Vasopressin formulations for use in treatment of hypotension

• US 9,744,209 B2
• Filed: 02/07/2017
• Issued: 08/29/2017
• 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:
  US15/426,693
• Publication Number:
  US 20170157202A1
• Time in Patent Office: 203 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• 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 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
• CPC Class Codes: G01N 2030/027 Liquid chromatography
• CPC Class Codes: G01N 2030/8831 involving peptides or proteins
• CPC Class Codes: G01N 30/34 of fluid composition, e.g. gradient G01N30/36 takes precedence
• CPC Class Codes: G01N 30/74 Optical detectors measurement of intensity, velocity, spectral content, polarisation, or phase of infrared, visible or ultraviolet light G01J
• CPC Class Codes: G01N 30/88 Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86

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 administering to the human a unit dosage form, wherein the unit dosage form comprises from about 0.01 mg/mL to about 0.07 mg/mL of vasopressin or a pharmaceutically acceptable salt thereof, wherein:

the unit dosage form has a pH of 3.7-3.9;

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;

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; 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 sodium acetate.

13. The method of claim 1, the unit dosage form further comprising a pH adjusting agent.