OXYTETRACYCLIN SOLUTIONS

Abstract: The invention relates to aqueous injectable solutions con­ taining oxytetracyclin, a magnesium compound and polyvinylpyrrolidone with a molecular weight between 500 and 10,000 with a pH of 8-9.5 and to a process for the prepara­ tion of these solutions.

Description: Oxytetracyclin solutions The invention relates to injectable solutions of oxytetracyclin and their preparation. Oxytetracyclin (OTC) as such is not stable in aqueous solution. Moreover, it is badly soluble in water. Acceptable solutions can be obtained by addition of certain excipients. It is known, for instance, that by addition of magnesium compounds a magnesium complex is formed which better dissolves than oxytetracyclin itself. It is further known to improve the solubility by addition of polyvinylpyrrolidone (PVP) and/or organic solvents. Preparations with magnesium and PVP, as described in Dutch patent 134511, are found to be very satisfactory in practice. Their only disadvantage is that the oxytetracyclin content is restricted by the limitation which is put in practice to the viscosity. With a content of 10% or more the viscosity increases to such an extent that the application is hampered. There is a need, however, for preparations with a higher concentration of oxytetracyclin for veterinary purposes. In the first place because one prefers to keep the injection volume as small as possible (particularly important for animals with a weight of more than 100 kg) and second because it has been found that when using higher dosages with more concentrated solutions a considerable longer therapeutical effect is achieved. Up till now it was only possible to prepare solutions with higher oxytetracyclin concentration with low viscosity by using certain organic solvents such as propylene glycol, dimethylacetamide, 2-pyrrolidone, polyethylene glycol and Nmethylpyrrolidone, to which solvents sometimes PVP also was added. Such solutions are described in British patent 1.427.882, Dutch patent application 7804455, Belgian patent 861885, German patent applications 2001604, 2501805 and 3104233 and U.S. patent 4.018.889. All the solvents used have the strong disadvantage that they cause a strong tissue irritation on the site of the injection, which even can lead to visible abnormalities in the meat on this place with a accompanying loss of value. When PVP is applied, a type is preferably chosen with a mean molecular weight between 10,000 and 40,000. It has now been found that one can reach higher concentrations of oxytetracyclins with a good stability, an acceptable viscosity and a minimal tissue irritation by using PVP with a relatively low molecular weight. The invention is characterized in that in aqueous oxytetracyclin solutions with a pH of 8-9.5, which contain a magnesium compound and PVP, one applies PVP with a molecular weight between 500 and 10,000, preferably between 1000 and 5000. The PVP concentration is preferably at least 18t (w/v) because solutions can thus be obtained which contain 10 or more percent by weight of oxytetracyclin. According to the invention, solutions can be obtained with OTC up to 20D (w/v). For that, maximally 40Z (w/v) of PVP is needed. The kind and the amount of magnesium compound can be the same as described in Dutch patent specification 134.511. Magnesium oxide and magnesium chloride 6aq are for instance suitable. The invention also includes the preparation of oxytetracyclin solutions by dissolving oxytetracyclin as salt or as a base with a suitable amount of a magnesium compound and PVP and to bring the pH in the range of 8.0 to 9.5, characterized in that PVP is used with a molecular weight between 500 and 10,000. The amount of magnesium compound to be used is preferable 1 to 1.5 mol per mol of oxytetracyclin. The pH can be brought to the desired value with the aid of a physological unharmful base, such as ammonia, ethylenediamine or ethanolamine. In order to promote the stability, the air in bottles or ampoules containing the oxytetracyclin solutions of the invention can be replaced by an inert gas, preferably nitrogen. It is also advantageous for the stability to add to the solution a small amount of a reducing agent, such as sodium metabisulfite, sodium sulfite or sodium formaldehydesulfoxylate. It was conceivable that substitution of the PVP commonly used in known preparations by PVP of lower molecular weight would lead to tissue irritation. Surprisingly this is not the case. The effect of lowering the molecular weight of PVP on the stability of the injection solution and the level of oxytetracyclin in the blood could not be predicted. It is therefore unobvious that the compositions of the invention possess a satisfactory stability and at higher dosages show a long lasting therapeutic blood level of the oxytetracyclin. An accompanying advantage of the use of low molecular PVP is that the likeness of tumours to be formed, as seen with PVP with higher molecular weight, will be minimal. The preparation of the oxytetracyclin-solutions according to the invention is illustrated by the following examples in which the percentages mentioned are weight by volume percents. Example 1 Preparation of a 10% oxytetracyclin solution with 18% of polyvinylpyrrolidone (K-value 11-14) Under a nitrogen atmosphere the following was added successively to 200 ml of pyrogen free water: 90 g of polyvinylpyrrolidone (K-value 11-14, molecular weight 2000-3500), 3 g of sodium formaldehydesulfoxylate, 4.34 g of magnesium oxide, 11 g of ethanolamine, and a solution of 56.7 g of oxytetracyclin hydrochloride in 100 ml of pyrogen free water. After being stirred for some time, a clear solution was formed. The solution was made up to 500 ml with pyrogen free water, which gave a solution with a pH of 8.7 and a viscosity of 17 centipoise at 220C. The solution contained 100 mg of oxytetracyclin per ml. This solution was filtered through a sterilizing filter after which stability studies were carried out. At 50 C the solution was stable for 3 to 4 weeks, but at 37"C the solution even remained stable after 6 months. As a test for the stability of the solution the absence of a precipitate was used. Example 2 Preparation of a 10X oxytetracyclin solution with 20% of polyvinylpyrrolidone (K-value 11-14) Under a nitrogen atmosphere the following was added successively to 200 ml of pyrogen free water: 100 g of polyvinylpyrrolidone (K-value 11-14), molecular weight 2000-3500), 3 g of sodium formaldehydesulfoxylate, 4.34 g of magnesium oxide, 11 g of ethanolamine and a solution of 56.7 g of oxytetracyclin hydrochloride in 100 ml of pyrogen free water After being stirred for some time a clear solution was formed which was made up to 500 ml of pyrogen free water. The solution obtained contained 100 mg of oxytetracyclin per ml and had a pH of 8.8 and a viscosity of 21 centipoise at 220C. After sterile filtration the solution remained stable for about 8 weeks at 5"C and at 37"C the stability was more than 6 months. After 6 months at 37"C the solution kept its light colour Example 3 Preparation of a 10% oxytetracyclin-solution with 20% of polyvinylpyrrolidone (K-value 11-14) starting from oxytetracylin base. a. Preparation of oxytetracyclin base 60 g of oxytetracyclin hydrochloride was dissolved in 800 ml of boiled pyrogen free water. With the aid of 4 N sodium hydroxid.e, which also was prepared with boiled pyrogen free water, the p11 was brought to 5.35 under stirring, which made the oxytetracyclin base precipitate. The precipitate was filtered off and washed thoroughly with pyrogen free water. b. Preparation of the oxytetracyclin/polyvinylpyrrolidone solution. Under a nitrogen atmosphere the following was added successively to 200 ml of pyrogen free water: 100 g of polyvinylpyrrolidone (K-value 11-14) molecular weight 2000-3500), 2.5 g of sodium formaldehydesulfoxylate, 4.34 g of magnesium oxide, and the oxytetracyclin base obtained by procedure a. With the aid of ethanolamine the pH was brought to 8.5 to 9.0. A clear solution was formed. Pyrogen free water was added to 500 ml and then the solution was filtered through a sterilizing filter. The solution obtained contained 100 mg of oxytetracyclin per ml, had a pH of 8.9 and a viscosity of 22 centipoise at 220C. The solution remained stable at 50"C for more than 8 weeks and at 37"C for more than 6 months. Example 4 Preparation of a 10% oxytetracyclin solution with 25% of polyvinylpyrrolidone (K-value 11-14). In the same way as in Example 2 a solution was made which contained 250 mg of polyvinylpyrrolidone per ml. However, instead of 100 g of polyvinylpyrrolidone (K-value 11-14) 125 g were added. The sterile filtered solution obtained had a pH of 8.7 and a viscosity of 31 centipoise at 220C. The stability at 50"C was more than 8 weeks, but the solution took on a dark colour. At 37"C the solution still had a light colour after 6 months and no precipitate had been formed. Example 5 Preparation of a 10t oxytetracyclin solution with 30% of polyvinylpyrrolidone (K-value 11-14) The preparation was carried out in the same way as in Example 2. However, in stead of 100 g of polyvinylpyrrolidone with a K-value of 11-14, 150 g were used. After filtration through a sterilizing filter the solution had a pH of 8.7 and a viscosity of 48 centipoise at 220C, The stability at 50"C was more than 8 weeks and at 37"C more than 6 months. Example 6 Preparation of a 10% oxytetracyclin solution with 30X of polyvinylpyrrolidone (K-value 11-14) starting from oxytetracyclin base In the same way as described in Example 3 under a the base was prepared. The procedure was then continued as described in Example 3 under b, except that instead of 100 g of polyvinylpyrrolidone (K-value 11-14) 150 g were used. After filtration through a sterilizing filter, a solution was obtained which contained 100 mg of oxytetracyclin per ml. The pH was 8.8 and the viscosity 43 centipoise at 220C. At 500C the solution remained clear for more than 8 weeks and at 37QC for more than 6'months. Example 7 Preparation of a Iti oxytetracyclin solution with 40t of polyvinylpyrrolidoe (K-value 11-14). The preparation was identical to that described in Example 2, except that instead of 100 g of polyvinylpyrrolidone with a K-value of 11-14, 20t g were used. After filtration through a sterilizing filter, the solution had a pH of 8.9 and a viscosity of 66 centipoise at 2200. The solution remained stable at 500C for more than 8 weeks and at 37"C for more than 6 months. Example 8 Preparation of a 10% oxytetracyclin solution with 40% of polyvinylpyrrolidone (K-value 11-14) starting from oxytetracyclin base. The preparation was identical to that described in Example 3, except that instead 100 g of polyvinylpyrrolidon with a Kvalue of 11-14, 200 g were used. After filtration through a sterilizing filter, the solution had a pH of 8.9 and a viscosity of 100 centipoise at 200C. At 50 C the solution remained stable for more than 8 weeks and at 370C for more than 6 months. Example 9 Preparation of a 15% oxytetracyclin solution with 20% of polyvinylpyrrolidone (K-value 11-14). The following was added successively under a nitrogen atmosphere to 200 ml of boiled pyrogen free water: 100 g of polyvinylpyrrolidone, 2.5 g of sodium formaldehydesulfoxylate, 6.5 g of magnesium oxide, 85.1 g of oxytetracyclin hydrochloride, and 17.9 g of ethanolamine. The solution was made up to 500 ml and it was subsequently filtered through a sterilizing filter. The pH of the solution was 9.0 and the viscosity 80 centipoise at 220C. Example 10 Preparation of a 15 oxytetracyclin solution with 20% of polyvinylpyrrolidone (K-value 11-14) starting from oxytetra cyclin base. Starting from 90 g of oxytetracyclin hydrochloride, the base was first prepared. The preparation was identical to the procedure described in Example 3 under a. Subsequently the following was added successively under a nitrogen atmosphere to 200 ml of pyrogen free water: 100 g of polyvinylpyrrolidone (K-value 11-14), 2.5 g of sodium formaldehydesulfoxylate, 6.5 g of magnesium oxide and the oxytetracyclin base. With the aid of ethanolamine the pH was brought to 8.5 to 9.0, after which the volume was made up to 500 ml. The clear solution was filtered through a sterilizing filter. A solution was obtained with a pH of 8.8 and a viscosity of 71 centipoise at 22 C. Example 11 Preparation of a 15 oxytetracyclin solution with 302 of polyvinylpyrrolidone (K-value 11-14). Under a nitrogen atmosphere the following was added successively to 20 ml of boiled pyrogen free water: 150 g of polyvinylpyrrolidone (K-value 11-14), 2.5 g of sodium formaldehydesulfoxylate, 6.5 g of magnesium oxide, 85.1 g of oxytetracyclin hydrochloride, and 17.9 g of ethanolamine. The solution was made up to 500 ml with pyrogen free water and filtered through a sterilizing filter. A solution was obtained which contained 150 mg of oxytetracyclin per ml. The solution had a pH of 9.0 and a viscosity of 180 centipoise at 220C, Example 12 Preparation of a 15 oxytetracyclin solution with 30% of polyvinylpyrrolidone (K-value 11-14) starting from oxytetracyclin base. Starting from 90 g of oxytetracyclin hydrochloride the base was prepared in the manner described in Example 3 under a. The following was added successively to 200 ml of pyrogen free water under a nitrogen atmosphere: 150 g of polyvinylpyrrolidone, (K-value 11-14), 2.5 g of sodium formaldehydesulfoxylate, 6.5 g of magnesium oxide, and the oxytetracyclin base described above. The volume was made up to 500 ml and the solution was filtered through a sterilizing filter. The solution obtained contained 150 mg of oxytetracyclin per ml. The pH of the solution was 8.9 and the viscosity at 220C was 120 centipoise. Example 13 Preparation of a 20% oxytetracyclin solution with 20% of polyvinylpyrrolidone (K-value 11-14). The following was added successively under a nitrogen atmosphere to 200 ml of pyrogen free water: 100 g of polyvinylpyrrolidone (K-value 11-14), 2.5 g of sodium formaldehydesulfoxylate, 8.7 g of magnesium oxide, 113.4 g of oxytetracyclin hydrochloride, and 23.8 g of ethanolamine. The volume was made up to 500 ml with pyrogen free water. The solution obtained contained 200 mg of oxytetracyclin per ml and had a pH of 9.0. The viscosity at 220C was 425 centipoise. Example 14 Preparation of a 20% oxytetracyclin solution with 30% of polyvinylpyrrolidone (K-value 11-14). The following was successively added under a nitrogen atmosphere to 2()0 ml of pyrogen free water: 150 g of polyvinylpyrrolidone (K-value 11-14), 2.5 g of sodium formaldehydesulfoxylate, 8.7 g of magnesium oxide, 113.4 g of oxytetracyclin hydrochloride, and 23.8 g of ethanolamine. The volume was made up to 500 ml with pyrogen free water. The solution obtained contained 200 mg of oxytetracyclin per ml. The pH of the solution was 9.0 and the viscosity at 220C was 650 centipoise. In the next example the preparation is described, by way of comparison, of a solution with polyvinylpyrrolidone with a higher molecular weight (K17). Example 15 Preparation of a 10% oxytetracyclin-solution with 25% of polyvinylpyrrolidone (K-value 15-17). Under a nitrogen atmosphere the following was added successively to 200 ml of pyrogen free water: 125 g of polyvinylpyrrolidone (K-value 15-17, mean molecular weight 10.000), 3 g of sodium formaldehydesulfoxylate, 4.34 g of magnesium oxide, 11 g of ethanolamine and a solution of 56.7 g of oxytetracyclin hydrochloride in 100 ml of pyrogen free water. After stirring for some time, a clear solution was formed which was made up to 5 ml with pyrogen free water. The solution obtained contained 10 mg of oxytetracyclin per ml and had a pH of 8.7 and a viscosity of 156 centipoise at 22"C. This solution was very difficult to filter through a sterilizing filter. The stability at 509C was about 6 weeks and at 37"C more than half a year. The preparation of Example 4 was administered intramuscularly to piglets and calves (groups of six animals). In the following tabels the average serum concentrations obtained are shown. Table I Piglets; body weight ca. 24 kg, dose 8mg/kg EMI11.1 <tb> Hours <SEP> post <SEP> treatment <SEP> oxytetracyclin <SEP> concentration <SEP> ( <SEP> g/ml) <tb> <SEP> 1 <SEP> 3.0 <tb> <SEP> 3 <SEP> 2.9 <tb> <SEP> 5 <SEP> 3.1 <tb> <SEP> 7 <SEP> 2.4 <tb> <SEP> 14 <SEP> 0.97 <tb> <SEP> 24 <SEP> 0.39 <tb> <SEP> 28 <SEP> 0.31 <tb> <SEP> 31 <SEP> 0.19 <tb> <SEP> 48 <SEP> 0.008 <tb> Tabel II Calves; body weight ca. 190 kg; dose 8 mg/kg EMI11.2 <tb> Hours <SEP> post <SEP> treatment <SEP> oxytetracyclin <SEP> concentration <SEP> ( <SEP> g/ml) <tb> <SEP> 1 <SEP> 1.7 <tb> <SEP> 3 <SEP> 2.4 <tb> <SEP> 5 <SEP> 2.1 <tb> <SEP> 7 <SEP> 2.5 <tb> <SEP> 12 <SEP> 1.9 <tb> <SEP> 24 <SEP> 0.85 <tb> <SEP> 28 <SEP> 0.55 <tb> <SEP> 31 <SEP> 0.41 <tb> <SEP> 48 <SEP> 0.13 <tb> <SEP> 55 <SEP> 0.10 <tb> are shown. Table III Piglets; body weight ca. 24 kg, dose 20mg/kg EMI12.1 <tb> Hours <SEP> post <SEP> treatment <SEP> oxytetracyclin <SEP> concentration <SEP> ( <SEP> g/ml) <tb> <SEP> 1 <SEP> 5.1 <tb> <SEP> 3 <SEP> 5.5 <tb> <SEP> 5 <SEP> 5.2 <tb> <SEP> 7 <SEP> 4.1 <tb> <SEP> 12 <SEP> 3.0 <tb> <SEP> 24 <SEP> 1.2 <tb> <SEP> 28 <SEP> 0.76 <tb> <SEP> 32 <SEP> 0.64 <tb> <SEP> 48 <SEP> 0.18 <tb> <SEP> 56 <SEP> 0.12 <tb> Tabel IV Calves; body weight ca. 175 kg; dose 20 mg/kg EMI12.2 <tb> Hours <SEP> post <SEP> treatment <SEP> oxytetracyclin <SEP> concentration <SEP> ( <SEP> g/ml) <tb> <SEP> 1 <SEP> 4.8 <tb> <SEP> 4 <SEP> 5.6 <tb> <SEP> 5 <SEP> 4.9 <tb> <SEP> 7 <SEP> 5.1 <tb> <SEP> 12 <SEP> 4.7 <tb> <SEP> 24 <SEP> 1.6 <tb> <SEP> 28 <SEP> 1.2 <tb> <SEP> 31 <SEP> 0.90 <tb> <SEP> 48 <SEP> 0.26 <tb> <SEP> 55 <SEP> t <SEP> <SEP> 0.19 <tb> <SEP> 78 <SEP> 0.06 <tb>

Claims: Claims 1. Aqueous injectable solutions containing oxytetracyclin, a magnesium compound and polyvinylpyrrolidone with a pH of 8-9.5 characterized in that the polyvinylpyrrolidone has a molecular weight between 500 and 10,000. 2. Aqueous injectable solutions according to claim 1, characterized in that the polyvinylpyrrolidone has a molecular weight between 1000 and 5000. 3. Aqueous injectable solutions according to claim 1 or 2, characterized in that the concentration of polyvinylpyrro lidone is at least 18 percent (w/v). 4. Process for the preparation of injectable oxytetracyclin solutions which comprises dissolving in water oxytetra cyclin as a salt or a base with an appropriate amount of a magnesium compound and polyvinylpyrrolidone and bringing the pH in the range of 8.0 to 9.5, characterized in that polyvinylpyrrolidone is applied with a molecular weight between 500 and 10,000. 5. Process according to claim 4, characterized in that poly vinylpyrrolidone is applied with a molecular weight between 1000 and 5000. 6. Process according to claim 4 or 5, characterized in that a solution is prepared with at least 18 percent (w/v) of polyvinylpyrrolidone. Claims for Austria 1. Process for the preparation of injectable oxytetracyclin solutions which comprises dissolving in water oxytetra cyclin as a salt or a base with an appropriate amount of a magnesium compound and polyvinylpyrrolidone and bringing the pH in the range of 8.0 to 9.5, characterized in that polyvinylpyrrolidone is applied with a molecular weight between 500 and 10,000. 2. Process according to claim 4, characterized in that poly vinylpyrrolidone is applied with a molecular weight between 1000 and 5000. 3. Process according to claim 4 or 5, characterized in that a solution is prepared with at least 18 percent (w/v) of polyvinylpyrrolidone.

Inventors: BEUKERS, ROBERT, DIJKGRAAF, BERNARDUS LEONARDUS J., TAN, HONG SHENG
Applicants: GIST - BROCADES N.V.
Application year: 1984
Main classification: A61K9
IPC codes: A61K47, A61K9, A61K31