MXPA00007410A - Liquid pharmaceutical formulation containing zotepine - Google Patents

Abstract

A liquid pharmaceutical formulation comprising a) 2 to 7%w/v of Zotepine;b) 0.5 to 35%w/v of an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid;c) 15 to 60%v/v of ethanol and d) a liquid diluent to 100%;which may be used as drops or in a drink.

Description

PHARMACEUTICAL FORMULATION This invention relates to a liquid pharmaceutical formulation containing zotepine. Zotepine is a 2- [(8-chlorodibenzo [b, f] thiepin-10-yl) oxy] -N, N-dimethylethylamine as shown in formula I.

The preparation and psychotropic and neurotropic activity of zotepine are described in British Patent Specification 1247067 (Fujisa a). The use of zotepine for the treatment of gout is described in US Patent Specification 4,443,469 (Fujisawa). The use of zotepine to prevent recurrence in chronic schizophrenic patients is described in British patent application 9526264.8 (Knoll AG). 2- [(8-Chlorodibenzo [b, f] thiepin-10-yl) oxy] -N, N-dimethylethylamine has been available with prescription for the treatment of schizophrenia in Japan since 1982 under the trade name "Lodopin®" , and in Germany since 1990 under the trade name "Nipolept®". Zotepine is also known under the trade name "Zoleptil®". Nowadays zotepine is in the form of tablets. However, compliance on the part of patients is a well-known problem in the case of antipsychotic drugs. It would be advantageous to provide the zotepine in a liquid formulation which can be added in the form of drops or administered in a drink. However, Zotepine has a low solubility in solvents commonly used in the pharmaceutical industry to prepare oral liquid formulations. The solubility of Zotepine can be improved by converting it into an acid addition salt, but solutions of acid addition salts are unstable during storage due to hydrolysis of acid which produces 8-chlorodibenzo [b, f] tiepin-10 (11H) -one. In addition, Zotepine in solution can be subjected to oxidation to provide the nitrogen oxide with the passage of time. Surprisingly, a formulation has been found that provides Zotepine in a stable liquid formulation during storage. Accordingly, the present invention offers a liquid pharmaceutical formulation comprising a) from 2 to 7% weight / volume of Zotepine b) from 0.5 to 35% weight / volume of an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid c) from 15 to 60% volume / volume of ethanol and d) a liquid diluent to complete up to 100%. Preferably, the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid, more preferably organic acid is lactic acid. Preferably the liquid diluent is water, polyethylene glycol or sesame oil or mixtures thereof. More preferably, the diluent is water or polyethylene glycol. Especially the diluent is polyethylene glycol. In a preferred embodiment, the present invention provides a liquid pharmaceutical formulation comprising a) from 4 to 6% weight / volume of Zotepine b) from 2 to 15% weight / volume of an organic acid selected from the group consisting of ascorbic acid , citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid, c) from 20 to 30% volume / volume of ethanol and d) polyethylene glycol to complete up to 100%. Preferably the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid, more preferably organic acid is lactic acid. Preferably, the amount of organic acid used is within the range of 3 to 7% weight / volume of the formulation. More preferably, the amount of organic acid that is employed is within the range of 4 to 6% weight / volume of the formulation. The above formulations overcome the problems of low solubility of Zotepine combined with the instability of Zotepine in acid solution. The formulations also overcome the unpleasant taste characteristics of Zotepine and allow easy dispersion in water. The above formulations have good shelf lives and are well preserved. Preferably, the formulation comprises from 22 to 28% volume / volume of ethanol. More preferably, the formulation comprises from 24 to 26% volume / volume of ethanol. In a second preferred embodiment, the present invention provides a liquid pharmaceutical formulation comprising a) from 4 to 6% weight / volume of Zotepine b) from 15 to 35% weight / volume of an organic acid selected from the group consisting of acid ascorbic, citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid c) from 20 to 50% volume / volume of ethanol and d) water up to 100% complete. Preferably the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid, more preferably, the organic acid is lactic acid.

Preferably, the amount of organic acid that is employed is within the range of 18 to 32% weight / volume of the formulation. More preferably, the amount of organic acid used is within the range of 20 to 30% weight / volume of the formulation. When the diluent is water, the amount of organic acid that is used is selected in such a way that the pH of the final formulation is within the range of 2.2 to 2.6. Optionally, the liquid pharmaceutical formulation contains a preservative. Preferably, the preservative is benzyl alcohol (which may further increase the solubility of Zotepine by acting as a solubilizer) or an antioxidant agent or an antioxidant synergist or mixtures thereof. The preparation may also include an antioxidant, or antioxidant synergy agents, in order to prevent degradation by oxidation. Any of the known antioxidants can be used, for example alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium ascorbate or sodium metabisulfite or their synergistic agents, for example disodium edetate. More preferably, the antioxidant is sodium metabisulfite. The level of antioxidant used will be optimized for each formulation, for example, for sodium metabisulfite it is within a range of 0.01 to 1.0% weight / volume, more preferably within the range of 0.075 to 0.2% weight / volume. The antioxidant prevents the formation of nitric oxide from Zotepine. A particularly preferred formulation of the present invention comprises a) from 2 to 7% weight / volume of Zotepine b) from 2 to 15% weight / volume of an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid , glutaric acid, lactic acid, malic acid, sorbic acid, tartaric acid, c) from 20 to 30% weight / volume of ethanol d) from 0.01 to 1.0% weight / volume of an antioxidant and e) polyethylene glycol up to 100% complete. Preferably the formulation comprises from 4 to 6% weight / volume of Zotepine. Preferably the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid, the organic acid is preferably lactic acid.

Preferably, the amount of organic acid that is employed is within the range of 3 to 7% weight / volume of the formulation. More preferably, the amount of organic acid used is within the range of 4 to 6% weight / volume of the formulation.

Preferably the antioxidant is sodium metabisulfite. Optionally, the liquid pharmaceutical formulation contains one or more flavoring agents. Preferably, the flavoring agent is a fruit flavor, for example, lemon, lime, apple and / or a sweetening agent such as aspartame. Preferably, the flavoring agent is present in an amount of 0.1% to 5% w / v, more preferably 0.5% to 1.5% w / v of the formulation. Optionally, the liquid pharmaceutical formulation contains a surfactant that is pharmaceutically acceptable. Preferably, the surfactant is a nonionic hydrophilic surfactant. More preferably, the surfactant is polysorbate 80, for example Tween® 80. Preferably, the surfactant is present in an amount of 0.1% to 2% w / v, more preferably 0.2 to 1% w / v of the formulation. The above liquid pharmaceutical formulations are stable during storage and provide commercial products. Preferably, the formulation shows a reduction in Zotepine content of less than 10% of the original Zotepine content by weight during storage at room temperature for 2 years. More preferably, the formulation shows a reduction in Zotepine content of less than 5% during storage at room temperature for 2 years. Those skilled in the art will note that the corresponding reductions in Zotepine content under accelerated storage conditions can be used to predict the shelf life of the product by extrapolating the stability data from accelerated studies to environmental conditions. The formulations of the present invention are suitable for use as drops. Therefore, a further aspect of the present invention offers the formulations described herein in combination with a means for administering the drops. Suitable means for administering the drops include a bottle with a cap in the form of a dropper as known to those skilled in the art. The formulations of the present invention are suitable for use in a metered dose delivery system such as, for example, spray by pump action or an aerosol can under pressure, wherein the impeller preferably does not contain oxygen. Accordingly, a further aspect of the present invention provides a metered dosage administration system comprising a liquid formulation in accordance with that described herein. Alternatively, the formulations can be administered in a beverage. The formulations of the present invention are surprisingly bioequivalent to tablet formulations. The formulations can be prepared according to the present invention which are bioequivalent to 25 mg, 50 mg and 100 mg tablets. Bioequivalence can be demonstrated in humans by methods known to those skilled in the art. The formulations of the present invention can be employed in any therapeutic use of Zotepine. Particularly, the formulations of the present invention can be used in the treatment of schizophrenia, gout, schizoaffective disorders as well as to prevent relapses in the case of chronic schizophrenic patients. The invention will be illustrated below through the following non-limiting examples. Example 1% weight / volume 1 Zotepine 5.0 2 Citric acid monohydrate 30.0 3 Ethanol 96% 42.0% volume / volume 4 Lemon flavor 1.5 4 Lime flavor 0.5 5 Aspartame 1.0 6 purified water up to 100.0 * This product contains the equivalent of 40% volume / volume of absolute alcohol. The above examples were prepared by mixing ingredients 1, 2, 4 and 5 in a container. Ingredient 3 was added with continuous stirring until complete dissolution. The formulation was adjusted to volume with ingredient 6 and stirred. The Zotepine content was assayed by High Performance Liquid Chromatography employing a constant flow of eluent through a reverse phase silica column in an aqueous / organic mobile phase with acidic pH modifier. The resulting eluents were quantified by means of electronic integration and visualization was obtained at an appropriate UV wavelength. The amount of Zotepine remaining, after storage under the given conditions during the set time, is given in mg / ml. The initial concentration in each example is 50 mg / ml. The formulations were tested for appearance, zotepine content, pH, density, degradation products and microbiological acceptability at regular intervals. Time of 4 ° C 25 ° C / 60% RH 30 ° C / 60% RH shows 2 weeks 50.2 49.4 48.9 1 month 49.7 48.9 47.4 3 months 49.0 46.7 46.3 4 months 49.8 46.9 45.0 6 months 50.7 47.2 44.3 HR = Relative humidity Examples 2 to 6 were prepared and tested in a manner similar to Example 1. Example 2% weight / volume (pH 2.4) 1 Zotepine 5.0 2 Malic acid 20.0 3 Ethanol (absolute) 40% volume / volume 4 Flavored lemon 1.5 4 Flavored lemon 0.5 5 Aspartame 1.0 6 Purified water until complete at 100.0 Sample Time 30 ° C / 60% RH 2 weeks 51 .4 3 months 51 .6 6 months 50 .2 9 months 51 .3 Example 3% weight / volume (pH 2.2) 1 Zotepine 5.0 2 Malic acid 20.0 3 Ethanol 96% * 42 .0% • volume / volume 4 Apple flavor 0.2 5 Purified water until complete to L 100.0 * This product contains the equivalent of 40% volume / volume of absolute alcohol Time < ie 4 '3C 25 ° C / 60% RH 30 ° C / 60% RH 50 ° C shows 2 weeks 49. .8 49.5 49.4 47.3 1 month 50., 1 49.3 49.2 49.3 3 months 50,, 1 49.1 47.2 6 months 50. .1 49.0 47.5 9 months 50., 5 48.5 46.3 E emplo 4% weight / volume (pH 2.3) 1 Zotepine 5.0 2 Malic acid 20.0 3 Ethanol 96% * 42.0% volume / volume 4 Lemon flavored 1.5 44 SSaabboorr aa lliimmaa 0.5 5 A Agpuua ppuurriiffiiccaaída up to 100.0 * This product contains the equivalent of 40% volume / volume of absolute alcohol Sample Time 30 ° C / 60% RH 2 weeks 51.4 3 months 51.6 6 months 50.2 9 months 51.3 Example 5% weight / volume (pH 2.3) 1 Zotepine 5.0 2 Lactic acid 30.0 3 Ethanol 96% * 31.5% volume / volume 4 Lemon flavor 1.5 4 Lime flavor 0.5 5 Purified water up to 100.0 * This product contains the equivalent of 30% volume / volume of absolute alcohol Time of 4 ° C 25 ° C / 60% RH 30 ° C / 60% RH 50 ° C shows 2 weeks 49.2 49. .8 49.8 49.7 1 month 51.3 51, .2 50.8 49.3 3 months 49.2 50. .1 49.8 6 months 50.0 49., 8 48.8 Example 6% weight / volume (pH 2.6) 1 Zotepine 5.0 2 Lactic acid 20.0 3 Ethanol 96% * 42.0% volume / volume 4 Lemon flavor 1.5 4 Lima flavor 0.5 5 Purified water up to 100.0 * This product contains the equivalent of 40% volume / volume of absolute alcohol Time Sample 30 ° C / 60% RH 50 ° C 1 month 49. 5 49. 7 3 months 50. 3 6 months 50. 6 9 months 51. 0 Example 7% weight / volume 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 40.0% volume / volume 4 Lemon flavor 1.0 5 Tween 80 0.5 6 Polyethylene glycol 300 up to 100.0 * This product contains the equivalent of 25% volume / volume of absolute alcohol. The previous example was prepared by mixing the ingredients 1, 2, 4 and 5 in a container. Ingredient 3 was added with continuous stirring until the dissolution was complete. The formulation was elaborated at volume with ingredient 6 and stirred. Examples 8-10 were prepared in a manner similar to Example 7. Sample time 30 ° C / 60% RH 50 ° C 2 weeks 49.7 49.4 1 month 50.9 50.4 3 months 50.7 6 months 50.3 - Example 8% weight / volume 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 26. 0% volume / volume 4 Flavoring 1. 0% _ volume / volume 5 Tween 80 0.5 6 Polyethylene glycol 300 up to 100.0 * This product contains the equivalent of 25 volume / volume of absolute alcohol. Sample time 30 ° C / 60% RH 30 ° C 40 ° 50 '' C 2 weeks 50.0 49.0 48,. 2 3 weeks 51.4 50.1 48. . 7 4 weeks 50.8 50.3 49.7 47,, 9 3 months 50.1 6 months 50.2 Example 9% weight / volume 1 Zotepine 5.0 2 Citric acid 4.5 3 Ethanol 96% * 26.0% volume / volume 4 Polyethylene glycol 300 up to 100.0 * This product contains the following: equivalent of 25% volume / volume of absolute alcohol. Sample time 30 ° C 40 ° C 50 ° C 2 weeks 49.8 50.3 49.1 3 weeks 50.1 49.9 50.3 4 weeks 49.8 48.8 48.8 Examples 11-13 are prepared similarly to the example 7 Example 11% weight / volume 1 Zotepine 5.0 2 Malic acid 3.0 3 Ethanol 96% * 26.0% volume / volume 4 Polyethylene glycol 300 to complete up to 100.0 * This product contains the equivalent of 25% volume / volume of absolute alcohol. Example 12% weight / volume 1 Zotepine 5.0 2 Tartaric acid 2.0 3 Ethanol 96% * 26.0% volume / volume 4 Flavor 1.0% volume / volume 5 Tween 80 0.5 6 Polyethylene glycol 300 up to 100.0 * This product contains the equivalent of 25% volume / volume of absolute alcohol. Example 13% weight / volume 1 Zotepine 5.0 2 Citric acid 2.5 3 Ethanol 96% * 26.0% volume / volume 4 Flavoring 1.0% volume / volume Tween 80 0.5 6 Polyethylene glycol 300 up to 100.0 * This product contains the equivalent of 25% volume / volume of absolute alcohol Example 14% weight / volume 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 26.0% volume / volume 4 Flavoring 1.0% volume / volume 5 Polysorbate 80 0.5 6 Polyethylene glycol 300 up to 100.0 Example 15% weight / volume 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 26.0% volume / volume 4 Flavoring 1.0% volume / volume 5 Sodium metabisulphite 0.1 6 Polysorbate 80 0.5 7 Polyethylene glycol 300 to complete up to 100.0 Table 1. Zotepine nitrogen oxide levels (% according to HPLC) in examples 14 and 15 after storage in bottles with amber glass cap; Weeks storage condition Example 14 Example 15 0 < L0D < L0D 2 40 ° C / 75% relative humidity 0.16 < L0D 50 ° C 0.56 < LOD 40 ° C / 75% relative humidity 0.15 < LOD 50 ° C 1.36 < L0D 8 40 ° C / 75% relative humidity 0.46 < L0D 50 ° C 3.48 1.07 12 25 ° C / 60% relative humidity 0.12 < LOD 30 ° C / 60% relative humidity 0.14 < LOD 40 ° C / 75% relative humidity 0.63 0.47 < LOD means less than the detection limit. These results show that the addition of an antioxidant, for example sodium metabilsulfite, is advantageous for the preparation of a commercial product with a suitable shelf life. Comparative Examples Formulations that are identical to those disclosed herein except that the organic acid employed was acetic acid gave unsatisfactory stability results.

Claims (21)

1. CLAIMS 1. A liquid pharmaceutical formulation comprising: a) from 2 to 7% weight / volume of Zotepine b) from 0.5 to 35% weight / volume of an organic acid selected from the group consisting of ascorbic acid, citric acid, acid fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid c) from 15 to 60% volume / volume of ethanol and d) a liquid diluent to complete up to 100%.
2. 2. A formulation according to claim 1 wherein the liquid diluent is water, polyethylene glycol or sesame oil.
3. 3. A formulation according to claim 1, comprising: a) from 4 to 6% weight / volume of Zotepine b) from 2 to 15% weight / volume of an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid c) from 20 to 20% volume / volume of ethanol and d) polyethylene glycol up to 100% complete.
4. 4. A formulation according to any of the preceding claims, wherein the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid.
5. A formulation according to any of the preceding claims, wherein the amount of organic acid used is within a range of 3 to 7% weight / volume of the formulation.
6. A formulation according to claim 1 comprising: a) from 4 to 6% weight / volume of Zotepine b) from 15 to 35% weight / volume of an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid c) from 20 to 50% volume / volume of ethanol and d) water up to 100% complete.
7. A formulation according to claim 6 wherein the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid.
8. A formulation according to claim 6 wherein the amount of organic acid that is employed is within a range of 18 to 32% weight / volume of the formulation.
9. A formulation according to any of claims 6 to 8 wherein the pH of the final formulation is within a range of 2.2 to 2.6.
10. 10. A formulation according to any of the preceding claims wherein the organic acid is lactic acid.
11. 11. A formulation according to any of the preceding claims further comprising a preservative.
12. 12. A formulation according to claim 11 wherein the preservative is benzyl alcohol or an antioxidant or an antioxidant synergist or mixtures thereof.
13. 13. A formulation according to claim 12 wherein the antioxidant is selected from one or more of the following: alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium ascorbate as well as sodium metabisulfite and the antioxidant synergy agent is disodium edetate.
14. 14. A liquid pharmaceutical formulation according to claim 1 comprising a) from 2 to 7% weight / volume of Zotepine b) from 2 to 15% w / v of an organic acid selected from the group consisting of ascorbic acid, citric acid, fumaric acid, glutaric acid, lactic acid, malic acid, sorbic acid and tartaric acid c) from 20 to 30% weight / volume of ethanol and d) from 0.01 to 1.0% weight / volume of an antioxidant and e) polyethylene glycol until complete up to 100%.
15. 15. A formulation according to claim 14 wherein the formulation comprises from 4 to 6% weight / volume of zotepine.
16. 16. A formulation according to claim 14 or according to claim 15 wherein the organic acid is selected from the group consisting of citric acid, malic acid and lactic acid.
17. 17. A formulation according to claim 16 wherein the organic acid is lactic acid.
18. 18. A formulation according to any of claims 14 to 17 wherein the amount of organic acid that is employed is within the range of 3 to 7% weight / volume of the formulation.
19. 19. A formulation according to claim 14 wherein the antioxidant is sodium metabisulfite.
20. 20. A formulation according to claim 14 wherein the sodium metabisulfite is within a range of 0.075 to 0.2% weight / volume.
21. 21. A formulation according to any of the preceding claims which further comprises one or more flavoring agents and / or one or more sweetening agents. . A formulation according to any of the preceding claims further comprising a surfactant. . A formulation according to any of the preceding claims wherein the formulation shows a reduction of the Zotepine content of less than 10% of the original content of Zotepine by weight in storage at room temperature for 2 years.