WO1993001835A1 - Stabilized human monoclonal antibody preparation - Google Patents
Stabilized human monoclonal antibody preparation Download PDFInfo
- Publication number
- WO1993001835A1 WO1993001835A1 PCT/JP1992/000914 JP9200914W WO9301835A1 WO 1993001835 A1 WO1993001835 A1 WO 1993001835A1 JP 9200914 W JP9200914 W JP 9200914W WO 9301835 A1 WO9301835 A1 WO 9301835A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- human monoclonal
- monoclonal antibody
- mannitol
- preparation
- glycine
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Definitions
- the present invention relates to a stabilized human monoclonal antibody preparation, and more particularly, to a solution state, a lyophilized state, and a stability in a frozen state, and in particular, excellent stability in reconstitution (reconstitution) after freeze-drying.
- a stabilized human monoclonal antibody preparation and more particularly, to a solution state, a lyophilized state, and a stability in a frozen state, and in particular, excellent stability in reconstitution (reconstitution) after freeze-drying.
- human monoclonal antibodies have been used in human clinical trials, and in particular, have attracted attention in the field of drugs for antitumor purposes.
- the purified human monoclonal antibody has the unfavorable pharmaceutical properties that it is liable to aggregate and precipitate when it is dissolved or reconstituted (reconstituted) after lyophilization. Therefore, the stabilized human monoclonal antibody does not have such undesirable properties. It is hoped that the developed monoclonal antibody formulation will be developed.
- a conventional method has been to add serum albumin or serum albumin and glycine, Z or mannitol to sulfonated immunoglobulin (Japanese Patent Publication No. Sho 62-209965). Gazette); a method of adding a relatively large amount of polyhydric alcohol (JP-A-63-818197); a method of adding dextran (JP-A-63-225530) Gazette) has been proposed.
- these conventionally proposed methods cannot sufficiently improve the above-mentioned undesirable properties in human monoclonal antibody preparations.
- the present inventors have studied the stability of human monoclonal antibody preparations by adding a specific small amount of mannitol to human monoclonal antibodies. However, they have found that the stability against precipitation is remarkably improved, and have completed the present invention.
- a stabilized human monoclonal antibody preparation containing 1 to 2 Omg of D-mannitol per 1 mg of human monoclonal antibody.
- the human monoclonal antibody that can be stabilized according to the present invention is not particularly limited, and various human monoclonal antibodies can be used.
- CJLN-IgG, SLN-IgG, CoLN-IgA, TOSXH8-IgM [Hideaki Hagiwara: BIO INDUSTRY, 4, 730 (1987)] can be exemplified as representative examples.
- Such human monoclonal antibodies are formulated for practical use as pharmaceuticals and the like.
- a method for formulating the purified human monoclonal antibodies is ultrafiltration and ammonium sulfate separation as necessary.
- the solution is concentrated by a filtration method and the like, replaced with a buffer solution suitable for the preparation by a gel filtration method, further adjusted in some cases, filtered, sterilized, and freeze-dried.
- D-mannitol as a stabilizing agent can be added at any stage of the above formulation, but generally, it is replaced by a buffer suitable for the formulation by gel filtration and then subjected to dialysis. Preferably, it is introduced into a monoclonal antibody preparation.
- concentration of D-mannitol in the D-mannitol solution that can be used in the dialysis method varies depending on the concentration of the human monoclonal antibody solution to be dialyzed.
- the concentration of the human monoclonal antibody is lmgZral
- the concentration is in the range of 0.1 to 2% (w / v), preferably 0.5 to 1.5% (w / v), and when the concentration of the human monoclonal antibody is 5 mgZml, it is generally 0.1 to 2%.
- a range of 10% (Zv), preferably 0.5-5% (w / v) is suitable.
- the content of D-mannitol can be in the range of 1 to 20 mg, preferably 5 to 15 mg per mg of human monoclonal antibody in the preparation. If the content of D-mannitol is less than 1 mg, the intended stabilizing effect cannot be obtained, and if it is more than 2 Omg, antibody aggregation will be observed.
- the amount of glycine used at this time is not strictly limited, but is generally in the range of 0.005 to 0.2 mol, preferably 0.1 to 0.15 mol per mg of human monoclonal antibody.
- Glycine can be introduced into the preparation of the present invention at the same time as the introduction of D-mannitol.
- the preparation of the present invention may further contain, if necessary, an appropriate amount of phosphate or the like for adjusting pH. ,
- Ammonium sulfate was added to the mixture, and the mixture was salt-broken to a final saturated solution of 70% to obtain an ammonium sulfate precipitate.
- the ammonium sulfate precipitate was dialyzed against 1 OmM phosphate buffer (hereinafter referred to as “PB”) twice at 20 liters x 2 times for a total of 24 hours, and then subjected to a cation exchange column (S-Sepharose, fast flow, manufactured by Pharmacia). ). After the column adsorbate was washed well with 1 OmM PB, it was eluted with a concentration gradient of 0.5 M NaCl in 0 mM PB in 10 mM PB to obtain a crude IgG fraction.
- PB OmM phosphate buffer
- S-Sepharose cation exchange column
- the obtained IgG was concentrated with an ammonium sulfate fraction (saturation concentration: 50%), and subjected to gel filtration using a Sephacryl S-300 column (Pharmacia) equilibrated with 10 mM phosphate buffered saline (hereinafter referred to as PBS). Perform purified IgG and did.
- phosphate buffered saline PBS
- 1.15 g Na 2 HP0 4 no water
- 8.0 g of NaC l 0.2 g of KH 2 P0 4
- distilled water 0.2 g KC 1 to about 900ml
- the physiological saline for injection was manufactured by Otsuka Pharmaceutical Co., Ltd.
- Mannitol solution is a 20% (w / v) D—Mannitol Injection manufactured by Otsuka Pharmaceutical Co., Ltd. diluted with distilled water to concentrations of 1%, 5%, and 10% (wio / v), respectively. did.
- D-mannitol was dissolved in 1% mannitol + saline for injection to 1% (w / v) in saline for injection.
- Example 1 Preparation of freeze-dried agent for human monoclonal antibody and its stability
- the human monoclonal antibody solution prepared in Reference Example 1 was dialyzed against each of the solutions prepared in Reference Example 2. Each of the obtained human monoclonal antibody solutions was adjusted at once.
- Example 2 According to the method described in Example 1, the amount of D-mannitol in one vial was 1, 2, 5, 10, 10, 15, 20, 50 or 100 O'mg and the amount of the monoclonal antibody. Lyophilized preparations containing 1, 2.5 or 5 mg were prepared and their solubility was compared. The results are shown in Table 2.
- the human monoclonal antibody preparation of the present invention is excellent in stability in a solution state, a lyophilized state, a frozen state, and particularly, agglutination and precipitation of the human monoclonal antibody when redissolved after lyophilization. It is useful as a medicine.
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE69228474T DE69228474T2 (de) | 1991-07-20 | 1992-07-17 | STABILISIERTE AUFBEREITUNG MONOKLONALER MENSCHLICHER CLN-IgG ANTIKÖRPER |
AU23305/92A AU662010B2 (en) | 1991-07-20 | 1992-07-17 | Stabilized human monoclonal antibody preparation |
EP92915866A EP0597101B1 (en) | 1991-07-20 | 1992-07-17 | STABILIZED HUMAN MONOCLONAL CLN-IgG ANTIBODY PREPARATION |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3204743A JP2966592B2 (ja) | 1991-07-20 | 1991-07-20 | 安定化されたヒトモノクローナル抗体製剤 |
JP3/204743 | 1991-07-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993001835A1 true WO1993001835A1 (en) | 1993-02-04 |
Family
ID=16495593
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1992/000914 WO1993001835A1 (en) | 1991-07-20 | 1992-07-17 | Stabilized human monoclonal antibody preparation |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0597101B1 (ja) |
JP (1) | JP2966592B2 (ja) |
AT (1) | ATE176868T1 (ja) |
AU (1) | AU662010B2 (ja) |
DE (1) | DE69228474T2 (ja) |
WO (1) | WO1993001835A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998022136A2 (de) | 1996-11-19 | 1998-05-28 | Roche Diagnostics Gmbh | Stabile lyophilisierte pharmazeutische zubereitungen von mono- oder polyklonalen antikörpern |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100377967B1 (ko) | 1995-03-21 | 2003-06-12 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Hcg액상조성물 |
CN1082368C (zh) * | 1995-03-21 | 2002-04-10 | 应用研究系统Ars股份公司 | 人绒毛膜促性腺激素液体制剂 |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
KR100548107B1 (ko) * | 1997-01-30 | 2006-02-02 | 바이오팜 게젤샤프트 쭈어 바이오테히놀로지셴 엔트비클룽 폰 파르마카 엠베하 | 뼈 유도 인자 인간 mp52 동결 건조 조성물 |
US20080050367A1 (en) | 1998-04-07 | 2008-02-28 | Guriq Basi | Humanized antibodies that recognize beta amyloid peptide |
PT1314437E (pt) | 2000-08-11 | 2014-08-29 | Chugai Pharmaceutical Co Ltd | Preparações estabilizadas contendo anticorpo |
IL155002A0 (en) | 2000-10-12 | 2003-10-31 | Genentech Inc | Reduced-viscosity concentrated protein formulations |
US8703126B2 (en) | 2000-10-12 | 2014-04-22 | Genentech, Inc. | Reduced-viscosity concentrated protein formulations |
KR101080021B1 (ko) | 2002-02-14 | 2011-11-04 | 추가이 세이야쿠 가부시키가이샤 | 항체함유 용액제제 |
RU2332986C2 (ru) | 2003-04-04 | 2008-09-10 | Дженентек, Инк. | Высококонцентрированные композиции антител и белков |
FR2853551B1 (fr) * | 2003-04-09 | 2006-08-04 | Lab Francais Du Fractionnement | Formulation stabilisante pour compositions d'immunoglobulines g sous forme liquide et sous forme lyophilisee |
US8496930B2 (en) * | 2003-10-01 | 2013-07-30 | Kyowa Hakko Kirin Co., Ltd | Method of stabilizing antibody and stabilized solution-type antibody preparation |
WO2006066089A1 (en) | 2004-12-15 | 2006-06-22 | Neuralab Limited | Humanized amyloid beta antibodies for use in improving cognition |
GT200600031A (es) * | 2005-01-28 | 2006-08-29 | Formulacion anticuerpo anti a beta | |
TWI398272B (zh) | 2005-03-08 | 2013-06-11 | Intervet Int Bv | 化學定義的安定劑 |
US9309316B2 (en) | 2005-12-20 | 2016-04-12 | Bristol-Myers Squibb Company | Stable subcutaneous protein formulations and uses thereof |
JO3076B1 (ar) | 2007-10-17 | 2017-03-15 | Janssen Alzheimer Immunotherap | نظم العلاج المناعي المعتمد على حالة apoe |
US9067981B1 (en) | 2008-10-30 | 2015-06-30 | Janssen Sciences Ireland Uc | Hybrid amyloid-beta antibodies |
CA2754528A1 (en) | 2009-03-06 | 2010-09-10 | Genetech, Inc. | Antibody formulation |
JP6265970B2 (ja) * | 2012-03-26 | 2018-01-24 | サノフイ | 安定なIgG4に基づく結合剤の製剤 |
US9592289B2 (en) | 2012-03-26 | 2017-03-14 | Sanofi | Stable IgG4 based binding agent formulations |
US8613919B1 (en) | 2012-08-31 | 2013-12-24 | Bayer Healthcare, Llc | High concentration antibody and protein formulations |
US9592297B2 (en) | 2012-08-31 | 2017-03-14 | Bayer Healthcare Llc | Antibody and protein formulations |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5347515A (en) * | 1976-10-13 | 1978-04-28 | Green Cross Corp:The | Gamma-globulin pharmaceutical preparation for intravenous injection |
JPS56127320A (en) * | 1980-03-10 | 1981-10-06 | Mochida Pharmaceut Co Ltd | Gamma-globulin pharmaceutical |
JPS6388197A (ja) * | 1986-09-30 | 1988-04-19 | Tosoh Corp | モノクロナル抗体の安定化方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4808621A (en) * | 1986-07-07 | 1989-02-28 | Warner-Lambert Company | Trans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)-ethyl]- or ethenyl]tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis |
ES2097120T3 (es) * | 1989-07-24 | 1997-04-01 | Bayer Ag | Estabilizacion de proteinas altamente purificadas. |
-
1991
- 1991-07-20 JP JP3204743A patent/JP2966592B2/ja not_active Expired - Fee Related
-
1992
- 1992-07-17 AU AU23305/92A patent/AU662010B2/en not_active Ceased
- 1992-07-17 DE DE69228474T patent/DE69228474T2/de not_active Expired - Fee Related
- 1992-07-17 EP EP92915866A patent/EP0597101B1/en not_active Expired - Lifetime
- 1992-07-17 WO PCT/JP1992/000914 patent/WO1993001835A1/ja active IP Right Grant
- 1992-07-17 AT AT92915866T patent/ATE176868T1/de not_active IP Right Cessation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5347515A (en) * | 1976-10-13 | 1978-04-28 | Green Cross Corp:The | Gamma-globulin pharmaceutical preparation for intravenous injection |
JPS56127320A (en) * | 1980-03-10 | 1981-10-06 | Mochida Pharmaceut Co Ltd | Gamma-globulin pharmaceutical |
JPS6388197A (ja) * | 1986-09-30 | 1988-04-19 | Tosoh Corp | モノクロナル抗体の安定化方法 |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998022136A2 (de) | 1996-11-19 | 1998-05-28 | Roche Diagnostics Gmbh | Stabile lyophilisierte pharmazeutische zubereitungen von mono- oder polyklonalen antikörpern |
EP0852951A1 (de) | 1996-11-19 | 1998-07-15 | Roche Diagnostics GmbH | Stabile lyophilisierte pharmazeutische Zubereitungen von mono- oder polyklonalen Antikörpern |
WO1998022136A3 (de) * | 1996-11-19 | 1998-08-20 | Boehringer Mannheim Gmbh | Stabile lyophilisierte pharmazeutische zubereitungen von mono- oder polyklonalen antikörpern |
Also Published As
Publication number | Publication date |
---|---|
EP0597101B1 (en) | 1999-02-24 |
AU662010B2 (en) | 1995-08-17 |
DE69228474D1 (de) | 1999-04-01 |
DE69228474T2 (de) | 1999-06-24 |
AU2330592A (en) | 1993-02-23 |
JP2966592B2 (ja) | 1999-10-25 |
EP0597101A4 (en) | 1994-06-15 |
ATE176868T1 (de) | 1999-03-15 |
JPH0525058A (ja) | 1993-02-02 |
EP0597101A1 (en) | 1994-05-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1993001835A1 (en) | Stabilized human monoclonal antibody preparation | |
US6165467A (en) | Stabilized human monoclonal antibody preparation | |
KR101280273B1 (ko) | 안정화된 항-b형 간염 바이러스 (hbv) 항체 제형 | |
US5945098A (en) | Stable intravenously-administrable immune globulin preparation | |
JP4644203B2 (ja) | 安定性を高めた免疫グロブリン配合物 | |
JP5478519B2 (ja) | 静脈投与用免疫グロブリン及び他の免疫グロブリン生成物の製造法 | |
US4478829A (en) | Pharmaceutical preparation containing purified fibronectin | |
JP5357391B2 (ja) | 液状形態及び凍結乾燥形態の免疫グロブリンg組成物用安定化配合物 | |
JPH0761956B2 (ja) | 静注可能な免疫グロブリン | |
JPH0565233A (ja) | モノクローナル抗体含有凍結乾燥製剤 | |
KR20130028894A (ko) | 항체의 제제 | |
CN107080842A (zh) | 抗体制剂 | |
US4168303A (en) | Lyophilized native gamma globulin preparation for intravenous administration | |
JPH0558000B2 (ja) | ||
JPS6013718A (ja) | B型肝炎ワクチン | |
EP0417191A1 (en) | FORMULA FOR ANTIBODY-CONTAINING REAGENTS. | |
DK147812B (da) | Fremgangsmaade til fremstilling af et stabilt lyofiliseret urokinasepraeparat | |
ES2213760T3 (es) | Preparacion de globulina de suero inmunizante inyectable por via intravenosa con virus inactivado. | |
JP2024023468A (ja) | 安定な融合タンパク質製剤 | |
JPS6160817B2 (ja) | ||
JP2004536129A (ja) | セツキシマブおよびポリオキシエチレンソルビタン脂肪酸エステルを含む液体製剤 | |
AU2014237111B2 (en) | Recombinant factor VIII formulations | |
JPH04502914A (ja) | 免疫グロブリンを可溶化するための塩基性アミノ酸の使用 | |
JPH04346934A (ja) | γ−グロブリンの液状製剤 | |
JPS6016406B2 (ja) | 静脈内に投与可能なガンマ・グロブリンの製造法ならびにそれにより調製したガンマ・グロブリン |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1992915866 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1992915866 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref country code: US Ref document number: 1997 970393 Date of ref document: 19971114 Kind code of ref document: A Format of ref document f/p: F |
|
WWG | Wipo information: grant in national office |
Ref document number: 1992915866 Country of ref document: EP |