FI59789B - FOERFARANDE FOER FRAMSTAELLNING AV ETANOL-VATTEN-SOLVATER AV ALKALIPOLYFOSFATKOMPLEX AV ALFA-6-DESOXY-5-HYDROXITETRACYKLIN - Google Patents

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lJ '' UTLAGG N I NGSSKRI FT 07/0 ^ ^ ^ (51) Kv.lk?/ln July-CI.3 C 07 G Ί 03/19 FINLAND | F! N LAN D (21) P »t« nttlh * k «mu * - Ptt« nt * n * öknlng 1919/7 ^ (22) H »k« mi * cloud - Ans6knlngsdag 24.06.7 ^ (23) AlkupUvt — Glltlghuttdag 24.06.74 (41) Tullut kiikikuksi - Bllvlt offuntllg 31.12.74 _ 1 (44) Date of departure from the date of issue. - ^ o.

Patent and registration law Antöktn utlagd och utUkrtftun publictnd 30.06. oi (32) (33) (31) Caught in curiosity — Bugird prloritet 30.o6.73

Portugal (PT) 54708 (71) (72) Ivan Villax, 3, Travessa do Ferreiro, Lisbon, Portugal (PT) (7U) Ruska & Co (54) Method <Ethanol of alkali polyphosphate complexes of K-6-deoxy-5-hydroxytetracycline This invention relates to a process for the preparation of α-6-deoxy-5-hydroxytetracycline, an aqueous metal polymethaphenaphthene polymethaphosphaphenate, and to a process for the preparation of α-6-deoxy-5-hydroxytetracycline. to prepare solvates of the general formula zi.

(ΜθΡ0 ^) χ, (HP0 ^) y, where Me is sodium or potassium, x, y and z are integers from 1 to 5, x + y $ 6 andz $ y, which solvates have high stability and solubility in water At 20 ° C it is above 4.5 mg / ml, whereby 6 molar equivalents of metaphosphoric acid in an inactive organic solvent are reacted with 1-5 molar equivalents of α-6-deoxy-5-hydroxytetracycline and then the remaining unreacted free metaphosphoric acid groups are neutralized. in whole or in part with a stoichiometrically equivalent amount of sodium or potassium hydroxide solution in methanol or ethanol.

Finnish Patent No. 5,799 describes the preparation of doxycycline alkali metal lipolymetaphosphate complexes from doxycycline. According to the present invention, improved products - ethanol-water solvates - are prepared by precipitating the ethanol-water complex of the complex thus formed by adding 95% ethanol or an inactive non-solvent containing 95% ethanol.

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To prepare doxycycline polymetaphosphate complexes, doxycycline base is preferably used which is reacted with metaphosphoric acid in an inactive organic solvent such as methanol, ethanol, ethyl acetate, dimethylformamide and dichloromethane, dichloromethane and minorimine, chloroform or mixtures thereof, is added as a solution in methanol or ethanol. When the formation of the complex is completed, the ethanol-water solvate of the complex is precipitated with a non-solvent in the form of ethanol, optionally mixed with isopropanol or, preferably, ethyl ether, isopropyl ether and / or hexane, and filtered.

The ethanol-water solvate thus formed retains its biological activity described in Experiment 3 for more than 3 years without any noticeable decrease when stored at room temperature, while the known doxycycline alkali metal polymetaphosphoric acid complex decomposes 3-3.5% in 3 years at room temperature. The present solvate thus has the advantage that it is more stable than the corresponding non-solvated complex and is also well crystallized.

The polymeric nature of metaphosphoric acid (ΗΡΟ ^) η is known and its degree of polymerization varies. The production process according to the invention offers the advantage over the process according to Finnish patent no. 5-799 that the degree of polymerization of the prepared complex does not vary, but a substantially homogeneous, homogeneous complex is prepared which can be metered accurately.

To prepare the complex, 6 moles of metaphosphoric acid (corresponding to 1 mole of (HPO-j) n, where n = 6) are reacted with 1-5 moles of doxycycline, neutralized with the desired amount of methanolic NaOH or KOH, and the solvate is precipitated with 95% ethanol. , optionally mixed with another non-solvent.

Metaphosphoric acid is preferably prepared immediately before use. Preferably, it can be prepared by dehydrating orthophosphoric acid or by reacting phosphorus pentoxide with an equimolar amount of water in an inactive organic medium, as listed above.

The empirical, analytically confirmed formula of the claim for a complex without a solvating agent, when Me is Ma, y and z = 5 and x = 1, is similar to the hexamethane-3,59789 taffosphate sodium complex of doxycycline prepared by the method of U.S. Patent 2,791,6Q. However, the two complexes differ in that the polyphosphate complex now treated, both solvated and unsolvated, is many times more soluble in water than the known hexametaphosphate sodium complex. In addition, the infrared absorption curves of these two complex groups, i.e. doxycycline sodium hexametaphosphate complex and alkali metal polyphosphate complexes, both unsolvated and solvated, show differences in the ranges of 7.9 to 8.1 μ and 9.2 to 9.8 μ, indicating that the complex

The differences between the two complex groups in terms of solubility and infrared curves indicate that there is a substantial difference in the intramolecular structure, so it can be concluded that the complex formation mechanism and the doxycycline groups involved in this complex formation are not identical in the two complex species. ,

For comparison and differentiation, both metaphosphoric acid complexes and acid addition salts of doxycycline were prepared in various molar ratios according to U.S. Patents 3,053,892 and 3,200,149. In addition, for differentiation, double salts with metaphosphoric acid as the cation with doxycycline and sodium as anions were prepared as described in Experiment 1. All of these complexes and acid addition salts had significantly lower solubility in water than the solvates of the alkali metal polymetaphosphate complexes in question, and the blood values obtained after ingestion were quantitatively and shorter in duration than those obtained with the solvates in question. All attempts to convert doxycycline metaphosphoric acid addition salts to alkali metal-polymetaphosphate complexes by treatment with aqueous sodium or potassium hydroxide were unsuccessful.

All blood values obtained after oral administration of simple mixtures of doxycycline hyclate and sodium hexametaphosphate and doxycycline base monohydrate and sodium hexametaphosphate were significantly lower than after oral administration of doxycycline hyclate. Thus, hexametaphosphate sodium does not improve the absorption of doxycycline when co-administered.

The ethanol-water solvates of the sodium or potassium polymetaphosphate complexes of doxycycline disclosed in this specification have a preferred acute tin. and chronic toxicity that can be compared to the doxis / k-4,59789 line and are pharmaceutically acceptable. The method of this invention represents a significant advance in improving the activity and clinical utility of doxycycline by increasing blood values when doxycycline is used as an ethanol-water solvate of alkali metal polymetaphosphate complexes. The main therapeutic advantage of the solvates of the alkali metal polymethaphosphate complexes in question is that the functional groups of doxycycline involved in the chelation of Ca ++ and Mg ++ ions are blocked in solvates. ethanol-water solvates of complexes.

The production method according to the invention is described in more detail below by means of some examples. These are followed by some experiments which, on the one hand, illustrate the preparation of certain double salts and the fact that solvates do not chelate with calcium and magnesium ions and, on the other hand, illuminate serum concentrations of doxycycline after administration of solvates compared to serum doxycyclic concentrations.

Example 1 65 ml of methanol was added to 26 ml of chloroform containing 2.07 g of freshly prepared metaphosphoric acid and stirred for 30 minutes. 10 g of doxycycline base monohydrate were then gradually added to a homogeneous solution of metaphosphoric acid. Stirring was therefore continued until a clear solution was obtained, after which 172 mg of sodium hydroxide dissolved in 4.7 ml of methanol was added, which initiated the precipitation of the complex. After stirring for 15 minutes, 175 ml of 95% ethanol were added. The small amounts of precipitate formed were redissolved and the mixture was slowly cooled in an ice-water bath.

After 3 hours, a crystalline suspension formed, which was then filtered and dried at 40 ° C to give 8.3 g of a doxycycline polyphosphate monosodium complex of the formula (C 22 H 24 N 2 O 8 · 5 'NaPO 4 · (HPO 2) 2) as a solvate with ethanol-water.

β 59789 5

Melting point 18-15 ° C. 1 g dissolved in 3 ml of water. = 302 at 268 mu. Optical rotation H D - -85 ° (c = 1 in methanol containing 1% concentrated hydrochloric acid). The water content is 4% (determined according to the Karl Fisher method).

Example 2 250 ml of methanol was added to 250 ml of chloroform containing 20 g of metaphosphoric acid with stirring at room temperature, followed by the addition of 74.14 g of anhydrous doxycycline base (analytical sample 998.8 mg / g), 375 ml of methanol and 3.32 g of sodium hydroxide. dissolved in 45 ml of methanol. After stirring for 15 minutes, 1600 ml of 95% ethanol was added to complete the precipitation. The precipitate was then filtered, washed with ethanol and dried at 40 ° C to give 68.7 g of the doxycycline polyphosphate disodium complex of formula (*) (NaPO 4) 2 · (HPO 2) 2 as an ethanol-water solvate at 262 at 268. my and at 242 349 my.

Example 3 To 4.74 g of freshly prepared metaphosphoric acid in 100 ml of chloroform was added with stirring 100 ml of methanol and stirring was continued for another 15 minutes. 50 ml of methanol were then added, followed by the gradual addition of 2.2 g of doxycycline base (992 mg / g). The resulting clear solution was maintained at a temperature not exceeding 35 ° C. After stirring in one turret, 0.56 g of potassium hydroxide dissolved in 6 ml of methanol was added and then stirred for a further 15 minutes. The product then precipitated on the addition of 400 ml of 95/5 ethanol, and after 10 minutes 100 ml of ethyl ether were added. After one hour, the product was filtered off and dried, yielding 19.1 g of a doxycycline polymetaphosphate monopotassium complex of the formula (C22H24N2O8 ^ 5 'KPO3 * (HPO4) ^) in the form of its ethanol-water solvate, m.p.

1 g was dissolved in 2.8 ml of water or 1.9 ml of 0.6- $ hydrochloric acid.

E ^ ^ = 294 for 268 my and 231 for 349 my (in methanol containing 1% concentrated hydrochloric acid.

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Test 1

For differentiation purposes, double salt metaphosphoric acid was prepared as a cation and doxycycline and sodium as an anion. The following experiment was performed: 1.84 g of phosphorus pentoxide was weighed in 25.9 ml of chloroform to avoid prolonged contact with air in a dry room, and 0.24 ml of water was added and the mixture was stirred overnight. The chloroform was removed by distillation in vacuo, and the metaphosphoric acid thus prepared was dissolved in 30 ml of water, to which 10 g of doxycycline base monohydrate suspended in 40 ml of water was added with stirring. After one minute, it dissolved and 172 mg of sodium hydroxide dissolved in 5 ml of water was added to the clear solution with stirring. The resulting clear solution was immediately frozen in a mixture of acetone and dry ice and lyophilized. Melting point 199-202 ° C; [cx] n = -95 ° (c = 1 in methanol containing 1% concentrated hydrochloric acid); EiCm = 268 mp at 312 and 349 mp at 240 in methanol containing 1% concentrated hydrochloric acid.

100 mg of the product obtained was dissolved in 3 ml of water, from which a compound which was not identical to doxycycline hexametaphosphate or doxycycline polyphosphate monosodium complex slowly began to precipitate.

Test 2

To demonstrate that the ethanol-water solvate of the doxycycline polyphosphate monosodium complex binds to a lesser extent to calcium phosphate than doxycycline, the following experiment was performed: to 20 ml of 1/100 molar aqueous solution of doxycycline hyclate as pH 6 and 6 ml of N / 5 sodium was 7.1. After 4 hours, the solution was still clear, and then 0.5 g of calcium phosphate was added to 29 ml of the above solution, and the solution was stirred for one hour. After this time, the pH was 8.1. The mixture was then filtered and the doxycycline content of the filtrate was determined by ultraviolet absorption at 350 sec.

In the same manner, the same experiment was performed with 20 ml of an aqueous solution of the ethanol-water solvate of the doxycycline polyphosphate monosodium complex obtained in Example 1 at a concentration of 6.3 g / l. The initial pH was 7.2 and the final pH was 7.95 · The results were as follows: 7,59789

Doxycycline content of the filtrate _mg_

Doxycycline hyclate 271.2

Doxycycline polyphosphate monosodium complex, ethanol-water 1184 solvate

It is noted that the binding of the ethanol-water solvate of the doxycycline polyphosphate monosodium complex to calcium phosphate is less than 1/4 of the binding of doxycycline in the vicinity of neutral pH.

Test 3

Gelatin capsules containing ethanol-water solvate of the polyphosphate monosodium complex of doxycycline prepared according to Example 1 (DMSC-EVS) corresponding to 100 mg of doxycycline were prepared, and capsules containing 100 mg of doxycycline dicycline (DCH) were prepared.

A dose of two capsules was administered to 11 healthy male volunteers in a controlled study to determine the serum values of the ethanol-water solvate complex compared to the serum values of doxycycline hyclate.

Blood tests were taken at 0, 2, 5, and 24 hours after administration of 2 x 100 mg capsules. Serum values were determined microbiologically in triplicate.

Table I shows the results obtained. Administration of the ethanol-water solvate of the polyphosphate monosodium complex of doxycycline gave, on average, almost 50% higher serum values than those obtained after administration of doxycycline hyclate.

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