Stable pharmaceutical formulation

Patent metadata

Field	Value
Publication number	US-11236146-B2
Application number	US-201716345453-A
Country	US
Kind code	B2
Filing date	Oct 26, 2017
Priority date	Oct 28, 2016
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

Disclosed is a stable pharmaceutical formulation, comprising a fusion protein in which the extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to the Fc domain of human IgG and a succinate buffering agent, without comprising a stabilizer. The stable pharmaceutical formulation enables the long-term storage of the TNFR-Fc fusion protein formulation and can exhibit superior storage stability without the need for demanding storage conditions, and is a simple formulation because no stabilizer is comprised therein and is thus more economical than other stabilizer-comprising formulations.

First claim

What is claimed is:

1. A stable pharmaceutical formulation comprising:
50 mg/ml of a fusion protein in which an extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to an Fc domain of human IgG;
an isotonic agent; and
5-25 mM of succinate, without comprising a stabilizer,
wherein the isotonic agent is sodium chloride at a concentration of 120 to 160 mM.

2. The stable pharmaceutical formulation of claim 1 , wherein the formulation is free of an amino acid, an ammonium salt, a saccharide or a mixture thereof as a stabilizer.

3. The stable pharmaceutical formulation of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:1.

4. The stable pharmaceutical formulation of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:2.

5. The stable pharmaceutical formulation of claim 1 , wherein the stable pharmaceutical formulation has a pH range from 5.5 to 6.5.

6. The stable pharmaceutical formulation of claim 2 , wherein the ammonium salt is ammonium chloride, ammonium sulfate, ammonium carbonate, ammonium nitrate or a mixture thereof.

7. The stable pharmaceutical formulation of claim 2 , wherein the amino acid is arginine, methionine, lysine, histidine, glycine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, tryptophan, cysteine, aspartic acid, glutamic acid, serine, asparagine, threonine, glutamine or a mixture thereof.

8. The stable pharmaceutical formulation of claim 2 , wherein the saccharide is sucrose.

9. The stable pharmaceutical formulation of claim 1 , wherein a high-molecular-weight component content is 12% or less, as measured using size-exclusion high-performance liquid chromatography (SE-HPLC) after storage at a temperature of 40° C.±2° C. for 12 weeks.

10. The stable pharmaceutical formulation of claim 1 , wherein the high-molecular-weight component content is 24% or less, as measured using hydrophobic-interaction high-performance liquid chromatography (HI-HPLC) after storage at a temperature of 40° C.±2° C. for 12 weeks.

11. A kit comprising: a container comprising said formulation of claim 1 and instructions for administration of said formulation to a patient.

12. A method of producing a stable liquid pharmaceutical formulation comprising the steps of:
(a) preparing 5-25 mM succinate buffer having a pH 5.5 to 6.5;
(b) adding 50 mg/ml of a fusion protein in which an extracellular ligand-binding domain of a human p75 tumor necrosis factor receptor is fused to an Fc domain of human IgG to said buffer of step (a) to form a buffer/protein mixture; and
(c) adding 120 to 160 mM of sodium chloride to said buffer/protein mixture of step (b) in order to form said stable liquid pharmaceutical formulation, wherein the formulation is free of a stabilizer, an amino acid, an ammonium salt, a saccharide, polysorbate, poloxamer, a polymer, or a mixture thereof.

13. The stable pharmaceutical formulation of claim 1 , wherein the formulation comprises:
a concentration of 50 mg/ml of the fusion protein;
a concentration of 120 to 160 mM of sodium chloride as the isotonic agent;
a concentration of 5-25 mM of succinate; and
a pH range from 5.5 to 6.5;
wherein the formulation is free of a stabilizer, an amino acid, an ammonium salt, a saccharide, polysorbate, poloxamer, a polymer, or a mixture thereof, and
wherein a high-molecular-weight component content is 12% or less, as measured using size-exclusion high-performance liquid chromatography (SE-HPLC) after storage at a temperature of 40° C.±2° C. for 12 weeks.

Assignees

• Celltrion Inc

Inventors

• Lee Joon Won
• Han Won Yong
• Kim Su Jung
• Oh Jun Seok
• Kim So Young
• Kim Kwang Woo
• Shin Yeon Kyeong

Classifications

• 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

• A61K9/08 Primary

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61K38/191

  Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title