Peptidomimetic macrocycles and formulations thereof

Patent metadata

Field	Value
Publication number	US-10905739-B2
Application number	US-201514864687-A
Country	US
Kind code	B2
Filing date	Sep 24, 2015
Priority date	Sep 24, 2014
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

Aqueous pharmaceutical formulations, for parenteral administration, comprising peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof wherein the peptidomimetic macrocycle binds to MDM2 and/or MDMX proteins are disclosed. Also disclosed are methods of treating diseases and disorders using the aqueous pharmaceutical formulations disclosed herein.

First claim

What is claimed is:

1. An aqueous pharmaceutical formulation in a unit dosage form comprising:
a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, wherein the peptidomimetic macrocycle has an amino acid sequence identical to a sequence of any one of SEQ ID NOs: 339, 350, 351, 446, 447, 453, 457-459, 472-475, 478-481, 484, 485, 486, 492, 493, and 499, and wherein the peptidomimetic macrocycle is present in the aqueous pharmaceutical formulation in an amount of about 15-20 mg/mL;
(ii) a buffering agent at a concentration of 20 mM, wherein the buffering agent is a sodium phosphate;
(iii) a stabilizing agent in an amount of 300 ppm in the aqueous pharmaceutical formulation, wherein the stabilizing agent is polysorbate 20;
(iv) a tonicity agent in a concentration of about 240 mM in the aqueous pharmaceutical formulation, wherein the tonicity agent is trehalose;
wherein the peptidomimetic macrocycle has a Formula I:

wherein
each D, Xaa 5 , Xaa 6 , Xaa 8 , Xaa 9 , and E is independently an amino acid;
each E is independently selected from Ala, D-Ala, Aib, Sar, and Ser;
[D] v is Leu 1 -Thr 2 ;
Xaa 3 is Phe;
Xaa 7 is Trp;
Xaa 10 is Leu;
each R 1 and R 2 is independently alkyl;
L is a macrocycle-forming linker;
R 7 is —H;
R 8 is —H; and
w is an integer from 1-10.

2. The aqueous pharmaceutical formulation of claim 1 , wherein the peptidomimetic macrocycle has a length value of from 14 to 20 amino acids.

3. The aqueous pharmaceutical formulation of claim 1 , wherein the peptidomimetic macrocycle has a von Heijne value of from 2 to 9.

4. The aqueous pharmaceutical formulation of claim 1 , wherein the peptidomimetic macrocycle has a percent alanine content of from 15% to 40%.

5. The aqueous pharmaceutical formulation of claim 1 , wherein a first, second, third, fourth, fifth, or sixth C-terminal amino acid of the peptidomimetic macrocycle is hydrophobic.

6. The aqueous pharmaceutical formulation of claim 1 , wherein the peptidomimetic macrocycle comprises an α-helix.

7. The aqueous pharmaceutical formulation of claim 1 , wherein the pharmaceutically acceptable salt of the peptidomimetic macrocycle is a sodium, potassium, lithium, calcium, zinc, or magnesium salt.

8. The aqueous pharmaceutical formulation of claim 1 , wherein total peptidomimetic degradation products formed in the aqueous pharmaceutical formulation is less than 1.0% when stored at a temperature of 40° C. for a period of one month.

9. The aqueous pharmaceutical formulation of claim 1 , wherein the aqueous pharmaceutical formulation upon storage for 24 months at from about 2° C. to about 8° C. comprises at least 95% of an amount of the peptidomimetic macrocycle present prior to the storage for 24 months.

10. The aqueous pharmaceutical formulation of claim 1 , wherein an osmolarity of the aqueous pharmaceutical formulation is from about 250 to about 1000 milliosmoles per kilogram.

11. The aqueous pharmaceutical formulation of claim 1 further comprising glucose, fructose, galactose, sucrose, lactose, maltose, or a mixture thereof.

12. The aqueous pharmaceutical formulation of claim 1 , wherein the tonicity agent is D-trehalose.

13. The aqueous pharmaceutical formulation of claim 1 , wherein the aqueous pharmaceutical formulation has a pH from about 6.0 to about 8.0.

14. The aqueous pharmaceutical formulation of claim 1 , wherein the aqueous pharmaceutical formulation has a pH from about 4.0 to about 9.0.

15. The aqueous pharmaceutical formulation of claim 1 , wherein the peptidomimetic macrocycle has a molecular weight in the range of 1800-2000 D.

16. A method of making an aqueous pharmaceutical formulation comprising adding greater than 15 mg/mL of a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof to water or an aqueous solution, wherein the aqueous pharmaceutical formulation comprises less than 2% w/v of any micelle forming agent.

17. The method of claim 16 , wherein the peptidomimetic macrocycle is capable of binding to the MDM2 and/or MDMX proteins.

18. The method of claim 16 , comprising adding a sodium salt of the peptidomimetic macrocycle to water or an aqueous solution.

19. The method of claim 16 , further comprising adjusting the pH of the solution comprising the buffering agent and the stabilizing agent during the addition of the peptidomimetic macrocycle.

20. The method of claim 16 , further comprising filtration of the aqueous pharmaceutical formulation obtained after the addition of the peptidomimetic macrocycle to the aqueous solution.

21. The method of claim 16 , wherein the method is used for commercial manufacturing of the aqueous pharmaceutical formulation.

22. The aqueous pharmaceutical formulation of claim 1 , wherein the amino acid sequence is SEQ ID NO. 339.

23. The aqueous pharmaceutical formulation of claim 1 , wherein the amino acid sequence is SEQ ID NO. 499.

24. The aqueous pharmaceutical formulation of claim 1 , wherein the aqueous pharmaceutical formulation is suitable for administration to a subject without dilution.

Assignees

• Aileron Therapeutics Inc

Inventors

• Annis David Allen
• Darlak Krzysztof
• Rhodes Chris
• Kanai Sonoko
• Hoernschemeyer Joerg
• Grass Michaela

Classifications

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K47/26

  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 title

• A61K9/0019

  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 title

• A61K38/12 Primary

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title