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Claims for Patent: 8,802,628

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Claims for Patent: 8,802,628

Title:Stable solid formulation of a GC-C receptor agonist polypeptide suitable for oral administration
Abstract: 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.
Inventor(s): Fretzen; Angelika (Somerville, MA), Witowski; Steven (Melrose, MA), Grossi; Alfredo (Somerville, MA), Zhao; Hong (Lexington, MA), Dedhiya; Mahendra (Pomona, NY), Mo; Yun (Commack, NY)
Assignee: Ironwood Pharmaceuticals, Inc. (Cambridge, MA) Forest Laboratories Holdings, Ltd. (Hamilton, BM)
Application Number:12/541,410
Patent Claims: 1. A solid pharmaceutical composition for oral administration comprising a pharmaceutically acceptable carrier, linaclotide, a Ca.sup.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.sup.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 ##STR00008## 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. 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.degree. C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40.degree. C. at 75% relative humidity in a sealed container containing a desiccant.

20. The solid pharmaceutical composition of claim 2, wherein said Ca.sup.2+ cation is provided as calcium chloride.

21. The solid pharmaceutical composition of claim 1, wherein the molar ratio of Ca.sup.2+ cation:leucine:linaclotide is 40-100:20-50:1.

22. The solid pharmaceutical composition of claim 21, wherein the molar ratio of Ca.sup.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.sup.2+ cation:leucine:linaclotide is 60:30:1.

24. The solid pharmaceutical composition of claim 23, wherein the Ca.sup.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.
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