CN116688139B - Crizotinib pharmaceutical composition, and preparation method and application thereof - Google Patents
Crizotinib pharmaceutical composition, and preparation method and application thereof Download PDFInfo
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- CN116688139B CN116688139B CN202310749155.4A CN202310749155A CN116688139B CN 116688139 B CN116688139 B CN 116688139B CN 202310749155 A CN202310749155 A CN 202310749155A CN 116688139 B CN116688139 B CN 116688139B
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- crizotinib
- pharmaceutical composition
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- 239000002146 L01XE16 - Crizotinib Substances 0.000 title claims abstract description 112
- 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 title claims abstract description 112
- 229960005061 crizotinib Drugs 0.000 title claims abstract description 112
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 239000007962 solid dispersion Substances 0.000 claims abstract description 41
- 229920002678 cellulose Chemical class 0.000 claims abstract description 13
- 239000001913 cellulose Chemical class 0.000 claims abstract description 13
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 56
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 56
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 12
- 235000010980 cellulose Nutrition 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 8
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 20
- 239000012458 free base Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 9
- 230000009477 glass transition Effects 0.000 abstract description 6
- 210000003296 saliva Anatomy 0.000 abstract description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 48
- 229940079593 drug Drugs 0.000 description 11
- 239000000843 powder Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000001694 spray drying Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 3
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- CNLWCVNCHLKFHK-UHFFFAOYSA-N aluminum;lithium;dioxido(oxo)silane Chemical compound [Li+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O CNLWCVNCHLKFHK-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 2
- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 229910052642 spodumene Inorganic materials 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 231100001127 band 4 compound Toxicity 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- WZNRVWBKYDHTKI-UHFFFAOYSA-N cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 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 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000004611 light stabiliser Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a crizotinib pharmaceutical composition, and a preparation method and application thereof. A pharmaceutical composition of crizotinib comprising an amorphous solid dispersion of crizotinib and a cellulose derivative and a second cellulose derivative. The composition is stable in the amorphous state and remains amorphous for at least 30 days under accelerated stability conditions (40 ℃,75% relative humidity). The composition has higher instantaneous solubility and dissolution rate than control under pH environment of saliva and intestinal tract; wherein the control is crizotinib free base. The composition has better thermal stability, and can bear higher process temperature in the preparation process according to the glass transition temperature.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to a crizotinib pharmaceutical composition, a preparation method and application thereof.
Background
Crizotinib is a targeted therapeutic drug for non-small cell lung cancer developed by the american pyroxene pharmacy, the trade name is sirolimus, which is a leading edge and epoch-making drug in the field of targeted therapy of lung cancer, the 2011 month is marketed in the united states in batches, and the year bottom is written into the international lung cancer therapeutic guideline as a first line drug for ALK positive patients. Day 25 of 2013, which was approved in china, is the first drug for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) positive for Anaplastic Lymphoma Kinase (ALK) as determined by SFDA approved assay.
The original spodumene reported in WO2007/066185, crystalline form 1 of crizotinib, the crystalline form used for commercial products. The preparation of amorphous forms of crizotinib and polymorphs of its salt forms by freeze-drying is reported in WO2013181251 A9.
According to the original description of the spodumene, the solubility of crizotinib in water has serious pH dependency, the pH is from 1 to 8.4, and the solubility is reduced by more than 10 times. It is BCS class IV with an oral relative bioavailability of 43% (range 32% -66%). Has the following characteristics ofFood effect, high fat diet can make AUC of crizotinib 0-INF And C max The reduction is about 14%.
In order to improve the solubility of crizotinib, CN104971054A discloses a preparation method of crizotinib capsules, wherein the patent mentions that the crizotinib raw material medicine is hardly dissolved in water in the research process, so that the dissolution rate of the crizotinib is lower, the bioavailability is influenced, and the curative effect of the medicine is poorer, but the patent adopts a conventional capsule preparation method for production, and does not mention the improvement of the dissolution behavior of the preparation method; CN104434880a invented a method for preparing a crizotinib microsphere slow-release capsule, and the improvement of dissolution is not mentioned; CN 115887406a is prepared by mixing crizotinib and micronized pregelatinized starch and preparing into capsule preparation, and the dissolution is only improved by 1.2 times under the condition of ph=6.8 for 30min, and the improvement degree is lower. Meanwhile, in CN 115887406a, it is mentioned that conventional methods known to those skilled in the art, such as reducing the particle size of the main drug and adding a solubilizing agent, cannot effectively improve the dissolution rate of crizotinib capsule during the production process.
The amorphous form of the drug has a higher dissolution rate in body fluids than the crystalline form because of the disordered arrangement of its molecules. However, the amorphous drug is also unstable and is easily converted into crystalline form, which is an obstacle to the preparation of the drug. Meanwhile, in some cases, the simple preparation of Cheng Ke tinib solid dispersion is found to have limited lifting amplitude, and the dose of crizotinib cannot be effectively reduced.
Disclosure of Invention
Therefore, in order to improve the dissolution rate of crizotinib and solve the problem of amorphous instability of the drug and avoid the toxicity of the surfactant, the patent provides a pharmaceutical composition and a pharmaceutical preparation prepared by adopting the pharmaceutical composition, and the pharmaceutical composition has higher dissolution rate in saliva and small intestine environments.
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides a crizotinib pharmaceutical composition and a preparation method thereof. The pharmaceutical composition exists in a stable amorphous state, has higher thermal stability, and has higher instantaneous solubility and dissolution rate than conventional solid dispersion, free alkali, salt and the like under the pH environment of saliva and intestinal tracts; the composition can be administered by preparing it in various forms of pharmaceutical preparations.
In a first aspect of the present invention, a pharmaceutical composition of crizotinib is presented, comprising an amorphous pharmaceutical composition of crizotinib and a cellulose derivative.
In some embodiments of the invention, the cellulose derivative is selected from at least one of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose Acetate Trimellitate (CAT), cellulose Acetate Phthalate (CAP), hydroxypropyl cellulose phthalate acetate (HPCAP), hydroxypropyl methylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP).
In some embodiments of the invention, the cellulose derivative is at least one of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP).
In some embodiments of the invention, the mass ratio of crizotinib to cellulose derivative is 1:10 to 10:1.
In some embodiments of the invention, the cellulose derivatives are hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP), crizotinib: HPMCP: the mass ratio of HPMCAS is 2:3:2.
in some embodiments of the invention, the cellulose derivative is hydroxypropyl methylcellulose acetate succinate (HPMCAS), crizotinib: HPMCAS (add-in): the mass ratio of HPMCAS (plus) is 2:3:2. in a second aspect of the present invention, a method for preparing the above-mentioned crizotinib pharmaceutical composition is provided, wherein crizotinib and a first cellulose derivative are dissolved in a solvent, and then the solvent is removed to obtain a solid dispersion. And then physically mixed with a second cellulose derivative.
Preferably, crizotinib and hydroxypropyl methylcellulose phthalate are dissolved in a solvent, and then the solvent is removed to obtain a solid dispersion, and then the solid dispersion is physically mixed with hydroxypropyl methylcellulose acetate succinate.
In some embodiments of the present invention, the solvent used is a mixed solvent formed by one or more of methanol, ethanol, isopropanol, dichloromethane, acetone and ethyl acetate.
In some embodiments of the invention, the solution is formed by dissolving crizotinib and the cellulose derivative in a solvent and removing the solvent by spray drying.
In a third aspect of the present invention, a pharmaceutical formulation comprising the crizotinib pharmaceutical composition of the present invention is presented. The pharmaceutical composition prepared by the invention can be formed into a preparation with a pharmaceutically acceptable carrier and common auxiliary materials according to the conventional technology disclosed. Mention may be made, as examples, of lubricants, fillers, disintegrants, colorants, emulsifiers, diluents, flavoring agents, binders, antioxidants, light stabilizers, free radical scavengers, surfactants, pH adjusters, pharmaceutical complexing agents or stabilizers against microbial attack or combinations thereof.
The fourth aspect of the invention provides an application of the crizotinib pharmaceutical composition or the pharmaceutical preparation thereof in preparing medicines for treating non-small cell lung cancer.
The pharmaceutical composition for implementing crizotinib has at least the following beneficial effects:
the composition is stable in the amorphous state and remains amorphous for at least 30 days under accelerated stability conditions (40 ℃,75% relative humidity). The composition has higher instantaneous solubility and dissolution rate than control under pH environment of saliva and intestinal tract; wherein the control is crizotinib free base. The composition has better thermal stability, and can bear higher process temperature in the preparation process according to the glass transition temperature.
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a schematic diagram of crizotinib prepared in example 1 of the present invention: x-ray powder diffraction pattern of HPMCP amorphous solid dispersion.
FIG. 2 is a schematic diagram of crizotinib prepared in example 2 of the present invention: HPMCP: x-ray powder diffraction pattern of HPMCAS pharmaceutical compositions.
FIG. 3 is a schematic diagram of crizotinib prepared in example 3 of the present invention: x-ray powder diffraction pattern of HPMCAS amorphous solid dispersion.
Fig. 4 is a crizotinib prepared in example 4 of the present invention: HPMCAS: x-ray powder diffraction pattern of HPMCAS pharmaceutical compositions.
FIG. 5 shows the preparation of crizotinib according to example 1: the HPMCP amorphous solid dispersion is measured by differential scanning calorimetry.
FIG. 6 shows the preparation of crizotinib according to example 3: the HPMCAS amorphous solid dispersion was mapped by differential scanning calorimetry.
FIG. 7 shows the preparation of crizotinib according to example 2: HPMCP: HPMCAS pharmaceutical composition, example 1, made crizotinib: comparative graph of dissolution measurement data of HPMCP amorphous solid dispersion, crizotinib free base in pH 6.8 medium.
FIG. 8 shows the preparation of crizotinib according to example 1: the HPMCAS amorphous solid dispersion accelerated PXRD pattern comparison around 1 month.
FIG. 9 shows the preparation of crizotinib according to example 2: HPMCP: the HPMCAS pharmaceutical composition accelerates PXRD pattern comparison around 1 month.
The specific embodiment is as follows:
the conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.
Example 1
Crizotinib: HPMCP amorphous solid dispersion preparation:
0.2g of crizotinib and 0.3g of HPMCP were added to 12mL of a methanol/dichloromethane (1:2 volume ratio) mixed solvent, which was completely dissolved by magnetic stirring. The powder was obtained by spray drying. The spraying process parameters are inlet temperature: the feed rate was 5mL/min at 85℃and the nitrogen flow rate was 40mm.
After spray drying, the powder was placed in a 35 ℃ vacuum oven and dried under reduced pressure for 18 hours at a vacuum of 0.1MPa. Excess solvent was removed to obtain crizotinib: HPMCP amorphous solid dispersion. The physical state was determined to be amorphous by detection with an X-ray powder diffractometer as shown in FIG. 1.
Example 2 crizotinib: HPMCP: HPMCAS pharmaceutical composition preparation:
crizotinib in example 1 was weighed: 200mg of HPMCP amorphous solid dispersion and 80mg of HPMCAS are placed in a penicillin bottle, and vortex is carried out for 60 minutes through a vortex instrument until the two are uniformly mixed, so as to obtain crizotinib: HPMCP: HPMCAS pharmaceutical compositions. The physical state was determined to be amorphous by detection with an X-ray powder diffractometer as shown in FIG. 2.
Example 3
Crizotinib: HPMCAS amorphous solid dispersion preparation:
0.2g of crizotinib and 0.3g of HPMCAS (AS-MF) were added to 16mL of a methanol/dichloromethane (1:1 volume ratio) mixture, which was completely dissolved by magnetic stirring. The obtained solution was spray-dried by a B290 mini spray dryer of the legendary system to obtain a powder. The spraying process parameters are inlet temperature: the feed rate was 5mL/min at 85℃and the nitrogen flow rate was 40mm. After spray drying, the product is placed in a vacuum drying oven at 35 ℃, dried for 18 hours under reduced pressure, and the redundant solvent is removed under the vacuum degree of 0.1MPa, so as to obtain crizotinib: HPMCAS amorphous solid dispersion. The physical state was determined to be amorphous by detection with an X-ray powder diffractometer as shown in FIG. 3.
Example 4
Crizotinib: HPMCAS: HPMCAS pharmaceutical composition preparation:
crizotinib in example 3 was weighed: the HPMCAS amorphous solid dispersion 200mg,HPMCAS 80mg is placed in a penicillin bottle and is uniformly mixed by vortex for 60min through a vortex instrument. Thereby obtaining crizotinib: HPMCAS: HPMCAS pharmaceutical compositions. The physical state was determined to be amorphous by detection with an X-ray powder diffractometer as shown in FIG. 4.
Comparative example 1
Crizotinib: HPMCP: HPMCP pharmaceutical composition preparation:
crizotinib in example 1 was weighed: 200mg of HPMCP amorphous solid dispersion and 80mg of HPMCP are placed in a penicillin bottle, and are uniformly mixed by vortex for 60min through a vortex instrument. Thereby obtaining crizotinib: HPMCP: HPMCP pharmaceutical composition.
Example 5: modulated differential scanning calorimetry (mDSC)
The thermal properties of the samples were analyzed using a differential scanning calorimeter Q2000 (american TA instrument). The sample was tested in the modulation mode, the sample chamber nitrogen purge flow was set at 50mL/min, equilibrated at 40 ℃, modulation period at 60s, modulation amplitude at 0.8 ℃, heating rate at 5 ℃/min to 200 ℃, data analysis software TAUniversal Analysis (american TA instrument).
Crizotinib obtained in example 1: HPMCP amorphous solid dispersion, crizotinib obtained in example 3: the amorphous solid dispersion of HPMCAS is analyzed and tested for glass transition temperature by using a modulated differential scanning calorimetry method, and graphs of test results are shown in figures 5 and 6, from which crizotinib is known: the glass transition temperature of the HPMCP amorphous solid dispersion was about 137 ℃, crizotinib: the glass transition temperature of the HPMCAS amorphous solid dispersion was about 119 ℃. The glass transition temperature of HPMCAS (AS-HF) is about 120 ℃. Therefore, the heat stability of the crizotinib amorphous solid dispersion and the pharmaceutical composition can meet the requirements of the general pharmaceutical process.
Example 6: crizotinib: HPMCP: dissolution test of HPMCAS pharmaceutical compositions
The crizotinib prepared in example 2 was subjected to a dissolution apparatus: HPMCP: the HPMCAS pharmaceutical composition was subjected to dissolution test taking 17.5mg of crizotinib prepared in example 2: HPMCP: HPMCAS pharmaceutical composition, while 12.5mg of crizotinib prepared in example 1: HPMCP amorphous solid dispersion, 5mg of crizotinib free base was additionally taken as control. 500mL of phosphate buffer (containing 0.05% SDS) having a pH of 6.8 was used as a dissolution medium, the temperature was maintained at 37.+ -. 0.5 ℃ and the stirring rotation speed was adjusted to 100 rpm. Starting timing after the material feeding, 3.0mL (simultaneously adding the isothermal dissolution medium in equal quantity) is sampled at 5, 10, 20 and 30 minutes respectively, and the mixture is filtered by a microporous filter membrane with the thickness of 0.22 microns to obtain a solution to be tested.
The absorbance of the samples was measured at a wavelength of 220nm using an ultraviolet spectrophotometer, the release of each sample at different times was calculated as ultraviolet absorbance by the external standard method, each group was tested 3 times in parallel, and the results were averaged (see fig. 7). The results show that, in a medium with a pH of 6.8, crizotinib of example 2, at dissolution for 5 minutes: HPMCP: the HPMCAS pharmaceutical composition had accumulated dissolution up to about 37%, crizotinib of example 1: the HPMCP amorphous solid dispersion dissolved up to about 25% whereas crizotinib free base dissolved only about 12%. At the time the dissolution test was run for 30 minutes, the crizotinib was dissolved about 74% cumulatively, crizotinib: HPMCP amorphous solid dispersion was about 75%, whereas crizotinib of example 2: HPMCP: the HPMCAS pharmaceutical composition is substantially soluble.
From the results, relative to crizotinib free base, crizotinib: HPMCP amorphous solid dispersion, crizotinib: HPMCP: HPMCAS pharmaceutical compositions have a substantial increase in dissolution rate and instantaneous solubility.
Example 7: dissolution test of crizotinib pharmaceutical composition at ph=7.4
For crizotinib prepared in example 2: HPMCP: the HPMCAS pharmaceutical composition was subjected to dissolution test, taking the crizotinib prepared in example 2, respectively: HPMCP: HPMCAS pharmaceutical composition, crizotinib prepared in example 4: HPMCAS: HPMCAS pharmaceutical composition, crizotinib prepared in comparative example 1: HPMCP: 7mg of HPMCP pharmaceutical compositions are respectively taken from the crizotinib prepared in example 1: HPMCP amorphous solid dispersion, crizotinib prepared in example 3: the HPMCAS amorphous solid dispersion was 5mg each, and 2mg (equivalent) of crizotinib free base was taken as a control. 50mL of phosphate buffer solution with pH of 7.4 is used as a dissolution medium, the temperature is kept at 25+/-0.5 ℃, and the rotating speed of a stirring paddle is regulated to 100 revolutions per minute. Stirring is carried out for 4 hours.
The absorbance of the samples was measured at a wavelength of 220nm using an ultraviolet spectrophotometer, the actual release of each sample at the endpoint was calculated as ultraviolet absorbance by an external standard method, each group was tested 3 times in parallel, and the results averaged showed that stirring was carried out for 4 hours in a medium at pH 7.4. The test results are shown in the following table:
from the results in the table above, with respect to crizotinib free base, crizotinib: the HPMCP amorphous solid dispersion has a great improvement in dissolution speed and instantaneous solubility, while crizotinib: HPMCP: HPMCAS pharmaceutical composition in crizotinib: the base of the HPMCP amorphous solid dispersion has higher dissolution rate and instant solubility. HPMCP is used as an additional auxiliary material to form crizotinib: HPMCP: HPMCP pharmaceutical composition is relative to crizotinib: the apparent solubility of HPMCP solid dispersions is lower.
In addition, relative to crizotinib free base, crizotinib: the HPMCAS amorphous solid dispersion has a great improvement in dissolution speed and instantaneous solubility, while crizotinib: HPMCAS: HPMCAS pharmaceutical composition in crizotinib: the base of the HPMCAS amorphous solid dispersion has a higher dissolution rate and instantaneous solubility.
Example 9: stability investigation of effect of crizotinib pharmaceutical composition
According to the guidelines of the stability test of the raw material medicines and the preparation in the Chinese pharmacopoeia 9001, the crizotinib obtained in the example 1 is: HPMCP amorphous solid dispersion, crizotinib obtained in example 2: HPMCP HPMCAS pharmaceutical compositions were placed in a climatic chamber at 40℃and 75% RH, and periodically sampled for testing PXRD. The results are shown in fig. 8 and 9. From the figure, the amorphous solid dispersions obtained in example 1 and example 2 were left to stand under accelerated conditions for 1 month, and remained amorphous.
Example 10: preparation of crizotinib capsules
The preparation method comprises the following steps:
1. weighing: the components were weighed according to the proportions prescribed in the table above.
2. Primary mixing: mixing the crizotinib-HPMCP-HPMCAS pharmaceutical composition (2:3:2, mass ratio) with microcrystalline cellulose and croscarmellose sodium, sieving with a 40-mesh sieve, and mixing the sieved powder in a multidirectional motion mixer for 15min.
3. Dry granulating: and adding the mixed materials into a dry granulator for granulating.
4. Total mixing: mixing the dry granulated granules with colloidal silicon dioxide, sieving with 20 mesh sieve, adding magnesium stearate, and mixing for 10min.
5. And (5) filling capsules and packaging.
Claims (4)
1. A crizotinib pharmaceutical composition is characterized in that,
an amorphous pharmaceutical composition comprising crizotinib and a cellulose derivative, said cellulose derivative being hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate, crizotinib: hydroxypropyl methylcellulose phthalate: the mass ratio of the hydroxypropyl methyl cellulose acetate succinate is 2:3:2; the crizotinib pharmaceutical composition is prepared by the following preparation method:
dissolving crizotinib and hydroxypropyl methylcellulose phthalate in a mixed solvent of methanol and dichloromethane, removing the solvent to obtain a solid dispersion, and physically mixing the solid dispersion with hydroxypropyl methylcellulose acetate succinate.
2. A process for preparing a pharmaceutical composition of crizotinib according to claim 1, wherein crizotinib and hydroxypropyl methylcellulose phthalate are dissolved in a mixed solvent of methanol and methylene chloride, and then the solvent is removed to obtain a solid dispersion, and then the solid dispersion is physically mixed with hydroxypropyl methylcellulose acetate succinate.
3. A pharmaceutical formulation comprising the crizotinib pharmaceutical composition of claim 1, wherein the pharmaceutical formulation comprises the crizotinib pharmaceutical composition of claim 1 and a pharmaceutically acceptable adjuvant.
4. Use of a pharmaceutical composition of crizotinib according to claim 1 or a pharmaceutical formulation according to claim 3 for the preparation of a medicament for the treatment of non-small cell lung cancer.
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