CN114762727A - Stable pharmaceutical composition of pertuzumab - Google Patents
Stable pharmaceutical composition of pertuzumab Download PDFInfo
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
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- 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
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- 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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- 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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- 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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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
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- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/812—Breast
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/80—Vaccine for a specifically defined cancer
- A61K2039/828—Stomach
Abstract
The invention relates to a stable pertuzumab pharmaceutical composition, which comprises: (a) pertuzumab 3-60 mg/ml; (b) 5-40mM of methionine; (c) a stabilizer selected from sucrose, trehalose or arginine hydrochloride; (d) a surfactant; (e) a buffer, wherein the pH of the composition is from 5.0 to 6.8. The pharmaceutical composition provided by the invention has greatly improved stability and very wide market application prospect.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a pharmaceutical composition of pertuzumab, which contains methionine as an antioxidant.
Background
Pertuzumab is a novel anti-HER 2 monoclonal antibody, first marketed in the united states at 6 months 2012, primarily in combination with trastuzumab for the treatment of HER2 positive patients with advanced metastatic breast cancer. By binding to HER2, pertuzumab blocked heterodimerization of HER2 with other receptors, slowing tumor growth.
Pertuzumab belongs to humanized monoclonal antibody and is on the marketRoss (Roche) 
For the water injection preparation, the prescription on the market contains 30mg/mL of pertuzumab, 120mM of sucrose, 0.2mg/mL of polysorbate 80 and 20mM of histidine-acetic acid buffer solution, and the pH value of the solution is 6.0. Wherein, in the prescription, the pertuzumab is taken as a main drug; sucrose is used as a stabilizer; polysorbate 20 is a surfactant; histidine-acetic acid is used as pH regulator.
Like most protein molecules, pertuzumab is unstable and undergoes a variety of chemical and physical degradation. Compared with the traditional synthesized small molecule drugs, the biological molecules have complex structures, such as primary, secondary, tertiary and other high-level structures. The structure of proteins, especially higher order structures, is very fragile and subject to structural changes such as denaturation, aggregation and precipitation. The maintenance of the high-order structure of antibodies is the most essential requirement for their biological activity. The products of these degradations can have a significant impact on biopharmaceutical safety. In particular, some protein aggregates can stimulate the immune response of human body, and the curative effect of biological medicines can be reduced in the mild case and even death of patients can be caused in the severe case. Thus, multimers are considered to be a Critical Quality Attribute (CQA) of biopharmaceutical safety, directly affecting the safety of biopharmaceuticals, which is particularly important for long-term administered products such as pertuzumab. Antibody pharmaceuticals are not only required to be manufactured in high purity, but also to remain structurally stable during shipping, storage and use.
Therefore, there is a need to develop a novel pertuzumab formulation to improve the stability of the antibody, thereby improving the uniformity and consistency of the product quality and improving the stability in clinical use.
Disclosure of Invention
The invention aims to provide a stable pertuzumab composition and application thereof, and the composition prepared by the invention can still maintain physical and chemical stability under the damage of illumination or for a longer time, and is greatly improved compared with the prior art.
In one aspect, the present invention relates to a pharmaceutical composition comprising:
(a) pertuzumab 3-60 mg/ml;
(b) 5-40mM methionine;
(c) a stabilizer selected from sucrose, trehalose or arginine hydrochloride, preferably arginine hydrochloride;
(d) a surfactant;
(e) a buffer solution;
wherein the pH of the formulation is 5.0-6.8, preferably 5.0-6.0.
In one embodiment, the pertuzumab is at a concentration of 3-30 mg/ml.
In one embodiment, the pertuzumab concentration is 30-60 mg/ml.
In a preferred embodiment, the methionine concentration is 10-40mM, preferably 20-40 mM.
In a preferred embodiment, the concentration of the stabilizer is 100-.
In a preferred embodiment, the buffer is selected from glycine, acetic acid/acetate, succinic acid/succinate, citric acid/citrate, ascorbic acid/ascorbate, tartaric acid/tartrate, maleic acid/maleate, lactic acid/lactate, carbonate/bicarbonate, benzoic acid/benzoate, histidine/hydrochloric acid, histidine/acetic acid, phosphoric acid/phosphate or tris/tris hydrochloride, preferably histidine-hydrochloric acid, histidine-acetic acid, phosphoric acid/phosphate, more preferably histidine-hydrochloric acid, histidine-acetic acid.
In a preferred embodiment, the buffer is present in a concentration of 10-30mM, preferably 15-25 mM.
In a preferred embodiment, the surfactant includes, but is not limited to, polysorbates, such as polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamers, triton, sodium lauryl sulfate, sodium lauryl glycoside, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene glycol or polypropylene glycol, preferably polysorbate 20 or polysorbate 80.
In a preferred embodiment, the concentration of the surfactant is from 0.01 to 5mg/ml, preferably from 0.05 to 0.5 mg/ml.
In one embodiment, the pharmaceutical compositions of the present invention further contain a pharmaceutically acceptable amount of a chelating agent, including, but not limited to, aminopolycarboxylic acids, hydroxyaminocarboxylic acids, N-substituted glycines, citric acid, niacinamide, deferoxamine, and deoxycholate, and mixtures thereof, such as ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), and salts thereof. The chelating agent used in the present invention may be present in the form of a free acid or a free base or a salt of the compound, or may be present in the form of an anhydrate, hydrate or other solvate of the compound or corresponding salt.
In one embodiment, the pharmaceutical composition of the present invention further contains a pharmaceutically acceptable amount of a preservative including, but not limited to, m-cresol, phenol, benzyl alcohol, benzalkonium chloride, phenoxyethanol, or methylparaben.
In a preferred embodiment, the pharmaceutical composition according to the invention comprises the following ingredients:
wherein the pH is 5.0-6.0.
In a preferred embodiment, the pharmaceutical composition according to the invention comprises the following ingredients:
wherein the pH is 5.0-6.0.
In a preferred embodiment, the pharmaceutical composition according to the invention comprises the following ingredients:
Wherein the pH was 6.0.
The pharmaceutical composition of the present invention may be in the form of a water-injection preparation, a lyophilized preparation, or a preparation prepared from a lyophilized powder and water for injection by double-chamber karya flask (dual-chamber cartridge), and may be administered by subcutaneous injection (s.c.), intravenous injection (i.v.), intravenous drip, intramuscular injection (i.m.), or other parenteral (parenteral) forms, preferably intravenous drip.
In one embodiment, the pharmaceutical composition of the present invention may not require additional addition of tonicity agents, such as sodium chloride, potassium chloride, etc., reducing the variety of excipients.
In one embodiment, the composition of the invention contains only pertuzumab protein to avoid potential stability risks due to interactions between two or more proteins.
The inventors have conducted extensive experiments and data screening to find that the ability of methionine to improve the stability of the composition is significantly limited when the concentration of methionine in the formulation of the present invention is less than 5mM, and that the amount of methionine is greater than the conventional amount of antibody drugs already on the market when the concentration of methionine is more than 40mM, and that the physical and chemical stability of the pertuzumab composition is significantly improved when the concentration of methionine is 5-40 mM.
In the present invention, the inventors have conducted intensive studies to screen a large amount of components and contents thereof, and obtained the pharmaceutical composition of the present invention with better stability, for example, screening a buffer solution to determine that the pharmaceutical composition has better physical and chemical stability in phosphate/phosphoric acid, histidine-acetate, and histidine-hydrochloric acid, wherein histidine-acetate has equivalent effect and is better than phosphate/phosphoric acid; the stabilizing agents are screened, and the stabilizing agents are determined to have better stability in sucrose, trehalose and arginine hydrochloride, wherein the stability in arginine hydrochloride is better.
In another aspect, the invention also relates to the use for the preparation of a medicament for the treatment of HER2 positive tumors, preferably, the HER2 positive tumor is breast cancer or gastric cancer.
The invention has the beneficial effects that:
the composition disclosed by the invention not only has good effects (colorless clear liquid and no foreign matters) on appearance, visible foreign matters and the like, but also has greatly improved physical stability and chemical stability, and has very wide market application prospects.
Detailed Description
SEC-HPLC purity test is mainly used to monitor the multimers of the samples (physical stability), IEC-HPLC purity test is mainly to monitor the charge isomer main peak purity (chemical stability).
A detection instrument: agilent 1200 liquid chromatograph; SEC-HPLC column: TSK-gel G3000SW of TOSOH corporation of JapanXL7.8X 300 mm; mobile phase: 0.06mol/L dipotassium hydrogen phosphate, 0.14mol/L potassium dihydrogen phosphate, 0.25mol/L potassium chloride and pH 6.2; flow rate: 0.5 ml/min; column temperature: 30 ℃; operating time: 30 min; wavelength: 280 nm. IEC-HPLC column: thermo Scientific ProPac WCX-10(4 × 250mm), detection wavelength: 280nm, flow rate: 0.8ml/min, column temperature: 34 ℃, sample introduction: 50 μ l, gradient: 0min, 18% mobile phase B; 3min, 18% mobile phase B; 8min, 28% mobile phase B; 45min, 46.5% mobile phase B; 45.5min, 100% mobile phase B; 52.5min, 100% mobile phase B; 53min, 18% mobile phase B; 60min, 18% mobile phase B. In the examples, the SEC-HPLC detection and the IEC-HPLC detection were carried out in accordance with this method.
The present invention is further illustrated by the following examples. It must be noted that these examples are intended to illustrate the invention and should not be construed as limiting it.
Example 1 Effect of different concentrations of methionine on the stability of Pertuzumab compositions
The protective effect of different concentrations of methionine (0-40mM) on pertuzumab compositions under strong degradation conditions was compared. Each formulation (water injection formulation) contained 30mg/ml pertuzumab, 120mM sucrose, 20mM histidine-HCl buffer, and 0.2mg/ml polysorbate 20, pH 6.0. The dosage of each preparation adjuvant is shown in Table 1.
TABLE 1 preparation of patupol with different concentrations of methionine
Note: "/" indicates no.
Influencing factor test scheme
The above formulations were subjected to high temperature and light damage tests, respectively.
High-temperature test: placing the sample in a thermostat with the temperature of 40 +/-2 ℃, and sampling and detecting at 2 weeks and 4 weeks respectively;
and (3) illumination test: the samples were taken 10 days after placing them in a light box (25 ℃ C. + -3 ℃ C., 4500Lx + -500 Lx).
And (4) carrying out appearance, visible foreign matter, SEC-HPLC and IEC-HPLC purity detection on the sample subjected to the influence factor test. The results are shown in Table 2.
TABLE 2 Perfect appearance/visible impurities, Polymer content and IEC-HPLC Main Peak purity of each formulation after high temperature and illumination Destruction
Experimental data are mean ± standard deviation, repeated 3 times.
The results show that compared with the pertuzumab composition without methionine, the addition of methionine of 5-40mg/ml can reduce the polymer content under the conditions of illumination damage and high temperature for 2 weeks (the polymer content is reduced more under the illumination condition), can improve the IEC-HPLC main peak purity under the illumination condition, and improve the physical and chemical stability of the pertuzumab composition, and especially the addition of methionine of 20-40mg/ml can obviously improve the physical and chemical stability of the pertuzumab.
Example 2 Effect of varying concentrations of pertuzumab on the stability of a pertuzumab composition
The effect of different concentrations of pertuzumab (3mg/ml and 60mg/ml) on the stability of pertuzumab compositions was compared. Formulation 7 and formulation 8 (water injection dosage forms) both contained 120mM sucrose, 0.2mg/ml polysorbate 20, 20mM histidine-acetate buffer, pH 6.0. The dosage of each preparation adjuvant is shown in Table 3.
TABLE 3 formulations of varying concentrations of pertuzumab
Influencing factor test scheme
The above formulations were subjected to high temperature and light damage tests, respectively.
High-temperature test: placing the sample in a thermostat with the temperature of 40 +/-2 ℃ and sampling and detecting the sample in the 2 nd week;
and (3) illumination test: the samples were taken 10 days after placing them in a light box (25 ℃ C. + -3 ℃ C., 4500Lx + -500 Lx).
Samples subjected to the above-described influencing factor tests were subjected to appearance, visible foreign matter, SEC-HPLC and IEC-HPLC purity tests. The results are shown in Table 4.
TABLE 4 appearance/visible foreign substances, Polymer content and IEC-HPLC main peak purity of pertuzumab after destruction of formulations 1-2 by high temperature and light
The results show that after the high temperature and light damage, the pertuzumab preparation containing the pertuzumab of 3-60 mg/ml has lower polymer content and higher IEC-HPLC main peak purity, which indicates that the corresponding preparation has better physical stability and chemical stability, and the low-concentration pertuzumab preparation has better physical stability and chemical stability than the high-concentration pertuzumab preparation.
Example 3 Effect of different buffers on the stability of pertuzumab compositions
The effect of different buffer solutions (histidine-acetic acid and phosphate/phosphate buffer) on the stability of pertuzumab compositions was compared. Wherein the pertuzumab concentration is 3 mg/ml. Formulations 9 and 10 both contained 120mM sucrose and 0.2mg/ml polysorbate 20, pH 6.0; the dosage of each preparation adjuvant is shown in Table 5.
TABLE 5 pertuzumab formulations in different buffers
Influencing factor test scheme
The above formulations were subjected to high temperature and light damage tests, respectively.
High-temperature test: placing the sample in a thermostat with the temperature of 40 +/-2 ℃ and sampling and detecting the sample in the 2 nd week;
and (3) illumination test: the sample was placed in a light box (25 ℃ C. + -3 ℃ C., 4500 Lx. + -. 500Lx) and sampled after 10 days.
And (4) carrying out appearance, visible foreign matter, SEC-HPLC and IEC-HPLC purity detection on the sample subjected to the influence factor test. The results are shown in Table 6.
TABLE 6 appearance/visible foreign substances, Polymer content and IEC-HPLC main peak purity of pertuzumab after destruction of formulations 9 and 10 by high temperature and light
Experimental data are mean ± standard deviation, repeated 3 times; N/A means that no experiment was performed
The results show that the pertuzumab composition containing the phosphate/phosphate buffer solution and the histidine-acetic acid buffer solution has lower polymer content and higher IEC-HPLC main peak purity, which indicates that the corresponding pertuzumab composition has better physical and chemical stability, wherein the histidine-acetic acid buffer solution is used, the polymer content is less after high temperature and light damage, and the physical stability is better.
Example 4 Effect of different pH on the stability of pertuzumab compositions
The effect on the stability of the pertuzumab composition under different pH conditions was compared. Each formulation (water injection formulation) contained 3mg/ml pertuzumab, 120mM sucrose, 20mM histidine-acetic acid and 0.2mg/ml polysorbate 20. The dosage of each preparation adjuvant is shown in Table 9.
TABLE 7 composition of formulations of different pH
Experimental protocol for influencing factors
The above formulations were subjected to high temperature and light damage tests, respectively.
High-temperature test: placing the sample in a thermostat with the temperature of 40 +/-2 ℃ and sampling and detecting the sample in the 2 nd week;
and (3) illumination test: the samples were taken 10 days after placing them in a light box (25 ℃ C. + -3 ℃ C., 4500Lx + -500 Lx).
Samples subjected to the above-described influencing factor tests were subjected to appearance, visible foreign matter, SEC-HPLC and IEC-HPLC purity tests. The results are shown in Table 8.
TABLE 8 Perfect formulation appearance/visible foreign bodies, Polymer content and IEC-HPLC main peak purity after high temperature and light damage
Experimental data are mean ± standard deviation, repeated 3 times.
The results show that under the condition of pH5.0-6.8, the content of polymers of the pertuzumab composition is lower, the IEC-HPLC main peak purity is higher, which indicates that the physical stability and the chemical stability are better, especially the pH value is between 5.0 and 6.0, and the IEC-HPLC main peak purity of the pertuzumab preparation is better (for example, 63.7 +/-0.1, 60.2 +/-0.1 and 54.6 +/-0.2 after 2 weeks at the high temperature of pH6.0/5.0/6.8, respectively, 66.4 +/-0.4, 68.1 +/-0.2 and 60.1 +/-0.5 after illumination failure), namely, the chemical stability effect is better.
Example 5 Effect of different surfactants on the stability of Pertuzumab compositions
The effect of different surfactants (polysorbate 80 and varying levels of polysorbate 20) on the stability of the pertuzumab composition was compared. Each formulation (water injection formulation) contained 3mg/ml pertuzumab, 120mM sucrose, and 20mM histidine-acetate buffer, pH 6.0. The dosage of each preparation adjuvant is shown in Table 9.
TABLE 9 pertuzumab compositions of different surfactants
Influencing factor test scheme
The above formulations were subjected to high temperature and light damage tests, respectively.
High-temperature test: placing the samples in a thermostat with the temperature of 40 +/-2 ℃ and sampling and detecting the samples in the 2 nd week respectively;
and (3) illumination test: the samples were taken 10 days after placing them in a light box (25 ℃ C. + -3 ℃ C., 4500Lx + -500 Lx).
Samples subjected to the above-described influencing factor tests were subjected to appearance, visible foreign matter, SEC-HPLC and IEC-HPLC purity tests. The results are shown in Table 10.
TABLE 10 appearance/visible foreign substances, polymer content and IEC-HPLC main peak purity of pertuzumab after destruction of the respective formulations by high temperature and light
The results show that in the pertuzumab composition with different contents of polysorbate 20 and polysorbate 80 as surfactants, the polymer content is lower, the IEC-HPLC main peak purity is higher, and the corresponding pertuzumab composition has better physical stability and chemical stability.
Example 6 Effect of different stabilizers on the stability of Pertuzumab compositions
The effect of different stabilizers on the stability of pertuzumab compositions was compared. Formulations 18 and 19 (hydro-acupuncture formulations) both contained 30mg/ml pertuzumab, 0.2mg/ml polysorbate 20, at pH 6.0. The dosage of each preparation adjuvant is shown in Table 11.
TABLE 11 pertuzumab compositions of different stabilizers
Experimental protocol for influencing factors
The above formulations were subjected to high temperature and light damage tests, respectively.
High-temperature test: placing the sample in a thermostat with the temperature of 40 +/-2 ℃ and sampling and detecting the sample in the 2 nd week;
and (3) illumination test: the samples were taken 10 days after placing them in a light box (25 ℃ C. + -3 ℃ C., 4500Lx + -500 Lx).
And (4) carrying out appearance, visible foreign matter, SEC-HPLC and IEC-HPLC purity detection on the sample subjected to the influence factor test. The results are shown in Table 12.
TABLE 12 Perfect appearance/visible foreign bodies, Polymer content and IEC-HPLC Main Peak purity of each formulation after high temperature and illumination Destruction
Experimental data are mean ± standard deviation, repeated 3 times.
The results show that after high temperature and illumination, the pertuzumab composition with sucrose and arginine hydrochloride as stabilizers has lower polymer content and higher IEC-HPLC main peak purity, which indicates that the composition has better physical stability and chemical stability, wherein compared with the pertuzumab preparation with sucrose as a stabilizer, the pertuzumab preparation with arginine hydrochloride as a stabilizer has better chemical stability (higher IEC-HPLC main peak purity, especially after illumination failure) and has equivalent physical stability.
To summarize
The inventors have extensively studied and found that a pharmaceutical composition comprising methionine at a specific concentration in combination with pertuzumab, a stabilizer (e.g., sucrose/arginine hydrochloride/trehalose), a buffer (e.g., histidine-hydrochloric acid, histidine-acetic acid, phosphoric acid/phosphate), and a surfactant (e.g., polysorbate 20 or 80) has superior physical and/or chemical stability at a pH of 5.0-6.8, particularly, the physical and/or chemical stability of the pertuzumab composition under the conditions of 3-30mg/ml of pertuzumab, 20-40mM of methionine, 115-125mM of sucrose or trehalose or arginine hydrochloride, 15-25mM of histidine-histidine hydrochloride or histidine-acetic acid buffer, pH5.0-6.0, 0.05-0.5mg/ml of polysorbate 20 and the like is better.
It will be apparent to those skilled in the art that many modifications and variations of the present invention can be made without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not meant to be limiting in any way. The true scope and spirit of the invention is indicated by the appended claims, and the specification and examples are exemplary only.
Claims (10)
1. A pharmaceutical composition, wherein the composition comprises:
(a) Pertuzumab 3-60 mg/ml;
(b) 5-40mM of methionine;
(c) a stabilizer selected from sucrose, trehalose or arginine hydrochloride, preferably arginine hydrochloride;
(d) a surfactant;
(e) a buffer solution;
wherein the pH of the formulation is 5.0-6.8, preferably 5.0-6.0.
2. The pharmaceutical composition of claim 1, wherein the pertuzumab is at a concentration of 3-30 mg/ml.
3. Pharmaceutical composition according to claim 1 or 2, characterized in that the concentration of methionine is 10-40mM, preferably 20-40 mM.
4. The pharmaceutical composition according to any one of claims 1-3, wherein the concentration of the stabilizer is 100-140mM, preferably 110-130mM, more preferably 115-125 mM.
5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the buffer is selected from glycine, acetic acid/acetate, succinic acid/succinate, citric acid/citrate, ascorbic acid/ascorbate, tartaric acid/tartrate, maleic acid/maleate, lactic acid/lactate, carbonic acid/bicarbonate, benzoic acid/benzoate, histidine-hydrochloric acid, histidine-acetic acid, phosphoric acid/phosphate or tris/tris hydrochloride, preferably histidine-hydrochloric acid, histidine-acetic acid, phosphoric acid/phosphate, more preferably histidine-hydrochloric acid, histidine-acetic acid.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the buffer has a concentration of 10 to 30mM, preferably 15 to 25 mM.
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the surfactant is selected from polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, poloxamer, triton, sodium lauryl sulfate, sodium octyl glycoside, lauryl-sulfobetaine, polyethylene glycol, or polypropylene glycol, preferably polysorbate 20 or polysorbate 80; the concentration of the surfactant is 0.01-5mg/ml, preferably 0.05-0.5 mg/ml.
8. A pharmaceutical composition comprising the following components:
wherein, the pH value is 5.0-6.0;
preferably, the composition contains the following components:
wherein the pH was 6.0.
9. The pharmaceutical composition of any one of claims 1 to 8 in the form of a hydro-acupuncture formulation, a lyophilized formulation, or a formulation prepared from a lyophilized powder and water for injection formulated in a double-chambered carafe, for administration by parenteral form, preferably said parenteral form is subcutaneous, intravenous or intramuscular injection, more preferably intravenous drip.
10. Use of a pharmaceutical composition according to any one of claims 1-9 for the preparation of a medicament for the treatment of HER2 positive tumors, preferably said HER2 positive tumor is breast cancer or gastric cancer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110052055.7A CN114762727A (en) | 2021-01-15 | 2021-01-15 | Stable pharmaceutical composition of pertuzumab |
| PCT/CN2021/140703 WO2022151940A1 (en) | 2021-01-15 | 2021-12-23 | Stable pharmaceutical composition of pertuzumab |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110052055.7A CN114762727A (en) | 2021-01-15 | 2021-01-15 | Stable pharmaceutical composition of pertuzumab |
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| CN114762727A true CN114762727A (en) | 2022-07-19 |
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Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| LT2335725T (en) * | 2003-04-04 | 2017-01-25 | Genentech, Inc. | High concentration antibody and protein formulations |
| US20140004131A1 (en) * | 2012-05-04 | 2014-01-02 | Novartis Ag | Antibody formulation |
| SG11201504897YA (en) * | 2012-12-21 | 2015-07-30 | Glenmark Pharmaceuticals Sa | Anti her2 antibody formulation |
| US11608357B2 (en) * | 2018-08-28 | 2023-03-21 | Arecor Limited | Stabilized antibody protein solutions |
| JPWO2018179138A1 (en) * | 2017-03-29 | 2020-02-06 | 持田製薬株式会社 | Antibody-containing liquid preparation |
| EP3824904A4 (en) * | 2018-07-19 | 2021-08-25 | Celltrion, Inc. | Stable liquid pharmaceutical preparation |
| CN110974958B (en) * | 2019-12-25 | 2020-08-21 | 北京东方百泰生物科技有限公司 | Injection preparation of anti-PD-L1 monoclonal antibody |
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