Claims for Patent: 9,968,649

Summary for Patent: 9,968,649

Title:	Vasopressin formulations for use in treatment of hypotension
Abstract:	Provided herein are peptide formulations comprising polymers as stabilizing agents. The peptide formulations can be more stable for prolonged periods of time at temperatures higher than room temperature when formulated with the polymers. The polymers used in the present invention can decrease the degradation of the constituent peptides of the peptide formulations.
Inventor(s):	Kenney; Matthew (New Haven, MI), Kannan; Vinayagam (Rochester, MI), Vandse; Sunil (Basking Ridge, NJ), Sanghvi; Suketu (Kendall Park, NJ)
Assignee:	Par Pharmaceutical, Inc. (Chestnut Ridge, NY)
Application Number:	15/688,336
Patent Claims:	1. A method of increasing blood pressure in a human in need thereof, the method comprising: providing a unit dosage form, wherein the unit dosage form comprises from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof, wherein the unit dosage form has a pH of 3.6 to 3.9; the unit dosage form further comprises impurities that are present in an amount of 0.9%-1.7%, wherein the impurities have from about 85% to about 100% sequence homology to SEQ ID NO.: 1, dextrose, and from about 1 mM to about 10 mM acetate buffer; storing the unit dosage form for at least about 24 hours at from about 0.1 units/ml to about 1 unit/ml vasopressin or a pharmaceutically-acceptable salt thereof; after the storing, intravenously administering the unit dosage form to the human; wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.1 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute, wherein the unit dosage form that is administered to the human comprises from about 0.1 units/mL to about 1 unit/mL of vasopressin or the pharmaceutically-acceptable salt thereof; and the human is hypotensive. 2. The method of claim 1, wherein the impurities comprise SEQ ID NO.: 2, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1% to 0.3%. 3. The method of claim 1, wherein the impurities comprise SEQ ID NO.: 3, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%. 4. The method of claim 1, wherein the impurities comprise SEQ ID NO.: 4, and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 5. The method of claim 1, wherein the impurities comprise SEQ ID NO.: 7, and SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%. 6. The method of claim 1, wherein the impurities comprise SEQ ID NO.: 10, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 7. The method of claim 1, wherein the impurities comprise SEQ ID NO.: 2 and SEQ ID NO.: 4, and SEQ ID NO.: 2 is present in the unit dosage form in an amount of 0.1% to 0.3% and SEQ ID NO.: 4 is present in the unit dosage form in an amount of 0.2% to 0.4%. 8. The method of claim 7, wherein the impurities further comprise SEQ ID NO.: 3, SEQ ID NO.: 7, and SEQ ID NO.: 10, and SEQ ID NO.: 3 is present in the unit dosage form in an amount of 0.1%, SEQ ID NO.: 7 is present in the unit dosage form in an amount of 0.3% to 0.6%, and SEQ ID NO.: 10 is present in the unit dosage form in an amount of 0.1%. 9. The method of claim 1, wherein the human's hypotension is associated with vasodilatory shock. 10. The method of claim 9, wherein the administration provides to the human from about 0.01 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute to about 0.07 units of vasopressin or the pharmaceutically-acceptable salt thereof per minute. 11. The method of claim 1, wherein the impurities comprise a plurality of peptides, wherein the impurities are determined based on: (a) injecting the unit dosage form into a high pressure liquid chromatography apparatus, wherein the apparatus comprises: (i) a chromatography column containing adsorbent particles as a stationary phase; (ii) a first mobile phase passing through the chromatography column, wherein the first mobile phase is phosphate buffer at pH 3; and (iii) a second mobile phase passing through the chromatography column, wherein the second mobile phase is a 50:50 acetonitrile:water solution; (b) running the unit dosage form through the chromatography column for 55 minutes; (c) eluting the vasopressin and the plurality of peptides from the chromatography column using a gradient of the first mobile phase, and a gradient of the second mobile phase, wherein each of the first and second mobile phase are run at a flow rate of 1 mL/min through the chromatography column; (d) passing the eluted vasopressin and the plurality of peptides through a UV detector to generate a UV spectrum of the eluted vasopressin and the plurality of peptides; (e) identifying a peptide of the plurality of peptides based on a retention time of the peptide of the plurality of peptides relative to a standard; and (f) calculating an amount of the peptide of the plurality of peptides based on an integration of a peak obtained for the peptide of plurality of peptides from the UV spectrum. 12. The method of claim 1, wherein the unit dosage form further comprises a pH adjusting agent. 13. The method of claim 1, wherein the pharmaceutically-acceptable salt of vasopressin is present in the unit dosage form. 14. The method of claim 1, wherein the pharmaceutically-acceptable salt of vasopressin is not present in the unit dosage form. 15. The method of claim 1, wherein the unit dosage form has a pH of 3.74-3.75. 16. The method of claim 1, wherein the unit dosage form comprises about 1 mM acetate buffer, and wherein the unit dosage form has a pH of 3.7 to 3.9. 17. The method of claim 1, wherein the unit dosage form comprises about 10 mM acetate buffer, and wherein the unit dosage form has a pH of 3.6 to 3.7.