FI57882B - FRAME STEERING FOR STABLE TETRACYKLINLOESNING - Google Patents

Description

ΓβΙ / ^ ANNOUNCEMENT γγιοολ LBJ (") utläggninosskrift 5/882 C Patent granted on 10 11 1930 (45)

Patent Med ^ 0 (51) K ».ik? /Inc.a3 A 61 K 31/65

FINLAND — FINLAND (21) p »» «tihrt ^ -iweMeta« ta * 79026U

(22) HaJcamlaplM — Aiw0knlngid «| 26.01.79 (23) AltopUvft — GlMghmdai 28.12.76 (41) Tiriiut fulklMkai - * llvH efftntllg 26.01.79

Date of filing of the Patent Office (44) NihtivUcsipvton j »kimL]. -

Paten ^ och ragistantyralaan An * 6k »n υάφ) och utiakrffun pubucvrad 31.07.80 (32) (33) (31) Requested« tuolkin - »H« rd prtartaM 02.01.7 6 USA (US) 61 * 6295 (71) Pfizer Inc., 235 East * + 2nd Street, New York, NY, USA (72) William Wellesley Armstrong, Mill Neck, New York, Saurabhkumar Jay-avantray Desai, Groton, Conn., USA (7 *) 0 Oy Kolster Ab (5 * +) Method for preparing a stable tetracycline solution - Förfarande för fraznställning av en stable tetracyclinlösning (62) Separated from application 763716 (patent 56116) -Avdelad frän trap 763716 (patent 56116)

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

Previous attempts to prepare stable, concentrated solutions of these tetracycline-type compounds have failed. Such solutions are particularly important in the case of injectable veterinary drug compositions for large animals.

Tetracycline is a widely used tetracycline antibiotic. It is described in detail in U.S. Patent No. 2,699,05 * + · 57882 U.S. Patent No. 3,010,717 discloses aqueous solutions for the parenteral administration of calcium complexes of tetracycline containing 35 "to 80 # of acetic or lactic acid amide, such as Ν , Ν-dimethylacetamide or N- (β-hydroxyethyl) lactamide The solutions have a pH of 7 to 9.5 and a concentration of 10 to 100 mg / ml.

The process according to the invention is characterized in that the tetracycline or a pharmaceutically acceptable acid addition salt thereof and the pharmaceutically acceptable magnesium compound soluble in the final solution in a molar ratio of 1 mol of tetracycline / 0.8-1.3 mol of the magnesium compound are dissolved at elevated temperature C, e.g. in aqueous 2-pyrrolidone, and the pH of the solution is adjusted, if necessary, to 7.5-9.5, and that about 10-70% by weight of 2-pyrrolidone, based on the weight of the total composition, is used, optionally further using in solution 1 to 7% by weight of the total composition of 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 tetracycline chelates in solution with tetracycline.

2-Pyrrolidone is also referred to as 2-pyrrolidinone, 2-oxopyrrolidine, cis-pyrrolidone and 2-ketopyrrolidine. When administered orally, its LD50 is 8 g / kg in rats and 3.8 g / kg intraperitoneally by injection in mice. When used, the volume of the medicinal product per dose is as low as possible and it makes the product easy to inject due to its low viscosity. 2-Pyrrolidone is preferably used in an amount of 60 to 70% by weight of the total solution.

The pH of the solution, which is preferably 8.5 to 9.0, may be adjusted with an organic base such as monoethanolamine or a pharmaceutically acceptable acid such as hydrochloric acid.

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

Solutions containing tetracycline are preferably prepared by mixing the magnesium compound with 2-pyrrolidone and water at 50 ° C and slowly adding the tetracycline antibiotic with stirring until it is 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.

•of.

3 57882

The solutions prepared in accordance with the present invention generally contain tetracycline in the form of about 1-15% by weight of the total weight of the free base or pharmaceutically acceptable acid addition salt. Preferably a free base is used and the preferred concentration is about 5 to 15% by weight and particularly preferred is 5 to 10% by weight.

Suitable acid addition salts of tetracycline include, for example, pharmaceutically acceptable acid addition salts and hydrochloride, hydrobromide and sulfate. However, the most preferred acid addition salt is tetracyclic dihydrochloride.

The tetracycline solutions prepared according to the invention 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 tetracycline content is almost constant even over long storage periods.

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

These tetracycline compositions are primarily used parenterally, but may also be used topically or orally.

The following examples illustrate the invention.

Example 1

The following solution containing 100 mg / ml tetracycline hydrochloride was prepared.

457888 g / 100 ml

Tetracycline (effective amount 955 ug / ml tetracycline hydrochloride + 5% excess) 10,995

Magnesium iodide 0.958 2-pyrrolidone 70.00

Sodium formaldehyde sulfoxylate 1, 00

Polyvinylpyrrolidone K-17 5.00

Monoethanolamine, to adjust the pH to 8.5

Water to 100 ml 2-pyrrolidone was mixed with water. Polyvinylpyrrolidone was then added and stirred until dissolved. 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. Tetracycline was added slowly with stirring until a clear solution was obtained. The solution was allowed to cool to room temperature and its pH was adjusted to 9.5 with monoethanolamine. The solution was then diluted to volume with water.

A reference solution was prepared using 2-pyrrolidone 60.00 g / 100 ml instead of 70.00 g.

Example 2

The following solution containing 50 mg / ml tetracycline hydrochloride was prepared by the method described in Example 1.

g / 100 ml

Tetracycline (effective amount 955 ug / mg tetracycline hydrochloride + 5% excess) 5,496

Magnesium oxide 0.479 2-pyrrolidone 70.00

Magnesium formaldehyde sulfoxylate 1.00

Polyvinylpyrrolidone K-17 5.00

Monoethanolamine to adjust the pH to 8.5

Water to 100 ml

A solution comparable to the above was also prepared using 2-pyrrolidone 50.00 g / 100 ml instead of 70.00 g.

Example 3

The following solution containing 50 mg / ml tetracycline hydrochloride was prepared by the method described in Example 1.

5 57882 g / 100 ml

Tetracycline (effective amount 955 ug / mg tetracycline hydrochloride + 5% excess) 5,496

Magnesium oxide 0.479 2-pyrrolidone 60.00

Magnesium formaldehyde sulfoxylate 0.44

Polyvinylpyrrolidone K-17 5.00

Monoethanolamine to adjust the pH to 8.5

Water to 100 ml

Example 4

The following solution containing 100 mg / ml tetracycline hydrochloride was prepared by the method otherwise described in Example 1, except without polyvinylpyrrolidone.

g / 100 ml

Tetracycline (effective amount 955 ug / mg tetracycline hydrochloride + 5% excess) 10,995

Magnesium oxide 0.958 2-pyrrolidone 60.00

Magnesium formaldehyde sulfoxylate 0.44

Monoethanolamine to adjust the pH to 8.9

Water to 100 ml

A reference solution containing 70.00 g / 100 ml of 2-pyrrolidone and adjusting the pH to 8.8 was also prepared.

Example 5

The following solution containing 50 mg / ml tetracycline hydrochloride was prepared by the method described in Example 4.

g / 100 ml

Tetracycline (effective amount 955 ug / mg tetracycline hydrochloride + 5% excess) 5,496

Magnesium oxide 0.479 2-pyrrolidone 60.00

Magnesium formaldehyde sulfoxylate 0.44

Monoethanolamine to adjust the pH to 8.8

Water to 100 ml

A reference solution containing 70.00 g / 100 ml of 2-pyrrolidone and adjusting the pH to 8.7 was also prepared.

57882

Example 6

The following solution containing 100 mg / ml tetracycline hydrochloride was prepared by the method described in Example 4.

g / 100 ml

Tetracycline (effective amount 980 ug / mg tetracycline hydrochloride + 5% excess) 10.714

Magnesium oxide 0.939 2-pyrrolidone 60.00

Sodium formaldehyde sulfoxylate 1.00

Monoethanolamine to adjust the pH to 8.5

Water to 100 ml

Example 7

The following solution containing 10 mg / ml tetracycline hydrochloride was prepared by the method otherwise described in Example 4, except that the pH was adjusted with concentrated hydrochloric acid.

g / 100 ml

Tetracycline (effective amount 955 ug / mg tetracycline hydrochloride + 5% excess) 1,099

Magnesium oxide 0.096 2-pyrrolidone 30.00

Sodium formaldehyde sulphoxylate 1.00 Concentrated hydrochloric acid to adjust the pH to 7.5 Water to 100 ml

Examples 8 to 14

Each of Examples 1-7 was repeated using the same ingredients in the same proportions, but heating the solution to about 70 ° C. In each case, the same result was obtained as in the corresponding Example 1-7.

Claims (2)

7 57882 A process for preparing a stable aqueous solution containing 1 to 15% by weight of tetracycline, characterized in that the tetracycline 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 mol of tetracycline / 0.8 to 1.3 mol. the magnesium compound is dissolved at elevated temperature, e.g. 50-7 ° C: as a chelate in aqueous 2-pyrrolidone, and the pH of the solution is adjusted, if necessary, to 7.5-9.5, and that 2-pyrrolidone is used in an amount of about 10-70% by weight: a based on the weight of the total composition, optionally using in addition 1 to 7% by weight 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.