CN115715764A - Apatinib oral patch and preparation method thereof - Google Patents
Apatinib oral patch and preparation method thereof Download PDFInfo
- Publication number
- CN115715764A CN115715764A CN202110972110.4A CN202110972110A CN115715764A CN 115715764 A CN115715764 A CN 115715764A CN 202110972110 A CN202110972110 A CN 202110972110A CN 115715764 A CN115715764 A CN 115715764A
- Authority
- CN
- China
- Prior art keywords
- certain
- apatinib
- carbomer
- hydroxypropyl
- mesylate
- 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.)
- Pending
Links
- 229960003982 apatinib Drugs 0.000 title claims abstract description 47
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- FYJROXRIVQPKRY-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 FYJROXRIVQPKRY-UHFFFAOYSA-N 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 239000000314 lubricant Substances 0.000 claims abstract description 11
- 239000000853 adhesive Substances 0.000 claims abstract description 10
- 230000001070 adhesive effect Effects 0.000 claims abstract description 10
- 239000000796 flavoring agent Substances 0.000 claims abstract description 10
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 10
- 239000000049 pigment Substances 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 5
- 239000003085 diluting agent Substances 0.000 claims abstract description 4
- 239000011241 protective layer Substances 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 44
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000007864 aqueous solution Substances 0.000 claims description 25
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 24
- 229920002125 Sokalan® Polymers 0.000 claims description 24
- 229960001631 carbomer Drugs 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical group CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 24
- 239000002245 particle Substances 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 18
- 239000004925 Acrylic resin Substances 0.000 claims description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 6
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 claims description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000001630 malic acid Substances 0.000 claims description 6
- 235000011090 malic acid Nutrition 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 230000008961 swelling Effects 0.000 claims description 6
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 5
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 5
- 229940041616 menthol Drugs 0.000 claims description 5
- 244000248349 Citrus limon Species 0.000 claims description 4
- 235000005979 Citrus limon Nutrition 0.000 claims description 4
- 229930002875 chlorophyll Natural products 0.000 claims description 4
- 235000019804 chlorophyll Nutrition 0.000 claims description 4
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound 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 3
- 239000003921 oil Substances 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims 2
- 235000012741 allura red AC Nutrition 0.000 claims 1
- 239000004191 allura red AC Substances 0.000 claims 1
- CEZCCHQBSQPRMU-UHFFFAOYSA-L chembl174821 Chemical compound [Na+].[Na+].COC1=CC(S([O-])(=O)=O)=C(C)C=C1N=NC1=C(O)C=CC2=CC(S([O-])(=O)=O)=CC=C12 CEZCCHQBSQPRMU-UHFFFAOYSA-L 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 abstract description 9
- 206010017758 gastric cancer Diseases 0.000 abstract description 9
- 201000011549 stomach cancer Diseases 0.000 abstract description 9
- 238000007908 dry granulation Methods 0.000 abstract description 4
- 239000007935 oral tablet Substances 0.000 abstract 1
- 229940096978 oral tablet Drugs 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000002200 mouth mucosa Anatomy 0.000 description 6
- 238000005259 measurement Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- 239000001116 FEMA 4028 Substances 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 4
- 229960004853 betadex Drugs 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000001055 blue pigment Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 230000003527 anti-angiogenesis Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000011255 standard chemotherapy Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010146 3D printing Methods 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- -1 apatinib compound Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KZFDVWZZYOPBQZ-UHFFFAOYSA-K bismuth;potassium;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [K+].[Bi+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KZFDVWZZYOPBQZ-UHFFFAOYSA-K 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003657 dexamethasone acetate Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000006101 laboratory sample Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000002137 ultrasound extraction Methods 0.000 description 1
- 239000001052 yellow pigment Substances 0.000 description 1
Images
Abstract
The invention discloses an apatinib oral patch and a preparation method thereof. The invention belongs to the technical field of pharmaceutical preparations. The prescription composition of the apatinib oral patch comprises the following components in percentage by weight: 1-15% of apatinib mesylate, 10-60% of film forming agent, 10-60% of adhesive, 5-20% of supporting agent, 0.1-5% of lubricant, 5-60% of diluent, 0.01-3% of flavoring agent, 0.01-3% of pigment, 10-60% of framework material and 5-20% of protective layer. The preparation method comprises the following steps: dry granulation and tabletting. The apatinib oral patch provided by the invention provides possibility for multiple administration modes of apatinib, and provides a new administration mode for patients with advanced gastric cancer who are not suitable for oral tablet administration modes.
Description
Technical Field
The invention relates to an apatinib oral patch and a preparation method thereof, in particular to a novel drug delivery method of a safe and effective small-molecule anti-angiogenesis targeted drug apatinib after the standard chemotherapy failure of late gastric cancer.
Technical Field
Apatinib mesylate (apatinib mesylate), which is N- [4- (1-cyanocyclopentyl) phenyl ] -2- [ (4-pyridylmethyl) amino ] -3-pyridinecarboxamide mesylate, is a tyrosine kinase vascular endothelial growth factor receptor VEGFR-2 inhibitor (TKI), and is used for inhibiting the phosphorylation of an ATP binding site in VEGFR-2 cells through competitively inhibiting downstream signal transduction, thereby inhibiting the generation of tumor blood vessels and inhibiting the growth of tumors.
Apatinib mesylate is developed by Jiangsu Henry pharmaceutical company, is marketed in China in 10 months 2014, has the trade name of Eitan, and is suitable for advanced gastric cancer or adenocarcinoma of the gastric-esophageal junction, which have progressed or recurred after receiving at least 2-system chemotherapy.
The apatinib mesylate is the first globally proven small-molecule anti-angiogenesis targeted drug which is safe and effective after the failure of the advanced gastric cancer standard chemotherapy, and meanwhile, the apatinib is the only oral preparation in the existing advanced gastric cancer targeted drugs, so that the survival time of patients with advanced gastric cancer can be remarkably prolonged, and the treatment compliance of the patients can be effectively improved. The molecular structure of apatinib mesylate is shown in figure 1.
The prior clinical application form of apatinib mesylate is tablets. The 'apatinib' is used as a keyword, the website of the 'national drug administration' is searched, 4 results are displayed, and the 4 results are all product batch numbers of the apatinib mesylate 'tablet formulation' of Hengrui pharmaceutical company of Jiangsu.
The patent 189, which is co-searched on the Chinese patent network by taking the apatinib as a key word, mainly relates to the synthesis of an apatinib compound and the clinical research of the compound.
The apatinib tablet is orally administered to patients with gastric cancer, but because the bioavailability of the compound in the gastrointestinal tract is not very ideal, other administration routes are developed and developed, and the bioavailability of the compound is very significant.
The apatinib oral patch is also called apatinib oral adhesive tablet. The oral patch can prolong the residence time of the medicine in the oral mucosa by using the viscosity of the oral patch, the medicine is continuously and slowly released and enters the blood circulation through the oral mucosa, sublingual blood vessels, oral cavity swallowing and other ways, thereby playing a local or systemic treatment role, improving the bioavailability of the medicine and achieving a better treatment effect.
The development of the apatinib oral patch can provide more possibilities for the diversity of apatinib clinical application choices.
Disclosure of Invention
The invention aims to provide a preparation method of an apatinib oral patch. The technical problem of the invention is realized by the following technical scheme.
The apatinib oral patch comprises: the disintegrant is microcrystalline cellulose; the film forming agent is carbomer 974 or carbomer 934P; the adhesive is polyvinylpyrrolidone K30 or hydroxypropyl methylcellulose; the lubricant is magnesium stearate or talcum powder; the diluent is hydroxypropyl-beta-cyclodextrin or starch, and the flavoring agent is menthol, orange peel oil, malic acid and citric acid. The pigment is lemon yellow or brilliant blue or allure red or chlorophyll, the framework material is polyacrylic resin, and the protective layer is polyvinyl alcohol.
As a preferable mode, the apatinib oral patch is mainly prepared from the following components (calculated according to 5000 tablets):
the apatinib oral patch is prepared by adopting a dry granulation tabletting process, and the process flow chart is shown in figure 2.
The dry granulation and tabletting process of the apatinib oral patch comprises the following specific steps of:
(1) The preparation method comprises the steps of respectively crushing the apatinib mesylate and hydroxypropyl-beta-cyclodextrin according to the prescription amount, and preparing the hydroxypropyl-beta-cyclodextrin inclusion compound of the apatinib mesylate by adopting a saturated aqueous solution method. The specific operation steps are that in a supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and 70% ethanol aqueous solution of menthol serving as a flavoring agent according to the prescription amount are added, and simultaneously 70% ethanol solution is added and fully stirred until an inclusion compound is formed. Then, evaporating under reduced pressure to remove ethanol in the solution, and drying at low temperature of 40 ℃ to obtain an apatinib mesylate inclusion compound for later use;
(2) Respectively crushing carbomer 974 and polyacrylic resin according to the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing for later use;
(3) Taking the formula amount of polyvinylpyrrolidone K30, swelling with pure water, and preparing into a solution with the concentration of 10% for later use;
(4) Uniformly mixing the hydroxypropyl-beta-cyclodextrin inclusion compound of the apatinib mesylate, the mixture of the carbomer 974 and the polyacrylic resin and the lemon yellow pigment according to the prescription amount, adding the aqueous solution adhesive of the polyvinylpyrrolidone K30, stirring to form large particles, and drying at low temperature of 40 ℃.
(5) And (4) taking the large particles obtained by drying, granulating by using a 40-mesh sieve, and uniformly mixing the lubricant magnesium stearate with the large particles according to the prescription amount.
(6) And (3) tabletting the mixture by using a round shallow concave punch with the diameter of 10mm to obtain the tablet.
Drawings
The invention is further illustrated below with reference to the figures and the examples.
FIG. 1 shows the molecular structure of apatinib mesylate.
Fig. 2 is a process flow diagram of a dry granulation tableting process for preparing an apatinib oral patch.
Detailed Description
The invention is further discussed in detail below with reference to specific examples, which are not intended to be limiting.
[ example 1] preparation of Apatinib oral Patch
(1) The apatinib mesylate and the hydroxypropyl-beta-cyclodextrin are respectively crushed according to the prescription amount, and the beta-cyclodextrin inclusion compound of the apatinib mesylate is prepared by adopting a saturated aqueous solution method. The specific operation steps are that in a supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and 70% ethanol aqueous solution of a prescription amount of flavoring agent malic acid are added, and simultaneously 70% ethanol solution is added and fully stirred until an inclusion compound is formed. Then, removing ethanol in the solution by decompression and volatilization, and drying at low temperature of 40 ℃ to obtain an apatinib mesylate clathrate compound for later use;
(2) Respectively crushing carbomer 974 and polyacrylic resin according to the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing for later use;
(3) Swelling polyvinylpyrrolidone K30 in a prescribed amount by using pure water to prepare a solution with the concentration of 10% for later use;
(4) Uniformly mixing the hydroxypropyl-beta-cyclodextrin inclusion compound of the apatinib mesylate, the mixture of the carbomer 974 and the polyacrylic resin and the brilliant blue pigment with the formula amount, adding the aqueous solution adhesive of polyvinylpyrrolidone K30, stirring to form large particles, and drying at low temperature of 40 ℃.
(5) And (4) taking the large particles obtained by drying, granulating by using a 40-mesh sieve, and uniformly mixing the lubricant magnesium stearate with the large particles according to the prescription amount.
(6) Tabletting the mixture with a round shallow concave punch with the diameter of 10mm to obtain the tablet.
[ example 2] preparation of Apatinib oral Patch
(1) The alpacatinib mesylate and the hydroxypropyl-beta-cyclodextrin in the prescription amount are respectively crushed and then are prepared into the beta-cyclodextrin inclusion compound of the alpacatinib mesylate by adopting a saturated aqueous solution method. The specific operation steps are that in a supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and 70% ethanol aqueous solution of a prescription amount of flavoring agent malic acid are added, and simultaneously 70% ethanol solution is added and fully stirred until an inclusion compound is formed. Then, evaporating under reduced pressure to remove ethanol in the solution, and drying at low temperature of 40 ℃ to obtain an apatinib mesylate inclusion compound for later use;
(2) Taking the formula amount of carbomer 934P and the polyacrylic resin, respectively crushing, sieving with a 80-mesh sieve, and uniformly mixing for later use;
(3) Swelling polyvinylpyrrolidone K30 in a prescribed amount by using pure water to prepare a solution with the concentration of 10% for later use;
(4) Uniformly mixing the hydroxypropyl-beta-cyclodextrin inclusion compound of apatinib mesylate, the mixture of carbomer 974 and polyacrylic resin with formula amount of brilliant blue pigment, adding an aqueous solution binder of polyvinylpyrrolidone K30, stirring to form large particles, and drying at low temperature of 40 ℃.
(5) And (4) taking the large particles obtained by drying, granulating by using a 40-mesh sieve, and uniformly mixing the lubricant magnesium stearate with the large particles according to the prescription amount.
(6) And (3) tabletting the mixture by using a round shallow concave punch with the diameter of 10mm to obtain the tablet.
[ example 3] preparation of Apatinib oral Patch
(1) The apatinib mesylate and the hydroxypropyl-beta-cyclodextrin are respectively crushed according to the prescription amount, and the beta-cyclodextrin inclusion compound of the apatinib mesylate is prepared by adopting a saturated aqueous solution method. The specific operation steps are that in supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and 70% ethanol aqueous solution of prescription amount of corrective malic acid are added, and at the same time, 70% ethanol solution is added and fully stirred until an inclusion compound is formed. Then, removing ethanol in the solution by decompression and volatilization, and drying at low temperature of 40 ℃ to obtain an apatinib mesylate clathrate compound for later use;
(2) Taking the formula amount of carbomer 934P and the polyacrylic resin, respectively crushing, sieving with a 80-mesh sieve, and uniformly mixing for later use;
(3) Swelling hydroxypropyl methylcellulose in a prescription amount by using pure water, and preparing a solution with the concentration of 10% for later use;
(4) Uniformly mixing the hydroxypropyl-beta-cyclodextrin inclusion compound of the apatinib mesylate, the mixture of the carbomer 974 and the polyacrylic resin and the brilliant blue pigment with the formula amount, adding the aqueous solution adhesive of polyvinylpyrrolidone K30, stirring to form large particles, and drying at low temperature of 40 ℃.
(5) And (4) taking the large particles obtained by drying, granulating by using a 40-mesh sieve, and uniformly mixing the lubricant magnesium stearate with the large particles according to the prescription amount.
(6) Tabletting the mixture with a round shallow concave punch with the diameter of 10mm to obtain the tablet.
[ example 4] preparation of Apatinib oral Patch
(1) The alpacatinib mesylate and the hydroxypropyl-beta-cyclodextrin in the prescription amount are respectively crushed and then are prepared into the beta-cyclodextrin inclusion compound of the alpacatinib mesylate by adopting a saturated aqueous solution method. The specific operation steps are that in a supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and 70% ethanol aqueous solution of citric acid serving as a flavoring agent according to the prescription amount are added, and simultaneously 70% ethanol solution is added and fully stirred until an inclusion compound is formed. Then, evaporating under reduced pressure to remove ethanol in the solution, and drying at low temperature of 40 ℃ to obtain an apatinib mesylate inclusion compound for later use;
(2) Respectively crushing carbomer 934P and polyacrylic resin according to the prescription amount, sieving with a 80-mesh sieve, and uniformly mixing for later use;
(3) Swelling hydroxypropyl methylcellulose in a prescription amount by using pure water, and preparing a solution with the concentration of 10% for later use;
(4) Uniformly mixing the hydroxypropyl-beta-cyclodextrin inclusion compound of the apatinib mesylate, the mixture of the carbomer 974 and the polyacrylic resin and the chlorophyll pigment according to the prescription amount, adding the aqueous solution adhesive of polyvinylpyrrolidone K30, stirring to form large particles, and drying at low temperature of 40 ℃.
(5) And (3) taking the large particles obtained by drying, finishing the particles by using a 40-mesh sieve, and uniformly mixing the lubricant talcum powder with the large particles according to the prescription amount.
(6) And (3) tabletting the mixture by using a round shallow concave punch with the diameter of 10mm to obtain the tablet.
[ example 5] content measurement of Apatinib oral Patch
The 5 pieces of apatinib oral patch prepared in example 1 were taken, ground thoroughly, respectively, 0.2g was precisely weighed, respectively, put into 5 50mL small beakers, respectively added with 15mL methanol for ultrasonic extraction 3 times, the extract was centrifuged to be clear, the extracts were combined, filtered with 0.22um microporous membrane and put into a 50mL volumetric flask, and the volume was adjusted to 50mL with methanol. Similarly, 5 apatinib oral patch extracts of example 2, example 3 and example 4 were prepared from 5 apatinib oral patch samples, respectively.
The content of apatinib in the apatinib oral patch is determined by direct ultraviolet spectrophotometry, and the maximum absorption wavelength is set to be 260nm. The content of apatinib is converted according to a standard curve. The results are shown in Table 1.
TABLE 1 Apatinib content in Apatinib oral Patches
From the measurement results, the content of the drugs in the products of examples 1 to 4 is 100% ± 2%, and the drug content satisfies the content difference and content uniformity regulation limit of the oral patch in the fourth part of the 2015 edition of the chinese pharmacopoeia.
The oral patch should be checked for dissolution rate or release rate (general rule 0931) as specified in the fourth part of the 2015 edition. In general, tablets in which the dissolution rate and the release rate were examined are not examined for disintegration time.
[ example 6] dissolution measurement of Apatinib oral Patch
The second method (slurry method) of the methods for measuring dissolution rate and release rate of the Chinese pharmacopoeia 0931 is adopted to carry out dissolution rate inspection.
Respectively measuring a dissolution medium (pH =7.0, adding a proper amount of saliva amylase water solution) and placing the dissolution medium into each dissolution cup, after the temperature of the dissolution medium is constant at 37 +/-0.5 ℃, respectively putting 6 test samples of example 1 into 6 dry dissolution cups, sampling 5mL into a 10mL volumetric flask at a fixed time point (0min, 5min,15min,30min,1h, 3h), fixing the volume to 10mL by using the dissolution medium, and measuring the medicine content of the sample by using an ultraviolet spectrophotometer. Similarly, 6 samples of the test samples of example 2, example 3 and example 4 were taken, and the dissolution rates of the samples were measured. The dissolution test results are shown in Table 2.
Table 2 dissolution rate measurement results of apatinib oral patch
Combining the experimental results of tables 1 and 2, the drug content and dissolution rate release results of example 1 are better.
Example 1 will be used as a preferred clinical laboratory sample.
[ example 7] measurement of adhesion time of Apatinib oral Patch
Clinical patients 10 were selected, and one oral apatinib patch of example 1 was administered to each patient, and the patient was instructed to place and use the same site on the oral mucosa, and the residence time of the oral patch on the oral mucosa was counted from the start of administration. The results are shown in Table 3.
TABLE 3 residence time (h) of the oral patch of example 1 on the oral mucosa
The average residence time of the apatinib oral patch on the oral mucosa was 3.98h.
Considering that the shortest meal interval between three meals a day is more than 3h, the oral patch is designed to have the adhesion time more than 3h, and the medicine release amount is required to reach about 90 percent within 3 h. As can be seen from the experimental results in tables 2 and 3, the oral patch of the present invention substantially meets the clinical requirements.
The above-described embodiments are intended to illustrate the technical idea and advantages of the invention, and the invention may also be subject to other variants, as known to the skilled person, which serve only as illustrations of the scope of protection of the invention described above, and many routine modifications and other embodiments are possible for a person skilled in the art within the scope of protection defined by the invention, which modifications and embodiments are also within the scope of protection of the invention as claimed.
Reference documents
[1] Zhaojie. The study on the drug tendency of gastric cancer in a certain trimethyl hospital in pharmacy and the centralized monitoring of adverse reactions of apatinib on gastric cancer. 2017 university of zheng university master academic thesis, south of the river: zhengzhou province
[2] Du Qiu Jiang. And (3) measuring the content of apatinib in the raw material medicine by an ultraviolet spectrophotometry. Proceedings of the institute of engineering and seas (natural science edition), 2013,2 (1): 38-40
[3] Compiled by the national pharmacopoeia committee. Pharmacopoeia of the people's republic of china (C2015 year edition, four parts) [ M ]. Beijing: chinese medical science and technology press. 2015
[4] Cao Di. Reviewed in abstra for cancer pain therapeutics. Chinese medical guideline, 2013 (1): 455-456
[5] Zhao Jianhong, xuting and Ma Zi. And (3) synthesizing apatinib mesylate. Journal of chinese medical industry, 2015, 46 (5): 449-452
[6] Zhanxinhua, ruyun, hao. Apatinib pharmaceutical composition and its preparation method are provided. The patent: CN 201810914090.3
[7] Always clear, in the case of the great potential, yun Hai Li, etc. An oral sticking tablet of bismuth potassium citrate and its preparation method are provided. The patent: CN 201710812346.5
[8] Huangjiaqi, zhengkang Yu, he Miaoshan, etc. Screening and in-vitro evaluation of auxiliary materials for 3D printing of the dexamethasone acetate oral patch. University of Guangdong pharmacy, 2019, 35 (2): 164-168.
Claims (9)
1. The apatinib oral patch is characterized by being mainly prepared from the following components in parts by weight: the prescription composition of the apatinib oral patch is as follows (in percentage): 1-15% of apatinib mesylate, 10-60% of film forming agent, 10-60% of adhesive, 5-20% of supporting agent, 0.1-5% of lubricant, 5-60% of diluent, 0.01-3% of flavoring agent, 0.01-3% of pigment, 10-60% of framework material and 5-20% of protective layer.
2. An apatinib oral patch according to claim 1, wherein said disintegrant is microcrystalline cellulose; the film forming agent is carbomer 974 or carbomer 934P; the adhesive is polyvinylpyrrolidone K30 or hydroxypropyl methylcellulose; the lubricant is magnesium stearate or talcum powder; the diluent is hydroxypropyl-beta-cyclodextrin or starch, and the flavoring agent is menthol, orange peel oil, malic acid and citric acid. The pigment is lemon yellow or brilliant blue or allure red or chlorophyll, the framework material is polyacrylic resin, and the protective layer is polyvinyl alcohol.
3. The apatinib oral patch according to claim 1 or 2, the method steps characterized by:
1) Preparing hydroxypropyl-beta-cyclodextrin inclusion compound of apatinib mesylate. The specific operation steps are that in a supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and a certain concentration ethanol aqueous solution of menthol serving as a flavoring agent according to the prescription are added, and simultaneously, a certain concentration ethanol solution is added and fully stirred until an inclusion compound is formed. Then, removing ethanol in the solution by reduced pressure volatilization, and drying at a certain temperature at a low temperature to obtain an apatinib mesylate inclusion compound for later use;
2) Taking a certain amount of carbomer and polyacrylic resin according to the prescription, respectively crushing, sieving by a sieve with a certain mesh number, and uniformly mixing for later use;
3) Taking a prescribed amount of polyvinylpyrrolidone K30, swelling with pure water, and preparing into a solution with a certain concentration for later use;
4) Uniformly mixing the hydroxypropyl-beta-cyclodextrin inclusion compound of the apatinib mesylate, a mixture of carbomer and polyacrylic resin in a certain model and a certain pigment in a prescription amount, adding an aqueous solution adhesive of polyvinylpyrrolidone K30, stirring to form large particles, and drying at a low temperature.
5) And (4) taking the dried large particles, granulating by using a sieve with a certain mesh number, and uniformly mixing the lubricant magnesium stearate with the large particles according to the prescription amount.
6) And tabletting the mixture by using a round shallow concave punch with a certain diameter to obtain the tablet.
4. The preparation of hydroxypropyl-beta-cyclodextrin inclusion complex of apatinib mesylate according to claim 3. The specific operation steps are that in supersaturated aqueous solution of hydroxypropyl-beta-cyclodextrin, apatinib mesylate and certain concentration ethanol solution of a certain corrective in the prescription amount are added and fully stirred until an inclusion compound is formed. Then, removing the ethanol in the solution by vacuum volatilization, and drying at a certain temperature at a low temperature to obtain the clathrate compound of apatinib mesylate for later use. The flavoring agent is preferably menthol or orange peel oil or malic acid or citric acid. The ethanol with a certain concentration is an ethanol solution with a concentration of 20-90%. Drying at a certain temperature at a low temperature of 10-45 ℃.
5. The method of claim 3, wherein the prescribed amounts of carbomer and the polyacrylic resin are separately ground, sieved through a sieve with a certain mesh number, and mixed uniformly for use. The carbomer is preferably carbomer 974 or carbomer 934P.
6. The method of claim 3, wherein the polyvinylpyrrolidone K30 is swelled with pure water to prepare a solution with a certain concentration. The concentration of the prepared solution with a certain concentration is 1-20%.
7. The preparation method as claimed in claim 3, wherein the hydroxypropyl-beta-cyclodextrin inclusion compound of apatinib mesylate, a mixture of carbomer of a certain type and polyacrylic resin and a certain pigment of a certain prescription amount are mixed uniformly, then an aqueous solution binder of polyvinylpyrrolidone K30 is added, the mixture is stirred to form large particles, and the large particles are dried at a certain temperature. The carbomer is preferably carbomer 974 or carbomer 934P. The prescribed amount of a certain pigment is preferably lemon yellow or brilliant blue or allura red or chlorophyll. The temperature of the certain-temperature low-temperature drying is 10-45 ℃.
8. According to claim 3, the dried large granules are selected and sized by a sieve with a certain mesh number, and then the lubricant magnesium stearate with the prescription amount is uniformly mixed with the large granules. The sieve with a certain mesh number is a sieve with 10-100 meshes.
9. The method of claim 3, wherein said mixture is compressed with a shallow punch having a diameter of a predetermined size. The certain size in the circular shallow concave punch head with certain size refers to
A punch of a size.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110972110.4A CN115715764A (en) | 2021-08-24 | 2021-08-24 | Apatinib oral patch and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110972110.4A CN115715764A (en) | 2021-08-24 | 2021-08-24 | Apatinib oral patch and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115715764A true CN115715764A (en) | 2023-02-28 |
Family
ID=85253412
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110972110.4A Pending CN115715764A (en) | 2021-08-24 | 2021-08-24 | Apatinib oral patch and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115715764A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103610722A (en) * | 2013-12-13 | 2014-03-05 | 沈阳药科大学 | Asarum heterotropoide extract, preparation method and application of extract |
| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
| CN105497068A (en) * | 2015-12-25 | 2016-04-20 | 张超 | Buccal patch containing artificial bezoar and metronidazole and preparation method of buccal patch |
| CN108354902A (en) * | 2018-05-22 | 2018-08-03 | 杭州市肿瘤医院 | A kind of Ah pa is for Buddhist nun's polymer micelle and preparation method thereof |
| CN109125281A (en) * | 2018-09-29 | 2019-01-04 | 深圳太太药业有限公司 | A kind of dexamethasone acetate mouth paster and preparation method thereof |
| CN109381436A (en) * | 2017-08-14 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | A Pa is for Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN111253505A (en) * | 2020-03-06 | 2020-06-09 | 西南交通大学 | Water-soluble cyclodextrin drug carrier with cell targeting and preparation method thereof |
| CN112891349A (en) * | 2019-12-03 | 2021-06-04 | 江苏恒瑞医药股份有限公司 | Apatinib oral pharmaceutical composition containing sedimentation inhibitor |
-
2021
- 2021-08-24 CN CN202110972110.4A patent/CN115715764A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103610722A (en) * | 2013-12-13 | 2014-03-05 | 沈阳药科大学 | Asarum heterotropoide extract, preparation method and application of extract |
| CN104069114A (en) * | 2014-07-10 | 2014-10-01 | 韩彬 | Alprostadil oral preparation |
| CN105497068A (en) * | 2015-12-25 | 2016-04-20 | 张超 | Buccal patch containing artificial bezoar and metronidazole and preparation method of buccal patch |
| CN109381436A (en) * | 2017-08-14 | 2019-02-26 | 江苏恒瑞医药股份有限公司 | A Pa is for Buddhist nun's pharmaceutical composition and preparation method thereof |
| CN108354902A (en) * | 2018-05-22 | 2018-08-03 | 杭州市肿瘤医院 | A kind of Ah pa is for Buddhist nun's polymer micelle and preparation method thereof |
| CN109125281A (en) * | 2018-09-29 | 2019-01-04 | 深圳太太药业有限公司 | A kind of dexamethasone acetate mouth paster and preparation method thereof |
| CN112891349A (en) * | 2019-12-03 | 2021-06-04 | 江苏恒瑞医药股份有限公司 | Apatinib oral pharmaceutical composition containing sedimentation inhibitor |
| CN111253505A (en) * | 2020-03-06 | 2020-06-09 | 西南交通大学 | Water-soluble cyclodextrin drug carrier with cell targeting and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 杨红梅: "药剂学", vol. 1, 天津科学技术出版社, pages: 378 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Suryadevara et al. | Studies on jackfruit seed starch as a novel natural superdisintegrant for the design and evaluation of irbesartan fast dissolving tablets | |
| TW201815384A (en) | Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde | |
| TWI235658B (en) | beta-carboline drug products | |
| CN102085191A (en) | Anastrozole oral disintegrating tablet and preparation method thereof | |
| CN108721243B (en) | Crizotinib pharmaceutical composition and preparation method thereof | |
| CN104042577A (en) | Stable topiroxostat tablet and preparation method thereof | |
| CN108578379A (en) | A kind of preparation method of indapamide slow release tablet | |
| CN103385876A (en) | Frovatriptan medicine composition and preparation method thereof | |
| CN117547534A (en) | Nicorandil sustained release preparation and preparation method thereof | |
| CN112294770A (en) | Isosorbide mononitrate compound preparation and application and preparation method thereof | |
| CN115715764A (en) | Apatinib oral patch and preparation method thereof | |
| WO2013189305A1 (en) | Valsartan-amlodipine compound solid preparation and preparation method therefor | |
| CN114557975B (en) | Sustained release tablet containing exemestane, process and use thereof | |
| CN107080741A (en) | Pirfenidone sustained release preparation and preparation method | |
| CN112168796B (en) | Controlled-release drug sustained-release preparation of biphasic sustained-release system and preparation method thereof | |
| JP3116970B2 (en) | Sustained-release preparation of pemirolast potassium | |
| CN109700773B (en) | Ticagrelor preparation composition and preparation method thereof | |
| CN112245402A (en) | Indapamide tablet and preparation method thereof | |
| CN114272219A (en) | Donepezil hydrochloride tablet and preparation method thereof | |
| CN106727375B (en) | Agomelatine tablet and preparation method thereof | |
| CN110575443A (en) | Doxofylline sustained release tablet and preparation method thereof | |
| CN110960501A (en) | Norfloxacin capsule and preparation method thereof | |
| CN108379235A (en) | It being capable of quickly disintegrated tacrolimus sustained-release tablet composition | |
| WO2023173460A1 (en) | Pharmaceutical composition of sglt-2 inhibitor | |
| CN102772377A (en) | Preparation method for ultra-micro co-grinding levonorgestrel tablets |
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 |