KR860000450B1 - Process for the preparation of alpha-6-deoxy-5-hydroxy tetra cycline and sodium tetrametaphosphate complexes - Google Patents

Abstract

A water-soluble complexes of α-6-deoxy-5-hydroxytetracycline (I) and Na tetrametaphosphate was prepd. from I. Thus, fleshly prepd. 4.33g of (HPO3)n (n=4) was treated with 1 ml of H2O and 20g of I H2O and later with 0.574g of NaOH in MeOH. After adding iso-PrOH, the growing cryst. compd. was filtered, washed, dried to give 21g of I and Na (HPO3)n (n=4) complexes. The major advantage of using this complexes is its decreased interference in the action in human serum of natural bactericides. The bioavailability of this complexes (4.32 μ g/ml/3h) was higher than that of I capsules.

Description

Method for preparing a water-soluble complex of α-6-deoxy-5-hydroxy tetracycline and sodium tetrametaphosphate

The present invention relates to a novel water soluble complex of α-6-decoxy-5-hydroxy tetracycline and sodium tetra metaphosphate and a process for solvating them with lower alcohols and water.

These new derivatives, the doxycycline tetramethaphosphate sodium complexes, show significant advantages in connection with doxycycline and known salts and complexes thereof, and human serum, one of the disadvantages of the tetracycline complex, which has long been known as an antibacterial agent. This is especially so when it comes to the incoherence of the natural bactericidal action of humanserum.

Some of the other benefits of the doxycycline tetramethaphosphate sodium complex include: bioavailability, widespread antibacterial spectrum, small doses, once daily, maintenance of blood and tissue levels for 24 hours or more, and alleviation of stomach side effects. In addition, the stability of the gastric fluid and the crystal form of the long-term stability.

Various tetracycline complexes with added salts and phosphoric acid are described in the literature.

US Pat. No. 2791609 describes tetracycline hexametaphosphate, a complex that causes low solubility and hypertension.

Similar, for example, doxycycline hexametaphosphate is poorly soluble in water and lacks clinical utility by causing hypotension.

US Patent No. 3053892 describes a method for preparing a complex of metaphosphoric acid and tetracycline at a ratio of 1-4 moles of HPO ₃ per mole of tetracycline.

US Patent No. 3068264 describes complexes of phosphoric acid with aluminum and tetracycline. These complexes dissolve at pH6.5-pH8.0 but practically do not dissolve at pH3-pH5.

The molar ratio between tetracycline and aluminum metaphosphate is 1: 4: 12 or 1: 4: 8.

The complexes mentioned above have not been clinically applied because aluminum interferes with tetracycline's antimicrobial activity and ViVo.

Portuguese Patent No. 54708 and an ancillary patent describe a method for preparing a polymethaphosphate complex of α-6-deoxy-5-hydroxy tetracycline as well as a method for preparing a new hexametaphosphate complex in anhydrous state.

While the technique of US Pat. No. 2791609 is reacted with a water soluble medium, other patents describe a process in which the complex is carried out using anhydrous medium.

The present invention describes the preparation of polymethaphosphate of alkali metals and the preparation of polymethaphosphate of α-6-decoxy-5-hydroxy tetracycline, wherein the degree of polymerization of metaphosphoric acid (HPO ₃ ) n is It is homogeneous in the complex and (HPO ₃ ) n is tetramer, ie n = 4. Polymethaphosphate composites and doxycycline of alkali metals are prepared using a strict anhydrous medium in accordance with the manufacturing process for Portuguese Patent No. 54708 and its related patents.

The present invention is completely different from that described in Portuguese Patent No. 54708 in that the process is to obtain a trimethaphosphate complex instead of a complex of hexametaphosphate and to proceed the reaction under conditions that strictly control a large amount of water instead of anhydrous medium.

·6H₂O인 솔베이트 형태로 침전된다.When the isolation proceeds with the addition of isopropanol, the new complex is formed by the molecular formula (C ₂₂ H ₂₄ N ₂ O ₃ ) ₃ · (HPO ₈ ) ₃ · NaPO ₃ ·

Precipitates in the form of a solution of 6H ₂ O.

Isolation of the above-mentioned precipitate with pure ethanol instead of isofuropanol results in crystallization of the new complex under ethanolate / hydrate form.

The amount of water in the reaction mixture should be at least 2 moles per 1 mole of doxycycline and should not be more than 4 moles. Metaphosphoric acid may be prepared by a known method, but before the composite is prepared. It is a preferred method to use stoichiometric amounts of water in an inert solvent such as phosphorus pentoxide and chloroform.

After the metaphosphoric acid is formed, it is diluted with the same amount of ethanol as the amount of the reaction mixture, and then water is added, followed by addition of monohydrate doxycycline.

3 moles of doxycycline monohydrate are added per 4 moles of metaphosphoric acid.

The rate of addition of doxycycline to the metaphosphoric acid solution should be controlled as in the method of maintaining the reaction mixture in the solution. Adding methanol in successive aliquots will eventually help complete the decomposition of doxycycline.

A methanol solution of sodium hydroxide is then added at a rate of 1 mole per 4 moles of metaphosphoric acid. The addition of isopropanol to the reaction compound results in crystallization of the tetramethaphosphate sodium complex, as isosorbate of isopropanol and water.

Tetramethaphosphate sodium complexes are absorbed very rapidly during oral administration, and serum concentrations are maintained above the lowest therapeutic effect level after 24 hours.

The following table summarizes the level of compliance after dosing 100 mg and 200 mg of doxycycline base to 12 healthy volunteers divided into two groups.

In the first group, one capsule containing the doxycycline tetraphosphate sodium complex and the excipient lactose was administered, and in the second group, two capsules of the complex were administered. Samples of blood were collected 0.1 / 2, 1, 2, 3, 4, 5, 6, 12, 24 hours after dosing. Serum concentrations were examined microbiologically.

These figures are much higher than those published in the literature on doxycycline or doxycycline complexes, and also show excellent biochemical utility.

However, the main advantage of the doxycycline tetramethaphosphate sodium complex according to the present invention compared to doxycycline and the prior art doxycycline derivative is that the interference with respect to the natural antibacterial action of human serum is significantly reduced. It is well known that tetracycline, especially doxycycline, is involved in the antimicrobial activity of serum in ViVo and Vitro (Forsgren, A. and Gnarpe, H .; Anrimicrobial Agents and Chemotherapy, 3,711-715 (1973)). Forsgren, A. and Gnarpe, H .: Nature New Biology, 244, 82-83 (1973).

The effect on the human serum bactericidal activity of the new complex, which is the object of the present invention, was compared with that of doxycycline hydrochloride.

The number of bacteria surviving in human serum for a period of time was investigated at the same time with an equivalent formulation comprising the same amount of doxycycline-based complex as the preparation of doxycycline hydrochloride.

The number of viable bacteria (E, Coli) in human serum was investigated with doxycycline hydrochloride (10 μg / ml) after incubation for 0-2 hours without the addition of antimicrobial agents and also with doxycycline tetramethaphosphate sodium complex (10 μg / ml). ) Were investigated.

After 2 hours of incubation, the number of bacteria that survived without the addition of antimicrobial agents was reduced from 2 × 10 ⁶ to 5.5 × 10 ³ , while the number of remaining bacteria in the experiments with doxycycline was 5 × 10 ^5- and doxycycline When tetramethaphosphate complex was used, it was 2.5 * 10 <^3> .

While the doxycycline tetramethaphosphate sodium compound does not interfere in the same two hours, it is fundamentally important that the doxycycline molecule is highly resistant to antimicrobial activity in serum.

In other words, the fact that the antimicrobial action of the serum can be fully functioned, the treatment period can be shortened, thereby minimizing the possibility of forming a hypoglycemic lineage in ViVo.

Isopropanol / water sorbate and ethanol / water sorbate exhibit the same microbiological and pharmaceutical activity and remain stable at room temperature.

EXAMPLE

(1) 100 ml of chloroform was added to 4.33 g of a metaphosphoric acid, which was newly prepared from phosphorus pentoxide, and then 100 ml of methanol was added with stirring. After stirring for about 15 minutes, 1 ml of water and 20 g of α-6-deoxyc-5-hydroxy tetracycline monohydrate (961mcg / mg) were added to keep the solution transparent.

The solution was filtered and 0.574 g sodium hydroxide was dissolved in 17.5 ml methanol. After stirring for 15 minutes, 430 ml of isopropanol was added. The product, which crystallized in this way, was filtered off, washed with isopropanol and dried at 35-40 ° C.

·6H₂O인 생성물 21g을 얻었다.Molecular formula (C ₂₂ H ₂₄ N ₂ O ₈ ) ₃ · (HPO ₃ ) ₃ · NaPO ₃ ·

21 g of product, 6H ₂ O, were obtained.

238,266nm에서

307(1% HCl-메탄올 용액)UV absorption: at 349nm

At 238,266nm

307 (1% HCl-Methanol Solution)

Natural light rotation: /α/D32°-86°(C=0.5, 1% HCl-methanol solution)

PH of 1% aqueous solution: 2.8, Doxycycline quantitative analysis: 70.21%

Solubility in water: 335 mg / ml

(2) The isopropanol was changed to pure ethanol and the item (1) was repeated.

·6H₂O인 물과 에탄올의 솔베이트와 같은 새로운 복합체가 침전되었다.As a result, the molecular formula _{(C 22 H 24 N 2 O} 8) 3 · (HPO 3) 3 · NaPO 3 ·

A new complex was precipitated, such as a sorbate of 6H ₂ O water and ethanol.

Claims (4)

(Correction) The molar ratio of metaphosphoric acid and α-6-deoxy-5-hydroxy tetracycline monohydrate at room temperature with HPO ₃ and α-6-deoxy-5-hydroxy tetracycline monohydrate as 4: 3. A structural formula characterized by neutralizing HPO ₃ in one of the tetraphosphate complexes obtained by reaction in a medium consisting of chloroform, methanol and water with an aqueous NaOH-methanol solution and adding isopropanol to crystallize the complex (C ₂₂ H ₂₄ N _{2). O 8) 3 · (HPO 3} ) 3 · NaPO 3 ·

A method for preparing a water-soluble complex of α-6-deoxy-5-hydroxy tetracycline and sodium tetramethaphosphate represented by 6H ₂ O, wherein the polymer of metaphosphoric acid is n = 4 in the complex Uniform). (Correction) The method according to claim 1, wherein the polymetaphosphoric acid is prepared from a solution in which water is mixed in a stoichiometric ratio with phosphorus pentoxide and chloroform. (Correction) The method according to claim 1, wherein the polymethaphosphoric acid is reacted by diluting with methanol containing 2 to 4 moles of water per mole of α-6-deoxy-5-hydroxy tetracycline monohydrate. Way. (Correction) At room temperature, metaphosphoric acid and α-6-deoxy-5-hydroxytetracycline monohydrate were used in the molar ratio of HPO ₃ and α-6-deoxy-5-hydroxy tetracycline monohydrate as 4: 3. Structural formula (C ₂₂ H ₂₄ N ₂ O) characterized by neutralizing HPO ₃ of one of the tetramethaphosphate complexes obtained by reaction in a medium consisting of chloroform, methanol and water with an aqueous NaOH-methanol solution and crystallizing the complex with anhydrous ethanol. _{8) 3 · (HPO 3)} 3 · NaPO 3 ·

A method for producing a water-soluble complex of α-6-deoxy-5-hydroxy tetracycline and sodium tetramethaphosphate represented by sorbent of 6H ₂ O and sorbate of water.