FI69565B - FOERFARANDE FOER FRAMSTAELLNING AV ETT STABILT INJEKTIONSPREPARAT AV INDOMETACIN - Google Patents

Description

69565

Method for the preparation of a stable injection formulation of indomethacin - Preparation of a stable injection formulation of indomethacin

The present invention relates to a process for the preparation of indomethacin, i.e. a stable injection preparation of N- (p-chlorobenzoyl) -2-methyl-5-methoxy-3-indolylacetic acid.

Indolylic acid derivatives are used as non-steroidal antirheumatic drugs with good analgesic, antipyretic and anti-inflammatory activity. However, when administered orally, the compounds have a strong gastrointestinal irritant effect, and the pharmacological effect obtained with orally administered compounds is not always satisfactory. Thus, a parenteral dosage form such as injection would be highly desirable. Injection as a dosage form has other advantages, such as rapid effect, topical applicability, and improved biological response. However, the preparation of the injection is difficult because the indolylic acid derivatives are very sparingly soluble in water. N- (p-chlorobenzoyl) -2-methyl-5-methoxy-3-indolylacetic acid, indomethacin, is a weak acid that is virtually insoluble in water, making it difficult to achieve a therapeutically effective concentration in water.

However, it is possible to prepare aqueous solutions of indole acid derivatives in the desired concentrations using their alkali salts. However, solutions prepared in this way must be used relatively quickly after preparation. In these solutions, the compounds decompose and the effect of the solutions disappears.

GB Patent 1,195,612 describes a process for preparing a stable injection preparation of indylic acid derivatives. According to this method, the indolyl acid derivative is dissolved in an anhydrous, pharmaceutically acceptable organic solvent, especially glycofurol or dimethylacetamide, and an aqueous solution containing an alkanolamine or a basic amino acid is added to the resulting solution to prepare an injection of 2,69565 moles of acid at 0.6 to 1 mol. The proportion of water in the solution of the indolylic acid derivative and the anhydrous organic solvent should be less than 50% to prevent precipitation of the acid derivative.

DE-A-19 23 574 describes attempts to eliminate the disadvantages caused by the poor solubility of indolylacetic acids by preparing dry sodium salts. In this case, water is removed from the aqueous solutions of the alkali salts as soon as they are formed, e.g. by freeze-drying. This gives a powder which can be easily redissolved in water. But, since complete removal of water is not possible, the resulting powders are relatively poorly preserved. The active substance is gradually hydrolytically degraded by water residues. In order to obtain a preservative alkali salt powder, DE application 19 23 574 proposes that the dry matter be prepared by adding strongly basic amines and 5-10 times by weight of filler. The solutions thus prepared have a temporal pH, which makes the preparation questionable.

It is known that surfactants can be used to make otherwise sparingly water-soluble substances more soluble. Thus, for example, in DE-A-27 30 570, a micellar former (bile acid) is added together with a phospholipid used as an excipient. As can be seen from the examples in the description, the addition of bile acids is necessary to achieve dissolution. DE-A-23 15 609 also describes a process for dissolving indomethacin in water. Here, too, the use of bile acids, such as dehydro-bile acid, is essential. Dehydro-bile acid is used in an amount of 110 x weight compared to indomethacin. However, only 0.18% by weight of indomethacin is soluble in water by this method.

According to the invention, it has now been found possible to prepare an injection of indomethacin which does not show precipitation and in which the active substance does not decompose during autoclaving or storage for a longer time by dissolving indomethacin 3 69565 in an organic solvent and combining the resulting indomethacin solution with an aqueous organic amine solution. The process according to the invention is characterized in that the organic solvent used is 5 to 8 times the weight of dimethyl isosorbide relative to indomethacin, optionally filled with ethanol to the desired volume, and that the organic amine is used in an amount of 0.5 to 1.50 mol per mol of indomethacin.

According to the invention, there is provided a stable aqueous injection preparation containing a therapeutically appropriate amount of indomethacin while maintaining a sufficiently high proportion of water. Depending on the intended use, the injection may contain, for example, from about 5 to about 60 mg / ml, preferably from about 10 to 50 mg / ml of indomethacin, at a concentration of about 50 mg / ml, which is particularly suitable for therapeutic use. Stability tests carried out show that, for example, the initial injection of indomethacin according to the invention containing 10 mg / ml showed no degradation after two months of storage, the active ingredient concentration was 9.8 mg / ml after six months and a further 9.74 mg / ml after eight months.

According to the invention, the proportion of water used in the injection can be increased without the risk of precipitation of the active substance. The proportion of water depends on the concentration of indomethacin used. For practical purposes, when the amount of the indolyl acid derivative varies from 5 to 60 mg / ml, the volume ratio between the aqueous solution and the organic solution may be between 90:10 and 40:60. For practical injections containing 50 mg / ml indomethacin, this ratio is suitably about 50:50.

As the organic solvent, dimethyl isosorbide is used, which, if desired, is diluted to a suitable volume with ethanol. Dimethyl isosorbide has previously been used, for example, as a carrier in topical pharmaceutical preparations of steroids and acetylsalicylic acid (U.S. Patents 4,082,881 and 4,126,681), as well as in some very sparingly 4,69565 soluble drugs such as metocarbamol, paraxamol and metaxalone. in which the active ingredient is dissolved in dimethyl isosorbide or aqueous dimethyl isosorbide solutions (U.S. Patent 3,699,230).

The injection according to the invention preferably also uses polyvinylpyrrolidone, which is added to the aqueous solution during the preparation. Its proportion in the total injection is at most about 20% w / v, preferably 5-10% w / v of the finished injection, although this amount is not critical. Suitable grades are those with a K value of 11-18. Polyvinylpyrrolidone acts as a solubility enhancer and allows the tissue to tolerate injection better. To prevent yellowing of the polyvinylpyrrolidone, it is convenient to include an antioxidant in the amount of about 0.5-3% of the amount of polyvinylpyrrolidone. Suitable antioxidants include sodium sulfite, sodium pyrosulfite and sodium disulfite.

As the organic amine, for example, ethanolamine, diethanolamine, triethanolamine, 2-dimethylaminoethanol or 2-diethylaminoethanol are used as the alkanoamine, and, for example, arginine and lysine are used as basic amino acids. The amount of the organic amine is preferably 0.7 to 1.0 moles per mole of the indolylic acid derivative.

Because the ingredients of the injection are sensitive to oxidation, sterile nitrogenous water is used as the water. Ampoules are also tyed immediately after filling immediately before sealing.

The injection preparation according to the invention can be administered as a single injection or as a continuous infusion, depending on the need for treatment.

The following examples illustrate the invention without, however, limiting it.

il 5,695 65

Example 1: g / 100 ml indomethacin 5.00 g dimethyl isosorbide 30.00 g ethanol per 50 ml sodium pyrosulfite 0.20 g polyvinylpyrrolidone, K-12 10.00 g diethanolamine 1.50 g water per 50 ml

Indomethacin is dissolved in dimethyl isosorbide and the solution is made up to 50 ml with ethanol. Sodium pyrosulfite is dissolved in about 40 any water, after which polyvinylpyrrolidone is dissolved. Lastly, diethanolamine is added and the solution is made up to 50 ml with water. The solutions are combined, and the solution thus obtained is sterile filtered and dispensed into ampoules, which are nitrogenated and sealed. The pH of the solution was 7.5. Its shelf life was excellent.

Example 2t g / 100 ml indomethacin 5.00 g dimethyl isosorbide 30.00 g ethanol 50 ml sodium pyrosulphite 0.10 g polyvinylpyrrolidone, K-12 5.00 g L-arginine 1.80 g water 50 ml

Prepared according to the previous example. The pH of the solution was 6.25. Its shelf life was excellent.

Example 3t g / 100 ml indomethacin 1.00 g dimethyl isosorbide 6.00 g ethanol per 20 ml 6 69565 sodium sulphite 0.20 g polyvinylpyrrolidone, (Plasdone C-15) 10.00 g L-arginine 0.61 g water 80 ml KSI

Prepared according to the previous example. The pH of the solution was 8.0. The ratio of organic to aqueous solution in this injection is 20:80 and the amount of amine is 1.25 moles per mole of indomethacin.

Example 4: g / 100 ml indomethacin 1.00 g dimethyl isosorbide 6.00 g ethanol per 20 ml sodium pyrosulfite 0.20 g polyvinylpyrrolidone, (Plasdone C-15) 10.00 g L-arginine 0.73 g water 80 ml

Prepared according to the previous example. The pH of the solution was 7.0. The ratio of organic to aqueous solution in this example is 20:80 and the amount of amine is 1.5 moles per mole of indomethacin.

Example 5: g / 100 ml indomethacin 2.00 g dimethyl isosorbide 12.00 g ethanol to 20 ml sodium pyrosulfite 0.10 g polyvinylpyrrolidone, (Kollidon 17 PF) 7.50 g L-arginine 1.12 g water 80 ml KSI

Prepared according to the previous example. The pH of the solution was 7.75. The ratio of organic to aqueous solution in this example is 20:80 and the amount of amine is 1.15 moles per mole of indomethacin.

11

Claims (10)

69565 Example 6: g / 100 ml indomethacin 2.00 g dimethyl isosorbide 12.00 g ethanol to 30 ml sodium sulphite 0.10 g polyvinylpyrrolidone, (Plasdone C-15) 5.00 g L-arginine 0.78 g water To 70 ml Prepare according to the previous example. The pH of the solution was 6.1. The ratio of organic to aqueous solution in this example is 30:70 and the amount of amine is 0.8 moles per mole of indomethacin. A process for preparing a stable injection preparation of indomethacin, which comprises dissolving indomethacin in an organic solvent and combining the resulting solution of indomethacin with an aqueous solution of an organic amine, characterized in that - 5-8 times the weight of volume, and that - 0.5 to 1.50 moles of organic amine are used per mole of indomethacin. Process according to Claim 1, characterized in that the concentration of indomethacin in the injection is about 5 to 60 mg / ml, in particular 50 mg / ml. Process according to Claim 1 or 2, characterized in that the volume ratio of the organic solution to the aqueous solution is from about 10:90 to 60:40, in particular from about 50:50. __ - τ 8 69565 Process according to Claim 1, characterized in that polyvinylpyrrolidone is added to the aqueous solution in a proportion of up to about 20, preferably about 5 to 10% (w / v) of the injection preparation. Process according to Claim 4, characterized in that polyvinylpyrrolidone having a K value of 11 to 18 is used. Process according to Claim 4 or 5, characterized in that 0.5 to 3% of an antioxidant, such as sodium sulfite, pyrosulfite or disulfite, is added to the preparation to prevent yellowing of the polyvinylpyrrolidone. Process according to one of the preceding claims, characterized in that ethanolamine, diethanolamine, triethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, arginine or lysine are used as the organic amine. Process according to one of the preceding claims, characterized in that 0.7 to 1.0 moles of amine are used per mole of indomethacin. A process for the preparation of a stable injection formulation of indomethacin, preferably an indetacin-containing formulation and an organic formulation, and a particular formulation of the formulation of a water-containing organic form, including an amine, dimethyl isosorbides in the form of indomethacin 5-8-fold in the form of an amount of hydrogen, ethanol in the form of an ethanolate in the amount of 0.5-1.5 mol per mol of indomethacin.