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Claims for Patent: 5,643,602

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Claims for Patent: 5,643,602

Title: Oral composition for the treatment of inflammatory bowel disease
Abstract:An oral pharmaceutical composition is described for targeted slow release in the treatment of inflammatory bowel diseases. Also described are pharmaceutical compositions for peroral treatment targeted to different areas of the intestinal tract afflicted by ulcerative colitis and certain aspects of Crohn's disease.
Inventor(s): Ulmius; Jan (Lund, SE)
Assignee: Astra Aktiebolag (Sodertalje, SE)
Application Number:08/240,078
Patent Claims: 1. A controlled release pellet formulation for oral administration in the treatment of inflammatory bowel diseases wherein the pellet, having a size between 0.3 mm and 5 mm diameter, comprises

(i)

a) a core consisting of a non-pareil seed or

b) a seed in which a glucocorticosteroid as defined in this claim is homogeneously distributed; and

(ii)

a) in the case of the core consisting of a non-pareil seed, a layer surrounding said core of

i)' a glucocorticosteroid selected from the group consisting of (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-1, 4-diene-3,20-dione (I); the 22R-epimer of (I); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta.,21-di hydroxy-pregna-1,4-diene-3,20-dione (II); the 22R-epimer of (II); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11. beta.,21-dihydroxy-pregna-1,4-diene-3,20-dione (III); the 22R-epimer of (III); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-11.beta.-hydroxypre gna-1,4-diene-3,20-dione (IA); the 22R-epimer of (IA); (22R, S)-21-acetoxy-16.alpha.-17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta. -hydroxy-pregna-1,4-diene-3,20-dione (IIA); the 22R-epimer of (IIA); (22R, S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluo ro-11.beta.-hydroxypregna-1,4-diene-3,20-dione (IIIA); the 22R-epimer of (IIIA); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-4- ene-3,20-dione (IV); the 22R-epimer of (IV); (22R,S)-16.alpha.,17.alpha.-pentylidenedioxy-11.beta.,21-dihydroxypregna-4 -ene-3,20-dione (V); the 22R-epimer of (V); (22R, S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-11.beta. hydroxypregna-4-ene-3,20-dione (IVA); the 22R-epimer of (IVA); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-pentylidenedioxy-11.beta. hydroxypregna-4-ene-3,20-dione (VA); the 22R-epimer of (VA); methyl (20R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.-hydroxy-androsta-1,4- diene-3-one-17.beta.-carboxylate (VI); the 20R-epimer of (VI); methyl (20R, S)-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta.-hydroxy-an drosta-1,4-diene-3-one-17.beta.-carboxylate (VII); the 20R-epimer of (VII); methyl (20R,S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11. beta.-hydroxy-androsta-1,4-diene-3-one-17.beta.-carboxylate (VIII); the 20R-epimer of (VIII); methyl (22R,S)-16.alpha.,17.beta.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11.b eta.-hydroxy-3,20-dioxo-pregna-1,4-diene-21-oate (IX) and the 22R-epimer of (IX), and

ii)' a pharmaceutically acceptable film-forming, water-insoluble or water-soluble polymer, the layer comprising about 0.5-30% of the pellet by weight, or

b) in the case of the core consisting of a seed in which a glucocorticosteroid as defined in this claim is homogeneously distributed, a layer surrounding said core of a pharmaceutically acceptable, film-forming, water-insoluble polymer or a pharmaceutically acceptable mixture of film-forming, water-insoluble polymers, or a pharmaceutically acceptable mixture of film-forming, water-soluble and film-forming, water-insoluble polymers; and

(iii) a membrane surrounding both said core and said surrounding layer and containing a pharmaceutically acceptable, film-forming, anionic carboxylic polymer being difficult to dissolve at a low pH but being soluble at a higher pH of about 4 to 7.5, the polymer being either alone or in combination with a pharmaceutically acceptable, film-forming, water-insoluble polymer, the membrane comprising about 1-50% of the pellet by weight, the thickness of said layer or said membrane, or the ratio of said anionic carboxylic polymer to said water-insoluble polymer being effective to prevent release of said glucocorticosteroid from said pellet in gastric fluids, but to permit release of said glucocorticosteroid from said pellet in intestinal fluids at a rate allowing treatment of the part of the intestinal tract where the disease resides, which rate corresponds to a release time in vivo of 1 to 50 hours.

2. A controlled release pellet formulation for oral administration in the treatment of inflammatory bowel diseases wherein the pellet, having a size between 0.3 mm and 5 mm diameter, comprises

(i)

a) a core consisting of a non-pareil seed or

b) a seed in which a glucocorticosteroid as defined in this claim is homogeneously distributed; and

(ii)

a) in case of the core consisting of a non-pareil seed, a layer surrounding said core of

i)' a glucocorticosteroid selected from the group consisting of (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-1, 4-diene-3,20-dione (I); the 22R-epimer of (I); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta.,21-di hydroxy-pregna-4,1-diene-3,20-dione (II); the 22R-epimer of (II); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11. beta.,21-dihydroxy-pregna-1,4-diene-3,20-dione (III); the 22R-epimer of (III); (22R, S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-11.beta.-hydroxypregna-1 ,4-diene-3,20-dione (IA); the 22R-epimer of (IA); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11. beta.-hydroxy-pregna-1,4-diene-3,20-dione (IIA); the 22R-epimer of (IIA); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-d ifluoro-11.beta.-hydroxypregna-1,4-diene-3,20-dione (IIIA); the 22R-epimer of (IIIA); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-4- ene-3,20-dione (IV); the 22R-epimer of (IV); (22R, S)-16.alpha.,17.alpha.-pentylidenedioxy-11.beta.,21-dihydroxypregna-4-ene- 3,20-dione (V); the 22R-epimer of (V); (22R, S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-11.beta. hydroxypregna-4-ene-3,20-dione (IVA); the 22R-epimer of (IVA); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-pentylidenedioxy-11.beta.hydroxypre gna-4-ene-3,20-dione (VA); the 22R-epimer of (VA); methyl (20R, S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.-hydroxy-androsta-1,4-diene -3-one-17.beta.-carboxylate (VI); the 20R-epimer of (VI); methyl (20R,S)-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta.-hydro xy-androsta-1,4-diene-3-one-17.beta.-carboxylate (VII); the 20R-epimer of (VII); methyl (20R, S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11.beta. -hydroxy-androsta-1,4-diene-3-one-17.beta.-carboxylate (VIII); the 20R-epimer of (VIII); methyl (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11. beta.-hydroxy-3,20-dioxo-pregna-1,4-diene-21-oate (IX) and the 22R-epimer of (IX), and

ii) ' a pharmaceutically acceptable, film-forming, water-insoluble or water-soluble polymer, the layer comprising about 0.5-30% of the pellet by weight, or

(b) in the case of the core consisting of a seed in which a glucocorticosteroid as defined in this claim is homogeneously distributed, a layer surrounding said core of a pharmaceutically acceptable, film-forming, water-insoluble polymer, or a pharmaceutically acceptable mixture of film-forming, water-insoluble polymers, or a pharmaceutically acceptable mixture of film-forming, water-soluble and film-forming, water-insoluble polymers; and

(iii) a membrane surrounding both said core and said surrounding layer and containing a pharmaceutically acceptable, film-forming, anionic carboxylic polymer being difficult to dissolve at a low pH but being soluble at a higher pH of about 4 to 7.5 the polymer being either alone or in combination with a pharmaceutically acceptable, film-forming, water-insoluble polymer, the membrane comprising about 1-50% of the pellet by weight, the thickness of said layer or said membrane, or the ratio of said anionic carboxylic polymer to said water-insoluble polymer being effective to prevent release of said glucocorticosteroid from said pellet in gastric fluids, but to permit release of said glucocorticosteroid from said pellet in intestinal fluids at a rate allowing treatment of the part of the intestinal tract where the disease resides, which rate corresponds to a release time in vivo of 1 to 50 hours, said rate being measured in vitro as a dissolution rate of a dosage unit in simulated gastric and intestinal fluids, when measured in a flow-through cell at 8 ml/min and 37.degree. C. and corresponds to a formulation for treating the small intestine wherein:

a) not more than 10% of the total glucocorticosteroid is released after two hours in simulated gastric fluid in said assembly,

b) from 15 to 55% of the total glucocorticosteroid is released after two hours in simulated intestinal fluid in said assembly,

c) from 35 to 80% of the total glucocorticosteroid is released after four hours in simulated intestinal fluid in said assembly,

d) not less than 60% of the total glucocorticosteroid is released after eight hours in simulated intestinal fluid in said assembly,

e) not less than 80% of the total glucocorticosteroid is released after twelve hours in simulated intestinal fluid in said assembly,

and a formulation for treating the large intestine wherein:

f) not more than 10% of the total glucocorticosteroid is released after two hours in simulated gastric fluid in said assembly,

g) from 5 to 30% of the total glucocorticosteroid is released after four hours in simulated intestinal fluid in said assembly,

h) from 20 to 65% of the total glucocorticosteroid is released after twelve hours in simulated intestinal fluid in said assembly,

i) from 40 to 95% of the total glucocorticosteroid is released after twenty-four hours in simulated intestinal fluid in said assembly, and

j) not less than 70% of the total glucocorticosteroid is released after forty-eight hours in simulated intestinal fluid in said assembly.

3. A controlled release pellet formulation for oral administration in the treatment of inflammatory bowel diseases wherein the pellet, having a size between 0.3 mm and 5 mm in diameter, comprises

(i)

a) a core consisting of a non-pareil seed or

b) a seed in which a glucocorticosteroid is homogeneously distributed; and

(ii)

a) in the case of the core consisting of a non-pareil seed, a layer surrounding said core of

(i)' a glucocorticosteroid selected from the group consisting of (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-1, 4-diene-3,20-dione (I); the 22R-epimer of (I); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta.,21-di hydroxy-pregna-1,4-diene-3,20-dione (II); the 22R-epimer of (II); (22R, S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11.beta. ,21-dihydroxy-pregna-1,4-diene-3,20-dione (III); the 22R-epimer of (III); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-11.beta.-hydroxypre gna-1,4-diene-3,20-dione (IA); the 22R-epimer of (IA); (22R,S)-21-acetoxy-16.alpha.-17.alpha.-butylidenedioxy-9.alpha.-fluoro-11. beta.-hydroxy-pregna-1,4-diene-3,20-dione (IIA); the 22R-epimer of (IIA); (22R,S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-d ifluoro-11.beta.-hydroxypregna-1,4-diene-3,20-dione (IIIA); the 22R-epimer of (IIIA); (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.,21-dihydroxypregna-4- ene-3,20-dione (IV); the 22R-epimer of (IV); (22R,S)-16.alpha.,17.alpha.-pentylidenedioxy-11.beta.,21-dihydroxypregna-4 -ene-3,20-dione (V); the 22R-epimer of (V); (22R, S)-21-acetoxy-16.alpha.,17.alpha.-butylidenedioxy-11.beta. hydroxypregna-4-ene-3,20-dione (IVA); the 22R-epimer of (IVA); (22R, S)-21-acetoxy-16.alpha.,17.alpha.-pentylidenedioxy-11.beta.hydroxypregna-4 -ene-3,20-dione (VA); the 22R-epimer of (VA); methyl (20R, S)-16.alpha.,17.alpha.-butylidenedioxy-11.beta.-hydroxy-androsta-1,4-diene -3-one-17.beta.-carboxylate (VI); the 20R-epimer of (VI); methyl (20R, S)-16.alpha.,17.alpha.-butylidenedioxy-9.alpha.-fluoro-11.beta.-hydroxy-an drosta-1,4-diene-3-one-17.beta.-carboxylate (VII); the 20R-epimer of (VII); methyl (20R, S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11.beta. -hydroxy-androsta-1,4-diene-3-one-17.beta.-carboxylate (VIII); the 20R-epimer of (VIII); methyl (22R,S)-16.alpha.,17.alpha.-butylidenedioxy-6.alpha.,9.alpha.-difluoro-11. beta.-hydroxy-3,20-dioxo-pregna-1,4-diene-21-oate (IX) and the 22R-epimer of (IX) , and

(ii)' a pharmaceutical acceptable, film-forming, water-insoluble or water-soluble polymer, the layer comprising about 0.5-30% of the pellet by weight, or

(b) in the case of the core consisting of a seed in which a glucocorticosteroid as defined in this claim is homogeneously distributed, a layer surrounding said core of a pharmaceutically acceptable, film-forming, water-insoluble polymer, or a pharmaceutically acceptable mixture of film-forming, water-insoluble polymers or a pharmaceutically acceptable mixture of film-forming, water-soluble and film-forming, water-insoluble polymers; and

(iii) a membrane surrounding both said core and said surrounding layer and containing a pharmaceutically acceptable, film-forming, anionic carboxylic polymer being difficult to dissolve at a low pH but being soluble at a higher pH of about 4 to 7.5, either alone or in combination with a pharmaceutically acceptable, film-forming, water insoluble polymer, the thickness of said layer or said membrane or the ratio of said anionic carboxylic polymer to said water-insoluble polymer being effective to prevent release of said glucocorticosteroid from said pellet in gastric fluids, but to permit release of said glucocorticosteroid from said pellet in intestinal fluids at a rate allowing treatment of the part of the intestinal tract where the disease resides, which rate corresponds to a release time in vivo of 1 to 50 hours said rate being measured in vitro as a dissolution rate of a dosage unit in simulated gastric and intestinal fluids, when measured in a flow through cell at 8 mL/min and 37.degree. C., and corresponds to the following formulation for treating the small intestine, wherein:

a) not more than 5% of the total glucocorticosteroid is released after two hours in simulated gastric fluid in said assembly,

b) from 20 to 50% of the total glucocorticosteroid is released after two hours in simulated intestinal fluid in said assembly,

c) from 40 to 70% of the total glucocorticosteroid is released after four hours in simulated intestinal fluid in said assembly,

d) 60% to 90% of the total glucocorticosteroid is released after eight hours in simulated intestinal fluid in said assembly,

e) not less than 80% of the total glucocorticosteroid is released after twelve hours in simulated intestinal fluid in said assembly,

and a formulation for treating the large intestine, wherein

f) not more than 5% of the total glucocorticosteroid is released after two hours in simulated gastric fluid in said assembly,

g) from 10 to 30% of the total glucocorticosteroid is released after four hours in simulated intestinal fluid in said assembly,

h) from 35 to 55% of the total glucocorticosteroid is released after twelve hours in simulated intestinal fluid in said assembly,

i) from 55 to 85% of the total glucocorticosteroid is released after twenty-four hours in simulated intestinal fluid in said assembly, and

j) not less than 80% of the total glucocorticosteroid is released after forty-eight hours in simulated intestinal fluid in said assembly.

4. The formulation according to claim 1 2 or 3 wherein the anionic carboxylic polymer ranges from 25% to 100% by weight of the total polymer content of said membrane.

5. The formulation according to claim 1, 2 or 3 wherein the anionic carboxylic polymer is selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl-methycellulose phthalate and methacrylic acid copolymer.

6. The formulation according to claim 1, 2 or 3 wherein the water insoluble polymer is selected from the group consisting of ethyl-cellulose, cellulose acetate, polyvinyl acetate, ethylene-vinyl acetate copolymer, amino methacrylate copolymers and polymethacrylic acid esters.

7. The formulation according to claim 1, 2 or 3 wherein the membrane includes one additional component selected from the group consisting of a plasticizer, an antiadhesive, a surfactant and a mixture thereof.

8. The formulation according to claim 1, 2 or 3 wherein the membrane ranges between 1 and 50% of the total weight of the pellet.

9. The formulation according to claim 1 2 or 3 wherein the glucocorticosteroid is budesonide or the 22R epimer thereof.

10. A formulation according to claim 1, 2 or 3, wherein the layer surrounding the core and beneath the membrane comprises budesonide or the 22R epimer thereof and a watersoluble or water insoluble film-forming polymer.

11. A formulation according to claim 10 wherein the layer includes one additional component selected from the group consisting of plasticizer, an antiadhesive, a surfactant and a mixture thereof.

12. The formulation according to claim 1, 2 or 3, wherein the layer beneath the membrane comprises a film-forming, water-insoluble polymer, a mixture of film-forming, water-insoluble polymers, or a mixture of water-insoluble and water-soluble, film-forming polymers.

13. A formulation according to claim 1, 2 or 3 wherein the polymeric material in which budesonide or the 22R epimer thereof is embedded is selected from the group consisting of polyvidone acetate, methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, ethylcellulose, cellulose acetate, polyvinyl acetate, ethylene-vinylacetate copolymer, an amino methacrylate copolymer and a polymethacrylic acid ester.

14. A formulation according to claim 12 wherein the layer includes one additional component selected from the group consisting of a plasticizer, an antiadhesive, a surfactant and a mixture thereof.

15. The formulation according to claim 12 wherein the polymeric material is selected from the group consisting of polyvidone acetate, methylcellulonse, hydroxypropylcellulose, ethylcellulose, cellulose acetate, polyvinyl acetate, ethylene vinylacetate copolymer, an amino methacrylate copolymer and a polymethacrylic acid ester.

16. The formulation according to claim 1, 2 or 3 wherein said core comprises budesonide or the 22R epimer thereof homogeneously distributed in pharmaceutically acceptable excipients or budesonide or the 22R epimer thereof in a layer on a non-pareil seed wherein the seed has a diameter between 0.2 and 1.5 mm.

17. The formulation according to claim 1, 2 or 3 wherein the release time in vivo is 5 to 10 hours for treating the small intestine or 25 to 50 hours for treating the large intestine.

18. The formulation according to claim 2 wherein the in vitro dissolution rate of the dosage unit for treating the small intestine is not more than 5% of the total glucocorticosteroid released after two hours in the simulated gastric fluid; from 20% to 50% thereof released after two hours in the simulated intestinal fluid; from 40% to 70% thereof released after four hours in simulated intestinal fluid; from 60% to 90% thereof released after eight hours in simulated intestinal fluid and not less than 80% thereof released after twelve hours in simulated intestinal fluid.

19. The formulation according to claim 2 wherein the dissolution rate for a dosage unit intended for treating the large intestine is not more than 5% of the total glucocorticosteroid being released after two hours in simulated gastric fluid; from 10% to 30% thereof is released after four hours in simulated intestinal fluid; from 35% to 65 % thereof is released after twelve hours in simulated intestinal fluid; 55% to 85% thereof is released after twenty-four hours in simulated intestinal fluid; and not less than 80% thereof is released after forty-eight hours in simulated intestinal fluid.

20. The formulation of claim 1, 2 or 3 wherein the pellet is substantially free of precipitating electrolyte salts or cross-linking additives.

21. The formulation according to claim 1, 2 or 3, wherein the layer comprises between 1% and 15% (w/w) of the total weight of the coated pellet.

22. A pharmaceutical composition comprising the formulation according to claim 1, 2 or 3, useful for the treatment by the oral route of a bowel disease selected from the group consisting of ulcerative colitis, Crohn's colitis in its active phase, Crohn's colitis in its chronic phase as relapse-preventing therapy and Crohn's disease in the small intestines as a relapse preventing treatment.

23. A pharmaceutical composition as claimed in claim 22 wherein the bowel disease is ulcerative colitis.

24. The pharmaceutical composition as claimed in claim 22 wherein the glucocorticosteroid is budesonide or the 22R epimer thereof.

25. A capsule comprising a formulation of pellets according to claim 1, 2 or 3.

26. A process for the production of a pellet formulation according to any one of claims 1, 2 or 3 which comprises

a) making a core of pharmaceutically acceptable excipients with the glucocorticosteroid homogeneously distributed therein and optionally enclosing the core with a water-insoluble polymer, or a mixture of water-insoluble polymers or a mixture of water-soluble and water-insoluble polymers, or

b) enclosing a core of a non-pareil seed in a layer of a glucocorticosteroid and a water-soluble or water-insoluble polymer, and thereafter enclosing the coated core with a membrane of a film-forming, anionic carboxylic polymer, or a mixture of a film-forming, anionic carboxylic polymer and a water-insoluble polymer which permits release of the glucocorticosteroid in a manner set out in claim 1, 2 or 3.
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