Lyophilized pharmaceutical compositions

Patent metadata

Field	Value
Publication number	US-2022016033-A1
Application number	US-202117189896-A
Country	US
Kind code	A1
Filing date	Mar 2, 2021
Priority date	Jul 2, 2015
Publication date	Jan 20, 2022
Grant date	—

Abstract

The invention provides a method of preparing a lyophilized pharmaceutical composition containing a compound described herein or a pharmaceutically-acceptable salt thereof. The process comprises dissolving the compound in a solvent comprising dimethylsulfoxide and optionally one or more co-solvents to form a solution, and then removing the solvent and any co-solvents by a freeze-drying process. Also provided by the invention are lyophilized pharmaceutical compositions and their use in medicine and in particular in the treatment of cancer.

First claim

1 .- 28 . (canceled)

29 . A method of treating a condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of a T-cell activating agent and a therapeutically effective amount of a pharmaceutical composition prepared by a process, wherein the process comprises:
(a) dissolving a compound of formula (1):

or a pharmaceutically-acceptable salt thereof, in a solvent comprising dimethylsulfoxide (DMSO) to form a solution, wherein the solvent is then removed by a freeze-drying process to give the lyophilized pharmaceutical product, wherein the freeze-drying process comprises:
(i) a first freezing stage in which the solution is frozen by reducing the temperature thereof to a temperature of no greater than about −20° C.;
(ii) a first warming stage in which the temperature of the frozen solution is raised to a temperature in the range from about −15° C. to about 5° C., wherein the temperature in the range from about −15° C. to about 5° C. keeps the solution frozen;
(iii) a second freezing stage in which the temperature of the solution is lowered to a temperature of no greater than about −20° C.;
(iv) a primary drying stage, wherein the primary drying stage comprises a sublimation step in which the DMSO is removed by sublimation from the solution in its frozen state under reduced pressure to give a partially dried product, wherein the reduced pressure in the primary drying stage is from about 5 μBar to about 40 μBar; and
(v) a secondary drying stage in which the DMSO is removed by evaporation from the partially dried product in a non-frozen state under reduced pressure to give the lyophilized pharmaceutical product, and

(b) reconstituting the lyophilized pharmaceutical product in a substantially anhydrous solvent to give the pharmaceutical composition.

30 . The method of claim 29 , wherein the substantially anhydrous solvent comprises about 65% (v/v) propylene glycol, about 25% (v/v) glycerin, and about 10% (v/v) ethanol.

31 . The method of claim 29 , wherein the reconstituting occurs without mechanized stirring.

32 . The method of claim 29 , wherein the pharmaceutical composition is an injectable liquid composition.

33 . The method of claim 29 , wherein the compound of formula (1) is in the form of a sodium salt.

34 . The method of claim 29 , wherein the T-cell activating agent is an anti-CTLA4 antibody.

35 . The method of claim 29 , wherein the condition is a leukemia.

36 . The method of claim 35 , wherein the leukemia is acute myelogenous leukemia, acute promyelocyte leukemia, acute lymphoblastic leukemia, or chronic myelogenous leukemia.

37 . A method of preparing a pharmaceutical composition, the method comprising:
(a) dissolving a compound of formula (1):

or a pharmaceutically-acceptable salt thereof, in a solvent comprising dimethyl sulfoxide (DMSO) to form a solution;
(b) removing the solvent by a freeze-drying process to give a lyophilized product; and
(c) reconstituting the lyophilized product in a substantially anhydrous solvent to give the pharmaceutical composition, wherein the substantially anhydrous solvent comprises 45% to 85% (v/v) propylene glycol, 5% to 45% (v/v) glycerin, and 0% to 30% (v/v) ethanol.

38 . The method of claim 37 , wherein the compound of formula (1) is in the form of a sodium salt.

39 . The method of claim 37 , wherein the substantially anhydrous solvent comprises about 65% (v/v) propylene glycol, about 25% (v/v) glycerin, and about 10% (v/v) ethanol.

40 . The method of claim 37 , wherein any residual DMSO present in the lyophilized product is in an amount corresponding to no more than 35 mg per 100 mg equivalent of a free base of the compound of formula (1).

41 . The method of claim 37 , the method further comprising packing the lyophilized product in a sealed pharmaceutical container.

42 . The method of claim 37 , wherein the reconstituting occurs without mechanized stirring.

43 . The method of claim 37 , wherein the pharmaceutical composition is an injectable liquid composition.

Assignees

• Otsuka Pharma Co Ltd

Inventors

• Joshi-Hangal Rajashree
• Redkar Sanjeev

Classifications

• 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

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K31/70

  Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047) · CPC title

• A61K47/20

  containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids · CPC title

• A01N43/04

  with one hetero atom · CPC title