WO2017057644A1 - Formulation liquide contenant une concentration élevée en anticorps - Google Patents

Formulation liquide contenant une concentration élevée en anticorps Download PDF

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Publication number
WO2017057644A1
WO2017057644A1 PCT/JP2016/078942 JP2016078942W WO2017057644A1 WO 2017057644 A1 WO2017057644 A1 WO 2017057644A1 JP 2016078942 W JP2016078942 W JP 2016078942W WO 2017057644 A1 WO2017057644 A1 WO 2017057644A1
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Prior art keywords
liquid preparation
recombinant monoclonal
amino acid
monoclonal antibody
histidine
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PCT/JP2016/078942
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English (en)
Japanese (ja)
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龍 奥脇
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持田製薬株式会社
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    • 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
    • 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
    • A61K47/16—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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • the present invention relates to a liquid preparation containing a high concentration antibody.
  • Recombinant monoclonal antibodies such as tocilizumab are currently used as active ingredients in pharmaceuticals.
  • the dose of the recombinant monoclonal antibody per administration may be large.
  • the amount of injection when using a preparation for subcutaneous injection capable of self-injection, the amount of injection once There are limitations. Therefore, it may be necessary to increase the concentration of the recombinant monoclonal antibody contained in the preparation.
  • Patent Document 1 a pharmaceutical formulation containing a specific amount of arginine, methionine, polysorbate
  • Patent Document 2 a pharmaceutical formulation containing a specific amount of arginine hydrochloride, histidine, polysorbate
  • the content of the recombinant monoclonal antibody is 150 mg / mL or more
  • the content of amino acid components such as arginine is 100 mM or more.
  • the present invention is a stable high-concentration recombinant monoclonal antibody liquid preparation that achieves dimer formation suppression and deamidation suppression during long-term storage, and also exhibits high-concentration recombination that exhibits kinematic viscosity that enables subcutaneous injection
  • An object is to provide a liquid preparation containing a monoclonal antibody at low cost.
  • the present invention is as follows. ⁇ 1> High-concentration recombination containing 150 mg / mL to 200 mg / mL recombinant monoclonal antibody and 45 mM to 94 mM amino acid component having a histidine component of less than 5 mM and a pH of 5.5 to 6.7 Monoclonal antibody-containing liquid preparation. ⁇ 2> The liquid preparation according to ⁇ 1>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride and methionine.
  • ⁇ 3> The liquid formulation according to ⁇ 1> or ⁇ 2>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.
  • ⁇ 4> The liquid preparation according to any one of ⁇ 1> to ⁇ 3>, comprising an amino acid component of 75 mM to 93 mM.
  • ⁇ 5> The liquid preparation according to any one of ⁇ 1> to ⁇ 4>, containing 90 mM amino acid component.
  • ⁇ 6> The liquid preparation according to any one of ⁇ 1> to ⁇ 5>, wherein the pH is 5.8 to 6.4.
  • ⁇ 7> The liquid preparation according to any one of ⁇ 1> to ⁇ 6>, wherein the pH is 6.0 to 6.2.
  • ⁇ 8> The liquid preparation according to any one of ⁇ 1> to ⁇ 7>, comprising 170 mg / mL to 190 mg / mL recombinant monoclonal antibody.
  • ⁇ 9> The liquid preparation according to any one of ⁇ 1> to ⁇ 8>, which contains 180 mg / mL recombinant monoclonal antibody.
  • ⁇ 10> The liquid preparation according to any one of ⁇ 1> to ⁇ 9>, further containing a polyol.
  • Recombinant monoclonal antibodies are tocilizumab, trastuzumab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab, rituximab At least one liquid selected from the group consisting of canakinumab, denosumab, mogamulizumab, ofatumumab, pertuzumab, trastuzumab emtansine, brentuximab vedotin, natalizumab, n
  • the present invention is a stable high-concentration recombinant monoclonal antibody liquid preparation that realizes dimer formation inhibition and deamidation inhibition during long-term storage, and has a high concentration that exhibits kinematic viscosity that enables subcutaneous injection.
  • a liquid preparation containing a recombinant monoclonal antibody can be provided at low cost.
  • a liquid preparation containing a high-concentration recombinant monoclonal antibody in the present invention (hereinafter also referred to as “liquid preparation”) comprises a recombinant monoclonal antibody of 150 mg / mL to 200 mg / mL and 45 mM to 94 mM having a histidine component of less than 5 mM.
  • the amino acid components (total) are contained, and the pH is 5.5 to 6.7.
  • the liquid preparation may contain other components.
  • the liquid preparation in the present invention contains an amino acid component of 45 mM to 94 mM in which the histidine component is less than 5 mM, and the pH is adjusted to the range of 5.5 to 6.7, and as high as 150 mg / mL to 200 mg / mL. Even if it contains a recombinant monoclonal antibody at a concentration, it has the effect of suppressing dimer formation and deamidation during long-term storage in liquid formulations, and exhibiting kinematic viscosity that enables subcutaneous injection Can be played.
  • the liquid preparation in the present invention contains a low-dose amino acid component of 45 mM to 94 mM amino acid component, it can be provided at a lower cost than conventional liquid preparations containing a high concentration recombinant monoclonal antibody.
  • a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the unit of molar concentration is M (molar), and mM is 10 ⁇ 3 mol / L.
  • long-term storage includes, for example, storage at 2 ° C. to 8 ° C. for 1 year or longer, preferably storage at 2 ° C. to 8 ° C. for 2 years or longer, more preferably 2 It can be stored for 2 to 3 years at -8 to 8 ° C.
  • a recombinant monoclonal antibody is an antibody produced by cells transformed by applying recombinant DNA technology.
  • the recombinant monoclonal antibody is preferable if it is expressed or secreted in animal cells, but the type of the recombinant monoclonal antibody is not particularly limited.
  • a recombinant monoclonal antibody that can be used as a pharmaceutical is preferable.
  • Recombinant monoclonal antibodies that can be contained in the liquid preparation of the present invention include not only recombinant monoclonal antibodies derived from animals such as humans, mice, and rats, but also recombinant monoclonal antibodies such as chimeric antibodies and humanized antibodies.
  • the immunoglobulin class of the antibody is not particularly limited, and any class such as IgG such as IgG1, IgG2, IgG3, and IgG4, IgA, IgD, IgE, and IgM may be used.
  • Recombinant monoclonal antibodies include antibody fragments such as Fv, Fab, F (ab) 2, and monovalent or bivalent or more single-chain Fvs (variable regions of antibodies bound by a linker such as a peptide linker). scFv, sc (Fv) 2 , Diabodies such as scFv dimer) and the like are also included. These recombinant monoclonal antibodies can be prepared according to the methods described in International Publication No. 92/019759 and International Publication No. 2005/090405.
  • Examples of the recombinant monoclonal antibody include, but are not limited to, for example, trastuzumab, rituximab, palivizumab, infliximab, basiliximab, gemtuzumab ozogamicin, bevacizumab, ibritumomab tiuxetane, tocilizumab, adalimumab, , Ranibizumab, Omalizumab, Eculizumab, Panitumumab, Usutekinumab, Golimumab, Kanakinumab, Denosumab, Mogamulizumab, Offatumumab, Pertuzumab, Trastuzumab Emtansin, Brentuximab, Beduminumab
  • Recombinant monoclonal antibodies include tocilizumab, trastuzumab, rituximab, paclitumumab, infliximab, infliximab, basiliximab, bevacizumab, adalimumab, cetuximab, ranibizumab, omalizumab, eculizumab, panitumabum , Nivolumab, alemtuzumab, secukinumab, ramcilumab or ipilimumab are preferred, trastuzumab, tocilizumab, infliximab, bevacizumab, adalimumab, ustekinumab, golimumab or denosumab, more preferred tocilizumab, infliximab, infliximab, infliximab
  • tocilizumab is most preferred as the recombinant monoclonal antibody.
  • Tocilizumab has only to have the same amino acid sequence as the amino acid sequence (Gln1-Gly448) and L chain amino acid sequence (Asp1-Cys214) of Actemra (registered trademark), which are generally commercially available.
  • the amino acid sequence of Actemura H chain (Glu1-Gly448) and L chain amino acid sequence (Asp1-Cys214) are described in the sequence listing attached to International Publication No. 2005/090405.
  • the N-terminal residue of the H chain may be pyroglutamic acid (pGlu) instead of glutamic acid.
  • the C-terminal residue of the H chain may be up to 447 proline (Pro) instead of the 448 amino acid residue, or 449 amino acid residue in which lysine (Lys) is added to the 448th glycine (Gly). Also good.
  • the liquid preparation in the present invention contains 150 mg / mL to 200 mg / mL recombinant monoclonal antibody. Further, from the viewpoint that the effects of the present invention can be sufficiently exerted, it is preferable to contain 170 mg / mL to 190 mg / mL recombinant monoclonal antibody, and more preferably 180 mg / mL recombinant monoclonal antibody.
  • the recombinant monoclonal antibody used in the present invention is preferably not lyophilized or reconstituted in the production method.
  • the liquid preparation in the present invention contains an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM.
  • the amino acid component other than the histidine component is not limited in type, but examples include arginine, arginine hydrochloride, methionine, glycine, phenylalanine, aspartic acid, glutamic acid, lysine, asparagine, tryptophan, cysteine and cysteine hydrochloride. Can be mentioned.
  • the amino acid component other than the histidine component is preferably at least one selected from the group consisting of arginine, arginine hydrochloride and methionine.
  • the amino acid component other than the histidine component preferably contains arginine, arginine hydrochloride and methionine, and more preferably contains arginine hydrochloride and methionine.
  • the histidine component is preferably at least one selected from the group consisting of histidine and histidine hydrochloride, and more preferably histidine and histidine hydrochloride.
  • the liquid preparation in the present invention may be any liquid preparation that contains less than 5 mM histidine, but preferably contains 1 mM or more and 4 mM or less histidine component from the viewpoint that the pH can be adjusted to a preferred range. More preferably, it contains a histidine component of 2 mM or more and 4 mM or less.
  • amino acid component it is preferable to contain an amino acid component of 45 mM to 94 mM in which the histidine component is less than 5 mM in the liquid preparation. Further, it preferably contains 75 mM to 93 mM amino acid components, more preferably 90 mM amino acid components.
  • the liquid preparation may further contain a polyol.
  • the polyol include propylene glycol, glycerin (glycerol), threose, threitol, erythrose, erythritol, ribose, arabinose, arabitol, lyxose, maltitol, sorbitol, sorbose, glucose, mannose, mannitol, levulose, dextrose, maltose, Examples include trehalose, fructose, xylitol, inositol, galactose, xylose, fructose, sucrose, and 1,2,6-hexanetriol.
  • sucrose As the polyol, sucrose, trehalose and the like are preferable, and sucrose is most preferable.
  • the liquid preparation may contain one or a combination of two or more of these polyols.
  • content of an amino acid component less than 70 mM, it is preferable to use combining a polyol from a viewpoint of dimer production
  • the content of the polyol is not particularly limited, and may be appropriately determined from the viewpoint of isotonicity of the liquid preparation. For example, it may be 30 mg / mL to 80 mg / mL, 40 mg / mL to 70 mg / mL, 50 mg / mL to 60 mg / mL.
  • the liquid formulation may contain other components necessary for formulating the liquid formulation.
  • a solubilizing agent for example, an isotonic agent, a preservative, an adsorption inhibitor, a sulfur-containing reducing agent, an antioxidant, preferably a solubilizing agent may be contained.
  • solubilizer examples include surfactants, particularly nonionic surfactants, specifically, polyoxyethylene hydrogenated castor oil, polysorbate (polysorbate 80, polysorbate 40, polysorbate 20, etc.), polyoxyethylene sorbitan mono Examples include laurate, castor oil fatty acid ethyl ester, and nicotinic acid amide.
  • isotonic agent examples include salts such as sodium chloride, potassium chloride, calcium chloride in addition to polyol.
  • preservative examples include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, sorbic acid, phenol, cresol, metacresol, and chlorocresol.
  • adsorption inhibitor examples include human serum albumin, lecithin, dextran, hydroxypropylcellulose, methylcellulose, and macrogol.
  • sulfur-containing reducing agent examples include N-acetylcysteine, N-acetylhomocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, and glutathione. Can be mentioned.
  • antioxidants examples include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, ⁇ -tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbyl palmitate, L-ascorbic acid stearate, sodium bisulfite Sodium sulfite, triamyl gallate, propyl gallate, disodium ethylenediaminetetraacetate (EDTA ⁇ 2Na), sodium pyrophosphate, sodium metaphosphate.
  • the pH of the liquid formulation is 5.5 to 6.7.
  • the pH is preferably 5.8 to 6.4, more preferably 6.0 to 6.2, from the viewpoint of adjusting the kinematic viscosity of the liquid preparation to the extent that subcutaneous injection is possible.
  • the pH can be measured by, for example, a pH meter (model number: HM-30G, manufactured by Toa DKK Corporation).
  • the pH may be measured according to the method described in the 16th revised Japanese Pharmacopoeia, for example, at room temperature (15 ° C. to 25 ° C.).
  • the pH of a liquid formulation can be adjusted with the histidine component contained in a liquid formulation, the pH of a liquid formulation can also be adjusted using another buffer as needed.
  • buffering agents include, for example, phosphate (sodium or potassium), sodium bicarbonate, citrate (sodium or potassium), sodium acetate, sodium oxalate, phosphoric acid, carbonic acid, citric acid, succinic acid, apple Examples include acids, gluconic acid, and glycine.
  • the liquid preparation in the present invention can be administered, for example, by injection (subcutaneous injection, intravenous injection, intramuscular injection, etc.), transdermal, transmucosal, nasal, or transpulmonary.
  • subcutaneous injection is performed, the dose of recombinant monoclonal antibody per administration is as large as 150 mg / mL to 200 mg / mL, but the amount of injection solution is limited.
  • the liquid preparation in the present invention exhibits kinematic viscosity that enables subcutaneous injection even when it contains a recombinant monoclonal antibody at a high concentration of 150 mg / mL to 200 mg / mL.
  • the liquid preparation in the present invention is preferably used for subcutaneous injection from the viewpoint that the effects of the present invention can be achieved.
  • Subcutaneous injection is not only performed by doctors and other specialists as medical professionals, but may also be performed by the patient himself. Depending on the ethnic group and region, many patients are concerned about self-injection. It is preferable that the viscosity is low and the stability over time is excellent.
  • the kinematic viscosity of the liquid preparation in the present invention is preferably 6 mm 2 / s to 15 mm 2 / s, more preferably 7 mm 2 / s to 14 mm 2 / s, and more preferably 8 mm 2 / s to 12 mm 2 immediately after liquid preparation preparation. / S is more preferable.
  • the kinematic viscosity may be measured with an Ubbelohde viscometer (16th revision Japanese Pharmacopoeia General Test Method 2.53 Viscosity Measurement Method Method 1).
  • the dimer product and the low molecular weight decomposition product can be measured by size exclusion chromatography using, for example, a high performance liquid chromatograph system (Prominence, manufactured by Shimadzu Corporation).
  • the deamidated substance can be measured by ion exchange chromatography using, for example, a high performance liquid chromatograph system (Prominence, manufactured by Shimadzu Corporation).
  • Example 1 Confirmation of stabilization effect of liquid preparation
  • a liquid preparation containing a high concentration of recombinant monoclonal antibody (180 mg / mL as tocilizumab) contains 94 mM amino acid component and has a pH of 5.5 to 6.7. The effect on the stabilization of the formulation was evaluated.
  • 1-No. Five evaluation samples were prepared. The prescription of each evaluation sample is as follows. Note that “-” in the compositions in Tables 1 and 5 indicates not blended.
  • tocilizumab used in the examples should be prepared according to the methods described in International Publication No. 92/0197759, International Publication No. 2005/090405, International Publication No. 99/063058, and International Publication No. 2002/072615. Can do.
  • the evaluation sample was diluted with a mobile phase so that the protein concentration became 1 mg / mL, and used as an evaluation sample solution.
  • the evaluation results of the size exclusion chromatography method obtained in this example are shown in Table 2, the evaluation results of the ion exchange chromatography method are shown in Table 3, and the kinematic viscosity evaluation results are shown in Table 4.
  • the formulation containing 94 mM amino acid component and adjusted to pH 6 had a total amount of amino acids and a small content of histidine component, but at 60 ° C. for 2 weeks, 50 ° C.
  • the evaluation samples No. 1 and No. 2 in which the amount of the high molecular fraction and the low molecular fraction are large in both the total amount of amino acids and the content of the histidine component are used. It was comparable to 1.
  • the evaluation sample No. 5 shows that the increase in the acidic fraction containing the deamidated product in the ion-exchange chromatography method was evaluated sample No.
  • evaluation sample No. 2 adjusted to pH 5
  • evaluation sample No. 3, 3 and 4 adjusted to pH 6.8
  • evaluation sample No. of the polymer fraction containing the dimer Since an increasing tendency was observed as compared to 5, and an increasing tendency was also observed in the acidic fraction containing the deamidated substance, it was revealed that the pH range was an important management item. From the evaluation results of the formulation (evaluation sample No. 3 and 4) comparing the presence or absence of histidine addition, it is clear that the histidine component is an important component from the point of adjusting the pH of the liquid preparation to the expected pH range became. In addition, evaluation sample No. The kinematic viscosity of No.
  • Example 2 Confirmation of stability effect when content of amino acid component is further reduced Stabilizing effect for liquid preparation containing recombinant monoclonal antibody (180 mg / mL as tocilizumab) when content of amino acid component is further reduced below 94 mM Evaluated.
  • evaluation sample No. 6-1 to No. 8 was prepared. The prescription of each evaluation sample is as follows.
  • the evaluation results of the size exclusion chromatography method obtained in this example are shown in Table 6, the evaluation results of the ion exchange chromatography method are shown in Table 7, and the kinematic viscosity evaluation results are shown in Table 8.
  • each formulation was compared with the evaluation sample (evaluation sample No. 1) in which the amino acid component concentration shown in Example 1 had an amino acid content higher than 94 mM.
  • evaluation sample No. 1 the evaluation sample in which the amino acid component concentration shown in Example 1 had an amino acid content higher than 94 mM.
  • the preparation of the present invention is a stable high-concentration recombinant monoclonal antibody liquid preparation that realizes suppression of dimer formation and deamidation during long-term storage, and also exhibits high kinematic viscosity that enables subcutaneous injection Since a liquid preparation containing a recombinant monoclonal antibody can be provided at low cost, it is highly industrially useful.

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Abstract

La présente invention peut fournir, à faibles coûts, une formulation liquide contenant une concentration élevée en anticorps monoclonaux recombinés comprenant de 150 mg/mL à 200 mg/mL d'anticorps monoclonaux recombinés, et de 45 mM à 94 mM d'un constituant d'acides aminés dans lequel le constituant histidine est présent en une concentration inférieure à 5 mM, et ayant un pH de 5,5 à 6,7. Ladite formulation liquide contenant une concentration élevée d'anticorps monoclonaux recombinés est stable, permet d'obtenir une génération limitée de dimères et une déamidation limitée pendant un stockage à long terme, et présente une viscosité cinématique qui lui permet d'être injectée de manière sous-cutanée.
PCT/JP2016/078942 2015-09-30 2016-09-29 Formulation liquide contenant une concentration élevée en anticorps WO2017057644A1 (fr)

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WO2018179138A1 (fr) * 2017-03-29 2018-10-04 持田製薬株式会社 Préparation de liquide contenant des anticorps
CN110831621A (zh) * 2017-04-18 2020-02-21 雷迪博士实验室有限公司 稳定的液体药物组合物
JP2020528894A (ja) * 2017-07-27 2020-10-01 アレクシオン ファーマシューティカルズ， インコーポレイテッド 高濃度抗ｃ５抗体製剤

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TW202033216A (zh) * 2018-11-16 2020-09-16 南韓商三星Ｂｉｏｅｐｉｓ股份有限公司 包含蛋白質的穩定液體組成物

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Publication number Priority date Publication date Assignee Title
WO2018179138A1 (fr) * 2017-03-29 2018-10-04 持田製薬株式会社 Préparation de liquide contenant des anticorps
CN110831621A (zh) * 2017-04-18 2020-02-21 雷迪博士实验室有限公司 稳定的液体药物组合物
JP2020528894A (ja) * 2017-07-27 2020-10-01 アレクシオン ファーマシューティカルズ， インコーポレイテッド 高濃度抗ｃ５抗体製剤
JP7079844B2 (ja) 2017-07-27 2022-06-02 アレクシオン ファーマシューティカルズ， インコーポレイテッド 高濃度抗ｃ５抗体製剤
JP2022105625A (ja) * 2017-07-27 2022-07-14 アレクシオン ファーマシューティカルズ， インコーポレイテッド 高濃度抗ｃ５抗体製剤
JP7277649B2 (ja) 2017-07-27 2023-05-19 アレクシオン ファーマシューティカルズ， インコーポレイテッド 高濃度抗ｃ５抗体製剤

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