Oral cholestyramine formulation and use thereof
The invention relates to an oral formulation for targeted delivery of cholestyramine to the colon, comprising a plurality of cholestyramine pellets that are coated with a colon release coating. The invention also relates to the use of this formulation in the treatment of bile acid malabsorption.
1. An oral dosage form comprising:
a) a plurality of extruded and spheronized pellets, each extruded and spheronized pellet comprising a homogenous mixture of at least 70% w/w cholestyramine and
i. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer and at least 2% w/w of an acrylate copolymer; or
ii. a combination of at least 5% w/w of a vinylpyrrolidone-based polymer and at least 3% w/w of an acrylate copolymer; or
iii. a combination of at least 6% w/w of a vinylpyrrolidone-based polymer, at least 1% w/w of an acrylate copolymer and at least 10% w/w microcrystalline cellulose;
wherein the vinylpyrrolidone-based polymer is selected from the group consisting of copovidone, povidone, and combinations thereof; and
b) a coating surrounding each extruded and spheronized pellet, wherein the coating is capable of targeting release of the cholestyramine in the colon;
wherein the oral dosage form exhibits less than about 30% sequestration of cholic acid, chenodeoxycholic acid, and deoxycholic acid after 2 hours in small intestinal incubations (“SI-2”) as measured in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) model.
2. The oral dosage form of claim 1 , wherein the oral dosage form exhibits less than about 25% sequestration of cholic acid, chenodeoxycholic acid, and deoxycholic acid after 2 hours in small intestinal incubations (“SI-2”) as measured in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) model.
3. The oral dosage form of claim 1 , wherein the oral dosage form exhibits less than about 20% sequestration of cholic acid after 2 hours in small intestinal incubations (“SI-2”) as measured in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME) model.
4. The oral dosage form of claim 1 , wherein the extruded and spheronized pellets comprise at least 75% w/w cholestyramine.
5. The oral dosage form of claim 4 , wherein the extruded and spheronized pellets comprise at least 80% w/w cholestyramine.
6. The oral dosage form of claim 5 , wherein the extruded and spheronized pellets comprise at least 85% w/w cholestyramine.
7. The oral dosage form of claim 6 , wherein the extruded and spheronized pellets comprise at least 90% w/w cholestyramine.
8. The oral dosage form of claim 1 , wherein the vinylpyrrolidone-based polymer is copovidone.
9. The oral dosage form of claim 1 , wherein the acrylate copolymer is an ammonio methacrylate copolymer.
10. The oral dosage form of claim 1 , wherein the extruded and spheronized pellets comprise microcrystalline cellulose.
11. The oral dosage form of claim 10 , wherein the extruded and spheronized pellets comprise at least 10% w/w microcrystalline cellulose.
12. The oral dosage form of claim 1 , wherein the extruded and spheronized pellets are free of microcrystalline cellulose.
13. The oral dosage form of claim 1 , wherein the coating is elastic.
14. The oral dosage form of claim 1 , wherein the coating comprises starch.
15. The oral dosage form of claim 14 , wherein the starch is resistant starch type 2 (RS2).
16. The oral dosage form of claim 1 , wherein the coating further comprises poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1.
17. The oral dosage form of claim 1 , wherein the coating does not comprise hypromellose acetate succinate HF.
18. The oral dosage form of claim 1 , wherein the coating does not comprise ethyl cellulose.
19. The oral dosage form of claim 1 , wherein the coating does not comprise cellulose acetate phthalate.
20. The oral dosage form of claim 1 , wherein the dosage form exhibits less than 20% sequestration of cholic acid after 6 hours at pH 5.5 as measured using a USP Dissolution Apparatus 2 (paddle) Ph. Eur. 2.9.3.
21. The oral dosage form of claim 1 , wherein the dosage form exhibits greater than 20% sequestration of cholic acid after 2 hours at pH 1 followed by 4 hours at pH 6.8 as measured using a USP Dissolution Apparatus 2 (paddle) Ph. Eur. 2.9.3.