CN112656939B - Pharmaceutical composition of humanized antibody for vascular endothelial growth factor - Google Patents
Pharmaceutical composition of humanized antibody for vascular endothelial growth factor Download PDFInfo
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- bevacizumab
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- growth factor
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 42
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 title abstract description 7
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 title abstract description 7
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 title abstract description 7
- 229960000397 bevacizumab Drugs 0.000 claims abstract description 42
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000000872 buffer Substances 0.000 claims abstract description 21
- 239000012064 sodium phosphate buffer Substances 0.000 claims abstract description 14
- 239000011780 sodium chloride Substances 0.000 claims abstract description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 11
- 229930195725 Mannitol Natural products 0.000 claims abstract description 11
- 239000000594 mannitol Substances 0.000 claims abstract description 11
- 235000010355 mannitol Nutrition 0.000 claims abstract description 11
- 239000007853 buffer solution Substances 0.000 claims abstract description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 14
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 14
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 14
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 9
- 239000001509 sodium citrate Substances 0.000 claims description 9
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 229920000642 polymer Polymers 0.000 abstract description 14
- 229940120638 avastin Drugs 0.000 abstract description 6
- 239000007857 degradation product Substances 0.000 abstract description 6
- 230000003204 osmotic effect Effects 0.000 abstract description 6
- 238000003860 storage Methods 0.000 abstract description 5
- 230000007774 longterm Effects 0.000 abstract description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 abstract description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 12
- 229940117880 bevacizumab injection Drugs 0.000 description 10
- 239000012490 blank solution Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000015556 catabolic process Effects 0.000 description 6
- 229960004106 citric acid Drugs 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 6
- 239000002808 molecular sieve Substances 0.000 description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 6
- 239000000427 antigen Substances 0.000 description 5
- 102000036639 antigens Human genes 0.000 description 5
- 108091007433 antigens Proteins 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004806 packaging method and process Methods 0.000 description 5
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 4
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960002303 citric acid monohydrate Drugs 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- -1 organic acid salts Chemical class 0.000 description 3
- 235000011007 phosphoric acid Nutrition 0.000 description 3
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 3
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229940090044 injection Drugs 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- DPVHGFAJLZWDOC-PVXXTIHASA-N (2r,3s,4s,5r,6r)-2-(hydroxymethyl)-6-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxane-3,4,5-triol;dihydrate Chemical compound O.O.O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DPVHGFAJLZWDOC-PVXXTIHASA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 206010052358 Colorectal cancer metastatic Diseases 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- ZRIUUUJAJJNDSS-UHFFFAOYSA-N ammonium phosphates Chemical class [NH4+].[NH4+].[NH4+].[O-]P([O-])([O-])=O ZRIUUUJAJJNDSS-UHFFFAOYSA-N 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000006240 deamidation Effects 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 235000019838 diammonium phosphate Nutrition 0.000 description 1
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 230000010494 opalescence Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The application belongs to the field of pharmaceutical chemicals, relates to a pharmaceutical composition of a humanized antibody aiming at vascular endothelial growth factor, and particularly relates to a pharmaceutical composition of bevacizumab with improved stability. The pharmaceutical composition adopts a combined buffer system of a sodium phosphate buffer and a second buffer, and adopts one or two of mannitol or sodium chloride as an osmotic pressure regulator; compared with avastin which only adopts sodium phosphate buffer and alpha, alpha-trehalose as osmotic pressure regulator, the polymer and degradation products are obviously reduced, and the stability is obviously improved, so the pharmaceutical composition of the application is particularly suitable for the requirements of large-scale production and long-term storage.
Description
The application relates to a divisional application, the application date of the original application is 2014, 9, 22 and 201410487742.1, and the name of the application is a humanized antibody pharmaceutical composition for vascular endothelial growth factor.
Technical Field
The application belongs to the field of pharmaceutical chemicals, relates to a pharmaceutical composition of a humanized antibody aiming at vascular endothelial growth factor, and particularly relates to a pharmaceutical composition of bevacizumab with improved stability.
Background
Bevacizumab (bevacizumab) is a humanized monoclonal antibody directed against Vascular Endothelial Growth Factor (VEGF) and is suitable for the treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy. Bevacizumab injection produced by rochanter corporation, trade name avastin, has been marketed in many ways in the united states, europe, china, etc.
The avastin is a sterile solution for intravenous injection, the pH is 6.1, the solution is colorless to slightly brown opalescence to clear liquid, the concentration is 25mg/mL, the two specifications of 100mg and 400mg exist, the corresponding volumes are 4mL and 16mL respectively, no preservative exists, and the solution is packaged in disposable vials.
The auxiliary materials in the avastin consist of the following components: alpha, alpha-trehalose dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, tween 20 and sterile water for injection.
The stability of avastin is not ideal, and the polymer and degradation product increase obviously during acceleration and long-term storage, especially the polymer increases obviously. High molecular weight polymers are easy to generate immunogenicity when entering the body, and have potential risks for clinical use safety; at the same time, low or inactive degradants affect the activity of the product. Therefore, there is a need to develop bevacizumab pharmaceutical compositions with better stability to accommodate the requirements of mass production and long-term storage, and the present application provides such pharmaceutical compositions.
Disclosure of Invention
The application aims to provide a bevacizumab pharmaceutical composition, which comprises the following components:
(a) Bevacizumab in 10-40 mg/mL,
(b) 0.1-200 mg/mL osmotic pressure regulator,
(c) Tween 20 in an amount of 0.1 to 10mg/mL, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the osmotic pressure regulator is selected from one or two of mannitol or sodium chloride,
wherein the second buffer is selected from the group consisting of a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate,
wherein the pH value of the pharmaceutical composition is 4.5-5.9.
The term "sodium phosphate buffer" is a buffer formed by the combination of disodium hydrogen phosphate and sodium dihydrogen phosphate.
It should be understood that the "sodium phosphate buffer" of the present application may also be phosphate buffers formed from other phosphoric acids or pharmaceutically acceptable salts thereof, including but not limited to various inorganic or organic acid salts of phosphoric acid, such as disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, or combinations of ammonium phosphates, specific examples of which are combinations of dipotassium hydrogen phosphate and potassium dihydrogen phosphate, and the use of other phosphoric acids or pharmaceutically acceptable salts thereof, or combinations of hydrates thereof, is within the scope of the present application.
It should be understood that the sodium citrate of the present application may also be other citrate salts or hydrates thereof, including but not limited to various inorganic or organic acid salts of citric acid, such as potassium citrate.
It should be understood that the sodium acetate of the present application may also be other acetates or hydrates thereof including but not limited to various inorganic or organic acid salts of acetic acid, such as potassium acetate.
A pharmaceutical composition of bevacizumab as described hereinbefore, wherein the concentration of bevacizumab is preferably 20-30 mg/mL, most preferably about 25mg/mL.
A pharmaceutical composition of bevacizumab as hereinbefore described wherein the concentration of the osmolality adjusting agent is preferably from 1 to 50mg/mL, most preferably from about 4.7 to 25mg/mL.
A pharmaceutical composition of bevacizumab as hereinbefore described wherein the concentration of tween 20 is preferably from 0.2 to 2mg/mL, most preferably about 0.4mg/mL.
The pH of the bevacizumab pharmaceutical composition as described above is preferably between 4.9 and 5.5, most preferably about 5.2.
In a specific embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 4.7 to 25mg/mL of osmotic pressure regulator,
(c) About 0.4mg/mL Tween 20, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the osmotic pressure regulator is selected from one or two of mannitol or sodium chloride,
wherein the second buffer is selected from the group consisting of a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet another specific embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 25mg/mL of mannitol,
(c) About 0.4mg/mL Tween 20, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the second buffer is selected from the group consisting of a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet another embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 9mg/mL of sodium chloride,
(c) About 0.4mg/mL Tween 20, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the second buffer is selected from the group consisting of a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet another embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 12mg/mL of mannitol,
(c) About 4.7mg/mL sodium chloride,
(d) About 0.4mg/mL Tween 20, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the second buffer is selected from the group consisting of a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In a more specific embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 25mg/mL of mannitol,
(c) About 0.4mg/mL tween 20,
(d) About 0.48mg/mL of monobasic sodium phosphate monohydrate,
(e) About 3.75mg/mL of disodium phosphate dodecahydrate,
(f) Sodium acetate trihydrate at about 1.725mg/mL, and
(g) About 0.02mg/mL of acetic acid,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet a more specific embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 25mg/mL of mannitol,
(c) About 0.4mg/mL tween 20,
(d) About 0.48mg/mL of monobasic sodium phosphate monohydrate,
(e) About 3.75mg/mL of disodium phosphate dodecahydrate,
(f) Citric acid monohydrate at about 1.21mg/mL, and
(g) About 0.68mg/mL sodium citrate dihydrate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet a more specific embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 9mg/mL of sodium chloride,
(c) About 0.4mg/mL tween 20,
(d) About 0.48mg/mL of monobasic sodium phosphate monohydrate,
(e) About 3.75mg/mL of disodium phosphate dodecahydrate,
(f) Citric acid monohydrate at about 1.21mg/mL, and
(g) About 0.68mg/mL sodium citrate dihydrate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet a more specific embodiment of the present application, the pharmaceutical composition comprises:
(a) About 25mg/mL bevacizumab,
(b) About 12mg/mL of mannitol,
(c) About 4.7mg/mL sodium chloride,
(d) About 0.4mg/mL tween 20,
(e) About 0.48mg/mL of monobasic sodium phosphate monohydrate,
(f) About 3.75mg/mL of disodium phosphate dodecahydrate,
(g) Citric acid monohydrate at about 1.21mg/mL, and
(h) About 0.68mg/mL sodium citrate dihydrate,
wherein the pharmaceutical composition has a pH of about 5.2.
The term "polymer" refers to a polymer produced by polymerization of bevacizumab due to interactions of amino acid residues on the peptide chain.
The term "degradation product" refers to a product of bevacizumab produced in an aqueous solution by deamidation or cleavage of peptide chains, etc., which has a smaller molecular weight than bevacizumab.
By using a combined buffer system of sodium phosphate buffer and said second buffer, and using either mannitol or sodium chloride or both as osmolality adjusting agents, the resulting polymer and degradation products of the pharmaceutical composition of the application are significantly reduced, and the stability is significantly improved compared to avastin using only sodium phosphate buffer and using alpha, alpha-trehalose as osmolality adjusting agent, which effect is unexpected to the person skilled in the art.
Detailed Description
The application will be further described with reference to specific examples, which are, however, only intended to illustrate and not limit the scope of the application. Also, the application is not limited to any particular preferred embodiment described herein. It should be understood by those skilled in the art that equivalent substitutions and corresponding modifications of the technical features of the present application are included in the scope of the present application.
Example 1 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the above formula, a blank solution without bevacizumab was prepared, with a pH of 5.2. And (3) replacing the purified bevacizumab antigen solution with a blank solution for 6 times to prepare a solution with the formula, sterilizing, filtering, sub-packaging in a sterile mode, and checking to be qualified.
Example 2 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the above formula, a blank solution without bevacizumab was prepared, with a pH of 5.2. And (3) replacing the purified bevacizumab antigen solution with a blank solution for 6 times to prepare a solution with the formula, sterilizing, filtering, sub-packaging in a sterile mode, and checking to be qualified.
Example 3 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the above formula, a blank solution without bevacizumab was prepared, with a pH of 5.2. And (3) replacing the purified bevacizumab antigen solution with a blank solution for 6 times to prepare a solution with the formula, sterilizing, filtering, sub-packaging in a sterile mode, and checking to be qualified.
Example 4 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the above formula, a blank solution without bevacizumab was prepared, with a pH of 5.2. And (3) replacing the purified bevacizumab antigen solution with a blank solution for 6 times to prepare a solution with the formula, sterilizing, filtering, sub-packaging in a sterile mode, and checking to be qualified.
Example 5 andpreparation of bevacizumab injection with same prescription
Prescription:
the preparation method comprises the following steps: according to the above formula, a blank solution without bevacizumab was prepared, with a pH of 6.1. And (3) replacing the purified bevacizumab antigen solution with a blank solution for 6 times to prepare a solution with the formula, sterilizing, filtering, sub-packaging in a sterile mode, and checking to be qualified.
Example 6 high temperature Heat stability of bevacizumab injection
Bevacizumab injections 5 batches were prepared as in examples 1-4 and example 5. Each batch of injection is placed in a constant temperature environment at 25 ℃ and is sampled and detected in 0 month, 1 month, 2 months, 3 months and 6 months, and the change condition of the bevacizumab purity is inspected by utilizing molecular sieve chromatography (Size-Exclusion chromatography, SEC) so as to evaluate the stability of the pharmaceutical composition.
Molecular sieve chromatography (SEC) assay method: the TSKgel G3000 SWXL molecular sieve chromatographic column was used at 20mmol/L Na 2 HPO 4 +200mmol/L NaCl, pH 7.4 buffer was used as mobile phase for elution, and the detection wavelength was 280nm. The sequence of the peak under the chromatographic condition is polymer peak, main peak and degradation product peak. The percentages of polymer, main peak and degradation were calculated by area normalization and the results are shown in Table 1.
TABLE 1 Bevacizumab purity variation
The results showed that the formulation of example 5 increased 5.1% polymer, 0.73% degradation, and 5.8% decrease in the main peak after 6 months at 25 ℃, whereas the formulations of examples 1-4 increased only 1.5-1.8% polymer, 0.16-0.42% degradation, and 1.7-2.2% decrease in the main peak after 6 months at 25 ℃. The results show that the prescriptions of the embodiments 1-4 are stable, the prescriptions of the embodiment 5 are poor in stability, and the stability of the bevacizumab injection is obviously improved.
EXAMPLE 7 long-term stability of bevacizumab injection
Bevacizumab injections 5 batches were prepared as in examples 1-4 and example 5. Each batch of injection is stored at the temperature of 2-8 ℃, sampled and detected at the temperature of 0 month, 3 months, 6 months, 9 months and 12 months, and the change condition of the bevacizumab purity is inspected by utilizing molecular sieve chromatography (Size-Exclusion chromatography, SEC) so as to evaluate the stability of the pharmaceutical composition.
Molecular sieve chromatography (SEC) assay method: the TSKgel G3000 SWXL molecular sieve chromatographic column was used at 20mmol/L Na 2 HPO 4 +200mmol/L NaCl, pH 7.4 buffer was used as mobile phase for elution, and the detection wavelength was 280nm. The sequence of the peak under the chromatographic condition is polymer peak, main peak and degradation product peak. The percentages of polymer, main peak and degradation were calculated by area normalization and the results are shown in Table 2.
TABLE 2 Bevacizumab purity variation
The results show that the formulation of example 5 showed 2.5% polymer growth, 0.38% degradation, and 2.9% major peak drop for 12 months of storage at 2-8deg.C, whereas the formulation of example 1-4 showed only 0.2-0.5% polymer growth, 0.06-0.12% degradation, and only 0.4-0.6% major peak drop for 12 months of storage at 2-8deg.C. The above results indicate that the prescriptions of examples 1 to 4 of the present application are relatively stable, while the prescriptions of example 5 are relatively poor in stability, and the stability of the bevacizumab injection of the present application is significantly improved.
Claims (3)
1. A pharmaceutical composition, which is composed of the following components:
(a) 25mg/mL bevacizumab,
(b) 25mg/mL of mannitol per mL of the extract,
(c) Tween 20 at 0.4mg/mL, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the second buffer is selected from the group consisting of a combination of citric acid and sodium citrate or a combination of acetic acid and sodium acetate, wherein the pharmaceutical composition has a pH of 5.2.
2. A pharmaceutical composition, which is composed of the following components:
(a) 25mg/mL bevacizumab,
(b) 9mg/mL of sodium chloride was added,
(c) Tween 20 at 0.4mg/mL, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the second buffer is selected from the group consisting of citric acid and sodium citrate,
wherein the pharmaceutical composition has a pH of 5.2.
3. A pharmaceutical composition, which is composed of the following components:
(a) 25mg/mL bevacizumab,
(b) Mannitol at a concentration of 12mg/mL,
(c) 4.7mg/mL of sodium chloride,
(d) Tween 20 at 0.4mg/mL, and
(d) A buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the second buffer is selected from the group consisting of citric acid and sodium citrate,
wherein the pharmaceutical composition has a pH of 5.2.
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| CN101199844A (en) * | 2006-12-14 | 2008-06-18 | 上海国健生物技术研究院 | Liquid agent of stable anti-EGFR chimeric antibody |
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| WO2014073842A1 (en) * | 2012-11-06 | 2014-05-15 | Hanmi Pharm. Co., Ltd. | Liquid formulation of protein conjugate comprising the oxyntomodulin and an immunoglobulin fragment |
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| CN112656939A (en) | 2021-04-16 |
| WO2016045570A3 (en) | 2016-05-19 |
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