Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/06—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies from serum
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production

Definitions

• the invention relates to an immunoglobulin G composition
• an immunoglobulin G composition comprising mannitol, glycine and a nonionic detergent.
• IgG immunoglobulin G
• 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, anticoagulant syndrome ion acquired by autoantibodies, rheumatoid arthritis, etc.
• Stiffman syndrome stiff man syndrome
• IgG compositions usually conditioned at acidic pH and injectable intravenously, for example from human plasmas.
• IgGIV intravenous IgG injectable compositions
• IgGIV it is known that it is necessary to stabilize IgGIV to avoid in particular the formation of aggregates (oligomers and polymers) capable of activating the complement system with associated risks of reactions. Anaphylactic. Moreover, the presence of dimers in IgGIV has been correlated with decreases in blood pressure in vivo (Bleeker WK et al, Blood, 95, 2000, pp. 6-18 6 1). Other physicochemical degradations may also occur during the storage of IgG such as, among others, oxidation and hydrolysis.
• the stabilization of IgG thus requires the addition of compounds, conventionally chosen from sugars and amino acids, in order to obtain not only non-degraded IgG compositions suitable for therapeutic use but also IgG compositions exhibiting stability. increased during storage.
• Lyophilized IgGIV compositions are commercially available, for example under the trade names Polygam TM (American Red Cross), Gammar IV TM (Armor Pharmaceutical Company) and Venoglobulin TM! (Alpha) containing stabilizers as 2% glucose, 5% sucrose and 2% D-mannitol respectively.
• liquid IgGIV compositions include specific stabilizers different from those used for the corresponding freeze-dried form.
• liquid compositions of IgGIV which contain, as stabilizers, 10% maltose, glycine of 0.16 to
• D-sorbitol 0.24 M and 5% D-sorbitol are respectively known under the brand names Octagam TM (Octapharma), Gamunex TM 10% (Talecris) and Venoglobulin TM (Alpha).
• Vigam Liquid solution is conditioned at an acidic pH (pH 5) which has the disadvantage of transforming, by hydrolysis, sucrose into reducing sugars (fructose and glucose) that condense with the amino residues of lysine of IgG and albumin to give an unstable Schiff base evolving into Maillard products (browning of the solution). It is of course not satisfactory to use excipients which evolve during the preservation of IgG because control of the reaction is not possible once it is initiated.
• the Applicant has developed a unique stabilizing formulation, which stabilizes both the liquid and lyophilized forms of IgG.
• a particularly effective formulation for stabilizing the immunoglobulin compositions is described in the international patent application WO 2004/091656 filed by the Applicant.
• This patent application discloses a composition containing 50 g / l of IgG, 50 g / l of mannitol, 10 g / l of glycine and 50 ppm of detergent, 50 ppm of detergent corresponds to a concentration of 50 mg / l of detergent .
• the excipients of IgG compositions can induce more or less important side effects. These side effects are often due to the excipients themselves which may be responsible, for example, for allergic reactions.
• the quantity of excipient administered to the patient will be 15 g of mannitol, 3 g of glycine. and 15 mg of detergent.
• 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 in the treated patient. This is undesirable and strictly controlled from the regulatory point of view.
• concentration of excipients must generally also be increased. This increase in excipient concentration stabilizes the IgG composition. Indeed the excipients have a stabilizing function and their amount is generally correlated to the amount of active ingredient, especially when the active ingredient is an immunoglobulin.
• the invention relates to an immunoglobulin G composition
• an immunoglobulin G composition comprising mannitol, glycine and a nonionic detergent characterized in that the concentration of immunoglobulin G is 100 g / l ⁇ 20 g / l.
• composition according to the invention comprising 100 g / l ⁇ 20 g / l of immunoglobulin G can also be called "composition of 10% IgG".
• the composition according to the invention is characterized by a concentration of immunoglobulins G of 100 g / L ⁇ 20 g / l, that is to say that the composition according to the invention may have a concentration of immunoglobulin G of between 80 g. / l and 120 g / l.
• the composition according to the invention has a concentration of immunoglobulins G of 100 g / l ⁇ 10 g / l, preferably 100 g / l ⁇ 5 g / l, preferably 100 g / l.
• Glycine formerly known as glycine or aminoacetic acid, is the simplest amino acid.
• the glycine concentration of the composition according to the invention is between 4 g / l and 10 g / l.
• Mannitol or 1, 2,3,4,5,6-hexanehexol is a polyol or "sugar-alcohol" similar to xylitol or sorbitol.
• Manitol was chosen by the Applicant on stability criteria at acidic pH conditioning IgG compositions, which avoids Maillard reactions on immunoglobulin G, on pharmaceutical compatibility criteria and on criteria relating to their stabilizing action of immunoglobulin compositions in liquid form.
• in mannitol sufficient to stabilize the composition according to the invention is less than or equal to 50 g / l.
• the mannitol concentration of the composition according to the invention is between 20 g / l and 50 g / l. All forms of mannitol can be used.
• a suitable nonionic detergent used in the composition according to the invention is advantageously chosen from Tween®80 or polysorbate 80 (polyoxyethylenesorbitan monooleate), Tween®20
• Nonionic detergents can also be combined with each other.
• the detergent is present at a concentration of between 20 and 100 mg / l, preferably between 30 and 60 mg / l, preferably between 40 and 60 mg / l and preferably between 40 and 50 mg / l.
• the detergent is polyoxyethylene sorbitan monooleate (polysorbate 80).
• composition of the invention comprises, or is preferably composed of:
• polysorbate 80 50 mg / l of polyoxyethylene sorbitan monooleate (polysorbate 80).
• composition of the invention has a pH of 4.6 ⁇ 0.2.
• the 10% IgG composition according to the invention may comprise, in addition to mannitol, glycine and a nonionic detergent, at least one other additive.
• This additive can also represent a compound chosen from among the various categories of stabilizers conventionally used in the technical field of the invention, such as surfactants, sugars and amino acids, that an excipient added to the formulation to adjust, for example, pH, ionic strength, etc.
• the 10% IgG composition according to the invention does not comprise other excipients than said mannitol, glycine and nonionic detergent.
• Such a 10% IgG composition consisting exclusively of these three compounds according to the invention has the advantage of offering good stabilization of the 10% IgG compositions and a reduction in the times and costs of preparation on the scale. by the presence of a minimum effective number of excipients and the presence of a minimum effective amount of excipients.
• composition according to the invention is advantageously in liquid form.
• liquid IgG compositions mean aqueous solutions of polyclonal IgG compositions directly obtained by fractionation of human plasma.
• the aqueous medium represents water for injection (PPI water) which can 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 (Rev.Fr. et.Clin, and Biol., XIV, 1054, 1969) and in WO 94/9334, these documents are 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 10% IgG composition of the invention in liquid form and / or in freeze-dried form may also be for therapeutic use and in particular injectable intravenously, parenterally or subcutaneously.
• the 10% IgG composition of the invention, in liquid form after storage for a period of 6 months at 5 ° C. or 25 ° C. has a level of polymers well below the standards set by the European Pharmacopoeia (3). %), preferably less than about 0.3%.
• composition of the invention may be a pharmaceutical composition, that is to say adapted for a therapeutic use.
• Figure 1 is a graph showing the measurement of turbidity on stressed and unstressed test compositions.
• FIG. 2 is a graph showing the percentage of anti-HBs activity of the batches during the 6 months of stability at the 2 storage temperatures relative to TO.
• FIG. 3 is a graph showing the anti-complementary activity of the solutions following stress of agitation or without stress (NS) as a function of the dose of detergent added.
• Example I Preparation of the 10% IgG compositions to be tested
• IgG composition was obtained according to the method developed by the Applicant in the international patent application WO 2007/077365 or WO 02/092632. This composition, containing approximately 100 g / l of IgG (10% IgG), is adjusted to a pH of between 4.6 and 4.8.
• Example 1 The compositions of Example 1 (F1, F2 and F3) are then subjected to various tests of heat stress, agitation and oxidation.
• the oxidation stress is carried out on 10 ml samples of test solution placed in 30 ml glass vials. Hydrogen peroxide (H2O2) is added to each sample in order to obtain a final concentration of [H2O2] equal to 9 mM. After capping and homogenization of the flasks, they are incubated for 1 h at 25 ° C.
• H2O2 Hydrogen peroxide
• Example 1 Each of the compositions of Example 1 (F1, F2 and F3) is subjected or not to stress as defined in Example 2.
• a measurement of the turbidity is carried out on each sample. The lower the measured turbidity values, the more stable the IgG solutions are to the applied stress.
• Example 4 Measurement of anti-complementary activity (AAC) (Method 2.6.17 of the European Pharmacopoeia) The compositions F1, F2 and F3, stressed or not, are subjected to the AAC test (Method 2.6.17 of the European Pharmacopoeia) before and after each stress as described in Example 2.
• AAC anti-complementary activity
• This test describes the ability of immunoglobulins to activate the complement system, a too powerful activation of complement that can affect the tolerance of the product during its injection.
• the oxidized solutions were not given to analyze, the presence of oxygenated water disrupting the assay.
• Table 3 presents the AAC of the before and after stress solutions.
• Example 1 Each of the compositions of Example 1 (F1, F2 and F3) are subjected or not to stress as defined in Example 2. It is then observed through a pharmacopoeia mireuse (Method 2.9.20 of the European Pharmacopoeia ) the visual appearance of each of the samples. The visual appearance makes it possible to detect the presence of particles of large sizes in the composition. The appearance of such particles reflects a denaturation of the protein solution.
• Table 4
• Example 1 Each of the compositions of Example 1 (F1, F2 and F3) are subjected or not to stress as defined in Example 2.
• the samples are then analyzed in a device measuring the particle size by dynamic light scattering. (Malvern nanosizer).
• the apparatus makes it possible to measure the radiation intensity of stokes emitted by particles of size between 0.6 nm and 6 ⁇ m.
• the particles> 100 nm correspond to the aggregates of proteins.
• Table 4 shows the intensity recorded for each sample for particles of size> 100 nm (and ⁇ 6 ⁇ m).
• composition F3 of Example 1 The formulation of the batches is practically as defined in the composition F3 of Example 1, that is to say at a final protein concentration of 100 g / l, in mannitol of 32 g / l, in glycine of 7 g. and polysorbate 80 of 40 + 5 mg / l.
• Turbidity, AAC, integrity of the Fc function, pKa and kallikrein contents and visual appearance for each lot LL01, LL02 and LL03 over time Turbidity, appearance, Fc function, pre-kallikrein and kallikrein contents are stable at 5 ° C and 25 ° C in the 3 lots and do not change significantly.
• Figure 2 gives a representation of the results obtained as a percentage of anti-HBs activity during the 6 months of stability at the two storage temperatures.
• the anti-HBs activity of the solutions at 25 ° C stability decreases from 1 month in the 3 batches to become non-compliant with the fixed internal specifications ( ⁇ 20%) for the LL01 and LL03, while the anti-HBs activity n does not evolve significantly at 5 ° C.
• This phenomenon of decrease of the anti-HBs activity is comparable to that observed on I 1 IgG 5% and is thus not related to the Ig concentration.
• a quantitative detergent study is performed to determine the optimal dose to ensure the stability of the product.
• a lower limit of 30 mg / l of polysorbate is therefore retained because the anticomplementary activity remains consistent for concentrations greater than 30 mg / l.
• Example 9 Stability of a formulation at 50 mg / l polysorbate 80
• polysorbate 80 50 mg / l of polyoxyethylene sorbitan monooleate (polysorbate 80). The pH is adjusted to 4.6 ⁇ 0.2.
• the three lots were stable at 5 ° C, the measured parameters being in accordance with the specifications of the European Pharmacopoeia after 18 months of storage.
• the three batches were stable at 25 ° C also, the measured parameters being in accordance with the specifications of the European Pharmacopoeia after 18 months of storage, only the rate of fragments showed an increase and the anti-HBs activity showed a decrease. , but which remains in conformity with the specifications of the European Pharmacopoeia.

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• 2008
  • 2008-12-30 FR FR0859117A patent/FR2940617B1/fr not_active Expired - Fee Related
• 2009
  • 2009-12-29 CA CA2771681A patent/CA2771681A1/fr not_active Abandoned
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