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Process for the preparation of highly concentrated liquid formulations containing biomolecules

A biomolecular, highly concentrated technology, applied in the preparation method of peptides, inorganic non-active ingredients, chemical instruments and methods, etc., can solve the problems of increased processing time, insufficient performance, increased percolation cycles, etc.

Pending Publication Date: 2019-09-03
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0042] However, the traditional three-step UF / DF method of the prior art has been found to have insufficient performance
While the above assumptions may hold for very low protein concentrations, e.g. <<80 mg / mL, our study shows that three-step UF / DF using a diafiltration step with water to obtain high protein concentrations has the following disadvantages: Concentrations of e.g. 4 to Residual levels of 10 mM initial buffer ion remain in solution
Additionally, those skilled in the art must bear in mind that increasing diafiltration cycles may negatively impact protein integrity and increase processing time

Method used

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  • Process for the preparation of highly concentrated liquid formulations containing biomolecules
  • Process for the preparation of highly concentrated liquid formulations containing biomolecules
  • Process for the preparation of highly concentrated liquid formulations containing biomolecules

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[0150] Possible buffers or buffer salts are based on N-(2-acetylamino)-taurine (ACES) and its salts, acetic acid and its salts, aconitic acid and its salts, adipic acid and its salts, ascorbic acid and its salts salt, N-(2-acetylamino)-iminodiacetic acid (ADA) and its salts, ammonia and its salts, ammonium chloride, 2-amino-2-methyl-1-propanol (AMP), 2- Amino-2-methyl-1,3-propanediol, 3-propanediol (AMPD), N-(1,1-dimethyl-2-hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid (AMPSO ) and its salts, N,N-bis-(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) and its salts, benzoic acid and its salts, bicarbonates such as sodium bicarbonate, N,N' - Bis(2-hydroxyethyl)-glycine (bicine), Tris buffers such as tris(hydroxymethyl)-aminomethane, [bis-(2-hydroxyethyl)-imino]-tris-(hydroxymethyl) Methane) (Bis-Tris), 1,3-bis[tris(hydroxymethyl)-methylamino]propane (Bis-Tris-Propane), boric acid and its salts, dimethylarsinic acid (Cacodylate) and its salts , 3-(cyclohexylamino)-propanes...

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Abstract

It is disclosed an improved multi-step process for the preparation of a highly concentrated liquid formulation containing biomolecules comprising the steps of (a) a first ultrafiltration UF1; (b) a first diafiltration DF1; (c) a second diafiltration DF2; and (d) a second ultrafiltration UF2; wherein an aqueous solution of one or more salts, as liquid medium B, is used for step (b) and water or anaqueous solution of one or more salts, as liquid medium C, is used for step (c), wherein the one or more salts used for step (b) are the same or different from the one or more salts used for step (c)and wherein the liquid medium B has an ionic strength which is higher than the ionic strength of the liquid medium C. The process according to the present invention allows the preparation of well-defined highly concentrated formulations containing biomolecules, particularly proteins, intended for pharmaceutical or non-pharmaceutical use. Unwanted excipient(s) of the starting liquid biomolecule formulation, may be reduced under solution conditions, to very low levels or levels lower than the detection limit.

Description

[0001] sequence listing [0002] This application contains a Sequence Listing, which is filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to an improved method of preparing highly concentrated liquid formulations containing biomolecules. Background technique [0004] The ability to prepare well-defined solutions of biomolecules is an important aspect in the development of biomolecule-based pharmaceutical formulations. Biomolecular stability, ionic strength, pH and biomolecule concentration, and biomolecule integrity are the main parameters to be controlled. [0005] As representatives of possible biomolecules, especially proteins will be considered in the following discussion, in particular the following scientific literature and patent publications. [0006] Protein stability is known to be improved by the presence of excipients that interact in some way with the protein in...

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/34
CPCC07K1/34C07K16/065A61K9/08A61K47/02A61K47/12
Inventor P·加里德尔S·巴伦布尔格T·舒尔茨-法德雷希特A·爱佩尔勒
Owner BOEHRINGER INGELHEIM INT GMBH