Vasopressin formulations for use in treatment of hypotension

• US 9,687,526 B2
• Filed: 10/10/2016
• Issued: 06/27/2017
• Est. Priority Date: 01/30/2015
• Status: Active Grant

• Current Assignee: Par Pharmaceutical, Inc. (Endo International PLC)
• Original Assignee: Par Pharmaceutical, Inc. (Endo International PLC)
• Inventors: Kenney, Matthew, Kannan, Vinayagam, Vandse, Sunil, Sanghvi, Suketu
• Primary Examiner(s): Bradley, Christina
• Application Number:
  US15/289,640
• Publication Number:
  US 20170035853A1
• Time in Patent Office: 260 Days
• CPC Class Codes: A61K 31/045 Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00

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.

Claims

1. A method of increasing blood pressure in a human in need thereof, the method comprising:

a) providing a pharmaceutical composition for intravenous administration comprising;

i) from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically-acceptable salt thereof;

ii) acetic acid; and

iii) water,

wherein the pharmaceutical composition has a pH of 3.8;

b) storing the pharmaceutical composition at 2-8°

C. for at least 4 weeks; and

c) intravenously administering the pharmaceutical composition 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 human is hypotensive,

wherein the pharmaceutical composition exhibits less than about 5% degradation after storage at 2-8°

C. for about four weeks.

2. The method of claim 1, wherein the pharmaceutical composition further comprises SEQ ID NO:

2 in an amount of about 0.01% after storage for about 4 weeks at 2-8°

C.

3. The method of claim 1, wherein the pharmaceutical composition further comprises SEQ ID NO:

3 in an amount of about 0.01% after storage for about 4 weeks at 2-8°

C.

4. The method of claim 1, wherein the pharmaceutical composition further comprises SEQ ID NO:

4 in an amount of about 0.01% after storage for about 4 weeks at 2-8°

C.

5. The method of claim 1, wherein the human'"'"'s mean arterial blood pressure is increased within 15 minutes of administration.

6. The method of claim 5, wherein the human'"'"'s hypotension is associated with vasodilatory shock.

7. The method of claim 6, wherein the vasodilatory shock is post-cardiotomy shock.

8. The method of claim 6, wherein the vasodilatory shock is septic shock.

9. The method of claim 8, 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.

10. The method of claim 1, further comprising attaining a target blood pressure in the human and continuing the administration for a period of about 8 hours.

11. The method of claim 10, further comprising, after the period of about 8 hours, reducing the administration by about 0.005 units per minute.

12. The method of claim 1, wherein the pharmaceutical composition is stored at about 5°

C.

13. The method of claim 1, wherein the pharmaceutical composition exhibits less than 1% degradation after storage at 2-8°

C. for about four weeks.

14. The method of claim 1, wherein the pharmaceutical composition is not lyophilized.

15. The method of claim 1, wherein the pharmaceutical composition form is not frozen.

16. The method of claim 1, wherein the pharmaceutical composition is diluted in a diluent prior to administration to the subject.

17. The method of claim 16, wherein the pharmaceutical composition is diluted to a concentration of from about 0.21 μ

g/mL to about 2.1 μ

g/mL of vasopressin or the pharmaceutically acceptable salt thereof.

18. The method of claim 16, wherein the diluent is 0.9% saline.

19. The method of claim 16, wherein the diluent is 5% dextrose in water.

20. The method of claim 1, wherein the pharmaceutical composition further comprises chlorobutanol.