CN117860874A - Pharmaceutical composition of recombinant human coagulation factor VIIa - Google Patents

Pharmaceutical composition of recombinant human coagulation factor VIIa Download PDF

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CN117860874A
CN117860874A CN202410278314.1A CN202410278314A CN117860874A CN 117860874 A CN117860874 A CN 117860874A CN 202410278314 A CN202410278314 A CN 202410278314A CN 117860874 A CN117860874 A CN 117860874A
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pharmaceutical composition
liquid pharmaceutical
polysorbate
recombinant human
human factor
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CN117860874B (en
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李盈淳
孔令婕
马瑞
程艳菊
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Shanghai Zhengda Tianqing Pharmaceutical Technology Development Co ltd
Nanjing Shunxin Pharmaceutical Co Ltd
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Shanghai Zhengda Tianqing Pharmaceutical Technology Development Co ltd
Nanjing Shunxin Pharmaceutical Co Ltd
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    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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    • A61K38/36—Blood coagulation or fibrinolysis factors
    • 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
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    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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Abstract

The present application belongs to the field of biological medicine, and specifically provides a pharmaceutical composition of recombinant human factor VIIa, provides a pharmaceutical composition or lyophilized preparation comprising the recombinant human factor VIIa, a preparation comprising the pharmaceutical composition or lyophilized preparation and application of the pharmaceutical composition or lyophilized preparation in preparing a medicament for preventing or treating hemorrhage in a subject.

Description

Pharmaceutical composition of recombinant human coagulation factor VIIa
Technical Field
The application belongs to the field of biological medicine, and in particular relates to a pharmaceutical composition of recombinant human blood coagulation factor VIIa, a preparation method and application.
Background
Human Factor VII (FVII) is a vitamin K dependent serine protease that can either initiate the extrinsic pathway or participate in the intrinsic pathway by activating human factor IX. FVII is synthesized in the liver and secreted into the blood, where it circulates in the form of a single chain glycoprotein (zymogen) with a molecular weight of about 50,000 da. The zymogen FVII is proteolytically cleaved at position R152-I153 to form a double-stranded molecule linked by a disulfide bond, which is converted to the active form FVIIa.
Novox developed by Daneno and Norde corporation is recombinant human factor VIIa, similar in structure to human plasma-derived factor VIIa, and has been approved for the treatment of bleeding in congenital hemophilia patients with > 5 Bethesda Units (BU) of inhibitors of factor VIII or IX, congenital hemophilia patients predicted to have a high memory response to injection of factor VIII or IX, acquired hemophilia patients, congenital Factor VII (FVII) deficiency patients, and platelet-membrane glycoprotein IIb-IIa (GPIIb-IIa) and/or Human Leukocyte Antigen (HLA) antibodies and in patients with platelet inotropic disorders who have been or are now ineffective or poor in platelet infusion, as well as for the prevention of bleeding in surgical or invasive procedures.
In practice, it has been found that the stability of nootken is not ideal and that a recombinant human factor VIIa pharmaceutical composition with better stability needs to be developed to accommodate the requirements of mass production, transportation and long-term storage.
Disclosure of Invention
In one aspect, the present application provides a liquid pharmaceutical composition comprising recombinant human factor VIIa, glycylglycine, sodium chloride, calcium chloride dihydrate, mannitol, sucrose, methionine and 0.2-0.75 mg/mL polysorbate 80.
In some embodiments, the liquid pharmaceutical composition comprises 0.67-1 mg/mL recombinant human factor VIIa, preferably 0.67 mg/mL or 1 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 0.88-1.32 mg/mL glycylglycine, preferably 0.88 mg/mL or 1.32 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 1.56-2.34 mg/mL sodium chloride, preferably 1.56 mg/mL or 2.34 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 0.98-1.47 mg/mL calcium chloride dihydrate, preferably 0.98 mg/mL or 1.47 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 16.7-25 mg/mL mannitol, preferably 16.7 mg/mL or 25 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 6.7-10 mg/mL sucrose, preferably 6.7 mg/mL or 10 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 0.33-0.5 mg/mL methionine, preferably 0.33 mg/mL or 0.5 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 0.2 mg/mL, 0.25 mg/mL, 0.3 mg/mL, 0.35 mg/mL, 0.4 mg/mL, 0.45 mg/mL, 0.5 mg/mL, 0.55 mg/mL, 0.6 mg/mL, 0.65 mg/mL, 0.7 mg/mL, or 0.75 mg/mL polysorbate 80.
In some embodiments, the liquid pharmaceutical composition comprises 0.67-1 mg/mL recombinant human factor VIIa, 0.88-1.32 mg/mL glycylglycine, 1.56-2.34 mg/mL sodium chloride, 0.98-1.47 mg/mL calcium chloride dihydrate, 16.7-25 mg/mL mannitol, 6.7-10 mg/mL sucrose, 0.33-0.5 mg/mL methionine, and 0.3-0.75 mg/mL polysorbate 80.
In some embodiments, the liquid pharmaceutical composition comprises 0.67-1 mg/mL recombinant human factor VIIa, 0.88-1.32 mg/mL glycylglycine, 1.56-2.34 mg/mL sodium chloride, 0.98-1.47 mg/mL calcium chloride dihydrate, 16.7-25 mg/mL mannitol, 6.7-10 mg/mL sucrose, 0.33-0.5 mg/mL methionine, and 0.3 mg/mL, 0.35 mg/mL, 0.4 mg/mL, 0.45 mg/mL, 0.5 mg/mL, 0.55 mg/mL, 0.6 mg/mL, 0.65 mg/mL, 0.7 mg/mL, or 0.75 mg/mL polysorbate 80.
In some embodiments, the liquid pharmaceutical composition comprises 0.67 mg/mL recombinant human factor VIIa, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.3-0.5 mg/mL polysorbate 80.
In some embodiments, the polysorbate 80 concentration is 0.3 mg/mL, 0.4 mg/mL, or 0.5 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 0.67 mg/mL recombinant human factor VIIa, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.3 mg/mL, 0.4 mg/mL, or 0.5 mg/mL polysorbate 80.
In some specific embodiments, the liquid pharmaceutical composition comprises 0.67 mg/mL recombinant human factor VIIa, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.3 mg/mL polysorbate 80.
In some specific embodiments, the liquid pharmaceutical composition comprises 0.67 mg/mL recombinant human factor VIIa, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.4 mg/mL polysorbate 80.
In some specific embodiments, the liquid pharmaceutical composition comprises 0.67 mg/mL recombinant human factor VIIa, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.5 mg/mL polysorbate 80.
In some embodiments, the liquid pharmaceutical composition comprises 1. 1 mg/mL recombinant human factor VIIa, 1.32 mg/mL glycylglycine, 2.34 mg/mL sodium chloride, 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10 mg/mL sucrose, 0.5 mg/mL methionine, and 0.45-0.75 mg/mL polysorbate 80.
In some embodiments, the polysorbate 80 concentration is 0.45 mg/mL, 0.6 mg/mL, or 0.75 mg/mL.
In some embodiments, the liquid pharmaceutical composition comprises 1. 1 mg/mL recombinant human factor VIIa, 1.32 mg/mL glycylglycine, 2.34 mg/mL sodium chloride, 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10 mg/mL sucrose, 0.5 mg/mL methionine, and 0.45 mg/mL, 0.6 mg/mL, or 0.75 mg/mL polysorbate 80.
In some specific embodiments, the liquid pharmaceutical composition comprises 1. 1 mg/mL recombinant human factor VIIa, 1.32. 1.32 mg/mL glycylglycine, 2.34. 2.34 mg/mL sodium chloride, 1.47. 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10. 10 mg/mL sucrose, 0.5. 0.5 mg/mL methionine, and 0.45. 0.45 mg/mL polysorbate 80.
In some specific embodiments, the liquid pharmaceutical composition comprises 1. 1 mg/mL recombinant human factor VIIa, 1.32. 1.32 mg/mL glycylglycine, 2.34. 2.34 mg/mL sodium chloride, 1.47. 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10. 10 mg/mL sucrose, 0.5. 0.5 mg/mL methionine, and 0.6. 0.6 mg/mL polysorbate 80.
In some specific embodiments, the liquid pharmaceutical composition comprises 1. 1 mg/mL recombinant human factor VIIa, 1.32. 1.32 mg/mL glycylglycine, 2.34. 2.34 mg/mL sodium chloride, 1.47. 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10. 10 mg/mL sucrose, 0.5. 0.5 mg/mL methionine, and 0.75. 0.75 mg/mL polysorbate 80.
In some embodiments, the liquid pharmaceutical composition does not contain or comprises histidine. In some specific embodiments, the liquid pharmaceutical composition is histidine-free. In some specific embodiments, the liquid pharmaceutical composition further comprises histidine.
In some embodiments, the histidine is at a concentration of 10 mM.
In some embodiments, the liquid pharmaceutical composition has a pH of 6.0±0.5.
In some embodiments, the recombinant human factor VIIa comprises the sequences shown as SEQ ID NO. 2 and/or SEQ ID NO. 3.
In another aspect, the present application provides a lyophilized formulation obtained from the liquid pharmaceutical composition after lyophilization or the lyophilized formulation may be reconstituted to form the liquid pharmaceutical composition.
In another aspect, the present application provides a pharmaceutical composition comprising 1. 1 mg recombinant human factor VIIa, 1.32. 1.32 mg glycylglycine, 2.34. 2.34 mg sodium chloride, 1.47. 1.47 mg calcium chloride dihydrate, 25. 25 mg mannitol, 10 mg sucrose, 0.5. 0.5 mg methionine and 0.45-0.75 mg polysorbate 80.
In some embodiments, the polysorbate 80 is 0.45 mg, 0.6 mg, or 0.75 mg.
In some embodiments, the pharmaceutical composition comprises 1 mg recombinant human factor viia, 1.32 mg glycylglycine, 2.34 mg sodium chloride, 1.47 mg calcium chloride dihydrate, 25 mg mannitol, 10 mg sucrose, 0.5 mg methionine, and 0.45 mg, 0.6 mg, or 0.75 mg polysorbate 80.
In some specific embodiments, the pharmaceutical composition comprises 1 mg recombinant human factor viia, 1.32 mg glycylglycine, 2.34 mg sodium chloride, 1.47 mg calcium chloride dihydrate, 25 mg mannitol, 10 mg sucrose, 0.5 mg methionine, and 0.45 mg polysorbate 80.
In some specific embodiments, the pharmaceutical composition comprises 1 mg recombinant human factor viia, 1.32 mg glycylglycine, 2.34 mg sodium chloride, 1.47 mg calcium chloride dihydrate, 25 mg mannitol, 10 mg sucrose, 0.5 mg methionine, and 0.6 mg polysorbate 80.
In some specific embodiments, the pharmaceutical composition comprises 1 mg recombinant human factor viia, 1.32 mg glycylglycine, 2.34 mg sodium chloride, 1.47 mg calcium chloride dihydrate, 25 mg mannitol, 10 mg sucrose, 0.5 mg methionine, and 0.75 mg polysorbate 80.
In some embodiments, the pharmaceutical composition has a pH of 6.0±0.5.
In some embodiments, the recombinant human factor VIIa comprises the sequences shown as SEQ ID NO. 2 and/or SEQ ID NO. 3.
In another aspect, the present application provides the use of the liquid pharmaceutical composition, the lyophilized formulation or the pharmaceutical composition in the manufacture of a medicament for preventing or treating bleeding in a subject.
In another aspect, the present application provides the use of said liquid pharmaceutical composition, said lyophilized formulation or said pharmaceutical composition for the preparation of a medicament for the treatment of congenital hemophilia patients with inhibitors of factor viii or ix > 5 Bethesda Units (BU), congenital hemophilia patients expected to have a high memory response to injection of factor viii or factor ix, acquired hemophilia patients, congenital factor vii (vii) deficiency patients, or patients with platelet membrane glycoprotein iib-iia (GP iib-iia) and/or Human Leukocyte Antigen (HLA) antibodies and bleeding from patients with platelet weakness who were or are not currently ineffective or ill with platelet infusion, or for the prevention and treatment of bleeding from surgical or invasive procedures.
In some embodiments, the liquid pharmaceutical composition, lyophilized formulation, or pharmaceutical composition is administered to the subject by a parenteral route. In some embodiments, the liquid pharmaceutical composition, lyophilized formulation, or pharmaceutical composition is administered to the subject subcutaneously, intravenously, or intramuscularly. In some specific embodiments, the liquid pharmaceutical composition, lyophilized formulation, or pharmaceutical composition is administered to the subject intravenously.
In yet another aspect, the present application provides an article of manufacture comprising a vial containing the pharmaceutical composition.
In some embodiments, the article further comprises a prefilled needle containing a histidine solution.
In some embodiments, the article of manufacture further comprises instructions for administering recombinant human factor VIIa to a subject to prevent or treat bleeding.
In some embodiments, the dose of histidine is 1.55 mg. In some embodiments, the histidine is at a concentration of 10 mM.
The Tagg of the pharmaceutical composition provided by the application is more than 50 ℃, and the visible foreign matters and the polymers generated after shaking are few, and the polymers generated after long-term storage are few. The pharmaceutical compositions provided herein have improved stability, such as colloidal stability, shaking stability, and improvement in the stability of lyophilized finished products.
Detailed Description
Terminology
The term "recombinant human factor VIIa" refers to an active form of natural (wild-type) human factor VII prepared by recombinant techniques, recombinant human factor VIIa in this applicationSequence and marketed product nocarpus ® (recombinant human factor VIIa for injection, novo Nordisk A/S, denmark) the recombinant human factor VIIa has the same sequence. Natural human factor VII consists of 406 amino acid residues (SEQ ID NO: 1), and its active form human factor VIIa consists of two peptide chains (SEQ ID NO: 2 and SEQ ID NO: 3) linked by disulfide bonds.
SEQ ID NO. 1 sequence is shown below:
ANAFLXLRXLRPGSLXRXCKQCXQXXQSXXARXIFKTKLFWISYQCASQNGSQQLQQLICFCLPAFEGRNGKDQGQNEGQSDGTKRCSchschargyslassmallTYPCGKIPILEKRREQGRIVGGKVCPKGECPQLLVQLCGGTLIWVVSAAHVKVQNKNW NKUVLPQSRSRVQVQVIQVIPTYVPGQGTTQLLHQVQVTQVTQVQVQVQQVQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQV V, the process comprises, the process comprises, X is gamma-carboxyglutamic acid.
SEQ ID NO. 2 sequence is shown below:
ANAFLXXLRPGSLXRXCKXXQQXXXXARXIFKFKTKTKLFKLFKWisQASDSQNGGSCKQLQSQSiCOCCLPFCLPAFEGTKDQLICVNENGGCEQYCSDHTKRCSchrchNGUGYSLLADGVSCTTVEYPYPQCGKIPILEKRNASKPQGR the process comprises, the process comprises, X is gamma-carboxyglutamic acid.
SEQ ID NO. 3 sequence is shown below:
IVGGKVCPKGECPWQVLLLVNGAQLCGGTLINTIWVVSAAHCFDKIKNWRNLIAVLGEHDLSEHDGDEQSRRVAQVIIPSTYVPGTTNHDIALLRLHQPVVLTDHVVPLCLPERTFSERTLAFVRFSLVSGWGQLLDRGATALELMVLNVPRLMTQDCLQQSRKVGDSPNITEYMFCAGYSDGSKDSCKGDSGGPHATHYRGTWYLTGIVSWGQGCATVGHFGVYTRVSQYIEWLQKLMRSEPRPGVLLRAPFP。
the term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application or pharmaceutical combinations thereof and pharmaceutically acceptable excipients.
The term "treatment" generally refers to an operation to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the prevention of the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partially or completely stabilizing or curing the disease and/or side effects resulting from the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including but not limited to preventing the occurrence or recurrence of the disease, alleviating symptoms of the disease, reducing any direct or indirect pathological consequences of the disease, preventing metastasis of the disease, slowing the progression of the disease, ameliorating or alleviating the status of the disease, extending the frequency and duration of the asymptomatic phase, and resolving or improving the prognosis of the disease.
The terms "subject" or "patient" are used interchangeably herein. "subject" or "patient" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the term "subject" or "patient" is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.
The term "lyophilization", i.e. "freeze-drying", encompasses the process of removing a liquid from a dissolved or at least partially dissolved composition under conditions involving at least one step of cooling the dissolved/partially dissolved solution to ice followed by vacuum drying.
The terms "comprising" or "including" are to be construed in an open, non-exclusive sense, i.e. "including but not limited to.
As used herein, "about" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation per the practice of the art. Alternatively, "about" may mean a range of up to + -5%, e.g., fluctuating within + -2%, within + -1%, or within + -0.5% of a given specific numerical range. When a particular value is given in the application or in the claims, unless otherwise indicated, the meaning of "about" is to be considered within the acceptable error of that particular value. In this context, all values relating to dose, time, step parameters or conditions are by default modified by "about" unless otherwise indicated.
Examples
Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this disclosure that certain changes and modifications may be additionally made thereto without departing from the spirit or scope of the appended claims. The following examples are provided by way of illustration only and are not intended to be limiting. Those skilled in the art will readily recognize a variety of non-critical parameters that may be changed or modified to produce substantially similar results.
All reagents used in the examples, unless otherwise indicated, were commercially available.
The present disclosure also provides the following specific embodiments, but is not limited thereto:
embodiment 1. A liquid pharmaceutical composition comprising 0.67-1 mg/mL recombinant human factor VIIa, 0.88-1.32 mg/mL glycylglycine, 1.56-2.34 mg/mL sodium chloride, 0.98-1.47 mg/mL calcium chloride dihydrate, 16.7-25 mg/mL mannitol, 6.7-10 mg/mL sucrose, 0.33-0.5 mg/mL methionine and 0.3-0.75 mg/mL polysorbate 80.
Embodiment 2. The liquid pharmaceutical composition of embodiment 1, comprising 0.67 mg/mL recombinant human factor VIIa, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.3-0.5 mg/mL polysorbate 80.
Embodiment 3. The liquid pharmaceutical composition of embodiment 2, the concentration of polysorbate 80 is 0.3 mg/mL, 0.4 mg/mL, or 0.5 mg/mL.
Embodiment 4. The liquid pharmaceutical composition of embodiment 1, comprising 1. 1 mg/mL recombinant human factor VIIa, 1.32 mg/mL glycylglycine, 2.34 mg/mL sodium chloride, 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10 mg/mL sucrose, 0.5 mg/mL methionine, and 0.45-0.75 mg/mL polysorbate 80.
Embodiment 5. The liquid pharmaceutical composition of embodiment 4, the concentration of polysorbate 80 is 0.45 mg/mL, 0.6 mg/mL, or 0.75 mg/mL.
Embodiment 6. The liquid pharmaceutical composition according to any of embodiments 1-5, which is histidine-free.
Embodiment 7. The liquid pharmaceutical composition according to any of embodiments 1-5, further comprising histidine.
Embodiment 8. The liquid pharmaceutical composition of embodiment 7, wherein the histidine is at a concentration of 10 mM.
Embodiment 9. The liquid pharmaceutical composition according to any of embodiments 1-8, having a pH of 6.0.+ -. 0.5.
Embodiment 10. A lyophilized formulation obtained from the liquid pharmaceutical composition of any one of embodiments 1-9 after lyophilization or the lyophilized formulation may be reconstituted to form the liquid pharmaceutical composition of any one of embodiments 1-9.
Embodiment 11. A pharmaceutical composition comprising 1 mg recombinant human factor viia, 1.32. 1.32 mg glycylglycine, 2.34. 2.34 mg sodium chloride, 1.47. 1.47 mg calcium chloride dihydrate, 25. 25 mg mannitol, 10 mg sucrose, 0.5 mg methionine, and 0.45-0.75 mg polysorbate 80.
Embodiment 12. The pharmaceutical composition of embodiment 11, the polysorbate 80 is 0.45 mg, 0.6 mg, or 0.75 mg.
Embodiment 13. The pharmaceutical composition according to any of embodiments 11-12, having a pH of 6.0.+ -. 0.5.
Embodiment 14. Use of the liquid pharmaceutical composition according to any of embodiments 1-9, the lyophilized formulation of embodiment 10 or the pharmaceutical composition of any of embodiments 11-13 in the manufacture of a medicament for preventing or treating bleeding in a subject.
Embodiment 15 use of the liquid pharmaceutical composition according to any of embodiments 1-9, the lyophilized formulation of embodiment 10 or the pharmaceutical composition of any of embodiments 11-13 for the manufacture of a medicament for the treatment of congenital hemophilia patients with inhibitors of blood coagulation factor viii or ix > 5 Bethesda Units (BU), congenital hemophilia patients expected to have a high memory response to injection of blood coagulation factor viii or ix, acquired hemophilia patients, congenital blood coagulation factor vii (vii) deficiency patients, or patients with platelet membrane glycoprotein iib-iia (GP iib-iia) and/or Human Leukocyte Antigen (HLA) antibodies and previous or now ineffective or poor platelet transfusion in platelet weakness patients, or for the prevention and treatment of bleeding in surgical or invasive procedures.
Embodiment 16. The use according to any of embodiments 14-15, the liquid pharmaceutical composition, lyophilized formulation or pharmaceutical composition is administered intravenously to a subject.
Embodiment 17 an article of manufacture comprising a vial containing the pharmaceutical composition of any one of embodiments 11-13.
Embodiment 18 the article of embodiment 17, further comprising a prefilled needle containing a histidine solution.
Embodiment 19 the article of manufacture of any of embodiments 17-18, further comprising instructions for administering recombinant human factor VIIa to a subject to prevent or treat bleeding.
Embodiment 20 the article of any one of embodiments 18-19, wherein the dose of histidine is 1.55 mg.
Embodiment 21 the article of any one of embodiments 18-20, wherein the histidine is at a concentration of 10 mM.
Embodiment 22. The liquid pharmaceutical composition according to any of embodiments 1-9 or the pharmaceutical composition according to any of embodiments 11-13, wherein the recombinant human factor VIIa comprises the sequences shown in SEQ ID NO. 2 and/or SEQ ID NO. 3.
EXAMPLE 1 Effect of different concentrations of Polysorbate 80 in pharmaceutical compositions on colloidal stability
Compositions are prepared from a large number of solutions of purified recombinant human factor VIIa, surfactants and other stabilizers are added, and the solution is diluted to the desired recombinant human factor VIIa concentration. Compositions containing different concentrations of polysorbate 80 as shown in Table 1 were prepared, compositions numbered F1-F5 contained fixed concentrations of recombinant human factor VIIa (0.67 mg/mL), glycylglycine (0. 0.88 mg/mL), sodium chloride (1.56 mg/mL), calcium chloride dihydrate (0.98 mg/mL), mannitol (16.7 mg/mL), sucrose (6.7 mg/mL), methionine (0.33 mg/mL) and different concentrations of polysorbate 80, the composition pH was 6.0.+ -. 0.5.
Table 1 concentration of polysorbate 80 in the compositions
Tagg (Aggregation Temperature ) detection: when the protein solution is subjected to heat treatment, the protein molecules in the solution gradually change from the folded state of the peptide chain to the stretched or unfolded state of the peptide chain (it is also possible that the folding of the individual domains of the protein molecules is opened); it is generally believed that the higher the thermal denaturation temperature, the more stable the protein molecule. Tagg refers to the initial phase of the aggregation behavior of protein molecules that begins during heating of a protein solution.
The Tagg detection method comprises the following steps: the Tagg of the samples was measured using Dynapro Plate Reader iii (Wyatt), the samples were added to 384 well sample trays, the plates were sealed, the 384 well sample trays were centrifuged to remove air bubbles, and the measurement was performed as follows: the temperature program was from 25℃to 85℃and the scan time was 5 seconds.
Colloidal stability was assessed by comparing Tagg of the different composition solutions. Tagg test results for different composition solutions are shown in Table 2. The results show that after the concentration of polysorbate 80 in the composition is increased, the colloidal stability of the composition solution is obviously improved.
TABLE 2 composition solution Tagg
EXAMPLE 2 Effect of different levels of Polysorbate 80 in pharmaceutical compositions on shaking stability
Compositions containing polysorbate 80 at various concentrations were prepared as described in example 1, and solutions of the above compositions were packaged into sterile glass vials at 1.5mL per vial containing fixed amounts of recombinant human factor VIIa (1 mg), glycylglycine (1.32 mg), sodium chloride (2.34 mg), calcium chloride dihydrate (1.47 mg), mannitol (25 mg), sucrose (10 mg), methionine (0.5 mg) and polysorbate 80 after secondary filtration using a 0.22 μm sterile filter membrane in an ultra clean bench. The polysorbate 80 content of the F1-F5 composition is shown in Table 3.
Table 3 polysorbate 80 content in the composition
Vials of the different compositions were shaken at 250 rpm and sampled at 1 and 3 minutes to detect visible foreign matter in the solution and size exclusion chromatography (SEC-HPLC) polymers to compare the shaking stability of the different compositions.
SEC-HPLC assay method: a Waters ACQUITY UPLC Protein BEH SEC Column (200 a, 1.7 μm,4.6 mm ×300× 300 mm) column was used, the pre-column being Waters ACQUITY UPLC Protein BEH SEC Guard Column (200 a, 1.7 μm,4.6 mm ×30 mm); the column temperature is not controlled; the mobile phase is 50 mmol/L phosphate-200 mmol/L sodium chloride solution; the flow rate is 0.3 mL/min; isocratic elution for 20 minutes; the ultraviolet detection wavelength was 215 nm. Taking 10 mug of each of the test sample solution and the physicochemical reference substance solution, and injecting the protein into a liquid chromatograph. The results were analyzed using an area normalization method.
The visible foreign matter and SEC-HPLC polymer detection results for the different composition solutions are shown in tables 4 and 5. After the content of polysorbate 80 is increased, the higher the content of polysorbate 80 in the composition, the less visible foreign matter is generated after shaking. The increase in polysorbate 80 content significantly inhibited the particle growth caused by shaking. Meanwhile, compared with the composition before shaking, the polymer content of the composition solution is increased after shaking, the SEC polymer increase amplitude of F3-F5 is smaller than that of F1, and the SEC polymer increase amplitude of F5 is minimum.
TABLE 4 visible foreign matter results for composition solutions
Note that: indicating that no visible foreign bodies were recorded anymore due to turbidity of the sample.
Table 5 results of SEC polymers before and after shaking of the composition solution
EXAMPLE 3 Effect of different Polysorbate 80 levels in pharmaceutical compositions on the stability of lyophilized finished products
1.5mL of the composition F1 and F5 per bottle was prepared as described in example 2. The samples in the vials were lyophilized and sealed with an aluminum plastic combination cap. The final product was placed at 25 ℃ and 40 ℃ and the stability of the lyophilized final product of each composition was compared. At the time points shown in Table 7, the lyophilized product was reconstituted with 1 mL histidine solution (10 mmol/L) to give compositions F1a and F5a, with the following concentrations of each component in F1a and F5 a: recombinant human factor VIIa (1 mg/mL), glycylglycine (1.32 mg/mL), sodium chloride (2.34 mg/mL), calcium chloride dihydrate (1.47 mg/mL), mannitol (25 mg/mL), sucrose (10 mg/mL), methionine (0.5 mg/mL), polysorbate 80 and histidine (1.55 mg/mL), the concentration of polysorbate 80 in the reconstituted solution is shown in Table 6, and the pH of the reconstituted solution is 6.0.+ -. 0.5.
TABLE 6 concentration of polysorbate 80 in reconstituted solution
The stability of the polysorbate 80 compositions with different contents was evaluated by SEC detection of the polymers by taking the redissolved solutions and the detection results are shown in table 7. The SEC-HPLC multimer detection showed that F1a multimer increased by 0.87% and F5a multimer increased by 0.15% by less than F1a when left at 40℃for 3 months.
The SEC-HPLC dimer/oligomer detection showed that F1a dimer/oligomer increased by 0.43% and F5a multimer increased by 0.1% by less than F1a when left at 40℃for 3 months.
The above results indicate that the stability of F5a is higher.
TABLE 7 stability of Polysorbate 80 compositions of varying levels
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Claims (21)

1. A liquid pharmaceutical composition comprising 0.67-1 mg/mL recombinant human factor viia, 0.88-1.32 mg/mL glycylglycine, 1.56-2.34 mg/mL sodium chloride, 0.98-1.47 mg/mL calcium chloride dihydrate, 16.7-25 mg/mL mannitol, 6.7-10 mg/mL sucrose, 0.33-0.5 mg/mL methionine, and 0.3-0.75 mg/mL polysorbate 80.
2. The liquid pharmaceutical composition of claim 1, comprising 0.67 mg/mL recombinant human factor viia, 0.88 mg/mL glycylglycine, 1.56 mg/mL sodium chloride, 0.98 mg/mL calcium chloride dihydrate, 16.7 mg/mL mannitol, 6.7 mg/mL sucrose, 0.33 mg/mL methionine, and 0.3-0.5 mg/mL polysorbate 80.
3. The liquid pharmaceutical composition of claim 2, wherein the concentration of polysorbate 80 is 0.3 mg/mL, 0.4 mg/mL, or 0.5 mg/mL.
4. The liquid pharmaceutical composition of claim 1, comprising 1. 1 mg/mL recombinant human factor viia, 1.32 mg/mL glycylglycine, 2.34 mg/mL sodium chloride, 1.47 mg/mL calcium chloride dihydrate, 25 mg/mL mannitol, 10 mg/mL sucrose, 0.5 mg/mL methionine, and 0.45-0.75 mg/mL polysorbate 80.
5. The liquid pharmaceutical composition of claim 4, wherein the concentration of polysorbate 80 is 0.45 mg/mL, 0.6 mg/mL, or 0.75 mg/mL.
6. The liquid pharmaceutical composition according to any one of claims 1-5, characterized in that it is histidine-free.
7. The liquid pharmaceutical composition of any one of claims 1-5, further comprising histidine.
8. The liquid pharmaceutical composition of claim 7, wherein the histidine is at a concentration of 10 mM.
9. The liquid pharmaceutical composition of claim 1, wherein the pH is 6.0±0.5.
10. A lyophilized formulation, characterized in that it is obtained from the liquid pharmaceutical composition according to any one of claims 1-9 after lyophilization or that the lyophilized formulation can be reconstituted to form the liquid pharmaceutical composition according to any one of claims 1-9.
11. A pharmaceutical composition comprising 1. 1 mg recombinant human factor vila, 1.32. 1.32 mg glycylglycine, 2.34. 2.34 mg sodium chloride, 1.47. 1.47 mg calcium chloride dihydrate, 25. 25 mg mannitol, 10 mg sucrose, 0.5 mg methionine, and 0.45-0.75 mg polysorbate 80.
12. The pharmaceutical composition of claim 11, wherein the polysorbate 80 is 0.45 mg, 0.6 mg or 0.75 mg.
13. The pharmaceutical composition according to any one of claims 11-12, wherein the pH is 6.0±0.5.
14. Use of a liquid pharmaceutical composition according to any one of claims 1-9, a lyophilized formulation according to claim 10 or a pharmaceutical composition according to any one of claims 11-13 in the manufacture of a medicament for preventing or treating bleeding in a subject.
15. Use of a liquid pharmaceutical composition according to any one of claims 1-9, a lyophilized formulation according to claim 10 or a pharmaceutical composition according to any one of claims 11-13 for the manufacture of a medicament for the treatment of congenital hemophilia patients with inhibitors of blood coagulation factor viii or ix > 5 Bethesda units, congenital hemophilia patients expected to have a high memory response to injection of blood coagulation factor viii or ix, acquired hemophilia patients, congenital hemophilia vii deficiency patients bleeding, or for the prevention and treatment of surgical or invasive procedure bleeding.
16. The use according to any one of claims 14-15, wherein the liquid pharmaceutical composition, lyophilized formulation or pharmaceutical composition is administered intravenously to a subject.
17. An article of manufacture comprising a vial containing the pharmaceutical composition of any one of claims 11-13.
18. The article of manufacture of claim 17, further comprising a prefilled needle containing a histidine solution.
19. The article of manufacture of claim 18, wherein the histidine is at a dose of 1.55 mg.
20. The article of manufacture of claim 18, wherein the histidine is at a concentration of 10 mM.
21. The liquid pharmaceutical composition according to claim 1 or the pharmaceutical composition according to claim 11, wherein the recombinant human factor vila comprises the sequence shown in SEQ ID No. 2 and/or SEQ ID No. 3.
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Citations (5)

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Publication number Priority date Publication date Assignee Title
RU94032143A (en) * 1992-10-02 1996-08-20 Каби Фармациа АБ (SE) Composition containing the preparation of coagulation factor viii, method of its preparing and the use of surface-active substance as stabilizing agent
US20040248793A1 (en) * 2002-06-21 2004-12-09 Jensen Michael Bech Stabilised solid compositions of factor VII polypeptides
CN101466400A (en) * 2006-04-07 2009-06-24 诺沃-诺迪斯克保健股份有限公司 Covalent factor VII-tissue factor complex
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US20040248793A1 (en) * 2002-06-21 2004-12-09 Jensen Michael Bech Stabilised solid compositions of factor VII polypeptides
AU2012213951A1 (en) * 2005-04-28 2012-09-06 Novo Nordisk Health Care Ag A closed container comprising an activated factor VII polypeptide, processes for the preparation of the same, and a kit and a method for use of the kit
CN101466400A (en) * 2006-04-07 2009-06-24 诺沃-诺迪斯克保健股份有限公司 Covalent factor VII-tissue factor complex
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