IE45201B1 - Solid choline salicylate compositions - Google Patents

Description

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. 3,069,521. The compound, however, possesses the inherent limitation of being highly hygroscopic so that it is not possible to prepare pharmaceutically accepcable, solid dosage forms whidi can be administered orally in the choline salicylate therapy of humans and animals. Although crystalline choline salicylate, melting at about 50°C.> is known, its hygroscopic properties 1 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 he 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.· 3,526,760 relates to the formation of an absorbate with poiygalaeturonic 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 4ί>3θΐ choline salicylate in stable, solid, unit· dosage-forms as desei' l bed above», have as yet proved to he pharmaceutically satisfactory. Λ 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.

In general, acc...ding to the present invention, choline salicylate is stabilized in solid form by admixture thereof with the salicylate salt of a physiologically acceptable metal having a valency of at least two. The preferred metal salicylates are aluminium, bismuth, calcium and magnesium salicylate. The molar ratio of the choline salicylate to the metal salicylate is preferably from 0.3 ;1 to 1.2:1. The choline salicylate and the metal salicylate are most preferably us.'-d in equimolar amounts.

According to a preferred embodiment of the present invention, carboxy-alkyl cellulose preferably carboxy methyl cellulose is added to the mixture of the choline salicylate and the metal salicylate. It has been found that the addition of the carboxy-alkyl cellulose has the effect of virtually doubling the shelf-life of the two-component mixture, There is a vide variation in the amount of carboxy-alkyl cellulose that may be added to achieve the stabilizing effect. Preferably, the amount of carboxy-alkyl cellulose added is frcm 2,5% by weight to 25% by weight, lhe smaller amounts are preferred when low hydration levels of the mixture are present and to maximize the choline salicylate levels of the exposition. - 3 ,45201 In Patent Specification No. 45202 ' there is described and claimed a chorine salieylate-carboxyalkyl cellulose-metal salicylate complex, in Which the metal is a physiologically compatible metal having a valency of at least two, and a process for its production.

The compositions of the present invention, i.e. the mixture of choline salicylate and metal salicylate and the mixture of choline salicylate, metal salicylate and carboxylalkyl cellulose 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 ihe art, and these new drysolid powder compositions of choline salicylate may be used in any of these dosage-forms to treat humans and animals.

The naw solid dosage forms prepared with the simple mixtures, e.g. the mixture of choline salicylate and magnesium salicylate and the mixture of choline salicylate, magnesium salicylate and carboxy methyl cellulose provide special advantages of convenience in administration of choline salicylate; an excellent physiological tolerance, 45goi with the virtual absence oi side reactions and superior therapeutic efficacy evidenced hy a rapid elevation of the salicylate ion level in the blood of humans and animals after the administration of tablets, capsules, granules or suppositories containing a thei-apeutically sufficient quantity of the appropriate mixture.

The shiipi;, mixture of choline salicylate and metal salicylate is obtained by mixing tlie component chemical compounds. However, since choline salicylate only exists for a short time in the dry state when exposed to the atmosphere; the mixture is preferably obtained by first forming a concentrated solution of choline salicylate, adding the metal salicylate, i.e., magnesium salicylate, and then permitting .tha solvent to evaporate. The mixture with the earboxv metnyl cellulose is prepared in the same way, e.g., either by dry mixing of the ingredients or by formation of a Solution of choline salicylate, dissolving the necessary ingredients therein and evaporating the solvent.

The hew 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 said solid powders are stable and also retain their potency over an extended period of time.

When formulated into solid pharmaceutically acceptable 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 powders are aluminium, bismuth, calcium and magnesium ions although other metal ions can be used. It should be noted that a valency ol' at least two is required lor the metal ion to enter into formation of the new 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 properties affecting the safety of the patient would not be used and these are specifically excluded.

It is known that carhoxy-metliyl 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 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 tha desired eoheentration, and then removing the solubilizing ion, that is the sodium or potassium ion, hy 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 ci’itical 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, - 7 45201 are known by the trade name of “Amberlite, more particularly as Amberlite IR or Amberlite IR-120 resins and are marketed by Rohm and Haas of Philadelphia, Pennsylvania, (Amberlite is a Registered Trade Mark). 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 Wo. 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.

When it is desired to use the mixtures according to the invention in the treatment of humans and animals to achieve an analgesic, antipyretic or anti-inflammatory effect, and to elevate the blood salicylate levels, then a therapeutically sufficient quantity of the appropiate mixture may be administered to humans and animals in the dosage form of a tablet, granule, capsule or suppository. - 8 ^30! The preparation of tablets is accarplished by mixing the appropiate quantity of the selected active ingredient, e.g. the mixture of choline salicylate and magnesium salicylate or the mixture of choline salicylate, magnesium salicylate and 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 table lubricant being selected from the pharmaceutically accepted tablet hinders and tablet lubricants which are well '«mown in the art. The mixture is tinm granulated with ethyl alcohol and dried and the dried granular material hs then compressed into pharmaceutical tablet.-:, of suitable size and shape.

An alternat·? tabletting procedure is to mix the appropriate crxti ty 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 grinaieg the slugged tablet thus formed into a granular powder with a particle size not greater than No. 16 K.S, standard mesli size and then compressing said granular - 9 powder into pharmaceutically acceptable tablets of suitable size and shape.

Capsules are prepared by filling appropriate capsules with the active ingredient either alone or mixed with, a diluent. Diluents such as these described above may be used for this purpose, Xt 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 glyeol having a molecular weight 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 #he desired dosage.

The following examples are given to illustrate further - 10 4530| the present invention.

EXAMPLE ΐ A solution oi' 165 g oi’ choline bicarbonate dissolved in 500 ce ol watei· was placed in a suitable reaction flask and 158 g of salicylic acid were added to this, in small increments, with constant stirring until the evolution of carbon dioxide ceased. The choline salicylate solution formed was concentrated so that tlie concentration of choline salicylate was at least 90 percent by weight of the solution and there was not more than 10 percent of water present. 300 g of anhydrous magnesium salicylate were added to this solution and tiie mixture was stirred, A pastelike mass soon formed which was then spread on a glass surface to dry. In a matter of a few hours a bard solid material was obtained which was pulverized to a fine powder and was useful for the preparation of tablets, capsules, granules and suppositories t ·· provide choline salicylate in solid unitdosage form.

The solid choline salicylate-containing material formed 2ό was a mixture which could lie separated into its component parts for example by treatment with water.

EXAMPLE 2 In place of the magnesium salicylate used as described in Example 1 above, there may be substituted in equimolar amounts, aluminium salicylate, aluminium hydroxy £53°1 salicylate, bismuth salicylate and or calcium salicylate.

It is important that the mctallo salicylate salt used was anhydrous and substantially free of impurities. The resultant mixture was a free-flowing powder useful to prepare solid pharmaceutical dosage forms containing choline salicylate.

EXAMPLE 3 To an aqueous solution of choline salicylate containing at least 90 percent by weight of choline salicylate was added an equimolar proportion of anhydrous aluminium hydroxy salicylate under constant stirring, and a soft putty-like mass resulted. From 2.5 percent to 25 percent by weight, based on the weight of choline salicylate and aluminium hydroxy salicylate present in the soft mass of carboxymethyl cellulose was added to this mixture while the mixture was being milled. The soft mass hardened rapidly and could be pulverized to a fine powder. The resultant dry, solid mixture was a stable, dry free-flowing powder which was useful in the preparation of pharmaceutically acceptable solid dosage forms of choline salicylate.

Jn place of the aluminium hydroxy salicylate used above there may be substituted in equimolar proportions any one or a mixture of the following anhydrous metallio salts: aluminium salicylate, magnesium salicylate, bismuth salicylate or calcium salicylate, the remainder of the process being the - 12 45301 same, .Γη place of tlie carboxy methyl cellulose as used above, thore may be substituted in equal parts by weight, carboxyethyl-cellulose or earboxy-propyl-eellulose or mixtures thereof, the remainder of the process being the same.

While the preferred range in concenti’ation of the amount of respective carboxy lower alkyl cellulose or mixtures thereof which a··*. described above are from 2.5 percent to 25 percent by weight, a preferred range in weight of the cellulose component to be added is from 2.5 percent to 5 percent, by weight, with a particularly preferred concentration range of between 5 percent and h percent hy weight. The exact amount of carboxy alkyl, preferably methyl, cellulose to b«> added vJU depend upon the amount of water present in tiie mixture. Tints, when fche concentration of water in the solution is 10 percent or greater, by weight, then the upper range of between lp percent and 25 percent by weight of carboxy alkyl cellulose will be used, hut when the amount of water is between 10 percent and 15 percent by weight, then the weight of carboxy alkyl cellulose component to be added will be between 5 percent and 15 percent by weight, and when the amount of water is less than 10 percent by weight, then the range in the amount of carboxy alkyl cellulose used, will be between 2 1/2 percent and 5 percent by weight.

EXAMPLE h Approximately 1 litre of a 4 percent solution of sodium carboxy methyl cellulose was cycled through a column containing an acidic ion exchange resin, as for example, Amberlite-IIl-120II, to remove the sodium ion from the solution. The eluate solution of carboxy methyl cellulose then contained approximately 75 percent by weight of solid matter. A sufficient quantity of said eluate to provide 53 6. of carboxy methyl cellulose was mixed with an equimolar proportion of aluminium hydroxy salicylate and the mixture stirred, while warming.

The water was removed under vacuum distillation and the resultant dry solid material pulverized. The dry material contained the aluminium carboxy methyl cellulose disalicylate and could be used to form a stable, solid free-flowing powder of choline salicylate suitable for pharmaceutical use. EXAMPLE 5 To an aqueous solution of choline salicylate containing 9 g. of choline salicylate dissolved in 10 g. of solution, was added an equimolar proportion of anhydrous aluminium carboxy methyl cellulose disalicylate, whereupon a solid, paste-like mass formed, which was then spread in thin layers for air-drying. The resulting solid matter was then ground to a fine free-l'lowing powder which was stable and non-hygroscopic, and was useful to prepare pharmaceutically acceptable solid dosage forms containing choline salicylate as the active ingredient. 4S301 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 ;1; respective composition and was placed in a taxed 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 Ho. j 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.

The mixture of choline salicylate and magnesium salicylate, obtained as a result, of Examples 1 to 4 liquified after 30 hours of exposure to an atmosphere of 60% relative humidity at 37°C; 2d hours of exposure to an atmosphere of 80# relative humidity at 37°C; and 20 hours of exposure to an atmosphere of 90# relative humidity.

The mixture of magnesium salicylate, choline salicylate and carboxy methyl' cellulose, obtained as a result of Example 3 above liquified after 4 days exposure to an atmosphere of 60# relative humidify at 37°C; after 3 days of exposure to an atmosphere of 80# relative humidity at 37°C, and about 2.5 days exposure to an atmosphere of 90# relative humidity at 37°C, The mixture of aluminium salicylate and choline salicylate obtained as a result of Example 2 liquified after * % days of exposure to an atmosphere of 80# relative humidity at 37°O and after approximately 3 days (3.2 days) atmosphere of 90# relative humidity at 37°C.

The mixture of aluminum salicylate, choline salicylate and carboxy methyl cellulose obtained as a result of Example 3 above, liquified after approximately li days (4.3 Gays) of exposure to an atmosphere of 80# relative humidity at 37°C and after 3-5 days of exposure to an atmosphere of 90# relative humidity at 37°C.

EXAMPLE 7 Measured portions of the mixtures or compounds obtained 48a (il as a result of Examples 1 to 5 above were compressed into tablets utilizing 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 content, of the conventional 5 grain of aspirin tablet.

EXAMPLE 8 A suitable measured quantity of the mixtures or compounds obtained as a result of Examples 1 to 5 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 ε 325 mg. aspirin tablet. Suitable inert pharmaceutically acceptable and compatible capsule excipients may be used xf necessary. 4¾¾°1 Any of tha mixtures of the present invention may be used to elevate the blood salicylate ion concentration by administration of such mixture in any form whatsoever..

These mixtures, however, provide the advantage of adminis5 tration in solid dosage form, e,g. in the form of granules, tablets, capsules or suppositories.

Throughout the Specification, In discussion of the compositions or mixtures, 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 S 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 (28)

1. A solid composi tion comprising a mixture of choline salicylate and the salicylate of at least one physiologically compatible metal having a valency of at least two.

2. A composition as claimed in claim 1 in which the physiologically compatible metal is aluminium, bismuth, calcium or magnesium.

3. Λ compost Sion as claimed in claim 2 in whieh the metal is magnesium.

4. A composition as claimed in any of claims 1 to 3 in which the molar ratio of choline salicylate to metal salicylate is from 0.8:1 to 1,2:1.

5. A composition as claimed in claim 4 in which the molar ratio of choline salicylate to metal salicylate is 1:1.

6. A composition as claimed in claim 1 substantially as herein described with reference to the Examples.

7. A solid coaip.-.3ition comprising a mixture of choline salicylate the salicylate of at least one physiologically compatible metal having a valency of at least two and a carboxy-alkyl cellulose.

8. A composition according to claim 7 in which the carboxy-alkyl cellulose is carboxy methyl cellulose.

9. A composition as claimed in claim 7 or claim 8 which contains from 2.5$ to 40$ by weight of carboxy alkyl cellulose, based on the total composition.

10. A composition as claimed in claim 9 which contains from 2.5% to 25% by weight of carboxy alkyl cellulose, based on the total composition.

11. A process for the production of a composition as claimed in any of claims 1 to 6 which comprises mixing together the component chemical compounds.

12. A process as claimed in claim 11 which comprises forming a concentrated solution of choline salicylate, adding the metal salicylate and then permitting the solvent to evaporate.

13. A process as claimed in claim 11 substantially as herein described with reference to the Examples.

14. A process for the production of a composition as I claimed in any of claims 7 to 10 which comprises mixing together the chemical components.

15. A process as claimed in claim 14 which comprises forming a concentrated solution of choline salicylate, adding the metal salicylate and carboxy alkyl cellulose and then permitting the solvent to evaporate to form a mixture of the three components.

16. A process as claimed in claim 14 substantially as herein described with reference to the Examples.

17. A solid composition as claimed in claim 1 which has been prepared by a process as claimed in any of claims 11 to 13.

18. A solid composition as claimed in claim 7 which has been prepared by a process as claimed in any of claims 14 to 16.

19. A pharmaceutical composition which comprises a therapeutically sufficient quantity of a composition as claimed in any of claims 1 to 6 or claim 17 in admixture with a pharmaceutically acceptable carrier or diluent. 20. 45201

20. A composition as claimed in claim 19 which is in the form of a tablet, granule, capsule or suppository.

21. A composition as claimed in claim 19 substantially as herein described.

22. A process for the preparation of a pharmaceutical composition as claimed in any of claims 19 to 21 which comprises mixing together the solid composition as claimed in any of claims 1 to 6 or claim 17 with the pharmaceutically acceptable carrier or diluent.

23. A pharmaceutical composition which comprises a therapeutically sufficient quantity of a composition as claimed in any of claims 7 to 10 or claim 18 in admixture with a pharmaceutically acceptable carrier or diluent.

24. A composition as claimed in claim 23 which is in the form of a tablet, granule, capsule or suppository.

25. A composition as claimed in claim 23 substantially as herein described.

26. A process fcr the preparation of a pharmaceutical comTXJSition as claimed in any of claims 23 to 25 which comprises mixing together the solid composition as claimed in any of claims 7 to 10 or claim 18 with the pharmaceutically acceptable carrier or diluent.

27. A method of treatment of a ncn-human animal which comprises administering to the animal a solid composition as claimed in any of claims 1 to 6 or claim 17 or a pharmaceutical composition as claimed in any of claims 19 to 21.

28. A method of treatment of a non-human animal which comprises administering to the animal a solid composition as claimed in any of claims 7 to 10 or claim 18 or a pharmaceutical composition as claimed in any of claims 23 to 25.