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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• • 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
  • 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
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • 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
  • A61K47/16—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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
  • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

• composition of concentrated human immunoglobulins Composition of concentrated human immunoglobulins
• the invention relates to the formulation of human immunoglobulin G, useful in therapy.
• IgG immunoglobulin G
• examples include primitive immune deficiencies with defective antibody production, Kawasaki disease, immunologic thrombocytopenic purpura in children and adults, secondary immune deficiencies with defective antibody production, in particular chronic lymphocytic leukemia or myeloma associated with recurrent infections, childhood HIV infection associated with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, severe acute or chronic parvovirus B19 infections Acquired or constitutional immunodeficiency, corticosteroid dermatomyositis, acute myasthenia, idiopathic chronic polyradiculoneuropathy, immune thrombocytopenic purpura, for example associated with HIV infection, stiff man syndrome (Stiffman syndrome) , autoimmune neutropenia, resistant autoimmune erythroblastopenia, anticoagula syndrome acquired by autoantibodies, rheumatoid arthritis, uveitis, etc.
• Stiffman syndrome autoimmune neutropenia
• the pathologies treated with immunoglobulins involve particularly high doses which represent doses of the order of 0.4 to 2 grams per patient's body weight per month.
• immunoglobulins G marketed today are intended for intravenous administration which allows infusions of several tens of grams of IgG in preparations of several hundred milliliters at the rate of one administration every 3 or 4 weeks.
• Intravenous administration requires the presence of caregivers; it is most often performed in the hospital. In young children and the elderly, intravenous administration can be very difficult because of a poor venous approach, which can in some cases prevent access to treatment.
• IgG subcutaneous administration
• SCIG subcutaneous immunoglobulin
• IgSC Intranet-to-Cret-associated erythema
• concentration of the IgSC is a determining characteristic that determines the injection volume and the number of injection sites. Given the doses injected and the maximum injectable volume per site, the concentration of the IgSC defines the number of injection sites and consequently the frequency of administration.
• Hizentra IgPro20® which can be administered by the subcutaneous route, is known.
• oligomers and polymers may be formed in said composition. Oligomers and polymers may activate the complement system with associated risks of anaphylactic reactions. These oligomers and polymers are also likely to induce hypotension phenomena in the treated patient. This is undesirable and is strictly controlled from a regulatory point of view.
• Another important technical constraint is related to the tangential ultrafiltration process commonly used in the IgG manufacturing process: at high IgG concentration, local overcentration of IgG at the membrane level can disturb the polarization layer thus making ultrafiltration less efficient tangentially or directly induce clogging of the membrane by blocking tangential ultrafiltration.
• the increase in viscosity associated with IgG concentration is also a major technical constraint.
• the viscosity can indeed cause problems both in the process for the aseptic formulation and distribution steps and in the final application with respect to the syringability of the IgG composition.
• IgG compositions at highly elevated concentrations to reduce injection volume, which are readily administrable and well tolerated for subcutaneous administration, e.g. of human plasmas, to improve patient comfort and reduce side effects.
• the Applicant has developed a novel method for obtaining highly concentrated IgG compositions, at least 230 g / L, more generally between 230 and 350g / L, and easy to administer subcutaneously.
• the new process makes it possible to obtain IgG compositions concentrated to at least 250 g / l, preferably from about 250 g / l to about 300 g / l.
• the method for preparing a pharmaceutical composition comprising human immunoglobulin G comprises the following steps: a) Provide an IgG preparation;
• a surfactant which may be the same or different from the surfactant of step b).
• step b) one or more compounds chosen from sugars, sugar derivatives and salts.
• the novel process for preparing a pharmaceutical composition comprising the following steps:
• a surfactant which may be the same or different from the surfactant that will be added in step b), to obtain the desired liquid pharmaceutical composition.
• step b) of the process according to the invention amino acids, sugars, sugar derivatives, salts and / or surfactants at a concentration lower than the critical micelle concentration of said surfactants
• amino acids, sugars, sugar derivatives, salts and / or surfactants at a concentration lower than the critical micelle concentration of said surfactants are added before the concentration step by ultrafiltration.
• step b) the process for preparing a liquid pharmaceutical composition is added to at least one amino acid which may be a hydrophilic amino acid or a positively charged side chain.
• step b) of the process for preparing a liquid pharmaceutical composition at least one amino acid
• said amino acid is an amino acid hydrophilic or carrying a positively charged side chain associated with at least one hydrophobic amino acid.
• step b) of the process for the preparation of a liquid pharmaceutical composition at least one sugar or a sugar derivative chosen from sucrose, di- and tri-saccharides and polysaccharides, such as dextrose, are added advantageously.
• a sugar derivative chosen from sucrose, di- and tri-saccharides and polysaccharides, such as dextrose are added advantageously.
• lactose, maltose, trehalose, cyclodextrins, maltodextrins and dextrans reducing sugars or polyols.
• step b) a salt chosen from a mineral salt and an organic salt is added.
• the surfactant added in step b) and / or d) is preferably a nonionic detergent.
• Another subject of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising human immunoglobulin G (IgG) obtained by this method, characterized in that the concentration of IgG is at least 230 g / l of the composition.
• the IgG concentration is at least 250 g / l of the composition.
• composition according to the invention is advantageously in liquid form.
• the composition according to the invention comprises an amino acid and a surfactant.
• the composition according to the invention comprises an amino acid, a salt and a surfactant.
• the composition according to the invention comprises a sugar or a sugar derivative and a surfactant.
• the composition according to the invention comprises an amino acid, a sugar or a sugar derivative, and a surfactant.
• the composition according to the invention comprises an amino acid, a sugar or a sugar derivative, a salt and a surfactant.
• compositions obtained or obtainable by the process described here are also part of the invention. These compositions are advantageously in a form suitable for subcutaneous or intramuscular administration, preferably subcutaneous administration.
• human immunoglobulins G or "human IgG” in the context of the invention means polyvalent immunoglobulins which are essentially IgGs, possibly including IgMs, which may be whole immunoglobulins, or fragments such as F (ab ') 2 or F (ab) and any intermediate fraction obtained during the manufacturing process of polyvalent immunoglobulins.
• Stability corresponds to the physical and / or chemical stability of IgG.
• physical stability refers to the reduction or absence of formation of insoluble or soluble aggregates of the dimeric, oligomeric or polymeric forms of Ig, as well as the reduction or absence of any structural denaturation of the molecule. .
• chemical stability refers to the reduction or absence of any chemical modification of IgG during storage, in the solid state or in dissolved form, under accelerated conditions. For example, the phenomena of hydrolysis, deamination, and / or oxidation are avoided or delayed. The oxidation of sulfur-containing amino acids is limited.
• c) carry out an IgG concentration by ultrafiltration, d) Then add a surfactant, which may be the same or different from the surfactant of step b).
• step b) More particularly the inventors have discovered that adding surfactant before ultrafiltration, and preferably fractionating the surfactant between step b) and step d), avoids degradation of immunoglobulins.
• liquid IgG compositions mean aqueous solutions of IgG compositions directly obtained by fractionation of human plasma.
• the aqueous medium is composed of water for injection (PPI water) which may contain pharmaceutically acceptable excipients and compatible with IgG.
• the IgG compositions may previously undergo specific virus inactivation / removal steps, such as detergent solvent treatment, pasteurization and / or nanofiltration.
• the composition according to the invention comprises IgG which can be polyclonal or monoclonal. IgGs can be isolated from human or animal blood or produced by other means, for example by molecular biology techniques, for example in cell systems well known to those skilled in the art.
• the composition according to the invention is particularly suitable for highly purified IgG.
• the IgGs of the present invention are obtained by fractionation of human plasma.
• Preferred fractionation methods of human plasma are described by Cohn et al (J. Am Chem Soc., 68, 459, 1946), Kistler et al. (Vox Sang, 7, 1962, 414-424), Steinbuch et al (French Rev. et.Clin, and Biol., XIV, 1054, 1969) and in the patent application WO 94/9334, these documents being incorporated by reference in their entirety.
• a method for preparing an immunoglobulin G composition is also described in the patent application WO 02/092632, incorporated by reference in its entirety.
• the IgG concentrates are generally subjected to a subsequent concentration step by tangential ultrafiltration, then to sterilizing filtration and can be packaged in flasks and preferably stored at temperatures in the region of 4 ° C.
• the IgGs of the present invention can be depleted in anti-A and anti-B antibodies as indicated in the patent application WO2007 / 077365.
• the step of concentration by tangential ultrafiltration according to the invention makes it possible to reach an immunoglobulin concentration of at least 230 g / l, preferably at least 250 g / l without causing the clogging of the membrane, the integrity of the immunoglobulins being maintained while avoiding aggregation at the interfaces and denaturation under flow or shear stress constraints.
• excipients are based on their stabilizing capacity and their ability to allow IgG concentration during the tangential ultrafiltration step.
• the excipients are added as follows:
• a human immunoglobulin G preparation purified from a plasma fraction of human blood, excipients which are at least one amino acid and / or at least one surfactant are added.
• excipients which are at least one amino acid and / or at least one surfactant are added.
• the surfactant or surfactants are added at a concentration lower than the critical micelle concentration of said surfactants;
• a surfactant which may be the same or different from the surfactant to be added in step b), is added to obtain the desired pharmaceutical composition.
• This method makes it possible to optimize the concentration of immunoglobulins G.
• the ultrafiltration step is a tangential ultrafiltration step, for example on a membrane with a cut-off threshold of less than 150 kD.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids, and / or one or more surfactants, and optionally one or more salts.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and a surfactant.
• the excipients which comprise or consist of one or more sugars or sugar derivatives are added to the IgG preparation before ultrafiltration.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and one or more sugars or sugar derivatives and a surfactant.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and one or more sugars or sugar derivatives and one or more salts.
• the excipients added to the IgG preparation before ultrafiltration comprise or consist of one or more amino acids and one or more sugars or sugar derivatives, one or more salts and a surfactant.
• the Applicant has surprisingly shown that highly concentrated IgGs can be obtained by formulating them before the IgG concentration step by ultrafiltration, by the addition of an amino acid and / or a surfactant, typically at a concentration lower than the critical micelle concentration of said surfactants, so as to ensure, on the one hand, obtaining the preparation directly to the required formulation of IgG, and on the other hand, the stability, the compatibility and the good tolerance of the pharmaceutical composition, further avoiding clogging phenomena at the ultrafiltration membrane.
• the amino acids that can be added during step b) of the process according to the invention are selected from the following group: a hydrophilic amino acid or carrying a positively charged side chain, and optionally also at least one hydrophobic amino acid. Hydrophilic (or polar) amino acids or amino acids carrying a positively charged side chain include Lysine, Arginine, Histidine, Glycine, Serine, Threonine, Tyrosine, Asparagine, Glutamine.
• hydrophilic amino acids or carrying a positively charged side chain it is preferable to use glycine or histidine.
• hydrophilic amino acid or carrying a positively charged side chain such as arginine
• a hydrophobic amino acid or an alkali metal salt, alkaline earth metal, or a metal transition promotes the stabilization of human IgG.
• hydrophobic amino acids include the following amino acids: Alanine, Valine, Leucine, Isoleucine, Phenylalanine, Tryptophan, Proline, etc.
• the amino acid of step b) is glycine, preferably at a concentration of 200 to 300mM.
• the sugars or sugar derivatives which may be added during step b) of the process according to the invention are selected from the following group: sucrose, di- and tri-saccharides and polysaccharides, such as dextrose, lactose, maltose, trehalose, cyclodextrins, maltodextrins and dextrans, reducing sugars or polyols.
• a reducing sugar mention may in particular be made of glucose or fructose.
• polyol there may be mentioned in particular mannitol, sorbitol and xylitol.
• salt is meant an alkali metal salt, alkaline earth metal or a transition metal.
• the salts that can be added during step b) of the process according to the invention are selected from the following group: mineral salts, organic salts or a mixture of several salts. Mention may be made in particular as mineral salts: sodium phosphate, sodium chloride, calcium chloride, or zinc chloride.
• organic salts sodium citrate, sodium succinate, sodium acetate or sodium thiocyanate.
• the salt used is an organic salt, preferably sodium acetate.
• 0 to 100 mM sodium acetate is added.
• Step b) of the process according to the invention may comprise the addition of one or more surfactants, for example of the nonionic detergent type, said surfactant is added during this step to a concentration lower than the critical micelle concentration.
• a suitable surfactant used in the composition according to the invention is advantageously chosen from polysorbate 80 (or Tween®80 which is polyoxyethylene sorbitan monooleate), polysorbate 20 (or Tween®20 which is polyoyethylene sorbitan monolaurate), Triton® X 100 (octoxinol 10), poloxamers, polyoxyethylene alkyl ethers, a co-polymer block of ethylene / polypropylene and Pluronic® F68 (polyethylenepolypropylene glycol).
• Tween®80, Tween®20 and poloxamer 188 are used.
• Nonionic detergents can also be combined with each other.
• the pH of the pharmaceutical composition is adjusted during step b) of the process according to the invention.
• the pH is adjusted between 4.0 and 8.0, preferably between 4.2 and 5.5 or between 6.8 and 7.8.
• the pH of the liquid pharmaceutical composition is between 6.9 and 7.6, preferably between 7.0 and 7.6, preferably between 7.1 and 7.5, preferably between 7.2 and 7.4, preferably 7.3.
• Step d) of the process according to the invention may comprise one or more surfactants, for example of the nonionic detergent type.
• a suitable surfactant used in the composition according to the invention is advantageously chosen from polysorbate 80 (or Tween®80 which is polyoxyethylenesorbitan monooleate), polysorbate 20 (or Tween®20 which is polyoyethylene sorbitan monolaurate), Triton® X 100 (octoxinol 10), poloxamers, polyoxyethylene alkyl ethers, a co-polymer block of ethylene / polypropylene and Pluronic® F68 (polyethylenepolypropylene glycol).
• Tween®80, Tween®20 and poloxamer 188 are used.
• Nonionic detergents can also be combined with each other.
• concentration of nonionic detergent sufficient to stabilize the composition according to the invention is preferably between 0 and 1000 ppm, preferably between 0 and 300 ppm, preferably between 0 and 50 ppm. Adding the surfactant to step d avoids the phenomenon of aggregation of the composition.
• the surfactant is a polysorbate, preferably polysorbate 20 or polysorbate 80.
• the surfactant is added to steps b) and / or d) at a total concentration of 50 to 300 ppm.
• the surfactant is added in step b) at a concentration of less than 75 ppm, preferably less than 50 ppm, and preferably less than 40 ppm.
• the inventors have furthermore demonstrated that a high temperature was not necessary, on the contrary. Excellent results have been obtained at a temperature below 30 ° C.
• step c) can therefore be carried out at a temperature below 30 ° C., preferably below 25 ° C.
• the ultrafiltration of step c) is carried out at a temperature between 15 ° C and 25 ° C, preferably about 20 ° C.
• the process according to the invention makes it possible to obtain a liquid pharmaceutical composition characterized in that the concentration of IgG is at least 230 g / l in the composition, preferably at least 250 g / l, typically between 230 g / l and 350 g / l, in said composition.
• the liquid pharmaceutical composition according to the invention comprising at least 230 g / l of immunoglobulin G, it preferably comprises 250 g / l of immunoglobulin G.
• the liquid pharmaceutical composition may further comprise an amino acid and a surfactant.
• the liquid pharmaceutical composition may comprise one or more hydrophilic amino acids or carrying a positively charged side chain, and optionally also at least one hydrophobic amino acid and a surfactant.
• the liquid pharmaceutical composition may further comprise an amino acid, a salt and a surfactant.
• the liquid pharmaceutical composition may further comprise a sugar or a sugar derivative and a surfactant.
• the liquid pharmaceutical composition may further comprise an amino acid, a sugar or a sugar derivative and a surfactant.
• the liquid pharmaceutical composition may further comprise an amino acid, a sugar or a sugar derivative, a salt and a surfactant.
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one surfactant, and optionally at least one salt, characterized in that the concentration of immunoglobulin G is at least 230 g / 1.
• the composition comprises an amino acid, a salt and a surfactant.
• the composition comprises:
• polysorbate 80 or 20 for example polysorbate 80 or 20, or a poloxamer.
• the pH of the composition being preferably between 4.2 and 5.5.
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one salt and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g / ml. 1.
• the immunoglobulin G concentration is at least about 250g / L and the composition comprises an amino acid, a salt and a surfactant.
• the composition comprises:
• IgG approximately 250 g / l
• polysorbate 80 or 20 preferably polysorbate 80 or 20, or a poloxamer.
• the pH of the composition being preferably between 4.2 and 5.5.
• composition may comprise
• the pH of the composition being preferably between 4.2 and 5.5.
• the composition comprises
• the pH of the composition being preferably between 4.2 and 5.5.
• the composition comprises:
• IgG at about 250 g / l
• the pH of the composition being preferably between 4.2 and 5.5.
• composition comprises
• the pH of the composition being preferably between 4.2 and 5.5.
• the invention provides an immunoglobulin G composition comprising at least one amino acid and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g / l.
• the immunoglobulin G concentration is at least about 250g / L and the composition comprises an amino acid and a surfactant.
• a preferred liquid pharmaceutical composition according to the invention comprises
• Human immunoglobulin G concentrated between 230 and 350 g / l, preferably at about 250 g / l,
• polysorbate preferably polysorbate 80, or a poloxamer.
• the pH of the composition being preferably between 4.2 and 5.5.
• composition comprises:
• Human immunoglobulin G concentrated between 230 and 350 g / l, preferably at about 250 g / l;
• the pH of the composition being preferably between 4.2 and 5.5.
• composition comprises:
• Human immunoglobulin G concentrated at about 250g / L; 200 mM glycine;
• the pH of the composition being preferably between 4.2 and 5.5.
• Another preferred composition comprises:
• Human immunoglobulin G concentrated at about 250g / L;
• the pH of the composition being preferably between 4.2 and 5.5.
• composition comprises
• composition comprises
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one sugar or a sugar derivative and at least one surfactant, characterized in that the concentration of immunoglobulins G is at least 230 g / l.
• the concentration of immunoglobulin G is at least about 250 g / l and the composition comprises an amino acid, a sugar and a surfactant, the pH of the solution being between 4.2 and 5.5.
• an immunoglobulin G composition comprising at least one sugar or a sugar derivative and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g / l.
• the concentration of immunoglobulin G is at least 250g / L and the composition comprises a sugar and a surfactant.
• composition described here comprises:
• the invention provides an immunoglobulin G composition comprising at least one amino acid, at least one salt and at least one surfactant, characterized in that the immunoglobulin G concentration is at least 230 g / ml. 1.
• the concentration of immunoglobulin G is 270 g / L and the composition comprises an amino acid, a salt and a surfactant.
• the composition comprises:
• acetate buffer sodium acetate / acetic acid
• the only excipients of the IgG composition according to the invention are said amino acids, salt and surfactant (preferably of the nonionic detergent type).
• Such an IgG composition consisting exclusively of these excipients (in addition to IgG) has the advantage of offering good stability, good compatibility and good local tolerance of the IgG compositions as well as a reduction in the durations and the costs of preparation on an industrial scale by the presence of a minimum effective number of excipients and the presence of a minimum effective amount of excipients
• the IgG composition of the invention is useful in therapy, and especially in injectable form, not only intravenously, but more interestingly, subcutaneously or intramuscularly.
• the subcutaneous route for the treatment of chronic autoimmune diseases has several advantages such as improving patient comfort and reducing side effects.
• Subcutaneous administration does not require venous access, which is, in some cases, a decisive advantage when the absence of venous access blocks access to treatment, especially for young children.
• subcutaneous immunoglobulins also reduces some of the side effects associated with intravenous infusions, particularly the risk of systemic reactions. Large changes in circulating levels observed intravenously are avoided, allowing a better regulation of the serum level in the physiological range between infusions.
• SCIG subcutaneous immunoglobulins
• IVIG intravenous immunoglobulins
• IgSC IgSC for home treatment
• It offers more flexibility and independence to the patient, improving the quality of life of patients.
• Increasing the concentration contributes to patient comfort by reducing the frequency of injection.
• the concentration of the IgSC is a defining characteristic that conditions the injection volume and number of injection sites and consequently the frequency of administration.
• the IgG composition of the invention in liquid form after storage for a period of 6 months at 25 ° C. has a level of polymers well below the standards set by the European Pharmacopoeia (3%), advantageously less than about 1%.
• composition of the invention may be a pharmaceutical composition, that is to say adapted for a therapeutic use.
• the pharmaceutical composition of the invention is thus useful as a medicament, especially in order to treat primitive immunodeficiency deficiency with lack of antibody production, Kawasaki disease, immunological thrombocytopenic purpura in children and adults, deficits secondary immune systems with defective antibody production, particularly chronic lymphocytic leukemia or myeloma associated with recurrent infections, HIV infection of the child with bacterial infections, multifocal motor neuropathies, Guillain-Barré syndrome, severe acute or chronic Parvovirus infections B19, acquired or constitutional immunodeficiency, corticosteroid-resistant dermatomyositis, acute myasthenia, idiopathic chronic polyradiculoneuropathy, immune thrombocytopenic purpura, for example associated with HIV infection, stiff man syndrome (Stiffman Syndrome) ), autoimmune neutropenia, resistant autoimmune erythroblastopenia, autoantibody-acquired anticoagulation syndrome, rheumatoid arthritis, uveitis.
• Example 1 Preparation of 25% IgG compositions.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• IgG 150 mM of glycine and 50 mM of NaCl are added to the IgG composition and the preformulated IgG solution is subjected to a tangential ultrafiltration on a cassette at a pH of between 4.6 and 5. This gives a composition of IgG formulated and concentrated at 250 g / L.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• An IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365. 200 mM proline are added to the IgG composition obtained and the preformulated IgG composition is subjected to a tangential ultrafiltration on a cassette at a pH between 4.6 and 5. 200 ppm of tween 80 are then added and the IgG composition formulated and concentrated at 250 g / L.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• IgG composition 150 mM glycine and 50 mM acetate buffer (25 mM sodium acetate and 25 mM acetic acid) were added to the resulting IgG composition and the preformed IgG composition was subjected to tangential ultrafiltration on a pH cassette. between 4.6 and 5. Then 200 ppm of poloxamer is added and the IgG composition formulated and concentrated at 250 g / L is obtained.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• 150 mM proline and 50 mM acetate buffer (25mM sodium acetate and 25mM acetic acid) were added to the IgG composition obtained and the preformulated IgG composition was subjected to tangential ultrafiltration on a pH cassette. between 4.6 and 5. Then 200 ppm tween 80 is added and thus obtained the composition of IgG formulated and concentrated at 250 g / L.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• 250 mM arginine and 5 ppm tween 80 are added to the IgG composition and the preformed IgG composition is subjected to a tangential ultrafiltration on a cassette at a pH between 6.8 and 7.8. Then 195 ppm tween 80 is added and thus the IgG composition formulated and concentrated at 250 g / L is obtained.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365. 200 mM glycine and 50 mM acetate buffer (25 mM sodium acetate and 25 mM acetic acid) were added to the IgG composition, and the preformed IgG composition was subjected to tangential ultrafiltration on a pH cassette. between 4.5 and 5 is then added 200 ppm tween 80 and the composition of IgG formulated and concentrated to 250 g / L.
• IgG composition was obtained according to the method developed by the Applicant in International Patent Application WO2007 / 077365.
• 250 mM of glycine are added to the IgG composition obtained and the preformulated IgG composition is subjected to a tangential ultrafiltration on a cassette at a pH between 4.5 and 5.5. Then 200 ppm of tween 80 is added and the IgG composition formulated and concentrated at 250 g / L.
• Protein aggregates or exogenous particles larger than about 50 ⁇ are visible to the naked eye.
• the flasks are placed under a white light beam by 3 different operators who note the presence or absence of visible particles. 2.1.2. Subvisible particles
• the obscuration method Light Obscuration; on camera Model LS-200 Particles Measuring Systems Inc.
• DLS makes it possible to measure the hydrodynamic diameters of the proteins and aggregates present in solution. This measurement makes it possible to follow aggregation phenomena at early stages of formation, since accessible sizes range from nanometer to micron.
• the measurement was made using the ALV ALV / CGS-3 Compact Goniometer System at a 90 ° angle.
• 0.04M NaCl have been added to all solutions to maintain sufficient ionic strength and allow consistent size measurement.
• the level of the polymers detected is below the standards imposed by the pharmacopoeia ( ⁇ 3) for all the compositions.
• the level of fragmentation is comparable to the 10% IgG reference product.
• the local tolerance study involved three animals treated by simultaneous subcutaneous administration of the F4 composition, 10% IgNG, Subcuvia® (160g / L or 16% IgG, Baxter) and formulation buffer. glycine-acetate-tween 80 at a flow rate of 10 ml / h. The infusion volume was set at 10 ml. A 27 G needle was used. To avoid injection site bias, the injection sites were randomized from one animal to another. Results:

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• 2010
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