What we Claim

1. Pharmaceutical composition comprising carvedilol accordig to the formula

(I)

in a form of a layered pellet, wherein said pellet contains a core (1) containing a solid organic acid, an enteric layer (2) on the surface of the core, a layer (3) containing carvedilol and a water-soluble binding agent on the surface of the enteric layer (2), and an external dissolution controlling layer (4) containing a mixture of water-soluble polymer and an enteric polymer on the surface of the layer containing the active ingredient.

2. Pharmaceutical composition containing carvedilol in a form of a layered pellet according to Claim 1, whrein the pellet has a core (1) containing 5-50 weight% of solid organic acid based on the total

weight of the pellet, and optionally 5-50 weight% of one or more auxiliary agents, an enteric layer (2) on the surface of the core containing 0,5-10 weight% of enteric polymer based on the total weight of the pellet, and optionally further auxiliary agents, a further layer (3) on the surface of the enteric layer containing 5-30 weight% carvedilol based on the total weight of the pellet, and 5-30 weight% of water-soluble binder based on the total weight of the pellet and optionally further auxiliary agents, a further dissolution controlling layer (4) on the surface of the layer containing the active ingredient, containing a mixture of 0.5-10 weight% of water- soluble polymer based on the total weight of the pellet and 0.5-10 weight% of enteric polymer based on the total weight of the pellet and optionally further auxiliary agents.

3. Pharmaceutical composition containing carvedilol in a form of layered pellet according to the Claim 1, wherein the pellet has a core (1) containing 10-40 weight% of solid organic acid based on the total weight of the pellet and optionally 10-40 weight% of one or more auxiliary agents, an enteric layer (2) on the surface of the core containing 1-5 weight% of enteric polymer based on the total weight of the pellet and optionally further auxiliary agents, on the

surface of the enteric layer a further layer (3) containing 10-20 weight% carvedilol based on the total weight of the pellet and 10-20 weight%, of water-soluble binder based on the weight of the total pellet and optionally further auxiliary agents, on the surface of the layer with the active ingredient a further dissolution cotrolling layer (4) containing a mixture of 1-5 weight% of water-soluble polymer based on the total weight of the pellet and 1-5 weight% of enteric polymer based on the total weight of the pellet and optionally further auxiliary agents.

4. Pharmaceutical composition containing carvedilol in a form of layered pellet according to the Claim 1, wherein the pellet has a core (1) containing 20-40 weight% of solid organic acid based on the total weight of the pellet and optionally 20-40 weight% of one or more auxiliary agents, an enteric layer (2) on the surface of the core containing 1-3 weight% of enteric polymer based on the total weight of the pellet and optionally further auxiliary agents, on the surface of the enteric layer a further layer (3) containing 10-15 weight% carvedilol based on the weight of the pellet and 10-15 weight%, of water- soluble binder based on the total weight of the pellet and optionally further auxiliary agents, on the surface

of the layer with the active ingredient, a further dissolution controlling layer (4) containing a mixture of 1-3 weight% of water-soluble polymer based on the total weight of the pellet and 1-3 weight% of enteric polymer based on the total weight of the pellet and optionally further auxiliary agents.

5. Pharmaceutical composition comprising carvedilol in a form of layered pellet according to any of the Claims 1-4 characterised in that the core contains a physiologically inert solid organic acid, preferably saturated or unsaturated, di- or tricarboxylic acid having 4-5 carbon atoms except fumaric acid, more preferably citric acid, tartaric acid, malic acid, maleic acid, succinic acid and most preferably succinic acid.

6. Pharmaceutical composition containing carvedilol in a form of layered pellet according to any of the Claims 1-4 whrerein the auxiliary agents used for preparation of pellet core (1) are generally accepted for the preparation of pellets in the pharmaceutical industry, preferably lactose, starch, powdered cellulose, microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixture thereof, most preferably microcrystalline cellulose and optionally dimethylpolysiloxane.

7. Pharmaceutical composition containing carvedilol in a form of layered pellet according to any of the Claims 1-6 , wherein the enteric layer (2) on the surface of the pellet core (1) contains enteric coating polymer, preferably methacrylic acid-ethyl acrylate copolymer, methacrylic acid - methyl methacrylate copolymer, cellulose acetate phtalate, hydroxypropylmethylcellulose acetate succinate or polyvinylacetate-phtalate, more preferably methacrylic acid-ethyl acrylate copolymer.

8. Pharmaceutical composition containing carvedilol in a form of layered pellet according to any of the Claims 1-6, wherein the enteric layer (2) on the surface of the pellet core (1) contains further auxiliary agents such as softeners or optionally antiadhesive agents.

9. Pharmaceutical composition containing carvedilol in the form of layered pellet according to the Claim 8, wherein the enteric layer (2) contains propylene glycol, triethylcitrate, polyethylene glycol or mixtures thereof as softener.

10. Pharmaceutical composition containing carvedilol in the form of layered pellet according to any of the Claims 8 or 9, wherein the enteric layer (2) contains

talc, dimethylpolysiloxane or mixtures thereof as antiadhesive agents.

11. Pharmaceutical composition containing carvedilol hi the form of layered pellet according to any of the Claims 1-10, wherein the layer comprising carvedilol (3) contains hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone vinylpyrrolidone/vinylacetate copolymer, polyvinylalcohol, polyethylene glycol polyvinylalcohol-polyethylene glycol graft copolymer or mixtures thereof preferably a mixture of hydroxypropylmethylcellulose and polyethylene glycol as water-soluble binding agents.

12. Pharmaceutical composition containing carvedilol in the form of layered pellet according to any of the Claims 1-11, wherein the layer (4) on the surface of the layer comprising carvedilol (3) contains hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone vinylpyrrolidon/vinylacetate copolymer, polyvinylalcohol, polyethylene glycol, polyvinylalcohol-polyethylene glycol graft copolymer or mixtures thereof preferably

hydroxypropylcellulose as water-soluble film coating agent.

13. Pharmaceutical composition containing carvedilol in the form of layered pellet according to any of Claims 1-12, wherein the layer (4) on the surface of the layer comprising carvedilol (3) contains methacrylic acid- ethyl acrylate copolymer, methacrylic acid - methyl methacrylate copolymer, cellulose acetate phtalate, hydroxymethylcellulose phtalate, hydroxypropylmethylcellulose acetate succinate or polyvinylacetate phtalate, or mixtures thereof preferably methacrylic acid-ethyl acrylate copolymer as enteric film coating agent.

14. Pharmaceutical composition containing carvedilol in the form of layered pellet according to the Claim 1, wherein the pellet has a core (1) containing 25-35 weight% of succinic acid based on the total weight of the pellet and 25-35 weight% of microcrystalline cellulose and 0.4-1 weight % of dimethylpolysiloxane, an enteric layer (2) on the surface of the core containing 1-5 weight% of methacrylic acid-ethyl acrylate copolymer and optionally further 0.1-0.35 weight % of propylene glycol, on the surface of the enteric layer a further

layer (3) containing 10-15 weight% carvedilol based on the total weight of the pellet and 10-15 weight%, of a mixture of hydroxypropylmethylcellulose and polyethylene glycol based on the total weight of the pellet, on the surface of the layer containing the active ingredient, and a further layer (4) containing a mixture of 1-3 weight% of hydroxypropylcellulose based on the total weight of the pellet and 1-3 weight% of methacrylic acid-ethyl acrylate copolymer based on the total weight of the pellet.

15. Controlled release pharmaceutical solid dosage form which contains pellets according to any of the Claims 1-14 and optionally other auxiliary agents used in the pharmaceutical industry.

16. Controlled release pharmaceutical solid dosage form according to Claim 15 characterized in that the dosage form is tablet or capsule.

17. Solid dosage form according to Claim 16, characterized in that the tablets contain 40-90 weight %, preferably 60-90 weight %, more preferably 80- 90 weight % of pellets, 10-50 weight %, preferably 10-40 weight %, more preferably 10-20 weight % of filler, 1-10 weight %, preferably 2-6 weight %, more preferably 3-5 weight % of disintegrating agent, 2-10

weight %, preferably 3-8 weight %, more preferably 0.1-5 weight % of binding agent, 0.1-1 weight %, preferably 0.1-1 weight %, of lubricant.

18. Solid dosage form according to Claim 16 characterized in that the capsules contain 40-100 weight %, preferably 60-100 weight %, more preferably 80-100 weight % of pellets, optionally 0.1-60 weight %, preferably 0.1-40 weight %, more preferably 0.1-20 weight % of filler, 0.1-10 weight %, preferably 0.1-5 weight % of disintegrating agent, 0.1-2 weight %, preferably 0.1-1 weight %, of lubricant.

19. Capsules according to Claim 18 characterized in that hard gelatine capsules are used.

20. Controlled release pharmaceutical solid dosage form containing pellets according to any of the Claims 15- 19, characterized in that pharmaceutically acceptable filler, preferably lactose, starch, powdered cellulose, microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixtures thereof, more preferably microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixtures thereof are used as fillers, pharmaceutically acceptable binding agent, preferably carboxymethylcellulose or

low-substituted hydroxypropylcellulose, pharmaceutically accepted disintegrating agent, preferably sodium-carboximethylcellulose, crosslinked polyvinylpyrrolidone, sodium carboxymethylstarch, or low-substituted hydroxypropylcellulose, more preferably crospovidone, pharmaceutically acceptable lubricants, preferably calcium and magnesium stearate, glyceryl behanate, stearic acid talc or hydrogenated vegetable oils.

21. Process for the preparation of a pharmaceutical composition containing carvedilol in a form of layered pellets, characterised in that a.) a solid organic acid and optionally one or more excipients are granulated in a known manner, the obtained pellet core (1) b.) is coated with an enteric coating polymer in a known manner, the obtained coated pellets are optionally dried, c.) the surface of the enteric layer (2) is coated with a mixture of carvedilol and a water-soluble binding agent optionally using other auxiliary agents in a manner known, optionally dried, d.) the obtained coated pellets are coated in a known manner with a mixture of a water-soluble and an enteric coating polymer.

22. Process for the preparation of a pharmaceutical composition containing carvedilol in a form of layered pellets according to Claim 21 characterised in that a.) 5-50 weight % of solid organic acid based on the total weight of the pellets and optionally 5-50 weight % of one or more auxiliary agents based on the total weight of the pellets are granulated in a known manner, the obtained pellet cores (1) are dried, and b.) coated with 0.5-10 weight % enteric film coating polymer based on the total weight of the pellets and optionally one or more auxiliary agents preferably softeners and antiadhesive agents in a usual manner and optionally dried, c.) the surface of the enteric layer (2) is coated with a mixture of 5-30 weight % of carvedilol based on the total weight of the pellets and 5-30 weight % of water-soluble binding agent and optionally using other auxiliary agents in a usual manner, the obtained coated pellets are optionally dried, then d.) the layer containing carvedilol (3) is coated with a dissolution controlling layer (4) in a usual manner with a mixture of 0.5-10 weight % of enteric coating polymer and 0.5-10 weight % of

water-soluble polymer based on the total weight of the pellets.

23. Process for the preparation of a pharmaceutical composition containing carvedilol in a form of layered pellets according to Claim 21 characterised in that a.) 10-40 weight % of solid organic acid based on the total weight of the pellets and optionally 10- 40 weight % of one or more excipients based on the total weight of the pellets are granulated in a known manner, the obtained pellet cores (1) are dried, and b.) coated with 1-5 weight % enteric film coating polymer based on the total weight of the pellets and optionally one or more auxiliary agents preferably softeners and antiadhesive agents in a usual manner and optionally dried, c.) the surface of the enteric layer (2) is coated with a mixture of 10-20 weight % of carvedilol based on the total weight of the pellets and 10-20 weight % of water-soluble binding agent and optionally using other auxiliary agents in a usual manner, the obtained coated pellets are optionally dried, then d.) the layer containing carvedilol (3) is coated with a dissolution controlling layer (4) in a usual

manner with a mixture of 1-5 weight % of enteric coating polymer and 1-5 weight % of water- soluble polymer based on the total weight of the pellets.

24. Process for the preparation of a pharmaceutical composition containing carvedilol in a form of layered pellets according to Claim 21 characterised in that a.) 20-40 weight % of solid organic acid based on the total weight of the pellets and optionally 20- 40 weight % of one or more auxiliary agents based on the total weight of the pellets are granulated in a known manner, the obtained pellet cores (1) are dried, and b.) coated with 1-3 weight % enteric film coating polymer based on the total weight of the pellets and optionally one or more auxiliary agents preferably softeners and antiadhesive agents in a known manner and optionally dried, c.) the surface of the enteric layer (2) is coated with a mixture of 10-15 weight % of carvedilol based on the total weight of the pellets and 10-15 weight % of water-soluble binding agent and optionally using other auxiliary agents in a known manner, the obtained coated pellets are optionally dried, then

d.) the layer containing carvedilol (3) is coated with a dissolution controlling layer (4) in a known manner with a mixture of 1-3 weight % of enteric coating polymer and 1-3 weight % of water- soluble polymer based on the total weight of the pellets.

25. Process according to any of the Claims 21-24 characterized in that a.) the organic acid and the auxiliary agents are homogenized, then the obtained homogenized mixture is granulated with water which can optionally contain further auxiliary agents, and the obtained granules are dried, b.) the obtained pellet cores (1) are coated by spraying a dispersion of a mixture of enteric film coating polymer dispersion and optionally other auxiliary agents on the cores, the obtained coated pellets are dried if necessary, c.) the enteric coated pellets are sprayed with a suspension of a mixture of carvedilol and a water-soluble binding agent, optionally other auxiliary agents are applied to the enteric coated pellets or, by subsequent application of the powdered carvedilol and the dispersion of the water-

soluble binding agent, and optionally the obtained coated pellets are dried, then d.) a mixture of enteric coating polymer, water- soluble polymer and optionally other auxiliary agents are sprayed in a form of solution or dispersion containing water or organic solvents, preferably in form of alcoholic solution or dispersion onto the layer containing carvedilol.

26. Process according to any of the Claims 21-25 characterized in that the organic acid used for the preparation of the pellet cores (1) are physiologically inert solid organic acids except funiaric acid, preferably saturated and unsaturated di- and tricarboxylic acids having 4-5 carbon atoms, more preferably citric acid, tartaric acid, malic acid, maleic acid, succinic acid and most preferably succinic acid.

27. Process according to any of the Claims 21-26 wherein the used auxiliary agents for the preparation of the pellet cores (1) are used in the pharmaceutical industry, preferably lactose, starch, powdered cellulose, microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixtures thereof, more preferably microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixtures thereof.

28. Process according to any of the Claims 21-27 characterized in that the surface of the pellet core (1) is coated with enteric film coating polymer or polymers, preferably methacrylic acid-ethyl acrylate copolymer, methacrylic acid - methyl methacrylate copolymer, cellulose acetate phtalate., hydroxypropyhnethylcellulose phtalate, hydroxypropyhnethylcellulose acetate succinate or polyvinylacetate-phtalate, more preferably methacrylic acid-ethyl acrylate copolymer.

29. Process according to Claim 28 characterized in that other auxiliary agents, optionally softeners and antiadhesive compounds are also used in the process of the application the enteric coating layer (2) onto the pellet core (1).

30. Process according to Claim 29 characterized in that propylene glycol, triethylcitrate, polyethylene glycol or mixture thereof are used as softener in the process of the application the enteric coating layer (2) onto the pellet core (1).

31. Process according to Claim 29 characterized in that talc, dimethylpolysiloxane or mixture thereof are used as antiadhesive agent in the process of the application the enteric coating layer (2) onto the pellet core (1).

32. Process according to any of the claims 21-31 characterized in that the layer containing carvedilol (3) is prepared by using hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone vinylpyrrolidon/vinylacetate copolymer, polyvinylalcohol, polyethylene glycol, polyvinylalcohol-polyethylene glycol graft copolymer or mixtures thereof, preferably a mixture of hydroxypropylcellulose and polyethylene glycol as water-soluble film coating agent.

33. Process according to Claim 32 characterized in that further auxiliary agents are used.

34. Process according to any of the Claims of 21-33 characterised in that the layer containing carvedilol (3) is prepared by the subsequent application of powdered carvedilol and the water-soluble binding agent or, with spraying of a suspension containing a mixture of the carvedilol and the aqueous mixture of the water-soluble binding agent.

35. Process according to any of the Claims 21-34 characterized in that hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, vinylpyrrolidon/vinylacetate

copolymer, polyvinylalcohol, polyethylene glycol, polyvinylalcohol-polyethylene glycol graft copolymer or mixtures thereof preferably hydroxypropylcellulose are used as water-soluble film coating compounds for the preparation of the external layer (4) on the surface of the layer containing carvedilol (3).

36. Process according to any of the Claims 21-34 characterized in that methacrylic acid-ethyl acrylate copolymer, methacrylic acid - methyl methacrylate copolymer, cellulose acetate phtalate, hydroxymemylcellulose-phtalate, hydroxypropyl- methylcellulose-acetate-succinate or polyvinylacetate- phtalate, or mixtures thereof, preferably methacrylic acid - ethylacrylate copolymer are used as water-soluble film coating compound for the preparation of the external layer (4) on the surface of the layer containing carvedilol (3).

37. Process for the preparation of a pharmaceutical composition containing carvedilol in a form of multi- layered pellets according to Claim 21 characterised in that

a.) 25-35 weight % of succinic acid and optionally 25-35 weight % of microcrystalline cellulose are granulated with water containing 0.4-1 weight %

of dimethylpolysiloxane based on the total weight of the pellets, the obtained pellet cores (1) are dried, and b.) coated with 1-5 weight % of methacrylic acid- ethyl acrylate copolymer, optionally with a mixture of 0.1-0.35 weight % of propylene glycol and 0.1-0.15 weight % of antiadhesive agent based on the total weight of the pellets by spraying onto the surface of the cores (1), the obtained coated pellets are optionally dried, then c.) onto the surface of the enteric layer (2) a further layer is applied by spraying the coated pellets with a mixture of 10-15 weight % of carvedilol based on the weight and 10-15 weight % of a mixture of hydroxypropylmethylcellulose, polyethylene glycol and optionally further auxiliary agents or, the layer is prepared by the subsequent application of 5-30 weight % of powdered carvedilol and 5-30 weight % of the mixture of hydroxymethylcellulose polyethylene glycol and optionally further auxiliary agents, the obtained pellets are optionally dried, then

d.) the obtained layer containing carvedilol (3) is coated by spraying with an alcoholic mixture of 1- 3 weight % of methacrylic acid-ethyl acrylate

copolymer and 1-3 weight % of hydroxypropylcellulose based on the total weight of the pellet.

38. Process for the preparation of controlled release solid dosage form according to any of the Claims 1-14 characterized in that the pellets are optionally mixed with auxiliary agents generally used in the pharmaceutical industry and then transformed to the galenic form.

39. Process for the preparation of controlled release solid dosage form according to Claim 38, wherein 40-90 weight %, preferably 60-90 weight %, more preferably 80-90 weight % of pellets according to any of the Claims 1-14, 10-50 weight %, preferably 10-40 weight %, more preferably 10-20 weight % of the filler, optionally 1-10 weight %, preferably 2-6 weight % of the disintegrating agent, 2-10 weight %, preferably 3-8 weight %, more preferably 0.1-5 weight % of the binding agent and optionally 0.1-1 weight % lubricant are mixed and pressed into tablets.

40. Process for the preparation of controlled release solid dosage form according to Claim 38 wherein 40-100 weight %, preferably 60-100 weight %, more preferably 80-100 weight % of the pellets according to any of the

Claims 1-14, optionally 0.1-60 weight %, preferably 0.1- 20 weight %, more preferably 0.1-10 weight % of the filler, optionally 0.1-20 weight %, preferably 0.1-10 weight %, more preferably 0.1-5 weight % of the disintegrating agent, 2-10 weight %, preferably 3-8 weight %, more preferably 0.1-5 weight % of the binding agent and optionally 0.1-2 weight %, preferably 0.1-1 weight % of the lubricant are mixed and filled into capsules.

41. Process for the preparation of capsules according to Claim 40 characterized in that hard gelatine capsules are used.

42. Process for the preparation of dosage forms according to any of the Claims of 38-41 characterised in that the generally acceptable excipients, preferably lactose, starch, powdered cellulose, microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixtures thereof, most preferably microcrystalline cellulose, colloid silicone dioxide, dimethylpolysiloxane or mixtures thereof are used, any pharmaceutically acceptable binding agent, preferably polyvinylpyrrolidone, hydroxypropylcellulose are used, any of the pharmaceutically accepted disintegrating agents, preferably sodium-carboxymethylcellulose, crosslinked polyvinylpyrrolidone, sodium

carboxymethylstarch, or low-substituted hydroxypropylcellulose, more preferably crospovidone are used, any of the pharmaceutically acceptable lubricants, preferably calcium and magnesium stearate, glyceryl behanate, stearic acid talc or hydrogenated vegetable oils can be used.