DK152118B - METHOD FOR PREPARING ALKALIMETAL POLYMETAPHOSPHATE COMPLEXES OF ALFA-6-DESOXY-5-HYDROXYTETRACYCLINE - Google Patents

Description

DK 152118B

The present invention relates to a process for the preparation of novel alkali metal polymetaphosphate complexes of α-6-deoxy-5-hydroxytetracycline (also called 6-epi-6-deoxy-5-hydroxy-tetracycline or doxycycline) having a solubility in water above 4, 5 mg / ml and the general formula (C22H24N2 ° 8 ^ z '(MePO3) x ^ HPO3) y / where Me is sodium or potassium and x, y and z are integers with values from 1 to 5, with x + y- 6'ogz-yl. The process of the invention is characterized by reacting α-6-dexoxy-5-hydroxytetracycline in an inert anhydrous organic medium with a sodium or potassium polymetaphosphate containing at least one free acid group, α-6-Dexoxy-5-hydroxytetracycline, also called doxycycline. , has a broad antibiotic spectrum with a long lasting effect also at 2

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oral administration and is today one of the best antibiotics in the tetracycline group.

Metal metaphosphate complexes of tetracycline are described in U.S. Patent No. 2,791,609 and metaphosphoric acid complexes of various tetra-cyclins in U.S. Patent 3,053,892. However, these writings deal with the preparation of "natural" tetracyclines having the methyl group at the C6 position in β configuration. Since doxycycline is a semi-synthetic antibiotic and different from the "natural" tetracyclines / ie. those produced by fermentation, having the methyl group at the C6 position in the unnatural α configuration, one could not expect to form hexametaphosphate complexes in analogy with the "natural" tetracyclines or that the pharmacological activity would be enhanced. at such eventual complexes. U.S. Patent No. 3,200,149 relates, inter alia, to doxycycline and acid addition salts and salts thereof. The "natural" tetracycline, which is chemically closest to doxycycline is oxytetracycline, which is approx. three times more soluble in 95% ethanol than doxycycline; doxycycline is eliminated three times as slowly from the organism as oxytetracycline.

The sodium hexametaphosphate complex of tetracycline described in U.S. Patent No. 2,791,609, in comparison with tetracycline, has decreased water solubility (3.2 mg / ml) and is more efficiently absorbed in the organism, thereby providing higher concentrations of the active substance in the blood. It has been found that by reacting sodium hexametaphosphate with doxycycline in aqueous medium according to the method of U.S. Patent No. 2,791,609, the sodium hexa-metaphosphate complex of doxycycline is precipitated. This complex is characterized by very low solubility in water, namely 0.6-0.8 mg / ml. Furthermore, the pharmacological properties of this complex are quite different from those of the tetracycline complex. Thus, the concentration of the active substance in the blood is significantly lower after administration of this complex than of the tetracycline complex, and in some patients no concentration of the active substance in the blood was detected, although its in vitro antibiotic activity was equivalent to its doxycycline content, confirming that there is no conspicuous chemical analogy between α-6-deoxy-5-hydroxytetracycline and the "natural" tetracyclines. Reaction of free hexametaphosphoric acid with α-6-deoxy-5-hydroxy-tetracycline in an inert organic medium according to U.S. Patent 3,053,892 provides the corresponding acid complex having higher solubility in water.

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3

The sodium and potassium polymetaphosphate complexes of doxycycline produced by the process of the present invention, which will also be referred to hereinafter as the polyphosphate complexes, have a solubility much higher than that of the sodium hexametaphosphate complex. doxycycline under anhydrous conditions with sodium or potassium salts of metaphosphoric acid having at least one free acid function (while known sodium hexametaphosphate can tetracycline complexes according to U.S. Patent No. 2,791,609 are prepared by reaction of the two components in the presence of water), then the novel metal metaphosphate complexes with a solubility in water greater than 4.5 and up to approx. 300 mg / ml and with the ability to produce significantly higher and longer lasting concentrations in the blood than is possible with metaphosphoric acid complexes.

The known doxycycline-sodium hexametaphosphate complex has a solubility in water of approx. 0.8 mg / ml giving lower blood concentrations than doxycycline hyclate or base.

In order to prepare the polyphosphate complex, the invention may conveniently proceed as set forth in claim 2, thereby providing a simple and effective operation and assurance that the phosphoric acid and alkali metal metaphosphate structure is as desired and has not undergone uncontrolled rearrangement.

The doxycycline can be used as a doxycycline base, acid addition salt with an organic or inorganic base, metal salt or chelate compound, amine salt or molecular complex with a quaternary ammonium compound or an amine or imino complex, especially as a base, hydrochloride or hyclate (hydrochloride hemihydrate ethanate).

For the preparation of the polyphosphate complexes, dimethylformamide, ethyl acetate, methanol, ethanol, dichloromethane, chloroform or mixtures thereof can be used as inert anhydrous medium. After formation of the complex compound, the polyphosphate complex is precipitated with a non-solvent, e.g., isopropyl alcohol, ethyl ether, isopropyl ether, hexane or a mixture thereof. Of course, the isolation may be carried out in other ways, for example, by evaporation of the solvent in vacuo, optionally followed by treatment of the residue with a non-solvent to obtain crystallization. The residue may also be stirred in water to obtain a solution / suspension which is then lyophilized.

Preparation of metaphosphoric acid may be effected by dehydration of orthophosphoric acid or by reaction of phosphorus pentoxide with an exact 4

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The initial empirical formula for the complex, when Me is sodium, y and z are 5 and x is 1, is identical to the empirical formula for the aforementioned and disclosed sodium hexametaphosphate of tetracycline in U.S. Patent No. 2,791,609. However, these two compounds are different in that the polyphosphate complex prepared by the present process is many times more soluble than the sodium hexametaphosphate complex. In addition, the infrared curve of the former has a single maximum at 8.07µ, while the latter has a double maximum in the range of 7.9 · μ-8.06µ. The former compound also has two completely spaced maxima at 9.3µ and 9.6µ, while the latter has a large twin maximum at 9.45µ and 9.6µ, which shows that the complexation takes place in different ways.

The differences in solubility and infrared curves of these two complex compounds are caused by the intramolecular structures being substantially different, and it can be concluded that the mechanism of complex formation as well as the functional groups of tetracycline and doxycycline involved in this complex formation are not identical in the two kinds of complexes.

For comparison purposes, metaphosphoric acid complexes and acid addition salts of doxycycline in various molar ratios have been prepared in accordance with U.S. Patent Nos. 3,053,892 and 3,200,149. These complexes of acid addition salts had lower solubility in water and gave lower and shorter lasting blood concentrations of the active substance than the complexes prepared by the process of the present invention. These comparisons have been explained in some comparative examples.

All attempts to convert (the known) metaphosphoric acid addition salts of doxycycline to alkali metal complexes by treatment with aqueous sodium or potassium hydroxide failed.

The concentrations of active substance in the blood obtained after oral administration of simple mixtures of doxycycline hyclate and sodium hexametaphosphate, as well as doxycycline base monohydrate and sodium hexametaphosphate, were significantly lower than the concentrations obtained after administration of doxycycline hyclate. Thus, the sodium hexametaphosphate salt does not improve the absorption of doxycycline by concomitant administration.

The toxicity of the complexes produced by the process of the invention is comparable to the acute and chronic 5

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toxicity of doxycycline and is pharmaceutically acceptable. Therefore, the present complexes are of pharmacological significance by providing higher concentrations of the active substance in the blood than obtained with doxycycline. Yet another advantage of these complexes is that they are more palatable than the doxycycline hydrochloride or hyclate and form stable or easily stabilizable solutions and / or suspensions. Finally, the side effects caused by doxycycline, especially the reaction in the stomach, are significantly reduced when administered as the present complexes. In particular, there is a significant decrease in the incidence of photosensitivity, a side effect that occurs with a certain frequency after administration of doxycycline as the hypclate or base.

The process according to the invention will now be described in more detail by some examples. After them there are some comparative examples as well as an account of the concentrations of active substance in the blood which are obtained partly by administration of the complexes prepared by the process according to the invention and other forms of doxycycline.

Example 1 0.5 g of sodium hydroxide dissolved in 10 ml of methanol is added to a solution containing 8 g of freshly prepared metaphosphoric acid in 20 ml of a mixture of methanol and chloroform 1: 1. After the momentarily formed precipitate dissolves, 23.1 g of doxycycline base (assay 961 µg / ml) is added in 100 ml of ethanol. After stirring for 1 hour, 350 ml of isopropyl alcohol are added to crystallize the desired sodium polyphosphate complex of doxycycline. Its composition is (C22H24N2 ° 8 ^ 3 ^ HPO3 ^ 5 * NaPO3 * Solubility in water 172 mg / ml, mp: 185-189 ° C. [Α] -85 (c = 1 in methanol containing 1% conc. The pH of a 1% aqueous suspension is 2.5 The infrared absorption curve of the mineral oil has the following main maxima: 3µ, 6.0µ , 6.19µ, 6.31µ, 6.49µ, 8.07µ, 8.65µ, 8.82µ, 9.45µ, 9.6µ, 9.9µ, 10.63µ, 11.8µ, 12.4µ and 14µ There is no maximum between 7.6 and 8µ The excess of doxycycline and metaphosphoric acid remains in solution in the form of the doxycycline-metaphosphoric acid complex.

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Example 2

Example 1 is repeated, adding 1 g of sodium hydroxide instead of 0.5 g to the solution of metaphosphoric acid. Mp: 187-194 ° c. λ max 267, 349 me. The pH of a 1% aqueous solution / suspension is 2.65. The composition of the product is (C22 H24N2 ° 8) 2 · (^ 3) 4- ^ 03, its solubility in water 193 mg / ml.

Example 3

Example 1 is repeated, adding 1.5 g of sodium hydroxide instead of 0.5 g to the solution of metaphosphoric acid. The desired complex thus obtained weighs 19.1 g. Mp: 172-182 C. E ^ cm 256 at 267/68 microns and 200 at 348/50 microns. The pH of a 1% aqueous suspension is 2.9. The composition of the complex is (C22H24N2 ° 8 ^ 3, (HPOg) ^ NaPOg, its solubility in water 210 mg / ml.

Example 4 250 ml of methanol are added under stirring at room temperature to 250 ml of chloroform containing 20 g of metaphosphoric acid, after which 92.67 g of anhydrous doxycycline base (analysis 998.8 µg / mg), 375 ml of methanol and 1.66 g of sodium hydroxide dissolved in 45 ml are added. ml of methanol.

After stirring for 15 minutes, 1600 ml of isopropyl alcohol are added to effect precipitation. The precipitate is filtered off, washed with isopropyl alcohol and dried to yield 86.8 g of sodium polyphosphate complex of doxycycline of formula (C22H2 ^ N2Og). NaPO4. (ΗΡΟ ^) Solubility in water at 20 ° C: 300 mg / ml. Mp. 184-188 ° C. E m: 327 at 268 nm and 254 at 349 nm (methanol containing 1% concentrated hydrochloric acid). Optical rotation [α] β = -100 ° C (c = 1 in methanol containing 1% concentrated hydrochloric acid) and [α] D = -55 ° (c = 1 in water). Water content by Karl-Fisher: 4.1. pH of a 1% aqueous solution: 2.9.

Gelatin capsules were prepared each containing 200 mg of both monosodium polyphosphate complex of doxycycline / as capsules containing 200 mg of disodium polyphosphate complex of doxycycline and as control capsules containing 200 mg of doxycycline hyclate.

The mean concentrations of active substance in the blood obtained with each of these three types of capsules in ten persons

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7 after administration of 1 capsule per day. person before breakfast is given in the table below.

Table 1

Mean serum concentration in µg / ml, expressed as 100% doxycycline

After hours 1/2 1 2 6 12 24

Monosodium polyphosphate doxycycline 1.3 2.4 3.1 2.9 2.0 1.1

Disodium Polyphosphate Complex of Doxycycline 1.20 2.30 3.30 3.00 2.10 1.10

Doxycycline Hyclate 0.8 1.5 2.3 2.4 1.6 0.7

Comparative Example A

For comparison, the sodium hexametaphosphate complex of doxycycline was prepared according to U.S. Patent No. 2,791,609.

2.31 g of sodium hexametaphosphate was dissolved in 23.1 ml of water, the pH was adjusted to 1.7 with concentrated hydrochloric acid and this solution was added dropwise with stirring at room temperature to a solution of 5.25 g of doxycycline hyclate in 52 ml of a mixture of equal parts water and ethanol. After the addition, the whole was stirred for an additional 1 hour. The precipitate thus formed was filtered off, washed with water and with 95% ethanol and then dried at 50 ° C. The resulting sodium hexametaphosphate complex of α-6-deoxy-5-hydroxytetracycline was decomposed at 210 ° C, after prior soaking, and the char was complete. at 220 ° C. E ^ = 296 at 268 nm and 234 at 349 nm. The content of humidity 7.6 according to Karl Fisher. [ct] D = “85 (c = 1 in methanol containing 1% concentrated hydrochloric acid). Solubility in water at 20 ° C was 0.65 mg / ml. The complex was poorly soluble in methanol and soluble in dimethylformamide. The pH value of a 1% aqueous solution was 3.6, the IR absorption curve had a main peak at 3.05µ, 6y, 6.2µ, 6.32µ, 7.9µ, 8.06µ, 8.63µ, 9.3µ, 9.6µ, 9.9µ, 10.65µ, 11.35µ and 12.1µ. After filtration, an additional portion of the mother liquor was crystallized with satisfactory properties, yielding 92.9%.

Gelatin capsules were prepared with this complex, each containing an amount equal to 200 mg of anhydrous doxycycline base. Such chancellors were cited as test subjects. while other persons

DK152118B

8 received capsules containing doxycycline hyclate in an amount equal to 200 mg of anhydrous doxycycline base. The administration was done before breakfast / and blood doxycycline concentration was determined at the values shown in the table below.

Table 2

Serum concentration in µg / ml, expressed in 100% doxycycline

After hours_1_4_8_24

Sodium doxycycline hexametaphosphate complex 0/33 0.64 0/5 0/2

Doxycycline Hyclate 1/10 2/2 1/6 0/6

That. It can be seen from the tables that this complex gives lower blood concentration than the complex or doxycycline hyclate prepared by the process of the invention.

Comparative Example B

For further comparison, metaphosphoric acid complexes of doxycycline were prepared in accordance with U.S. Patent 3,053,892. A. 23/1 g of doxycycline base in 65 ml of methanol was added to a solution of 4 g of metaphosphoric acid in 130 ml of a mixture of equal parts of chloroform and methanol. After one hour of stirring, precipitation was effected by the addition of isopropyl alcohol and 24.9 g of metaphosphoric acid complex of doxycycline (1: 1 mole) was obtained. Mp. 191-194 ° C with decomposition at 202 ° C. 327 at 267 nm and 251 at 349 nm (c = 1 in methanol containing 1% concentrated hydrochloric acid). The pH of a 1% aqueous suspension was 2/5. The solubility in water at 2 ° C was 7/7 mg / ml. The IR absorption curve for the suspension in mineral oil had the following main maxima: 3 / 08µ # δ / ΟΙµ, 6 / 2µ7 6 / 22µ7 8 / 06µ / 8725µ / 8 / 64µ7 8 / 88µ, 9 / 43µ7 9 / 6µ7 9 / 82µ / 10 / 62µ / 12 / 4µ and 14 / 8µ.

The composition of this complex was (C22H24N2 ° 8 '> HPO3 ^ n / where n = 1-4. The blood concentrations obtained after administration of this complex did not last as long as those obtained by administering it prepared by the process of the invention sodium polyphosphate complex of doxycycline.

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9 B. Metaphosphoric acid complex of doxycycline was prepared according to Example 1 of U.S. Patent 3,053,892.

Placed in a 500 ml round bottom flask with stirrer, condensation and thermometer, 7.1 g (0.05 mole) of P2 ° s were immediately covered with 100 ml of chloroform. To the mixture was added 0.9 ml (0.05 mole) of distilled water with stirring. Within a few minutes, a lower oil-like layer appeared. To this mixture was added 100 ml of methanol and with continued stirring, the oily layer in methanol disappeared to form a complete solution.

50 ml of methanol was added and then 22.2 g (0.05 mole) of doxycycline, neutral form was added portionwise with an additional 50 ml of methanol. A clear solution was maintained by the addition of the doxy cyclin. After addition of all doxycycline, the temperature of the reaction flask was 35 ° C.

One hour after the addition of doxycycline, the clear reaction solution was poured into 500 ml of chloroform. A yellow product was separated which was collected on a coarse sintered glass filter and dried at 40 ° C. The formed metaphosphoric acid complex of doxycycline weighed approx.

The solubility in water at 20 ° C was 2.23 mg / ml. Mp. 180-188 ° C

l9 * during decomposition. E 21 m 214 at 348-352 nm, 274 at 268-269 nm (in methanol containing 1% hydrochloric acid). [α] β = -80 ° (c = 1 in methanol containing 1% concentrated hydrochloric acid). Water content after Karl Fisher 3.1%.

1.3 g of this product was suspended in 4 ml of water and stirred with 2.5 ml of N NaOH. The product did not dissolve but formed a rubbery mass. The content of the above layer of doxycycline was 1.03 mg / ml after 1 hour. The mass was decomposed with isopropyl alcohol and crystallized to form doxycycline monohydrate base.

The last step was repeated but using 5 ml of N NaOH. Here again, a gummy product was formed and the content of the above layer was 7.05 mg / ml.

1.3 g of the doxycycline metaphosphoric acid complex obtained in the above manner were suspended in 4 ml of water and 2.5 ml of N KOH was added to give a rubbery product consisting of doxycycline base. The doxycycline content of the above layer was 19.4 mg / ml.

C. Section B was repeated only with the difference of the clear reaction 10

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instead of chloroform. Yield 1.46 g. Solubility in water at 20 ° C

2.74 mg / ml. Mp. 188-189 ° C (dec.). E m = 239 at 348-352 nm and 317 at 268-269 nm in (methanol containing 1% concentrated hydrochloric acid). [α] D = -85 ° (c = 1 in methanol containing 1% concentrated hydrochloric acid). Water content according to Karl Fisher 4.2%. The IR curve of the product was identical to the product of Example A, with the exception that the latter exhibited traces of chloroform through the strong maximum at ca. 13 µ.

D. 4.2 g of phosphorus pentoxide was covered with 100 ml of chloroform and 0.54 ml of water was added. After stirring for 2.5 hours, 100 ml of methanol was added and stirring was continued for a further 15 minutes. Then, 50 ml of methanol was added followed by portion addition of 23 g of doxycycline base (assay 961 µg / mg) and 50 ml of methanol; the temperature did not exceed 35 ° C during the addition and during this the solution was constantly clear. After one hour of stirring, 400 ml of isopropanol was added to precipitate the metaphosphoric acid complex of doxycycline (5 mole of C22H24N2 ° 8 ° 9 ° mole of HPO3®), and then filtered, washed with isopropanol and dried.

at 40 ° C. The complex weighed 22.4 g. Solubility in water at 20 ° C

o in% 5.15 mg / ml. Mp. 181-198 C (decomposition). E cm = 249 at 349-354 nm and 326 at 268-269 nm (methanol containing 1% concentrated hydrochloric acid). Water content according to Karl Fisher 4.1%.

To 2.7 g of this complex in 10 ml of water was added 1 ml of N sodium hydroxide to produce of the metaphosphoric acid complex the water-soluble sodium polymetaphosphate complex of doxycycline (C22H24N2 ° 8 ^ 5'NaP03 * ^ HP03 ^ 5 * Pr ° did not dissolve, however) After stirring for 24 hours, the gummy product formed crystallized during the night and its IR curve was identical to that of the doxycycline monohydrate base.

E. Section C was repeated with the addition of 18.4 g of doxycycline monohydrate base (961 µg / mg) instead of 23 g. The resulting metaphosphoric acid complex of doxycycline (4 moles C22H24N2 ° 8 and ® m ° 1 HPO) weighed 13 , 5 g. The solubility in water at 20 ° C. was 3.05 mg / ml.

Y o 1%

Mp. 190-195 C. E E cm 257 at 348-254 nm and 336 at 268 nm (methanol containing 1% concentrated hydrochloric acid). [α] β = "90 ° (c = 0.5 in methanol containing 1% concentrated hydrochloric acid). Water content after Karl Fisher: 4.03%.

11

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To 2.25 g of this complex in 10 ml of water was added 2 ml of N sodium hydroxide to prepare from this metaphosphoric acid complex the aqueous sodium polymetaphosphate complex of doxycycline ^ C22H24N2 ° 8 ^ 4 '^ NaP03 ^ 2 * 4 * the acid complex did not dissolve, however. after stirring for 24 hours. The insoluble material which crystallized during the night consisted essentially of doxy-cyclin monohydrate base.

Table 3 below shows some comparative properties of the alkali metal polymetaphosphate complexes of doxycycline and the complexes obtained by the known methods.

♦ -T. * · 12

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Claims (2)

A process for the preparation of alkali metal polymetaphosphate complexes of α-6-deoxy-5-hydroxytetracycline having a solubility in water above 4.5 mg / ml and the general formula (C22H24N2 ° 8 wherein Me is sodium or potassium and x, y and z are integers having values from 1 to 5, wherein x + y - 6 and z - y, characterized in that α-6-deoxy-5-hydroxytetracycline is reacted in an inert anhydrous organic medium having a sodium or potassium polymetaphosphate containing at least one free acid group. Process according to claim 1, characterized in that the sodium or potassium polymetaphosphate is prepared by partially neutralizing t metaphosphoric acid with 1-5 moles of sodium or potassium hydroxide per liter. and adding α-6-deoxy-5-hydroxytetracycline to the sodium or potassium metaphosphate solution thus obtained, and the complex thus formed is precipitated by the addition of an inert non-solvent.