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WO2023011502A1 - Formulation stable comprenant un anticorps anti-il-4r - Google Patents

Formulation stable comprenant un anticorps anti-il-4r Download PDF

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Publication number
WO2023011502A1
WO2023011502A1 PCT/CN2022/109805 CN2022109805W WO2023011502A1 WO 2023011502 A1 WO2023011502 A1 WO 2023011502A1 CN 2022109805 W CN2022109805 W CN 2022109805W WO 2023011502 A1 WO2023011502 A1 WO 2023011502A1
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Prior art keywords
buffer
formulation
antibody
pharmaceutical preparation
polysorbate
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PCT/CN2022/109805
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English (en)
Chinese (zh)
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WO2023011502A9 (fr
Inventor
焦娇
王震
鲍志浩
李若微
黄燕飞
王茜
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Gan and Lee Pharmaceuticals Co Ltd
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Gan and Lee Pharmaceuticals Co Ltd
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Priority to CN202280043783.4A priority Critical patent/CN117693362A/zh
Publication of WO2023011502A1 publication Critical patent/WO2023011502A1/fr
Publication of WO2023011502A9 publication Critical patent/WO2023011502A9/fr
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    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present invention relates to a subcutaneous formulation of anti-IL-4R antibody, which is stable at room temperature for at least 6 months, and which can be administered subcutaneously to treat related diseases suitable for treatment with anti-IL-4R antibody.
  • Monoclonal antibody drugs are the fastest-growing industry in the field of biopharmaceuticals in recent years. Compared with chemical small molecule drugs, monoclonal antibody drugs have more complex physical and chemical properties, lower stability, and easy to form aggregates during storage. Changes in physical and chemical properties may cause changes in the immunogenicity of pharmaceutical active agents. Therefore, it is necessary to screen prescriptions based on the characteristics of monoclonal antibody drugs and develop appropriate preparations to ensure the safety, effectiveness and stability of protein drugs (see recombinant monoclonal antibody drugs). The role of the prescription of antibody drug preparations and related review points, Qiu Xiao, Luo Jianhui, Chinese Journal of New Drugs, Volume 28, Issue 16, 2019).
  • Protein formulations should help maintain the stability and bioactivity of the biopolymer during production, packaging, storage, and transportation until eventual delivery to the target site in the patient.
  • Intravenous delivery is usually high-dose or multi-dose, the injection time is relatively long, generally takes about 90 minutes or more, and intravenous delivery requires the assistance of personnel with medical knowledge and preliminary preparation procedures, so it is important for patients, doctors and medical staff It is inconvenient to say, and additional costs will be incurred.
  • Intramuscular injection generally has side effects such as tissue hardening and edema due to the small area of the injection site, so the injection volume should not be too large, generally considered to be no more than 20 ml, and the injection time should not be too long.
  • subcutaneous injection has the advantage of being able to be administered immediately and is convenient for patient self-administration, but compared with intravenous injection, the absorption rate is relatively low, and when the injection volume is 3-5 mL or more, it may be due to Absorbs slowly and causes swelling and pain at the injection site. For this reason, subcutaneous injection of protein therapeutics is usually limited to small injections of 2 mL or less of the solution.
  • the currently marketed anti-IL-4R antibody is mainly Sanofi’s dupilumab, and other clinical ones include AZD-1402 (Pieris Pharmaceuticals Inc, AstraZeneca plc), AK-120 (Akeso Biopharma Inc ), CM-310 (KeyMed Biosciences Co Ltd, CSPC Pharmaceuticals Group Limited).
  • Dupilumab is an interleukin-4 receptor alpha antagonist used to treat or prevent diseases such as atopic dermatitis, allergic asthma, chronic rhinosinusitis with nasal polyps and other conditions.
  • the anti-IL-4R antibody preparations on the market are suitable for subcutaneous injection, up to 2 mL can be injected once a week.
  • the existing preparation forms limit the single dosage of the drug, and the administration cycle is relatively short. Therefore, there is an urgent need to develop a new formulation that can reduce the number of administrations to patients and reduce the frequency of subcutaneous injections.
  • the problem to be solved by the present invention is to provide a stable pharmaceutical preparation containing a high concentration of anti-IL-4R antibody, which can be injected subcutaneously, and whose single injection volume is greater than 2ml, for example, the single injection volume is 3ml, 4ml, 5ml, 6ml, 7ml , 8ml, or larger volumes.
  • Subcutaneous injection is a classic micro-volume injection method, and the injection must enter the target site through the skin interstitium, and this structural macromolecule composed of collagen, elastin, fibronectin and hyaluronic acid (HA)
  • the composed skin stroma has a complex three-dimensional structure, which limits the diffusion rate and infusion volume of subcutaneous injection.
  • the inventors unexpectedly found that the anti-IL-4R antibody of the present invention and hyaluronidase can form a stable preparation, and the presence of hyaluronidase does not affect the activity of the antibody of the present invention, and the stable preparation can achieve the following Higher volumes are administered subcutaneously.
  • the present invention unexpectedly obtains a stable pharmaceutical formulation containing a high concentration of anti-IL-4R antibody, which can be used for subcutaneous injection, with a single dose exceeding 2 ml.
  • the first aspect of the present invention provides a pharmaceutical preparation comprising an anti-IL-4R antibody, which comprises the following components:
  • an anti-IL-4R antibody preferably, said antibody comprises a heavy chain variable region comprising SEQ ID NO: 1 and a light chain variable region comprising SEQ ID NO: 2; and
  • the pharmaceutical preparation further includes
  • said formulation has a pH of about 4.5 to about 7.5.
  • the pharmaceutical preparation further includes:
  • the formulation has a pH of about 4.5 to about 7.5.
  • the concentration of the antibody is from about 100 mg/ml to about 200 mg/ml, preferably from about 115 mg/ml to about 185 mg/ml, preferably from about 135 mg/ml to about 175 mg/ml, preferably from 150 mg/ml to About 175 mg/ml, more preferably about 150 mg/ml or 175 mg/ml.
  • the “mM” mentioned in the present invention is specifically “mmol/L”.
  • Hyaluronidase is an enzyme that degrades hyaluronic acid and reduces the viscosity of hyaluronic acid in the extracellular matrix, thereby increasing tissue permeability.
  • Enzyme activity of hyaluronidases, including rHuPH20, can be defined by units per ml (U/ml) or by total enzyme activity (U) in a particular formulation, as explained further below.
  • a standard definition of a unit of enzyme activity (U) is the amount of enzyme that catalyzes a defined amount of substrate reaction per unit of time, eg, one mole or nanomole of substrate per minute.
  • Techniques for determining the activity of hyaluronidase preparations are known in the art, and the activity of hyaluronidase is usually expressed in USP units or units, and the activity of hyaluronidase is represented by "U/ml" hereinafter .
  • Hyaluronidase activity refers to the ability of an enzyme to catalyze the cleavage of hyaluronan.
  • USP United States Pharmacopeia
  • hyaluronidase activity can be determined indirectly by measuring the remaining higher molecular weight hyaluronic acid after allowing the enzyme to react with HA for 30 minutes at 37°C , or the amount of hyaluronan substrate (see USP XXII-NFXVII (1990) 644-645United States Pharmacopeia Convention, Inc, Rockville, Md.).
  • a reference standard solution can be used in the assay to determine the relative activity (in units) of any hyaluronidase.
  • In vitro assays for determining the hyaluronidase activity of hyaluronidases such as rHuPH20 are known in the art and described herein.
  • the hyaluronidase is produced by recombinant DNA technology, derived from human samples or extracted from animal tissues.
  • the concentration of hyaluronidase rHuPH20 is about 1000U/ml-about 12000U/ml, preferably about 1000U/ml-about 10000U/ml, preferably about 2000U/ml-about 6000U/ml, preferably about 2000U /ml-about 4000U/ml.
  • the amount of hyaluronidase should be such that increased dispersion and absorption of dupilumab for use is possible.
  • the antioxidant is selected from at least one of methionine, ascorbic acid, citric acid, tartaric acid, or any other excipient for minimizing oxidation.
  • the antioxidant is methionine.
  • the concentration of the antioxidant is about 1 mM to about 50 mM, preferably about 5 mM to about 25 mM, preferably about 10 mM to about 20 mM, preferably about 10 mM, about 15 mM or about 20 mM.
  • the formulation has a pH of about 5.0 to about 7.5, preferably about 5.5 to about 7.0, preferably about 5.5 to about 6.5, preferably about 5.5 to 6.0, preferably about 5.5 to about 5.9.
  • the first buffer is selected from at least one of acetate buffer, histidine buffer, phosphate, citrate, boric acid, Tris buffer, HEPES, preferably histidine buffer liquid; and/or
  • the second buffer is selected from at least one of acetate buffer, histidine buffer, phosphate, citrate, boric acid, Tris buffer, HEPES, preferably acetate buffer;
  • the first buffer is different from the second buffer.
  • the concentration of the first buffer is about 1 mM to about 100 mM, preferably about 10 mM to about 50 mM, preferably about 15 mM to about 35 mM, preferably about 20 mM; and/or
  • the concentration of the second buffer is about 1 mM to about 100 mM, preferably about 5 mM to about 50 mM, preferably about 10 mM to about 20 mM, preferably about 12.5 mM.
  • the first buffer is a histidine buffer with a concentration of about 15mM to about 35mM, preferably about 20mM histidine buffer, and/or
  • the second buffer is an acetate buffer having a concentration of about 10 mM to about 20 mM, preferably about 12.5 mM.
  • the concentration of the salt ion enhancer is about 5mM-100mM, preferably about 5mM-50mM, more preferably about 5mM-25mM, even more preferably about 12.5mM.
  • the salt ion enhancer is sodium chloride or potassium chloride.
  • the concentration of the thermal stabilizer is about 100mM-about 300mM, preferably about 100mM-about 250mM, preferably about 150mM-about 250mM, preferably about 155mM-about 210mM.
  • the thermal stabilizer is at least one selected from sucrose, trehalose and mannitol, preferably sucrose or trehalose.
  • the organic co-solvent is selected from polysorbate 20, polysorbate 80, poloxamer, propylene glycol, Triton (polyethylene glycol octylphenyl ether), polyethylene glycol 3350 and dodecane
  • the organic co-solvent is polysorbate 20 or polysorbate 80, more preferably, the organic co-solvent is polysorbate 80.
  • the difference between polysorbate 20 and polysorbate 80 mainly lies in the structure of the fatty acid side chain, and the different length and degree of saturation of the fatty acid side chain lead to different affinity between polysorbate and protein.
  • the addition of organic co-solvents reduces the aggregation of proteins during stirring, shaking, freeze-thawing and freeze-drying, and prevents proteins from being adsorbed to the surface of the container.
  • polysorbate such as polysorbate 20
  • polysorbate 20 in a specific formulation can inhibit protein aggregation caused by shaking when it reaches a certain concentration.
  • polysorbate 20 lower than this concentration cannot reduce the protein instability caused by shaking (see the role of recombinant monoclonal antibody pharmaceutical preparations and related review points, Qiu Xiao, Luo Jianhui, Chinese Journal of New Drugs 2019 No. 28 Volume 16).
  • the organic co-solvent is in a concentration of about 0.05% w/v to about 1.2% w/v, preferably about 0.05% w/v to about 0.5% w/v, preferably about 0.05% w/v - about 0.25% w/v, more preferably 0.05% w/v - about 0.2% w/v of polysorbate 20 or polysorbate 80.
  • the viscosity reducing agent is an amino acid selected from at least one of arginine, lysine and proline, preferably, the viscosity reducing agent is arginine.
  • the concentration of the viscosity reducing agent is 1 mM to about 100 mM, preferably about 5 mM to about 80 mM, preferably 10 mM to about 50 mM, preferably about 10 mM to about 30 mM, preferably about 12.5 mM to about 25 mM.
  • the invention also provides a stable pharmaceutical formulation wherein at least 96.0% of the antibody is present in monomeric form after storage at 4°C for 20 weeks as determined by size exclusion chromatography.
  • the invention also provides a stable liquid pharmaceutical formulation wherein at least 95.5% of the antibody is present in monomeric form after storage at 25°C for 20 weeks as determined by size exclusion chromatography;
  • the invention also provides a stable pharmaceutical formulation wherein at least 95.0% of the antibody is present in monomeric form after storage at 37°C for 12 weeks as determined by size exclusion chromatography.
  • the present invention also provides a stable pharmaceutical formulation comprising: i. about 150 mg/ml to about 175 mg/ml anti-IL-4R antibody, wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO: 1 and Comprising the light chain variable region of SEQ ID NO: 2; ii. about 2000U/ml - about 4000U/ml rHuPH20; iii. about 10mM - about 20mM methionine; iv. about 10mM - about 15mM acetate buffer And/or about 18mM-about 22mM histidine buffer; v. about 150mM-about 160mM sucrose; vi. about 0.05% w/v- about 0.25% w/v polysorbate 80; vii. 27 mM arginine; wherein said formulation has a pH of about 5.5 to about 6.5, preferably about 5.5-5.9.
  • the present invention also provides a stable liquid pharmaceutical formulation comprising: i. about 150 mg/ml to about 175 mg/ml anti-IL-4R antibody, wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO:1 and a light chain variable region comprising SEQ ID NO: 2; ii. about 2000U/ml-about 4000U/ml rHuPH20; iii. about 10mM-about 20mM methionine; iv. about 10mM-about 15mM acetate buffer and/or about 18mM-about 22mM histidine buffer; v. about 190mM- about 230mM trehalose; vi.
  • the present invention also provides a stable liquid pharmaceutical formulation comprising: i. about 150 mg/ml to about 175 mg/ml anti-IL-4R antibody, wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO:1 and a light chain variable region comprising SEQ ID NO: 2; ii. about 2000U/ml-about 4000U/ml rHuPH20; iii. about 10mM-about 20mM methionine; iv. about 18mM-about 22mM histidine buffer v.
  • a stable pharmaceutical formulation comprising: i. about 150 mg/ml to about 175 mg/ml anti-IL-4R antibody, wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO: 1 and comprising SEQ ID NO: 2 light chain variable region; ii. about 2000U/ml-about 4000U/ml rHuPH20; iii. about 10mM-about 20mM methionine; iv. about 12.5mM-about 20mM histidine buffer and about 12.5mM- About 15mM acetate buffer; v. about 150mM-about 210mM trehalose; vi. about 0.05% w/v- about 0.2% w/v polysorbate 80; and vii. about 12.5mM-about 25mM arginine acid; wherein said formulation has a pH of about 5.9 to about 6.5.
  • a stable pharmaceutical formulation comprising: i. about 150 mg/ml to about 175 mg/ml anti-IL-4R antibody, wherein said antibody comprises a heavy chain variable region comprising SEQ ID NO: 1 and comprising SEQ ID NO: 2 light chain variable region; ii. about 2000U/ml-about 4000U/ml rHuPH20; iii. about 10mM-about 20mM methionine; iv. about 12.5mM-about 20mM histidine buffer and about 12.5mM- about 15 mM acetate buffer; v. about 155 mM to about 210 mM sucrose; vi. about 0.05% w/v to about 0.2% w/v polysorbate 80; and vii. about 12.5 mM to about 25 mM arginine ; wherein said formulation has a pH of about 5.9 to about 6.5.
  • the present invention also provides a freeze-dried preparation, which is prepared by any one of the above-mentioned preparations.
  • the second aspect of the present invention provides a container comprising the stable liquid pharmaceutical preparation according to any one of the first aspect.
  • the container is a tube, bottle, vial or syringe.
  • the third aspect of the present invention provides a medicine kit, which comprises the container described in the second aspect and a device for infusing the preparation.
  • the fourth aspect of the present invention provides the use of the pharmaceutical preparation described in any one of the first aspects in the preparation of medicines for related diseases treated with anti-IL-4 antibodies.
  • the present invention also provides the pharmaceutical preparation according to any one of the first aspect, which is used for treating related diseases suitable for treatment with anti-IL-4 antibody.
  • the present invention also provides a method for treating IL-4-related diseases, comprising administering a therapeutically effective amount of the preparation described in any one of the first aspects.
  • FIG. 1 AD model construction: Days 0, 6, 7, 9, 11, 14, 16, 18, 21, 23, and 25 from left to right, that is, the experiment was carried out for 26 days; Apply 25 ⁇ L 0.8% Oxazolone solution evenly on the right ear and back to sensitize the mice, and then apply 25 ⁇ L 0.4% Oxazolone solution on the same part on the 7th, 9th, 11th, 14th, 16th, 18th, 21st, 23rd, and 25th day of the experiment for stimulation .
  • Figure 2 Changes in body weight of mice in different groups within 0-25 days, the horizontal axis is the number of days of the experiment (unit: day), and the vertical axis is body weight (unit: gram).
  • Figure 3 Changes in mouse ear thickness during the experiment, the horizontal axis is the number of days of the experiment (unit: day), and the vertical axis is the thickness of the mouse ear (unit: mm).
  • Fig. 4 The total IgE content in the serum of different groups of mice on the 26th day of the experiment, the vertical axis is the total IgE content in the mouse serum (unit: ng/ml).
  • the term "about” or “approximately” as used herein generally means within 20%, preferably within 10%, and more preferably within 5% of the given value or range Inside.
  • IL-4R means a human cytokine receptor that specifically binds to interleukin-4 (IL-4), IL-4R ⁇ .
  • anti-IL-4R antibody means a human antibody or antigen-binding fragment thereof that specifically binds to human IL-4R.
  • antibody generally refers to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains, interconnected by disulfide bonds, and polymers thereof (e.g., IgM ); however, immunoglobulin molecules consisting only of heavy chains (ie, lacking light chains) are also included within the definition of the term "antibody”.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region.
  • the heavy chain constant region comprises three domains: CH1, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region.
  • the light chain constant region comprises one domain (CL1).
  • CL1 The VH and VL regions can be further subdivided into regions of hypervariability, called complementarity determining regions (CDRs), which alternate with more conserved regions called framework regions (FRs).
  • CDRs complementarity determining regions
  • FRs framework regions
  • Each VH and VL contains 3 CDRs and 4 FRs, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
  • antibody as used herein is used in the broadest sense to refer to and include immunoglobulin molecules, specifically including monoclonal antibodies, antigen-binding fragments, bispecific, polyheterogeneous antibodies, dimeric, tetrameric or polymeric antibodies Polybodies, single chain antibodies, domain antibodies, and any other modified configuration of immunoglobulin molecules comprising an antigen-binding site with the desired specificity, so long as they exhibit the desired biological activity.
  • mAb is an abbreviation for monoclonal antibody and refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., except for possible variants that may be produced during the production of monoclonal antibodies (such variants generally exist in small amounts) Furthermore, the individual antibodies comprising the population are identical and/or bind to the same epitope. Each monoclonal antibody is directed against a single determinant on the antigen, in contrast to polyclonal antibody preparations, which usually include different antibodies directed against different determinants (epitopes). Monoclonal antibodies can be monovalent, bivalent or multivalent.
  • Hyaluronidases are divided into three major groups, mammalian hyaluronidases, bacterial hyaluronidases, hyaluronidases from leeches, other parasites and crustaceans, which can be manufactured from recombinant DNA techniques, derived from human samples Or animal tissue extraction.
  • the term "rHuPH20” refers to recombinant human hyaluronidase rHuPH20 (SEQ ID NO: 5), which is a humanized recombinant protein.
  • pharmaceutical preparation refers to a combination containing one or more pharmaceutically active ingredients and multiple excipients to achieve the effect of treating patients with stable storage, safe and effective.
  • Pharmaceutical active ingredients refer to antibodies, chemical molecules, natural compounds, etc. that exert therapeutic effects.
  • excipient broadly refers to any ingredient other than the active therapeutic ingredient. Excipients can be inert substances, inactive substances and/or non-pharmaceutically active substances.
  • Excipients may serve various purposes, eg as carriers, vehicles, diluents, tableting aids, and/or to improve the administration, and/or absorption of the active substance.
  • Non-limiting examples of excipients are: solvents, diluents, organic co-solvents, viscosity reducing agents, antioxidants, buffers, preservatives, isotonic agents, chelating agents and stabilizers.
  • stable means that all the proteins therein substantially retain their physical, chemical and biological activities after storage at the expected storage temperature, such as 0-40°C.
  • the antibody in the preparation does not maintain 100% physical, chemical and biological activity after storage for a certain period of time, and the preparation can also be stable. After storage for a certain period of time, the antibody structure and function of more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% can be maintained, and the preparation can be considered as " stable".
  • the stability of formulations can be measured by various parameters. It can be characterized, for example, by determining the percentage of monomer remaining in the formulation after storage at a given temperature for a period of time. The percentage of monomer can be determined by size exclusion chromatography. The given temperature can be selected from 4°C, 25°C, 37°C, and the stable storage time can be selected from 2 weeks, 6 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, etc. A formulation is considered "stable" if the percentage of monomer by size exclusion chromatography exceeds 90%, 92%, 95%, 96%, 97%, 98%, 99%.
  • the present invention provides containers comprising the stable pharmaceutical formulations provided herein.
  • the term "container” may be a tube, bottle, vial or syringe.
  • the container further includes an injection needle. Accordingly, the present invention provides containers containing stable liquid formulations for single or multiple dose administration.
  • kit may comprise a pharmaceutical formulation described herein and a device for administration, eg, the pharmaceutical formulation may be packaged with a device for administration such as a syringe, inhaler, measuring cup, dropper, or applicator.
  • the pharmaceutical formulation may be filled in a container as defined above.
  • the kit optionally includes instructions for use including instructions for dosage, dosing regimen and mode of administration.
  • an effective amount refers to an amount that provides the desired effect. In the case of pharmaceutical drug formulations, it is the amount of the active ingredient effective to treat the disease in the patient. An effective amount can prolong progression-free survival, produce an objective response, increase overall survival time, and/or ameliorate one or more IL-4-associated symptoms.
  • diseases related to anti-IL-4R (interleukin-4 receptor) antibody treatment includes, for example, arthritis (including septic arthritis), herpes, chronic primary urticaria, scleroderma, hypertrophic scars, Whipple disease, benign prostatic hyperplasia, lung disease such as asthma (mild, moderate and severe), inflammatory disease such as inflammatory bowel disease, anaphylaxis, Kawasaki disease, sickle cell disease, Churg-Strauss syndrome, Graves' disease, preeclampsia, Sjögren's syndrome, autoimmune lymphoproliferative syndrome, autoimmune hemolytic anemia, Barrett's esophagus, autoimmune uveitis, tuberculosis, atopic dermatitis , ulcerative colitis, fibrosis and kidney disease, etc. (see patent CN201410018529.6).
  • the stable pharmaceutical preparation obtained by the present invention unexpectedly has the following beneficial technical effects: on the one hand, the obtained pharmaceutical preparation is stable at 25°C for 6 months, 7 months, 8 months, 9 months, 10 months months, 11 months, 12 months or longer, stable at 37°C or 40°C for 3 months, 4 months, 5 months, 6 months or longer; on the other hand the obtained pharmaceutical preparation Verified by animal models, it can achieve a single injection volume of at least 4ml, and obtain better pharmacokinetic data.
  • the anti-IL-4R antibody used in the following specific embodiments is dupilumab.
  • Reagents or instruments used in the present invention without indicating the manufacturer or source are all conventional products that can be purchased commercially.
  • the sources of dupilumab and rHuPH20 enzymes used are as follows:
  • Dupilumab the Dupilumab used in the examples of the present invention is the self-made Dupilumab by conventional antibody preparation methods, and the prepared Dupilumab sequence (heavy chain is SEQ ID NO: 3. The light chain is SEQ ID NO:4) which is consistent with the sequence of dupilumab sold on the market.
  • Dupilumab is produced by generally known recombinant protein technology, specifically by a known method to prepare a genetically engineered Chinese hamster ovary cell line (CHO) and expand in cell culture.
  • Dupilumab was harvested from the cell culture fluid and recovered using immobilized protein A affinity chromatography, cation exchange chromatography, a filtration step to remove viral contamination, followed by anion exchange chromatography and ultrafiltration/diafiltration steps. purification.
  • rHuPH20 enzyme The rHuPH20 enzyme used in the examples of the present invention was produced by generally known recombinant protein production techniques. The process begins by thawing cells from a working or mother cell bank and expands through cell culture in a series of spinner bottles. The rHuPH20 enzyme is secreted into the culture fluid. The harvest is clarified by filtration and then treated with solvents, detergents to inactivate the virus. The protein is then purified by a series of column chromatography processes to remove process and product related impurities.
  • the rHuPH20 standard product used in the detection of rHuPH20 enzyme activity was purchased from China National Institutes for Food and Drug Control (formerly known as: China Institute for the Control of Pharmaceutical and Biological Products), the product number is YZ-140603.
  • the pharmaceutical active ingredient and different excipients are formulated by the formulation methods known in the art.
  • purified dupilumab was buffer exchanged against diafiltration buffer containing the expected buffer composition and, where necessary, concentrated to antibody concentrations greater than the target concentration. After reaching the target concentration, excipients (eg, trehalose, rHuPH20, polysorbate, etc.) were added to the antibody solution as stock solutions. Finally, adjust the protein concentration to the target concentration with the final reconstitution buffer.
  • excipients eg, trehalose, rHuPH20, polysorbate, etc.
  • All prepared preparation solutions are filtered (for example, a 0.22 ⁇ m sterile filter membrane can be selected), and filled into a sterile glass vial (such as a 4ml glass vial) under aseptic conditions, and stoppered (for example, available Fluororesin laminated butyl rubber stopper) and cap (aluminum/plastic flip-off seal available).
  • the fill volume may be about 2ml.
  • the formulated formulation solutions were stored at different temperatures (4°C, 25°C, 37°C or 40°C) for different time periods.
  • the preparation of the freeze-dried formulation of dupilumab of the present invention is not particularly limited, and the known preparation method of the freeze-dried formulation can be used.
  • the lyophilized preparation can be prepared by the following method: as described above about the dupilumab liquid preparation, the liquid preparation is first prepared, filtered, and the filtered liquid preparation is equally divided into sterile glass tubes. shaped bottle. The vial was partially sealed with an ETFE (copolymer of ethylene and tetrafluoroethylene) coated rubber stopper suitable for use in a lyophilization process, followed by a freeze-drying cycle.
  • ETFE copolymer of ethylene and tetrafluoroethylene
  • Lyophilization is carried out, for example, in a LyoStar II freeze-dryer (FTS Systems, Stone Ridge, NY, USA): the product is first cooled from room temperature to, for example, about 5°C (pre-cooling), followed by a cooling rate of, for example, about 1°C/min A freezing step is performed, eg, at about -40°C, followed by a holding step, eg, at about -40°C, eg, for about 2 hours. The first drying step is carried out, for example, for about 72 hours at a temperature of, for example, about -25°C and a chamber pressure of, for example, about 80 ⁇ bar.
  • a second drying step is started from -25°C with a temperature ramp up to 25°C at 0.2°C/min, followed by a hold step at eg about 25°C for at least 8 hours at a chamber pressure of eg about 80 ⁇ bar.
  • the freeze-dried preparation powder was stored in a -80°C refrigerator.
  • Each of the resulting formulations was evaluated to determine the overall physicochemical stability of pilumab and rHuPH20 in the resulting formulations.
  • the resulting formulations were analyzed for formulation stability by the following method:
  • SEC-HPLC was used to detect soluble high molecular weight species (aggregates, HMW) and low molecular weight hydrolysis products (LMW) in the formulation.
  • SEC-HPLC refers to size exclusion chromatography, which is used to quantify protein aggregates and fragments. Monomers, aggregates and fragments elute from the column at different times and are detected with a standard UV detector. For example, Shimadzu LC-20AT high performance liquid chromatography, and Waters column XBridge Protein BEH SEC, 7.8*300mm, 3.5 ⁇ m, Implement the method.
  • BCA biquinolinecarboxylic acid
  • rHuPH20 enzyme activity is based on the formation of precipitates when hyaluronic acid (HA) combines with acidified serum. This activity was measured by incubating hyaluronidase with HA in a 96-well plate format for 30 minutes at 37°C, followed by the addition of acidified serum to precipitate undigested HA. The resulting turbidity is measured at 640 nm, and the drop in turbidity caused by enzymatic cleavage of the HA substrate is a measure of hyaluronidase activity. Sample activity was read from a standard curve generated from dilutions of the rHuPH20 assay reference standard.
  • rHuPH20 activity can be determined according to the following steps: first, prepare a standard curve of enzyme activity, add 30 ⁇ L per well into a 96-well plate, and preheat it with hyaluronic acid working solution in a 37°C water bath for 5 minutes; second, dilute the sample within the range of the standard curve; add 30 ⁇ L/well of the hyaluronic acid working solution into a preheated 96-well plate, mix well and put it in a 37°C water bath for 6 minutes; finally, add 240 ⁇ L/well of the serum working solution to terminate the interaction between the substrate and the enzyme After reacting at room temperature for 30 minutes, measure the absorbance value of OD640nm.
  • Example 1 Co-formulation 1 of dupilumab and hyaluronidase.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer, 12.5mM sodium acetate/acetic acid, 210mM trehalose, 0.05% (w/v) polysorbate 80 , 25mM Arginine, 20mM Methionine, rHuPH20 2000U/ml, pH 5.9.
  • Example 2 Co-formulation 2 of dupilumab and hyaluronidase.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 210mM trehalose, 0.2% w/v polysorbate 80, 25mM Arginine, 20mM Methionine, rHuPH20 2000U/ml, pH 5.9.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 155mM sucrose, 0.05% w/v polysorbate 80, 25mM essence Amino acid, 20mM methionine, rHuPH20 2000U/ml, pH 5.9.
  • Example 4 Co-formulation 4 of dupilumab and hyaluronidase.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer, 12.5mM sodium acetate/acetic acid, 155mM sucrose, 0.2% w/v polysorbate 80, 25mM essence Amino acid, 20mM methionine, rHuPH20 2000U/ml, pH 5.9.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 155mM sucrose, 0.2% w/v polysorbate 80, 12.5mM Arginine, 20mM Methionine, rHuPH20 2000U/ml, pH 5.9.
  • Formulation Dupilumab at 150mg/ml, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 155mM sucrose, 0.2% w/v polysorbate 80, 25mM essence Amino acid, 10mM methionine, rHuPH20 2000U/ml, pH 5.9.
  • Formulation Dupilumab at 175mg/ml, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 155mM sucrose, 0.2% w/v polysorbate 80, 25mM essence Amino acid, 20mM methionine, rHuPH20 2000U/ml, pH 5.7.
  • Formulation Dupilumab at 150mg/ml, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 155mM sucrose, 0.2% w/v polysorbate 80, 25mM essence Amino acid, 20mM methionine, rHuPH20 2000U/ml, pH 6.4.
  • Formulation 175 mg/ml dupilumab, 20 mM histidine hydrochloride/histidine hydrochloride buffer; 12.5 mM sodium chloride, 155 mM sucrose, 0.2% w/v polysorbate 80, 25 mM arginine acid, 20mM methionine, rHuPH20 2000U/ml, pH 5.9.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium chloride, 155mM sucrose, 0.2% w/v polysorbate 80, 25mM arginine acid, 20mM methionine, rHuPH20 2000U/ml, pH 5.7.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium chloride, 155mM sucrose, 0.2% w/v polysorbate 80, 25mM arginine acid, 20mM methionine, rHuPH20 2000U/ml, pH 6.4.
  • Formulation 160 mg/ml dupilumab, 20 mM histidine hydrochloride/histidine hydrochloride buffer; 155 mM sucrose, 0.2% w/v polysorbate 80, 25 mM arginine, 20 mM methionine acid, rHuPH20 2000U/ml, pH 5.9.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 155mM sucrose, 0.2% w/v polysorbate 80, 25mM arginine, 20mM methionine acid, rHuPH20 2000U/ml, pH 5.7.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 155mM sucrose, 0.2% w/v polysorbate 80, 25mM arginine, 20mM methionine acid, rHuPH20 2000U/ml, pH 6.4.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 210mM trehalose, 0.2% w/v polysorbate 80, 25mM arginine, 20mM methyl sulfide Amino acid, rHuPH20 2000U/ml, pH 5.9.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 210mM trehalose, 0.2% w/v polysorbate 80, 25mM Arginine, 20mM Methionine, rHuPH20 2000U/ml, pH 7.8.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 210mM trehalose, 0.2% w/v polysorbate 80, 25mM Arginine, rHuPH20 2000U/ml, pH 5.9
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 210mM trehalose, 0.2% w/v polysorbate 80, 25mM Arginine, 55mM Methionine, rHuPH20 2000U/ml, pH5.9.
  • Formulation 150mg/ml dupilumab, 20mM histidine hydrochloride/histidine hydrochloride buffer; 12.5mM sodium acetate/acetic acid, 310mM trehalose, 0.2% w/v polysorbate 80, 25mM Arginine, 20mM Methionine, rHuPH20 2000U/ml, pH 5.9.
  • Example 16 Although the co-preparation formulation of dupilumab and hyaluronidase in Example 16 has two buffers, it still shows poor stability, indicating that the pH value will also affect the stability of the formulation.
  • Example 17-18 Compared with Examples 1-11, the formulation of dupilumab and hyaluronidase in Examples 17-18, wherein there is no methionine in Example 17, the stability of the preparation is poor; Example 18 Containing methionine of 55mM in , the stability of preparation is also worse than the preparation of embodiment 1-11.
  • Example 19 contains 310 mM trehalose. Compared with other examples, it is shown that the content of heat stabilizers such as trehalose is too high It will also affect the stability of the formulation.
  • the above stability test results show that the co-formulation of the present invention is stable at 4°C, 25°C, 37°C and/or 40°C for 5 months or longer. At least 96.0% of antibody in monomeric form was present after 20 weeks at 4°C as determined by size exclusion chromatography; at least 95.5% of antibody in monomeric form was present after 20 weeks at 25°C; Chromatography determined that at least 95.0% of the antibody was present in monomeric form after 12 weeks of storage at 37°C.
  • the formulations of Examples 1-11 of the present invention meet the formulation stability requirements.
  • mice were housed in IVC (individually ventilated cages) with sterile water provided ad libitum. Mice were fed twice daily (AM and PM) except on study days. Before starting the study, the general health of the animals was assessed and body weight was recorded. The study was performed after the mice were determined to be healthy.
  • AD Atopic dermatitis, atopic dermatitis model construction: According to Figure 1, on the 0th day, evenly smear 25 ⁇ L of 0.8% Oxazolone (oxazolone) solution on the right ear and back of the mouse to sensitize the mouse, and then on the 7th, On days 9, 11, 14, 16, 18, 21, 23, and 25, 25 ⁇ L of 0.4% Oxazolone solution was applied to the same site for stimulation. Weigh twice a week after the start of the experiment and measure the thickness of the ears of the mice, and start subcutaneous administration on the 6th day. As shown in Table 20, blood was collected from the orbital venous plexus on the 26th day, and the IgE level in the serum was detected by using the kit MOUSE IgE ELISA KIT (Ekase).
  • mice Through the weight change of the mice, the thickness of the ears, and the detection of the total amount of IgE in the serum, it was found that compared with the blank control group (MC), the weight changes of the mice in the groups A, B, and C were basically the same, indicating that the experimental groups Administration has no toxic and side effects on mice, and the ear thickness and serum total IgE concentration are negatively correlated with the administration amount, indicating that groups A, B, and C all have obvious drug effects, and the drug effects are equivalent, indicating that in animals, by combining with The combination of PH20 and increasing the subcutaneous dosage can prolong the dosing period, reduce the dosing frequency, and achieve the same efficacy as common preparations (non-hyaluronidase joint preparations).
  • the co-preparation of the present invention can achieve a single injection volume greater than 2ml, such as 3ml, 4ml, 5ml, 6ml, 7m, 8ml, or larger volume, and obtain better pharmacokinetic data.

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Abstract

Formulation pharmaceutique stable comprenant un anticorps anti-IL-4R. La formulation pharmaceutique comprend un anticorps anti-IL-4R, de l'hyaluronidase et un excipient approprié. D'une part, la formulation pharmaceutique comprend une concentration élevée de l'anticorps anti-IL-4R, et après plusieurs mois de stockage, la formulation pharmaceutique présente toujours une stabilité élevée d'anticorps. D'autre part, la formulation pharmaceutique peut être injectée en sous-cutané, et le volume d'injection est très supérieur à un dosage d'injection sous-cutané typique, ce qui réduit efficacement le nombre d'administrations sous-cutanées pour des patients et réduit la douleur des injections sous-cutanées pour les patients.
PCT/CN2022/109805 2021-08-02 2022-08-02 Formulation stable comprenant un anticorps anti-il-4r Ceased WO2023011502A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024199665A1 (fr) * 2023-03-30 2024-10-03 Sandoz Ag Composition stable comprenant une concentration protéique élevée
WO2025017034A1 (fr) * 2023-07-17 2025-01-23 Formycon Ag Formulation d'anticorps liquide stable pour dupilumab
EP4623903A1 (fr) * 2024-03-28 2025-10-01 Fresenius Kabi Deutschland GmbH Composition pharmaceutique comprenant dupilumab
WO2025223497A1 (fr) * 2024-04-26 2025-10-30 湖南麦济生物技术股份有限公司 FORMULATION STABLE D'ANTICORPS MONOCLONAL ANTI-IL-4 Rα HUMAIN

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102943067A (zh) * 2003-03-05 2013-02-27 海洋酶公司 可溶性透明质酸酶糖蛋白(sHASEGP)、制备它们的方法、它们的用途和包含它们的药物组合物
US20180333493A1 (en) * 2017-05-16 2018-11-22 Bhami's Research Laboratory, Pvt. Ltd. High concentration protein formulations with reduced viscosity
WO2020108497A1 (fr) * 2018-11-29 2020-06-04 和铂医药（香港）有限公司 Préparation d'un anticorps anti-pd-l1
CN111437387A (zh) * 2013-06-21 2020-07-24 赛诺菲生物技术公司 通过施用il-4r拮抗剂治疗鼻息肉症的方法
US20210130492A1 (en) * 2019-09-18 2021-05-06 Genentech, Inc. Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use
CN113134081A (zh) * 2020-01-20 2021-07-20 上海君实生物医药科技股份有限公司 抗btla抗体药物组合物及其用途
WO2021143826A1 (fr) * 2020-01-17 2021-07-22 信达生物制药(苏州)有限公司 Protéine de mort cellulaire 1 anti-programmée recombinante et préparation d'anticorps bispécifique anti-cluster d'antigène de différenciation 137 et son utilisation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102943067A (zh) * 2003-03-05 2013-02-27 海洋酶公司 可溶性透明质酸酶糖蛋白(sHASEGP)、制备它们的方法、它们的用途和包含它们的药物组合物
CN111437387A (zh) * 2013-06-21 2020-07-24 赛诺菲生物技术公司 通过施用il-4r拮抗剂治疗鼻息肉症的方法
US20180333493A1 (en) * 2017-05-16 2018-11-22 Bhami's Research Laboratory, Pvt. Ltd. High concentration protein formulations with reduced viscosity
WO2020108497A1 (fr) * 2018-11-29 2020-06-04 和铂医药（香港）有限公司 Préparation d'un anticorps anti-pd-l1
CN111228479A (zh) * 2018-11-29 2020-06-05 四川科伦博泰生物医药股份有限公司 一种抗pd-l1抗体制剂
US20210130492A1 (en) * 2019-09-18 2021-05-06 Genentech, Inc. Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use
WO2021143826A1 (fr) * 2020-01-17 2021-07-22 信达生物制药(苏州)有限公司 Protéine de mort cellulaire 1 anti-programmée recombinante et préparation d'anticorps bispécifique anti-cluster d'antigène de différenciation 137 et son utilisation
CN113134081A (zh) * 2020-01-20 2021-07-20 上海君实生物医药科技股份有限公司 抗btla抗体药物组合物及其用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024199665A1 (fr) * 2023-03-30 2024-10-03 Sandoz Ag Composition stable comprenant une concentration protéique élevée
WO2025017034A1 (fr) * 2023-07-17 2025-01-23 Formycon Ag Formulation d'anticorps liquide stable pour dupilumab
EP4623903A1 (fr) * 2024-03-28 2025-10-01 Fresenius Kabi Deutschland GmbH Composition pharmaceutique comprenant dupilumab
WO2025202487A3 (fr) * 2024-03-28 2025-11-06 Fresenius Kabi Deutschland Gmbh Composition pharmaceutique de dupilumab
WO2025223497A1 (fr) * 2024-04-26 2025-10-30 湖南麦济生物技术股份有限公司 FORMULATION STABLE D'ANTICORPS MONOCLONAL ANTI-IL-4 Rα HUMAIN

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