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
  • A61K9/08—Solutions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
• • 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
  • A61P35/00—Antineoplastic agents
• • 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
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• the present invention relates to a stable liquid pharmaceutical formulation comprising the chimeric monoclonal antibody C225 (cetuximab ®) against the receptor of epidermal growth factor
• Cetuximab ® is a promising antibody that binds to the EGF receptor. Cetuximab ® and C225 is recombined different species from the DNA, and was first described by Naramura et al. (Cancer Immunol Immunotherapy 37, 343-349, 1993). With regard to the production of Cetuximab ® referenced called scientific literature.
• Cetuximab ® is administered parenterally as a solution for therapeutic use.
• a particular problem with antibody solutions is their tendency to aggregate and form protein multimers. In the case of reducible multimers, this may be due to unintended intermolecular disulfide bridge formation through an interaction between approaching moieties. Also suitable are hydrophobic interactions and the associated formation of non-reducible multimers. Furthermore, there are deamidation reactions, which subsequently lead to protein degradation reactions. As a result of the mentioned tendency to aggregation, product precipitations occur during storage of antibody solutions, so that a reproducible removal from the container containing the solution is called into question. In addition, parenteral administration of particle-containing solution can lead to embolisms. As a result, a reproducible
• a common method for stabilizing monoclonal antibodies is the freeze-drying of solutions containing antibodies as well as excipients.
• lyophilization is very time and energy consuming and therefore expensive.
• the lyophilisate must first be reconstituted before administration.
• EP 0 073 371 describes intravenously administrable compositions containing immunoglobulins which have a pH of from 3.5 to 5.0 for stabilization. However, such low pH values lead to undesirable incompatibility reactions at the injection site.
• US 6,171,586 B1 discloses the use of an acetate buffer pH 4.48 to 5.5, a surfactant and a polyol in a liquid formulation of antibodies, excluding NaCl for isotonization. Due to the low pH value as well as the lack of isotonization, incompatibility reactions at the injection site can also occur.
• EP 0 280 358, EP 0 170 983 and US Pat. No. 5,945,098 may be mentioned at this point.
• EP 0 280 358 describes the addition of dextran to a
• Antibody solution for stabilization against certain hormones achieving stability over nine months.
• EP 0 170 983 describes the stabilization of a thermolabile monoclonal antibody by heating together with hydrolyzed
• Ovalbumin whereby the antibody after 7 days of storage at 45 ° C was still stable.
• the addition of proteins of other species to administrable formulations intended for parenteral administration is undesirable because of the problems involved, in particular their possible antigenicity.
• US 5,945,098 discloses the use of glycine, polysorbate 80 and polyethylene glycol to stabilize a liquid formulation of immunoglobulin G.
• cetuximab ® suitable for parenteral administration, fluid formulation that is well tolerated and when stored at room temperature over a year is at least stable.
• the formulation should have a simple structure and contain no toxicologically harmful excipients.
• cetuximab ® contains a phosphate buffer in the range of approximately pH 6 to approximately pH 8 and a polyoxyethylene sorbitan fatty acid ester.
• the subject of the present invention is therefore a stable liquid pharmaceutical composition containing a phosphate buffer in the range of pH 6 to pH 8 and a polyoxyethylene sorbitan fatty acid ester.
• the pH is in the range of 6.5 to 7.5, more preferably a pH of about 7.2.
• Suitable phosphate buffers are solutions of mono- and / or di-
• phosphate buffer can in the formulation of the invention in a
• Concentration range from 2 mM to 100 mM. Preferred is a concentration range of 5 mM to 20 mM, more preferably about 10 mM.
• Cetuximab ® can in the formulation of the invention in a
• 2 mg / ml to 10 mg / ml, more preferably about 5 mg / ml are included.
• polyethylene sorbitan fatty acid esters are also known under the trademark Tween.
• Polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, and polyoxyethylene (20) sorbitan monostearate are particularly useful in the formulation of this invention.
• Polyoxyethylene (20) sorbitan monolaurate and polyoxyethylene (20) sorbitan monooleate are preferred, of which polyoxyethylene (20) sorbitan monooleate is particularly preferred.
• Polyethylene sorbitan fatty acid esters may be included in the formulation in a concentration of 0.001% to 1.0%. Preferably, 0.005% to 0.1%, more preferably about 0.01% are included.
• the formulation according to the invention additionally contains a
• Isotonizing agent preferably a physiologically acceptable salt, such as sodium chloride or potassium chloride, or a physiological compatible polyol, such as glucose or glycerol, in a concentration required for isotonization.
• the invention is therefore a liquid formulation comprising Cetuximab ®, a phosphate buffer in the range of approximately pH 6 to approximately pH 8, a polyoxyethylene sorbitan fatty acid ester and an isotonizing agent in a concentration necessary for establishing isotonicity.
• the formulation contains sodium chloride as an isotonizing agent.
• the liquid formulation of approximately 5mg / ml Cetuximab ® contains about 10 mM
• Phosphate buffer with a pH of about 7.2, about 145 mM sodium chloride and about 0.01% polyoxyethylene (20) sorbitan monooleate Phosphate buffer with a pH of about 7.2, about 145 mM sodium chloride and about 0.01% polyoxyethylene (20) sorbitan monooleate.
• the formulation of the invention can be prepared by a cetuximab ® solution containing the ingredients listed are added. Conveniently, this is a solution with a defined concentration of cetuximab ®, as it is obtained in its preparation, mixed with defined volumes of stock solutions containing the said further ingredients in defined concentration and and optionally diluted with water to the pre-calculated concentration. Alternatively, the ingredients of the cetuximab ® containing feed solution may also be added as solids. Is cetuximab ® as a solid, for example as a lyophilisate, the formulation of the invention can be prepared by cetuximab ® one or more of the further first in water or an
• one or more of the ingredients contained in the inventive formulation are already during or added at the end of the manufacturing process of cetuximab ®.
• this can be done by using Cetuximab ®, several or all further ingredients containing aqueous solution is dissolved in the last step of carried out after its preparation purification directly in a one.
• the respective further ingredient (s) need only be added in a lesser amount and / or not at all to prepare the formulation. It is particularly preferred if, in the last step of the purification carried out after its preparation, the particular ingredient is dissolved directly in an aqueous solution containing all further ingredients, so that the formulation according to the invention is obtained directly.
• the preparation was carried out by mixing defined volumes of the respective ingredients in a defined concentration containing aqueous
• Solution A drug solution containing:
• Solution B (buffer / salt solution): corresponds to solution A, but contains no active ingredient.
• Solution C polyoxyethylene sorbitan fatty acid ester solution: corresponds to solution B, but additionally contains 1% by weight of polyoxyethylene (20) sorbitan monooleate.
• the prepared solution was filtered with a sterile filter before filling.
• the vials were filled with a pipette with 2 ml solution each.
• Example 2 (comparative formulation) Aqueous solution containing:
• Example 3 To prepare the comparative formulation, 10 ml each of the solutions A and B described in Example 1 were combined with each other.
• the preparation was carried out by mixing defined volumes of the respective ingredients in a defined concentration containing aqueous solutions.
• the following solutions were used:
• Solution B polyoxyethylene sorbitan fatty acid ester glucose solution
• Example 1 and for comparison purposes vials containing solution according to Example 2 stored at 40 ° C and 75% relative humidity. Prior to storage and after defined storage periods, 3 vials were assessed visually by direct irradiation with a cold light source and the absorption of the solutions at 350 and 550 nm was determined, which represents a measure of the turbidity. Furthermore, 3 vials were each removed and analyzed for the content of cetuximab ® and decomposition products by HPLC-gel filtration examined.
• phosphate buffer pH 7.2 was used as a flow agent.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Immunology (AREA)
• General Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Mycology (AREA)
• Microbiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Medicinal Preparation (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 2001
  • 2001-07-13 DE DE10133394A patent/DE10133394A1/de not_active Withdrawn
• 2002
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  • 2002-06-18 CA CA002453342A patent/CA2453342A1/en not_active Abandoned
  • 2002-06-18 BR BR0211060-1A patent/BR0211060A/pt not_active IP Right Cessation
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  • 2002-06-18 WO PCT/EP2002/006696 patent/WO2003007988A1/de not_active Application Discontinuation
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  • 2002-06-18 US US10/483,404 patent/US20040170632A1/en not_active Abandoned
  • 2002-06-18 HU HU0401046A patent/HUP0401046A3/hu unknown
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  • 2002-06-18 EP EP02751038A patent/EP1406658A1/de not_active Withdrawn
  • 2002-06-18 CN CNB028141059A patent/CN1231264C/zh not_active Expired - Fee Related
  • 2002-07-11 PE PE2002000618A patent/PE20030433A1/es not_active Application Discontinuation
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