Background of the Invention WO 98/28293 describes a series of substituted indane and dihydroindole compounds having effect at dopamine D4 receptors. The compounds described are considered useful for the treatment of a range of psychiatric and neurological disorders, including the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders and for the improvement of sleep.

(S)- (+)-3- [1- [2- (l-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6- chloro-1H-indole is described in WO 98/28293 as a crystalline base.

It has now been found that (S)- (+)-3- [l- [2- (l-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl] - 1, 2,3, 6-tetrahydropyndin-4-yl]-6-chloro-lH-indole having the formula

which is described in WO 98/28293 as a potent dopamine D4 ligand, may be particularly useful as a pharmaceutical.

(S)- (+)-3- [l- [2- (l-Acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]- 6-chloro-lH-indole has, however, proven to be very difficult to formulate into a pharmaceutical composition that has good storage stability, is feasible for oral administration and provides a high bioavailability of the compound.

(S)- (+)-3- [l- [2- (l-Acetyl-2, 3-dihydro-lH-indol-3-yl) etliyl]-1, 2,3, 6-tetrahydropyridin-4-yl] - 6-chloro-lH-indole as the free base has a very low solubility in aqueous solutions as well as in many other pharmaceutically acceptable solvent systems, such as liquid, semisolid or solid solvent systems. Associated with the very low solubilities are very low dissolution rates. The very low solubilities and dissolution rates together result in a low bioavailability of the compound.

The hydrochloride of (S)- (+)-3- [l- [2- (l-acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indole has improved aqueous solubility and dissolution rates as compared to the free base. Conventional pharmaceutical compositions, such as conventional melt granulations, comprising the hydrochloride does, however, result in a bioavailability of the (S)- (+)-3- [l- [2- (l-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indole that is considerably lower than by oral gavage administration of the compound dissolved in a 5% aqueous solution of sulfobutylether-ß- cyclodextrin (Captisol@). Various tablet excipients used in the composition may also have negative impact on the storage stability of the pharmaceutical composition.

(S)- (+)-3- [l- [2- (l-Acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]- 6-chloro-1H-indole, in particular in the form of the free base, is very susceptible to decomposition under influence by various agents comprising water, moisture and oxidising agents such as oxygen or peroxides.

Hence, there is a desire for a storage stable pharmaceutical composition comprising (S)- (+)- 3- [1- [2- (l-acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl] -6-chloro-

lH-indole which is feasible for oral administration and provides an improved bioavailability of the compound.

Summary of the Invention Thus, the present invention relates to a pharmaceutical composition comprising a melt granulate comprising (S)- (+)-3- [l- [2- (1-acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indole or a phannaceutically acceptable acid addition salt thereof ; a surfactant; a saturated mono-, di-or triglyceride; and a filler.

Furthermore, the invention relates to a method for the treatment of the positive and negative symptoms of schizophrenia, other psychoses, anxiety disorder, such as generalised anxiety disorder, panic disorder and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia, cardiovascular disorders and for the improvement of sleep, in particular the positive and negative symptoms of schizophrenia, other psychoses and depression, comprising administering a pharmaceutically acceptable amount of the pharmaceutical composition described above.

Detailed Description of the Invention The compound (S)- (+)-3- [l- [2- (l-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indole was first disclosed in WO 98/28293 as a crystalline base.

The crystalline base of (S)- (+)-3- [l- [2- (1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl] - 1,2, 3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indole has a very low solubility and a low intrinsic dissolution rate, which affect the bioavailability of the compound The hydrochloride of (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indole may be prepared as a stable crystalline salt with improved solubility and dissolution rate.

The aqueous solubility for the hydrochloride salt of the invention is 130 p. g/ml whereas the solubility of the crystalline free base is 0.2 jg/ml. The intrinsic dissolution rate, i. e the amount of substance released pr minute and pr cm2 from a tablet of pure compound of formula I in water at 35 °C is 0.016 for the hydrochloride and 0.0005 for the free crystalline base.

It has now, surprisingly, been found that pharmaceutical compositions comprising (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro- lH-indole hydrochloride and one or more compounds selected from the group comprising surfactants, such as Cs-20 linear alkyl sulphates, Tween 80 and poloxamer ; and saturated mono-, di-or triglycerides may result in bioavailabilities for (S)- (+)-3- [1- [2- (1-acetyl-2, 3- dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-1H-indole which are comparable to that for oral gavage administration of the compound dissolved in a 5% aqueous solution of sulfobutylether-ß-cyclodextrin (Captisolt) Preferably, the composition comprises one or more saturated mono-, di-or triglycerides.

Preferably the glycerides are selected from medium and long chain glycerides. As used herein the term'medium chain glycerides'comprises glycerides with C8-14 chains, whereas the term'long chain glycerides'comprises glycerides with chains longer than Cl4.

Throughout this application concentrations are given as percent w/w unless otherwise stated.

Preferably, the composition comprises a medium chain monoglyceride or a mixture of medium chain monoglycerides, preferably a C8 chain monoglyceride or a Cg-Cio chain monoglyceride mixture, in a concentration in the range of 0-12%, preferably in the range of 2-10% and more preferred in the range of 4-8%.

Preferably, the composition comprises a medium chain triglyceride, in a concentration in the range of 0-12%, preferably in the range of 2-10% and more preferred in the range of 4-8%.

Preferably, the composition comprises a long chain mono-or triglyceride, preferably a Cl6 l8 chain mono-or triglyceride, in a concentration in the range of 0-12%, preferably in the range

of 2-10% and more preferred in the range of 4-8%. Preferably the long chain glyceride is a monoglyceride.

Preferably, the composition comprises a surfactant. Preferably the surfactant is selected from the group comprising Cl-20 linear alkyl sulphates, Poloxamer, polyoxyethylene sorbitan fatty acid esters, such as the Tween products, in particular Tween 80, polyoxyethylene fatty acid esters, polyethylene glycol alkyl esters and alcohol-oil transesterified products, such as the Cremophor and Labrafil products, in particular Cremophor RH40; more preferred are Cl0 l6 linear alkyl sulphates; and most preferred sodium lauryl sulphate (SLS).

Preferably, the surfactant is present in a concentration in the range of 0-25%, preferably in the range of 5-20% and more preferred in the range of 10-15%.

Preferably, the active ingredient is present in a concentration in the range of 0-25%, preferably in the range of 5-20% and more preferred in the range of 12-16%.

The beneficial effects of these surfactants on the bioavailability of (S)- (+)-3- [1- [2- (1-acetyl- 2, 3-diliydro-IH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropylidin-4-yl]-6-chloro-1H-indole may be attributed to their high hydrophile-lipophile balance (HLB). The surfactants used in this patent are classified after the empirical hydrophile-lipophile balance approach devised by (Griffin, W. C., J. Soc. Cosmetic Chem. 1949,1, 311). In this system the HLB number of a surfactant is calculated according to a empirical formula: where S is the saponification number of the ester and A is the acid number of the fatty acid. Although this formula is mainly applied to non-ionic surfactants it is possible to obtain numbers for ionic surfactants; the numbers for ionic surfactants are obtained empirically and may have a value above 20.

Surfactants used according to the invention have a HLB of at least 10, preferably in the range of 10-60, more preferred in the range of 25-55, even more preferred in the range of 35 to 50, and most preferred in the range of 37-45.

The pharmaceutical compositions according to the invention comprise (S)- (+)-3- [1- [2- (1- acetyl-2, 3-diliydro-1H-indol-3-yl) etliyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indole in the form of the free base or a pharmaceutically acceptable acid addition salt. Preferably the pharmaceutical composition comprises (S)- (+)-3- [l- [2- (I-acetyl-2, 3-dihydro-IH-indol- 3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indole in the form of a pharmaceutically acceptable acid addition salt, more preferred a hydrohalogenide and most preferred a hydrochloride. Preferably the salts are anhydrous.

The pharmaceutical compositions according to one embodiment of the invention comprise an antioxidant. Preferably the antioxidant is selected from the group comprising ascorbyl palmitate, propyl gallate, tochepherol, butylhydroxyanisole (BHA) and butylhydroxytoluene (BHT), and more preferably the antioxidant is ascorbyl palmitate. Preferably, the antioxidant is present in a concentration in the range of 0-3%, preferably in the range of 0.1-2% and more preferred in the range of 0.2-1%.

Specific examples of fillers are e. g. calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrans, dextrin, dextrose, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar etc. Preferably the filler is lactose.

Preferably, the filler is present in a concentration in the range of 30-80%, preferably in the range of 40-70% and more preferred in the range of 50-60%.

Disintegrants may also be included in the composition. Examples include alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinized starch, carboxymethyl starch (e. g. Primogelg and Explotab@) etc.

Glidants and lubricants may also be included in the composition. Examples include stearic acid, magnesium stearate, calcium stearate or other metallic stearate, talc, waxes and glycerides, light mineral oil, PEG, glyceryl behenate, colloidal silica, hydrogenated

vegetable oils, corn starch, sodium stearyl fumarate, polyethylene glycols, alkyl sulfates, sodium benzoate, sodium acetate etc.

Other excipients which may be included in the second composition (and/or in the carrier composition) are e. g. colouring agents, taste-masking agents, pH-adjusting agents, solubilizing agents, stabilising agents, wetting agents, surface active agents, antioxidants, agents for modified release etc.

In one embodiment of the invention the pharmaceutical composition is compressed into a tablet or contained in a capsule, preferably a gelatine or hydroxypropyl methyl cellulose (HPMC) capsule, and most preferred a gelatine capsule.

In one embodiment of the invention the composition does not comprise significant amounts of compounds that easily form peroxides. Exemplary of such compounds are compounds containing double bonds or PEG chains. In another embodiment of the invention the composition may contain such compounds that easily form peroxides as long as the compounds that may form peroxides are physically separated from the active ingredient in such a way that they will not interact until dissolution in the gastrointestinal tract.

The crystalline hydrochloride salt of (S)- (+)-3- [1- [2- (l-acetyl-2, 3-dihydro-lH-indol-3- yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indole may be prepared by dissolving the base in a solvent at room temperature and thereafter introducing HC1 (g) or a solution containing HC1 while keeping the temperature below 35 °C. The crystalline hydrochloride fonned is then filtered off and optionally washed and dried.

Suitable solvents for the precipitation of the hydrochloride salt are solvents in which the base of (S)- (+)-3- [l- [2- (1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4- yl]-6-chloro-lH-indole may be dissolved at room temperature. An example of such a solvent is N, N-dimethylacetamide, or mixtures of N, N-dimethylacetamide and tetrahydrofurane.

Acetone may also be used but is less preferred in industrial scale.

In general alcohols are not suitable as a solvent for the preparation of the hydrochloride of the invention because alkoxy derivatives of the compound of the invention are formed.

The crystalline free base of (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl] - 1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indole may be prepared as described in example 34 of WO 98/28293.

Hydrates and solvates of the hydrochloride used in the invention are combinations of the molecule of the invention with water molecules or other solvent molecules, such as the hemihydrate, the hydrate and the anhydrate.

Suitably, the hydrochloride used in the invention is in the form of an anhydrate.

(S)- (+)-3- [1- [2- (1-Acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]- 6-chloro-lH-indole as the free base as well as other salts may be formulated into pharmaceutical compositions according to the invention analogous to the hydrochloride.

Pharmaceutical Compositions The pharmaceutical compositions according to the invention may be produced by conventional melt granulation whereby the components of the compositions are mixed in a mixer and heated to a temperature above the melting point for the glycerides resulting in granulation of the material whereafter the granulate is cooled to ambient temperature.

The melt granulate according to the invention may be mixed with compressing agents, such as microcrystalline cellulose, solutol or mannitol, and compressed into tablets.

Example 1 Precipitation of (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-lH-indole-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indol hydrochloride with HCl (g) 10 g (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl] -1,2, 3,6-tetrahydropyridin-4- yl]-6-chloro-1H-indole is slurried in water and filtered. The wet filter cake is dissolved in 18 mL dimethylacetamide and 100 mL THE at room temperature. 1.1 g HCl-gas is added and the temperature is kept below 30 degrees. (S)- (+)-3- [l- [2- (l-acetyl-2, 3-dihydro-177-mdol-3-

yl) ethyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indole hydrochloride precipitates and the crystals are collected by filtration. The crystals are washed with 150 mL water until pH above 3, and then with 17 mL THF. The crystals are dried over night in vacuum at 50 degrees. Yield: 10. 6 g (98%) Example 2 Precipitation of (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-1H indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indol hydrochloride with HCI (aq) 1.4 kg S)-(+)-3-[1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-1, 2,3, 6-tetrahydropyridin- 4-yl]-6-chloro-1H-indole is dissolved in 9.4 kg dimethylacetamide. A mixture of 0,4 kg cone. HCI and 0,2 kg water is added and the solution is cooled to 0-5 degrees. S)- (+)-3- [1- [2- (l-acetyl-2, 3-dihydro-lH-indol-3-yl) etliyl]-1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH- indole hydrochloride is collected by filtration and then slurried in 6.85 kg acetone, filtered and finally dried. Yield: 1.046 kg (69%) Example 3 Large scale precipitation of S)-(+)-3-[1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl) ethyl] - 1, 2,3, 6-tetrahydropyridin-4-yl]-6-chloro-lH-indol hydrochloride The wet filtercake of S)- (+)-3- [I- [2- (l-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-chloro-lH-indole is dissolved in 10 times tetrahydrofuran and 1.8 times N, N-dimethylacetamid. 1.17 eq. HCl-gas is added at a temperature below 35 degrees.

After stirring at least lh at room temperature, the title compound is collected by filtration.

The filtercake of (S)- (+)-3- [1- [2- (1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-1, 2,3, 6- tetrahydropyridin-4-yl]-6-cliloro-lH-indole hydrochloride is washed with water and tetrahydrofuran and finally dried.

Example 4 (S)-3-{1-[2-(1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl]-3, 6-dihydro-2H-pyridin-4-yl}-6- chloro-lH-indole hydrochloride (S)-3- {1-[2-(1-acetyl-2, 3-dihydro-lH-indol-3-yl) ethyl] -3, 6-dihydro-2H-pyridin-4-yl}-6- chloro-lH-indole (22.9 g, 0.055 mol) was dissolved in hot acetone (1300 mL) and subsequently added a solution of hydrochloric acid in diethyl ether and acetone until pH 2.5.

The solution was slowly cooled to room temperature. (The hydrochloric acid solution was prepared by mixing a saturated solution of hydrochloric acid in diethyl ether (50 mL) with acetone (500 mL) ). The crystalline compound formed was collected by filtration and dried in vacuo to give the title compound (24.8 g, 100%).

Example 5 Capsules containing melt granulate comprising (S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H- indol-3-yl) ethyl-3, 6-dihydro-2H-pyridin-4-yl3-6-chloro-lH-indole hydrochloride Lactose (109.8 g), monoglyceride stearate (IJSP quality) (14.0 g), (6)-3- {l- [2- (l-acetyl-2, 3- dihydro-1H-indol-3-yl) ethyl] -3, 6-dihydro-2H-pyridin-4-yl}-6-chloro-lH-indole hydrochloride (27.8 g), ascorbyl palmitate (1.00 g) and sodium lauryl sulphate (25.0 g) were filled into the production bowl with a temperature between 70 and 90 °C and mixed for 3 minutes at 300 rpm. Medium chain triglyceride (PhEur) (11.5 g) and monoglyceride (Kirnol) (11.5 g) was heated to 40 °C and poured onto the powder in the high shear mixer.

Subsequently the impeller speed was raised to 1200 rpm, and the mixture was granulated for 1 minute and 30 seconds.

The granulate was thereafter emptied from the high shear mixer and allowed to cool to ambient temperature, and sieved first through a 1 mm sieve and subsequently through a 0.71 mm sieve. The granulate was then filled into hard gelatine capsules (240 mg/capsule).

The capsules were administered to fasted beagle dogs and the bioavailability relative to a captisol solution administered by oral gavage was compared with the bioavailability for a

conventional melt granulate of ()-3-f 1- [2- (1-acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl]-3, 6- dihydro-2H-pyridin-4-yl}-6-chloro-lH-indole hydrochloride. The composition of the two granulates and the bioavailability relative to that of a captisol solution, wherein (S)-3-{1-[2- (1-acetyl-2, 3-dihydro-1H-indol-3-yl) ethyl] -3, 6-dihydro-2H-pyridin-4-yl}-6-chloro-1H- indole hydrochloride is dissolved in an aqueous 5 % solution of captisol, a sulfobutylether-p- cyclodextrin, is given in table 1. The comparative example was made in similar way as example 5 except for the composition. The relative bioavailability (Fre,) was calculated as: Frei. infwas calculated as Fret = AUC0-ttest#Doseref/AUC0-tref#Dosetest Wherein AUCo tteSt and AUC0-tref respectively are the serum concentration time curve to the last measurable concentration for the test and reference, and Doseref and Dosetest similarly are the doses. Table 1. Melt granulated formulations examined in dogs, containing (5)-3-{1-[2-(1-acetyl- 2, 3-dihydro-lH-indol-3-yl) ethyl]-3, 6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole hydrochloride.

Sample Example 5 Comparative example Process Melt granulation according Conventional melt to the invention granulation Drug product Capsule (240 mg) Capsule (240 mg) Active ingredient Milled Milled 13.59% 13.59% SLS 12. 5% Kirnol 5. 75% 5. 71% C8: 0 monoglyceride Medium-chain 5. 75% 5. 71 % triglyderide PhEur Rylo MG 18 Pharma 7. 0% 6.95% C16-C18 monoglyceride USP quality Lactose 350M 54. 91% 66.80% Ascorbyl palmitate 0. 5% 0.5% Bioavailability relative 0.97 0. 29 0. 61 ~ 0. 19 to captisol solution (Fl. el)