Crystalline form of linaclotide
View Patent ↗The present invention relates to crystalline forms of linaclotide, as well as to various methods and processes for the preparation and use of the crystalline forms.
1. A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof a pharmaceutical oral dosage form comprising a crystalline form of linaclotide having an X-ray powder diffraction pattern comprising peaks at about 6.2, about 7.8, about 22.6 and about 23.9+/−0.5 degrees 2θ.
2. The method of claim 1 , wherein the X-ray power diffraction pattern further comprises a peak at about 19.5+/−0.5 degrees 2θ.
3. The method of claim 1 , wherein the X-ray power diffraction pattern further comprises a peak at about 20.9+/−0.5 degrees 2θ.
4. The method of claim 1 , wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome.
5. The method of claim 1 , wherein the gastrointestinal disorder is chronic constipation.
6. A method of treating a gastrointestinal disorder selected from constipation-predominant irritable bowel syndrome and chronic constipation in a patient in need thereof wherein the method comprises administering to a patient diagnosed with the gastrointestinal disorder a pharmaceutical oral dosage form comprising a pharmaceutically acceptable carrier and a form of linaclotide having a melting endotherm at about 270° C. as determined by differential scanning calorimetry and further comprising a linaclotide hydrolysis product.
7. The method of claim 6 , wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome.
8. The method of claim 6 , wherein the pharmaceutical oral dosage form further comprises a linaclotide hydrolysis product of SEQ ID NO 2.
9. The method of claim 8 , wherein the linaclotide hydrolysis product is present in the pharmaceutical oral dosage form in an amount from about 0.05% to about 5% by weight.
10. The method of claim 8 , wherein the linaclotide hydrolysis product is present in the pharmaceutical oral dosage form in an amount from about 0.05% to about 2% by weight.
11. The method of claim 6 , wherein the gastrointestinal disorder is chronic constipation.
12. The method of claim 6 , wherein the pharmaceutical oral dosage form further comprises a linaclotide acetylation product.
13. The method of claim 12 , wherein the linaclotide acetylation product is present in the pharmaceutical oral dosage form in an amount of up to 2% by weight relative to the total weight of linaclotide and linaclotide acetylation product.
14. The method of claim 6 , wherein the pharmaceutical oral dosage form further comprises a linaclotide formylation product.
15. The method of claim 14 , wherein the linaclotide formylation product is present in the pharmaceutical oral dosage form in an amount of up to 5% by weight relative to the total weight of linaclotide and linaclotide formylation product.
16. The method of claim 6 , wherein the pharmaceutical oral dosage form further comprises water-mediated degradation product of linaclotide.
17. The method of claim 16 , wherein the water-mediated degradation product of linaclotide is present in the pharmaceutical oral dosage form in an amount of up to 5% by weight relative to the total weight of linaclotide and water-mediated degradation product of linaclotide.
18. The method of claim 16 , wherein the water-mediated degradation product of linaclotide is present in the pharmaceutical oral dosage form in an amount of up to 2% by weight relative to the total weight of linaclotide and water-mediated degradation product of linaclotide.
19. The method of claim 6 , wherein the pharmaceutical oral dosage form further comprises up to 5% by weight of a linaclotide deamidation product relative to the total weight of linaclotide and linaclotide deamidation product.
20. The method of claim 19 , wherein the linaclotide deamidation product is present in the pharmaceutical oral dosage form in an amount of up to 2% by weight relative to the total weight of linaclotide and linaclotide deamidation product.
21. The method of claim 6 , wherein the pharmaceutical oral dosage form further comprises up to 2% by weight of a linaclotide oxidation product relative to the total weight of linaclotide and linaclotide oxidation product.