Stable solid formulation of a GC-C receptor agonist polypeptide suitable for oral administration
View Patent ↗Solid, stable formulations of linaclotide suitable for oral administration are described herein as are methods for preparing such formulations. The formulations described herein contain a polypeptide consisting of the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (“linaclotide”; SEQ ID NO:1) or a pharmaceutically acceptable salt thereof. The linaclotide formulations described herein are stable and have a sufficient shelf life for manufacturing, storing and distributing the drug.
1. A solid pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier, linaclotide, a Ca 2+ cation and leucine, wherein linaclotide has the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (SEQ ID NO:1) and activates the guanylate cyclase C (GC-C) receptor.
2. The solid pharmaceutical composition of claim 1 , wherein said Ca 2+ is provided as calcium chloride, calcium phosphate, or calcium sulfate.
3. The solid pharmaceutical composition of claim 1 , further comprising one or more of a pharmaceutically acceptable binder or a pharmaceutically acceptable filler.
4. The solid pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable binder is selected from polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether.
5. The solid pharmaceutical composition of claim 3 , wherein the pharmaceutically acceptable binder is a cellulose ether selected from methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
6. The solid pharmaceutical composition according to claim 3 , wherein the pharmaceutically acceptable filler is cellulose, isomalt, mannitol or dibasic calcium phosphate.
7. The solid pharmaceutical composition of claim 6 , wherein the cellulose is selected from microfine cellulose and microcrystalline cellulose.
8. The pharmaceutical composition according to claim 1 , further comprising a hydrolysis product having a structure of
wherein the hydrolysis product comprises less than 2% by weight compared to the weight of the linaclotide.
9. The pharmaceutical composition of claim 8 , wherein the hydrolysis product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide.
10. The pharmaceutical composition according to claim 1 , further comprising a linaclotide oxidation product having a molecular weight of 1542.8, wherein the linaclotide oxidation product comprises less than 2% by weight compared to the weight of the linaclotide.
11. The pharmaceutical composition according to claim 10 , wherein the linaclotide oxidation product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide.
12. The solid pharmaceutical composition according to claim 1 , wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
13. The solid pharmaceutical composition according to claim 12 , wherein the chromatographic purity of the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5%, or 4% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
14. The solid pharmaceutical composition according to claim 1 , wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
15. The solid pharmaceutical composition according to claim 1 , wherein the chromatographic purity of the linaclotide is greater than or equal to 90% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
16. The solid pharmaceutical composition according to claim 1 , wherein an assay value for linaclotide in a unit dosage form determined on a weight/weight basis decreases by less than 10%, after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
17. The solid pharmaceutical composition according to claim 16 , wherein the assay value for the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
18. The solid pharmaceutical composition according to claim 1 , wherein an assay value of the linaclotide decreases by less than 10% after (a) 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
19. The solid pharmaceutical composition according to claim 1 , wherein an assay value for linaclotide determined on a weight/weight basis is greater than or equal to 90% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant.
20. The solid pharmaceutical composition of claim 2 , wherein said Ca 2+ cation is provided as calcium chloride.
21. The solid pharmaceutical composition of claim 1 , wherein the molar ratio of Ca 2+ cation:leucine:linaclotide is 40-100:20-50:1.
22. The solid pharmaceutical composition of claim 21 , wherein the molar ratio of Ca 2+ cation:leucine:linaclotide is 100:30:1, 80:40:1, 80:30:1, 80:20:1, 60:30:1, 60:20:1, 50:30:1, 50:20:1, 40:20:1, 20:20:1, 10:10:1, 10:5:1, 5:10:1 or 5:5:1.
23. The solid pharmaceutical composition of claim 22 , wherein the molar ratio of Ca 2+ cation:leucine:linaclotide is 60:30:1.
24. The solid pharmaceutical composition of claim 23 , wherein the Ca 2+ cation is provided as calcium chloride.
25. The solid pharmaceutical composition of claim 22 , wherein the solid pharmaceutical composition is a bead-containing capsule.
26. The solid pharmaceutical composition of claim 23 , wherein the solid pharmaceutical composition is a bead-containing capsule.