GB1575978A - Solid choline salicylate compositions - Google Patents

Abstract

Novel cholinesalicylate-carboxy-lower alkyl-cellulose-metal complexes are obtained by forming an aqueous solution of a carboxy-lower alkyl-cellulose and cholinesalicylate, adding a source of a physiologically tolerated, at least doubly charged, metal ion in a quantity such that a complex is formed of the components, allowing the reaction mixture to stand until it thickens, and subsequently drying it. The novel compounds are stable, pharmaceutically active, cholinesalicylate compounds.

Description

PATENT SPECIFICATION

( 11) 1 575 978 ( 21) Application No 9401/79 ( 22) Filed 21 Jan 1977 ( 19) i N ( 62) Divided out of No 1575977 ( 31) Convention Application No's 651110 ( 32) Filed 21 Jan 1976 705056 14 Jul 1976 in ( 33) United States of America (US) ( 44) Complete Specification Published 1 Oct 1980 ( 51) INT CL 3 A 61 K 31/235 31/015 31/05 31/14 31/28 31/735 C 08 B 11/20 15/05 ( 52) Index at Acceptance A 5 B 170 180 232 23 Y 285 28 Y 381 38 Y 392 402 40 X 411 413 41 Y 481 482 48 Y 586 58 Y J C 3 A 4 C 1 ( 54) SOLID CHOLINE SALICYLATE COMPOSITIONS ( 71) We, MUNDIPHARMA AG, a Swiss corporation organised under the laws of Switzerland, of Alban-Vorstadt 94, Postfach, 4006, Basel, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following

statement:

This invention relates to stabilized solid form choline salicylate compositions.

Choline salicylate is a well known analgesic compound having desirable pharmacological and therapeutic properties, as described in U S Patent No 3,069,321 The compound, however, possesses the inherent limitation of being highly hygroscopic so that it is not possible to prepare pharmaceutically acceptable, solid dosage forms which can be administered orally in the choline salicylate therapy of humans and animals Although crystalline choline salicylate melting at about WC, is known, its hygroscopic properties are such that trace amounts of moisture are sufficient to reduce the crystalline compound to the liquid state and no matter how stringent the effort to remove the absorbed moisture the product remains in liquid state so that it cannot be used in forming stable solid dosage forms for pharmaceutical use.

Much effort has been made to prepare solid pharmaceutical dosage forms of choline salicylate Thus, U S Patent No 3,297,529 provides mixtures of choline salicylate and magnesium sulphate to produce a solid product U S Patent No 3,326,760 relates to the formation of an absorbate with polygalacturoric acid U S Patent No.

3,759,980 relates to the formation of a chemical compound of choline salicylate and magnesium salicylate, which is a solid However, none of the methods described as solving the problem of providing choline salicylate in stable, solid, unit dosage-forms as described above, have yet proved to be pharmaceutically satisfactory A solid unit dosage form to provide a therapeutically sufficient quantity of choline salicylate for the required therapeutic purposes and also remain stable over sufficiently long periods of time to permit marketing of the same, has not as yet been made available commercially.

The present invention provides a choline salicylate carboxy-alkyl-cellulose-metal salicylate complex in which the metal is a physiologically acceptable metal having a valency of at least two The preferred metals are aluminium, bismuth, calcium and magnesium.

The new complex compound is formed from choline, salicylic acid, metal ion and carboxy alkyl cellulose While this complex may contain wide variations in the proportions of its component moieties, choline salicylate, metal ion and carboxy alkyl cellulose, its composition is homogeneous, reproducible and constant, and it has been found to have a shelf-life in dry, solid form of over four years, which from the commercial standpoint may be considered as practically indefinite Thus, the complexing of the choline salicylate with a metal ion and carboxy alkyl cellulose results in the formation of an extremely stable, solid complex compound useful to prepare solid pharmaceutical dosage forms, which remains stable in excess of at least four years.

Furthermore, the complex compounds formed between choline salicylate, carboxy alkyl cellulose and metal ion, such as mag1,575,978 nesium, aluminium, calcium and bismuth, may be distinguished from the solid compounds described in the prior art also from the simple mixtures of its component moieties, which are described and claimed in our copending application No 2512/77 (Ser No 1575977) on the basis of their chemical composition as well as their chemical, physical and pharmaceutical properties.

The difference between the different compositions is apparent on comparison of the critical solubility in polar solvents of magnesium-carboxy methyl cellulosecholine salicylate, that is the new complexed compound, with that of the simple mixture of choline salicylate and magnesium salicylate, with that of the simple mixture of choline salicylate, magnesium salicylate, and carboxy methyl cellulose and with that of the prior art chemical compound of U S Patent

3,759,980 choline magnesium salicylate.

Electrical conductivity data determined for the compounds are in excellent agreement with the critical solubility data and establish that the compound formed, magnesium-carboxy-methylcellulose-choline salicylate, is materially different from the known compound magnesium choline salicylate in that it has a chelate intramolecular structure in contrast to the hydrogen-bonded structure of the prior art compound Furthermore, the specific electrical conductivity of magnesium-carboxymethylcellulose-choline salicylate, is distinguished from the simple mixture of its moieties, which in turn are distinguished from the known hydrogenbonded compound, magnesium choline salicylate.

The proportions of choline salicylate, metal ion and carboxy-methyl cellulose necessary to form the new complex compound of the present invention may vary within a wide range The amount by weight of carboxy-methyl cellulose is preferably from 2 5 % to 25 % The amount of choline salicylate is preferably from 40 % by weight to 95 % by weight The amount of metal ion is preferably from 2 5 % to 35 % by weight.

The complex compounds of the present invention, provide stable, dry, free-flowing powders of choline salicylate The dried powders are useful to prepare pharmaceutically acceptable capsules, granules, tablets and suppositories by methods known in the art, and these new dry-solid powder compositions of choline salicylate may be used in any of these dosage-forms to treat humans and animals.

The new solid dosage forms prepared with the choline salicylate-carboxy-alkyl cellulose-metal ion complexes provide special advantages of convenience in administration of choline salicylate; an excellent physiological tolerance, with the virtual absence of side reactions and superior therapeutic efficiency evidence by a rapid elevation of the salicylate ion level in the blood of humans or animals after the administration of tablets, capsules, granules or suppositories containing a therapeutically 70 sufficient quantity of the appropriate choline salicylate-carboxy-methyl-cellulose-metal ion formed compound.

The new free-flowing choline salicylate complex compounds are prepared by first 75 forming a solution of carboxy-alkyl cellulose and then adding the choline component, the salicylic acid and the metal ion, for example, aluminium, bismuth, calcium or magnesium ion The metal carboxy-alkyl cellulose 80 choline salicylate compound formed is allowed to set, whereupon it becomes thickened and then the mass is dried, preferably at a temperature of about 40 C Analysis of the resultant dried powders comprising the com 85 plexed choline salicylate carboxy alkylcellulose metal compound is in good agreement for the theoretical quantities of choline salicylate, carboxy alkyl cellulose, and the respective metallic ion 90 The new powders retain their free-flowing solid characteristics for long periods of time without evidence of decomposition Solid dosage forms, such as tablets, capsules, granules or suppositories, prepared with the 95 solid powders are stable and also retain their potency over an extended period of time.

When 10 g of metal ion carboxy methyl choline salicylate complex compound according to the invention are placed in an 10 ( open petri-dish and exposed to the atmosphere for an extended period, the powder remains in its original solid free-flowing state, without decomposition When formulated into solid pharmaceutically acceptable 10.

dosage forms which are packaged and stored at ambient room temperatures, these pharmaceutical preparations are stable for periods in excess of four years.

The preferred metal ions to obtain the new 11 powders are aluminium, bismuth, calcium and magnesium ions although other metal ions can be used It should be noted that a valency of at least two is required for the metal ion to enter into formation of the new 11 solid free-flowing powders Since the product is intended for therapeutic use, the choice of metal ion is limited by its safety and activity Thus, mercury, arsenic or other metal ions which have inherent noxious 12 properties affecting the safety of the patient would not be used and these are specifically excluded.

The general method used to form the complexes according to the present inven 12 tion is illustrated in detail below.

It is known that carboxy-methyl cellulose is insoluble in water in the dry acid form It is necessary that the carboxy-methyl cellulose acid be converted into an aqueous solution 13 1,575,978 and this may be carried out by dissolving in water, a metal salt of carboxy-methyl cellulose, for example, sodium or potassium carboxy-methyl cellulose, in the desired concentration, and then removing the solubilizing ion, that is the sodium or potassium ion, by means of an acid exchange column such as is well known in the art The exact composition of the acid ion exchange column is not essential nor is it critical since any of the metal ion exchange resins used to remove sodium and potassium ions from a solution, can be used for this purpose The ion exchange resins which are known in the art as sulfonated polystyrene polymers, which are cross-linked polyamine resins, are known by the trade name of "Amberlite", (Amberlite is a Registered Trade Mark) more particularly as Amberlite IR or Amberlite IR-120 resins and are marketed by Rohm and Haas of Philadelphia, Pennsylvania Resins of the same type are also marketed by other chemical concerns under different trade names which are well known in the art and some of these resins, together with the process for their preparation, are described in U S.

Patent No 2,402,384 These resins are used in the hydrogen form in the manner as is well known to the art in order to remove sodium and/or potassium ions.

By way of illustration, one gram molecular weight of choline bicarbonate is added to the prepared aqueous solution of carboxymethyl cellulose obtained as the eluate from the acid ion exchange column after removal of the sodium or potassium ions, and the whole stirred while the mixture is warmed to about 70 'C Stirring is continued for about an hour or until there is no effervescence.

The p H of the mixture is then determined and is within the range of 7 to 7 8, with an average value of 7 4.

Preferably three gram molecular weight of salicylic acid is then added to the choline bicarbonate-carboxy-methyl cellulose solution while stirring and the mixture is warmed maintaining the heat at about 550 C for one hour When all of the salicylic acid has been added and a solution obtained the mixture is allowed to return to room temperature and one gram molecular weight of the metal ion donor is added The addition of the metal ion donor compound is accomplished with vigorous stirring while the temperature is again increased to about 70 WC When all of the metal donor compound has been incorporated into the mixture and the solution is clear, stirring is stopped and the batch set aside to set overnight After standing the mass becomes thick and the whole is then dried over about a 24 hour period in an oven at 80 WC The resultant essentially dry material is pulverised and then dried further in the vacuum oven at a temperature of about 40 WC and 2 mm/Hg pressure, to constant weight The dry powder thus obtained is the metal-choline salicylate-carboxy-methyl cellulose compound which is stable and possesses unique and reproducible properties useful to prepare solid dosage forms such as 70 capsules, tablets, granules and suppositories which contain a therapeutically sufficient quantity of the above described active ingredient.

The metal ion donor compound referred 75 to above provides a source of metal ion, and the following donor compounds are preferred for this purpose:

a) As a source of Aluminium ions:

aluminium isopropoxide or aluminium 80 hydroxide, b) As a source of Magnesium ions:

magnesium hydroxide or magnesium ethoxide, c) As a source of Bismuth ions: 85 bismuth citrate, bismuth phosphate or bismuth hydroxide, d) As a source of Calcium ions:

calcium hydroxide, calcium carbonate, calcium bicarbonate 90 When choline salicylate is prepared in situ then choline chloride, choline carbonate or any other soluble salt of choline may be substituted at equivalent molecular quantity as is described above for choline bicarbonate 95 The new solid powders of choline salicylate may also be obtained when choline salicylate is added to the carboxy-alkyl cellulose solution prior to the addition of the metal ion.

The dry powders of complex obtained by 10 ( the present process are white, free-flowing and stable, having reproducible physical and chemical properties The analysis of the respective compounds, where the molar ratio of choline: salicylate: metal is 1:3:1 is as 10 follows: aluminium choline salicylate carboxy-methyl cellulose compound contains substantially 5 1 percent of aluminium ion; 91 65 percent of choline salicylate and 3.25 percent of carboxy-methyl cellulose; 11 ( magnesium choline salicylate carboxymethyl cellulose compound contains substantially 30 percent of magnesium ion; 92 3 percent of choline salicylate and 5 16 percent carboxy-methyl cellulose; calcium choline 11 ' salicylate carboxy-methyl cellulose compound contains 4 35 percent of calcium; 91 percent of choline salicylate and 4 65 percent of carboxy-methyl cellulose and bismuth choline salicylate carboxy-methyl cellulose 12 ' compound contains 27 28 percent of bismuth 49 5 percent of choline salicylate and 21.2 percent of carboxy-methyl cellulose.

When it is desired to use the new complex compounds in the treatment of humans and 12 animals to achieve an analgesic, antipyretic or anti-inflammatory effect, and to elevate the blood salicylate levels, then a therapeutically sufficient quantity of the appropriate new compound may be administered to 13 :1 )O 1,575,978 humans and animals in the dosage form of a tablet, granule, capsule, or suppository The preferred unit dosage concentration of the respective new dry choline salicylate carboxy-alkyl cellulose metal ion complexes in the tablet, capsule, granule or suppository dosage form is a sufficient quantity of the respective compound to provide approximately 250 mg of salicylate moiety per unit dose or about 339 mg of aluminium choline salicylate carboxy-methyl cellulose compound; 370 mg of magnesium choline salicylate carboxy-methyl cellulose compound; 395 mg of calcium choline salicylate carboxy-methyl cellulose compound or 693 mg of bismuth choline salicylate carboxymethyl cellulose compound The range in concentration per unit dose is from 0 1 g to 1.0 g of active compound per unit dose The exact dosage concentration required depends upon the therapeutic goal to be achieved and the needs of the individual patient.

The preparation of tablets is accomplished by mixing the appropriate quantity of the selected active ingredient, e g complex of choline salicylate-metal ion-carboxy methyl cellulose, with a diluent, such as lactose, sucrose, starch, povidone or any other pharmaceutically acceptable tablet diluent and adding to this mixture a binder and a tablet lubricant, said binder and tablet lubricant being selected from the pharmaceutically accepted tablet binders and tablet lubricants which are well known in the art The mixture is -then granulated with ethyl alcohol and dried and the dried granular material is then compressed into pharmaceutical tablets of suitable size and shape.

An alternative tabletting procedure is to mix the appropriate quantity of the selected active ingredient described above with a pharmaceutically acceptable tablet diluent such as lactose, sucrose, starch or crystalline microcellulose, then, compressing the mixture into dry tablets by the method known in the art as slugging, and then grinding the slugged tablet thus formed into a granular powder with a particle size not greater than No 16 U S Standard mesh size and then compressing said granular powder into pharmaceutically acceptable tablets of suitable size and shape.

Capsules are prepared by filling appropriate capsules with the active ingredient either along or mixed with a diluent Diluents such as these described above may be used for this purpose.

It may be desired to dispense the granules obtained from the tablet manufacturing procedure, but prior to compression into tablets, as a dispensing form, in which case the concentration of the selected active ingredient is adjusted on the basis of a 5 gram unit dose or such weight as would be conveniently dispensed in a standard unit dose.

Suppositories are prepared by mixing the selected active ingredient with an appropriate weight of cocoa butter or polyoxyethylene glycol having a molecular weight 70 of greater than 1500 or in a compatible pharmaceutically acceptable suppository base The suppositories are then shaped into the well known dosage form and dispensed in a unit weight so as to deliver the desired 75 dosage.

When any of the above solid dosage forms containing the new compounds is used in therapy of humans and animals it may be administered from one to six times daily in 80 the dosage concentration sufficient to achieve the desired therapeutic daily dose.

The following examples are given to illustrate further the present invention.

EXAMPLE 1 85

Approximately 4 5 litres of a 4 percent solution of sodium carboxy-methyl cellulose was cycled through a column containing an acidic ion exchange resin, for example Amberlite-IR-120 H to remove the sodium 90 The eluate solution of carboxy-methyl cellulose in water contained approximately 0 75 percent by weight of solid matter A sufficient quantity of this eluate to provide 32 7 g.

of carboxymethyl cellulose was placed in a 95 glass flask fitted with a stirrer and a warming jacket The carboxy-methyl cellulose solution was warmed to about 30 C and 22 47 g.

of choline bicarbonate was added in small increments under rapid stirring Vigorous 100 ebulition occurred when the choline bicarbonate increments were added and the heat was increased slowly to 70 C during the addition process When all of the choline bicarbonate had been added, the mixture 105 was stirred for approximately one hour while warming and then allowed to cool to room temperature The p H of the solution was approximately p H 7 4 with a range of from p H 7 0 to p H 7 8 To this solution, at room 110 temperature, 48 g of salicylic acid were now added in divided increments under constant stirring The mixture was heated for one hour and then the temperature raised to 70 C and a sufficient quantity of aluminium isopropox 115 ide to provide 2 9 g of aluminium ion was added The stirring and warming were continued for one hour; at the end of which time the batch was allowed to stand overnight.

The next day the thickening mass was 120 spread out in a thin layer to dry under a hot oven at 80 C When the material had dried, it was pulverized and then placed in a vacuum oven to continue the drying process at a temperature of 40 C, 29 inches of vacuum, 125 until two successive samples showed no further weight loss The dried powder was then reground, packaged and filled into glass bottles The compound formed was aluminium-choline salicylate-carboxy 130 1,575,978 methyl-cellulose, a white powder containing 5.1 percent of aluminium 91 65 percent of choline salicylate and 3 25 percent of carboxy-methyl cellulose The powder was insoluble in water and stable on exposure to air at room temperature.

In place of the aluminium isopropoxide described as the aluminium ion source aluminium-hydroxide dry gel or aluminium wet gel may be substituted in a quantity sufficient to provide an equivalent amount of aluminium ion as set forth above.

EXAMPLE 2

166 g of choline bicarbonate were added to an aqueous solution of carboxy-methyl cellulose containing 16 3 g of carboxymethyl cellulose The mixture was stirred and warmed until gas ebulition ceased and 414 4 g of salicylic acid were then added.

The mixture was warmed and stirred until all of the solids had gone into solution The stirring was continued while heating at 70 C for about one hour and then 114 3 g of magnesium ethoxide were added The mixture was stirred until all of the solid material entered into solution, the heating was continued for one hour and the mixture set aside overnight.

The next day the solution was dried to constant weight and the dry powder pulverized The compound formed was magnesium-choline salicylate-carboxymethyl-cellulose which contained 2 5 percent of magnesium; 92 3 percent of choline salicylate and 5 16 percent of carboxymethyl cellulose The dry white powder was insoluble in water and nonhygroscopic and was stable for prolonged periods of time when exposed to the atmosphere.

In place of the magnesium ethoxide used as magnesium ion donor, 61 78 g of magnesium hydroxide may be substituted.

EXAMPLE 3

One gram molecular weight of choline bicarbonate and two gram molecular weight salicylic acid were added to an aqueous solution of carboxy-methyl cellulose containing approximately 17 g of carboxy-methyl cellulose on an anhydrous basis The mixture was stirred until complete solution was achieved and warmed to 70 C while stirring and then 398 g of bismuth citrate was added, sufficient to provide approximately 1 gram molecular weight of bismuth ion.

In place of bismuth citrate, any soluble bismuth salt could be used, for example, bismuth chloride or bismuth phosphate as the bismuth ion donor When all of the bismuth compound has been added the mixture was stirred while heating until a clear solution resulted and then set aside overnight at room temperature The material was then dried to constant weight in a vacuum.

The dry white powder was bismuthcholine salicylate-carboxy methyl-cellulose which was stable at room temperature and was not hygroscopic The analysis of compound was in good agreement with the theoretical values.

EXAMPLE 4 70

91 g of choline salicylate dissolved in 100 cc of solution was added to a solution of 4 6 g.

of carboxy-methyl cellulose diluent in 100 cc of water The mixture was warmed to 70 C for three hours, after which time 4 35 g of 75 calcium ion obtained from calcium hydroxide or calcium bicarbonate was added When all of the calcium salt had entered into solution, the mixture was set aside to stand for at least ten hours and the product was then 80 dried in vacuum to constant weight The resultant white powder formed was calcium-choline salicylate -carboxy-methyl cellulose, a stable, nonhygroscopic powder whose analysis was in good agreement with 85 its theoretical values.

EXAMPLE 5

When 19 g of aluminium-cholinesalicylate -carboxy-methyl cellulose, magnesium-choline salicylate 90 -carboxy-methyl-cellulose, bismuth-cholinesalicylate-carboxy -methyl-cellulose, or calcium-choline salicylate carboxy-methylcellulose were extracted with chloroform and the solvent evaporated the residue was not 95 more than 10 mg This test established that there was no separation of the salicylic acid from the respective compound, obtained as a result of Examples 1 to 4 described above.

A 10 g sample of the choline salicylate 100 carboxy-methyl cellulose metal compound, obtained as a result of Examples 1 to 4 above was placed on a tared petri dish which was then exposed to the atmosphere on an open shelf An equal quantity of crystalline 105 choline salicylate, melting at about 50 C.

which has been prepared according to the method described in U S Patent No.

3,069,321 was then placed on another petri-dish placed side-by-side with the petri 110 dish containing the choline salicylate carboxy-methyl cellulose metal compound prepared as described in Example 1 to 4 above Both petri dishes were examined at hourly intervals for the first day and at 115 eight-hour intervals thereafter At each observation point, each petri dish was weighed to determine any increase in weight due to absorption of water and the physical state of the solid material was evaluated to 120 determine whether any changes occured in the respective compounds After one hour of exposure to the atmosphere, the crystalline choline salicylate compound, prepared according to U S Patent No 3,069,321, 125 liquified while the new compounds prepared according to the method described in Example 1 to 4 remained in their original solid state The liquified choline salicylate showed an increase in weight of 1,963 mg which 130 1,575,978 indicated an absorption of water of almost 20 percent whereas the formed new compounds showed an increase in weight of only 67 mg.which indicated that there was virtually no hygroscopic activity.

After three days of exposure to the atmosphere on the open shelf, the liquified choline salicylate compound absorbed about 40 percent by weight ( 4 136 g) of water, whereas the new compounds showed an increase in weight of less than one percent or 331 mg.

The free-flowing powder characteristics of the new compounds remained unchanged throughout the test period This test established that complexing of the moieties occurred which modified the ability of choline salicylate to absorb water from the atmosphere It is known that hydrogen bonding does occur between choline salicylate and water and the effect of the said new compounds is to block preferentially the site of hydrogen bonding to prevent the absorption of water molecules by the hygroscopic compound.

When an equal quantity of the solid choline salicylate composition comprising a mixture of choline salicylate and magnesium salicylate was placed in a tared petri dish and exposed to the atmosphere at room temperature, the petri dish was examined at hourly intervals the first day and at 8 hour intervals thereafter There was an increase in weight of about 8 7 % after 3 days of exposure to the atmosphere When this test was repeated with the solid composition obtained by mixing choline salicylate, magnesium salicylate and carboxy methyl cellulose, after 3 days of exposure to the atmosphere in an open petri dish there was a gain in weight of 4 2 % In all of the tests conducted with the solid choline salicylate compositions described above, the free flowing powder characteristics were not modified by atmospheric exposure for 3 days / EXAMPLE 6

The ability of the solid choline salicylate compositions obtained as a result of Examples 1 to 5 above to retain their solid state characteristics was evaluated by exposing a 2 g sample of the respective composition and was placed in a tared glass dish and stored under different humid atmospheric conditions up to 97 % relative humidity at the elevated controlled temperature of 37 C At predetermined intervals the samples were examined and the physical state of the exposed powder recorded.

Choline salicylate, melting at 49 3 , prepared according to U S Patent 3,069,321, liquified within 2 minutes exposure at all relative humidities studied.

Magnesium choline salicylate, prepared according to U S Pat No 3,759,980, liquified after 32 hours of exposure to an atmosphere of 60 % relative humidity at 37 C, 20 hours of exposure to an atmosphere of 80 % relative humidity at 37 C and 18 hours of exposure to an atmosphere of 90 % relative humidity at 37 C.

Magnesium-carboxy methyl cellulose 70 choline salicylate obtained as a result of Example 2, remained solid when exposed for seven days to an atmosphere of 90 % relative humidity at 37 C, but liquified after seven days exposure to an atmosphere of 97 %rela 75 tive humidity at 37 C.Aluminium carboxy methyl cellulose

choline salicylate obtained as a result of Example 1, was partially solid after seven days exposure to an atmosphere of 90 %rela 80 tive humidity at 37 C.

Calcium carboxy methyl cellulose choline salicylate, obtained as a result of Example 4, liquified after seven days exposure to an atmosphere of 60 % relative humidity and 85 greater relative humidities at 37 C.

EXAMPLE 7

Measured portions of the mixtures or compounds obtained as a result of Example 1 to 4 were compressed into tablets utilizing 90 conventional tableting procedures and inert tablet excipients so as to provide tablets containing dosage units of about 435 mg of choline salicylate which is the approximate equivalent, with respect to salicylic acid con 95 tent, of the conventional 5 grain of aspirin tablet.

EXAMPLE 8

A suitable measured quantity of the mixtures or compounds obtained as a result of 100 Examples 1 to 4 above were filled into gelatin capsules of suitable size and shape to provide a unit dose of at least 435 mg of choline salicylate which is the approximate equivalent in salicylic acid content to a 325 mg 105 aspirin tablet Suitable inert pharmaceutically acceptable and compatible capsule excipients may be uised if necessary.

EXAMPLE 9

A measured portion of choline salicylate 110 of the respective solid metal choline salicylate carboxy-methyl cellulose compound obtained as a result of Examples 1 to 4 above, sufficient to provide 435 mg of choline salicylate per unit dose, was mixed 115 with a sufficient quantity of a pharmaceutically acceptable suppository dose carrier as for example, polyoxethylene glycol with a molecular weight greater than 1500 and the mixture shaped into suppositories of suitable 120 size and shape so that each suppository contains 558 mg of choline and salicylate per suppository.

EXAMPLE 10

A suitable quantity of the respective metal 125 choline salicylate carboxy-methyl cellulose compound obtained as a result of Examples 1 to 4 above was mixed with a quantity of a pharmaceutically acceptable diluent so that a mixture sufficient to provide 435 mg of 130 71,575,978 choline salicylate for 5 g of the mixture was obtained The mixture was granulated with ethanol, passed through a No 16 granulating screen and dried.

Any of the complexes of the present invention may be used to elevate the blood salicylate ion concentration by administration of such complex in any form whatsoever These complexes, however, provide the advantage of administration in solid dosage form, e g in the form of granules, tablets, capsules or suppositories.

Throughout the specification, in discussion of the complexes, reference has been had mainly with respect to carboxy methyl cellulose It should be understood, however, that any carboxy alkyl cellulose in which the alkyl group contains 1 to 6 carbon atoms can be used such as carboxy ethyl cellulose or carboxy propyl cellulose Carboxy methyl cellulose is most preferred from the standpoint of availability and economy.

Claims (17)

WHAT WE CLAIM IS:

1 A choline salicylate-carboxy-alkyl cellulose-metal salicylate complex in which the metal is a physiologically compatible metal having a valency of at least two.

2 A choline salicylate-carboxy alkyl cellulose-metal salicylate complex as claimed in claim 1 in which the metal is aluminium, bismuth, calcium or magnesium.

3 A complex as claimed in claim 1 or claim 2 in which the carboxy alkyl cellulose is carboxy methyl cellulose.

4 A complex as claimed in any of claims 1 to 3 which contains from 2

5 % to 25 % by weight of carboxy methyl cellulose.

A complex as claimed in any of claims 1 to 4 which contains from 40 % to 95 % by weight of choline salicylate.

6 A complex as claimed in any of claims 1 to 5 which contains from 2 5 % to 35 % by weight of metal ion.

7 A process for the production of a complex as claimed in any of claims 1 to 6 which comprises first forming a solution of carboxy alkyl cellulose, adding the choline component, salicylic acid and metal ion, allowing the compound formed to set and drying the mass.

8 A process as claimed in claim 7 in which the mass is dried at a temperature of about 40 WC.

9 A process as claimed in claim 7 or 8 in which the source of metal ions is aluminium peroxide; aluminium hydroxide; magnesium hydroxide; magnesium ethoxide; bismuth citrate; bismuth phosphate; bismuth hydroxide; calcium hydroxide; calcium carbonate or calcium bicarbonate.

A process as claimed in claim 7 substantially as herein described with reference to the Examples.

11 A complex as claimed in claim 1 which has been prepared by a process as claimed in any of claims 7 to 10.

12 A pharmaceutical composition which comprises a therapeutically sufficient quantity of a complex as claimed in any of claims 1 to 6 or claim 11 in admixture with a 70 pharmaceutically acceptable carrier or diluent.

13 A composition as claimed in claim 12 which is in the form of a tablet, granule, capsule or suppository 75

14 A composition as claimed in claim 12 substantially as herein described.

A composition as claimed in any of claims 12 to 14 which contains the complex in such a quantity as to provide 250 mg of 80 salicylate moiety per unit dose.

16 A composition as claimed in any of claims 12 to 15 which contains from 0 1 g to 1.0 g of active compound per unit dose.

17 A process for the preparation of a 85 pharmaceutical composition as claimed in any of claims 12 to 16 which comprises mixing together the complex as claimed in any of claims 1 to 6 or claim 11 with a pharmaceutically acceptable carrier or diluent 90 18 A method of treatment of a nonhuman animal which comprises administering to the animal a complex as claimed in any of claims 1 to 6 or claim 11 or a pharmaceutical composition as claimed in any of claims 95 12 to 16.

Agents for the Applicants ELKINGTON AND FIFE Chartered Patent Agents High Holborn House 52/54 High Holborn London WC 1 V 65 H Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1980.

Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.