Pharmaceutical composition and preparation method thereof

Patent metadata

Field	Value
Publication number	US-11872237-B2
Application number	US-201916758272-A
Country	US
Kind code	B2
Filing date	Dec 12, 2019
Priority date	Dec 28, 2018
Publication date	Jan 16, 2024
Grant date	Jan 16, 2024

Abstract

The present invention relates to a pharmaceutical composition comprising a sulfonamide as an inhibitor of Bcl-2/Bcl-xL, especially compound (3R)-1-(3-(4-(4-(4-(3-(2-(4-chlorophenyl)-1-isopropyl-4-methylsulfonyl-5-methyl-1H-pyrrol-3-yl)-5-fluorophenyl)piperazin-1-yl)-phenylaminosulfonyl)-2-trifluoromethyl sulfonyl-anilino)-4-phenylthio-butyl)-piperidine-4-carboxylic acid 3-phosphonopropyl ester or a pharmaceutically acceptable salt thereof and suitable excipients, preferably a pharmaceutical composition in the form of a lyophilized powder. The invention also relates to a method for preparing the pharmaceutical composition.

First claim

What is claimed is:

1. A pharmaceutical composition, comprising:

or a pharmaceutically acceptable salt thereof;
at least one polyethylene glycol selected from the group consisting of polyethylene glycol PEG200 to PEG1000;
at least one pH adjusting agent selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, and sodium acetate;
at least one skeleton agent selected from mannitol and trehalose; and
at least one surfactant selected from polysorbate 80, polyethylene glycol-15 hydroxystearate, and Polyoxyl 35 Castor Oil ester.

2. The pharmaceutical composition of claim 1 being in the form of a lyophilized powder.

3. The pharmaceutical composition of claim 1 , being an aqueous solution, wherein the pharmaceutical composition further comprises:
at least one monohydric alcohol selected from the group consisting of ethanol, propanol, and tert-butanol.

4. The pharmaceutical composition of claim 3 , wherein the at least one monohydric alcohol is ethanol.

5. The pharmaceutical composition of claim 3 , being a solution of deionized water, a solution of purified water, a solution of water for injection, or a solution of sterilized water for injection.

6. The pharmaceutical composition of claim 1 , wherein the at least one polyethylene glycol is selected from the group consisting of polyethylene glycol PEG200, PEG300, PEG400 and PEG600.

7. The pharmaceutical composition of claim 1 , wherein the at least one pH adjusting agent is selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, and disodium hydrogen phosphate.

8. The pharmaceutical composition of claim 1 , wherein the at least one skeleton agent is mannitol.

9. The pharmaceutical composition of claim 1 , wherein:
the at least one polyethylene glycol is PEG400;
the at least one pH adjusting agent is sodium hydroxide and sodium dihydrogen phosphate;
the at least one skeleton agent is mannitol; and
the at least one surfactant is selected from the group consisting of Polyoxyl 35 Castor Oil ester and polyethylene glycol-15 hydroxystearate.

10. The pharmaceutical composition of claim 1 , wherein:
Compound 1 or the pharmaceutically acceptable salt thereof is present at an amount ranging from about 1.0% to about 5.5% by weight based on the total weight of the pharmaceutical composition;
the at least one polyethylene glycol is present at an amount ranging from about 45% to about 60% by weight based on the total weight of the pharmaceutical composition;
the at least one skeleton agent is present at an amount ranging from about 35% to about 50% by weight based on the total weight of the pharmaceutical composition; or
the at least one surfactant is present at an amount ranging from about 1.0% to about 18.0% by weight based on the total weight of the pharmaceutical composition.

11. The pharmaceutical composition of claim 1 , wherein:
Compound 1 or the pharmaceutically acceptable salt thereof is present at an amount ranging from about 3.5% to about 5.5% by weight based on the total weight of the pharmaceutical composition;
the at least one polyethylene glycol is present at an amount ranging from about 48% to about 55% by weight based on the total weight of the pharmaceutical composition;
the at least one skeleton agent is present at an amount ranging from about 45% to about 50% by weight based on the total weight of the pharmaceutical composition; or
the at least one surfactant is present at an amount ranging from about 2.0% to about 5.0% by weight based on the total weight of the pharmaceutical composition.

12. The pharmaceutical composition of claim 3 , having a pH value ranging from about 8.5 to about 10.3.

13. A pharmaceutical composition, comprising:

or a pharmaceutically acceptable salt thereof; wherein
at least one polyethylene glycol selected from the group consisting of polyethylene glycol PEG200 to PEG1000;
at least one pH adjusting agent selected from the group consisting of sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium hydroxide, sodium citrate, sodium carbonate, sodium bicarbonate, and sodium acetate;
at least one skeleton agent selected from mannitol and trehalose; and

at least one surfactant selected from polysorbate 80, polyethylene glycol-15 hydroxystearate, and Polyoxyl 35 Castor Oil ester,
wherein the pharmaceutical composition is an aqueous solution, having a pH of 9.0-10.0.

14. The pharmaceutical composition of claim 3 , comprising:
Compound 1 or the pharmaceutically acceptable salt thereof is present at an amount ranging from about 0.1% to about 1.5% by weight based on the total weight of the pharmaceutical composition;
the at least one polyethylene glycol is present at an amount ranging from about 10% to about 14% by weight based on the total weight of the pharmaceutical composition;
the at least one monohydric alcohol is present at an amount ranging from about 3% to about 10% by weight based on the total weight of the pharmaceutical composition;
the at least one skeleton agent is present at an amount ranging from about 5% to about 15% by weight based on the total weight of the pharmaceutical composition; or
the at least one surfactant is present at an amount ranging from about 0.2% to about 4.5% by weight based on the total weight of the pharmaceutical composition.

15. The pharmaceutical composition of claim 3 , wherein:
Compound 1 or the pharmaceutically acceptable salt thereof is present at an amount ranging from about 0.5% to about 1.5% by weight based on the total weight of the pharmaceutical composition;
the at least one polyethylene glycol is present at an amount ranging from about 9% to about 12% by weight based on the total weight of the pharmaceutical composition;
the at least one monohydric alcohol is present at an amount ranging from about 4% to about 6% by weight based on the total weight of the pharmaceutical composition;
the at least one skeleton agent is present at an amount ranging from about 8% to about 12% by weight based on the total weight of the pharmaceutical composition; or
the at least one surfactant is present at an amount ranging from about 0.4% to about 1.0% by weight based on the total weight of the pharmaceutical composition.

Assignees

• Ascentage Pharma Suzhou Co Ltd
• Ascentage Pharma Group Corp Ltd

Inventors

• Guo Ming
• Lin Yanqiong
• Shao Zhenzhong
• Cao Pengfei

Classifications

• A61K31/675 Primary

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K47/10

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