the drug particles then~elves or granules thereo made wi~h, for example, sucrose and o a size up to 2 ~m in diamete~ wi~h 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 sema-penmeable membranes through which the drugs can diffuse when the preparations are ingested. The compositions may contain drug particles or granules which are uncoated in admixture with particles or granules *-trade mark : : . . . . .
- : : . .

.
.
. .

~ L~ 16/C~87 , .~

having one or more coats of the coating medium, and may be in the ~orn of a capsule containing the particles or granules or alternatively a tab}et, for which other adjuvants may be rcquiredg such as glidants or lubricants. The mixture may be administered as an enteric coated com~osition to make the drugs available at the appropriate part of the gastrointestinal tract. This m~y be achieved by coating the ~ablet wqth a continuous film of ~aterial which is resistant and impermeable to gastric secretions, but which is susceptible to intestinal secretions. Typical film materials are sllellac and its derivatives and cellulose acetate phthalate.
The active ingredient and the sulphasalazine may, if des.ired, be used .in a specific form, e.g. having a mass medi~n diam~er o~
less than 10 mQcrons.
The active ingredient and the sulphasalazine may also be ~o~mulated as an aqueous, e.g. a water chloroform ~400:13, solution containing from 0.001 ~o 10.0~ by weight o the total content of the active ingredient and the sulphasalazine.
~ Ye prefer compositions containing disodium cromoglycate.
The compositions desirable contain from 0.1 to 85~o by weight of the or each active ingredient presen~, and more des * ably from 0.1 to lO~o by weigh~ thereo.
The mven~ion is illustrated, but in no way limited by -~he following ~ les.

.

: ~ .. .. , . - .

': :' . , ' . ~ , . ,' :
- ~' . ' . .:
:'. ' , ' ' ' .' :
'' ' ' '. " '~ ':' '' ~' ' '': . ' : . , ' .: .

. ' . : . - ' .
' ' ' ' ' , ' ': ': . . . , Exa~ple 1 (Retention Enema) Formula Disodium Cromoglygate ~00 mg Sulphasala~ me 4Q0 mg ~Ionobasic Sodium phosphate ~anhydrous) 160 mg Dibasic Sodium phosphate ~anhydrous)758 mg Sodium Chloride 440 mg ~Yater for Injection BP to 100 ml 0.2~ w/v Disodium Cromoglycate and 0.4~ Sulphasalazine m USP
Isotonic Vehicle Bu~er pH 7~4. Unit dose 100 ml.
Packed in a flexible PVC pack.and sterilised by heating in a balanced autoclave 115C - 116 & for 30 minutes.
Example 2 Granules _.
F mula lS Disodium Cromoglycate 0.5 g Sulphasalaz me l.Og : .
Water q S
An app~opriate quantity of Disodium Cromoglycate and sulphasala2ine were mixed together to give a dose of 0.5 g and 1.0 g respec~i~ely.
S~ficient water to oxm a granular ~ass ~a~ sprayed into a suitable ~ixer with a cooling jacket to keep the temperature below 35C.
The wet mass was passed through an 8 mesh screen on an oscillating granulator. ~he granLles were dried in a fluidised bed drier at 70C.
When dry~ ~hey were passed ~ ~ough a 16 mesh screen ~n an oscillating ~5 granulator.

. ~

: , :
~ ' , ,. ~ . . . . : .
.

3~L 18/C~87 The ~anules can be filled loose into sachets or capsules.

~0 ~:

..

.

. .

, .

: , ~ : ~, ~ ' ~, , . . , -,' '' ', ~ '

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS

1. A pharmaceutical composition comprising a compound having sodium cromoglycate like activity, as active ingredient, in combination with sulphasalazine.

2. A composition according to Claim 1, wherein the active ingredient is 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol or a pharmaceutically acceptable derivative thereof.

3. A composition according to Claim 2, wherein the active ingredient is sodium cromoglycate.

4. A composition according to Claim 2 comprising from 0.5 to 80,000 parts by weight of sulphasalazine for each part by weight of 1,3-bis(2-carboxychromon -5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, calculated as the sodium salt.

5. A composition according to Claim 4 comprising from 1 to 40,000 parts by weight of sulphasalazine.

6. A composition according to Claim 5 comprising from 2.5 to 4,000 parts by weight of sulphasalazine.

7. A composition according to Claim 1 comprising from 250 mg to 8g of sulphasalazine in a dosage form suitable for administration at one time.

8. A composition according to Claim 7 comprising from 500 mg to 4g of the sulphasalazine.

9. A composition according to Claim 1 comprising from 0.1 to 500 mg of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, calculated as the sodium salt in a form suitable for administration at one time.

10. A composition according to Claim 9 comprising from 1 to 200 mg of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol or a pharmaceutically acceptable salt thereof, calculated as the sodium salt.

11. A composition according to Claim 10 comprising from 1 to 50 mg of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, or a pharmaceutically acceptable salt thereof, calculated as the sodium salt.

12. A composition according to Claim 1 in a form adapted to be administered oesophageally.

13. A composition according to Claim 1 in the form of a suppository or enema.

14. A composition according to Claim 1, wherein the composition, or one or more of the components thereof, is formulated in sustained release form.