CN117298055A - Rezotinib phosphate tablet and preparation method thereof - Google Patents
Rezotinib phosphate tablet and preparation method thereof Download PDFInfo
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- CN117298055A CN117298055A CN202311203499.1A CN202311203499A CN117298055A CN 117298055 A CN117298055 A CN 117298055A CN 202311203499 A CN202311203499 A CN 202311203499A CN 117298055 A CN117298055 A CN 117298055A
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- phosphate
- mixing
- granulator
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- reed
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- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 50
- 239000010452 phosphate Substances 0.000 title claims abstract description 50
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 238000002156 mixing Methods 0.000 claims abstract description 53
- 239000000853 adhesive Substances 0.000 claims abstract description 28
- 230000001070 adhesive effect Effects 0.000 claims abstract description 28
- 238000001035 drying Methods 0.000 claims abstract description 28
- 239000000945 filler Substances 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 39
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 29
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 29
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 23
- 239000000463 material Substances 0.000 claims description 22
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 21
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 20
- 239000008101 lactose Substances 0.000 claims description 20
- 239000000843 powder Substances 0.000 claims description 16
- 239000008187 granular material Substances 0.000 claims description 15
- 229960003943 hypromellose Drugs 0.000 claims description 15
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- 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 14
- 239000007788 liquid Substances 0.000 claims description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 14
- 229940069328 povidone Drugs 0.000 claims description 14
- 235000014676 Phragmites communis Nutrition 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- 239000008213 purified water Substances 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 8
- 238000007873 sieving Methods 0.000 claims description 8
- 239000007779 soft material Substances 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- 238000000889 atomisation Methods 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 159000000007 calcium salts Chemical class 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- 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 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 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 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 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
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 238000010008 shearing Methods 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 229940083542 sodium Drugs 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 22
- 239000003814 drug Substances 0.000 abstract description 12
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 3
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- 230000000694 effects Effects 0.000 description 9
- 238000009472 formulation Methods 0.000 description 6
- 206010028537 myelofibrosis Diseases 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000005022 packaging material Substances 0.000 description 3
- 238000004806 packaging method and process Methods 0.000 description 3
- 208000003476 primary myelofibrosis Diseases 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 2
- 206010041660 Splenomegaly Diseases 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000005033 polyvinylidene chloride Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010200 validation analysis Methods 0.000 description 2
- 238000004260 weight control Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- -1 hydroxypropyl Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 238000009512 pharmaceutical packaging Methods 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- 239000012602 primary packaging material Substances 0.000 description 1
- JFMWPOCYMYGEDM-XFULWGLBSA-N ruxolitinib phosphate Chemical compound OP(O)(O)=O.C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 JFMWPOCYMYGEDM-XFULWGLBSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to the technical field of medicine preparation, and discloses a reed-ketinib phosphate tablet, which comprises the following raw materials in percentage by mass: 3-6% of poncirtinib phosphate, 85-90% of filler, 2-6% of adhesive, 1-5% of disintegrating agent and 0.5-3% of glidant, and is obtained by pretreatment, premixing, granulating, drying, granulating, total mixing and tabletting of raw materials. The prepared reed-calitinib phosphate tablet meets the quality standard, has good dissolution and excellent drug stability, can effectively get rid of the limitation that the drug can only be obtained through import, reduces the drug cost and benefits more patients.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a reed-ketinib phosphate tablet and a preparation method thereof.
Background
The chemical name (R) -3- (4- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1H-pyrazol-1-yl) -3-cyclopentylpropionitrile phosphate is used for treating adult patients with moderate or high risk of Primary Myelofibrosis (PMF) (also known as chronic idiopathic myelofibrosis), myelofibrosis secondary to polycythemia vera (PPV-MF or myelofibrosis secondary to essential thrombocythemia (peMF), and for treating disease-related splenomegaly or disease-related symptoms.
Myelofibrosis (MF) is a rare myeloproliferative neoplasm disease with unknown etiology, its incidence is about 0.4-1.4/10 ten thousand people in europe and america, and china has no definite epidemiological data, and it is shown from incomplete statistics that the disease has a small number of disease onset in china, and for medium-high risk patients, the median survival time is only 2.9 years and 1.3 years, respectively. At present, no definite and effective treatment means exist in China. Clinically, the treatment of symptoms is mainly carried out, and the chemotherapy effect is poor, so that urgent clinical demands exist. Two key global random control III-phase multicenter researches prove that the poncirib treatment can obviously reduce splenomegaly, improve clinical symptoms, has long-term survival benefit, reduces death risk, has acceptable tolerance at the research dosage, and has main adverse reactions consistent with the expected action mechanism of the medicaments and clinical controllability compared with the prior treatment options or placebo. However, the current preparation technology of the domestic rucotinib tablet is lack, and the use of the tablet mainly depends on foreign importation, so that the tablet is high in price and cannot be popularized for most patients.
Disclosure of Invention
In view of the above, the invention provides a phosphoric acid pontinib tablet and a preparation method thereof, which are used for solving the technical problems that the existing preparation technology of the phosphoric acid Lu Ke tentinib tablet is still immature and has low popularity.
In order to solve the technical problems, the invention adopts the following technical scheme:
the invention provides a reed ketinib phosphate tablet, which comprises the following raw materials in percentage by mass: 3-6% of poncirtinib phosphate, 85-90% of filler, 2-6% of adhesive, 1-5% of disintegrating agent and 0.5-3% of glidant.
Preferably, in the aforementioned phosphoric acid ruketinib tablet, the filler comprises any one or a mixture of several of lactose, microcrystalline cellulose, starch, dextrin, inorganic calcium salt, mannitol and sorbitol;
the adhesive is a mixture of hypromellose and povidone with the mass ratio of 1:0.2-2;
the disintegrating agent comprises any one or a mixture of several of croscarmellose sodium, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch;
the glidant comprises any one or a mixture of more of magnesium stearate, micro-powder silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol and sodium dodecyl sulfate.
The second object of the invention is to provide a preparation method of the reed ketinib phosphate tablet, which comprises the following steps:
(1) Mixing prescribed amounts of poncirtinib phosphate, povidone and filler to obtain a premix;
(2) Placing the premix into a granulator, adding hydroxypropyl methylcellulose adhesive liquid into the granulator in an atomization mode, stirring and granulating to obtain wet granules;
(3) And (3) drying and granulating the wet granules, adding a prescribed amount of glidant and a disintegrating agent, uniformly mixing, and tabletting to obtain the reed-ketinib phosphate tablets.
Preferably, in the above preparation method of the phosphoric acid ruketinib tablet, the step (1) specifically includes:
(1-1) adding prescription amount of the poncirtinib phosphate, povidone and filler into a mixing tank, stirring and mixing, and then sieving and dispersing by using a swing granulator to obtain a premixed intermediate;
(1-2) adding the premix intermediate to a wet mix granulator for dry powder mixing to obtain a premix.
Preferably, in the above-mentioned method for preparing the tablet of the lacteib phosphate, the lacteib phosphate is sieved with a 50-70 mesh sieve and the filler is sieved with a 50-100 mesh sieve before the mixing in the step (1-1).
Preferably, in the preparation method of the reed canatinib phosphate tablet, the rotating speed of the mixing tank in the step (1-1) is 5-50rpm, the mixing time is 5-30min, and the swing granulator is sieved and dispersed to pass through a 50-70 mesh screen;
and/or the stirring speed of the wet mixing granulator in the step (1-2) is 50-500rpm, the shearing speed is 1000-5000rpm, and the mixing time is 1-10min.
Preferably, in the method for preparing the ruketinib phosphate sheet, the hypromellose adhesive liquid in the step (2) is a solution prepared by a prescribed amount of hypromellose and purified water, wherein the solid content of the hypromellose adhesive liquid is 2-5%, and the temperature of the purified water is 60-70 ℃.
Preferably, in the above preparation method of the phosphoric acid ruketinib tablet, the step (2) specifically includes:
(2-1) placing the premix in a granulator, adding hypromellose binder solution to the granulator in an atomized manner, and setting the bottom stirring speed to 240-260rpm and the side stirring speed to 2200rpm;
(2-2) setting the bottom stirring speed to 240-260rpm and the side stirring speed to 2200rpm after the hydroxypropyl methylcellulose adhesive liquid is added, and continuing stirring to obtain a soft material without obvious lumps;
(2-3) passing the soft material through a 20-50 mesh screen by using a swing type granule finishing machine to obtain wet granules.
Preferably, in the preparation method of the reed rhizome of the crizotinib phosphate, the drying in the step (3) adopts a hot air circulation oven or a fluidized bed for drying, the temperature is 50-80 ℃, and the moisture content at the drying end point is not more than 4.0%;
and/or the granulating is to granulate the dried material through a 50-70 mesh screen of a swing type granulating machine.
Preferably, in the preparation method of the reed canatinib phosphate tablet, the mixing in the step (3) is performed in a hopper mixer, the mixing rotating speed is 10-50rpm, and the mixing time is 5-30min.
The invention provides a reed ketinib phosphate tablet and a preparation method thereof, which have the beneficial effects that compared with the prior art:
the prepared reed-calitinib phosphate tablet meets the quality standard, has good dissolution and excellent drug stability, can effectively get rid of the limitation that the drug can only be obtained through import, reduces the drug cost and benefits more patients.
Detailed Description
Embodiments of the present invention are described in detail below. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In one aspect of the invention, the invention provides a reed-ketinib phosphate tablet, which comprises the following raw materials in percentage by mass: 3-6% of poncirtinib phosphate, 85-90% of filler, 2-6% of adhesive, 1-5% of disintegrating agent and 0.5-3% of glidant; preferably, the material comprises the following raw materials in percentage by mass: 4.125% of ponatinib phosphate, 87.375% of filler, 4% of adhesive, 3% of disintegrating agent and 1.5% of glidant.
Wherein the filler comprises any one or a mixture of a plurality of lactose, microcrystalline cellulose, starch, dextrin, inorganic calcium salt mannitol and sorbitol, and the inorganic calcium salt comprises but is not limited to calcium sulfate, calcium hydrophosphate and calcium carbonate; preferably, the filler is a mixture of lactose and microcrystalline cellulose, more preferably, the mass ratio of lactose to microcrystalline cellulose is 1-2:1-2, and the model of microcrystalline cellulose is preferably PH101; the filler can adjust the size of the tablet, increase the volume and weight of the tablet, facilitate dosage control and improve appearance quality.
Further, the adhesive is a mixture of hypromellose and povidone in a mass ratio of 1:0.2-2, preferably, the mass ratio of hypromellose to povidone is 1:0.5-1.5; more preferably, the mass ratio of the hypromellose to the povidone is 1:1; the adhesive is favorable for bonding the medicinal powder into a sheet shape, fixing the position of the active ingredient and enhancing the mechanical strength of the tablet.
The disintegrating agent comprises any one or a mixture of a plurality of cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch, and is preferably cross-linked sodium carboxymethyl cellulose; the tablet can be rapidly broken into fine particles in gastrointestinal fluid, so that the functional components are rapidly dissolved and absorbed to play a role.
The glidant comprises any one or a mixture of more of magnesium stearate, micro-powder silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol and sodium dodecyl sulfate, preferably magnesium stearate; the glidant can improve interaction among various factors, so that the fluidity of the powder is improved, friction among the powder is reduced, surface charge is reduced, repose angle is reduced, and the fluidity of the powder is enhanced.
In another aspect of the present invention, the present invention provides a method for preparing the aforementioned pontetinib phosphate tablet, comprising the steps of:
and S100, mixing the prescription amount of the poncirtinib phosphate, the povidone and the filler to obtain a premix.
The step S100 specifically includes:
s101, adding the prescription amount of the poncirtinib phosphate, the povidone and the filler into a mixing tank, stirring and mixing, and then sieving and dispersing by using a swing granulator to obtain a premixed intermediate.
Further, before the mixing in the step S101, the poncirinib phosphate is screened by a 50-70 mesh screen and the filling agent is screened by a 50-100 mesh screen; specifically, when lactose and microcrystalline cellulose are selected as the filler, the lactose is crushed and then passes through a 70-100 mesh screen, and the microcrystalline cellulose passes through a 50-70 mesh screen.
Further, in the step S101, the rotation speed of the mixing tank is 5-50rpm, and the mixing time is 5-30min, and the swing granulator is sieved and dispersed to pass through a 50-70 mesh screen;
and S102, adding the pre-mixed intermediate into a wet mixing granulator to mix dry powder, so as to obtain a pre-mixture.
Further, in step S102, the stirring speed of the wet mixing granulator is 50-500rpm, the shearing speed is 1000-5000rpm, and the mixing time is 1-10min, so that the filler, the rucotinib phosphate and the povidone can be fully and uniformly mixed.
And S200, placing the premix into a granulator, adding hydroxypropyl methylcellulose adhesive liquid into the granulator in an atomization mode, stirring and granulating to obtain wet granules.
The step S200 specifically includes:
s201, placing the premix into a granulator, adding hydroxypropyl methylcellulose adhesive liquid into the granulator in an atomization mode, and setting the bottom stirring rotating speed to be 240-260rpm and the side stirring rotating speed to be 2200rpm;
further, the hydroxypropyl methylcellulose adhesive liquid is a solution prepared from a prescription amount of hydroxypropyl methylcellulose and purified water, wherein the solid content of the hydroxypropyl methylcellulose adhesive liquid is 2-5%, and the temperature of the purified water is 60-70 ℃; specifically, adding purified water into a proper container, adjusting the stirring speed until vortex appears, slowly adding a prescription amount of hypromellose for a small amount for many times, continuously stirring until the solution is clear, avoiding the occurrence of lumps in the adding process, and cooling for later use.
S202, setting the bottom stirring speed to 240-260rpm and the side stirring speed to 2200rpm after the hydroxypropyl methylcellulose adhesive liquid is added, and continuing stirring to obtain a soft material without obvious lumps;
s203, passing the soft material through a 20-50 mesh screen by using a swing type granule finishing machine to obtain wet granules.
And S300, drying and granulating the wet granules, adding a prescribed amount of glidant and a disintegrating agent, uniformly mixing, and tabletting to obtain the reed-ketinib phosphate tablets.
In the step, the drying is performed by adopting a hot air circulating oven or a fluidized bed, the temperature is 50-80 ℃, and the moisture content at the drying end point is not more than 4.0%;
further, the granulating is to granulate the dried material by a 50-70 mesh screen of a swing granulator, the mixing is carried out in a hopper mixer, the mixing rotating speed is 10-50rpm, and the mixing time is 5-30min
Further, detecting the properties, the content and the moisture of the intermediate before tabletting, and tabletting after the intermediate is qualified; in the tabletting process, a rotary tablet press is used, the tablet weight is calculated according to the content of the intermediate, the average tablet weight control range is +/-3.0%, and the single-preparation tablet weight difference control range is +/-5.0%; wherein 5mg gauge die: a shallow concave circular punch with the diameter of 7.5 and mm; 15mg gauge die: 15X 7mm elliptic shallow concave punch; 20mg gauge die: 16.5X7.4 mm elliptical dimple.
The invention is illustrated below by means of specific examples, which are given for illustrative purposes only and do not limit the scope of the invention in any way, as will be understood by those skilled in the art. In addition, in the examples below, reagents and equipment used are commercially available unless otherwise specified. If in the following examples specific treatment conditions and treatment methods are not explicitly described, the treatment may be performed using conditions and methods well known in the art.
The bulk drug of the cricotinib phosphate provided by the embodiment of the invention is white powder, does not absorb moisture, is slightly soluble in water, is slightly soluble in ethanol, is slightly soluble in acetonitrile, has PKa of 4.3 and 11.8 and has a melting point of 194-198 ℃.
The embodiment of the invention provides a reed rhizome-cotinib phosphate tablet which can be prepared into various specifications of 5mg, 15mg, 20mg and the like, wherein the raw material composition and the dosage of each specification tablet are shown in a table 1.
TABLE 1
The preparation method of the poncirtinib phosphate tablet provided by the embodiment of the invention comprises the following steps:
(1) Pretreatment of
Passing the poncirtinib phosphate through a 60-mesh screen, passing microcrystalline cellulose through a 60-mesh screen, and crushing lactose and passing through an 80-mesh screen for later use;
preparing hydroxypropyl methylcellulose adhesive liquid: weighing the hydroxypropyl methylcellulose with the prescription amount and purified water at 60-70 ℃, adding the purified water into a proper container, adjusting the stirring speed until vortex appears, slowly adding the hydroxypropyl methylcellulose with the prescription amount a small number of times, continuously stirring until the solution is clear, avoiding the occurrence of lumps, preparing an adhesive solution with the solid content of 4%, and cooling for later use;
(2) Premixing
Sequentially adding lactose, rucotinib phosphate, povidone and microcrystalline cellulose with the prescription amount into a mixing tank, mixing for 15min by using a mixer, setting the mixing rotating speed to 10 revolutions per minute, and sieving and dispersing by using a swinging granulator through a 60-mesh screen to obtain a premix-1 material; adding the premixed material 1 into a wet mixing granulator for dry powder mixing, and setting the stirring rotating speed: 100rpm; shear rotational speed: 2000rpm; mixing time: 3min, obtaining a premix-2 material;
(3) Granulating
Slowly adding hydroxypropyl methylcellulose adhesive liquid into the premix-2 material of the granulator in an atomization mode, and setting the bottom stirring speed to be 100rpm and the side stirring speed: 2200rpm; setting the bottom stirring speed after the adhesive liquid is added: 240rpm, side stirring speed: 2200rpm, to produce a soft mass without distinct lumps; wet finishing and discharging the prepared soft material through a 30-mesh screen by adopting a swing type finishing machine;
(4) Drying
Drying by adopting a hot air circulation oven at the temperature of 60 ℃, monitoring moisture, wherein the moisture limit of a drying end point is not more than 4.0% (the detection method is that the temperature is 105 ℃, automatic end point judgment is adopted, the moisture measurement method (the rule 0832 of four parts of the 2020 edition of Chinese pharmacopoeia) is referred to), the material temperature after the moisture of the material is qualified is collected, and the material temperature is used as an auxiliary judgment index of the drying end point;
(5) Finishing and mixing
The dried materials pass through a 60-mesh screen mesh of a swing type granulator, the granulated materials are added into a hopper mixer, the prescribed amount of magnesium stearate and croscarmellose sodium are added, the mixing rotating speed is set to be 20 revolutions per minute, and the mixing time is set to be 15 minutes;
(6) Intermediate detection
Detecting the properties, content and moisture of the intermediate;
repeated tests were performed according to the protocol described above to give intermediate 22080901 and intermediate 22081001, which were tested and the results are shown in Table 2.
TABLE 2 intermediate product detection results
(7) Tabletting and packaging
After the detection is qualified, a rotary tablet press is used, the tablet weight is calculated according to the content of the intermediate, the average tablet weight control range is +/-3.0%, and the single-preparation tablet weight difference control range is +/-5.0%; wherein, 5mg specification die: a shallow concave circular punch with the diameter of 7.5 and mm; 15mg gauge die: 15X 7mm elliptic shallow concave punch; 20mg gauge die: 16.5X7.4 mm elliptic shallow concave punch; tabletting and packaging.
Tablets of three specifications, 5mg, 15mg and 20mg, were prepared as intermediate 22080901, and the three tablets were tested and the dissolution data were statistically determined, as shown in tables 3-4.
TABLE 3 Table 3
TABLE 4 Table 4
For this particular embodiment, the applicant has examined and validated in several respects, and a detailed description of some of the examining factors follows.
1. Inspection of filler
Taking 5mg of the standard lactetinib phosphate tablet as an example, the dosage proportion of lactose to microcrystalline cellulose is 2:1 and 1:2, the dosage of the diluent is inspected, and meanwhile, the influence of lactose of different manufacturers and the influence of microcrystalline cellulose types are inspected.
TABLE 5 lactose and microcrystalline cellulose information
TABLE 6 lactose and microcrystalline cellulose dosage ratio
Remarks: prescription 21121003 the prescription is prepared by adopting an additional way of carboxymethyl starch sodium
(1) Process for producing a solid-state image sensor
a. Pre-mixing bulk drug of lacteib phosphate with 50% of prescription amount of lactose and colloidal silicon dioxide, and sieving with a 40-mesh sieve once; sequentially adding microcrystalline cellulose, premix-1 material, carboxymethyl starch sodium, hydroxypropyl cellulose-L, povidone K30 and residual lactose, mixing, sieving with 40 mesh sieve for 3 times, mixing, adding about 30% purified water to make soft material, sieving with 24 mesh sieve, granulating, drying at 60deg.C for drying time to water content less than or equal to 2.5%, taking out, sieving with 30 mesh sieve, granulating, adding adjuvants, mixing, and tabletting.
(2) Quality index
The quality indexes and process parameter control of the prescription are examined, and the results are shown in Table 7.
TABLE 7 results of lactose manufacturer and diluent dose screening and validation together
As can be seen from the dissolution results of the prescription 21121601 and the prescription 21121301 in table 7, lactose from different manufacturers has no significant effect on the dissolution curve trend and the data result, and the dissolution curves of the two have no significant difference, preferably lactose 314WG of Kerry Inc in usa is used as the diluent of the prescription;
effect of the prescribed dose ratio of microcrystalline cellulose and lactose on dissolution profile: recipe 21121601 (1:1) had no significant differences from the dissolution profile trend and data results of recipe 21121303 (1:2), and had a slow trend with the reference formulation; prescription 21121302 (2:1) has a tendency to increase in dissolution profile, is substantially consistent with the tendency of the reference formulation, and may be the effect of microcrystalline cellulose, so that the ratio of lactose to microcrystalline cellulose in the tablet is preferably about 1:1, and can be specifically adjusted;
comparing the dissolution data and curves of formulations 21121601 and 21121003 and the reference formulation, it can be seen that formulation 21121003 is slower than the reference formulation due to the effect of the type of microcrystalline cellulose; after the model of microcrystalline cellulose is changed, the overall trend of the dissolution curve of the prescription 21121003 is faster than that of the reference preparation, the dissolution curve of the sample can be continuously improved by optimizing the granulating parameters, and the model of microcrystalline cellulose is preferably PH101.
2. Investigation of the adhesive usage
The adhesive is taken as a prescription-21112601 with the addition amount of 4 percent, the adhesive is taken as a prescription-21112602 with the addition amount of 6 percent, and the mass ratio of the hypromellose to the povidone in the adhesive is 1:1.
The quality indexes and process parameter control of the prescription are examined, and the results are shown in Table 8.
TABLE 8
As is clear from Table 8, the addition amount of the binder was satisfactory at both 4% and 6%, and the particle size distribution of the intermediate product was more uniform at the addition amount of 4%, so that it was preferably 4%, and specifically, it was possible to adjust it according to the actual situation.
3. Influence of pelletization parameters (bottom stirring speed) on sample quality
Based on the determined prescription, the prescription proportion is unchanged, the process and the process parameters are unchanged except the bottom stirring speed, the prescription samples are prepared respectively, and the dissolution curve change condition of the samples is examined, see tables 9-10.
TABLE 9
Table 10
From the experimental data, the granulating parameters have obvious influence on the powder properties of the materials and the dissolution curve of the samples, and the obtained materials have obvious powder property change, obviously increased particles, reduced powder and increased material fluidity under high stirring speed; further, the secondary disintegration time of the sample is increased during dissolution, so that the tendency of the dissolution curve becomes slow, and even complete dissolution is not achieved; the dissolution profile trends of three specifications of the reed ketinib tablets (specification: 5mg, 15mg and 20 mg) are basically consistent with those of the reference preparation under the conditions of the stirring speed of 260rpm and 240rpm, and the material powder property and the sample dissolution profile trend are excellent under the conditions of the stirring speed of 260rpm, so that the bottom stirring speed of 260rpm is preferable.
4. Examination of granulation Process-drying procedure parameters
The materials after wet granulation are required to be dried, a drying oven and a fluidized bed are commonly used drying equipment, and comparison research is carried out on parameters of the drying equipment and the drying procedure, wherein the main parameters are the research on drying temperature and drying time; based on the prescription, samples were prepared and examined for indicators mainly of moisture, related substances and dissolution profile, see in particular table 11.
TABLE 11
As can be seen from table 11, the drying process-drying temperature has no significant effect on the relevant substances of the product; the drying time has no significant effect on the product quality (related substances and dissolution profile), and therefore it was confirmed that the above-described parameters of the drying process were viable and had no significant effect on the product quality.
5. Inspection of packaging Material
The effect of the reed ketinib phosphate on the stability of the drug by direct contact with the drug packaging material (primary packaging material) was used to initially select the appropriate packaging material, and the screening information is shown in table 12.
Table 12
The pilot test validation batches 22080901 and 22081001 are packaged by the packing materials, and then subjected to pre-stability lofting to examine related substances, content, moisture and dissolution curves of the samples, wherein specific lofting conditions and detection results are shown in table 13.
TABLE 13
As can be seen from Table 10, the packaging of the present invention provides a selection of aluminum plastic bag, PVC, PVDC, and PVDC plus composite film bags, which do not significantly affect the tablet properties.
In the description of the present specification, reference to the terms "one embodiment," "another embodiment," "yet another embodiment," "some embodiments," "other embodiments," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction. In addition, it should be noted that, in this specification, the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. The reed ketinib phosphate tablet is characterized by comprising the following raw materials in percentage by mass: 3-6% of poncirtinib phosphate, 85-90% of filler, 2-6% of adhesive, 1-5% of disintegrating agent and 0.5-3% of glidant.
2. The reed canatinib phosphate tablet of claim 1, wherein the filler comprises any one or a mixture of several of lactose, microcrystalline cellulose, starch, dextrin, inorganic calcium salt, mannitol, sorbitol;
the adhesive is a mixture of hypromellose and povidone with the mass ratio of 1:0.2-2;
the disintegrating agent comprises any one or a mixture of several of croscarmellose sodium, low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch;
the glidant comprises any one or a mixture of more of magnesium stearate, micro-powder silica gel, talcum powder, hydrogenated vegetable oil, polyethylene glycol and sodium dodecyl sulfate.
3. A process for the preparation of the ponteib phosphate tablet according to any one of claims 1-2, comprising the steps of:
(1) Mixing prescribed amounts of poncirtinib phosphate, povidone and filler to obtain a premix;
(2) Placing the premix into a granulator, adding hydroxypropyl methylcellulose adhesive liquid into the granulator in an atomization mode, stirring and granulating to obtain wet granules;
(3) And (3) drying and granulating the wet granules, adding a prescribed amount of glidant and a disintegrating agent, uniformly mixing, and tabletting to obtain the reed-ketinib phosphate tablets.
4. A process for the preparation of a ponteib phosphate tablet according to claim 3, wherein step (1) comprises:
(1-1) adding prescription amount of the poncirtinib phosphate, povidone and filler into a mixing tank, stirring and mixing, and then sieving and dispersing by using a swing granulator to obtain a premixed intermediate;
(1-2) adding the premix intermediate to a wet mix granulator for dry powder mixing to obtain a premix.
5. The method for preparing a tablet of poncirtinib phosphate according to claim 4, wherein, before said mixing in step (1-1), the poncirtinib phosphate is sieved with a 50-70 mesh sieve and the filler is sieved with a 50-100 mesh sieve.
6. The method for preparing the phosphoric acid reed can tinib tablet according to claim 4 or 5, wherein the rotating speed of the mixing tank in the step (1-1) is 5-50rpm, the mixing time is 5-30min, and the swinging granulator is sieved and dispersed to pass through a 50-70 mesh screen;
and/or the stirring speed of the wet mixing granulator in the step (1-2) is 50-500rpm, the shearing speed is 1000-5000rpm, and the mixing time is 1-10min.
7. A method of preparing a sheet of tricutinib phosphate according to claim 3, wherein the hypromellose binder solution in step (2) is a solution prepared from a prescribed amount of hypromellose and purified water, wherein the solid content of the hypromellose binder solution is 2 to 5%, and the temperature of the purified water is 60 to 70 ℃.
8. The method for preparing the phosphoric acid reed ketinib tablet according to claim 3 or 7, wherein the step (2) specifically comprises:
(2-1) placing the premix in a granulator, adding hypromellose binder solution to the granulator in an atomized manner, and setting the bottom stirring speed to 240-260rpm and the side stirring speed to 2200rpm;
(2-2) setting the bottom stirring speed to 240-260rpm and the side stirring speed to 2200rpm after the hydroxypropyl methylcellulose adhesive liquid is added, and continuing stirring to obtain a soft material without obvious lumps;
(2-3) passing the soft material through a 20-50 mesh screen by using a swing type granule finishing machine to obtain wet granules.
9. A process for the preparation of a sheet of tricutinib phosphate according to claim 3, wherein in step (3) the drying is carried out by means of a hot air circulation oven or a fluidised bed at a temperature of 50-80 ℃ and at a drying end point moisture content of not more than 4.0%;
and/or the granulating is to granulate the dried material through a 50-70 mesh screen of a swing type granulating machine.
10. The method for preparing a sheet of poncir-cotinib phosphate according to claim 3 or 9, wherein the mixing in step (3) is performed in a hopper mixer at a mixing speed of 10-50rpm for a mixing time of 5-30min.
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| CN105007901A (en) * | 2012-11-15 | 2015-10-28 | 因赛特公司 | Sustained-release dosage forms of ruxolitinib |
| CN105919955A (en) * | 2016-06-13 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Ruxolitinib preparation and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105007901A (en) * | 2012-11-15 | 2015-10-28 | 因赛特公司 | Sustained-release dosage forms of ruxolitinib |
| CN105919955A (en) * | 2016-06-13 | 2016-09-07 | 佛山市腾瑞医药科技有限公司 | Ruxolitinib preparation and application thereof |
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