Oral composition for the treatment of inflammatory bowel disease
DC CAFCFirst Claim
Patent Images
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 orb) 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 ofi)'"'"' a glucocorticosteroid selected from the group consisting of (22R,S)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-1,4-diene-3,20-dione (I);
the 22R-epimer of (I);
(22R,S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
,21-dihydroxy-pregna-1,4-diene-3,20-dione (II);
the 22R-epimer of (II);
(22R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11.beta.,21-dihydroxy-pregna-1,4-diene-3,20-dione (III);
the 22R-epimer of (III);
(22R,S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
-hydroxypregna-1,4-diene-3,20-dione (IA);
the 22R-epimer of (IA);
(22R, S)-21-acetoxy-16α
-17α
-butylidenedioxy-9α
-fluoro-11β
-hydroxy-pregna-1,4-diene-3,20-dione (IIA);
the 22R-epimer of (IIA);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
-hydroxypregna-1,4-diene-3,20-dione (IIIA);
the 22R-epimer of (IIIA);
(22R,S)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (IV);
the 22R-epimer of (IV);
(22R,S)-16α
,17α
-pentylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (V);
the 22R-epimer of (V);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (IVA);
the 22R-epimer of (IVA);
(22R,S)-21-acetoxy-16α
,17α
-pentylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (VA);
the 22R-epimer of (VA);
methyl (20R,S)-16α
,17α
-butylidenedioxy-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VI);
the 20R-epimer of (VI);
methyl (20R, S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VII);
the 20R-epimer of (VII);
methyl (20R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11.beta.-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VIII);
the 20R-epimer of (VIII);
methyl (22R,S)-16α
,17β
-butylidenedioxy-6α
,9α
-difluoro-11.beta.-hydroxy-3,20-dioxo-pregna-1,4-diene-21-oate (IX) and the 22R-epimer of (IX), andii)'"'"' a pharmaceutically acceptable film-forming, water-insoluble or water-soluble polymer, the layer comprising about 0.5-30% of the pellet by weight, orb) 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.
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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.
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Citations
26 Claims
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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)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-1,4-diene-3,20-dione (I);
the 22R-epimer of (I);
(22R,S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
,21-dihydroxy-pregna-1,4-diene-3,20-dione (II);
the 22R-epimer of (II);
(22R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11.beta.,21-dihydroxy-pregna-1,4-diene-3,20-dione (III);
the 22R-epimer of (III);
(22R,S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
-hydroxypregna-1,4-diene-3,20-dione (IA);
the 22R-epimer of (IA);
(22R, S)-21-acetoxy-16α
-17α
-butylidenedioxy-9α
-fluoro-11β
-hydroxy-pregna-1,4-diene-3,20-dione (IIA);
the 22R-epimer of (IIA);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
-hydroxypregna-1,4-diene-3,20-dione (IIIA);
the 22R-epimer of (IIIA);
(22R,S)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (IV);
the 22R-epimer of (IV);
(22R,S)-16α
,17α
-pentylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (V);
the 22R-epimer of (V);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (IVA);
the 22R-epimer of (IVA);
(22R,S)-21-acetoxy-16α
,17α
-pentylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (VA);
the 22R-epimer of (VA);
methyl (20R,S)-16α
,17α
-butylidenedioxy-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VI);
the 20R-epimer of (VI);
methyl (20R, S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VII);
the 20R-epimer of (VII);
methyl (20R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11.beta.-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VIII);
the 20R-epimer of (VIII);
methyl (22R,S)-16α
,17β
-butylidenedioxy-6α
,9α
-difluoro-11.beta.-hydroxy-3,20-dioxo-pregna-1,4-diene-21-oate (IX) and the 22R-epimer of (IX), andii)'"'"' 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. - View Dependent Claims (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 20, 21, 22, 23, 24, 25, 26)
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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)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-1,4-diene-3,20-dione (I);
the 22R-epimer of (I);
(22R,S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
,21-dihydroxy-pregna-4,1-diene-3,20-dione (II);
the 22R-epimer of (II);
(22R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11.beta.,21-dihydroxy-pregna-1,4-diene-3,20-dione (III);
the 22R-epimer of (III);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
-hydroxypregna-1,4-diene-3,20-dione (IA);
the 22R-epimer of (IA);
(22R,S)-21-acetoxy-16α
,17α
-butylidenedioxy-9α
-fluoro-11.beta.-hydroxy-pregna-1,4-diene-3,20-dione (IIA);
the 22R-epimer of (IIA);
(22R,S)-21-acetoxy-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
-hydroxypregna-1,4-diene-3,20-dione (IIIA);
the 22R-epimer of (IIIA);
(22R,S)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (IV);
the 22R-epimer of (IV);
(22R, S)-16α
,17α
-pentylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (V);
the 22R-epimer of (V);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (IVA);
the 22R-epimer of (IVA);
(22R,S)-21-acetoxy-16α
,17α
-pentylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (VA);
the 22R-epimer of (VA);
methyl (20R, S)-16α
,17α
-butylidenedioxy-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VI);
the 20R-epimer of (VI);
methyl (20R,S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VII);
the 20R-epimer of (VII);
methyl (20R, S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VIII);
the 20R-epimer of (VIII);
methyl (22R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11.beta.-hydroxy-3,20-dioxo-pregna-1,4-diene-21-oate (IX) and the 22R-epimer of (IX), andii) '"'"' 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°
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. - View Dependent Claims (18, 19)
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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)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-1,4-diene-3,20-dione (I);
the 22R-epimer of (I);
(22R,S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
,21-dihydroxy-pregna-1,4-diene-3,20-dione (II);
the 22R-epimer of (II);
(22R, S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
,21-dihydroxy-pregna-1,4-diene-3,20-dione (III);
the 22R-epimer of (III);
(22R,S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
-hydroxypregna-1,4-diene-3,20-dione (IA);
the 22R-epimer of (IA);
(22R,S)-21-acetoxy-16α
-17α
-butylidenedioxy-9α
-fluoro-11.beta.-hydroxy-pregna-1,4-diene-3,20-dione (IIA);
the 22R-epimer of (IIA);
(22R,S)-21-acetoxy-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
-hydroxypregna-1,4-diene-3,20-dione (IIIA);
the 22R-epimer of (IIIA);
(22R,S)-16α
,17α
-butylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (IV);
the 22R-epimer of (IV);
(22R,S)-16α
,17α
-pentylidenedioxy-11β
,21-dihydroxypregna-4-ene-3,20-dione (V);
the 22R-epimer of (V);
(22R, S)-21-acetoxy-16α
,17α
-butylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (IVA);
the 22R-epimer of (IVA);
(22R, S)-21-acetoxy-16α
,17α
-pentylidenedioxy-11β
hydroxypregna-4-ene-3,20-dione (VA);
the 22R-epimer of (VA);
methyl (20R, S)-16α
,17α
-butylidenedioxy-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VI);
the 20R-epimer of (VI);
methyl (20R, S)-16α
,17α
-butylidenedioxy-9α
-fluoro-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VII);
the 20R-epimer of (VII);
methyl (20R, S)-16α
,17α
-butylidenedioxy-6α
,9α
-difluoro-11β
-hydroxy-androsta-1,4-diene-3-one-17β
-carboxylate (VIII);
the 20R-epimer of (VIII);
methyl (22R,S)-16α
,17α
-butylidenedioxy-6α
,9α
-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°
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.
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Specification