Linaclotide compositions
The present invention is directed to stable linaclotide compositions and methods of treating gastrointestinal disorders in patients in need thereof by providing the stable linaclotide compositions.
1. A linaclotide composition comprising linaclotide, a sterically hindered primary amine, a divalent metal cation and a formaldehyde scavenger compound and further comprises a peptide having the structure of formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 3):
2. The composition of claim 1 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 5% by weight as compared to the weight of linaclotide.
3. The composition of claim 1 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 3% by weight as compared to the weight of linaclotide.
4. The composition of claim 1 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 2% by weight as compared to the weight of linaclotide.
5. The composition of claim 1 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 1% by weight as compared to the weight of linaclotide.
6. The composition of claim 1 comprising a formaldehyde scavenger compound and an oral pharmaceutical dosage form comprising about 145 μg or about 290 μg of linaclotide or a pharmaceutically acceptable salt thereof, Ca 2+ or a salt thereof, leucine, and a peptide having the structure of formula (I) or a pharmaceutically acceptable salt thereof (SEQ ID NO: 3):
7. The composition of claim 6 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 2 wt. % relative to the total weight of the dosage form.
8. The composition of claim 6 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 1 wt. % relative to the total weight of the dosage form.
9. The composition of claim 6 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.75 wt. % relative to the total weight of the dosage form.
10. The composition of claim 6 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.5 wt. % relative to the total weight of the dosage form.
11. The composition of claim 1 , wherein the divalent metal cation is Ca 2+ or a salt thereof, the sterically hindered primary amine is leucine, and wherein the linaclotide composition comprises a molar ratio of divalent metal cation:sterically hindered primary amine:linaclotide of about 57-63:28-32:1.
12. The composition of claim 6 , wherein the Ca 2+ or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1.
13. The composition of claim 8 , wherein the Ca 2+ or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1.
14. The composition of claim 9 , wherein the Ca 2+ or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1.
15. The composition of claim 10 , wherein the Ca 2+ or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1.
16. The composition of claim 8 , wherein the oral pharmaceutical dosage form further comprises an oxidation product having a structure of (SEQ ID NO: 4):
in an amount from about 0.05% to about 5% by weight relative to the total weight of the dosage form.
17. The composition of claim 16 , wherein the oxidation product in present in the dosage form in an amount of about 0.05% to about 2% relative to the total weight of the dosage form.
18. The composition of claim 16 , wherein the oxidation product in present in the dosage form in an amount of about 0.05% to about 1% relative to the total weight of the dosage form.
19. The composition of claim 6 , wherein the Ca 2+ or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1, wherein the formaldehyde scavenger compound is selected from the group consisting of d-meglumine and histidine, and wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 1 wt. % relative to the total weight of the dosage form.
20. The composition of claim 19 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.75 wt. % relative to the total weight of the dosage form.
21. The composition of claim 19 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.5 wt. % relative to the total weight of the dosage form.
22. The composition of claim 1 , wherein the formaldehyde scavenger compound is d-meglumine.