FI56770C - FOERFARANDE FOER FRAMSTAELLNING AV ETT TERAPEUTISKT ANVAENDBART STABILT FAST KOLINSALICYLATKOMPLEX - 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

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Patent- och registerstyrelsen '' Ansakan utlajd och utl. «Krlft« n publlc «red 31.12.79 (32) (33) (31) Pyydetty etuoikeus— Begird prloritet 21.01.76

Ik.07.76 USA 65IIIO, 705056 (71) Mundipharma AG, Alban-Vorstadt 9 * +> Postfach, 1 + 006 Basel, Switzerland-Switzerland (CH) (72) Ernest J. Sasmor, Yonkers, New York, USA (US) (7 ^) Oy Kolster Ab (5 ^) Method for the preparation of a therapeutically stable stable choline salicylate complex - Förfarande för framställning av ett therapeutisktvvbbart stabilt fast kolinsalicylatkomplex

Choline salicylate is a well-known analgesic with pharmacological and therapeutic properties, as described in U.S. Patent No. 3,069,321. However, its use is limited by its hygroscopicity, which precludes the preparation of pharmaceutically acceptable solid dosage forms useful. orally during human and animal choline salicylate therapy. Although crystalline choline salicylate, which melts at about 50 ° C, is known, its hygroscopic properties are such that even the slightest amounts of moisture are sufficient to convert the crystalline compound to a liquid state from which no great effort is made to remove absorbed water, but remains liquid and thus unsuitable for stable pharmaceutical formulations.

Many attempts have been made to prepare solid pharmaceutical dosage forms of choline salicylate. U.S. Patent No. 3,297,529 discloses the use of mixtures of choline salicylate and magnesium sulfate to make a solid product.

U.S. Patent No. 3,532,760 discloses the formation of an absorbent with polygalacturonic acid. U.S. Patent No. 3,759,980 relates to the formation of a solid chemical compound of mildallyl silylate and magnesium salicylate.

However, none of these described methods has solved the problem of preparing stable, solid unit dosage forms of collagen in a pharmaceutically satisfactory manner. A solid unit dosage form from which a therapeutically sufficient amount of choline salicylate is released And which remains stable for a sufficient period of time for sale is not yet commercially available.

The present invention relates to a process for the preparation of a therapeutically useful, stable, el, hygroscopic mole of 1'Insalicylacylate, carboxyl (alemplylalkyl) cellulose and a metal compound. The process according to the invention is characterized in that the mole isylate, preferably prepared in situ from mole 11 carbonyl carbonate and salicylic acid, carboxymethyl, carboxylethyl or carboxypropylcellulose and in the presence of physiologically acceptable aluminum, water, magnesium or calcium compounds. to form a mole in a molar ratio of choline: acidic acid: metal ion and the complex is dried and ground, the product obtained containing, by dry weight, about 2.5-25% by weight of carboxyl (lower alkyl) cellulose, about 40-95 palno-fc. sal Isy-tate and about 2.5-35% by weight of metal ions.

The complex compound prepared by the process of the invention is homogeneous, reproducible and stable and has a storage solid in dry solid form of more than four years, which can be considered practically unlimited. The complex prepared is thus very suitable for the preparation of solid pharmaceutical dosage forms which must remain stable for at least four years.

The complex compounds prepared according to the invention differ from the solid compounds of the prior art and also from pure mixtures of their components both in terms of their chemical composition and their chemical, physical and pharmaceutical properties.

The difference between the different compositions is evident when comparing the solubility of the novel complex compound, magnesium carboxymethylcellulose-choline salicylate and keel isylate, magnesium sulphylacylate and carboxymethyl silylose to the soluble polysaccharine compound according to U.S. Pat. No. 3,759,950.

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The electrical conductivity values determined for the compounds correspond quite well to the values of critical solubility. structure based on hydrogen bonds. The intrinsic electrical conductivity of the formed magnesium carboxymethyl-cellulose-choline salicylate also differs from the intrinsic electrical conductivity of pure mixtures of components.

In the process according to the invention, the ratios of carbonic salicylate, metal ions and carboxy (lower alkyl) cellulose can vary within wide limits. The amount of carboxy (lower alkyl) cellulose is preferably about 2.5 to 25% by weight, the amount of keel salicylate is preferably about 40 to 95% by weight, and the amount of metal ions is preferably about 2.5 to 35% by weight of the total weight of the complex.

The dried powders prepared by the process of the invention are suitable for the preparation of pharmaceutically acceptable capsules, granules, tablets and suppositories by methods known in the art. The obtained preparations containing choline salylate can be used in various dosage forms for the treatment of humans and animals. The new choline salicylate-carboxyl (lower alkyl) cellulose-metal-methyl complex has many advantages in drug delivery. They are physiologically well-fed And essentially Without a side reaction, they have a very good therapeutic effect, which can be ascertained after a therapeutically adequate dose of the drug from the rapid elevation of salyl ions in human or animal blood.

The general process used to form the novel complexes of this invention is described in detail below, wherein carboxymethylcellulose is used as the carboxyl (lower alkyl) cellulose.

Carboxymethylcellulose is insoluble in water in dry acidic form. To form an aqueous solution of carboxymethylcellulose acid, its usual metal salts, such as sodium or copper carboxymethylcellulose, are used in a suitable volume and then the solubilizing ion, i.e. sodium or potassium ion! by means of an acidic ion exchange column as is well known in the art, the exact composition of the ion exchange column is neither essential nor critical, as Any metal ion resin used to remove sodium or potassium ion from solution is useful for this purpose. Suitable ion exchange sites include crosslinked polyamine resins, e.g., Amberlite® IR or AmberMte® IR-120 (Rohm-Haas, Philadelphia, PA). Mold resins of the same type are available under various trade names, and some of these resins and methods for their preparation are described in U.S. Patent 2,402,384. These resins are used in the hydrogen form for the purpose of removing sodium and / or potassium ions.

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To the aqueous solution of carboxymethylcellulose obtained after removal of the sodium and potassium ions from the acidic ion exchange column is added one mole of choline bicarbonate, and the whole amount is stirred while heating to about 70 ° C. Stirring is continued for about an hour or until effervescence ceases. The pH of the mixture is then 7-7.8, with an average pH of 7.4.

To the solution made of choline bicarbonate and carboxymethylcellulose is then added, with stirring, preferably three moles of salicylic acid, and the mixture is heated at about 55 ° C for one hour. After all the salicylic acid has been added and the solution obtained, the mixture is allowed to cool to room temperature and one mole of metal ion donor is added. The addition of the metal ion donor compound is performed with vigorous stirring while raising the temperature again to about 70 ° C. After all the metal ion donor compound has been added to the mixture and a clear solution is obtained, the mixing is stopped and the batch is set aside to clot overnight. After standing, the mass thickens and is then dried for 24 hours at 80 ° C. The resulting substantially dry material is finely ground and further dried at about 40 ° C at 2 mm / Hg to constant weight. The powder thus obtained is a metal choline salicylate carboxymethylcellulose compound which is stable and has unique and reproducible properties useful in preparing solid therapeutically sufficient dosage forms containing the above-mentioned active ingredient, such as capsules, tablets, granules and suppositories.

When the choline salicylate is prepared in situ, an equivalent amount of choline chloride, choline carbonate, or any other soluble salt of choline may be used in place of the choline bicarbonate. Novel solid powders of choline salicylate can also be obtained by adding choline salicylate to the carboxymethylcellulose solution before adding metal ions.

The dry powders of the complex compound obtained by this method are white free-flowing and stable and have reproducible physical and chemical properties. The analysis of the corresponding compounds (molar ratio choline: salicylate'.metal ion at 1: 3: 1) is as follows: the aluminum choline salicylate-carboxymethylcellulose compound contains essentially 5.1% Al, 91.65% choline salicylate and 3.25% % carboxymethylcellulose, magnesium choline salicylate-carboxymethylcellulose compound contains substantially 3.0% Mg, 92.3% choline salicylate, 5.16% carboxymethylcellulose, calcium choline salicylate-carboxymethylcellulose compound contains 91%% ca , 65 ft and the bismuth choline salicylate-carboxymethylcellulose compound contains 27.28% Bi, choline salicylate 49.5% and carboxymethylcellulose 21.2%.

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If the novel complex compounds are to be used in human and veterinary medicine to achieve an analgesic, antipyretic or anti-inflammatory effect and to increase the blood acylate content, a therapeutically sufficient amount may be administered to humans or animals in the form of tablets, granules, capsules or suppositories. The unit dose preferably contains about 250 mg of salicylate, i.e. about 339 mg of aluminum-collin-salicylate-carboxymethylsilylose, 370 mg of magnesium-collin-salicylate-carboxymethylcellulose * compound, 395 mg of calcium-collinyl-salosyl -sylaattl-carboxymethyl cellulose-yhdlstettä. The concentration of the unit dose may vary from 0.1 g to 1.0 g of each of said active compounds. The exact dosage of the required concentration will depend on the desired therapeutic goal and the needs of the patient.

The following examples illustrate the invention.

Example 1

To a solution of choline carbonate (165 g) in a suitable reaction flask in water at 500 g is added 138 g of salicylic acid in small portions with constant stirring until bubbling of carbon dioxide ceases. The collinyl salicylate solution thus formed is concentrated so that the concentration of koi I salicylate is at least 90% by weight and no more than 10% water is present.

An equimolar amount of anhydrous aluminum hydroxysalicylate is added to an aqueous solution of mole IIsylate containing at least 90% by weight, with constant stirring, to obtain a soft flaky mass.

To this pulp is added carboxymethylsilulose 2.5 * 25% by weight of the arithmetic sum of the weights of colognyl salicylate and aluminum hydroxysalicylate while stirring the mixture. The soft mass hardens quickly and can be ground to a fine powder. The resulting dry solid mixture is a stable, free-flowing powder useful in preparing pharmaceutically acceptable solid dosage forms of koi Uni salicylate.

Carboxy (alemplalkyl I) cellulose is added in an amount of about 2.5 to 25% by weight, preferably 2.5 to 5% by weight and especially 3 to 3% by weight. The exact amount of carboxyalkyl (preferably methyl) cellulose to be added depends on the amount of water present in the mixture. Thus, when the water content of the solution is 10 palno% or more, carboxyalkylcellulose 15-15 palno% is used, but when the water content is 10-15 patno%, the amount of carboxylic acid cellulose component to be added is 5-15% by weight. the amount of water is less than 10% by weight, then the amount of carboxyalkyl-1-cellulose used is 25-5% by weight.

Example 2

To a solution containing at least 90% by weight of collinium 6 5G770 salicylate prepared as described in Example 1 is added an equimolar amount of anhydrous aluminum hydroxylic acid as in Example 1. To the resulting mass is added, with stirring, a mixture of carboxyethyl and ethylene 5% by weight of aluminum. The hardened mass is ground. The product obtained is stable, non-hygroscopic and particularly well suited for pharmaceutical preparations.

Example 3

The procedure is the same as in Example 2, but instead of the carboxyethyl moiety, 5% by weight of carboxypropylsulphosylate and aluminium isylsilylate and aluminum hydroxysalcate salicylate are added to the pulp containing collinyl salicylate and aluminum hydroxyl salicylate. The ground pulp has similar properties to that prepared in Example 2.

Example 4

Approximately 1 liter of a 4% solution of sodium carboxymethylcellulose is recycled through a column of acidic ion exchange resin, e.g., Amberl te-1R-120H, to remove sodium ion from the solution. The carboxymethyl cell eluate solution now contains about 0.75% by weight solids. An amount of the eluate containing 33 g of carboxymethylcellulose is mixed with an equimolar amount of aluminum hydroxysalicylate and the mixture is stirred with heating. The water is removed by vacuum distillation, and the resulting dry solid is finely ground. The dry matter contains the formed aluminocarboxymethyl-1-cellulose diacalylate and can be used to form a stable, solid free-flowing powder with coin salicylate. Koi 1 In 1 obtained 1sy-plate In an aqueous solution containing 5 g of koi 1 salsalylate in 10 g of solution, an equimolar amount of anhydrous aluminum carboxymethylmethylcellulose-dlsal isylate is added to form a solid pasty mass which is applied as a thin layer. The resulting solid is ground to a fine free-flowing powder which is stable and el-hygroscopic and is useful in preparing pharmaceutically acceptable solid dosage forms containing choline salicylate as the active ingredient.

Example 5

About 4.5 liters of a 4% solution of sodium carboxymethylcellulose is recycled through a column containing an acidic ion exchange resin, e.g., AmberlIte-IR-120H, to remove sodium. The aqueous solution of carboxymethylcellulose in water contains about 0.75% by weight of solids. An amount of this eluate containing 32.7 g of carboxymethyl-1-cellulose is introduced into a glass flask equipped with a stirrer and a heating mantle. The carboxymethylcellulose solution is heated to about 30 ° C and 22.47 g of choline bicarbonate are added in small portions with rapid stirring. When increasing the doses of Koi I Inibicarbonate, 7 56770 strong effervescences occur and the heat is slowly raised to 70 ° C during the addition step. After all the koilinibicarbonate has been added, the mixture is stirred for about an hour with heating and then allowed to cool to room temperature. The pH of the solution is about 7, A, with a range of pH 7 * 0 "7» 8 · At room temperature, A8 g of salicylic acid is added portionwise to this solution with constant stirring. The mixture is heated for 1 hour, then the temperature is raised to 70 ° C and aluminum luminesopropoxide is added in an amount corresponds to 2.9 g of aluminum snow Stirring and heating Continue for one hour, then allow the mixture to stand overnight.

The next day, the thickened mass is applied in a thin layer to dry in a hot oven at 80 ° C. After the material has dried, it is finely ground and drying is continued in a vacuum oven at 40 ° C under a vacuum of 737 mm to constant weight. The dried powder is then re-ground, packaged and filled into glass bottles. The compound formed is aluminium choline sulphate carboxylmethylcellulose containing 5.1% Al, 91.65% choline azalylate and 3.25% carboxymethylcellulose. The powder is insoluble in water and stable at room temperature under the influence of air.

Instead of aluminum isopropoxide, a dry gel or wet gel of aluminum hydroxide can be used in an amount equivalent to the amount of aluminum isopropopropane shown above.

Example 6

To an aqueous solution of carboxymethylcellulose containing 16.3 g of carboxymethylcellulose is added 166 g of koi 1 in Ib [carbonate a. The mixture is stirred and heated until gas evolution ceases and then M, 4 g of salicylic acid is added. The mixture is heated and stirred until all solids have dissolved. Stirring is continued with heating at 7 ° C for about an hour and then 11A, 3 g of magnesium di a are added. The mixture is stirred until all the solid has dissolved, heating is continued for one hour and the mixture is allowed to stand overnight.

The next day the mixture is dried to constant weight, and dry. The powder is finely ground. The compound formed is magnesium collinyl sulfate with carboxymethyl 1-cellulose containing 2.5% magnesium, 92.3% with collinyl sulfate and 5.16% carboxymethylcellulose. The dry white powder is insoluble in water and is not hygroscopic and is stable for long periods of time under the influence of the atmosphere.

61.78 g of magnesium hydroxide can be used instead of magnesium ethoxide. Example 7

To an aqueous solution of carboxy) methyl (cellulose containing about 17 g of carboxymethylcellulose on a dry basis) is added 1 mole of mole II carbonyl carbonate and 2 moles of salicylic acid. The mixture is stirred until complete dissolution of 8 56770, then the mixture is heated to 70 ° C with stirring. 398 g of bismuth citrate are added, corresponding to 1 Bmol.

Instead of bismuth citrate, any soluble vls mut salt can be used, e.g. bismuth chloride a or bismuth phosphate. After the addition of the compound, the mixture is stirred with heating until a clear solution is formed, and then the solution is left overnight at room temperature. The material is then dried in vacuo to constant weight.

The dry white powder is bismuth-co-methylsalicylate-carboxymethyl-cellulose which is stable at room temperature and is not hygroscopic. Example 8 - 3

To a solution of 4.6 g of carboxymethylcellulose in 100 cm of water 3 is added 100 cm of a solution of 91 g of koolinic salicylate. The mixture is heated to 70 [deg.] C. for three hours, after which 4.35 g of cadmium ion (a) obtained from sodium hydroxide or calcium bicarbonate are added. When all the calcium salt has dissolved, the mixture is left to stand for at least 10 hours, and then the product is dried under vacuum to constant weight. The resulting white powder, kalslum-choline salicylate-carboxymethylcellulose, is a stable, non-hygroscopic powder.

Investigation of the structure of koi 1-tinsalicylate complexes

When 19 g of aluminum-choline-salicylate-carboxymethyl-cellulose, magnesium salt of isylate-carboxymethyl-cellulose, This experiment shows that salicylic acid does not differ from the compounds prepared in Examples 5 "8.

Examination of the stability of the choline salicylate complex A 10 g sample of the choline salicylate complexes prepared in Examples 5-8 were placed in tared petroleum dishes, which were then exposed to air. An equal amount of crystalline choline salicylate melting at about 50 ° C, prepared according to the method described in U.S. Patent No. 3,069,321, was placed in a petri dish adjacent to the above petri dishes. Petroleum plates were examined hourly on the first day and every eight hours thereafter. At each time point, each petri dish was weighed to determine the weight gain due to water absorption, and the physical condition of the material in them was evaluated to detect any changes in the compounds. After one hour of exposure to the atmosphere, the crystalline choline salicylate compound prepared according to U.S. Patent No. 3,669,321 became liquid, while the novel compounds prepared in Examples 3-6 remained in the original solid state. The liquefied choline-salicylate salivylate was 1963 mg, indicating almost 20% water absorption, while the weight gain of the new compounds was only 67 mg, indicating that they were not hygroscopic.

After three days of exposure to atmospheric liquids, about 1 * 0% by weight (4.136 g) of water was absorbed, while the weight gain of the new compounds was less than 1% (331 mg). The free-flowing powder properties of the new compounds remain unchanged throughout the test period. This experiment showed that there was a complex formation, which altered the ability of the choline sal isylate to absorb water from the atmosphere. It is known that a hydrogen bond exists between choline salicylate and water, and due to the effect of the new compounds, the salary of the hydrogen bond is no longer free to absorb water molecules.

When an equal amount of the solid choline salicylate composition consisting of a mixture of choline saline and magnesium salylate was placed in a tared petri dish and exposed to atmospheric bleaching at room temperature, and the petri dish was examined at 3% on the first day and every 8 hours thereafter. When this experiment was repeated, keeping the solid mixture of choline salicylate, magnesium salicylate and carboxymethylcellulose in an open petroleum dish for 3 days under atmospheric weight gain was 4.2%.

The ability of the solid collinlsallylate complexes prepared in Examples 1-8 above to be kept solid was evaluated by maintaining a 2 g sample of each mixture in a tared glass dish under various humidity conditions up to $ 97 relative humidity at 37 ° C. At regular intervals, samples were examined and their physical condition was recorded.

The 49.3 ° melting keel salicylate prepared according to U.S. Patent 3,069,321 became liquid in 2 minutes at all relative humidities studied.

The magnesium choline solysylate prepared according to U.S. Patent No. 3,759,980 became liquid after 32 hours in an atmosphere of 60% relative humidity at 37 ° C, after 20 hours in an atmosphere of $ 80 relative humidity at 37 ° C, and after 18 hours. In an atmosphere of 90% relative humidity at 37 ° C.

The magnesium carboxymethylcellulose-choline salicylate prepared in Example 6 remained solid after seven days at 90% relative humidity at 37 ° C, but became liquid after seven days at 97% relative humidity at 37 ° C.

The aluminum carboxymethylcellulose column prepared in Example 5 was partially solid after exposure to 80% 10 ο O 7 7 0 relative humidity at 37 ° C for seven days and also after seven days exposure to an atmosphere of 90% relative humidity 37 ° C.

The kamin-carboxymethyl 1-outer compound prepared in Example 8! salicylate became liquid after exposure to an atmosphere of 60% relative humidity and higher relative humidities at 37 ° C for seven days.

A mole of a 1: 1, dried mixture of koilisnalisylast and magnestum salicylate became liquid at 60% relative humidity at 37 ° C in 30 hours, 80% relative humidity at 37 ° C in 2b hours, and 90% relative humidity at 20 ° C. per hour.

In Example 1, a complex of aluminosalicylate, choline salylate, and carboxymethylcellulose became liquid in about k days (* t, 3 days) at 80% relative humidity at 37 ° C and 3.3 days at 90% relative humidity at 37 ° C. :in.

Claims (1)

11,55770 Claim: A process for the preparation of a therapeutically useful, stable, non-hygroscopic choline alkaliylate, carboxy (alemplal alkyl) cellulose and metal compound complex, characterized in that the choline salicylate, "carboxyethyl" or carboxypropylcellulose and a physiologically acceptable compound of aluminum, bismuth, calcumum or magnesium are complexed in the presence of water in a molar ratio of about 1: 3, and the complex is obtained, and the complex is dried and dried. based on about 2.5 to 25% by weight of carboxy (lower alkyl) cellulose, about 10 to 95% by weight of chlorine isylate and about 2.5 to 35 weight percent metal 11 ions.