SE411424B - PROCEDURE FOR PREPARING A WATER SOLUTION OF DOXYCYCLINE, IDE ALFA-6-DEOXI-5-HYDROXITETRACYCLINE - Google Patents

Description

7314529-4 2 sodium salt and doxycycline 3: 1-8; l, and that, if necessary, adjust the pH of the solution at a value in the range 1.0-3.5 by adding ascorbic acid, tartaric acid, gluconic acid, glucuronic acid, citric acid, gentisinic acid, acid, isonicotinic acid or glutamic acid and optionally add solvents with a water-soluble local anesthetic component.

Doxycycline, the therapeutically active component of the new ones The pharmaceutic compositions, is a tetracycline-type antibiotic with high activity and excellent oral absorption characteristics and superior half-life. It is specifically described in the American U.S. Pat. No. 3,200,149 under the chemical name, α-G-deoxy-S-oxytetra- cyclin. An effective concentration range for doxycycline in aqueous The solutions obtained according to the invention usually vary from approx. less than 10% by weight, calculated on. the whole, in the form of a pharmaceutical technically acceptable acid addition salt.

Magnesium ions are combined with doxycycline in solution during the magnesium doxycycline linkers. Magnesium chloride is a suitable source for magnesium ions, but other magnesium compounds can also be used for the purpose of the invention, such as magnesium oxide, magnesium ascorbate, magnesium lactate, magnesium gluconate, etc. The molar ratio of magnesium The sodium and doxycycline in these compositions are about 3: 1-8: 1, in particular about 3: 1-4: 1.

The doxycycline antibiotic component was used in the form of an acid addition salt. Examples of suitable doxycyclinic acid addition salts, such as may be used for this purpose, such pharmaceutically acceptable only acid addition salts such as the hydrochloride, hydrobromide, sulphate, the nitrate, ascorbate, citrate, gluconate, lactate, isonicotinate, gentisinate, pantothenate, salicylate, glucuronate, formate, glutamate food, etc. The most suitable acid addition salt is doxycycline hydrochloride. rid, such as in the form of doxycycline-hyclate, i.e. doxycycline hydrochloride -hemiethanolate-hemihydrate. Doxycycline may be introduced in the form of the free base, in which case the salt is formed in situ by that in it, the following described pH position. The pH is adjusted to the desired range, approximately 1.0- 3.5, by means of a solid acid, which is pharmaceutically acceptable the above kind. Of these compounds, ascorbic acid is the most suitable, since it also has the function of antioxidant for the mixture. at use of higher doxycycline concentration, such as 80-100 mg / ml, no acid buffer is required, as the pH will be within the desired pH range of about 1.0-3.5. It especially suitable However, the pH range is about 1.5-3.0.

An additional component which may be used in the present invention is position with a favorable effect, is a water-soluble local 3 average. The most useful of these compounds is procaine hydrochloride and lidocaine hydrochloride. Other dialkylaminoalkanol esters of p-amino benzoic acid in the form of the water-soluble salts, such as hydrochloride, is also useful for this purpose.

These compositions can be prepared by simply mixes the doxycyclinic acid addition salt with the desired proportions of the other components. It is usually advisable to appoint everyone solid components in finely divided form and mix the mixture for of a uniform product. Standard pharmaceutical equipment can be used for this purpose. The mixture can also be ground, if desired. You should however, avoid prolonged exposure to high temperatures.

An essential component of the invention is a water-soluble alkali metal phosphate. such as sodium or potassium orthophosphate, phosphate, pyrophosphate, tripolyphosphate or hexametaphosphate. The appropriate However, the most common salt is sodium orthophosphate, also known as sodium dihydrogen phosphate. The introduction of a water-soluble alkali metal phosphate in the compositions provides effective blood levels of doxycycline, prevents gelling of the compositions when water is added and prevents precipitation doxycycline in blood serum. Molar ratio of water soluble alkali metal phosphate and doxycycline in these compositions are approx 3: 1-8: 1, especially about 3: 1-4: 1.

The invention is further illustrated by the following examples, wherein the doxycycline hydrochloride is used in the form of hemiethanolate hemichloride hydrate (hypocritical). : Example 1. A dry, pharmaceutical composition is prepared by 635.0 mg doxycycline hydrochloride is intimately mixed with 641.77 mg of magnesium sodium chloride tetrahydrate, 529.7 mg sodium dihydrogen phosphate and 675.99 mg ascorbic acid. The mixed powder was then dissolved in 8.4 ml of sterile water, which increased the volume to 10 ml. The solution formed turned out have a pH of 2.0. The solution remained liquid and clear for 24 hours at room temperature.

Animal protection tests were performed on mice against Staphylococcus aureua 0lAO05 by intramuscular and intravenous administration. The results showed that satisfactory protection was achieved by means of this composition.

Example 2. Dry, solid compositions can be prepared by uses an equivalent amount of sodium metaphosphate, sodium pyrophosphate, sodium tripolyphosphate or sodium hexametaphosphate instead of sodium dihydrogen phosphate according to Example 1. 7314529 ~ §> __ g_ 7314529-4 Example gel 3. A mixture of the following materials was prepared: EE Doxycycline hydrochloride 9,635.00 Magnesium chloride.4H20 641.77 Sodium dihydrogen phosphate 529.70 Ascorbic acid 675.99 Lidocaine hydrochloride 200.00 When this composition was dissolved in 8.1 ml of water, one was obtained clear product with pH 2.0.

Example gel 4. A mixture of the following materials was prepared: EE Doxycycline hydrochloride 635.00 Magnesium gluconate 308.66 Sodium dihydrogen phosphate 529.70 Ascorbic acid 675.99 When this mixture was diluted with 8.0 ml of water, one was obtained clear solution with pH 2.0.

Example gel 5. A mixture of the following materials was prepared: EE Doxycycline ~ hydrochloride 635.00 Magnesium chloride.4H2O 855.69 Sodium dihydrogen phosphate 529.70 Ascorbic acid _ 655.8 When this composition was dissolved in 8.1 ml of water, one was obtained clear product with pH 2.0.

Example gel 6. A mixture of the following materials was prepared: EE Doxycycline hydrochloride 1,265.0 Magnesium chloride.4H20 1,755.9 Sodium dihydrogen phosphate 1,190.0 When this composition was dissolved in 8.2 ml of water, a clear was obtained solution containing 100 mg fi ml doxycycline activity at pH 2.0.

Example gel 7. A mixture of the following materials was prepared: EE Docycline hydrochloride 127.55 Magnesium chloride.4H2O 128.39 Sodium dihydrogen phosphate 105.94 Ascorbic acid 131.10 -1 When this composition was dissolved in 8.3 ml of water, a clear was obtained solution with pH 2.0, containing 10 mg fi nl doxycycline activity. 731452941 5 Example 8. A mixture of the following materials was prepared: i as Doxycycline hydrochloride 255.10 Magnesium chloride.4H2O 256.78 Sodium dihydrogen phosphate 211.88 Ascorbic acid 400.00 When this composition was dissolved in 9.4 ml of water, one was obtained clear solution, containing 20 mg fi nl doxycycline activity. pH 1.9.

Example 9. A mixture of the following materials was prepared: % Doxycycline hydrochloride 1,020.4O Magnesium chloride.4H2O 1,164.7 Sodium dihydrogen phosphate 960.7 When this composition was dissolved in 8.3 ml of water, a clear was obtained solution, containing 80 mg fi ml doxycycline activity and showing a pH of 1.66. 5 Example 10. A mixture of the following materials was prepared: EE Doxycycline hydrochloride 635.00 Magnesium chloride.4H2O 641.77 Potassium dihydrogen phosphate 522.3 Ascorbic acid 675.99 When this mixture was diluted with 8.5 ml of water, one was obtained clear solution with pH 2.0. 7Example ll. A mixture of the following materials was prepared: EE Doxycycline hydrochloride 635.00 Magnesium chloride.4H2O 642.00 Potassium dihydrogen phosphate "522.00 Citric acid 3,570.00 When this composition was dissolved in 6.5 ml of water, a clear was obtained solution, containing 10 ml of doxycycline activity and having a pH of 1.1. - 7 Example 12. A mixture of the following materials was prepared: mg.

Doxycycline hydrochloride 635.00 .Magnesium chloride.4H20 725.00 Sodium dihydrogen phosphate 598.00 Sodium nitrate, hydrated 300.00 When this composition was dissolved in 9.1 ml of water, a clear was obtained solution with pH 3.5. 7314529 ~ l + l 6 Exemgal lay. A mixture of the following materials was prepared: EE Doxycycline hydrochloride at 635.00 Magnesium chloride.4H20 l.506.00 Sodium dihydrogen phosphate l.367.00 When this composition was dissolved in 8.1 ml of water, one was obtained clear solution with pH 2.0.

Claims (4)

7314529-4 PATENT REQUIREMENTS 1. Process for the preparation of an aqueous solution of doxycycline, i.e. x-6-deoxy-5-hydroxytetracycline, which is resistant and suitable for parenteral administration, characterized in that a pharmaceutically acceptable acid addition salt of doxycycline is dissolved in water to a content of 1-10% by weight thereof, based on the the total weight of the finished solution, together with a water-soluble alkali metal phosphate and a pharmaceutically acceptable, water-soluble magnesium salt, the molar ratio of alkali metal phosphate to doxycycline being 3: 1-8: 1 and between magnesium salt and doxycycline 3: 1-8: 1, and that if necessary, adjust the pH of the solution to a value in the range of 1.0-3.5 by adding ascorbic acid, tartaric acid, gluconic acid, glucuronic acid, citric acid, gentisic acid, isonicotinic acid or glutamic acid and optionally adding the solution with a water-soluble local anesthetic. 2. A process according to claim 1, characterized in that the doxycyclinic acid addition salt is doxycycline hydrochloride. 3. A process according to claim 1 or 2, characterized in that the alkali metal phosphate is sodium or potassium orthophosphate, pyrophosphate, tripolyphosphate or hexametaphosphate. 4. A process according to any one of claims 1-3, characterized in that the water-soluble magnesium salt is magnesium chloride or magnesium gluconate. PROMISED PUBLICATIONS: United Kingdom 827 580