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 diffusion-controlled inner coating and an enteric outer 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 pellets, each pellet comprising 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;
b) a diffusion-controlled inner coating surrounding each pellet; and
c) an enteric outer coating;
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 a 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 each pellet comprises at least 75% w/w cholestyramine.
5. The oral dosage form of claim 4 , wherein each pellet comprises at least 80% w/w cholestyramine.
6. The oral dosage form of claim 5 , wherein each pellet comprises at least 85% w/w cholestyramine.
7. The oral dosage form of claim 6 , wherein each pellet comprises 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 each pellet further comprises microcrystalline cellulose.
11. The oral dosage form of claim 10 , wherein each pellet comprises at least 10% w/w microcrystalline cellulose.
12. The oral dosage form of claim 1 , wherein each pellets is free of microcrystalline cellulose.
13. The oral dosage form of claim 1 , wherein the diffusion-controlled inner coating is elastic.
14. The oral dosage form of claim 1 , wherein the diffusion-controlled inner coating comprises poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2, poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1, or a combination thereof.
15. The oral dosage form of claim 1 , wherein the enteric outer coating comprises hydroxypropyl methylcellulose acetate succinate.
16. The oral dosage form of claim 1 , wherein the coating does not comprise hypromellose acetate succinate HF.
17. The oral dosage form of claim 1 , wherein the coating does not comprise ethyl cellulose.
18. The oral dosage form of claim 1 , wherein the coating does not comprise cellulose acetate phthalate.
19. 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.
20. The oral dosage form of claim 1 , wherein the dosage form exhibits greater than 30% sequestration of cholic acid after 4 hours at pH 6.8 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 30% sequestration of cholic acid after 4 hours at pH 7.4 as measured using a USP Dissolution Apparatus 2 (paddle) Ph. Eur. 2.9.3.