FI57881C - FOER FARING FOR FRAMSTAELLNING AV EN STABILIZED DOXICYKLINLOESNING - Google Patents

Description

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LBJ (11) utlAggningsskrift 5 7881 C Patent granted on 10 11 1930

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Patani OCh r * gi «t * rttyr« lMn 'AnaOkan utltgd och utUkrtfwn publfcvnd 31.07.80 (32) (33) (31) Pyydetty atuoikw * —Begird priortu * 02.01.76 USA (us) 61 + 6295 (71) Pfizer Inc., 235 East l + 2nd Street, New York, NY , USA (US) (72) William Wellesley Armstrong, Mill Neck, New York, Saurabhkumar Jayavantray Desai, Groton, Conn., USA (US) (Jk) Oy Kolster Ab (51+) Method for preparing a stable doxycycline solution - Förfarande för framställning av en stable doxicyklinlösning (62) Divided by application 763716 (patent 56116) -Avdelad frän ansökan 763716 (patent 56II6)

The invention relates to a process for the preparation of a stable doxycycline solution suitable for pharmaceutical use. More specifically, the invention relates to a process for the preparation of aqueous solutions of doxycycline containing 2-pyrrolidone.

Previous attempts to prepare stable, concentrated solutions of tetracyclines have not been successful. Such solutions are particularly important in the case of injectable veterinary drug compositions for large animals.

Doxycycline is a widely used tetracycline antibiotic with high potency and long half-life. It is detailed in U.S. Patent No. 3,200 li + 9 under the chemical name O (-6-deoxy-5-oxotetracycline).

FI-A-52269 discloses aqueous injectable solutions of doxycycline containing from 1 to 10 parts by weight of doxycycline and about 3 to 8 moles of phosphoric acid, sodium or potassium orthophosphate, metaphosphate, tripolyphosphate, pyrophosphate, per mole of doxycycline. hexametaphone phosphate and about 3 to 8 moles of a pharmaceutically acceptable magnesium salt soluble in this pharmaceutical composition having a pH of about 1 to 3.5.

2 57881 FI Patent Publication No. hh395 discloses aqueous solutions of doxycycline containing about 1-5 # doxycycline and about 5-1 + 0 weight # polyvinylpyrrolidone having an average molecular weight of about 10 h00-60,000. The pH of the solutions is about 5-8.

The process according to the invention is characterized in that doxetracycline or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable magnesium compound soluble in the final solution, in a molar ratio of 1 mole of doxycycline / 1.8-2.2 moles of magnesium compound, are dissolved at elevated temperature, e.g. In C, as a chelate in aqueous 2-pyrrolidone, and the pH of the solution is adjusted, if necessary, to 3-7.5, and that 2-pyrrolidone is used in an amount of about 10 to 70% by weight, based on the weight of the whole composition, optionally further using 1-J by weight of # in the solution, based on the weight of the total composition, polyvinylpyrrolidone having an average molecular weight of about 5,000 to 100,000.

The preferred magnesium compound is magnesium oxide. Magnesium chloride, magnesium acetate and magnesium sulfate are also suitable for use.

Magnesium ions are known to form magnesium doxycycline chelates in solution with doxycycline.

2-Pyrrolidone is also referred to as 2-pyrrolidinone, 2-oxypyrrolidine, O'-pyrrolidone and 2-ketopyrrolidine. When administered orally, its LD50 is 8 g / kg in rats and 3.8 g / kg when injected intraperitoneally in mice. when used, the volume of the pharmaceutical preparation per dose is as low as possible and it makes the preparation easy to inject due to its low viscosity.

The pH of the solution may be adjusted with a pharmaceutically acceptable acid such as hydrochloric acid or an organic base such as monoethanolamine.

The polyvinylpyrrolidone optionally used in the solution preferably has an average molecular weight of about 10,000 to 17,000 (where the K value = 17). It acts as an additional solvent and allows the tissues to tolerate the composition better.

Compositions containing doxycycline are preferably prepared by mixing the magnesium compound with 2-pyrrolidone and water at about 50 ° C and slowly adding the doxycycline antibiotic with stirring until dissolved. The pH is then adjusted to the desired range. If polyvinylpyrrolidone is to be used, it is added to 2-pyrrolidone and water before adding the magnesium compound as described above.

The solutions prepared in accordance with the present invention generally contain doxycycline in the form of about 1 to 25% by weight of the total weight free base or pharmaceutically acceptable acid addition salt. The preferred concentration is 5-20 wt.% And the particularly preferred 10-20 wt.

Suitable acid addition salts of doxycycline include e.g.

3 57881 Pharmaceutically acceptable acid addition salts such as hydrochloride, hydrobranide and sulfate. However, the most preferred acid addition salt is doxycycline hydrochloride, e.g. doxycycline hyclate, which is doxycycline hydrochloride hemiethanolate hemihydrate.

These doxycycline compositions are easily injectable over a wide temperature range, are well tolerated, rapidly obtain therapeutic blood levels, and have good physical and chemical stability, i. the solutions remain clear and their doxycycline content is almost constant even during fractional storage times.

By using these high potency doxycycline compositions, the number of injections to be given to large animals, such as bulls, can be reduced while still obtaining an adequate dosage.

These doxycycline compositions are primarily administered parenterally, but may also be administered topically or orally.

The following examples illustrate the invention.

* 57881

Example 1

A solution containing 100 mg / ml doxycycline was prepared.

g / 100 ml

Doxycycline (effective amount 930 μg / mg + 5% excess) 11.29

Magnesium oxide 1,921 2-pyrrolidone 50.00

Sodium formaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 7.2

Water to 100 ml 2-pyrrolidone was mixed with water. The solution was heated to about 50 ° C and sodium formaldehyde sulfoxylate was added, which was dissolved with stirring. The magnesium oxide was then slurried in solution. Doxycycline was then added slowly with stirring and the pH of the solution was adjusted with concentrated hydrochloric acid. The solution was allowed to cool to room temperature and the pH was further adjusted to 7.3 with concentrated hydrochloric acid. The solution was then diluted to volume with water.

Solutions comparable to the above were also prepared by adjusting the pH to 5.0 and 6.5, respectively.

Example 2

A solution containing 100 mg / ml doxycycline was prepared by the method described in Example 1.

g / 100 ml

Doxycycline (effective amount 930 μg / mg + 5% excess) 11.29

Magnesium oxide 1,921 2-pyrrolidone 40.00

Sodium formaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 7.2 Water per 100 ml

A solution comparable to the above was also prepared by adjusting the pH to 5.2.

Example 3

A solution containing 200 mg / ml doxycycline was prepared by the method described in Example 1.

5 57881 g / 100 ml

Doxycycline (effective amount 930 μg / μg + 5% excess) 22.58

Magnesium oxide 3,828 2-pyrrolidone 50.00

Sodium formaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 7.2 Water to 100 ml

A solution comparable to the above was also prepared by adjusting the pH to 5.2.

Example * 4

A solution containing 200 mg / ml doxycycline was prepared by the method described in Example 1.

g / 100 ml

Doxycycline (effective amount 930 μg / mg + 5% excess) 22.58

Magnesium oxide 3,828 2-pyrrolidone 40.00

Sodium formaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 7.0 Water to 100 ml

Example 5

A solution containing 200 mg / ml doxycycline was prepared by the method described in Example 1.

g / 100 ml

Doxycycline (effective amount 930 μg / mg + 5% excess) 22.58

Magnesium oxide 3,828 2-pyrrolidone 30.00

Sodium formaldehyde sulfoxylate 1.00

Polyvinylpyrrolidone, K-17 5.00 Concentrated hydrochloric acid to adjust the pH to 5.8 Water to 100 ml 57881

Example 6

A solution containing 200 mg / ml doxycycline was prepared.

g / 100 ml

Doxycycline (effective amount 930 μg / mg + 5% excess) 22.58

Magnesium oxide 3,828 2-pyrrolidone 40.00

Sodium formaldehyde sulfoxylate 1.00

Polyvinylpyrrolidone, K-17 5.00 Concentrated hydrochloric acid to adjust the pH to 6.6 Water to 100 ml 2-pyrrolidone was mixed with water. Polyvinylpyrrolidone was then added and stirred until dissolved. The procedure described in Example 1 was then followed.

A solution comparable to the above was prepared using 30 g of 2-pyrrolidone instead of 40 g.

Example 7

A solution containing 100 mg / ml doxycycline was prepared by the method described in Example 1.

g / 100 ml

Doxycline (effective amount 930 μg / mg + 5% excess) 12,353

Magnesium oxide 2.02 2-pyrrolidone 60.00

Sodium formaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 7.2 Water to 100 ml

Solutions comparable to the above were also prepared by adjusting the pH to 6.5 and 5.0, respectively.

Example 8

A solution containing 100 mg / ml doxycycline was prepared by the method described in Example 1.

7 57881 g / 100 ml

Doxycycline (effective amount 930 μg / mg + 5 excess) 11.29

Msignium oxide 0.059

Sodium formaldehyde sulphoxylate 1.00 2-pyrrolidone 70.00 Concentrated hydrochloric acid to adjust the pH to 7.2 Water to 100 ml

Example 9

A solution containing 10 mg / ml doxycycline was prepared by the method described in Example 1.

g / 100 ml

Doxycycline (effective amount 930 yUg / mg + excess # 5) 1.129

Magnesium oxide 0.206 2-pyrrolidone 10.00

Sodium umformaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 6.7 Water to 100 ml

A solution comparable to the above was also prepared by adjusting the pH to 5 · Examples 10-18

Each of Examples 1-9 was repeated using the same ingredients in the same proportions, but heating the solution to about 75 ° C. In each case, the same result was obtained as in the corresponding Example 1-9 *

Claims (2)

5,788 1 A process for preparing a stable aqueous solution containing 1 to 25% by weight of doxycycline, characterized in that doxetracycline or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable magnesium compound soluble in the final solution are present in a molar ratio of 1 mole of doxycycline to 8 moles. the magnesium compound is dissolved at elevated temperature, e.g. 50-75 ° C, as a chelate in aqueous 2-pyrrolidone, and the pH of the solution is adjusted, if necessary, to 3-7.5 and that 2-pyrrolidone is used in an amount of about 10-70% by weight. based on the weight of the entire composition, optionally using in addition 1 to 7% by weight of # of the total composition based on polyvinylpyrrolidone having an average molecular weight of about 5,000 to 100,000. Process according to Claim 1, characterized in that the magnesium compound is magnesium oxide.