CN114306271B - Lunvatinib composition - Google Patents
Lunvatinib composition Download PDFInfo
- Publication number
- CN114306271B CN114306271B CN202111403157.5A CN202111403157A CN114306271B CN 114306271 B CN114306271 B CN 114306271B CN 202111403157 A CN202111403157 A CN 202111403157A CN 114306271 B CN114306271 B CN 114306271B
- Authority
- CN
- China
- Prior art keywords
- ranvatinib
- pharmaceutical composition
- acid
- potassium carbonate
- regulator
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000203 mixture Substances 0.000 title abstract description 18
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims abstract description 37
- 230000002378 acidificating effect Effects 0.000 claims abstract description 17
- 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 57
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 26
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 18
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- 239000000463 material Substances 0.000 claims description 13
- 239000003607 modifier Substances 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 10
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 229960005070 ascorbic acid Drugs 0.000 claims description 8
- 239000011668 ascorbic acid Substances 0.000 claims description 8
- 235000010323 ascorbic acid Nutrition 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 239000011975 tartaric acid Substances 0.000 claims description 6
- 235000002906 tartaric acid Nutrition 0.000 claims description 6
- 239000000853 adhesive Substances 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 3
- 235000011010 calcium phosphates Nutrition 0.000 claims description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 13
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 abstract description 3
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 abstract description 3
- 229960002965 pravastatin Drugs 0.000 abstract description 3
- 230000009467 reduction Effects 0.000 abstract description 2
- 230000001419 dependent effect Effects 0.000 abstract 1
- 229960004106 citric acid Drugs 0.000 description 15
- 235000011181 potassium carbonates Nutrition 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 10
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 229950006605 varlitinib Drugs 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- -1 silicate compound Chemical class 0.000 description 5
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 210000004051 gastric juice Anatomy 0.000 description 4
- 229960003784 lenvatinib Drugs 0.000 description 4
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 102220042174 rs141655687 Human genes 0.000 description 4
- 102220076495 rs200649587 Human genes 0.000 description 4
- 102220043159 rs587780996 Human genes 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 238000001879 gelation Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 2
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 2
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 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 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 229960001429 lenvatinib mesylate Drugs 0.000 description 1
- HWLFIUUAYLEFCT-UHFFFAOYSA-N lenvatinib mesylate Chemical compound CS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 HWLFIUUAYLEFCT-UHFFFAOYSA-N 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 229960001289 prazosin Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a Ranuncutinib composition, which solves the problem that the Ranuncutinib is gelatinized when meeting water by adding an acidic regulator and a basic regulator. The addition of the acidic regulator reduces the pH value of a dissolution system, further avoids the problem of pH-dependent reduction in solubility of the pravastatin mesylate, and increases the bioavailability of the pravastatin.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a ranvatinib composition.
Background
Ranvatinib (Lenvatinib) is a tyrosine kinase (RTK) receptor inhibitor that inhibits the kinase activity of Vascular Endothelial Growth Factor (VEGF) receptors, and additionally inhibits other RTKs associated with the angiogenic and tumorigenic pathways.
On one hand, the preparation and the quality of the preparation are seriously influenced because the varlitinib mesylate is seriously gelated in water or aqueous solution. CN101001629A discloses a pharmaceutical composition of ranvatinib, which uses silicate as a gelation preventing agent. However, the dosage of the silicate compound in the composition is large, the density of the silicate compound is extremely low, the silicate compound is easy to fly in production, and the silicate compound causes serious damage to the respiratory system of operators. Meanwhile, in the mixing process, the difference between the density of the silicic acid compound and other auxiliary materials is large, so that the materials are not mixed uniformly, and the industrial production of the composition is not facilitated.
On the other hand, the solubility of the prandial varenib is very low in a solution system with a pH value of more than 4.0, the prandial varenib is almost insoluble in a solution system with a pH value of more than 6.8, the pH value of gastric juice of a human body is about 3.0-7.0 after meal, the pH value of gastric juice of a patient with reduced gastric acid secretion is about more than 6.0, and the solubility of the prandial varenib is influenced by the pH value, so that the in-vivo dissolution difference among different people is large. CN102470133A discloses a pharmaceutical composition of varenib containing calcium carbonate; CN106999483A and CN106139156A disclose a pharmaceutical composition of ranvatinib containing a basic amino acid or meglumine, potassium carbonate or potassium bicarbonate, respectively. The above documents improve the dissolution of the composition of ranvatinib by adding a basic inorganic compound to the composition, but the effect is not satisfactory and the dissolution is low in all dissolution systems at ph 6.8.
It is well known to those skilled in the art that the main factors affecting the bioavailability of a drug are the permeability and solubility of the drug. When a drug has a high permeability, increasing its solubility increases the bioavailability of the drug if it is less soluble. The evaluation report of the capsules of varlitinib mesylate published by the european medical administration on day 26/3/2015 shows that: varenib mesylate is a poorly soluble drug and its in vivo permeability cannot be judged as it does not provide in vivo absorption data. However, in vitro data indicate that the permeability of the compound lenvatinib is comparable to that of the highly permeable compound prazosin, 10 times higher than that of the poorly permeable compound mannitol, and it can be presumed that the permeability in vivo is good. Therefore, the low solubility is the rate limiting step in increasing the bioavailability of the pravastatin mesylate.
In view of the defects of the prior art, the invention provides the ranvatinib composition, and the specific acidic and basic auxiliary materials are added, so that the problem of gelation of the ranvatinib in water is solved, and the dissolution speed of the ranvatinib in a dissolution environment with the pH value of more than 6.8 is improved.
Disclosure of Invention
Through a great deal of research, the inventor finds that the phenomenon of gelation of the varlitinib mesylate when meeting water is greatly improved by adopting the matching use of the acidic and basic regulators, and simultaneously solves the problem of poor dissolution rate of the varlitinib mesylate in a dissolution environment with the pH value of more than 6.8.
The invention provides a pharmaceutical composition of Ranuncutinib, which consists of methane sulfonic acid Ranuncutinib, an alkaline regulator, a filler, a disintegrating agent, an adhesive, an acidic regulator and a lubricant, wherein:
a. the filler is selected from mannitol, microcrystalline cellulose;
b. the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, sodium carboxymethyl starch or crospovidone, preferably low-substituted hydroxypropyl cellulose;
c. the binder is selected from hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, preferably hydroxypropyl cellulose;
d. the lubricant is selected from pulvis Talci, magnesium stearate, and sodium fumarate stearate, preferably pulvis Talci;
e. the alkaline regulator is selected from potassium carbonate, sodium carbonate, calcium sulfate, and calcium phosphate;
f. the acidity regulator is selected from citric acid, tartaric acid, ascorbic acid;
and wherein the raw materials: alkaline regulators: the mass ratio of the acidity regulator is 1.
Further, the pharmaceutical composition of Ranuncutinib comprises the following raw materials: alkaline regulators: the mass ratio of the acidity regulator is 1.
Further, the pharmaceutical composition of ranvatinib, wherein the basic/acidic modifier is selected from the group consisting of potassium carbonate/citric acid, potassium carbonate/tartaric acid, potassium carbonate/ascorbic acid, sodium carbonate/ascorbic acid, preferably potassium carbonate/citric acid.
Further, the weight percentage of the rivastigmine mesylate medicine composition is 3.52% -5%.
Further, the pharmaceutical composition of ranvatinib is prepared from the following raw materials: alkaline regulators: the mass ratio of the acidity regulator is 1.
Further, the pharmaceutical composition of the ranvatinib is as follows in percentage by weight:
| name of material | Percent by weight/%) |
| Filler | 21.83～31 |
| Disintegrating agent | 17.61～25 |
| Adhesive agent | 2.11～3 |
| Lubricant agent | 2.11～3 |
。
Further, the pharmaceutical composition of Ranuncutinib comprises the following components in percentage by weight:
| name of material | Percent by weight/%) |
| Rivatinib mesylate | 3.52 |
| Potassium carbonate | 17.61 |
| Mannitol | 11.27 |
| Microcrystalline cellulose | 10.56 |
| Low-substituted hydroxypropyl cellulose | 17.61 |
| Hydroxypropyl cellulose | 2.11 |
| Citric acid | 35.21 |
| Talcum powder | 2.11 |
。
Further, the pharmaceutical composition of Rankine, vannib comprises the following components in percentage by weight:
| name of material | Percent by weight/%) |
| Lunvatinib mesylate | 3.93 |
| Potassium carbonate | 19.69 |
| Mannitol | 12.60 |
| Microcrystalline cellulose | 11.81 |
| Low-substituted hydroxypropyl cellulose | 19.69 |
| Hydroxypropyl cellulose | 2.36 |
| Citric acid | 27.56 |
| Talcum powder | 2.36 |
。
Further, the pharmaceutical composition of the ranvatinib is a capsule.
Has the advantages that:
1. according to the invention, the problem that the Ranatinib is gelatinized in water is solved by adding the acidic and alkaline regulators into the Ranatinib composition. The addition of the acidic regulator reduces the pH of a dissolution system, further avoids the problem of the reduction of the solubility of the lenvatinib mesylate which has dependency on the pH, and increases the bioavailability of the lenvatinib.
2. The composition of the invention adopts unmicronized raw materials to achieve good dissolution effect, and simplifies the production steps of the preparation.
Detailed Description
The composition of the present invention will now be illustrated in detail by way of some of the examples, but the invention is not limited to the examples described below. Any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are exemplary only.
The examples do not indicate any specific conditions, and are carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.
Test example 1: test for pH dependence of Rivatinib mesylate
1. Preparation of dissolution media with different pH values
pH1.0-2.0 and pH4.5-8.0: the preparation method of the dissolution medium of pH1.0-2.0 (hydrochloric acid solution) and pH4.5-8.0 (phosphate buffer solution) recorded in the determination and comparison guide principle of the dissolution curve of the common oral solid preparation disclosed by the drug evaluation center of the State drug administration is adopted for preparation.
pH3.0: taking 17.91g of disodium hydrogen phosphate dodecahydrate, adding water to dissolve and diluting to 1000ml to obtain 0.05mol/L disodium hydrogen phosphate solution; and adding water to dissolve 5.25g of citric acid monohydrate and diluting to 1000ml to obtain 0.025mol/L citric acid solution. And then adjusting the disodium hydrogen phosphate solution by using a citric acid solution to enable the final pH value to be 3.0.
pH4.0: taking 17.91g of disodium hydrogen phosphate dodecahydrate, adding water to dissolve and diluting to 1000ml to obtain 0.05mol/L disodium hydrogen phosphate solution; and adding water to dissolve 5.25g of citric acid monohydrate and diluting to 1000ml to obtain 0.025mol/L citric acid solution. And then adjusting the disodium hydrogen phosphate solution by using a citric acid solution to enable the final pH value to be 4.0.
2. Determination of the solubility of Rivastigtinib mesylate at different pH
Solubility determination method: taking a proper amount of the varenib mesylate, adding a certain amount of dissolution media with different pH values preheated to 37 ℃, placing the dissolution media in a water bath with the temperature of 37 ℃, and shaking.
The results are shown in the following table:
TABLE 1 solubility of varlitinib mesylate in media of different pH
| Medium | Solubility (mg/ml) |
| pH1.0 | 1.199 |
| pH2.0 | 0.920 |
| pH3.0 | 1.884 |
| pH4.0 | 0.078 |
| pH4.5 | 0.060 |
| pH5.5 | 0.056 |
| pH6.0 | 0.003 |
| pH6.8 | 0.001 |
| pH8.0 | 0.001 |
From the above table, it can be seen that the varlitinib mesylate has a pH dependency, and the solubility gradually decreases at pH4.0 or more and is almost insoluble at pH6.0 or more.
The pH of the human postprandial gastric juice is 3.0-7.0 on average, the pH range is wide, the individual difference is large, and the pH dependence of the methane sulfonic acid ranvatinib can seriously influence the in-vivo dissolution behavior of the drug. Therefore, the dissolution rate of the varlitinib mesylate in the medium with the pH value of 4.0-6.8 can be improved, and the bioavailability can be improved, and meanwhile, the difference and the variability of absorption can be reduced. In addition, partial patients with insufficient gastric acid secretion have higher pH value of gastric juice (about more than 6.0), and the absorption condition of the patients with insufficient gastric acid secretion can be improved by improving the dissolution of the cefaclor.
Comparative example 1:
capsule samples were prepared according to the weight percentages of the components of the prescription in example 2 of patent CN102470133A, and the specific prescription information is as follows:
TABLE 2 prescription information for comparative example 1 (example 2 in the patent)
The preparation method comprises the following steps:
1. weighing: respectively weighing calcium carbonate, mannitol, microcrystalline cellulose Type101, low-substituted hydroxypropyl cellulose, methanesulfonic acid ranvatinib and purified water according to the prescription amount.
2. Preparing an adhesive: adding hydroxypropyl cellulose into purified water while stirring, and dissolving without bubbles for use.
3. Mixing: pouring calcium carbonate, mellitinib mesylate, mannitol, low-substituted hydroxypropyl cellulose and microcrystalline cellulose Type101 into a hopper of a wet granulator for mixing.
4. Adding slurry: starting the wet granulator, stirring, rotating and shearing, and pumping the prepared adhesive into a granulation pot through a peristaltic pump.
5. And (3) granulating: and starting the wet granulator to stir and shear, and granulating.
6. And (3) drying: drying in an electrothermal blowing drying oven until the water content is below 2.0 percent, and discharging.
7. Straightening:
and (5) finishing the grains by using a screen.
8. Total mixing: the microcrystalline cellulose Type102 and the talcum powder are sequentially weighed according to the prescription amount, and the materials are added and mixed in equal amount.
9. And (5) filling the capsules.
Micronized starting material (particle size distribution: D10=1.90 μm, D50=6.98 μm, D90=17.63 μm) the dissolution results of the samples were prepared.
Table 3 dissolution results (n = 12)
Unmicronised starting material (particle size distribution: D10=2.45 μm, D50=23.4 μm, D90=186 μm) dissolution results for the samples were prepared.
Table 4 dissolution results (n = 12)
It is confirmed from tables 3 and 4 that the dissolution of the mevalonic capsules in ph6.8 media is slower and that the samples prepared from the unmicronized material dissolve significantly slower than the samples prepared from the micronized material.
Example 1: selection of different acid/base modifier classes
Different capsule formulations were prepared according to the preparation method of comparative example 1 (addition of alkaline regulator) using unmicronized raw materials (particle size distribution: D10=2.45 μm, D50=23.4 μm, D90=186 μm) using the following formulation, and 12 capsules of different formulations were taken respectively to test dissolution.
TABLE 5 prescription information-1
TABLE 6 prescription information-2
And (3) determining the dissolution results of the mellitinib mesylate capsules prepared by adopting different acidic and basic regulators under the condition of a dissolution medium with pH 6.8.
Table 7 dissolution results (n = 12)
As can be seen from the dissolution results in table 7, the dissolution was slightly improved, 8% in 10min, 16% in 30min and 22% in 120min, after adding a certain amount of citric acid to the calcium carbonate used in comparative example 1 (example 1-1), compared to the dissolution of the formulation prepared from the unmicronized starting material in comparative example 1.
When the alkali/acid regulator combination of sodium carbonate/citric acid (examples 1-5), sodium carbonate/tartaric acid (examples 1-6), calcium sulfate/citric acid (examples 1-8) and calcium phosphate/citric acid (examples 1-9) is selected, the dissolution rate is improved to a certain extent, the dissolution rate at 30min can reach more than 40%, and the dissolution rate at 120min can reach more than 55%.
When alkali/acid regulators of potassium carbonate/citric acid (examples 1-2), potassium carbonate/tartaric acid (examples 1-3), potassium carbonate/ascorbic acid (examples 1-4) and sodium carbonate/ascorbic acid (examples 1-7) are selected to be combined, the dissolution effect is good, the dissolution rate in 30min can reach more than 60%, and the dissolution rate in 120min can reach more than 65%.
In example 1-2, when the alkaline modifier is potassium carbonate and the acidic modifier is citric acid, the dissolution effect is the best, and the dissolution rate of the Rankine reaches 69% in 30min and 84% in 120 min.
Example 2: effect of different ratios of acidic and basic modifiers on dissolution
Different capsule formulations were obtained according to the preparation method of comparative example 1 (addition of alkaline regulator) using unmicronized raw materials (particle size distribution: D10=2.45 μm, D50=23.4 μm, D90=186 μm) using the following formulation, and 12 capsules of different formulations were taken respectively to test dissolution.
TABLE 8 prescription information
And (3) determining the dissolution results of the methanesulfonic acid ranvatinib capsule prepared by adopting different proportions of acidic and alkaline regulators under the condition of a dissolution medium with pH 6.8.
Table 9 dissolution results (n = 12)
| Prescription | Time/min | 10 | 15 | 20 | 30 | 45 | 60 | 90 | 120 |
| 2-1 | Mean value% | 2 | 4 | 8 | 15 | 26 | 32 | 39 | 42 |
| 2-2 | Mean value% | 20 | 42 | 53 | 69 | 80 | 83 | 83 | 84 |
| 2-3 | Mean value% | 31 | 57 | 68 | 78 | 82 | 88 | 89 | 89 |
| 2-4 | Mean value% | 38 | 65 | 73 | 82 | 87 | 90 | 92 | 92 |
| 2-5 | Mean value% | 39 | 62 | 71 | 80 | 85 | 88 | 90 | 90 |
The results in Table 9 show that the higher the amount of acid modifier used, the faster the dissolution rate of the lenvatinib. When the mass ratio of the raw materials, the alkaline modifier and the acidic modifier is in the range of 1. When the mass ratio of the raw material, the alkaline modifier and the acidic modifier is 1. When the dosage of the acid regulator is increased on the basis of the examples 2 to 4 (the mass ratio is 1.
Claims (14)
1. A pharmaceutical composition of Lunvatinib is composed of Lunvatinib mesylate, an alkaline regulator, a filler, a disintegrant, a binder, an acidic regulator and a lubricant, wherein:
a. the filler is selected from mannitol, microcrystalline cellulose;
b. the disintegrant is selected from low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch or crospovidone;
c. the binder is selected from hydroxypropyl cellulose, polyvinylpyrrolidone, and methylcellulose;
d. the lubricant is selected from pulvis Talci, magnesium stearate, and sodium fumarate stearate;
e. the alkaline regulator is selected from potassium carbonate, sodium carbonate, calcium sulfate, and calcium phosphate;
f. the acidity regulator is selected from citric acid, tartaric acid, ascorbic acid;
and wherein the molar ratio of the methanesulfonic acid: alkaline regulators: the mass ratio of the acidity regulator is 1.
2. The pharmaceutical composition of ranvatinib of claim 1, wherein the disintegrant is a low substituted hydroxypropylcellulose.
3. The pharmaceutical composition of ranvatinib of claim 1, wherein the binder is hydroxypropylcellulose.
4. The pharmaceutical composition of ranvatinib of claim 1, wherein the lubricant is talc.
5. The pharmaceutical composition of ranvatinib of claim 1, wherein the ratio of methanesulfonic acid ranvatinib: alkaline regulators: the mass ratio of the acidity regulator is 1.
6. The pharmaceutical composition of ranvatinib of claim 1, wherein the ratio of methanesulfonic acid ranvatinib: alkaline regulators: the mass ratio of the acidity regulator is 1.
7. The pharmaceutical composition of ranvatinib of claim 1, wherein the basic/acidic modifier is selected from the group consisting of potassium carbonate/citric acid, potassium carbonate/tartaric acid, potassium carbonate/ascorbic acid, sodium carbonate/ascorbic acid.
8. The pharmaceutical composition of ranvatinib of claim 1, wherein the basic/acidic modulator is potassium carbonate/citric acid.
9. The pharmaceutical composition of ranvatinib of claim 1, wherein the weight percentage of ranvatinib mesylate is 3.52% -5%.
10. The pharmaceutical composition of ranvatinib of claim 1, wherein the ratio of methanesulfonic acid ranvatinib: alkaline regulators: the mass ratio of the acidity regulator is 1.
11. The pharmaceutical composition of ranvatinib as claimed in claim 1, wherein the weight percentages of the components are as follows:
。
12. The pharmaceutical composition of ranvatinib as claimed in claim 1, wherein the weight percentages of the components are as follows:
13. the pharmaceutical composition of ranvatinib as claimed in claim 1, wherein the weight percentages of the components are as follows:
。
14. The pharmaceutical composition of ranvatinib as claimed in claim 1, wherein said pharmaceutical composition of ranvatinib is a capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111403157.5A CN114306271B (en) | 2021-11-24 | 2021-11-24 | Lunvatinib composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111403157.5A CN114306271B (en) | 2021-11-24 | 2021-11-24 | Lunvatinib composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114306271A CN114306271A (en) | 2022-04-12 |
| CN114306271B true CN114306271B (en) | 2023-04-07 |
Family
ID=81045790
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111403157.5A Active CN114306271B (en) | 2021-11-24 | 2021-11-24 | Lunvatinib composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114306271B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117442621B (en) * | 2023-11-15 | 2025-02-14 | 武汉大学中南医院 | A neratinib maleate pharmaceutical composition and tablet for treating breast cancer and a preparation method thereof |
| CN117860686B (en) * | 2024-01-11 | 2025-06-17 | 山东新时代药业有限公司 | A kind of lenvatinib mesylate pharmaceutical composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102470133A (en) * | 2009-08-19 | 2012-05-23 | 卫材R&D管理有限公司 | Pharmaceutical compositions containing quinoline derivatives |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11980610B2 (en) * | 2017-10-31 | 2024-05-14 | Samyang Holdings Corporation | Oral solid dosage form composition having improved disintegration and preparation method therefor |
| US10583133B2 (en) * | 2018-03-12 | 2020-03-10 | Shilpa Medicare Limited | Pharmaceutical compositions of lenvatinib |
-
2021
- 2021-11-24 CN CN202111403157.5A patent/CN114306271B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102470133A (en) * | 2009-08-19 | 2012-05-23 | 卫材R&D管理有限公司 | Pharmaceutical compositions containing quinoline derivatives |
Non-Patent Citations (2)
| Title |
|---|
| Charge-assisted bond and molecular self-assembly drive the gelation of lenvatinib mesylate;Meiling Su等;《International Journal of Pharmaceutics》;20210818;第607卷;第1-12页 * |
| 仑伐替尼治疗恶性实体瘤的研究进展;牟迪;《中国肿瘤生物治疗杂志》;20200430;第27卷(第4期);第445-451页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114306271A (en) | 2022-04-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4757872B2 (en) | Tablet formulation with extended release comprising pramipexole or a pharmaceutically acceptable salt thereof, process for its production and use thereof | |
| CN101184489B (en) | pharmaceutical composition | |
| CN114306271B (en) | Lunvatinib composition | |
| CN112220770B (en) | Pharmaceutical composition of selepag and preparation method thereof | |
| CN112022825A (en) | Alvatripopa maleate tablet and preparation method thereof | |
| CN104490835B (en) | A kind of Azilsartan tablet and preparation method thereof | |
| CN102885792A (en) | Oral solid rapid release preparation of cinacalcet hydrochloride | |
| CN108778281B (en) | Pyridone derivative pharmaceutical composition and preparation method thereof | |
| CN112137979B (en) | Teposinib tablet and preparation method thereof | |
| CN101912373B (en) | Stable cefeclor dispersible tablet and preparation method thereof | |
| US20090215756A1 (en) | Formulations containing losartan and/or its salts | |
| CN109745295B (en) | Rivaroxaban oral solid preparation and preparation method thereof | |
| WO2022042646A1 (en) | Lurasidone hydrochloride composition and preparation method therefor | |
| CN111053753A (en) | Rivaroxaban pharmaceutical composition and preparation method thereof | |
| CN102784115B (en) | oral tablet containing iloperidone and preparation method thereof | |
| CN108078945B (en) | Canagliflozin pharmaceutical composition | |
| CN117695285A (en) | JAK kinase inhibitor pharmaceutical composition | |
| CN111467317A (en) | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof | |
| EP4085902B1 (en) | Pharmaceutical composition containing nitroxoline, nitroxoline tablet, preparation method therefor and use thereof | |
| CN111035619B (en) | Gefitinib tablet and preparation method thereof | |
| KR101428018B1 (en) | Orally disintegrating tablet containing aripiprazole and manufacturing method thereof | |
| EP2438920B1 (en) | Controlled-release formulations of quetiapine | |
| CN108379234B (en) | A kind of glipizide composition based on microenvironment pH regulation and preparation method thereof | |
| CN109419778A (en) | A kind of razaxaban tablet and preparation method thereof | |
| WO2021136089A1 (en) | Anti-tumor pharmaceutical composition and method for increasing solubility of compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |