WO2022231481A1 - Pharmaceutical composition of pembrolizumab and use thereof - Google Patents

Pharmaceutical composition of pembrolizumab and use thereof Download PDF

Info

Publication number
WO2022231481A1
WO2022231481A1 PCT/RU2022/050140 RU2022050140W WO2022231481A1 WO 2022231481 A1 WO2022231481 A1 WO 2022231481A1 RU 2022050140 W RU2022050140 W RU 2022050140W WO 2022231481 A1 WO2022231481 A1 WO 2022231481A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cancer
concentration
pembrolizumab
composition according
Prior art date
Application number
PCT/RU2022/050140
Other languages
English (en)
French (fr)
Inventor
Alina Aleksandrovna KOSTANDIAN
Anastasiia Alekseevna ANDREEVA
Ekaterina Aleksandrovna LOMKOVA
Aleksandr Olegovich IAKOVLEV
Dmitry Valentinovich MOROZOV
Original Assignee
Joint Stock Company "Biocad"
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from RU2021112111A external-priority patent/RU2791857C2/ru
Application filed by Joint Stock Company "Biocad" filed Critical Joint Stock Company "Biocad"
Priority to CN202280030892.2A priority Critical patent/CN117835965A/zh
Priority to EP22796265.1A priority patent/EP4329729A1/en
Priority to CR20230527A priority patent/CR20230527A/es
Priority to MA62939A priority patent/MA62939A1/fr
Publication of WO2022231481A1 publication Critical patent/WO2022231481A1/en
Priority to CONC2023/0014166A priority patent/CO2023014166A2/es

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • 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
    • 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
    • A61K47/16—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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to the field of pharmacy and medicine, specifically to pharmaceutical compositions of anti -PD- 1 antibody pembrolizumab, which may be used for treating malignant neoplasms or infectious diseases.
  • PD-1 Programmed cell death protein 1
  • PD-1 is an inhibitory member of the CD28 receptor family and is located on the cell surface of T-lymphocytes, B-cells, monocytes, NK cells and dendritic cells (lin H.T., Ahmed R., Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol. 2011; 350: 17-37).
  • PD-1 is a transmembrane receptor from the immunoglobulin family and consists of 288 amino acids.
  • the protein structure includes an extracellular IgV domain, a spacer arm, a transmembrane domain and a cytoplasmic domain.
  • the latter includes 2 tyrosine-containing sequences (ITIM and ITSM) involved in signaling in a cell (Francisco LM, Sage PT, Sharpe AH.
  • ITIM and ITSM 2 tyrosine-containing sequences
  • ITSM 2 tyrosine-containing sequences
  • PD-1 has 2 inhibitory ligands, PD-L1 and PD-L2, which are also transmembrane receptors and play an important role in immune homeostasis.
  • PD-L1 is expressed on T- and B-cells, dendritic cells, macrophages, endothelial, hematopoietic and epithelial cells.
  • PD-L1 expression has been detected on cells of many types of malignant tumors, such as melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck tumors, gastrointestinal tract tumors, ovarian cancer, lymphomas, leukemias (Han Y., Liu D., Li L. PD-1/PD-L1 pathway: current researches in cancer.
  • PD-L2 has limited expression on activated macrophages and dendritic cells and binds mainly to the PD-1 receptor.
  • the main factor increasing the expression of PD-L1 and PD-L2 is the anti-inflammatory cytokine IFNy.
  • the PD-1 receptor and the PD-L1 ligand thereof play a significant role in the survival and progression of malignant neoplasms.
  • PD-L1 receptor expression is increased on the surface of many types of malignant cells.
  • the PD-Ll/PD-1 interaction stimulates the development of immunosuppression in the tumor microenvironment, and thus protects tumor cells from the activity of cytotoxic CD8+ T cells.
  • the PD-1/PD-L1 system is a promising therapeutic target (Wu Y., Chen W., Xu Z.P., Gu W. PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition. Front Immunol. 2019; 10: 2022, Ju X., Zhang H., Zhou Z., Wang Q. Regulation of PD-L1 expression in cancer and clinical implications in immunotherapy. Am J Cancer Res. 2020; 10(1): 1-11).
  • anti-PD-1 antibody pembrolizumab which is a humanized monoclonal G4 (IgG4) antibody to human PD-1 receptor (PCT/US2008/007463). It was produced by combining variable sequences of a murine high-affinity antibody to PD-1 receptor and a human IgG4 kappa framework containing a stabilizing S228P mutation in the Fc fragment. It selectively blocks the binding of the PD-IgG4 (IgG4) antibody to human PD-1 receptor (PCT/US2008/007463). It was produced by combining variable sequences of a murine high-affinity antibody to PD-1 receptor and a human IgG4 kappa framework containing a stabilizing S228P mutation in the Fc fragment. It selectively blocks the binding of the PD-
  • Pembrolizumab has shown high efficacy in treatment of various types of malignant tumors: melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, stomach cancer, high microsatellite instability malignant neoplasms, hepatocellular carcinoma, esophageal cancer, cervical cancer, Merkel cell carcinoma, renal cell cancer, endometrial cancer, etc.
  • Pembrolizumab is also known to be used for treatment of infectious diseases.
  • pembrolizumab is also known to be used for treatment of infectious diseases.
  • pembrolizumab is also known to be used for treatment of infectious diseases.
  • pembrolizumab there is an ongoing study of pembrolizumab in the therapy of other diseases or disorders in which inhibition of PD-1 activity may be desirable.
  • the prior art provides Keytruda, a therapeutic product which includes pembrolizumab, sucrose, polysorbate 80 and a histidine buffer (PCT/US2012/031063). Despite this, there is still a need for novel improved stable pharmaceutical compositions of pembrolizumab.
  • Figure l is a graph of aggregate content determined by SE HPLC (%) versus storage time at a temperature of 25 ⁇ 2 °C for the monoclonal antibody pembrolizumab in the test formulations.
  • Figure 2 is a graph of monomer content determined by SE HPLC (%) versus storage time at a temperature of 25 ⁇ 2 °C for the monoclonal antibody pembrolizumab in the test formulations.
  • Figure 3 is a graph of basic fraction content determined by IE HPLC (%) versus storage time at a temperature of 25 ⁇ 2 °C for the monoclonal antibody pembrolizumab in the test formulations.
  • Figure 4 is a graph of monomer content determined by CE under non-reducing conditions (%) versus storage time at a temperature of 25 ⁇ 2 °C for the monoclonal antibody pembrolizumab in the test formulations.
  • Figure 5 is a graph of the content of the sum of heavy and light chains determined by CE under reducing conditions (%) versus storage time at a temperature of 25 ⁇ 2 °C for the monoclonal antibody pembrolizumab in the test formulations.
  • Figure 6 is a graph of relative specific activity (%) versus storage time at a temperature of 25 ⁇
  • composition refers to a composition and/or formulation comprising pembrolizumab in a therapeutically effective amount and excipients or auxilliary substances (carriers, diluents, fillers, solvents, etc.), the choice and proportions of which depend on the type and route of administration and dosage.
  • auxilliary substances carriers, diluents, fillers, solvents, etc.
  • aqueous composition refers to a water-based composition, the water in the composition may be: water, water for injections, physiologic saline (0.9%-1.0% aqueous solution of sodium chloride).
  • freeze-dried refers to a formulation that has been subjected to a process known in the art as freeze-drying, which includes freezing the formulation followed by removal of ice from the frozen contents.
  • the pharmaceutical composition is "stable" if the active agent retains physical stability and/or chemical stability and/or biological activity thereof during the specified shelf life at storage temperature, for example, of 2-8 °C. Further, the active agent may retain both physical and chemical stability, as well as biological activity. Storage period is adjusted based on the results of stability test in accelerated or natural aging conditions.
  • long-term storage or “long term stability” is understood to mean that a pharmaceutical composition may be stored for three months or more, for six months or more, for one year or more, and the composition may have a minimum stable shelf life of at least two years as well.
  • long term storage and “long term stability” further include stable storage durations that are at least comparable to or better than the stable shelf life typically required for currently available commercial formulations of the anti-PD-1 antibody pembrolizumab, without losses in stability that would render the formulation unsuitable for its intended pharmaceutical application.
  • buffering agent refers to an acid or base component (typically a weak acid or weak base) of the buffer or buffer solution.
  • a buffering agent helps to maintain the pFl value of a given solution at or near to a pre-determined value, and the buffering agents are generally chosen to complement the pre-determined value.
  • a buffering agent may be a single compound which gives rise to a desired buffering effect, especially when said buffering agent is mixed with (and suitably capable of proton exchange with) an appropriate amount (depending on the pre-determined value desired) of corresponding "aci d/base conjugate" thereof.
  • buffer refers to an aqueous solution comprising a mixture of an acid (typically a weak acid, such as e.g. acetic acid, citric acid) and a conjugated base thereof (such as e.g. an acetate or citrate salt, e.g. sodium acetate, sodium citrate, as well as hydrates of said salts, e g. sodium acetate trihydrate) or alternatively a mixture of a base (typically a weak base, e.g. histidine) and a conjugated acid thereof (e.g.
  • an acid typically a weak acid, such as e.g. acetic acid, citric acid
  • a conjugated base thereof such as e.g. an acetate or citrate salt, e.g. sodium acetate, sodium citrate, as well as hydrates of said salts, e g. sodium acetate trihydrate
  • a base typically a weak base, e.g. histidine
  • a conjugated acid thereof
  • the pH value of a “buffer solution” changes only slightly upon addition thereto of a small quantity of strong base or strong acid, as well as upon dilution or concentration due to the “buffering effect” imparted by a “buffering agent”.
  • a “buffer system” comprises one or more buffering agent(s) and/or an acid/base conjugate(s) thereof, and more suitably comprises one or more buffering agent(s) and an acid/base conjugate(s) thereof, and most suitably comprises one buffering agent and an acid/base conjugate thereof.
  • any concentrations referred herein to a “buffer system” may suitably refer to the combined concentration of buffering agent(s) and/or acid/base conjugate(s) thereof.
  • concentrations referred herein to a “buffer system” may refer to the combined concentration of all the relevant buffering species (i.e. the species in dynamic equilibrium with one another, e.g. citrate/citric acid).
  • the overall pH of the composition comprising the relevant buffer system is a reflection of the equilibrium concentration of each of the relevant buffering species (i.e. the balance of buffering agent(s) to acid/base conjugate(s) thereof).
  • Buffer solutions may be, for example, acetate, phosphate, citrate, histidine, succinate and other buffer solutions.
  • the pharmaceutical composition preferably has a pH in the range from 4.0 to 8.0.
  • Stabilizer refers to an excipient or a mixture of two or more excipients that provide the physical and/or chemical stability of the active agent.
  • Stabilizers may be amino acids, for example, but not limited to, arginine, histidine, glycine, lysine, glutamine, proline; surfactants, for example, but not limited to, polysorbate 20 (trade name: Tween 20), polysorbate 80 (trade name: Tween 80), polyethylene- polypropylene glycol and copolymers thereof (trade names: Poloxamer, Pluronic, sodium dodecyl sulfate (SDS); antioxidants, for example, but not limited to, methionine, acetylcysteine, ascorbic acid, monothioglycerol, sulfurous acid salts, etc.; chelating agents, for example, but not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTP A), sodium cit
  • osmotic agent or “tonicity-regulating agent”, as well as “osmolyte”, as used herein, refer to an excipient that can provide the required osmotic pressure of a liquid antibody solution.
  • the tonicity -regulating agent may increase the osmotic pressure of a liquid antibody liquid antibody formulation to isotonic pressure such that said liquid antibody formulation is physiologically compatible with the cells of the tissue of a subject's organism.
  • the tonicityregulating agent may contribute to increased stability of antibodies.
  • “Isotonic” formulation is a formulation that has an osmotic pressure equivalent to that of human blood.
  • Isotonic formulations typically have an osmotic pressure from about 239 to 376 mOsm/kg.
  • a tonicity agent may be in an enantiomeric (e.g. L- or D-enantiomer) or racemic form; in the form of isomers such as alpha or beta, including alpha, alpha; or beta, beta; or alpha, beta; or beta, alpha; in the form of a free acid or free base; in the form of a salt; in a hydrated form (e.g. monohydrate or dihydrate), or in an anhydrous form.
  • Exemplary osmotic agents are, but not limited to, sugars (trehalose, trehalose dihydrate, sucrose, glucose), polyols (mannitol, sorbitol), amino acids (proline or L-proline, arginine, glycine), or salts (sodium chloride, potassium chloride, magnesium chloride).
  • solubilizer refers to a pharmaceutically acceptable non-ionic surfactant. Both one solubilizer and combinations of solubilizers may be used. Exemplary solubilizers are, without limitation, polysorbate 20 or polysorbate 80, poloxamer 184 or poloxamer 188, or PLURONIC®.
  • amino acids are L-amino acids.
  • histidine and histidine hydrochloride monohydrate are used, it is typically L-histidine and L-histidine hydrochloride monohydrate.
  • proline it is typically L-proline.
  • Amino acid equivalents for example, pharmaceutically acceptable proline salts (for example, proline hydrochloride) may also be used.
  • medicament or “formulation” is a substance (or a mixture of substances as a pharmaceutical composition) in the form of tablets, capsules, solutions, ointments and other ready forms intended for restoration, improvement or modification of physiological functions in humans and animals, and for treatment and prophylaxis of diseases, for diagnostics, anesthesia, contraception, cosmetology and others.
  • use applies to the possibility to use the pharmaceutical composition of pembrolizumab according to the present invention to treat, relief the course of diseases, expedite the remission, reduce the recurrence rate for diseases or disorders.
  • “Treat” or “treatment”, “prophylaxis” of a disease, disorder or condition may comprise the prevention or delay of the onset of clinical symptoms of a disease, disorder or condition developing in human, the inhibition of a disease, disorder or condition, i.e. stop, reduction or delay of the development of a disease or a relapse thereof (in case of maintenance therapy) or at least one clinical or subclinical symptom thereof, or the alleviation or easement of a disease, i.e. the causing of regression of a disease, disorder or condition.
  • parenteral administration refers to administration regimens, typically performed by injection (infusion), and includes, in particular intravenous, intramuscular, intraarterial, intratracheal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, intraarticular, subcapsular, subarchnoid, intraspinal, epidural and intrasternal injection or infusion.
  • UV - quality parameter following photo stress dose ICHxl
  • the present invention discloses pharmaceutical compositions of anti -PD- 1 antibody pembrolizumab, which may be used as a medicinal product for treating malignant neoplasms or infectious diseases.
  • formulation selection we took into account the purpose, route of administration and tolerability of the drug product (for example, reduction of discomfort during administration), as well as the stability and preservation of activity of protein molecule within the formulation.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • concentration of pembrolizumab contained in the pharmaceutical compositions of the present invention may vary depending on the desired properties of the compositions, as well as on the particular conditions, methods and purposes of use of the pharmaceutical compositions.
  • pembrolizumab is present at a concentration of 5-50 mg/ml.
  • histidine is present at a concentration of 0.087-0.432 mg/ml.
  • histidine hydrochloride monohydrate is present at a concentration of 0.464-0.931 mg/ml.
  • glycine is present at a concentration of 1-2 mg/ml.
  • trehalose is present at a concentration of 70-130 mg/ml.
  • poloxamer 188 is present at a concentration of 0.8-1.2 mg/ml.
  • proline is present at a concentration of 20-34 mg/ml.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • pembrolizumab is present at a concentration of 15-35 mg/ml, or 20-30 mg/ml, or 25 mg/ml.
  • histidine is present at a concentration of 0.200-0.319 mg/ml, or 0.200-0.250 mg/ml, or 0.210-0.240 mg/ml, or 0.210-230 mg/ml, or 0.215-0.230 mg/ml, or 0.215-0.225 mg/ml, or 0.220-0.225 mg/ml, or 0.221 mg/ml.
  • histidine is L-histidine.
  • histidine hydrochloride monohydrate is present at a concentration of 0.600-0.900 mg/ml or 0.650-0.850 mg/ml, or 0.700-0.800 mg/ml, or 0.730-0.770 mg/ml, or 0.750 mg/ml.
  • histidine hydrochloride monohydrate is L-histidine hydrochloride monohydrate.
  • glycine is present at a concentration of 1.3 -1.7 mg/ml, 1.4-1.6 mg/ml, or 1.5 mg/ml.
  • trehalose is present at a concentration of 70-100 mg/ml, or 70-90 mg/ml, or 70-85 mg/ml, or 75-85 mg/ml, or 80 mg/ml.
  • trehalose is trehalose dihydrate.
  • poloxamer 188 is present at a concentration of 0.9- 1.1 mg/ml, or 0.95-1.05 mg/ml, or 1.0 mg/ml.
  • proline is present at a concentration of 22-32 mg/ml, or 24-30 mg/ml, or 27 mg/ml.
  • proline is L-proline.
  • the composition has pH 5.1-6.1, 5.2-6.0, 5.3-5.9, 5.4-5.8 or 5.5-5.7.
  • the composition has pH 5.6.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition has pH 5.6.
  • the present invention relates to a pharmaceutical composition of pembrolizumab, which is provided in dry (i.e. powder or granular) form for reconstitution in a suitable solvent (e.g. water) prior to administration.
  • a suitable solvent e.g. water
  • Such formulation may be prepared by, for example, lyophilisation, i.e. a process which is known in the art as freeze drying, and which involves freezing a product followed by removal of solvent from frozen material.
  • the present invention relates to a pharmaceutical composition of pembrolizumab produced by lyophilization of any of the above pharmaceutical compositions of pembrolizumab.
  • the pharmaceutical compositions according to the present invention may be either aqueous pharmaceutical compositions or lyophilized pharmaceutical compositions (lyophilizates).
  • Lyophilizates are used to produce other dosage forms. For example, a lyophilizate for producing an injectable solution, a lyophilizate for producing a concentrate for producing an injectable solution. Lyophilizates are reconstituted by dissolving same in a suitable solvent, most typically in water for injection. Also, lyophilized compositions are first reconstituted in the required volume of solvent (most typically in water) and then further diluted in a suitable solvent (e.g. 5% glucose solution, 0.9% sodium chloride solution). In some embodiments of the invention, the pharmaceutical composition of pembrolizumab is produced by lyophilization of the pharmaceutical composition of pembrolizumab according to the present invention.
  • the pharmaceutical composition of pembrolizumab is produced by lyophilization of the pharmaceutical composition of pembrolizumab, comprising:
  • the pharmaceutical composition of pembrolizumab is produced by lyophilization of the pharmaceutical composition of pembrolizumab, comprising:
  • the pharmaceutical composition of pembrolizumab is produced by lyophilization of the pharmaceutical composition of pembrolizumab, comprising:
  • the pharmaceutical composition of pembrolizumab is produced by lyophilization of the pharmaceutical composition of pembrolizumab, comprising:
  • the pharmaceutical composition of pembrolizumab, from which the lyophilized composition is produced has pH 5.6.
  • the present invention relates to the use of the above pharmaceutical composition of pembrolizumab for treating a malignant neoplasm or an infectious disease.
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab comprising:
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab comprising:
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab comprising:
  • the pharmaceutical composition of pembrolizumab has pH 5.6.
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab produced by lyophilization of the above pharmaceutical composition of pembrolizumab for treating a malignant neoplasm or an infectious disease.
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab produced by lyophilization of the pharmaceutical composition of pembrolizumab comprising:
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab produced by lyophilization of the pharmaceutical composition of pembrolizumab comprising:
  • the invention relates to the use of the pharmaceutical composition of pembrolizumab produced by lyophilization of the pharmaceutical composition of pembrolizumab comprising:
  • the pharmaceutical composition of pembrolizumab, from which the lyophilized composition is produced has pH 5.6.
  • the present invention relates to the use of the above pharmaceutical composition of pembrolizumab for producing a medicinal product for treating a malignant neoplasm or an infectious disease.
  • the malignant neoplasm is selected from the group: melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, primary mediastinal large B-cell lymphoma, urothelial cancer, stomach cancer, high microsatellite instability/DNA mismatch repair deficient (MMR) malignant neoplasms, hepatocellular cancer, cervical cancer, Merkel cell carcinoma, renal cell carcinoma, endometrial cancer, esophageal cancer, squamous cell skin cancer, basal cell carcinoma, breast cancer, colorectal cancer, prostate cancer, thyroid cancer, bladder cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, pancreatic cancer, ovarian cancer, gallbladder cancer, malignant brain tumor, glioblastoma, tumor with high mutational burden.
  • MMR microsatellite instability/DNA mismatch repair deficient
  • the infectious disease may be caused by a viral, bacterial or fungal infection.
  • the infectious disease may be caused, for example, by human immunodeficiency virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, human papillomavirus, Epstein-Barr virus, human cytomegalovirus and herpes virus. Many of said diseases may be chronic diseases.
  • said pharmaceutical composition of pembrolizumab of the present invention is intended for parenteral administration.
  • said pharmaceutical composition of pembrolizumab of the present invention is intended for intramuscular, intravenous, or subcutaneous administration. In some embodiments of the invention, said pharmaceutical composition of pembrolizumab of the present invention may be administered intravenously as an infusion.
  • the pharmaceutical composition of pembrolizumab according to the present invention may be used following dilution.
  • the required volume of the composition is transfered from a vial to an infusion container comprising a sterile 0.9% sodium chloride solution or a sterile 5% dextrose solution.
  • the resulting solution is stirred by gently turning the infusion container over.
  • the therapeutically effective amount of pharmaceutical composition of pembrolizumab according to the present invention depends on the condition of the subject, the severity of the condition, the previous therapy and the patient's history and response to the therapeutic agent.
  • a suitable dose can be adjusted by the decision of the attending physician so that it can be administered to the patient once or through several injections.
  • the subject of treatment, or patient is a mammal, preferably a human subject.
  • Said subject may be either male or female, of any age.
  • compositions according to the present invention may be stored in any suitable container.
  • a suitable container for example, a glass or plastic container, vial, ampoule, syringe, cartridge, or bottle of the desired volume.
  • the containers may be provided with additional means for administration, such as droppers, auto-injectors.
  • a pharmaceutical composition according to the invention may be manufactured, packaged, or widely sold in the form of a single unit dose or a plurality of single unit doses in the form of a ready formulation.
  • single unit dose refers to discrete quantity of a pharmaceutical composition containing a predetermined quantity of an active ingredient.
  • the quantity of the active ingredient typically equals the dose of the active ingredient to be administered in a subject, or a convenient portion of such dose, for example, half or a third of such dose.
  • the pharmaceutical compositions may be administered as a single therapeutic agent or in combination with additional therapeutic agents as needed.
  • the present methods for treatment and/or prophylaxis are used in combination with administration of a therapeutically effective amount of another active agent.
  • the other active agent may be administered before, during or following the administration of the pharmaceutical compositions according to the present invention.
  • the other active agent may be administered as part of the present composition or, alternatively, as a separate formulation.
  • Protein samples at a concentration of 20 mg/ml or greater were prepared in Pellicon cassettes (Millipore) in a tangential flow mode.
  • the initial antibody formulation was placed in a diafiltration tank, the protein was concentrated to a desired concentration, at least 10-fold volume of the solution with the target formulation comprising buffering agents, and, if necessary, additional water soluble stabilizers was then supplied to the system.
  • the target formulation comprising buffering agents
  • additional water soluble stabilizers was then supplied to the system.
  • a concentrate of poloxamer 188 and an appropriate solution of excipients were then added to the sample to prepare a solution with protein at the target concentration.
  • the surfactant concentrates were added to the antibody following diafiltering and concentrating, with the final dilution of the antibody to the target concentration with a solution of excipients.
  • the antibody solution was filtered using a 0.22 pm sterilizing membrane.
  • the protein concentration was measured by UV spectroscopy at a wavelength of 280 nm in UV transparent plates.
  • Each sample was diluted with the appropriate solution of excipients to a concentration of - 0.5 mg/ml.
  • 150 pi of the diluted sample was placed into a well of UV spectrophotometry plate.
  • Optical density of solutions in the plate wells was measured using a plate spectrophotometer at a wavelength of 280 nm.
  • An appropriate solution of excipients was used as a reference solution.
  • A280 is a value of optical density at a wavelength of 280 nm; 8 is an extinction coefficient of test protein; b is the total dilution factor for a sample;
  • test proteins at a concentration of 1 to 5 mg/ml was determined using DynaPro Plate Reader II. To this end, 35 m ⁇ of the solution was placed into a well of a black polymer plate with an optically clear bottom, which was gradually heated in the instrument while constantly measuring scattered light intensity.
  • the temperature trend and aggregation point were determined using the Dynamics V7 software.
  • Sypro Orange fluorescent stain was added to the protein sample.
  • the sample was analyzed in a CFX96 C1000 Touch Thermal Cycler amplifier in real time mode. Heating was from 25 to 85 °C, the detection channel was ROX.
  • CFX Manager Bio-Rad software was used to process the results.
  • a number of protein solutions from 30 mg/ml to 0.94 mg/ml were produced by stepwise dilution. Appropriate solutions of excipients were used as a solvent.
  • Test samples were divided into 2 aliquots of 150 m ⁇ each and placed into glass vials, 1 vial per formulation was stored in a refrigerator at 5 ⁇ 3 °C, the rest vials were placed into a thermal shaker and shaken at 800 rpm at 5 ⁇ 3 °C for 96 hours. During the selection of control points or following stress, the vials were removed from the thermal shaker and transferred for analysis.
  • test samples were divided into 2 aliquots and placed into plastic vials: 1 vial per formulation was stored in a refrigerator at 5 ⁇ 3 °C, the rest vials were stored in a freezer at not higher than -18 °C until completely frozen. Thereafter, the vials were removed from the freezer, kept at room temperature until the contents were completely thawed; the solutions were mixed using a vortex and placed back into the freezer. This was repeated at least 3 times. Following stress, the vials were removed from the freezer, kept at room temperature until the contents were completely thawed; the solutions were mixed using a vortex and transferred for analysis.
  • Test samples were divided into 2 aliquots and placed into polymer vials: 1 vial per formulation was stored in a refrigerator at 5 ⁇ 3 °C (input control may be transferred for analysis once for all studies at the start of storage), pH for the rest vials was adjusted to 3.5 ⁇ 0.1 with hydrochloric acid solution while stirring, thereafter, they were transferred to a refrigerator for storage at 5 ⁇ 3 °C. After 1 hour, hydrolysis was quenched while stirring by adding sodium hydroxide solution to the initial pH value. The solutions were then transferred for analysis.
  • Test samples were divided into 2 aliquots and placed into polymer vials: 1 vial per formulation was stored in a refrigerator at 5 ⁇ 3 °C (input control may be transferred for analysis once for all studies at the start of storage), pH for the rest vials was adjusted to 8.5 ⁇ 0.1 with sodium hydroxide solution while stirring, thereafter, they were transferred to a refrigerator for storage at 5 ⁇ 3 °C. After 1 hour, hydrolysis was quenched while stirring by adding hydrochloric acid solution to the initial pH value. The solutions were then transferred for analysis.
  • test samples were divided into separate aliquots (one aliquot for the input control - it is allowed to transfer for analysis once for all studies at the start of storage) and placed in separate sterile glass vials: part of the vials for each formulation was placed in the refrigerator for storage at 5 ⁇ 3 °C (input control), the rest vials were placed in a thermostat and incubated at 25 ⁇ 2 °C for 6 months, periodically selecting control points according to the plan. When selecting control points and following storage, the vials were removed from the thermostat and transferred for analysis.
  • Detector wavelength 214 and 360 nm.
  • the mobile phase pH was adjusted to 6.9 with orthophosphoric acid.
  • Test samples were adjusted to a protein concentration of 1 mg/ml by diluting or concentrating in 0.5 ml Amicon Ultra 10 kDa centrifuge filters (Millipore) (depending on the initial concentration of samples). Protein content was followed by UV spectrophotometry at a wavelength of 280 nm.
  • a 96-well plate was loaded with amounts, as specified in the instructions, of Labelling Buffer solution, Dye Mixture solution and 25 pi of the test sample, the plate was placed in a dark place for 10 minutes, each well was then loaded with 60 pi of water and mixed.
  • the plate with solutions was centrifuged using a plate centrifuge rotor and placed in the Caliper LabChip GX P instrument.
  • the analysis used a special chip which was filled with Running Buffer solution with pH in accordance with the instructions.
  • the results were processed using LabChip GX software. 15. Determination of charge variant profile by ion exchange high performance liquid chromatography (IE HPLC).
  • Pre-column ProPac WCX-10G, 4x50 mm, particle size: 10 pm (Thermo Scientific, USA).
  • Reference wavelength 360 nm, 100 nm bandwidth
  • test sample was diluted to a concentration of 1.0 mg/ml and treated with carboxypeptidase B in a ratio of 100: 1 for 20 minutes at a temperature of 37 ⁇ 2 °C.
  • Elution mode Eluent A from 100% to 80%, eluent B from 0% to 20%.
  • the sample was diluted to a concentration of 4.0 mg/ml. 23 pi of the resulting solution was placed in a 1.5 ml microtube; 70 pi of SDS-MW Sample Buffer, 2 pi of internal standard having a molecular weight of 10 kDa, 5 pi of 0.5M iodoacetamide solution (CE non-red.) or 5 pi of 2- mercaptoethanol (CE red.) were added thereto. The resulting solution was stirred for 15 seconds, centrifuged for 5 seconds at a speed of 2800 rpm and placed in a solid-state thermostat at 70°C for 30 minutes. The solution was cooled to room temperature.
  • the SDS MW Separation - PA 800 plus.met analysis method was used in 32Karat Software.
  • Detection wavelength 220 nm. 17. Determination of relative specific activity.
  • test sample of antibody was diluted using the assay medium (medium for quantitative determination) to a concentration of 1 mg/ml and placed into the robotic platform.
  • the robotic platform Liquid Handling Arm (LiHa) was used to prepare three independent dilutions of the standard and test sample at concentrations of 1 000, 50, 10, 1, 0.5, 0.25, 0.1, 0.025, 0.01, 0.001 pg/ml using the assay medium.
  • the culture plates were kept at room temperature for at least 15 minutes, and BioGlo luciferase substrate was added.
  • the luminescence level was measured in relative luminescence units (RLU) using a microplate reader and Magellan 7.2 software.
  • RLU relative luminescence units
  • UV Detector UV, 280 nm, bandwidth: 16 nm.
  • Reference wavelength 360 nm, 100 nm bandwidth
  • test sample was diluted to a concentration of 3.0 mg/ml and treated with carboxypeptidase B in a ratio of 100: 1 for 20 minutes at a temperature of 37 ⁇ 2 °C.
  • Elution mode Eluent A from 0% to 100%, eluent B from 100% to 0%.
  • Test samples were divided into 2 aliquots of 150 m ⁇ each and placed into separate glass vials: 1 vial per formulation was stored in a refrigerator at 5 ⁇ 3 °C, hydrogen peroxide was added to the rest of the samples to final concentration of hydrogen peroxide of 0.1% in samples, the samples were aged for 4 hours at (5 ⁇ 3) °C. Oxidation was quenched by adding an equivalent amount of L-methionine.
  • test samples were divided into two aliquots and placed in individual glass vials. As dark controls, we used the product in the secondary package, tightly wrapped with aluminum foil. All samples were placed in a climate chamber with a light source, and a photo stress program was launched at 1.2 million lux » h and 200 W » h/m2 (dose ICHx 1). Elpon reaching the desired stress level, all samples were removed from the chamber and transferred for analysis.
  • the diffusion interaction parameter (ko) reflects sample's diffusion coefficient as a function of concentration of molecules. If the diffusion coefficient is decreased with increasing concentration (ko ⁇ 0), then polydispersity of the given solution is increased and larger particles are formed therein. Such samples have low solubility and tend to aggregate, and formulations thereof are not recommended for use.
  • the aggregation temperature and melting point make it possible to assess the protein's tendency to aggregation. The most stable samples are those in which particle aggregation begins at a higher temperature and where smaller particles are formed under heating.
  • Thermal stability was assessed by method 7. Before and following thermal stress, we determined: purity by SE HPLC by method 13, charge variant profile in capillary by method 14, hydrodynamic radius by method 5. The results are shown in Table 3. The best results have a lighter shade of color. Table 3 - Results of determination of thermal stability
  • pH may deviate slightly from the desired value and vary in the pH range of 5.5 - 5.7 (pH 5.6 ⁇ 0.1).
  • This formulation showed the best stabilizing properties among all the test samples. According to the results of the model, a minimal change in the content of the monomer (protein) and aggregates is expected in the histidine buffer solution under thermal exposure, and high values of the aggregation temperature and diffusion interaction parameter are also expected.
  • the optimal composition as compared to the Keytruda buffer solution, exhibits a smaller change in the monomer content under thermal exposure, a smaller change in the aggregate content and an increased diffusion interaction parameter, which indicates greater colloidal stability.
  • Test formulations Excipients suitable for parenteral administration were studied to be used as osmotic agents. The test formulations are shown in Table 4. Table 4 - Test formulations
  • Thermal stability was assessed by method 7. Before and following thermal stress, we determined: purity by SE HPLC by method 13, charge variant profile in capillary by method 14, hydrodynamic radius by method 6. The results are shown in Table 6. The best results have a lighter shade of color. Table 6 - Results of determination of thermal stability
  • the formulations comprising trehalose showed the best stabilizing properties among all the test samples.
  • the sample comprising trehalose dihydrate showed the best results in terms of aggregation temperature and melting point. Also, this sample showed the smallest change in quality indicators under thermal exposure, minor changes under shaking were observed.
  • the sample comprising L-proline also showed one of the best results for aggregation temperature and an average result for melting point.
  • the composition with L-proline showed average results under thermal exposure, small change in quality indicators under shaking, and the best result under freeze-thaw.
  • trehalose dihydrate or L-proline selected for the next step, reduces the formation of aggregates under freeze-thaw and thermal stress. Also, the selected formulations exhibit a slight change in quality under shaking.
  • the selected osmotic agents when compared with the formulation containing sucrose, provide increased thermal stability; in particular, we observed increased melting point/aggregation temperature, a lower rate of formation of aggregates under thermal exposure and a smaller change in the monomer content, and we also observed a smaller absolute change in the acid-base profile.
  • the sample containing trehalose dihydrate in the excipients showed better results in terms of the diffusion interaction parameter, which indicates increased stability and less tendency to aggregation during concentration and diafiltration.
  • the studied formulations containing trehalose dihydrate, sorbitol or L-proline show a significantly smaller increase in the particle hydrodynamic radius under shaking and freezing, which indicates the formation of large high-molecular particles.
  • Example 3 Screening of osmotic agents and stabilizers.
  • test formulations are shown in Table 9.
  • Pharmaceutical compositions containing pembrolizumab in the test formulations were prepared in accordance with method 2.
  • Thermal stability was assessed by method 7. Before and following thermal stress, we determined: purity by SE HPLC by method 13, charge variant profile in capillary by method 14, hydrodynamic radius by method 6. The results are shown in Table 11. The best results have a lighter shade of color.
  • Stability under acid hydrolysis for formulations devoid of poloxamer 188 was assessed by method 10 with adjusting to pH 3.5 and ageing for 1 hour. Before and following hydrolysis, we determined: purity by SE HPLC by method 13, charge variant profile in capillary by method 14, hydrodynamic radius by method 6. The results are shown in Table 12. The best results have a lighter shade of color.
  • L-histidine hydrochloride monohydrate 0.750 mg/ml
  • L-proline 30 mg/ml
  • Poloxamer 188 0.5 mg/ml
  • Formulations containing trehalose dihydrate, compositions of trehalose dihydrate in combination with glycine, as well as compositions with L-proline, as well as compositions with L-proline in combination with glycine or methionine were selected for further development, since they showed positive stability results under stress.
  • Poloxamer 188 was selected to be used as a surfactant in the next step.
  • Protein concentration from 10 to 40 mg/ml
  • pH from 5.1 to 6.1
  • osmotic agent concentration from 70 to 130 mg/ml
  • L-glycine concentration from 1.5 to 15 mg/ml
  • poloxamer concentration 188 from 0.10 to 1.0 mg/ml
  • buffer solutions refer to the following formulations described in Table 17.
  • Thermal stability was assessed by method 7. Before and following thermal stress, we determined: purity by SE HPLC by method 13, charge variant profile in capillary by method 14, hydrodynamic radius by method 6. The results are shown in Table 19. The best results have a lighter shade of color. Table 19 - Results of determination of thermal stability Determination of stability under shaking.
  • Example 5 Determination of stability of the final formulation under stress conditions
  • the final formulation of Pembrolizumab and the formulation of Keytruda excipients were selected.
  • the test formulations are shown in Table 22.
  • Pharmaceutical compositions containing pembrolizumab in the test formulations were prepared in accordance with method 2.
  • the excipient formulation of Pembrolizumab as compared to that of of Keytruda showed a smaller change in quality indicators under thermal stress, specifically, a smaller change in the hydrodynamic radius, a smaller increase in aggregates and changes in the monomer content, a significantly lower tendency to form oxidized forms, and a smaller change in the charged variant profile.
  • a smaller change in the charged variant profile following stress was observed.
  • Example 6 Determination of stability under accelerated ageing at a temperature of 37 ⁇ 2 °C.
  • compositions in the range of protein concentration from 25 to 50 mg/ml), pH (from 5.1 to 6.1), trehalose dihydrate concentration (from 70 to 90 mg/ml), glycine concentration (from 1.0 to 2.0 mg/ml) and poloxamer 188 concentration (from 0.8 to 1.2 mg/ml) were prepared by method 1 and stored for stability test at a temperature of 37 ⁇ 2 °C.
  • test formulations are shown in Table 30.
  • compositions comprising protein at a concentration of 25, 50 and 37.5 mg/ml were prepared by diafiltration according to technique 1 and placed for accelerated storage at a temperature of 37 ⁇ 2 °C in accordance with technique 8. The results of the study are shown in Table 31.
  • the pharmaceutical composition is stable in the provided range of concentrations, pH and excipients under accelerated aging at 37 ⁇ 2 °C for 4 weeks.
  • Example 7 Determination of stability under long-term accelerated ageing.
  • compositions in the range of protein concentration from 25 to 50 mg/ml), pH (from 5.1 to 6.1), trehalose dihydrate concentration (from 70 to 90 mg/ml), glycine concentration (from 1.0 to 2.0 mg/ml) and poloxamer 188 concentration (from 0.8 to 1.2 mg/ml) were prepared by method 1 and stored for stability test at a temperature of 25 ⁇ 2 °C. Further, we selected, among all compositions, the most critical cases, with lowest and highest excipient content and the maximum protein content, as well as formulations with excipient content being at the central point of the range in question.
  • test formulations are shown in Table 32.
  • compositions comprising protein at a concentration of 25, 50 and 37.5 mg/ml were prepared by diafiltration according to technique 1 and placed for accelerated storage at a temperature of 25 ⁇ 2 °C in accordance with technique 8. The results of the study are shown in Table 33 and in Fig. 1, 2, 3, 4, 5 and 6.
  • a pharmaceutical composition containing histidine buffer solution in the pH range from 5.1 to 6.1, trehalose dihydrate from 70 to 90 mg/ml, L-glycine from 1.0 to 2.0 mg/ml and poloxamer 188 from 0.8 to 1.2 mg/ml demonstrated an acceptable level of aggregation (increase in aggregates over 6 months at 25 ⁇ 2 °C was no more than 0.32%), as well as a small change in the acid-base profile (change in the basic fraction content of no more than 13.0%) and a slight change in specific activity under accelerated aging both at a concentration of the monoclonal antibody Pembrolizumab of 25 mg/ml and at an increased concentration of up to 50 mg/ml.
  • trehalose dihydrate contributed to an increase in the aggregation temperature and melting point of pembrolizumab.
  • glycine has a positive effect on aggregation temperature and melting point, as well as on diffusion interaction parameter.
  • the positive effect of glycine on protein quality parameters under acid and basic hydrolysis was observed.
  • the addition of poloxamer 188 to the formulation contributes to stabilization of the test protein under shaking and freezing.
  • Pembrolizumab excipients showed significant advantages over the Keytruda formulation under thermal stress, acid and basic hydrolysis; also, we observed a significantly lower tendency to oxidation under photo stress, which has a significant effect on the structure and specific activity of the protein, and an increased tendency to aggregation
  • Table 34 Aqueous pharmaceutical composition of pembrolizumab.
  • compositions containing trehalose and poloxamer 188 in formulations thereof are further characterized by a low tendency to form high-molecular weight impurities under longterm storage, as well as a low tendency to oxidation, loss of specific activity and increase in impurities under photo stress and long-term storage.
  • the resulting data related to the stability of pharmaceutical compositions indicate the compatibility of excipients with each other and with the active substance.
PCT/RU2022/050140 2021-04-27 2022-04-27 Pharmaceutical composition of pembrolizumab and use thereof WO2022231481A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN202280030892.2A CN117835965A (zh) 2021-04-27 2022-04-27 派姆单抗的药物组合物及其用途
EP22796265.1A EP4329729A1 (en) 2021-04-27 2022-04-27 Pharmaceutical composition of pembrolizumab and use thereof
CR20230527A CR20230527A (es) 2021-04-27 2022-04-27 Composición farmacéutica de pembrolizumab y su uso
MA62939A MA62939A1 (fr) 2021-04-27 2022-04-27 Composition pharmaceutique de pembrolizumab et son utilisation
CONC2023/0014166A CO2023014166A2 (es) 2021-04-27 2023-10-23 Composición farmacéutica de pembrolizumab y su uso

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
RU2021112111 2021-04-27
RU2021112111A RU2791857C2 (ru) 2021-04-27 Фармацевтическая композиция пембролизумаба и ее применение

Publications (1)

Publication Number Publication Date
WO2022231481A1 true WO2022231481A1 (en) 2022-11-03

Family

ID=83848424

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/RU2022/050140 WO2022231481A1 (en) 2021-04-27 2022-04-27 Pharmaceutical composition of pembrolizumab and use thereof

Country Status (9)

Country Link
EP (1) EP4329729A1 (zh)
CN (1) CN117835965A (zh)
AR (1) AR125470A1 (zh)
CO (1) CO2023014166A2 (zh)
CR (1) CR20230527A (zh)
EC (1) ECSP23081880A (zh)
MA (1) MA62939A1 (zh)
TW (1) TW202308692A (zh)
WO (1) WO2022231481A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016168716A1 (en) * 2015-04-17 2016-10-20 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-pd-1 antibody and another antibody
WO2018211517A1 (en) * 2017-05-16 2018-11-22 Bhami's Research Laboratory, Pvt. Ltd. High concentration protein formulations with reduced viscosity
US20200071352A1 (en) * 2018-08-28 2020-03-05 Arecor Limited Stabilized antibody protein solutions
WO2020097141A1 (en) * 2018-11-07 2020-05-14 Merck Sharp & Dohme Corp. Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016168716A1 (en) * 2015-04-17 2016-10-20 Bristol-Myers Squibb Company Compositions comprising a combination of an anti-pd-1 antibody and another antibody
WO2018211517A1 (en) * 2017-05-16 2018-11-22 Bhami's Research Laboratory, Pvt. Ltd. High concentration protein formulations with reduced viscosity
US20200071352A1 (en) * 2018-08-28 2020-03-05 Arecor Limited Stabilized antibody protein solutions
WO2020097141A1 (en) * 2018-11-07 2020-05-14 Merck Sharp & Dohme Corp. Stable formulations of programmed death receptor 1 (pd-1) antibodies and methods of use thereof

Also Published As

Publication number Publication date
ECSP23081880A (es) 2023-11-30
CO2023014166A2 (es) 2024-02-05
CN117835965A (zh) 2024-04-05
MA62939A1 (fr) 2024-02-29
AR125470A1 (es) 2023-07-19
TW202308692A (zh) 2023-03-01
EP4329729A1 (en) 2024-03-06
CR20230527A (es) 2024-02-13

Similar Documents

Publication Publication Date Title
US20240058263A1 (en) Formulations of antibody
US20230047111A1 (en) Pharmaceutical formulations of tnf-alpha antibodies
TWI721020B (zh) 一種抗ｐｄ-１抗體製劑及其在醫藥上的應用
TWI734233B (zh) 抗體調配物
WO2017104778A1 (ja) 抗ヒトｔｓｌｐ受容体抗体含有医薬組成物
WO2022231481A1 (en) Pharmaceutical composition of pembrolizumab and use thereof
TW202031289A (zh) 含高濃度抗ｖｅｇｆ抗體之蛋白質溶液配製物
RU2791857C2 (ru) Фармацевтическая композиция пембролизумаба и ее применение
JP2021521232A (ja) メグルミン塩を使用して製剤を含むタンパク質を安定化するための方法
WO2021034228A1 (ru) Водная фармацевтическая композиция антитела к pd-1 пролголимаба и ее применение
CN117159703B (zh) 含抗lag-3抗体的药物组合物及其用途
RU2806320C2 (ru) Водная фармацевтическая композиция антитела к pd-1 пролголимаба и ее применение
WO2023146437A1 (en) Pharmaceutical composition of anti-trbv9 antibody and use thereof
JP2023509354A (ja) 抗体ニモツズマブの安定で高濃度の製剤
OA17126A (en) Pharmaceutical formulations of TNF-alpha antibodies

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22796265

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2301006986

Country of ref document: TH

Ref document number: P6002774/2023

Country of ref document: AE

WWE Wipo information: entry into national phase

Ref document number: MX/A/2023/012745

Country of ref document: MX

Ref document number: 202392707

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 002957-2023

Country of ref document: PE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112023022389

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: 2022796265

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2022796265

Country of ref document: EP

Effective date: 20231127

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112023022389

Country of ref document: BR

Free format text: EXPLIQUE A DIVERGENCIA, COM DOCUMENTOS COMPROBATORIOS SE NECESSARIO, NO DEPOSITANTE CONSTANTE NO PEDIDO INTERNACIONAL COMO JOINT STOCK COMPANY ?BIOCAD? E O CONSTANTE NO FORMULARIO DA PETICAO INICIAL COMO JOINT STOCK COMPANY BIOCAD. A EXIGENCIA DEVE SER RESPONDIDA EM ATE 60 (SESSENTA) DIAS DE SUA PUBLICACAO E DEVE SER REALIZADA POR MEIO DA PETICAO GRU CODIGO DE SERVICO 207.

WWE Wipo information: entry into national phase

Ref document number: 523451326

Country of ref document: SA

ENP Entry into the national phase

Ref document number: 112023022389

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20231026