NO145295B - PROCEDURE FOR THE PREPARATION OF A CHOLINE-SALICYLATE (CARBOXY-LOW REALCYL-CELLULOSE) METAL COMPLEX - Google Patents

Description

The present invention relates to a method for the production of a choline salicylate (carboxy-lower alkyl cellulose) metal complex. The complex can be used in fixed dosage forms such as granules, tablets, capsules and suppositories for administration to humans and animals, during choline salicylate therapy, to increase the amount of salicylations in the blood.

Choline salicylate is a well-known analgesic compound with desirable pharmacological and therapeutic properties, as described in US patent 3,069,321. However, the compound suffers from the disadvantage that it is very hygroscopic, so that it is not possible to prepare pharmaceutically acceptable dosage forms useful for oral administration to humans and animals during choline salicylate therapy. Although crystalline choline salicylate which melts at approx. 50°C is known, its hygroscopic properties are such that trace amounts of moisture are sufficient to transfer the crystalline compound into liquid form, and no matter how strong attempts are made to remove the absorbed moisture, the product remains in liquid form, so that this cannot be used to form stable, solid dosage forms for pharmaceutical use.

Many efforts have been made to prepare solid pharmaceutical dosage forms of choline salicylate. Thus, US patent 3,297,529 relates to mixtures of choline salicylate and magnesium sulfate to form a solid product. US patent 3,326,760 relates to the formation of an absorbate with polygalacturonic acid. US Patent 3,759,980 relates to the formation of a chemical compound of choline salicylate and magnesium salicylate, which compound is a solid. However, none of the methods which purportedly solve the problem of providing choline salicylate in stable, fixed unit dosage forms as described above have yet been found to be pharmaceutically satisfactory. A solid unit dosage form which provides a therapeutically sufficient amount of choline salicylate for the desired therapeutic purposes, and which also remains stable for a sufficiently long time to permit its sale, has not yet been made commercially available.

However, it has now succeeded in bringing choline salicylate in

a stabilized form where, in addition to having the desired non-hygro-

scopicity is also present in high concentration. With the help of the invention, a method is thus provided for the production of a stable choline salicylate (carboxy-lower alkyl cellulose) metal complex, which method is distinguished by the fact that an aqueous solution of a carboxy lower alkyl cellulose and choline salicylate is formed, that adding a physiologically compatible compound of aluminum or magnesium in an amount sufficient to form a complex with the choline salicylate and the carboxy-lower alkyl cellulose in the molar ratio choline:salicylic acid:metal 1:3:1, that the reaction mass formed is allowed to stand until it thickens, and that the thus thickened reaction mass is dried.

Although the prepared complex may contain widely varying amounts of its individual constituents, choline salicylate, metal ion and carboxy-lower alkyl cellulose, the various compositions are homogeneous, reproducible and constant, and it has been shown to be stable in dry, solid form for more than four years, which from a commercial point of view can be considered very satisfactory. Thus, the complexation of the choline salicylate with a metal ion as indicated and carboxy-lower alkyl cellulose leads to the formation of an exceptionally stable, solid complex compound which is useful for preparing solid pharmaceutical dosage forms which remain stable for at least four years. The dried powder of the complex is thus useful for preparing pharmaceutically acceptable capsules, granules, tablets and suppositories by methods known per se, and these new dry solid powder preparations of choline salicylate can be used in any of these dosage forms for treatment of humans and animals.

The prepared complexes can be distinguished from the previously described solid compounds, and also from simple mixtures of their constituents, by virtue of their chemical composition and their chemical, physical and pharmaceutical properties.

The difference between the individual preparations is shown by

comparison of the critical solubility of e.g. magnesium carboxymethylcellulose choline salicylate, which is one of the new grain-plex compounds, with the previously known chemical compound according to US patent 3,759,950, choline magnesium salicylate, in polar

solvents. Electrical conductivity data support the critical solubility data and confirm that magnesium carboxy-

The methylcellulose-cholinesalicylate is significantly different from the previously formed compound magnesium-cholinesalicylate,

in that it has a chelate intramolecular structure, in contrast to the hydrogen bonding structure that characterizes the molecule according to the state of the art. Furthermore, the specific electrical conductivity of the formed magnesium carboxymethylcellulose choline salicylate differs from the conductivity of the simple mixture of its constituents, which in turn differs from the conductivity of the hydrogen bonding compound formed according to the state of the art, i.e. magnesium choline salicylate.

The quantity ratios between choline salicylate, metal ion and carboxy-lower alkyl cellulose which are necessary to form the new complex compound can vary within a wide range. Thus, the amount by weight of carboxymethylcellulose is between 2.5% and 25%, while the amount of choline salicylate is between 40% by weight and 95% by weight, and the amount of metal ion between 2.5% and 35% by weight.

The new solid dosage forms prepared with choline salicylate (carboxy-lower alkyl cellulose) metal ion complexes offer special advantages in the administration of choline salicylate, namely an excellent physiological tolerance, with essentially the absence of side effects, and better therapeutic efficacy, indicated by a rapid increase in the amount of salicylations in the blood in humans and animals following the administration of tablets, capsules, granules or suppositories containing a therapeutically sufficient amount of the appropriate choline salicylate (carboxy-lower alkyl cellulose) aluminum complex or

-magnesium complex.

The new choline salicylate complex compounds are prepared by first preparing a solution of carboxy-lower alkyl cellulose and then adding the choline component, the salicylic acid and the aluminum or magnesium ion.

The metal (carboxy-lower alkyl cellulose) choline salicylate compound formed is allowed to settle, whereupon it is thickened, and then the mass is dried, preferably at a temperature of

about. 40°C. The obtained dry powders containing the choline salicylate-carboxy-lower alkyl-cellulose metal complex give an analysis in good agreement with the theoretical amounts of choline salicylate, carboxy-lower alkyl cellulose and the respective metal ion.

When 10 g of either aluminum or magnesium carboxymethylcellulose choline salicylate complex is placed in an open petri dish and exposed to the atmosphere for extended periods of time, the powders remain in their original solid, free-flowing state, without decomposition. When they are processed into solid pharmaceutically acceptable dosage forms that are packaged and stored at room temperature, these pharmaceutical preparations are stable for periods of more than four years.

The general method used to produce

the new complexes, are illustrated below in detail.

It is known that carboxymethylcellulose in the dry acid form is insoluble in water. It is necessary that the carboxymethylcellulose acid be transferred to an aqueous solution, and this can be achieved by dissolving in water the usual metal salts of carboxymethylcellulose such as e.g. sodium or potassium carboxymethyl cellulose, in the desired concentration, and then remove the solubilizing ion, i.e. the sodium or potassium ion by means of an acidic ion exchange column in a manner known per se. The exact composition of the acid ion exchange column is neither essential nor critical as any of the metal ion exchange resins used to remove sodium and potassium ions from a solution are useful for this purpose. The ion exchange resins known in the art as sulfonated polystyrene polymers and which are

crosslinked polyamine resins, are known in the trade under the trademark "Amberlite" or more particularly "Amberlite IR" or "Amberlite IR-120" resins. Resins of this type are described in US patent 2,402,384. These resins are used in the hydrogen form in a well-known manner to remove sodium and/or potassium ions.

f For example, 1 <q>frame molecule of choline carbonate is added to the prepared aqueous solution of carboxymethylcellulose obtained as eluate from the ion exchange column after removal of ff. the sodium or potassium ions, and the whole thing is stirred while the mixture is heated to approx. 70°C. Stirring is continued for approx. 1 hour or until there is no more effervescence. The pH of the mixture is then determined

and will be in the range 7 - 7.8 with an average pH value of 7.4.

Preferably, 3 gram molecules of salicylic acid are then added to the choline bicarbonate-carboxymethylcellulose solution while stirring, and the mixture is heated and kept at approx. 55°C for 1 hour. When all the salicylic acid has been added and a solution is obtained, the mixtures are allowed to reach room temperature, and 1 gram molecule of the metal ion donor is added. The addition of the metal ion donor compound is carried out under vigorous stirring, while the temperature is again increased to approx. 70 C.

When all of the metal donor compound has been incorporated into the mixture and the solution has become clear, stirring is stopped and the batch is set aside to settle overnight. After a period of time, the mass becomes thick, and the whole thing then dries within approx. 24 hours in an oven set at 80°C. The essentially dry material obtained is pulverized and then further dried in a vacuum oven at a temperature of approx. 40 C and 2 rooms of Hg to constant weight. The dry powder thus obtained is the metal-choline salicylate-carboxymethylcellulose complex which is stable and has unique and reproducible properties.

The metal ion donor compound described above is one source

to metal ion, and the following donor compounds are preferred for this purpose:

(a) as a source of aluminum ions:

aluminum isopropoxide and aluminum hydroxide,

(b) as a source of magnesium ions:

magnesium hydroxide and magnesiumethoxide,

When choline salicylate is prepared in situ, choline chloride, choline carbonate or any other soluble salt of choline may be used instead in equimolar amounts as described above for choline bicarbonate. The new solid powders of choline salicylate can also be obtained when choline salicylate is added to the carboxymethylcellulose solution before adding the metal ion.

The dry powder of complex obtained by the present process is white, free-flowing and stable, with reproducible physical and chemical properties. The respective compounds (molar ratio of choline:salicylic acid:metal is 1:3:1) give the following analysis: the aluminium-choline salicylate-carboxymethylcellulose complex contains essentially 5.1% aluminum ion; 91.65% choline salicylate and 3.25% carboxymethylcellulose; the magnesium-choline salicylate-carboxymethylcellulose complex essentially contains 3.0% magnesium ion, 92.3% choline salicylate and 5.16% carboxymethylcellulose. For comparison, it should be mentioned that the choline salicylate polygalacturonate according to the above-mentioned US patent 3,326,760 contains between 55% and 65% choline salicylate.

When it is desired to use the new complex compounds for the treatment of humans and animals to achieve an analgesic, anti-pyretic or anti-inflammatory effect, and to raise blood salicylate levels, a therapeutically sufficient amount of the appropriate new complex can be administered to humans and animals in the dosage form of a tablet, granule, capsule or suppository. The preferred unit dose concentration of the respective new dry choline salicylate (carboxy-lower alkyl cellulose) metal ion complexes in tablet, capsule, granule or suppository dosage form is a sufficient amount of the complex to provide approx. 250 mg salicylate group per unit dose or approx. 339 mg aluminum-choline salicylate-carboxymethylcellulose complex and 370 mg aluminum-choline salicylate-carboxymethylcellulose complex.

The concentration range per unit dose is from 0 1 g of each of the mentioned active complex per dose to 1.0 of the selected active complex per dose. The exact dose concentration required depends on the therapeutic goal to be achieved and the needs of the individual patient.

The following examples are given to further illustrate the invention.

Example 1

About. 4.5 liters of a Lfø-±g solution of sodium carboxymethylcellulose is circulated through a column containing an acidic ion exchange resin such as, for example "Amberlite-IR-120H" to remove the sodium. The eluate solution of carboxymethylcellulose in water contains approx. 0.75% by weight solids. A sufficient amount of this eluate to give 32.7 g of carboxymethylcellulose is placed in a glass flask fitted with a stirrer and heating jacket. The carboxymethyl cellulose solution is heated to approx. 30°C, and 22.47 g of choline bicarbonate are added in small portions with rapid stirring.

Strong effervescence occurs when the choline bicarbonate portions are added, and the heat is slowly increased to 70°C during the addition process. When all the choline bicarbonate has been added, stir the mixture for approx. 1 hour under heating and then allowed to cool to room temperature. The pH of the solution is approx. 7.4 with a range from 7.0 to 7.8- To this solution at room temperature, 48 g of salicylic acid are now added in divided portions with constant stirring. The mixture is heated for 1 hour, and the temperature is then raised to 70°C,

and a sufficient amount of aluminum isopropoxide to give 2.99 aluminum ion is added. Stirring and heating are continued for 1 hour, and then the batch is set aside overnight.

The next day, the thickened mass is spread out in a thin layer for drying in an oven at 80°C. When the material is dry, it is pulverized and then placed in a vacuum oven to continue the drying process at a temperature of 40°C and 737 mm vacuum, until two consecutive samples show no further weight loss. The dried powder is then ground again, packed and filled into glass bottles. The complex formed is aluminum-choline salicylate-carboxymethylcellulose, a white powder containing 5.1% aluminum, 91.65% choline salicylate and 3.25% carboxymethylcellulose. The powder is insoluble in water and stable when exposed to air at room temperature.

Instead of the aluminum isopropoxide described as a source

to the aluminum ion, aluminum hydroxide in the form of a dry gel or aluminum in the form of a wet gel can be used, in an amount sufficient to give an equivalent amount of aluminum ion as indicated above.

Example 2

To an aqueous solution of 16.3 g of carboxymethylcellulose

166 g of choline bicarbonate are added. The mixture is stirred and heated until gas evolution ceases, and then 4l4.49 salicylic acid is added. The mixture is heated and stirred until all solids have dissolved. Stirring is continued under heating at 70°C for approx. 1 hour, and then 114.3 9 magnesiumethoxyd are added. The mixture is stirred until all solid material dissolves,

and heating is continued for 1 hour, after which the mixture is allowed to stand overnight.

The next day, the solution is dried to constant weight, and the dry powder is pulverized. The compound formed is magnesium-choline-salicylate-carboxymethylcellulose containing 2.5% magnesium, 92.3% choline salicylate and 5.16% carboxymethylcellulose. The dry, white powder is insoluble in water and non-hygroscopic. It is stable for a long time when exposed to the atmosphere.

Instead of the magnesium ethoxide used as magnesium ion donor, 61.78 g of magnesium hydroxide can be used.

Example 3

When 19 g of either aluminum choline salicylate carboxymethyl cellulose or magnesium choline salicylate carboxymethyl cellulose is extracted with chloroform and the solvent is evaporated, the residue is no more than 10 mg. This test shows that no excretion of salicylic acid takes place from the respective formed compound obtained as a result of examples 1 and 2.

A 10 g sample of the choline salicylate-carboxymethylcellulose metal complex - obtained in examples 1-2, is placed on a tared Petri dish which is then exposed to the atmosphere on an open shelf. An equal amount of crystalline choline salicylate which melts at approx. 50°C, is prepared by the method described in U.S. patent 3,069,321 and then placed on another petri dish placed next to the petri dish containing the formed choline salicylate-carboxymethylcellulose metal compound as described in example 1-2. Both petri dishes are examined at one-hour intervals on the first day and then at eight-hour intervals. At each test time, each petri dish is weighed to determine any increase in weight due to absorption of water, and the physical state of the solid material is assessed to determine if any change has occurred in the respective compounds. After 1 hour of exposure to the atmosphere, the crystalline choline salicylate compound prepared according to U.S. Pat. patent 3,069,321, while the new . complexes prepared according to the procedure described in examples 1-2, remain in their original, solid form. The transferred choline salicylate showed an increase in weight of 1.963 mg, indicating an absorption of water of nearly 20%, while the new compounds formed showed an increase in weight of only 67 mg, indicating that there was practically no hygroscopic activity.

After 3 days of exposure to the atmosphere on the open shelf, the transferred choline salicylate compound absorbed approx. 40% by weight

(4.136 g), while the new complexes formed showed an increase in weight of less than 1% or 331 mg. The free-distributing powder properties of the new complexes formed remain unchanged throughout the trial period. This experiment shows that complex formation of the units occurs, which modifies the choline salicylate's ability to absorb water from the atmosphere. Hydrogen bonding is known to occur between choline salicylate and water, and the effect of the new complexes is a preferential blocking of the site of hydrogen bonding, preventing the absorption of water molecules.

In all of the tests performed with solid choline salicylate complexes described above, the free-triggering powder properties were not affected by exposure to the atmosphere for 3 days.

Example

The ability of the solid choline salicylate preparations obtained in Examples 1-3 above to retain their solid state properties was assessed by placing 2 g samples of the respective preparations in tared glass dishes and keeping them under various humid atmospheric conditions with up to 97% relative humidity at a controlled temperature of 37°C. At predetermined intervals the samples were examined and the physical condition of the exposed powder noted.

Choline salicylate melting at 49.3°C, prepared according to US Patent 3,069,321, floated within 2 minutes of exposure at all relative humidities tested.

Magnesium choline salicylate, prepared according to US patent 3,759,980, floated after 32 hours exposure to an atmosphere of 60% relative humidity at 37°C, 20 hours exposure to an atmosphere of 80% relative humidity at 37°C and 18 hours exposure to an atmosphere with 90% relative humidity at 37°C.

Magnesium carboxymethylcellulose choline salicylate obtained as a result of Example 2 remained solid when exposed for 7 days to an atmosphere of 90% relative humidity at 37°C, but floated after 7 days of exposure to an atmosphere of 97% relative humidity at 37 °C.

Aluminum carboxymethylcellulose choline salicylate obtained as a result of Example 1 was partially solid after 7 days of exposure to 80% relative humidity at 37°C, and also after 7 days of exposure to an atmosphere of 90% relative humidity at 37°C.

In the description, under the mention of the complexes, carboxymethylcellulose is mainly mentioned. However, any carboxy-lower alkyl cellulose can be used, such as carboxymethyl cellulose, carboxypropyl cellulose, etc. Carboxymethyl cellulose is most preferred from the considerations of availability and economy.

Claims (2)

1. Process for the production of a stable choline salicylate (carboxy-lower alkyl cellulose) metal complex, characterized in that an aqueous solution of a carboxy lower alkyl cellulose and choline salicylate is formed, that a physiologically compatible compound of aluminum or magnesium in an amount sufficient to form a complex with the choline salicylate and the carboxy-lower alkyl cellulose in the molar ratio choline:salicylic acid:metal 1:3:1, that the formed reaction mass is allowed to stand until it thickens, and that the thus thickened reaction mass is dried. 2. Method according to claim 1, characterized in that the aqueous solution of a carboxy-lower alkyl cellulose and choline salicylate is formed by adding choline bicarbonate to an aqueous solution of carboxymethylcellulose and adding salicylic acid to the formed solution until the pH is between 7.0 and 7.8.