Formulations comprising linaclotide
View Patent ↗The present invention relates to stable compositions comprising linaclotide, as well as to various methods and processes for the preparation and use of the compositions.
1. A method of treating chronic constipation or constipation-predominant irritable bowel syndrome in a patient in need thereof, comprising administering to the patient an oral, solid pharmaceutical dosage form comprising:
between 100 μg and 300 μg of a peptide consisting of the amino acid sequence Cys 1 Cys 2 Glu 3 Tyr 4 Cys 5 Cys 6 Asn 7 Pro 8 Ala 9 Cys 10 Thr 11 Gly 12 Cys 13 Tyr 14 (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof, wherein the peptide includes disulfide bonds between Cys 1 and Cys 6 , Cys 2 and Cys 10 , and Cys 5 and Cys 13 ;
leucine in a molar ratio of leucine to the peptide between 40:1 and 20:1; and
Ca 2+ or a salt thereof in a molar ratio of Ca 2+ the peptide between 70:1 and 50:1.
2. The method of claim 1 , wherein the oral, solid pharmaceutical dosage form further comprises a polymer selected from polyvinyl pyrrolidone, polyvinyl alcohol, hydroxylpropyl methyl cellulose and mixtures thereof in an amount between 0.01 wt. % and 2 wt. % relative to the total weight of the oral dosage form.
3. A method of treating chronic constipation or constipation-predominant irritable bowel syndrome in a patient in need thereof, comprising administering to the patient an oral, solid pharmaceutical dosage form comprising a peptide consisting of the amino acid sequence Cys 1 Cys 2 Glu 3 Tyr 4 Cys 5 Cys 6 Asn 7 Pro 8 Ala 9 Cys 10 Thr 11 Gly 12 Cys 13 Tyr 14 (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof, wherein the peptide includes disulfide bonds between Cys 1 and Cys 6 , Cys 2 and Cys 10 , and Cys 5 and Cys 13 in an amount between 0.2% by weight and 0.4% by weight, leucine in an amount between 0.5% by weight and 0.8% by weight, and a Ca 2+ salt in an amount between 1.4% by weight and 1.65% by weight relative to the total weight of the oral dosage form.
4. The method of claim 3 , wherein the leucine is present in the oral pharmaceutical dosage form in an amount between 0.6% by weight and 0.75% by weight, and the Ca 2+ salt is present in the oral pharmaceutical dosage form in an amount between in an amount between 1.45% by weight and 1.65% by weight relative to the total weight of the oral dosage form.
5. The method of claim 3 , wherein the amino acid is leucine and wherein the Ca 2+ salt is in the form of calcium chloride.
6. The method of claim 1 , wherein the amino acid is leucine and wherein Ca 2+ is in the form of calcium chloride.
7. The method of claim 3 , wherein the oral, solid pharmaceutical dosage form further comprises a polymer selected from polyvinyl pyrrolidone, polyvinyl alcohol, hydroxylpropyl methyl cellulose and mixtures thereof in an amount between 0.01 and 2 wt. % relative to the total weight of the oral dosage form.
8. The method of claim 1 , wherein the Ca 2+ or salt thereof and leucine are present in a molar ratio of at least 1.5:1.
9. The method of claim 1 , wherein the dosage form further comprises a hydrolysis product of linaclotide at a concentration between 0.1 and 4 wt. %.
10. The method of claim 3 , wherein the dosage form further comprises a hydrolysis product of linaclotide at a concentration between 0.1 and 4 wt. %.