WO2009069916A1 - Formulation pharmaceutique contenant un anticorps humain neutralisant le virus de l'hépatite b - Google Patents

Formulation pharmaceutique contenant un anticorps humain neutralisant le virus de l'hépatite b Download PDF

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Publication number
WO2009069916A1
WO2009069916A1 PCT/KR2008/006866 KR2008006866W WO2009069916A1 WO 2009069916 A1 WO2009069916 A1 WO 2009069916A1 KR 2008006866 W KR2008006866 W KR 2008006866W WO 2009069916 A1 WO2009069916 A1 WO 2009069916A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical formulation
formulation
antibody
buffer
polyoxyethylene sorbitan
Prior art date
Application number
PCT/KR2008/006866
Other languages
English (en)
Inventor
Se-Ho Kim
Kwang-Won Hong
Yong-Nam Shin
Yong-Won Shin
Ki-Hwan Chang
Kyung-Hwan Ryoo
Jin-Seol Choi
Pan-Kyung Kim
Ki-Tae Bong
Dong-Hyuck Seo
Sun-Jeong Oh
Original Assignee
Green Cross Corporation
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 Green Cross Corporation filed Critical Green Cross Corporation
Priority to CN2008801184077A priority Critical patent/CN101896199A/zh
Publication of WO2009069916A1 publication Critical patent/WO2009069916A1/fr

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Classifications

    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • 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
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/082—Hepadnaviridae, e.g. hepatitis B virus
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to a pharmaceutical liquid formulation comprising a stabilized hepatitis B virus (HBV) neutralizing human antibody.
  • HBV hepatitis B virus
  • a protein drug tends to undergo degradation, precipitation, or conformational changes, due to e.g., the formation of soluble/insoluble particles during long-term storage, particularly when the protein is formulated as a liquid composition.
  • various techniques depending on the physical properties of the protein drug of interest, to preserve the protein's functional groups and structure related to the protein activity.
  • EP Patent No. 73371 discloses an intravenously injectable liquid formulation comprising an immuno globulin maintained at a pH of 3.5 to 5.0. However, such a formulation having a low pH may induce undesirable effects when injected.
  • US Patent No. 6,171,586 discloses an aqueous antibody formulation comprising an acetate buffer having pH of 4.48 to 5.5, a surfactant, and a polyol. This formulation which does not comprise an isotonic controlling agent may also induce adverse side effects.
  • Korean Patent Publication No. 2006-1 10305 discloses an aqueous i pharmaceutical formulation comprising an antibody against epithelial growth factor receptor (EGF receptor), and the formulation contains an amino acid which functions to enhance the long term storage stability of the antibody.
  • EGF receptor epithelial growth factor receptor
  • Korean Patent Publication No. 2006-7016023 discloses a highly concentrated, liquid formulation comprising an anti-EGFR antibody, but this method for preparing the formulation comprises a step of concentrating the formulation by ultrafiltration, which makes the process highly uneconomical.
  • a pharmaceutical formulation which can stabilize a hepatitis B virus (HBV) neutralizing human antibody dispersed in a liquid phase during a long-term storage.
  • a pharmaceutical formulation comprising a hepatitis B virus (HBV) neutralizing human antibody, buffer, isotonic adjusting agent and surfactant for preventing or treating hepatitis B.
  • the formulation of the present invention comprises a hepatitis B virus (HBV) neutralizing human antibody, a buffer, an isotonic adjusting agent and a surfactant.
  • a part of the solvent of the inventive liquid formulation may be water.
  • the HBV neutralizing human antibody may be a recombinant antibody, preferably an antibody against a surface antigen of HBV (Hepabig-Gene) produced from cell line HBAb-49 (Accession No.: KCLRF-BP-00054).
  • the antibody is preferably a human antibody comprising a heavy chain variable region (V H ) of the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (V L ) having the amino acid sequence of SEQ ID NO: 2.
  • the antibody concentration of the inventive formulation ranges from 0.1 to 50 mg/m£, preferably, 2 to 10 mg/m£, and most preferably, 5 mglmi.
  • the buffer may be any material having a physiological drug tolerance and pH control ability, e.g., citrate salt, acetate salt, phosphate salt, or a free acid or base form thereof, or a mixture thereof.
  • the term "mixture” includes both of a mixture of salts derived from different acids such as a mixture of citrate salt and acetate salt; and a mixture of different salts derived from one acid such as a mixture of different citrate salts.
  • the buffer may be citrate salt, acetate salt, or free acid thereof, preferably.
  • the free acid of the citrate salt may include citric acid, citrate monohydrate, trisodium citrate dehydrate and tripotassium citrate monohydrate, and the free acid of the acetate salt may include acetic acid, sodium acetate and sodium acetate trihydrate.
  • the concentration of the buffer is in the range of 10 to 100 mmol/1, preferably 2 to 50 mmol/1, and the most preferably 20 mmol/1.
  • the isotonic adjusting agent may be a salt having a physiological drug tolerance such as sodium chloride or potassium chloride, preferably sodium chloride.
  • the concentration of the isotonic adjusting agent is in the range of 20 to 250 mmol/1, preferably 100 to 200 mmol/1.
  • the surfactant may be any surfactant commonly used in a pharmaceutical formulation, preferably polyoxyethylene sorbitan fatty acid ester (TweenTM 80), for example, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate or polyoxyethylene sorbitan monooleate, preferably polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monooleate, the most preferably polyoxyethylene sorbitan monooleate.
  • TweenTM 80 polyoxyethylene sorbitan fatty acid ester
  • the concentration of the surfactant is in the range of 0.001 to 1.0 weight %.
  • the concentration thereof is in the range of 0.005 to 0.1 weight %, preferably about 0.05 weight %.
  • the pharmaceutical formulation of the present invention has an osmolarity in the range of 250 to 350 mOsmol/kg. Therefore, the formulation may be directly administered into a vein or an artery, a hypodermis, or a muscle without inflicting pain.
  • the pH of the formulation may be 4.0 to 7.0, preferably 5.0 to 6.0, and the most preferably 5.5.
  • the pharmaceutical formulation contains 10,000 units (5 mg/m-C) of Hepabig-Gene, 20 mmol/1 of acetate buffer (pH 5.5), 150 mmol/1 of sodium chloride and 0.05 weight % of polyoxyethylene sorbitan monooleate.
  • the pharmaceutical formulation in accordance with the present invention may be prepared by mixing the acetate buffer (pH 5.5) comprising the antibody, or a further solution of sodium chloride, with the remaining ingredients as supplements.
  • a specific dose of the storage solution comprising the supplement may be added to a solution comprising a specific amount of the antibody, and if needed, the mixture may be diluted with water or a buffer solution to the pre-determined concentration.
  • the supplements in the form of a solid may be added to the starting solution comprising the antibody.
  • the inventive formulation may be prepared by dissolving the antibody in water or a solution comprising at least one ingredient, and then adding a storage solution comprising the ingredients, solid supplements and/or water thereto in a required amount. Further, the antibody may be directly dissolved in a solution comprising all ingredients.
  • At least one ingredient of the inventive pharmaceutical formulation may be optionally added during the course of the recombinant antibody preparation or at the last step.
  • the Hepabig-Gene was directly dissolved in a solution comprising at least one or all ingredients during the last purification step.
  • inventive formulation may optionally include a small amount of additional supplement having a physiological drug tolerance, e.g., an antioxidant such as ascorbic acid and glutathione; preservative such as phenol, m-cresol, methyl- or propylparaben, chlorobutanol, thiomersal and benzalkoniumchloride; polyethylene glycol (PEG) such as PEG 400, PEG 3000, PEG 3500, PEG 4000 and PEG 6000; disaccharide such as trehalose and saccharose; or cyclodextrin such as hydroxypropyl- ⁇ -cyclodextrin, sulfobutylethyl- ⁇ -cyclodextrin, a-cyclodextrin and ⁇ -cyclodextrin.
  • an antioxidant such as ascorbic acid and glutathione
  • preservative such as phenol, m-cresol, methyl- or propylparaben, chlorobutanol, thio
  • the additional supplement is directly dissolved in a solution comprising all ingredients at the last step of the purification for the antibody preparation.
  • the pH can be adjusted by adding an acid or base, preferably the acid or base which is already present in the buffer. Further, the pH adjusted solution may be subjected to sterile filtration.
  • the pharmaceutical formulation of the present invention can be easily prepared, and has excellent physiological drug tolerance, high administration accuracy and stability so that it minimize the formation of degradation products and aggregate during the storage period.
  • the inventive formulation is capable of maintaining the antibody stability for 1 year or more when stored at 2 to 8 "C , or 3 months and more when stored at 25 ° C and 60% relative humidity.
  • the pharmaceutical formulation of the present invention may be used for preventing or treating the hepatitis B, preferably for a liver transplantation through the neutralization of the HBV or chronic hepatitis B treatment.
  • a solution comprising 10,000 units (5 mg/m£) of Hepabig-Gene, 10 mmol/1 of sodium phosphate buffer ( 1.2 g/1 sodium dihydrogen phosphate) (pH 7.2) and 150 mmol/1 of sodium chloride was prepared, and subjected to sterile filtration. The filtrate was stored at 25 ° C and 60% relative humidity.
  • Example IA The procedure of Example IA was repeated except for storing the solution at 5 °C .
  • Example 3A Preparation of Hepabig-Gene formulation
  • Example 3 A The procedure of Example 3 A was repeated except for storing the solution at 5 ° C .
  • Example 4A The procedure of Example 4A was repeated except for storing the solution at 5 ° C .
  • the aging characteristics of each of the solutions of Examples IA to 4B and Comparative Examples IA to 4B were determined by measuring the amounts of the protein before and after aging, by visual evaluation, absorbance measurement (280 nm), titer measurement by ELISA, HPLC size exclusion chromatography (SEC), reduced and non-reduced electrophoresis analysis (SDS-PAGE), western blot, isoelectric focusing (IEF) analysis and pH measurement as follows. The results are shown in Tables 1 and 2.
  • Each vial containing a sample formulation was visually checked at room temperature under a white fluorescent light to evaluate the color, appearance and transparency of the solution.
  • Each solution was diluted by 5 to 10 times, 15 to 30 times, or more, and the absorbance thereof (280 nm) was measured with a spectrophotometer, to determine the protein concentration by determining the absorbance coefficient at I AO (mg/ mi) '1 cm '1 .
  • Size exclusion chromatography was performed using a column (TSK G3000 SWXLTM, 7.8x300 mm), Gilson 321 pump and UV/VIS-155 system.
  • a sample solution was diluted with a mobile phase (50 mmol/1 MES, 150 mmol/1 sodium chloride, 1.5 mole/1 L-arginine monohydrochloride; pH 6.0) to a concentration of 1 mg/m£, and isocratically eluted for 30 min at 0.5 m£/min (Injection volume: 50 ⁇ Jl).
  • the absorbance of the eluted solution at 280 nm was monitored, and the integration was carried out using Gilson TrillutionTM LC 1.4 software.
  • a sample solution was heated in a buffer at 70 ° C for 5 min, and 5 ⁇ g of the resulting proteins were loaded on a protein electrophoresis gel (Invitrogen, USA).
  • the resulting gel was stained with Coomassie, and destained to observe the resulting bands.
  • a sample solution was heated in a buffer at 70 ° C for 5 min, 1 ⁇ g of the obtained proteins were loaded on a protein electrophoresis gel (Invitrogen, USA).
  • the proteins on the gel were electrically transferred to a nitrocellulose (NC) membrane, and the membrane was blocked with 5% skimmed milk powder/PBS for 1 hour, reacted with a goat anti-human IgG peroxidase, and washed three times with PBST.
  • TMB membrane substrate KPL, USA
  • Isoelectric focusing analysis was carried out using Ampholine PAGplateTM gel (pH 3.5-9.5) and MultiphorTM II system (GE healthcare, Sweden).
  • Examples IA to 4 A stored for up to 6 months at 25 ° C and 60% relative humidity were analyzed. Further, among the formulation stored at 5 "C , the formulations of Comparative Examples IB to 4B containing no surfactant were observed during a storage period of up to 6 months. The formulations of Examples IB to 4B containing all the ingredients were observed during a storage period of up to 12 months.
  • Example 4A As shown in Tables 1 and 2, the formulations of Examples IA to 4 A stored at 25 °C and 60% relative humidity, particularly of Example 4A showed excellent stability.
  • the inventive formulation may maintain the antibody stability for a long period when the antibody is stored in a liquid phase.
  • the possibility of hemolysis thereof was measured by allowing the formulation to react with the blood of a monkey or a human.
  • Example 4A (1 , 5 or 10 mg/ml), a liquid composition having the antibody removed from the formulation (20 mM sodium acetate, 150 mM sodium chloride and 0.05% TweenTM 80; pH 5.5), 1% saponin (positive control), and either monkey plasma (negative control); or human plasma (negative control) were each treated with the same volume of the blood of monkey or human.
  • the mixture obtained therefrom was centrifuged, the supernatant was separated and analyzed by measuring the hemoglobin concentration of the hemolyzed erythrocyte with a spectrophotometer. The results are shown in Table 3.
  • the antibody of the present invention showed no hemolysis when treated with the monkey or human blood.
  • Example 4A (1, 5 or 10 mg/m£) or the liquid composition having the antibody removed from the formulation was mixed with the same volume of the monkey or human plasma, and the resulting mixture was evaluated to see whether aggregation or precipitation occurred as the consequence.
  • Table 4 The results are shown in Table 4.
  • the rabbits were divided into groups 1 and 2.
  • 1.0 mi and 0.21 mi of the formulation of Example 4 A (5 mg/mi (10,000 unit)) were respectively injected into the veins (Test region C) and the peri vein (Test region D) of the left ear, and to each of rabbits in the control group, 1.0 mi and 0.21 mi of the liquid composition having the antibody removed from the formulation (20 mM sodium acetate, 150 mM sodium chloride and 0.05% Tween 80; pH 5.5) were respectively injected into the veins (Test region A) and the perivein (Test region B) of the right ear.
  • each 0.5 mi of the formulation of Example 4A (5 mg/m-C (10,000 unit)) and the liquid composition having the antibody removed from the formulation (20 mM sodium acetate, 150 mM sodium chloride and 0.05% Tween 80; pH 5.5) were respectively injected into the veins of the left ear (Test region F).
  • the presence of edema or erythema was observed for 3 rabbits each, and the number of the rabbits having edema or erythema is listed in Tables 6 to 9.
  • the formulation of the present invention does not exhibit any serious side effect after intravenous, perivenous and intraartery injections.
  • the microorganism identified under I above was accompanied by

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Abstract

La présente invention concerne une formulation pharmaceutique contenant un anticorps humain neutralisant le virus de l'hépatite B (VHB), un tampon, un agent d'ajustement isotonique et un tensioactif. La formulation liquide selon l'invention est appropriée à une administration parentérale et est capable de maintenir l'activité de l'anticorps lors d'un stockage de longue durée.
PCT/KR2008/006866 2007-11-30 2008-11-21 Formulation pharmaceutique contenant un anticorps humain neutralisant le virus de l'hépatite b WO2009069916A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN2008801184077A CN101896199A (zh) 2007-11-30 2008-11-21 含有中和乙型肝炎病毒的人抗体的药物制剂

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020070123747A KR20090056543A (ko) 2007-11-30 2007-11-30 Ｂ형 간염 바이러스(ｈｂｖ) 중화 인간 항체를 포함하는약학적 제제
KR10-2007-0123747 2007-11-30

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WO2009069916A1 true WO2009069916A1 (fr) 2009-06-04

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KR (1) KR20090056543A (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9683029B2 (en) 2012-07-10 2017-06-20 Green Cross Corporation Antibody composition for prevention or treatment of mutant hepatitis B virus infection

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102988984B (zh) * 2012-12-21 2015-05-20 嘉和生物药业有限公司 增强稳定性的抗TNF-α人单克隆抗体的含水药物制剂
CN111234011B (zh) * 2018-11-29 2022-01-11 清华大学 乙肝病毒的中和抗体b826及其应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022136A2 (fr) * 1996-11-19 1998-05-28 Roche Diagnostics Gmbh Preparations pharmaceutiques lyophilisees stables d'anticorps monoclonaux ou polyclonaux
EP1516628A1 (fr) * 1995-07-27 2005-03-23 Genentech, Inc. Formulation de protéine stabile, lyophilisée et isotonique
US20050175611A1 (en) * 2003-11-26 2005-08-11 Hanns-Christian Mahler Pharmaceutical preparation comprising an antibody against the EGF receptor
WO2006112838A1 (fr) * 2005-04-18 2006-10-26 Xtl Biopharmaceuticals Ltd. Preparations d'anticorps anti-hepatite b (vhb) stabilises

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1516628A1 (fr) * 1995-07-27 2005-03-23 Genentech, Inc. Formulation de protéine stabile, lyophilisée et isotonique
WO1998022136A2 (fr) * 1996-11-19 1998-05-28 Roche Diagnostics Gmbh Preparations pharmaceutiques lyophilisees stables d'anticorps monoclonaux ou polyclonaux
US20050175611A1 (en) * 2003-11-26 2005-08-11 Hanns-Christian Mahler Pharmaceutical preparation comprising an antibody against the EGF receptor
WO2006112838A1 (fr) * 2005-04-18 2006-10-26 Xtl Biopharmaceuticals Ltd. Preparations d'anticorps anti-hepatite b (vhb) stabilises

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9683029B2 (en) 2012-07-10 2017-06-20 Green Cross Corporation Antibody composition for prevention or treatment of mutant hepatitis B virus infection

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CN101896199A (zh) 2010-11-24

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