Production method of the stable injection chelate solution of the oxytetracycline

The present invention relates to a process for the manufacture of a stable oxytetracycline chelate injection solution for pharmaceutical purposes. These are especially mixed chelates of oxytetracycline, magnesium and calcium in solution in aqueous 2-pyrrolidone.

U.S. Patent No. 4,018,889 discloses an aqueous solution of oxytetracycline containing 2-pyrrolidone as a co-solvent. Oxytetracycline is present in the form of magnesium chelate.

US Patent No. 3,017,323 discloses a solution of oxytetracycline in aqueous glycol containing calcium and magnesium. The ratio of calcium to magnesium and oxytetracycline is 1: 1: 3.

U.S. Pat. No. 3,929,989 discloses a suspension of a calcium-magnesium-oxytetracycline complex wherein the molar ratio of calcium and magnesium to oxytetracycline is 4: 1 in aqueous 1,2-propanediol.

SUMMARY OF THE INVENTION The present invention provides a process for the production of a stable injection solution of oxytetracycline chelate with high efficacy and long-term effect for injection use in a solvent consisting of aqueous 2-pyrrolidone and optionally polyvinylpyrrolidone, glycerol formal or propylene glycol. oxytetracycline, magnesium and calcium by reacting 20 to 30% (w / v) of oxytetracycline with 0.8 to 0.95 molar fraction of magnesium oxide, based on the amount of oxytetracycline and 0.15 to 0.3 mole fraction of a pharmaceutically acceptable calcium compound soluble in said solution based on the amount of oxytetracycline and the resulting mixed chelate is dissolved in said solution containing 2-pyrrolidone in an amount of 40- 60% (w / v%).

The oxytetracycline that is used to make the solution of the invention is a widely used antibiotic of the tetracycline type. This antibiotic has been particularly described in U.S. Patent No. 2,516,081. The effective concentration of oxytetracycline in the solutions prepared by the process of the invention is in the range of 20-30% (w / v), expressed as the free base. A preferred concentration range is 20 to 25% (w / v).

Magnesium and calcium ions form chelates with oxytetracycline in solution. Magnesium oxide is in this case a source of magnesium ions and is present in the solutions prepared according to the invention in an amount of 0.8 to 0.95 molar parts, based on the amount of oxytetracycline. A suitable source of calcium ions is calcium acetate, but other soluble, pharmaceutically acceptable calcium compounds, such as lactate or calcium propionate, may also be used. The calcium compound should be present in a concentration of 0.15 to 0.3 molar, based on the amount of oxytetracycline.

2-pyrrolidone is present in the solutions as a co-solvent at a concentration of 40 to% (w / v%). The preferred concentration is 50-55%. 2-pyrrolidone is also known as 2-pyrrolidinone, 2-oxopyrrolidine, α-pyrrolidone and 2-ketopyrrolidine. The oral LD ​​50 is 8 g / kg for the rat and 3.8 g / kg for the mouse by intraperitoneal injection. The use of this substance makes it possible to achieve good throughput in the syringe at a small volume and to achieve a low viscosity of the resulting solution.

As an optional ingredient, polyvinylpyrrolidone having a molecular weight in the range of 5,000 to 100,000 (K-12 to 30) at a concentration of 1 to 14% (w / v) may still be included in the solutions produced by the process of the invention. A preferred type of polyvinylpyrrolidone for use herein is a compound having an average molecular weight of 10,000 to 17,000 (K12 to 17). This substance is a co-solvent in this case and at the same time improves tissue tolerance.

The solution prepared by the process according to the invention may contain still further optional co-solvents, for example propylene glycol and glycerol formal, in a concentration of up to 15% (w / v).

The stability of said solutions for medical use can be further increased by incorporating antioxidants, for example sodium or magnesium formaldehyde sulfoxylate or monothioglycerol, in an amount of 0.01 to 1% (w / v).

The pH should be in the range

7.5 to 9.5. The preferred range is 8.5 to 9.0. The pH can be adjusted with organic bases such as monoethanolamine, dimethylaminoethanol, dimethylamine and the like. Of these, monoethanolamine is most preferred.

The solutions of the invention may be prepared by dissolving the calcium compound in a portion of water. Then, 2-pyrrolidone is mixed with the bulk of water and polyvinylpyrrolidone, if present in the solution. The resulting solution was heated to 45-75 ° C and an antioxidant was added with stirring. In this solution, magnesium oxide is suspended in the solution and oxytetracycline is slowly added under stirring to form a solution. The calcium compound solution is then added to this solution with stirring until a clear solution is obtained. After cooling the resulting solution to room temperature, the pH is adjusted if necessary, then the solution is made up to volume with water.

These solutions are very suitable for injection use over a wide temperature range, are well tolerated by the tissues and provide effective blood levels for up to 15 days. Thus, the mixed magnesium and calcium chelate provides for the possibility of depot administration of the antibiotic when an unusually long period of effective blood levels persists. This time cannot be achieved with magnesium chelate alone.

8 Magnesium oxide 2,221 Calcium acetate

2-pyrrolidone 50.00 polyvinylpyrrolidone, K-17 3.00 sodium formaldehyde sulfoxylate 0.30 monoethanolamine to pH 8.5 water to 100 ml

Example 1

The solution for injection can be made from the following ingredients:

g / 100 ml oxytetracycline (potency)

927 (g / mg + 2% extra) 27.51 magnesium oxide 1.844 calcium acetate1.931

2-pyrrolidone50.00 polyvinylpyrrolido.n, K-175.00 sodium formaldehyde sulfoxylate0.30 monoethanolamine to pH 8.5 water to 100 ml

Dissolve calcium acetate in 10 ml of water. Mix 2-pyrrolidone with 30 ml. Add polyvinylpyrrolidone and dissolve. The solution is heated to 45 ° C and sodium formaldehyde sulfoxylate is added while stirring and dissolved. Magnesium oxide is then suspended in the solution. Oxytetracycline is then slowly added with stirring until a solution is formed. The calcium acetate solution is then slowly added to the magnesium-oxytetracycline solution with stirring until a clear solution is obtained. This solution was then allowed to cool to room temperature and the pH was adjusted to 8.5 by addition of monoethanolamine. Then the solution is made up to the required volume of water.

The above solution contained 250 mg / ml oxytetracycline and had a viscosity of 45 xx10^-6 m²/ s at 25 ^CC.

Example 2

The following solution containing 250 mg / ml oxytetracycline was prepared as described in Example 1.

<td></td><td>g / 100 ml</td>

<td>Oxytetracycline (efficacy 927 ^ g / mg and 2% extra)</td><td> 27,51</td>

<td>magnesium oxide</td><td> 1,844</td>

<td>calcium acetate</td><td> 1,931</td>

<td>2-pyrrolidone</td><td> 55,00</td>

<td>sodium formaldehyde sulfoxylate</td><td> 0,30</td>

<td>monoethanolamine to pH 8.5 water</td><td>to 100 ml</td>

<td colspan="2">The viscosity of the resulting solution is 49 χ 10⁶</td>

m²/ s at 25 ^andC.

Example 1 and 3

The following solution containing 300 mg / ml oxytetracycline can be obtained as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 (g / mg and 2% extra) 33.00

The resulting solution had a viscosity of 173 x 10 &amp; quot;⁶m²/ s at 25 ° C.

Example 4

The following solution containing 300 mg / ml oxytetracycline can be obtained as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 (µg / mg and 2% extra) 33.00 magnesium oxide2.221 calcium acetate2.111

2-pyrrolidone55.00 sodium formaldehyde sulfoxylate 0.30 monoethanolamine to pH 8.5 water to 100 ml

The resulting solution had a viscosity of 138 x 10O^-6m²/ s at 25 ° C.

Example 5

A solution containing 250 mg / ml oxytetracycline can be obtained as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 (ig / mg and 2% extra) 27,51 magnesium oxide1,844 calcium acetate1,931

2-pyrrolidone50.00 polyvinylpyrrolidone, K-173.00 sodium formaldehyde sulfoxylate0.30 monoethanolamine to pH 8.5 water to 100 ml

The resulting solution had a viscosity of 69 χ 10^-6m²/ s at 25 ° C.

Example 6

The following solution containing 250 mg / ml oxytetracycline was prepared as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 (g / mg and 2% extra). Magnesium oxide 1,844 Calcium acetate

2-pyrrolidone 50.00 polyvinylpyrrolidone, K-17 3.00 sodium formaldehyde sulfoxylate 0.30 monoethanolamine to pH 8.5 water to 100 ml

The resulting solution had a viscosity of 72 x 10⁶m²/ s at 25 ⁴C.

Example 7

The following solution containing 250 mg / ml oxytetracycline was prepared as described in Example 1.

g / 100 ml oxytetracycline [efficacy

927 , «G / mg and 2% extra) 27,51 magnesium oxide2,075 calcium acetate1,931

2-pyrrolidone50.00 polyvinylpyrrolidone, K-173.00 sodium formaldehyde sulfoxylate0.30 monoethanolamine to pH 8.5 water to 100 ml

The resulting solution had a viscosity of 58 x 10^-6m²/ s at 25 ^QC.

Example

The following solution containing 250 mg / ml oxytetracycline was prepared as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 g / mg and 2% extra) 27.51 magnesium oxide 1.844 calcium acetate3.379

2-pyrrolidone50.00 polyvinylpyrrolidone, K-125.00 sodium formaldehyde sulfoxylate0.30 monoethanolamine to pH 8.5 water to 100 ml

The resulting solution had a viscosity of 75 χ 10^-6m²/ -s at 25 ° C.

Example 9

The following solution containing 250 mg / ml oxytetracycline was prepared as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 jUg / mg and 2% extra) 27.51 magnesium oxide1.844 calcium acetate2.897

2-pyrrolidone50,00 polyvinylpyrrolidone, K-127.50 sodium formaldehyde sulfoxylate 0.30 monoethanolamine to pH 8.5 water to 100 ml

The resulting solution had a viscosity of 115 x 10^-6 m²/ s at 25 ^QC.

Example 10

The following solution containing 250 mg / ml oxytetracycline is prepared as described in Example 1 except that:

<td colspan="2">glycerol formal is added directly to the 2-pyrrolldone prior to the addition of water.</td>

<td></td><td>. g / 100 ml</td>

<td>Oxytetracycline (efficacy</td><td></td>

<td>927 µg / mg and 2 ° / o extra)</td><td> 27,51</td>

<td>magnesium oxide</td><td> 1,844</td>

<td>calcium acetate</td><td> 2,897</td>

<td>2-pyrrolidone</td><td> 50,00</td>

<td>polyvinylpyrrolidone, K-12</td><td> 7,50</td>

<td>glycerol formal</td><td> 15,00</td>

<td>sodium formaldehyde sulfoxylate</td><td> 0,50</td>

<td>monoethanolamine to pH 8.5</td><td></td>

<td>water</td><td>to 100 ml</td>

<td>The resulting solution had a viscosity</td><td>138 χ ΙΟ '⁶</td>

m²/ s at 25 ° C.

Example 1 ad 11

<td colspan="2">Following solution containing 200 mg / ml</td>

<td>oxytetracycline can be obtained</td><td>way,</td>

<td>as described in Example 1.</td><td></td>

<td></td><td>g / 100 ml</td>

<td>Oxytetracycline (efficacy</td><td></td>

<td>927 ^ g / mg and 2% extra)</td><td> 22,008</td>

<td>magnesium oxide</td><td> 1,844</td>

<td>calcium acetate</td><td> 2,897</td>

<td>2-pyrrolidone</td><td> 55,00</td>

<td>polyvinylpyrrolidone, K-12</td><td> 10,00</td>

<td>sodium formaldehyde sulfoxylate</td><td> 0,30</td>

<td>monoethanolamine to pH 8.0</td><td></td>

<td>water</td><td>to 100 ml</td>

The resulting solution had a viscosity of 84 x 10⁶m²/ s at 25 ° C.

Example 12

The following solution containing 200 mg / ml oxytetracycline can be obtained as described in Example 8.

g / 100 ml oxytetracycline (potency)

927 / zg / mg and 2% extra) 22,008 magnesium oxide1,844 calcium acetate2,897

2-pyrrolidone50,00 polyvinylpyrrolidone, K-127.50 glycerol formal 15.0 sodium formaldehyde sulfoxylate 0.30 monoethanolamine to ipH 8.5 water to 100 ml g / 100 ml

The resulting solution had a viscosity of 83 x 10 &amp; quot;⁶ m²/ s at 25 ^QC.

Example 13

The following solution containing 250 mg / ml oxytetracycline can be obtained as described in Example 1.

g / 100 ml oxytetracycline (potency)

927 g / mg and 2% extra) 27.51 magnesium oxide 1.844 calcium acetate 1.931

2-pyrrolidone50,00 polyvinylpyrrolidone, K-173,00 sodium formaldehyde sulfoxylate0,30 monothioglycerol1,00 water up to 100 ml

The resulting solution had a viscosity of 45 χ 10 "⁶m²/ s at 25 ° C.

Example 14

The following solution containing 250 mg / ml oxytetracycline was prepared as described in Example 8 except that propylene glycol was used instead of glycerol formal.

Oxytetracycline (efficacy

927 (g / ml and 2% extra) 27.51 magnesium oxide 1.844 calcium acetate 2.897

2-pyrrolidone 50.00 polyvinylpyrrolidone, K-127.50 propylene glycol15.00 sodium formaldehyde sulfoxylate 0.50 monoethanolamine to pH 8.5 water to 100 ml

Viscosity of final pitch x 10 "⁶ m²/ s at 25 ° C.

Example 15

A solution containing oxytetracycline chelate, magnesium and calcium, and a solution containing oxytetracycline chelate and magnesium were administered intramuscularly to two different sites on the same limb at a dose of 30 mg oxytetracycline / kg. Blood samples were then taken at the intervals indicated in the table below and the blood plasma oxytetracycline levels were determined.

µg / ml oxytetracycline Time after injection

<td></td><td>4 hours</td><td>1 day</td><td>4 days</td><td>7 days</td><td>10 days</td><td>13 days</td><td>15 days</td>

<td>magnesium chelate</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>and calcium of Example 6</td><td> 1,72</td><td> 1,30</td><td> 0,38</td><td> 0,35</td><td> 0,31</td><td> 0,26</td><td> 0,23</td>

<td>magnesium chelate of Example 1 of US Patent No. 4,018,889</td><td> 5,07</td><td> 2,27</td><td> 0,27</td><td> 0,20</td><td> 0</td><td> 0</td><td> 0</td>

From the results shown in the table, it is apparent that administration of a mixed chelate solution produced by the method of the invention can achieve an effective blood plasma oxytetra level over a prolonged period of time.