CN113117071A - Freeze-dried preparation of aglycosylated anti-PD-1 monoclonal antibody - Google Patents
Freeze-dried preparation of aglycosylated anti-PD-1 monoclonal antibody Download PDFInfo
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Classifications
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- 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
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
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- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
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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
- A61K47/26—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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
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- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a freeze-dried preparation of a glycosylation-free anti-PD-1 monoclonal antibody, which comprises the glycosylation-free anti-PD-1 monoclonal antibody, a buffer channel system, an excipient and a solubilizer. The invention adds an annealing step in the freeze-drying process, and the freeze-drying preparation has simple formula and fewer auxiliary materials, further reduces the water content of the freeze-drying powder, improves the stability of the medicine, and is convenient to store and transport.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a freeze-dried preparation of a sugarless anti-PD-1 monoclonal antibody.
Background
Programmed Death receptor-1 (PD-1) is a 288 amino acid type I membrane protein, is consistent with one of the major Immune checkpoints (Immune Checkpoint). PD-1 is used as an immunosuppressive receptor, is mainly used in activating T cells and B cells, is used as a T cell inhibitory receptor, is combined with a ligand PD-L1, can inhibit the activity of T lymphocytes and related in vivo cellular immune response, can limit the functions of T cell effectors in tumor cells, and has an important role in tumor immune escape. Tumor immunotherapy, i.e. the use of the body's own immune system to combat cancer, is a breakthrough method for tumor therapy, but the tumor microenvironment protects tumor cells from effective immune destruction, so how to break the tumor microenvironment is the focus of anti-tumor research.
The role of PD-1 in the tumor microenvironment has been determined by prior work: PD-L1 is expressed in many mouse and human tumors (and can be induced by IFN γ in most PD-L1 negative tumor cell lines) and is presumed to be an important target for mediating tumor immune evasion. Biopsies were evaluated by immunohistochemistry, and acetonitrile found expression of PD-1 (on tumor infiltrating lymphocytes) and/or PD-L1 on tumor cells in many primary tumors in humans. Such tissues include lung cancer, liver cancer, ovarian cancer, cervical cancer, skin cancer, colon cancer, glioma, bladder cancer, breast cancer, kidney cancer, esophageal cancer, stomach cancer, oral squamous cell carcinoma, urothelial cell carcinoma, pancreatic cancer, head and neck tumors, and the like. Therefore, the blocking of the interaction of PD-1/PD-L1 can improve the immunocompetence of tumor specific T cells and is beneficial to the immune system to eliminate tumor cells, so that PD-1 is called a hot target for developing tumor immunotherapy drugs.
Currently, the development of anti-PD-1 monoclonal antibodies such as opdivo, keytruda, etc. has been approved for the market in foreign countries. However, the antibodies have low response rate as single drugs, glycosylation modification on the monoclonal antibody is knocked out, the process development is stable, the uniformity is improved, and better clinical effect is expected to be obtained, but compared with other anti-PD-1 monoclonal antibodies, the sensitivity of the monoclonal antibody to trypsin and the like is obviously improved due to glycosylation removal, the structural flexibility is enhanced, the monoclonal antibody has a tendency of polymer formation under low pH, and the monoclonal antibody is easy to aggregate and precipitate. In order to prevent the proteins from being denatured during storage before use, and loss of activity or structural integrity due to aggregation, it is necessary to develop a formulation process for the aglycosylated anti-PD-1 monoclonal antibody.
Generally, proteins have a very short half-life and undergo denaturation (e.g., aggregation, dissociation and adsorption to container surfaces) after exposure to various factors (e.g., unfavorable temperatures, water-gas interface, high pressure, physical/mechanical stress, organic solvents and microbial contamination). Thus, denatured proteins lose their intrinsic physicochemical properties and physiological activities. Denaturation of proteins is generally irreversible, and thus, proteins, once denatured, may not return to their original state in their native nature.
The prior art formulations of PD-1 are mostly liquid formulations, however, in the biopharmaceutical industry, long-term storage of proteins prepared using recombinant DNA techniques in aqueous formulations is often a difficult task. In order to overcome the problem of stability of proteins in aqueous formulations, the present invention provides a lyophilized formulation of aglycosylated anti-PD-1 monoclonal antibody.
Disclosure of Invention
The invention aims to provide a stable aglycosylated anti-PD-1 monoclonal antibody freeze-dried preparation which is simple in formula, less in auxiliary materials, good in stability and convenient to store and transport.
The specific technical scheme of the invention is as follows:
a lyophilized preparation of aglycosylated anti-PD-1 monoclonal antibody contains the aglycosylated anti-PD-1 monoclonal antibody, a buffer system, an excipient and a solubilizer.
Wherein the buffer system is selected from one of acetic acid/sodium acetate, citric acid/sodium citrate and histidine/histidine hydrochloride.
Wherein the excipient is one or more selected from sucrose, trehalose, mannitol and sorbitol.
Wherein the solubilizer is selected from polysorbate 20 or polysorbate 80.
The pH value is adjusted by a buffer system, and the preferable pH value is 5.5-6.0.
Preferably, the lyophilized formulation of the stable aglycosylated anti-PD-1 monoclonal antibody comprises the following components:
further preferably, the lyophilized formulation of the stable aglycosylated anti-PD-1 monoclonal antibody comprises the following components:
the invention can be used as a protective agent without adding an amino acid stabilizer, and an excipient can be used for surrounding the protein, so that the movement of macromolecular substances is hindered, the spatial structure of protein molecules is maintained, and the aggregation of the protein molecules is prevented, thereby increasing the stability of the anti-PD-1 monoclonal antibody. The invention takes polysorbate 20 or polysorbate 80 as a solubilizer which is a nonionic surfactant, and can reduce the aggregation of antibodies in the preparation, the formation and adsorption of particles in the preparation and the like in a certain dosage range.
In a preferred embodiment, a stable lyophilized formulation of aglycosylated anti-PD-1 monoclonal antibody comprises the following components:
the invention also provides a preparation method of the antibody drug lyophilized preparation, which comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and antibody, adding the excipient, solubilizer and antibody into the buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, packaging, and lyophilizing.
Preferably, the lyophilization process comprises the following three steps of freezing control, primary drying and resolution drying, and specifically comprises the following steps:
(1) and (3) freezing control: placing a penicillin bottle filled with an antibody drug solution on a clapboard of a freeze dryer, pre-freezing at 5 ℃, maintaining for 15-60 min, cooling to-45 to-40 ℃, and maintaining for 2-6 h for freezing;
(2) primary drying: heating the temperature of the clapboard system to-20 to-15 ℃, maintaining the temperature for 40 to 50 hours, heating the temperature to 0 to 5 ℃, maintaining the temperature for 8 to 10 hours, and finishing primary drying;
(3) and (3) resolving and drying: and (3) heating the temperature of the clapboard system to 20-30 ℃, maintaining for 8-10 h for desorption and drying, and completing the freeze-drying process.
Further preferably, the freeze-drying process comprises the following three steps of freezing control, primary drying and resolution drying, and specifically comprises the following steps:
(1) and (3) freezing control: placing a penicillin bottle filled with an antibody drug solution on a partition board, keeping the temperature at 5 ℃ for 15-60 min, then setting the temperature of the partition board to-45-40 ℃, setting the time at 40-60 min to reach the preset temperature, maintaining the temperature for 2-6 h, setting the temperature of the partition board to-30-15 ℃, setting the time at 30-40 min to reach the preset temperature, maintaining the temperature for 1-3 h, finally resetting the temperature of the partition board to-45-40 ℃, setting the time at 30-40 min to reach the preset temperature, maintaining the temperature for 2-3 h, and ending the freezing control step;
(2) primary drying: carrying out primary drying on the system under the ultimate vacuum condition, setting the temperature of a partition plate to be-20 to-15 ℃, setting the time to reach the preset temperature for 40 to 60min, maintaining the preset temperature for 40 to 50h, then setting the temperature of the partition plate to be 0 to 5 ℃, setting the time to reach the preset temperature for 30 to 40min, and maintaining the preset temperature for 8 to 10h, thereby completing primary drying;
(3) and (3) resolving and drying: setting the temperature of the partition plate to be 20-30 ℃, setting the time to reach the set temperature for 40-60 min, and carrying out analysis drying for 8-10 h under the condition that the pressure of the box body is 0.1-0.2 mbar to finish the freeze-drying process.
The antibody drug of the invention is an anti-PD-1 monoclonal antibody, including but not limited to a glycosylated or aglycosylated anti-PD-1 monoclonal antibody.
In one embodiment, the lyophilization process for a lyophilized formulation of an aglycosylated anti-PD-1 monoclonal antibody is as follows:
in another embodiment, a lyophilization process for a lyophilized formulation of a aglycosylated anti-PD-1 monoclonal antibody is as follows:
in a preferred embodiment, the lyophilization process for a lyophilized formulation of aglycosylated anti-PD-1 monoclonal antibody is as follows:
the invention optimizes the formulation of the preparation and further improves the freeze-drying process to obtain the freeze-dried preparation of the aglycosylation anti-PD-1 monoclonal antibody, which has simple formulation, low water content of the freeze-dried preparation and good stability.
The amino acid sequence of the aglycosylated anti-PD-1 monoclonal antibody has been protected by a patent, and reference can be made to patent CN 106519034A. Experiments prove that the preparation can also be suitable for other glycosylated and non-glycosylated anti-PD-1 monoclonal antibodies.
The aglycosylated anti-PD-1 monoclonal antibody freeze-dried powder preparation has less auxiliary materials, further reduces the potential safety hazard of clinical medication, has low water content, good stability, full appearance, uniform texture and quick redissolution, and has multiple indexes of pH, clarity, color, purity, sterility and the like which meet the quality standard and are superior to the prior art. The preparation method of the aglycosylated anti-PD-1 monoclonal antibody freeze-dried powder preparation is simple in preparation process, suitable for amplification, capable of ensuring stable and controllable quality, good in drying effect, low in product moisture content and convenient to store and transport.
Detailed Description
The invention is further illustrated by the following examples, which are only part of a formulation screening assay and are not intended to limit the invention thereto. Test methods in which specific conditions are not specified in the following examples were selected in accordance with conventional methods and conditions, or in accordance with commercial instructions. The stability tests and related biological tests in the examples were performed according to the specifications of the Chinese pharmacopoeia, and the preparations described in the examples are all pharmaceutical grade and commercially available.
Example 1
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 2
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 3
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 4
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 5
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 6
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 7
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, arginine as a stabilizing agent, a solubilizer and a sugarless anti-PD-1 monoclonal antibody, adding the mixture into a buffer solution, and uniformly mixing to obtain a semi-finished product solution; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 8
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Example 9
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Comparative example 1
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Comparative example 2
Prescription:
the preparation process comprises the following steps:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Comparative example 3
Prescription:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Comparative example 4
Prescription:
weighing a prescription amount of buffer salt, dissolving the buffer salt with a proper amount of water for injection, adjusting the pH, sampling, detecting the qualified pH and endotoxin, accurately weighing a prescription amount of excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody, adding the excipient, solubilizer and aglycosylated anti-PD-1 monoclonal antibody into a buffer solution, and uniformly mixing to obtain a semi-finished product liquid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, bottling, and lyophilizing according to the following lyophilization process.
Verification examples
Stability test
Samples were prepared according to examples 1 to 9 and comparative examples 1 to 4, respectively, and 200 bottles were taken for each and the storage stability was examined by accelerated stability test and long-term test. The accelerated test was carried out at 25 ℃. + -. 2 ℃ for 12 months. The used equipment can control the temperature to +/-2 ℃ and monitor the actual temperature. Samples were taken at the end of 0, 3, 6, and 12 months during the test period and examined according to stability stress. The long-term test is carried out at the temperature of 2-8 ℃, and the test is carried out according to the stability key investigation items at the end of 0 month, 3 months, 6 months, 12 months and 24 months respectively; (wherein purity examination is determined by molecular sequencing chromatography and general rule 0542 capillary electrophoresis of the general rule 0514 of Chinese pharmacopoeia 2015 edition), and activity is determined by reporter gene method based on bioluminescence); the water content was measured by the coulometric method specified in the third general regulation of "2015 edition of Chinese pharmacopoeia" using a Mettler-Zaliduo DL37 Karl Fischer titrator. The results are shown in tables 1 and 2.
TABLE 12-8 ℃ long-term stability test results
TABLE 2 accelerated stability test results at 25 + -2 deg.C
Claims (10)
1. A lyophilized preparation of an aglycosylated anti-PD-1 monoclonal antibody, characterized by comprising the aglycosylated anti-PD-1 monoclonal antibody, a buffer system, an excipient and a solubilizer.
2. The lyophilized formulation according to claim 1, wherein the buffer system is selected from one of acetic acid/sodium acetate, citric acid/sodium citrate, histidine/histidine hydrochloride.
3. The lyophilized formulation according to claim 1, wherein the excipient is one or more selected from sucrose, trehalose, mannitol, and sorbitol.
4. The lyophilized formulation according to claim 1, wherein the solubilizer is selected from polysorbate 20 or polysorbate 80.
5. The lyophilized formulation according to claim 1, comprising the following components in amounts:
6. a method for preparing the freeze-dried preparation according to any one of claims 1 to 5, characterized in that, the prescription amount of buffer salt is weighed and dissolved by using a proper amount of water for injection, the pH is adjusted, after sampling and detecting the qualification of the pH and endotoxin, the prescription amount of excipient, solubilizer and sugar-free anti-PD-1 monoclonal antibody are accurately weighed and added into the buffer body fluid, and the mixture is uniformly mixed to obtain a semi-finished product fluid; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, packaging, and lyophilizing.
7. A preparation method of an antibody drug lyophilized preparation is characterized in that a prescription amount of buffer salt is weighed and dissolved by a proper amount of water for injection, the pH is adjusted, after sampling and detecting the qualification of the pH and endotoxin, a prescription amount of excipient, solubilizer and antibody are accurately weighed and added into buffer body fluid, and a semi-finished product liquid is obtained after uniform mixing; sterile filtering the semi-finished product with 0.22 μm filter membrane, detecting endotoxin, packaging, and lyophilizing.
8. The preparation method according to claim 6 or 7, wherein the lyophilization process comprises three stages of freeze drying, primary drying and desorption drying, and specifically comprises the following steps:
(1) and (3) freezing control: placing a penicillin bottle filled with an antibody drug solution on a clapboard of a freeze dryer, pre-freezing at 5 ℃, maintaining for 15-60 min, cooling to-45 to-40 ℃, and maintaining for 2-6 h for freezing;
(2) primary drying: heating the temperature of the clapboard system to-20 to-15 ℃, maintaining the temperature for 40 to 50 hours, heating the temperature to 0 to 5 ℃, maintaining the temperature for 8 to 10 hours, and finishing primary drying;
(3) and (3) resolving and drying: and (3) heating the temperature of the clapboard system to 20-30 ℃, maintaining for 8-10 h for desorption and drying, and completing the freeze-drying process.
9. The method of claim 8, comprising the steps of:
(1) and (3) freezing control: placing a penicillin bottle filled with an antibody drug solution on a partition board, keeping the temperature at 5 ℃ for 15-60 min, then setting the temperature of the partition board to-45-40 ℃, setting the time at 40-60 min to reach the preset temperature, maintaining the temperature for 2-6 h, setting the temperature of the partition board to-30-15 ℃, setting the time at 30-40 min to reach the preset temperature, maintaining the temperature for 1-3 h, finally resetting the temperature of the partition board to-45-40 ℃, setting the time at 30-40 min to reach the preset temperature, maintaining the temperature for 2-3 h, and ending the freezing control step;
(2) primary drying: carrying out primary drying on the system under the ultimate vacuum condition, setting the temperature of a partition plate to be-20 to-15 ℃, setting the time to reach the preset temperature for 40 to 60min, maintaining the preset temperature for 40 to 50h, then setting the temperature of the partition plate to be 0 to 5 ℃, setting the time to reach the preset temperature for 30 to 40min, and maintaining the preset temperature for 8 to 10h, thereby completing primary drying;
(3) and (3) resolving and drying: setting the temperature of the partition plate to be 20-30 ℃, setting the time to reach the set temperature for 40-60 min, and carrying out analysis drying for 8-10 h under the condition that the pressure of the box body is 0.1-0.2 mbar to finish the freeze-drying process.
10. The production method according to claim 7, wherein the antibody drug is an anti-PD-1 monoclonal antibody.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022268887A1 (en) * | 2021-06-23 | 2022-12-29 | Formycon Ag | Formulations of anti-pd1 antibodies |
| CN117825688A (en) * | 2024-01-19 | 2024-04-05 | 武汉鹰达生物科技有限公司 | Animal IgG antibody freeze-dried powder preparation and preparation process thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105708811A (en) * | 2014-12-01 | 2016-06-29 | 西藏海思科药业集团股份有限公司 | Stable lyophilized preparation of recombinant human anti-CD20 monoclonal antibody |
| CN110354073A (en) * | 2018-04-09 | 2019-10-22 | 鲁南制药集团股份有限公司 | A kind of liquid preparation of immunosuppressor monoclonal antibody |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105708811A (en) * | 2014-12-01 | 2016-06-29 | 西藏海思科药业集团股份有限公司 | Stable lyophilized preparation of recombinant human anti-CD20 monoclonal antibody |
| CN110354073A (en) * | 2018-04-09 | 2019-10-22 | 鲁南制药集团股份有限公司 | A kind of liquid preparation of immunosuppressor monoclonal antibody |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022268887A1 (en) * | 2021-06-23 | 2022-12-29 | Formycon Ag | Formulations of anti-pd1 antibodies |
| CN117825688A (en) * | 2024-01-19 | 2024-04-05 | 武汉鹰达生物科技有限公司 | Animal IgG antibody freeze-dried powder preparation and preparation process thereof |
| CN117825688B (en) * | 2024-01-19 | 2024-05-31 | 武汉鹰达生物科技有限公司 | Animal IgG antibody freeze-dried powder preparation and preparation process thereof |
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