GRANULAR PREPARATIONS OF 5-(2-ETHYL- 2H-TETRAZOL- 5-YL)-1-METHYL-1, 2,3,6-TETRAHYDROPYRIDINE

Abstract: The present invention relates to a granulated product containing 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate, a melt granulation process for the preparation therof and to solid pharmaceutical unit dosage forms prepared from said granular preparation of 5-(2-ethyl-2H-tetrazol-5-yl)-1-methyl-1,2,3,6-tetrahydropyridine maleate.

Description: Granular preparations of 5-(2-ethyl-2//-tetrazoI-5-yl)-l-methyl-l,2,3,6-tetrahydro- pyridine The present invention relates to a granulated product containing 5-(2-ethyl-2H-tetrazol-5- yl)-l-methyl-l,2,3,6-tetrahydropyridine, a melt granulation process for the preparation thereof and to solid pharmaceutical unit dosage forms prepared from said granular product. Background Solid, shaped pharmaceutical unit dosage forms, such as tablets, are prepared by compression of the dry ingredients which are in the form or powders or small particles. The methods and excipients used for the compression of tablets are well known in the art. The choice of pharmaceutical excipients for a particular formulation largely depends on the physico/chemical properties including the tabletting properties of the active ingredient. Reproducible dosing for tabletting requires that all the dry ingredients have good fluidity properties. In some cases, where the active ingredient has good fluidity properties, tablets can be prepared by direct compression of the ingredients. However, in many cases where the particle size of the active substance is small, the active substance will be cohesive and have poor fluidity properties. In such cases, enlarging the particle size of the active substance, usually by granulation of the active ingredient either alone or in combination with a filler or other conventional tablet ingredient, will improve the fluidity properties of the active ingredient. One such granulation method is the "wet" granulation process. Using this method, the dry solids (active ingredients, binder etc.) are blended and moistened with water or another wetting agent (e.g. an alcohol) and agglomerates or granules are build up of the moistened solids. Blending is continued until a desired homogenous particle size has been achieved whereafter the granulated product is dried. The "wet" granulation process is widely employed for the granulation of powders or fine particles where water can be used as the wetting agent. Where the active ingredient is moisture sensitive or highly soluble in water, it is not convenient to use water as the wetting agent, because the active ingredient is dissolved in the water phase. A well known alternative to the "wet" granulation process is the "melt" granulation process which is also known as the "thermal plastic" granulation process, where a low melting solid is used as the granulation agent. Initially the dry solids are blended and heated until the binder melts. As the binder is liquefied and spreads over the surface of the particles, the particles will adhere to each other and form granules. The binder solidifies upon cooling forming a dry granular product. Conventional binders for melt granulation are lipophilic melt binders having a melting point over 40 °C , preferably between 50 to 100 °C, or most preferably between 60 to 70°C. Suitable lipophilic melt binders include fatty esters, fatty acids and salts thereof, fatty alcohols, fatty amides, glycerides, glycolipids, steroids or natural or synthetic waxes (US patent No. 5,403,593). Hydrophilic granulation media, such as polyethylene glycols (PEG's) of various molecular weight, can also be used as binders in melt granulation processes (US patent No. 5,476,667). The use of a mixture of a lipophilic and a hydrophilic melt binder as a granulation agent has also been described. DE-C2-4315664 describes the use of PEG for stabilisation of Molsodomin against the degradative effects of moisture and high temperatures. According to the technique described therein, PEG is added to Molsodomin in the form of solid particles. There are no examples suggesting that melt granulation using PEG as the binder would improve the stability of Molsodomin. US-A-5.476.667 describes a melt granulation process using a melt binder having a melting point between 40 and 100 °C, e.g. polyethylene glycols, for the preparation of pellets containing the active ingredient. The granulation process described therein is carried out as a two step process and results in a pelletized product. The two step process described therein is characterised by a first granulation step where the ratio between active substance and binder is selected so that the granules formed are overmoist and become tacky and a second step were more dry substance is added to build up pellets with a larger particle size. The compound, 5-(2-ethyl-2H-tetrazol-5-yl)-l -methyl- 1, 2,3, 6-tetrahydropyridine, which has the formula is a valuable partial agonist at muscarinic Ml receptors and an antagonist at M2 and M3 receptors. The compound is considered of particular interest for the treatment of Alzheimer's disease, traumatic brain injury (TBI) and psychoses or other schizophreniform diseases (US patent No. 4.866.077, DK-A-1223/95 and DK-A-620/97). The 5-(2-ethyl-2H- tetrazol-5-yl)-l -methyl- 1, 2,3, 6-tetrahydro-pyridine free base is a liquid and as such not useful for the preparation of solid pharmaceutical unit dosage forms. Various salt forms of 5-(2-ethyl-2H-tetrazol-5-yl)-l -methyl- 1, 2,3, 6-tetrahydropyridine have been described in US patent No. 4.866.077 and in Moltzen et al, J. Med. Chem. 1994, 37, 4085-4099. DK-A-781/97 describes the maleate of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6- tetrahydropyridine. The synthesis of 5-(2-ethyl-2H-tetrazol-5-yl)-l -methyl- 1, 2,3, 6-tetrahydropyridine maleate results in a crystalline product with a small particle size and poor flowability, which means that direct compression of the 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydro- pyridine maleate is not suitable for the preparation of tablets containing this compound. As the maleate and tartrate salts of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetra- hydropyridine are highly water soluble and sensitive to moisture, granulation using water as the wetting agent is not convenient for large scale production of granulated product from these salts. Further, tablets prepared from a wet granulated product containing 5-(2-ethyl- 2H-tetrazol-5-yl)-l -methyl- 1, 2,3, 6-tetra-hydropyridine maleate are chemically and physically instable. Thus, melt granulation of these salts using a lipophilic melt binder would seem to be the most obvious choice for the granulation of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6- tetrahydropyridine and could offer some protection of the active ingredient. Unfortunately, tablets prepared from a melt granulated product containing 5-(2-ethyl-2H-tetrazol-5-yl)-l- methyl-l,2,3,6-tetrahydropyridine maleate using a lipophilic melt binder have shown an unacceptable decrease in the ability to disintegrate upon storage. It has now, surprisingly, been found that a hydrophilic granulation media can be used for the granulation of hydrophilic salts of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6- tetrahydropyridine. Tablets prepared from the granular product of the invention show immediate release and improved physical and chemical stability compared to tablets prepared from a wet granulated product where water or ethanol have been used as the granulation agent. Objects of the Invention It is the object of the present invention to provide a granular preparation containing 5-(2- ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine which can be used for large scale preparation of solid, shaped pharmaceutical unit dosage forms containing 5-(2-ethyl- 2H-tetrazol-5-yl)- 1 -methyl- 1 ,2,3 ,6-tetrahydropyridine. Summary of the Invention The invention then inter alia comprises the following alone or in combination: A melt granulated product containing a) 10-40% of a hydrophilic melt binder having a melting point between 40 °C and 100 °C b) 0-90% filler, and c) a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl- 1 ,2,3 ,6-tetrahydropyridine. Suitably the melt granulated product contains 30-60% filler. Suitable fillers for the granulated product include lactose, sugars (sorbitol, mannitol, dextrose, sucrose), calcium phosphates (dibasic, tribasic, hydrous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulfate, calcium carbonate. In a preferred embodiment of the invention, the filler granulated together with the pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l -methyl- 1,2,3, 6-tetra- hydropyridine is lactose or a calcium phosphate. Suitably the hydrophilic melt binder is added in an amount from 10 to30 %, or from 10 to 20%, or more preferred in an amount around 15-16%. In one embodiment of the invention, the hydrophilic melt binder is a polyethylene glycol of the formula ΗO-(CΗ 2 CΗ 2 O) n -Η which is available with various average molecular weights. PEG having an average molecular weight from 3000 to 10000 is suitable for the preparation of the granular product according to the invention. PEG 3000 (PEG with an average molecular weight around 3000) has a melting point around 48-54 °C; PEG 4000 has a melting point around 50-58 °C, PEG 6000 has a melting point around 55-63 °C and PEG 8000, which is a waxy solid at room temperature, has a melting range around 60- 63°C. Other polyether glycols such as polypropylene glycol, polyethylene glycol esters or acids, as well as polyoxypropylene and polyethylene oxide and copolymers thereof may also be used as the hydrophilic melt binder. In a preferred embodiment of the invention, the melt binder used is PEG 6000. The active ingredient suitably amount to up to 50% of the granulated product, preferably 10-50 % of the granulated product, and most preferably 25-50%. In a preferred embodiment of the invention, the pharmaceutically acceptable salt of 5-(2- ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine is the maleate. As used herein, % means %(w/w). The invention also relates to a method for the preparation of a granulated product containing a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl- 1,2,3,6-tetrahydropyridine which comprises blending of the dry ingredients while heating to a temperature above the melting point of the hydrophilic melt binder, followed by mechanical working until a uniform granular product is formed. The ingredients are preferably granulated in one step starting with the total amount of all ingredients. Where the granulating agent is PEG 6000, a suitable temperature for the granulation process is between 60-80 °C. The granulation process may be carried out in a jacketed bowl equipped with blending means, in fluidised bed or any other apparatus suitable for carrying out granulation provided heat can be induced. The granulating agent is dry-blended with the other ingredients (i.e. active ingredient and filler) prior to heating. Alternatively, the granulating agent is melted and continuously added to or sprayed on an agitated mixture of the other ingredients. The granulation mixture is heated to substantially liquefy the granulating agent, and thereafter heated and mechanically worked or agitated until the desired particle size is achieved. The granulated product is cooled to a temperature below the melting point of the binder. The granulated product may be continuously agitated or worked throughout the heating and the cooling phase in order to obtain a homogenous granulate. As an alternative, granulation can be carried out in fluid bed. Using this technique, the melted granulating agent can be sprayed on the fluidised bed of the other components. Fluid bed melt granulation can also be carried out as described in DE 21 27 683. In a final embodiment, the invention comprises a composition containing the melt granulated product containing 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydro- pyridine together with conventional pharmaceutical excipients. Besides the active ingredient, which may be in the form of a granulated product, solid pharmaceutical unit dosage forms usually include various other conventional excipients such as additional fillers, binders, disintegrants, and optionally minor amounts of lubricants, colorants, and sweeteners. The choice of the excipients largely depends on the physico/chemical properties of the active ingredient, including the tabletting properties of the active ingredients. Suitable fillers for the preparation of solid, unit dosage forms according to the invention include lactose, sugars (sorbitol, mannitol, dextrose, sucrose), calcium phosphates (dibasic, tribasic, hydrous and anhydrous), starch, modified starches, microcrystalline cellulose, calcium sulphate, calcium carbonate. The filler may be added to or mixed with the granulated product after granulation or it can be granulated together with the active ingredient, or both. Disintegrants include sodium starch glycolate, croscarmellose, crospovidone, low substituted hydroxypropylcellulose, modified cornstarch, pregelatizined starch, and natural starch. Examples of lubricants include metallic stearates (magnesium, calcium, sodium), stearic acid, wax, hydrogenated vegetable oil, talc, colloidal silica, sodium benzoate. In a preferred embodiment of the invention, the composition according to the invention is in the form of a solid, shaped pharmaceutical unit dosage form, i.e. a tablet. The solid and shaped, pharmaceutical unit dosage form may be prepared by conventional methods and apparatus for the compression of tablets. In the following the invention is illustrated by way of examples. However, the examples are merely intended to illustrate the invention and should not be construed as limiting. Example 1 Preparation of a melt granulated product containing 5-(2-ethyl-2//-tetrazol-5-yl)-l- methyl-l,2,3,6-tetrahydropyridine maleate as the active ingredient and compression of 200 mg tablets containing 25 mg active ingredient. Ingredients for granulation: Active ingredient 300.2 g (25%) Polyethylene glycol 6000 195 g (16%) Lactose monohydrate 704.8 g (59%) The temperature regulator of a heat jacketed high shear mixer (PP1) was set to 80 °C . Lactose monohydrate was combined with 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6- tetrahydropyridine maleate and PEG 6000 in the mixer and blended at 1200 rpm until peak power consumption of the motor was measured. Blending was continued at 800 rpm for 2- 4 minutes while the temperature was allowed to rise to a temperature between 65-80 °C. The granulated product was cooled and passed through a 1 mm mesh screen. Screen analysis Granule size distribution (irregular shaped granules): Geometric weight mean diameter (dgw): 150-250 μm Geometric standard deviation (Sg): 2.0-3.0 Preparation of tablets Tablet ingredients: Granulate (6 batches) 7200 g (79.6 %) 5 Avicel Ph 102, Ph.Eur. 1350 g (14.9 %) Talc, Ph.Eur. 405 g (5 %) Magnesium stearate 45 g (0.5 %) Avicel PH 102 and talc was passed through a 0.71 mm mesh screen. Magnesium stearate l o was passed through a 0.2 mm mesh screen. The 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine-M granulate, talc and Avicel PΗ 102 was blended at 20 rpm for 500 sec. in a Bohle LM 40 mixer. Magnesium stearate was added and blending continued for 180 sec. 15 The resulting composition was loaded into a Korch PΗ 106 tabletting machine mounted with 8 mm punches and pressed into tablets. Tablet properties: 20 Diametrical crushing strength: 2.0-5.0 kP. Apparatus: Schleuniger 4M Disintegration time: 1-10 min. Apparatus: Erweka ZT6-2DP Friability: < 0.5%. Apparatus: Erweka TA(D) Weight variation: < 1-2% 25 Results of stability testing of the tablets are presented in example 3. 30 Example 2 Preparation of a melt granulated product containing 5-(2-ethyl-2//-tetrazol-5-yl)-l- methyl-l,2,3,6-tetrahydropyridine maleate and 200 mg tablets containing 50 mg active substance. Ingredients for granulation: Active substance 10800 g (25%) Polyethylene glycol 6000 NF 3456 g (16%) Lactose monohydrate 7344 g (59%) Lactose monohydrate was combined with 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6- tetrahydropyridine maleate and PEG 6000 in a heat jacketed high shear mixer (PMA 100). The temperature regulator of the mixer was set to 80 °C and the combined ingredients were blended at 292 rpm until the product temperature reached 69 °C. Heating was stopped and replaced by cooling to below 40 °C at 25 rpm. The product was passed through a Frewitt MG 336 1 mm screen. Screen analysis Granule size distribution (irregular shaped granules): Geometric weight mean diameter (dgw): 150-250 μm Geometric standard deviation (Sg): 2.0-3.0 Preparation of tablets Tablet ingredients: Granulate 21600 g (80%) Avicel Ph 102, Ph.Eur. 4050 g (15%) Talc, Ph.Eur. 1215 g (4.5%) Magnesium stearate 135 g (0.5%) Avicel PH 102 and talc were passed through a 0.71 mm mesh screen. Magnesium stearate was passed through a 0.2 mm mesh screen. The granulate, talc, avicel PH 102 and magnesium stearate were blended in a PTM 200 Bohle mixer. The resulting composition was loaded into a Korch PH 106 tabletting machine mounted with 8 mm punches and pressed into tablets. The tablet properties measured were the same as in example 1. Example 3 Preparation of a melt granulated product containing 5-(2-ethyl-2H-tetrazol-5-yl)-l- methyl-l,2,3,6-tetrahydropyridine maleate and preparation of 100.000 200 mg tablets containing 50 mg active substance. Ingredients for granulation Active substance 8005 g (50%) Polyethylene glycol 6000 NF 2600 g (16%) Lactose ( Ph. Eur.) 5395 g (34%) Tablet ingredients: Granulate 16000 g (80%) Avicel Ph 102, Ph.Eur. 3200 g (16%) Kollidon CL (crospovidone) 600 g (3 3 / 4 %) Magnesium stearate Ph.Eur 200 g (1V 4 %) Granulation and compression into tablets were carried out as in example 2. Example 4 Tablets prepared from the melt granulated product according to the invention and wet granulated products, and tablets prepared by direct compression were subjected to accelerated stability testing for 6 month. The tablets were prepared using conventional techniques and as described above. Direct compression was complicated by the ingredients adhering to the punches. The composition of the tablets appears from the table below. The tablets were packaged in 50 ml DUMA-containers with 50 tablets in each and subjected to accelerated stability testing for 6 month under the following conditions: (I) 25 °C and 60% RH (II) 35 °C and 60% RH (III) 40 °C and 75% RH Visual inspection of the tablets after 2, 4 and 6 month revealed that at 25 °C and 60%) RH, both the direct compressed tablets and the tablets according to the invention show no change in appearance after storage for 6 month, while the tablets prepared from the wet granulated products had turned slightly yellow after 4 to 6 month storage at 25 °C and 60% RH. After 4 month storage at 35 °C and 60% RH, the tablets prepared from the wet granulated products had become swollen and slightly yellow and after 2 month storage at 40 °C and 75%o RH the tablets were yellow, porous and sticky. The tablets prepared from the melt granulated product had become slightly yellow after storage for 2 month at 40 °C and 75% RH whereas the direct compressed tablets turned yellow and porous after 2 month storage at 40 °C and 75% RH. In figure 1 , the relationship between the total amount of degradation products and storage conditions after 4 months of storage is illustrated. Degradation was measured using HPLC. For the tablets prepared from the melt granulated product according to the invention, the total amount of degradation products is about 0.1 %> both when stored at 25 °C and 60% RH and 35 °C and 60%> RH. For the tablets prepared by direct compression, the degree of degradation increases going from 25 °C and 60%> RH to 35 °C and 60%. The other two batches of tablets which are prepared from the wet granulated products have a total impurity level over 0.2% at 25 °C and 60%> RH, increasing with the temperature and relative humidity. It can be concluded that tablets prepared from wet granulated Lu-25- 109-M cannot be considered stable whereas melt granulation of Lu-25-109-M using PEG provides some protection against physical and chemical degradation of the active substance. It was quite unexpected that PEG, which is a hydrophilic compound itself, would have a protective effect on 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine- maleate. Example 5 Preparation of 5-(2-ethyl-2i7-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydro- pyridine maleate 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine, oxalate (5.6 kg) was suspended in demineralized water (22 1). Ethyl acetate (17 1) was added, and a cooled solution (15-20 °C) of potassium hydroxide (2.8 kg) in demineralized water (12.5 1) was added with stirring and cooling. pΗ was adjusted to 10 by adding aqueous potassium hydroxide. The aqueous layer was further extracted with ethyl acetate (2 x 11 1). The combined organic extracts were dried with sodium sulphate (3.8 kg) and evaporated in vacuo until a pot temperature of 75-80 °C was reached. The residue was dissolved in tetrahydrofuran (11 1), and a solution of maleic acid (2.4 kg) in tetra-hydrofuran (11 1) was added with stirring. The solution was cooled to approximately 15 °C and stirred for a minimum of 1 hour. The precipitate was isolated on a nutche filter, and washed with tetrahydrofuran (2 x 2 1). The wet filtercake was recrystallised once from tetrahydrofuran (13 1). The recrystallised material was isolated on a nutche filter, washed with tetrahydrofuran (5 1), and finally dried in vacuo at 65 °C overnight. Yield 5.0. kg (83%>) mono-maleate. M.p. 116 °C. Example 6 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine maleate Liberation of the free base: A nitrogen purged reactor was charged with 62-64 kg 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl-l,2,3,6-tetrahydropyridine, oxalate,water, and toluene. The mixture was stirred and cooled to below 10 °C while adding potassium hydroxide pellets dissolved in water until pΗ > 12 was achieved. The layers were separated, the aqueous layer re-extracted with toluene and subsequently discarded. The combined organic phases were washed with water. Toluene was distilled off in vacuo at a temperature of not more than 50 °C. Precipitation: The residue was re-dissolved by adding TΗF and maleic acid (26.5- 27.5 kg) while heating to reflux. The temperature of the reaction mixture was adjusted to approx. 50°C. The solution was left with slow agitation and voluntary cooling for crystallization 0 The slurry was cooled to below 20 °C and isolated. The product was washed with tetrahydrofuran and dried in vacuo yielding 5-(2-ethyl-2Η-tetrazol-5-yl)-l-methyl-l,2,3,6- tetra-hydropyridine maleate. Recrvstallisation: A reactor was charged with 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl- 1,2,3,6-tetrahydropyridine, maleate, and tetrahydrofuran. The solution was heated to reflux and then allowed to crystallise (1) . The product was isolated, washed several times with TΗF, and dried in vacuo. (1) If necessary the solution may be seeded with 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl- 1,2,3,6-tetrahydropyridine maleate from a previous batch.

Claims: Claims 1. A melt granulated product containing a) 10-40% of a hydrophilic melt binder having a melting point between 40 °C and 100 °C and b) 0-90% filler and c) a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l -methyl- 1,2,3, 6- tetrahydropyridine . 2. The granulated product according to claim 1 which contains 25-50% of a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l -methyl- 1,2,3,6- tetrahydropyridine . 3. The granulated product according to claims 1 to 2 wherein the pharmaceutically acceptable salt of 5-(2-ethyl-2Η-tetrazol-5-yl)-l -methyl- 1,2,3,6-tetrahydro-pyridine is selected from the maleate and the tartrate acid addition salts. 4. The granulated product according to claims 1 to 3 wherein the hydrophilic melt binder is polyethylene glycol having an average molecular weight of about 4000 to 8000. 5. The granulated product according to claim 4 wherein the hydrophilic melt binder is PEG 6000. 6. The granulated product according to claims 1 to 5 which contains 10 to 20% hydrophilic melt binder. 7. The granulated product according to claims 1 to 6 which contains 0 to 60%, preferably 30-60% filler. 8. The granulated product according to claims 1 to 7 wherein the filler is selected from lactose and dicalciumphosphates. 9. A process for the preparation of a granulated product according to claims 1 to 8 comprising 5 heating and mechanically working of a mixture containing a) a hydrophilic binder having a melting point between 40 °C and 100 °C b) 0-90% filler and c) a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl- l o 1 ,2,3 ,6-tetrahydropyridine to a temperature above the melting point of the hydrophilic melt binder, until a homogenous granular product is formed. 15 10. A melt granulated product according to claims 1 to 8 obtainable by heating and mechanical working of a mixture containing a) a hydrophilic binder having a melting point between 40 °C and 100 °C 20 b) 0-90% filler and c) a pharmaceutically acceptable salt of 5-(2-ethyl-2H-tetrazol-5-yl)-l-methyl- 1 ,2,3,6-tetrahydropyridine to a temperature above the melting point of the hydrophilic melt binder, until a 25 homogenous granular product is formed. 11. A composition comprising a melt granulated product according to claims 1 to 8 or 10 together with conventional pharmaceutical excipients. 30 12. A composition according to claim 11 which is in the form of a solid, shaped pharmaceutical unit dosage form.

Inventors: HOLM PER, MOELLGAARD BIRGITTE, HOLM, PER, MOELLGAARD, BIRGITTE
Applicants: HOLM PER, LUNDBECK & CO AS H, MOELLGAARD BIRGITTE, H. LUNDBECK A/S, HOLM, PER, MOELLGAARD, BIRGITTE
Application year: 1998
Main classification: A61K31
IPC codes: A61K9, A61K31, A61K47, A61P25, A61P43, C07D401