CN112656939A - 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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- pharmaceutical composition
- bevacizumab
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- sodium
- tween
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 65
- 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 54
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 32
- 239000000872 buffer Substances 0.000 claims abstract description 23
- 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 16
- 229930195725 Mannitol Natural products 0.000 claims abstract description 16
- 239000000594 mannitol Substances 0.000 claims abstract description 16
- 235000010355 mannitol Nutrition 0.000 claims abstract description 16
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 239000012064 sodium phosphate buffer Substances 0.000 claims abstract description 15
- 239000007853 buffer solution Substances 0.000 claims abstract description 14
- 230000003204 osmotic effect Effects 0.000 claims abstract description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 22
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 22
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 22
- 235000017281 sodium acetate Nutrition 0.000 claims description 13
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- 229960004106 citric acid Drugs 0.000 claims description 11
- 239000001632 sodium acetate Substances 0.000 claims description 11
- 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 11
- 239000001509 sodium citrate Substances 0.000 claims description 11
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims description 9
- 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 claims description 8
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 6
- 229960000999 sodium citrate dihydrate Drugs 0.000 claims description 6
- 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 claims description 6
- 239000008181 tonicity modifier Substances 0.000 claims description 4
- 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 claims description 2
- 229940087562 sodium acetate trihydrate Drugs 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 abstract description 14
- 229940120638 avastin Drugs 0.000 abstract description 6
- 230000007774 longterm Effects 0.000 abstract description 4
- 238000003860 storage Methods 0.000 abstract description 3
- 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
- 239000007857 degradation product Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000001488 sodium phosphate Substances 0.000 abstract description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 abstract description 2
- 239000006172 buffering agent Substances 0.000 abstract 1
- 229940117880 bevacizumab injection Drugs 0.000 description 11
- 239000012490 blank solution Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 239000008380 degradant Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 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
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000001954 sterilising effect Effects 0.000 description 5
- 239000011550 stock solution Substances 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- -1 organic acid salts Chemical class 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003556 assay Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 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
- 229910000397 disodium phosphate Inorganic materials 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
- 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
- 238000005070 sampling Methods 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
- 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
- 150000001242 acetic acid derivatives Chemical class 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
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application 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
- 229910000388 diammonium phosphate Inorganic materials 0.000 description 1
- 235000019838 diammonium phosphate Nutrition 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
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 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
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 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
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention belongs to the field of pharmaceutical chemicals, and relates to a pharmaceutical composition of a humanized antibody for vascular endothelial growth factor, in particular 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 a sodium phosphate buffering agent and adopts alpha, alpha-trehalose as an osmotic pressure regulator, the polymer and degradation products of the pharmaceutical composition are obviously reduced, and the stability is obviously improved, so that the pharmaceutical composition is particularly suitable for the requirements of large-scale production and long-term storage.
Description
The application is a divisional application, the application date of the original application is 9-22 days 2014, the application number is 201410487742.1, and the name of the invention is 'a pharmaceutical composition of humanized antibody aiming at vascular endothelial growth factor'.
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and relates to a pharmaceutical composition of a humanized antibody for vascular endothelial growth factor, in particular 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 manufactured by rochon corporation, which is sold under the trade name avastin, is already marketed in many places in the united states, europe, china, and the like.
Avastin is an intravenous sterile solution, pH 6.1, colorless to slightly brownish opalescent to clear liquid, concentration 25mg/mL, two specifications of 100mg and 400mg, corresponding volumes of 4mL and 16mL, respectively, without preservative, packaged in disposable vials.
The auxiliary materials in avastin comprise the following components: alpha, alpha-trehalose dihydrate, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, tween 20 and sterile water for injection.
Avastin is not very stable and the polymer and degradants grow significantly during accelerated and long term storage, especially the polymer grows significantly. The high molecular weight polymer is easy to generate immunogenicity when entering the body, and has potential risk on clinical use safety; meanwhile, the active degradation products with low activity or no activity can influence the activity of the product. Therefore, there is a need to develop a pharmaceutical composition of bevacizumab with better stability to meet the requirements of large-scale production and long-term storage, and the present invention provides such a pharmaceutical composition.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition of bevacizumab, which comprises the following components in part by weight:
(a) 10-40 mg/mL of bevacizumab,
(b)0.1 to 200mg/mL of an osmotic pressure regulator,
(c)0.1 to 10mg/mL of Tween 20, and
(d) a buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the osmotic pressure regulator is one or two of mannitol or sodium chloride,
wherein the second buffer is selected from the group consisting of citric acid and sodium citrate or 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 from the combination of disodium hydrogen phosphate and sodium dihydrogen phosphate.
It is to be understood that the "sodium phosphate buffer" of the present invention may also be a phosphate buffer formed by combination of other phosphoric acids or pharmaceutically acceptable salts or hydrates thereof, wherein the pharmaceutically acceptable salts of phosphoric acid include, but are not limited to, various inorganic or organic acid salts of phosphoric acid, such as one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, diammonium hydrogen phosphate, ammonium dihydrogen phosphate, or ammonium phosphate, and a specific example is a combination of dipotassium hydrogen phosphate and potassium dihydrogen phosphate, and it is within the scope of the present invention to use other combinations of phosphoric acid or pharmaceutically acceptable salts or hydrates thereof.
It is to be understood that the sodium citrate of the present invention 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 is to be understood that the sodium acetate of the present invention 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.
The pharmaceutical composition of bevacizumab as described above, wherein the concentration of bevacizumab is preferably 20-30 mg/mL, most preferably about 25 mg/mL.
The pharmaceutical composition of bevacizumab as described above, wherein the concentration of the osmolality adjusting agent is preferably 1 to 50mg/mL, most preferably about 4.7 to 25 mg/mL.
The pharmaceutical composition of bevacizumab as described above, wherein the concentration of tween 20 is preferably 0.2-2 mg/mL, most preferably about 0.4 mg/mL.
The pH value of the bevacizumab pharmaceutical composition as described above is preferably 4.9-5.5, most preferably about 5.2.
In a specific embodiment of the present invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 4.7-25mg/mL of an osmotic pressure regulator,
(c) about 0.4mg/mL of Tween 20, and
(d) a buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the osmotic pressure regulator is one or two of mannitol or sodium chloride,
wherein the second buffer is selected from the group consisting of citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet another embodiment of the present invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 25mg/mL of mannitol in a concentration of about,
(c) about 0.4mg/mL of 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 citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet another embodiment of the present invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 9mg/mL of sodium chloride,
(c) about 0.4mg/mL of 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 citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In yet another embodiment of the present invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 12mg/mL of mannitol in a concentration of about,
(c) about 4.7mg/mL of sodium chloride,
(d) about 0.4mg/mL of 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 citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
In a more specific embodiment of the present invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 25mg/mL of mannitol in a concentration of about,
(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) about 1.725mg/mL of sodium acetate trihydrate, 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 invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 25mg/mL of mannitol in a concentration of about,
(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) about 1.21mg/mL citric acid monohydrate, 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 invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of 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) about 1.21mg/mL citric acid monohydrate, 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 invention, the pharmaceutical composition comprises:
(a) about 25mg/mL of bevacizumab,
(b) about 12mg/mL of mannitol in a concentration of about,
(c) about 4.7mg/mL of 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) about 1.21mg/mL citric acid monohydrate, 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 the polymerization of bevacizumab due to the interaction of amino acid residues on the peptide chain.
The term "degradant" refers to a product with a molecular weight smaller than that of bevacizumab, which is produced by the reaction of bevacizumab in aqueous solution, such as deamidation or peptide chain cleavage.
By using a combined buffer system of sodium phosphate buffer and said second buffer, and one or both of mannitol or sodium chloride as the tonicity modifier, the resulting pharmaceutical composition of the present invention has significantly reduced polymer and degradants, and significantly improved stability compared to avastin using only sodium phosphate buffer and alpha, alpha-trehalose as the tonicity modifier, which is an effect that would be unpredictable to those skilled in the art.
Detailed Description
The present invention is further described below with reference to specific examples, which, however, are only illustrative and not intended to limit the scope of the present invention. Likewise, the present invention is not limited to any particular preferred embodiment described herein. It will be appreciated by those skilled in the art that equivalent substitutions for the features of the invention, or corresponding modifications, may be made without departing from the scope of the invention.
Example 1 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the formula, a blank solution without bevacizumab is prepared, and the pH value is 5.2. And (3) replacing the purified bevacizumab stock solution with a blank solution for 6 times to prepare a solution of the formula, sterilizing, filtering, performing sterile subpackage, and inspecting to be qualified to obtain the bevacizumab.
Example 2 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the formula, a blank solution without bevacizumab is prepared, and the pH value is 5.2. And (3) replacing the purified bevacizumab stock solution with a blank solution for 6 times to prepare a solution of the formula, sterilizing, filtering, performing sterile subpackage, and inspecting to be qualified to obtain the bevacizumab.
EXAMPLE 3 preparation of bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the formula, a blank solution without bevacizumab is prepared, and the pH value is 5.2. And (3) replacing the purified bevacizumab stock solution with a blank solution for 6 times to prepare a solution of the formula, sterilizing, filtering, performing sterile subpackage, and inspecting to be qualified to obtain the bevacizumab.
EXAMPLE 4 preparation of Bevacizumab injection
Prescription:
the preparation method comprises the following steps: according to the formula, a blank solution without bevacizumab is prepared, and the pH value is 5.2. And (3) replacing the purified bevacizumab stock solution with a blank solution for 6 times to prepare a solution of the formula, sterilizing, filtering, performing sterile subpackage, and inspecting to be qualified to obtain the bevacizumab.
Example 5 and
preparation of bevacizumab injection with same prescription
Prescription:
the preparation method comprises the following steps: according to the formula, a blank solution without bevacizumab is prepared, and the pH value is 6.1. And (3) replacing the purified bevacizumab stock solution with a blank solution for 6 times to prepare a solution of the formula, sterilizing, filtering, performing sterile subpackage, and inspecting to be qualified to obtain the bevacizumab.
Example 6 high temperature Heat stability of Bevacizumab injection
5 batches of bevacizumab injections were prepared according to the methods of examples 1 to 4 and example 5. Each batch of injection is placed in a constant temperature environment of 25 ℃, sampling detection is carried out for 0 month, 1 month, 2 months, 3 months and 6 months, and the change condition of the purity of the bevacizumab is inspected by using molecular sieve chromatography (SEC) so as to evaluate the stability of the pharmaceutical composition of the invention.
Molecular sieve chromatography (SEC) assay method: using TSKgel G3000 SWXL molecular sieve chromatographic column at 20mmol/L Na2HPO4+200mmol/L NaCl and pH 7.4 buffer solution as mobile phase, and the detection wavelength is 280 nm. The appearance order of the peaks under the chromatographic condition is a polymer peak, a main peak and a degradation peak in sequence. The percentage of polymer, main peak and degradent were calculated by area normalization and the results are shown in table 1.
TABLE 1 Bevacizumab State Change in purity
The results show that the polymer increases by 5.1%, the degradant increases by 0.73%, and the main peak decreases by 5.8% after the formula of example 5 is placed at 25 ℃ for 6 months, while the polymer increases by only 1.5-1.8%, the degradant increases by only 0.16-0.42%, and the main peak decreases by only 1.7-2.2% after the formula of examples 1-4 is placed at 25 ℃ for 6 months. The results show that the prescriptions of the embodiments 1-4 of the invention are stable, the prescription of the embodiment 5 is poor in stability, and the stability of the bevacizumab injection disclosed by the invention is remarkably improved.
Example 7 Long-term stability of Bevacizumab injection
Bevacizumab injection was prepared in 5 batches as in examples 1-4 and example 5. Storing each batch of injection at 2-8 ℃, sampling and detecting at 0 month, 3 months, 6 months, 9 months and 12 months, and inspecting the change condition of the purity of the bevacizumab by using a molecular sieve chromatography (SEC) to evaluate the stability of the pharmaceutical composition.
Molecular sieve chromatography (SEC) assay method: using TSKgel G3000 SWXL molecular sieve chromatographic column at 20mmol/L Na2HPO4+200mmol/L NaCl and pH 7.4 buffer solution as mobile phase, and the detection wavelength is 280 nm. The appearance order of the peaks under the chromatographic condition is a polymer peak, a main peak and a degradation peak in sequence. The percentage of polymer, main peak and degradent were calculated by area normalization and the results are shown in table 2.
TABLE 2 Bevacizumab purity Change
The results show that the polymer increases by 2.5%, the degradant increases by 0.38%, and the main peak decreases by 2.9% in the formula of example 5 at 2-8 ℃ for 12 months, while the polymer increases by only 0.2-0.5%, the degradant increases by only 0.06-0.12%, and the main peak decreases by only 0.4-0.6% in the formula of examples 1-4 at 2-8 ℃ for 12 months. The results show that the formulas of the embodiments 1 to 4 of the invention are relatively stable, the formula of the embodiment 5 is relatively poor in stability, and the stability of the bevacizumab injection disclosed by the invention is remarkably improved.
Claims (17)
1. A pharmaceutical composition comprising:
(a) 10-40 mg/mL of bevacizumab,
(b)0.1 to 200mg/mL of an osmotic pressure regulator,
(c)0.1 to 10mg/mL of Tween 20, and
(d) a buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the osmotic pressure regulator is one or two of mannitol or sodium chloride,
wherein the second buffer is selected from the group consisting of citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pH value of the pharmaceutical composition is 4.5-5.9.
2. The pharmaceutical composition of claim 1, wherein the concentration of bevacizumab is 20-30 mg/mL.
3. The pharmaceutical composition of claim 2, wherein the concentration of bevacizumab is about 25 mg/mL.
4. The pharmaceutical composition of claim 1, wherein the concentration of the tonicity modifier is 1 to 50 mg/mL.
5. The pharmaceutical composition of claim 4, wherein the concentration of the tonicity modifier is 4.7 to 25 mg/mL.
6. The pharmaceutical composition of claim 1, wherein tween 20 is at a concentration of 0.2 to 2 mg/mL.
7. The pharmaceutical composition of claim 6, wherein tween 20 is at a concentration of 0.4 mg/mL.
8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a pH of 4.9 to 5.5.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition has a pH of 5.2.
10. The pharmaceutical composition of claim 1, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 4.7 to 25mg/mL of an osmotic pressure modulator,
(c) about 0.4mg/mL of Tween 20, and
(d) a buffer system consisting of a sodium phosphate buffer and a second buffer,
wherein the osmotic pressure regulator is one or two of mannitol or sodium chloride,
wherein the second buffer is selected from the group consisting of citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
11. The pharmaceutical composition of claim 10, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 25mg/mL of mannitol in a concentration of about,
(c) about 0.4mg/mL of 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 citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
12. The pharmaceutical composition of claim 10, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 9mg/mL of sodium chloride,
(c) about 0.4mg/mL of 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 citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
13. The pharmaceutical composition of claim 10, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 12mg/mL of mannitol in a concentration of about,
(c) about 4.7mg/mL of sodium chloride,
(d) about 0.4mg/mL of 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 citric acid and sodium citrate or acetic acid and sodium acetate,
wherein the pharmaceutical composition has a pH of about 5.2.
14. The pharmaceutical composition of claim 11, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 25mg/mL of mannitol in a concentration of about,
(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) about 1.725mg/mL of sodium acetate trihydrate, and
(g) about 0.02mg/mL of acetic acid,
wherein the pharmaceutical composition has a pH of about 5.2.
15. The pharmaceutical composition of claim 11, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 25mg/mL of mannitol in a concentration of about,
(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) about 1.21mg/mL citric acid monohydrate, and
(g) about 0.68mg/mL sodium citrate dihydrate,
wherein the pharmaceutical composition has a pH of about 5.2.
16. The pharmaceutical composition of claim 12, comprising:
(a) about 25mg/mL of 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) about 1.21mg/mL citric acid monohydrate, and
(g) about 0.68mg/mL sodium citrate dihydrate,
wherein the pharmaceutical composition has a pH of about 5.2.
17. The pharmaceutical composition of claim 13, comprising:
(a) about 25mg/mL of bevacizumab,
(b) about 12mg/mL of mannitol in a concentration of about,
(c) about 4.7mg/mL of 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) about 1.21mg/mL citric acid monohydrate, and
(h) about 0.68mg/mL sodium citrate dihydrate,
wherein the pharmaceutical composition has a pH of about 5.2.
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| WO2016045570A3 (en) | 2016-05-19 |
| CN105435221A (en) | 2016-03-30 |
| CN105435221B (en) | 2021-09-28 |
| WO2016045570A2 (en) | 2016-03-31 |
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