GB1592053A - Oxytetracycline compositions - Google Patents

Description

(54) OXYTETRACYCLINE COMPOSITIONS (71) We, NORBROOK LABORATORIES LIMITED, of Greenbank Industrial Estate, Newry, County Down, Northern Ireland, a Northern Ireland Company do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to pharmaceutical compositions. More particularly the invention relates to the preparation of stable solutions of oxytetracycline which are suitable for parenteral administration either by intramuscular or intravenous routes.

It is known that the solubility of tetracycline derivatives can be increased by the addition of calcium or magnesium ions to form soluble complexes but the solubility of those complexes is still insufficient to prepare a water soluble dose form of sufficient concentration and stability at physiologically acceptable pH. This can be achieved if water is replaced by an organic solvent such as propylene glycol or a concentrated solution of certain carboxamides such as dimethylacetamide or B-hydroxy-ethyllactamide.

Injections with high concentration of organic solvents (e.g. around 40-50% w/v of amide is required) which are hypertonic cause pain at the site of the injection; they are also undesirable because of the physiological unacceptability of the organic solvents in quantity.

Solutions for injection have also been made from certain amino compounds such as piperazine formaldehyde with tetracycline but these resultant compounds apart from not being the pure tetracycline derivatives per se are also susceptible to precipitation on prolonged storage.

Stable solutions of oxytetracycline have been prepared by the use of polyvinylpyrrolidone as a stabilizer in concentrations of between 10-25%. Solutions with concentrations of 10-15% of polyvinylpyrrolidone show increase in viscosity and are inclined to cause discomfort at the site of injection. As the significance of a substantial amount of polyvinylpyrrolidone being stored in the body tissues has not yet been established it is advisable to minimise the total intake of this substance.

According to our Patent Specification No. 1508601 a painless oxytetracycline injection may be made by using a vehicle which contains polyvinylpyrrolidone, an aliphatic C1 to C6 amide and water, to stabilise a complex of oxytetracycline with an alkaline-earth metal, preferably magnesium. The composition is stable at a pH of from 5 to 9 but our copending application recommends that it be used at pH 8.0 to 9.5.

It has now been found that the composition is eminently suitable for administration at a pH of 5 to 7.5 which is of course much more physiologically compatible with blood and body fluids than pH 8.5 A pH of 6.2 is particularly preferred.

According to the present invention there is provided a pharmaceutical composition comprising in aqueous solution, up to 15 weight percent of oxytetracycline, sufficient alkaline earth metal ions to complex with the oxytetracycline, from 4 to 6 weight percent of polyvinyl pyrrolidone and from 15 to 40 weight percent of a aliphatic amide having from 1 to 6 carbon atoms in the molecule or salicylamide, the pH of the solution being from 5.0 to 7.5 Aqueous solutions of oxytetracycline which are stabilised by formation of a complex with an alkaline earth metal ion are well known. On practical considerations from 0.7 to 4.0 gram ions per mole of oxytetracycline will suffice.

Simple aqueous solutions of the oxytetracyline/magnesium (Mg OTC) complex are stable at acidic pH (less than 5) and at alkaline pH (greater than about 8.0) but the stability of the solutions in the absence of stabilisers is insufficient to permit the preparation of useful concentrations of the MgOTC. At the pharmaceutically useful concentrations (e.g. 5% OTC) the complex MgOTC is unstable at both acidic and alkaline pH. It may be stabilised at pH values above 8.0 by adding polyvinylpyrrolidone (PVP). To obtain useful shelf-life it is necessary to use a PVP concentration of around 10% by weight. It should be noted that PVP itself is not a solvent for the MgOTC complex; it merely exerts a stabilising influence on the aqueous MgOTC solution.

On the other hand the solution of this invention uses an aliphatic amide which is a proper solvent: its use extends the stable shelf life of the solution and also permits a significant reduction in the amount of PVP stabiliser which is required and in addition allows a pH of 5.0 to 7.5 to be used. This is of important medical significance.

The aggregate effect of the PVP and amide is that a synergism occurs. Aqueous amide solutions have been used before at concentrations of about 50% by weight. PVP has been used at concentration of about 10%. The present invention will normally use for a 5-7% OTC solutions, an aqueous solution of 5% PVP and 25% dimethylacetamide and still obtain shelf-stability as good as, if not better than, that which would be obtained by the use of PVP alone or amide alone. For higher concentrations of OTC the amount of amide would be increased accordingly.

A widely used veterinary product is a nominal 5% (50mg/ml) oxytetracycline solution.

According to this invention such a product comprises Oxytetracyline (as magnesium complex) (OTC) 5g Polyvinylpyrrolidone (PVP) 5g dimethylacetamide (DMA) 20 ml Water to 100ml pH 6.2 Another advantage accruing from the present invention is that the amount of PVP is significantly lower than is used in the prior composition. Although PVP was used extensively as a plasma substitute and as such acquired a reputation as a "safe" additive to drugs, recent work has expressed concern as to its safety. It tends to be retained in or expelled only slowly from the body and therefore repeated use leads to an accumulation in a specific metabolic pathway of the body. We have found that the metabolic pathway by which the amide is excreted is different from that of PVP. The composition of the invention overloads neither pathway; the amide is of acceptably low concentration and can be excreted normally, and the PVP concentration is low enough to avoid accumulation of large amounts in the body.

Preferably the aliphatic amide is an amide of one of the following acids; acetic acid; lactic acid; B-hydroxybutyric acid; succinic acid; adipic acid; tartaric acid; gluconic acid; Preferably the aliphatic amide is dimethylacetamide.

Preferably the polyvinylpyrrolidone has molecular weight within the range from 10,000 to 100,000, more preferably 10,000 to 40,000.

The oxytetracycline may be in the form of a salt such as oxytetracycline hydrochloride or ocytetracycline citrate.

Further according to the invention there is provided a method of preparing the composition of the invention comprising dissolving oxytetracycline as a base or a salt in an aqueous solution of the polyvinylpyrrolidone and the amide, and containing magnesium ions and adjusting the pH of the solution to a value of from 5.0 to 7.5 by the addition of a suitable physiologically acceptable base.

Preferably the composition is formed by dissolving in an aqueous medium, the polyvinylpyrrolidone and the amide adding thereto oxytetracycline either as a salt or as a base and a magnesium compound ionizable in the medium and adjusting the pH to a value in the range of 5.0 to 7.5 by addition of a suitable physiologically-acceptable substance.

The pH adjustment may be carried out with a non-toxic inorganic or organic base for example, sodium hydroxide or ammonia, ethanolamine and ethylene diamine.

Dilutions of the composition with water or serum remain clear so that solutions are acceptable for intravenous use.

Preferably there are from 0.7 to 1.5 moles of magnesium compound for each 1 mole of tetracycline. The magnesium compound can be a magnesium salt, preferably the chloride, or the oxide depending on whether a salt or base of oxytetracycline is used. The increase the stability of the said composition the addition of a small quantity of reducing substance such as sodium metabisulphite or sodium formaldehyde sulphoxylate may be used and the air above the liquid may be replaced by nitrogen. The reducing substance is preferably dissolved in the aqueous medium prior to addition of the oxytetracycline.

An embodiment of the present invention will now be described generally by way of illustration.

Polyvinylpyrrolidone is dissolved in water and then an alkaline earth metal salt and the reducing substance is added to the aqueous solution and dissolved. An aliphatic amide is added to the solution. The resulting solution is allowed to stand for some time to equilibrate and then oxytetracycline or a salt thereof is added and a clear solution is obtained. The pH is then adjusted to from 5.0 to 7.5 using ethanolamine.

This solution may then be sterilised by any known means such as filtration and then the sterilised solution is stored in ampoules until required.

The pH of the solution is adjusted to within the range from 5.0 to 7.5 preferably by the addition of sodium hydroxide or aqueous ammonia or a physiologically acceptable water soluble aliphatic amme having 1 to 6 carbon atoms such as ethanolamine.

An advantage of the method of the invention accrues for the fact that the composition is stable around the neutral pH point. It is normal after mixing of the components the pH is acidic and requires adjustment to a value at which the solution is stable. Solutions containing PVP alone, when adjusted to the stable value of 8.0 to 9.5 have to pass through pH 7.0 at which, because of its amphoteric nature, OTC is normally insoluble. When these prior solutions are adjusted to pH around 7.0 the OTC precipitates as a fine colloidal suspension which makes subsequent adjustment difficult. A lengthy period is required for the suspension to redissolve in the alkaline pH. On the other hand when making the solution of this invention the OTC always remains in solution and such precipitation is avoided. It is the solvent effect of the amide which confers this advantage.

Examples of the method of the invention are given by way of further illustration of the present invention.

Example 1 In 50 ml. of distilled sterile and pyrogen free water are dissolved 5 g polyvinylpyrrolidone (K = 30) 0.2 g sodium metabisulphite and 4.0 g magnesium chloride hexahydrate.

Subsequently 25ml. of dimethylacetamide are added, and the mixture allowed to cool. 5.5 g (equivalent to 5 g oxytetracycline) of oxytetracycline hydrochloride is added and the pH adjusted to 6.2 with ethanolamine. The volume is then adjusted to 100 ml. with apyrogenic water as a result of which a clear solution containing 50 mg. of oxytetraycline per ml. is obtained. The solution is sterilized by means of filtration through a sterilizing pyrogen absorbing filter and distributed into bottles or ampoules.

Example 2 Compositions were prepared as in Example 1 substituting for the magnesium chloride an equivalent quantity of magnesium acetate, magnesium sulphate, magnesium gluconate or any ionizable physiologically acceptable magnesium salt or magnesium oxide.

Example 3 In 50 ml. of distilled apyrogenic water are dissolved 5 g of polyvinylpyrrolidone and 0.2 g sodium metabisulphite; subsequently 20 ml. N-(B-hydroxyethyl) lactamide is added and the mixture allowed to cool. 0.75 g magnesium oxide is suspended in this solution and 5.5.g oxytetracycline dihydrate added. The pH of this solution is adjusted to 6.5 with ammonia, 0.5 g sodium formaldehyde sulphoxylate is then added and the resulting clear solution is sterilized and treated as in Example 1.

Example 4 In 50 ml. of distilled apyrogenic water are dissolved 6 g polyvinyl pyrrolidone (K = 17), 0.1 g sodium metabisulphite and 3.5 g magnesium chloride. Subsequently 20 ml. of dimethylacetamide are added and the mixture allowed to cool. 5.5 g oxytetracycline hydrochloride are dissolved in this mixture, the pH is adjusted to 7.5 with ethanolamine and the volume adjusted to 100 ml. using apyrogenic water. The resulting solution is sterilized and treated as in Example 1.

Claims (10)

WHAT WE CLAIM IS:

1. A pharmaceutical composition comprising, in aqeuous solution, up to 15 weight percent oxytetracycline, sufficient alkaline earth metal ions to complex the oxytetracycline, from 4 to 6 weight percent of polyvinylpyrrolidone and from 15 to 40 weight percent of an aliphatic amide having from 1 to 6 carbon atoms in the molecule or salicylamide, the pH of the said solution being from 5.0 to 7.5.

2. A composition according to claim 1, in which the amide is an amide of an acid selected from acetic acid, lactic acid, ss-hydroxybutyric acid, succinic acid, adipic acid, tartaric acid, and gluconic acid.

3. A composition according to claim 2, in which the amide is dimethylacetamide.

4. A composition according to any preceding claim, in which the polyvinylpyrrolidone has a molecular weight of from 10,000 to 100,000.

5. A composition according to claim 4, in which the molecular weight of the polyvinylpyrrolidone is from 10,000 to 40,000.

6. A composition according to any preceding claim, in which the oxytetracycline is in the form of its hydrochloride or citrate.

7. A method of preparing the composition claimed in claim 1, comprising dissolving the respective amounts, defined in claim 1, of polyvinylpyrrolidone, aliphatic amide and magnesium ions in water and dissolving the relevant amount of oxytetracycline as a base or a salt in the solution obtained and adjusting the pH of the solution to a value of from 5.0 to 7.5 by the addition of a suitable physiologically acceptable base.

8. A method according to claim 7, in which the pH adjustment is carried out with a suitable non-toxic inorganic or organic base for example, sodium hydroxide or ammonia, ethanolamine and ethylene diamine.

9. A method of preparing the pharmaceutical composition claimed in claim 1, according to any one of the Examples.

10. A pharmaceutical composition whenever prepared by the method claimed in any one of claims 7, 8 and 9.