EP1176979A1 - Preparation a forte teneur en immunoglobuline et ses procedes de production - Google Patents

Preparation a forte teneur en immunoglobuline et ses procedes de production

Info

Publication number
EP1176979A1
EP1176979A1 EP00924972A EP00924972A EP1176979A1 EP 1176979 A1 EP1176979 A1 EP 1176979A1 EP 00924972 A EP00924972 A EP 00924972A EP 00924972 A EP00924972 A EP 00924972A EP 1176979 A1 EP1176979 A1 EP 1176979A1
Authority
EP
European Patent Office
Prior art keywords
immunoglobulin
preparation
concentration
aggregates
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00924972A
Other languages
German (de)
English (en)
Other versions
EP1176979A4 (fr
Inventor
Germano Coppola
Joseph Bertolini
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CSL Ltd
Original Assignee
CSL Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by CSL Ltd filed Critical CSL Ltd
Publication of EP1176979A1 publication Critical patent/EP1176979A1/fr
Publication of EP1176979A4 publication Critical patent/EP1176979A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present invention relates to a stable, high concentration immunoglobulin preparation and to a method of producing such an immunoglobulin preparation.
  • the present inventors have now surprisingly found that if an immunoglobulin solution is exposed to conditions to deliberately enhance the formation of aggregates, and the aggregates are then removed, an immunoglobulin preparation is obtained which is stable at high concentrations for prolonged periods.
  • the present inventors have also made the observation that this clarification of the immunoglobulin solution to remove aggregates increases the stability and thus the clinical acceptability of the product.
  • the immunoglobulin solution prepared by this method is sufficiently stable that it may be formulated into a product which is room temperature stable and capable of being administered intramuscularly, intravenously or subcutaneously.
  • the present invention consists in a clinically acceptable immunoglobulin preparation, the preparation comprising about 5% to about 25% (w/v) immunoglobulin and an osmolality agent and /or a stabilizer and having a pH of about 5.0 to about 8.0, wherein the concentration of immunoglobulin aggregates present in the imiminoglobulin preparation after storage at 27°C for 3 months is less than 2% (w/v).
  • the present invention consists in a clinically acceptable imrmmoglobulin preparation, the preparation comprising about 5% to about 25% (w/v) immunoglobulin and an osmolality agent and /or a stabilizer and having a pH of about 4.0 to about 8.0, wherein the concentration of immunoglobulin aggregates present in the immunoglobulin preparation after storage at 4°C for 3 months is less than 1% (w/v).
  • the concentration of immunoglobulin is about 10% to about 25% (w/v), preferably about 20% (w/v) or about 25% (w/v).
  • the pH of the immunoglobulin preparation is about 5.0 to about 6.0, more preferably aboLit 5.5. This is particularly so when the immunoglobulin preparation is to be stored for prolonged periods at room temperature, eg 27°C.
  • the preparation of the present invention will include an osmolality agent such that the osmolality of preparation is suitable for administration.
  • This osmolality agent may also be a compound which stabilizes the imiminoglobulin.
  • Stabilizers are well known in the art and include saccharides, such as sucrose, maltose and glucose, sugar alcohols, S ich as sorbitol and mannitol, and amino acids.
  • the concentration of immunoglobulin aggregates present in the immunoglobulin preparation after storage at 27°C for 6 months is less than 1% (w/v).
  • the concentration of immunoglobulin aggregates present in the immunoglobulin preparation after storage at 4°C for 6 months is less than 1% (w/v), and preferably the concentration of immunoglobulin aggregates present in the immunoglobulin preparation after storage at 4°C for 9 months is less than 1% (w/v).
  • step (2) comprises incubating the immunoglobulin solution at a pH of about 5.8 to about 8.0 at temperature of about 4° to about 27°C for at least about 6 hours. It is preferred that the immunoglobulin solution is incubated at a pH of about 6.8 for about 12 hours.
  • the aggregates are removed from the aggregate containing solution by filtration, precipitation or size exclusion chromatography.
  • the aggregates are removed from the aggregate containing solution by precipitation using a precipitation enhancing agent.
  • a preferred precipitation enhancing agent is polyethylene glycol.
  • the precipitation is performed at a protein concentration of about 2 to about 10% (w/v) and a polyethylene glycol concentration of about 6 to about 12% w/w and at a pH of about 6 to about 8.
  • the aggregates formed may be removed using any of a number of well known techniques, however it is presently preferred that the aggregates are removed by filtration or precipitation, optionally using a precipitation enhancing agent such as PEG.
  • the aggregates may be removed by membrane filtration using a filter of exclusion limits greater than 300,000 kDa.
  • the aggregates may be removed using size exclusion chromatography eg using a resin of exclusion limits of 10,000 - 1,5000,000.
  • the present invention will also have applicability for a range of protein preparations other than immv oglobulins, where the removal of protein aggregates is desirable.
  • the preparation of the present invention may be administered intravenously, intramuscularly or subcutaneously.
  • IgG preparation produced by a combination of Cohn fractionation and chromatographic methods.
  • the preparation had been pasteurised in the presence of sucrose, followed by diafiltration against water, the final protein concentration being approximately 2% (w/v).
  • the solution was then adJ isted to pH 6.8 and maintained at this pH for 12hrs. Prior to membrane passage the solution was adjusted to pH 4.2.
  • Example 2 A similar procedure as described in Example 1 was used to prepare an aggregate depleted IgG solution. The solution was then concentrated and formulated to 16% w/v containing 0.25 Glycine pH 4.25 or 5.5. Samples of the final product were placed on stability trial and aggregate content determined (Tables 3a -3d.). Table 3a: 16% IgG, pH 4.25, 4 °C
  • Table 7a Determination of monomer, dimer, and aggregate content of PEG treated IgG 20% w/v, pH 5.5 following storage at 4°, 27°, 32° & 37°C for 1 month.
  • Table 7b Determination of monomer, dimer, and aggregate content of PEG treated IgG 25% w/v, pH 5.5 following storage at 4°, 27°, 32° & 37°C for 1 month.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne des préparations d'immunoglobuline à administrer par voie intraveineuse qui sont stables pendant des périodes prolongées de stockage. L'invention concerne également un procédé de production d'une préparation d'immunoglobuline cliniquement acceptable. Ce procédé consiste 1) à obtenir une solution d'immunoglobuline; 2) à soumettre cette solution à des conditions qui augmentent la formation d'agrégats d'immunoglobulines pour former une solution contenant des agrégats d'immunoglobulines et 3) à séparer les agrégats d'immunoglobulines de la solution contenant les agrégats d'immunoglobulines afin d'obtenir une préparation d'immunoglobuline pratiquement exempte d'agrégats d'immunoglobulines.
EP00924972A 1999-05-10 2000-05-10 Preparation a forte teneur en immunoglobuline et ses procedes de production Withdrawn EP1176979A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
AUPQ026799 1999-05-10
AUPQ0267A AUPQ026799A0 (en) 1999-05-10 1999-05-10 Method of increasing protein stability by removing immunoglobulin aggregates
PCT/AU2000/000433 WO2000067789A1 (fr) 1999-05-10 2000-05-10 Preparation a forte teneur en immunoglobuline et ses procedes de production

Publications (2)

Publication Number Publication Date
EP1176979A1 true EP1176979A1 (fr) 2002-02-06
EP1176979A4 EP1176979A4 (fr) 2005-05-04

Family

ID=3814474

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00924972A Withdrawn EP1176979A4 (fr) 1999-05-10 2000-05-10 Preparation a forte teneur en immunoglobuline et ses procedes de production

Country Status (3)

Country Link
EP (1) EP1176979A4 (fr)
AU (1) AUPQ026799A0 (fr)
WO (1) WO2000067789A1 (fr)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
NZ576986A (en) 2004-01-30 2010-12-24 Shire Pharmaceuticals Ireland Ltd Production and purification of recombinant arylsulfatase A
PL2631242T3 (pl) 2006-04-04 2023-03-20 Takeda Pharmaceutical Company Limited Sposób zatężania polipeptydu
CN101679507A (zh) 2007-03-29 2010-03-24 艾博特公司 结晶抗人类il-12抗体
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
WO2010030222A1 (fr) * 2008-09-12 2010-03-18 Ge Healthcare Bio-Sciences Ab Séparation protéine-agrégat améliorée avec des échangeurs d'anions multimodaux en présence de zwitterions exclus de la protéine
AR076607A1 (es) 2009-05-27 2011-06-22 Baxter Int Composicion acuosa. metodo para producir una preparacion altamente concentrada de inmunoglobulina de uso subcutaneo
ES2625511T3 (es) 2011-07-08 2017-07-19 Shire Human Genetic Therapies, Inc. Métodos para la purificación de arylsulfatasa A
KR102362829B1 (ko) 2012-09-07 2022-02-15 코히러스 바이오사이언시즈, 인코포레이티드 아달리무맙의 안정한 수성 제형
CN112126634A (zh) 2013-01-09 2020-12-25 夏尔人类遗传性治疗公司 含用于纯化芳基硫酸酯酶a的方法
US11229702B1 (en) 2015-10-28 2022-01-25 Coherus Biosciences, Inc. High concentration formulations of adalimumab
WO2017184880A1 (fr) 2016-04-20 2017-10-26 Coherus Biosciences, Inc. Procédé de remplissage d'un récipient sans espace libre

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656730A (en) * 1995-04-07 1997-08-12 Enzon, Inc. Stabilized monomeric protein compositions
WO1998042376A1 (fr) * 1997-03-20 1998-10-01 Common Services Agency Composition contenant de l'immunoglobuline

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3310150A1 (de) * 1983-03-21 1984-09-27 Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München Verfahren zur herstellung einer nebenwirkungsfreien igg-immunglobulinloesung fuer die intravenoese applikation
US4597966A (en) * 1985-01-09 1986-07-01 Ortho Diagnostic Systems, Inc. Histidine stabilized immunoglobulin and method of preparation
CA1310267C (fr) * 1986-07-09 1992-11-17 Yutaka Hirao Procede pour le thermotraitement de _-globuline non modifiee
DE3641115A1 (de) * 1986-12-02 1988-06-16 Lentia Gmbh Verfahren zur herstellung eines intravenoes anwendbaren und in fluessiger form stabilen immunglobulins
AU3429797A (en) * 1996-07-18 1998-02-10 Csl Limited Pasteurization of immunoglobulin solutions
HU228076B1 (en) * 1998-06-09 2012-10-29 Csl Behring Ag Process for producing immunoglobulins for intravenous administration and other immunoglobulin products

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656730A (en) * 1995-04-07 1997-08-12 Enzon, Inc. Stabilized monomeric protein compositions
WO1998042376A1 (fr) * 1997-03-20 1998-10-01 Common Services Agency Composition contenant de l'immunoglobuline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0067789A1 *

Also Published As

Publication number Publication date
EP1176979A4 (fr) 2005-05-04
WO2000067789A1 (fr) 2000-11-16
AUPQ026799A0 (en) 1999-06-03

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