Zotepine is 2- [ (8-chlorodibenzo [b, f] thiepin-10-yl) oxy}-N, N-dimethylethylamine as shown in formula I.

The preparation and the psychotropic and neurotropic activity of Zotepine are described in British Patent Specification 1247067 (Fujisawa). The use of Zotepine in the treatment of gout is described in United States patent specification 4,443,469 (Fujisawa). The use of Zotepine for preventing relapse 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 on prescription for the treatment of schizophrenia in Japan since 1982 under the tradename"Lodopin@", and in Germany since 1990 under the tradename "Nipolept@". Zotepine is also known under the tradename"Zoleptil@".

Zotepine is currently only available in tablet form. However, patient compliance is a well-known problem with anti-psychotic drugs. It would be advantageous to provide Zotepine in a liquid formulation which might be added as drops to food or administered in a drink. However, Zotepine has a low solubility insolents which would commonly be used in the pharmaceutical industry to prepare oral liquid formulations.

Solubility of Zotepine may be improved by converting it into an acid addition salt, but solutions of acid addition salts are unstable on storage due to acid hydrolysis which produces 8-chlorodibenzo [b, f] thiepine-10 (11 H)-one. In addition Zotepine in solution may undergo oxidation to give the N-oxide over time. Surprisingly a formulation has now been found which provides Zotepine in a liquid formulation which is stable to storage.

Accordingly, the present invention provides 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%.

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 liquid diluent is water, polyethylene glycol or sesame oil or mixtures thereof. More preferably the diluent is water or polyethylene glycol. Most preferably the diluent is polyethylene glycol.

In a preferred embodiment the present invention provides a liquid pharmaceutical formulation comprising a) 4 to 6% w/v of Zotepine b) 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) 20 to 30% v/v of ethanol and d) polyethylene glycol to 100%.

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 used is in the range of 3 to 7% w/v of the formulation. Most preferably the amount of organic acid used is in the range of 4 to 6% w/v of the formulation.

The above formulations overcome the problems of the low solubility of Zotepine combined with the instability of the Zotepine in acidic solution. The formulations also overcome the poor taste characteristics of Zotepine and allow ease of dispersion into water. The above formulations have good shelf-lives and are well preserved.

Preferably the formulation comprises 22 to 28% v/v of ethanol. More preferably the formulation comprises 24-26% v/v of ethanol.

In a second preferred embodiment the present invention provides a liquid pharmaceutical formulation comprising a) 4 to 6% w/v of Zotepine b) 15 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) 20 to 50% v/v of ethanol and d) water to 100%.

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 used is in the range of 18 to 32% w/v of the formulation. Most preferably the amount of organic acid used is in the range of 20 to 30% w/v of the formulation.

When the diluent is water the amount of organic acid used is selected such that the pH of the final formulation lies in the range of 2.2 to 2.6.

Optionally the pharmaceutical liquid formulation contains a preservative.

Preferably the preservative is benzyl alcohol (which can further enhance the solubility of Zotepine by acting as a solubilizer) or an anti-oxidant or an anti-oxidant synergist or mixtures thereof. The preparation may also include an antioxidant, or antioxidant synergists, to prevent oxidative degradation. Any of the known antioxidants may be used, for example alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium ascorbate or sodium metabisulphite or their synergists for example disodium edetate. More preferably the antioxidant is sodium metabisulphite. The level of antioxidant used will be optimised for each formulation, for example for sodium metabisulphite is in the range 0.01 to 1.0% w/v, more preferably in the range 0.075 to 0.2% w/v. The anti-oxidant prevents the formation of Zotepine N-oxide.

A particularly preferred formulation of the present invention comprises a) 2 to 7% w/v of Zotepine b) 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, tartaric acid c) 20 to 30% w/v of ethanol d) 0.01 to 1.0% w/v of an anti-oxidant and e) polyethylene glycol to 100%.

Preferably the formulation comprises 4 to 6% w/v of zotepine.

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 used is in the range of 3 to 7% w/v of the formulation. Most preferably the amount of organic acid used is in the range of 4 to 6% w/v of the formulation.

Preferably the anti-oxidant is sodium metabisulphite.

Optionally the liquid pharmaceutical formulation contains one or more flavouring agents. Preferably the flavouring agent is a fruit flavour for example lemon, lime, apple and/or a sweetening agent for example aspartame.

Preferably the flavouring agent is present in an amount of from 0.1 % to 5% w/v, more preferably from 0.5% to 1.5% w/v of the formulation.

Optionally the liquid pharmaceutical formulation contains a surfactant which is pharmaceutically acceptable. Preferably the surfactant is a hydrophilic non-ionic surfactant. More preferably the surfactant is polysorbate 80 for example Tweens 80.

Preferably the surfactant is present in an amount of from 0.1 % to 2% w/v, more preferably from 0.2 to 1 % w/v of the formulation.

The above liquid pharmaceutical formulations are stable on storage and provide commercial products. Preferably the formulation shows a reduction of Zotepine content of less than 10% of the original Zotepine content by weight on storage at ambient temperature for 2 years. More preferably the formulation shows a reduction of Zotepine content of less than 5% on storage at ambient temperature for 2 years. It will be appreciated by those skilled in the art that corresponding reductions in Zotepine content under accelerated storage conditions may also be used to predict the shelf life of the product by extrapolating stability data from accelerated studies to ambient conditions.

The formulations of the present invention are suitable for use as drops.

Therefore a further aspect of the present invention provides the formulations described herein in conjunction with a means for delivering drops. Suitable means for delivering 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 dosage delivery system such as a pump-action spray or a pressurised aerosol can, in which the propellant is preferably free of oxygen.

Therefore a further aspect of the invention provides a metered dosage delivery system which comprises a liquid formulation as described herein.

Alternatively the formulations may be administered in a drink.

The formulations of the present invention are surprisingly bioequivalent to tablet formulations. Formulations may be prepared according to the present invention which are bioequivalent to 25 mg, 50 mg and 100 mg tablets. Bioequivalence may be demonstrated in humans by methods known to those skilled in the art.

The formulations of the present invention may be used in any known therapeutic uses of Zotepine. In particular, the formulations of the present invention may be used in the treatment of schizophrenia, gout, schizoaffective disorders and for preventing relapse in chronic schizophrenic patients.

The invention will now be illustrated by the following non-limiting examples.

Example 1 % w/v 1 Zotepine 5.0 2 Citric acid monohydrate 30.0 3 Ethanol 96% 42.0 % v/v 4 Lemon Flavour 1.5 4 Lime Flavour 0.5 5 Aspartame 1.0 6 Purified water to 100.0 * This product contains the equivalent of 40% v/v Absolute Alcohol.

The above example was prepared by mixing ingredients 1,2,4 and 5 in a vessel.

Ingredient 3 was added with continuous stirring until dissolution was complete. The formulation was made up to volume with ingredient 6 and stirred.

The Zotepine content was assayed by High Performance Liquid Chromatography using constant flow of eluent through a reversed phase silica column in an aqueous/organic mobile phase with acidic pH modifier. The resulting eluents were quantified by electronic integration and visualisation was achieved at an appropriate UV wavelength. The amount of Zotepine remaining, after storage under the conditions given for the time stated, is given in mg/ml. The starting 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. Sample Time 4°C 25°C/60% Rh 30°C/60% Rh weeks 5. 49. 4 4. 1 mont 49.7 48. 9 47. 4 3 months 49. 0 46. 7 46. 3 4 months 49. 8 46. 9 45. 0~~ 6 months 5.7 47. 2 44.

Rh = Relative humidity Examples 2 to 6 were prepared and tested in a similar manner to Example 1.

Example 2 % w/v (pH 2.4) 1 Zotepine 5.0 2 Malic acid 20.0 3 Ethanol (absolute) 40.0 v/v 4 Lemon Flavour 1.5 4 Lime Flavour 0.5 5 Aspartame 1.0 6 Purified water to 100.0 Sample Time 30°C/60% Rh weeks51.4 3 months 51. 6 50.26months 9 months 51.3 Example 3 % w/v (pH 2.2) 1 Zotepine 5.0 2 Malic acid 20.0 3 Ethanol 96% * 42.0 % v/v 4 Apple Flavour 0.2 5 Purified water to 100.0 * This product contains the equivalent of 40% v/v Absolute Alcohol ample Time 4°C 25°C/60% Rh 30°C/60% Rh 50°C 2 weeks 49. 8 49. 5 49. 4 47. 3 1 month 50.1 49.3 49.2 49. 50.149.147.2-3months 50.149.047.5-6months 50.548.5463-9months Example 4 % w/v (pH 2.3) 1 Zotepine 5.0 2 Malic acid 20.0 3 Ethanol 96% * 42.0 % v/v 4 Lemon Flavour 1.5 4 Lime Flavour 0.5 5 Purified water to 100.0 * This product contains the equivalent of 40% v/v Absolute Alcohol Sample Time 30"C/60% Rh 2 #s 51. 4 ~ 3 months 51. 6 months50.2 9 months 51. 3 Example 5 % w/v (pH 2.3) 1 Zotepine 5.0 2 Lactic acid 30.0 3 Ethanol 96% * 31.5 % v/v 4. Lemon Flavour 1.5 4 Lime Flavour 0.5 5 Purified water to 100.0 * This product contains the equivalent of 30% v/v Absolute Alcohol Sample Time Rh30°C/60%Rh50°C25°C/60% 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 - 50.049.848.8-6months Example 6 % w/v (pH 2.6) 1 Zotepine 5.0 2 Lactic acid 20.0 3 Ethanol 96% * 42.0 % v/v 4. Lemon Flavour 1.5 4 Lime Flavour 0.5 5 Purified water to 100.0 * This product contains the equivalent of 40% v/v Absolute Alcohol Sample Time 30°C/60% Rh 50°C 1month 49. 5 49. 7 3months 50. 3 650. 9 51.

Example 7 % w/v 1 Zotepine 5.0 2 Lactic acid4.5 3 Ethanol 96% * 40.0 % v/v 4 Lemon flavour 1.0 % v/v 5 Tween 80 0.5 6 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol.

The above example was prepared by mixing ingredients 1,2, 4 and 5 in a vessel. ingredient 3 was added with continuous stirring until dissolution was complete. The formulation was made up to volume with ingredient 6 and stirred. Examples 8-10 were prepared in a similar manner to Example 7. Sample 30°C/60% Rh 50°C Time 2 weeks 49. 7 49.4 1 month 50.4 50.7-3months 50.3-6months Example 8 % w/v 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 26.0 % v/v 4 Flavour 1.0 % v/v 5 Tween 80 0.5 6 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol. Sample 30°C60% Rh 40°C50°CTime30°C 2 weeks - 50.0 49.0 48.2 351.450.148.7- 50.850.349.747.94weeks 3 months 50.1 - - - 6 ---50.2 Example 9 % w/v 1 Zotepine 5.0 2 Citric acid 4.5 3 Ethanol 96% * 26.0 % v/v 4 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol. ample Time 30°C 40°C 50°C 2 weeks 50. 0 49.6 48. 2 3 weeks 50. 2 49.5 48. 2 4weeks 50. 5 48. 4 47. 9 Example 10 % w/v 1 Zotepine 5.0 2 Malic acid 4.5 3 Ethanol 96% * 26.0% v/v 4 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol. Sample Time 30°C 40°C 50°C 2 weeks 49. 8 50. 3 49. 1 wee s. 1 4. 5. 4 weeks 49. 8 48. 8 48. 8 Examples 11-13 are prepared in a similar manner to Example 7.

Example 11 % w/v 1 Zotepine 5.0 2 Malic acid 3.0 3 Ethanol 96% * 26.0 % v/v 4 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol.

Example 12 % w/v 1 Zotepine 5.0 2 Tartaric acid 2.0 3 Ethanol 96% * 26.0 % v/v 4 Flavour 1.0 % v/v 5 Tween 80 0.5 6 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol.

Example 13 % w/v 1 Zotepine 5.0 2 Citric acid 2.5 3 Ethanol 96% * 26.0 % v/v 4 Flavour 1.0 % v/v 5 Tween 80 0.5 6 Polyethylene glycol 300 to 100.0 * This product contains the equivalent of 25% v/v Absolute Alcohol.

Example 14 % w/v 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 26.0 % v/v 4 Flavour* 1.0 % v/v 5 Polysorbate 80 0.5 6 Polyethylene glycol 300 to 100.0 Example 15 % w/v 1 Zotepine 5.0 2 Lactic acid 4.5 3 Ethanol 96% * 26.0 % v/v 4 Flavour* 1.0 % v/v 5 Sodium metabisulphite 0.1 6 Polysorbate 80 0.5 7 Polyethylene glycol 300 to 100.0 Table 1. zotepine-N-Oxide levels (% by HPLC) in Example 14 and 15 after storage in amber glass screw-capped bottles; Weeks Storage condition Example 14 Example 15 0 <LOD <LOD 0.16< 50°C 0. 56'LOD 4 <0.15 50°C 1. 36 <LOD 0.46<LOD840°C/75%RH 50°C 3. 48 1. 07 12 25°C/60% RH 0. 12 <LOD 30°C/60% RH 0.14 <LOD 40°C/75% RH 0. 63 0. 47 <LOD means less than limit of detection.

These results demonstrate that the addition of an anti-oxidant e. g. sodium metabisulphite is advantageous in the preparation of a commercial product with a suitable shelf-life.

Comparative Examples Formulations which are identical to those disclosed herein except that the organic acid used was acetic acid gave unsatisfactory stability results.