Peptidomimetic macrocycles and formulations thereof

Patent metadata

Field	Value
Publication number	US-2016101145-A1
Application number	US-201514864687-A
Country	US
Kind code	A1
Filing date	Sep 24, 2015
Priority date	Sep 24, 2014
Publication date	Apr 14, 2016
Grant date	—

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

1 .- 293 . (canceled)

294 . An aqueous pharmaceutical formulation comprising:
(i) a peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof, wherein the amount of the peptidomimetic macrocycle in the aqueous pharmaceutical formulation is equal to or greater than 15 mg/mL; (ii) a buffering agent; (iii) a stabilizing agent; and (iv) a tonicity agent
wherein the molar ratio of the peptidomimetic macrocycle to the buffering agent is in the range of 0.01-2.5.

295 . The aqueous pharmaceutical formulation of claim 294 , wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof has a length value of from 14 to 20 amino acids.

296 . The aqueous pharmaceutical formulation of claim 294 , wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof has a von Heijne value of from 2 to 9.

297 . The aqueous pharmaceutical formulation of claim 294 , wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof has a percent alanine content of from 15% to 40%.

298 . The aqueous pharmaceutical formulation of claim 294 , wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof comprises a first, second, third, fourth, fifth or sixth C-terminal amino acid that is hydrophobic.

299 . The aqueous pharmaceutical formulation of claim 294 , wherein the peptidomimetic macrocycle or pharmaceutically acceptable salt thereof comprises an α-helix.

300 . The aqueous pharmaceutical formulation of claim 294 , wherein:
(i) the amount of the buffering agent in the aqueous pharmaceutical formulation is 0.001-10% w/v; (ii) the amount of the stabilizing agent in the aqueous pharmaceutical formulation is 0.001-10% w/v; and (iii) the amount of the tonicity agent in the aqueous pharmaceutical formulation 1.0-10% w/v.

301 . The aqueous pharmaceutical formulation of claim 294 , wherein the pharmaceutically acceptable salt of the peptidomimetic macrocycle is a sodium, potassium, lithium, calcium, zinc or magnesium salt.

302 . The aqueous pharmaceutical formulation of claim 294 , wherein the amount of the peptidomimetic macrocycle present in the aqueous pharmaceutical formulation is from about 0.1 to about 10% w/v.

303 . The aqueous pharmaceutical formulation of claim 294 , wherein the concentration of the peptidomimetic macrocycle present in the aqueous pharmaceutical formulation is about 15-100 mg/mL.

304 . The aqueous pharmaceutical formulation of claim 294 , wherein the buffering agent is a phosphate buffer.

305 . The aqueous pharmaceutical formulation of claim 294 , wherein the amount of the buffering agent is from about 0.001-10% w/v.

306 . The aqueous pharmaceutical formulation of claim 294 , wherein the stabilizing agent is a non-ionic stabilizing agent, a fatty acid ester, a surfactant, or an anti-oxidant.

307 . The aqueous pharmaceutical formulation of claim 294 , wherein the stabilizing agent is polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85 or polysorbate 120.

308 . The aqueous pharmaceutical formulation of claim 294 , wherein the amount of the stabilizing agent present in the aqueous pharmaceutical formulation is from about 0.001% to about 10% w/v.

309 . The aqueous pharmaceutical formulation of claim 294 , wherein the aqueous pharmaceutical formulation comprises from about 250 ppm to about 350 ppm of polysorbate 20.

310 . The aqueous pharmaceutical formulation of claim 294 , wherein the aqueous pharmaceutical formulation is dissolved into a diluent prior to administration into a subject.

311 . The aqueous pharmaceutical formulation of claim 294 , wherein the tonicity agent is selected from a group consisting of glucose, fructose, galactose, sucrose, lactose, maltose, trehalose, and mixtures thereof.

312 . The aqueous pharmaceutical formulation of any one of claim 294 , wherein the tonicity agent is D-trehalose.

313 . The aqueous pharmaceutical formulation of claim 294 , wherein the amount of the tonicity agent present in the aqueous pharmaceutical formulation is from about 1% to about 15% w/v.

314 . The aqueous pharmaceutical formulation of claim 294 , wherein the concentration of the tonicity agent is from about 200 mM to about 300 mM.

315 . The aqueous pharmaceutical formulation of claim 294 , wherein the pH of the aqueous pharmaceutical formulation is from about 4.0 to about 9.0.

316 . The aqueous pharmaceutical formulation of claim 294 , wherein the aqueous pharmaceutical formulation upon storage for 24 months at from about 2° C. to about 8° C. comprises at least 95% of the initial amount of the peptidomimetic macrocycle.

317 . The aqueous pharmaceutical formulation of claim 294 , wherein aqueous pharmaceutical formulation is prepared by adding the peptidomimetic macrocycle or a pharmaceutically acceptable salt thereof to water or an aqueous solution, wherein the peptidomimetic macrocycle is capable of binding to the MDM2 and/or MDMX proteins.

318 . The method of claim 317 , wherein the pharmaceutically acceptable salt is a sodium salt, potassium salt or calcium salt.

319 . The aqueous pharmaceutical formulation of claim 294 , wherein the molecular weight of the peptidomimetic macrocycle is in the range of 1800-2000 D.

320 . The aqueous pharmaceutical formulation of claim 294 , wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% identical to an amino acid sequence in any of Table 1, Table 1a, Table 1b, and Table 1c, and wherein the peptidomimetic macrocycle has the formula:

wherein:
each A, C, D and E is independently an amino acid;
each B is independently an amino acid,

[—NH-L 3 -CO—], [—NH-L 3 -SO 2 —], or [—NH-L 3 -];
each R 1 and R 2 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo; or forms a macrocycle-forming linker L′ connected to the alpha position of one of said D or E amino acids;
each R 3 independently is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R 5 ;
each L and L′ is independently a macrocycle-forming linker;
each L 3 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, heteroarylene, or [—R 4 —K—R 4 -] n , each being optionally substituted with R 5 ;
each R 4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene, each being optionally substituted with R 5 ;
each K is independently O, S, SO, SO 2 , CO, CO 2 , or CONR 3 ;
each R 5 is independently halogen, alkyl, —OR 6 , —N(R 6 ) 2 , —SR 6 , —SOR E , —SO 2 R 6 , —CO 2 R 6 , a fluorescent moiety, a radioisotope or a therapeutic agent;
each R 6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic

Assignees

• Aileron Therapeutics Inc

Inventors

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

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• 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