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CN108014089A - A kind of Montelukast Sodium enteric-coated pellet capsule of stabilization and preparation method thereof - Google Patents

  • ️Fri May 11 2018
A kind of Montelukast Sodium enteric-coated pellet capsule of stabilization and preparation method thereof Download PDF

Info

Publication number
CN108014089A
CN108014089A CN201711328786.XA CN201711328786A CN108014089A CN 108014089 A CN108014089 A CN 108014089A CN 201711328786 A CN201711328786 A CN 201711328786A CN 108014089 A CN108014089 A CN 108014089A Authority
CN
China
Prior art keywords
enteric
capsule
coated
weight ratio
coated pellet
Prior art date
2017-12-13
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.)
Withdrawn
Application number
CN201711328786.XA
Other languages
Chinese (zh)
Inventor
蒋磊
朱生良
刘亚
张世龙
王凯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hefei Kshi Pharmaceutical Science And Technology Co Ltd
Original Assignee
Hefei Kshi Pharmaceutical Science And Technology Co Ltd
Priority date (The priority date 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 date listed.)
2017-12-13
Filing date
2017-12-13
Publication date
2018-05-11
2017-12-13 Application filed by Hefei Kshi Pharmaceutical Science And Technology Co Ltd filed Critical Hefei Kshi Pharmaceutical Science And Technology Co Ltd
2017-12-13 Priority to CN201711328786.XA priority Critical patent/CN108014089A/en
2018-05-11 Publication of CN108014089A publication Critical patent/CN108014089A/en
Status Withdrawn legal-status Critical Current

Links

  • 239000008188 pellet Substances 0.000 title claims abstract description 72
  • 239000002775 capsule Substances 0.000 title claims abstract description 50
  • 238000002360 preparation method Methods 0.000 title claims abstract description 29
  • 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 27
  • LBFBRXGCXUHRJY-HKHDRNBDSA-M montelukast sodium Chemical compound [Na+].CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC([O-])=O)CC1 LBFBRXGCXUHRJY-HKHDRNBDSA-M 0.000 title claims abstract description 27
  • 230000006641 stabilisation Effects 0.000 title claims abstract description 14
  • 238000011105 stabilization Methods 0.000 title claims abstract description 14
  • 239000012055 enteric layer Substances 0.000 claims abstract description 21
  • 239000010410 layer Substances 0.000 claims abstract description 21
  • 239000000463 material Substances 0.000 claims abstract description 18
  • 239000003605 opacifier Substances 0.000 claims abstract description 18
  • 238000000926 separation method Methods 0.000 claims abstract description 16
  • 239000011248 coating agent Substances 0.000 claims abstract description 12
  • 238000000576 coating method Methods 0.000 claims abstract description 12
  • 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 abstract description 10
  • 239000000853 adhesive Substances 0.000 claims abstract description 10
  • 230000001070 adhesive effect Effects 0.000 claims abstract description 10
  • 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 10
  • 239000000945 filler Substances 0.000 claims abstract description 10
  • 239000003340 retarding agent Substances 0.000 claims abstract description 10
  • 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims abstract description 10
  • 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims abstract description 10
  • 239000007884 disintegrant Substances 0.000 claims abstract description 9
  • 239000004014 plasticizer Substances 0.000 claims abstract description 7
  • LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
  • GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical group O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 18
  • 239000006187 pill Substances 0.000 claims description 15
  • 239000012530 fluid Substances 0.000 claims description 14
  • UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 10
  • 239000007788 liquid Substances 0.000 claims description 10
  • 238000003756 stirring Methods 0.000 claims description 10
  • 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 9
  • 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 9
  • 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 9
  • 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 9
  • 239000004408 titanium dioxide Substances 0.000 claims description 9
  • 238000001125 extrusion Methods 0.000 claims description 8
  • 238000005563 spheronization Methods 0.000 claims description 8
  • WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
  • 230000004888 barrier function Effects 0.000 claims description 7
  • HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
  • 238000001035 drying Methods 0.000 claims description 6
  • 229960003943 hypromellose Drugs 0.000 claims description 6
  • 239000000843 powder Substances 0.000 claims description 6
  • CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
  • 229960000913 crospovidone Drugs 0.000 claims description 5
  • 238000002955 isolation Methods 0.000 claims description 5
  • XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 5
  • 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
  • 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
  • FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
  • 239000001856 Ethyl cellulose Substances 0.000 claims description 4
  • ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
  • PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
  • 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 claims description 4
  • 229930195725 Mannitol Natural products 0.000 claims description 4
  • VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
  • XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 4
  • 239000003795 chemical substances by application Substances 0.000 claims description 4
  • 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
  • 229920001249 ethyl cellulose Polymers 0.000 claims description 4
  • 239000000594 mannitol Substances 0.000 claims description 4
  • 235000010355 mannitol Nutrition 0.000 claims description 4
  • 239000000203 mixture Substances 0.000 claims description 4
  • 239000000741 silica gel Substances 0.000 claims description 4
  • 229910002027 silica gel Inorganic materials 0.000 claims description 4
  • 229910052708 sodium Inorganic materials 0.000 claims description 4
  • 239000011734 sodium Substances 0.000 claims description 4
  • LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 3
  • 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 3
  • 239000002702 enteric coating Substances 0.000 claims description 3
  • 238000009505 enteric coating Methods 0.000 claims description 3
  • 239000003292 glue Substances 0.000 claims description 3
  • 239000008101 lactose Substances 0.000 claims description 3
  • 229960003511 macrogol Drugs 0.000 claims description 3
  • 229920000609 methyl cellulose Polymers 0.000 claims description 3
  • 238000002156 mixing Methods 0.000 claims description 3
  • 238000012545 processing Methods 0.000 claims description 3
  • 239000002994 raw material Substances 0.000 claims description 3
  • 239000011122 softwood Substances 0.000 claims description 3
  • 238000005507 spraying Methods 0.000 claims description 3
  • 239000000080 wetting agent Substances 0.000 claims description 3
  • 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 claims description 2
  • 239000007963 capsule composition Substances 0.000 claims description 2
  • 239000008199 coating composition Substances 0.000 claims description 2
  • 239000007771 core particle Substances 0.000 claims description 2
  • BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
  • 235000011187 glycerol Nutrition 0.000 claims description 2
  • 239000001923 methylcellulose Substances 0.000 claims description 2
  • 239000011787 zinc oxide Substances 0.000 claims description 2
  • KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
  • VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims 1
  • 229920003081 Povidone K 30 Polymers 0.000 claims 1
  • 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 1
  • 239000001761 ethyl methyl cellulose Substances 0.000 claims 1
  • 235000010944 ethyl methyl cellulose Nutrition 0.000 claims 1
  • 239000000835 fiber Substances 0.000 claims 1
  • 239000003814 drug Substances 0.000 abstract description 17
  • 238000004519 manufacturing process Methods 0.000 abstract description 5
  • 238000000034 method Methods 0.000 description 14
  • 238000004128 high performance liquid chromatography Methods 0.000 description 13
  • 239000000047 product Substances 0.000 description 12
  • 238000005286 illumination Methods 0.000 description 11
  • 239000000243 solution Substances 0.000 description 11
  • 229940079593 drug Drugs 0.000 description 10
  • 239000003826 tablet Substances 0.000 description 10
  • 238000001514 detection method Methods 0.000 description 8
  • 239000008187 granular material Substances 0.000 description 7
  • OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
  • 230000015556 catabolic process Effects 0.000 description 6
  • 238000006731 degradation reaction Methods 0.000 description 6
  • 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 5
  • DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
  • 235000013305 food Nutrition 0.000 description 3
  • 210000004051 gastric juice Anatomy 0.000 description 3
  • 239000012535 impurity Substances 0.000 description 3
  • 230000000968 intestinal effect Effects 0.000 description 3
  • 210000000936 intestine Anatomy 0.000 description 3
  • 239000002075 main ingredient Substances 0.000 description 3
  • 230000002265 prevention Effects 0.000 description 3
  • 210000001187 pylorus Anatomy 0.000 description 3
  • 239000013558 reference substance Substances 0.000 description 3
  • 239000007921 spray Substances 0.000 description 3
  • 210000002784 stomach Anatomy 0.000 description 3
  • 239000001069 triethyl citrate Substances 0.000 description 3
  • 235000013769 triethyl citrate Nutrition 0.000 description 3
  • VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
  • NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
  • 238000010521 absorption reaction Methods 0.000 description 2
  • 239000002253 acid Substances 0.000 description 2
  • 208000006673 asthma Diseases 0.000 description 2
  • 230000033228 biological regulation Effects 0.000 description 2
  • 239000008280 blood Substances 0.000 description 2
  • 210000004369 blood Anatomy 0.000 description 2
  • 239000007910 chewable tablet Substances 0.000 description 2
  • 239000007857 degradation product Substances 0.000 description 2
  • 238000005516 engineering process Methods 0.000 description 2
  • 239000000706 filtrate Substances 0.000 description 2
  • 238000009472 formulation Methods 0.000 description 2
  • 239000002609 medium Substances 0.000 description 2
  • 210000004400 mucous membrane Anatomy 0.000 description 2
  • 238000011017 operating method Methods 0.000 description 2
  • 239000002245 particle Substances 0.000 description 2
  • 125000006850 spacer group Chemical group 0.000 description 2
  • 239000012085 test solution Substances 0.000 description 2
  • BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
  • 206010006482 Bronchospasm Diseases 0.000 description 1
  • 208000019505 Deglutition disease Diseases 0.000 description 1
  • XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
  • 206010013786 Dry skin Diseases 0.000 description 1
  • RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 1
  • ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
  • ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
  • WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
  • 229960001138 acetylsalicylic acid Drugs 0.000 description 1
  • 239000003929 acidic solution Substances 0.000 description 1
  • 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
  • 230000009286 beneficial effect Effects 0.000 description 1
  • 230000007885 bronchoconstriction Effects 0.000 description 1
  • 239000007853 buffer solution Substances 0.000 description 1
  • 235000013339 cereals Nutrition 0.000 description 1
  • 208000029771 childhood onset asthma Diseases 0.000 description 1
  • 150000001875 compounds Chemical class 0.000 description 1
  • 235000009508 confectionery Nutrition 0.000 description 1
  • 238000013270 controlled release Methods 0.000 description 1
  • 238000004132 cross linking Methods 0.000 description 1
  • 230000007547 defect Effects 0.000 description 1
  • SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical class CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
  • 238000010790 dilution Methods 0.000 description 1
  • 239000012895 dilution Substances 0.000 description 1
  • 238000004090 dissolution Methods 0.000 description 1
  • 239000012738 dissolution medium Substances 0.000 description 1
  • 238000011978 dissolution method Methods 0.000 description 1
  • 230000000857 drug effect Effects 0.000 description 1
  • 230000000694 effects Effects 0.000 description 1
  • 238000002474 experimental method Methods 0.000 description 1
  • 238000010812 external standard method Methods 0.000 description 1
  • 210000004211 gastric acid Anatomy 0.000 description 1
  • 239000004519 grease Substances 0.000 description 1
  • 229910052739 hydrogen Inorganic materials 0.000 description 1
  • 239000001257 hydrogen Substances 0.000 description 1
  • 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
  • 239000000543 intermediate Substances 0.000 description 1
  • 238000011068 loading method Methods 0.000 description 1
  • 238000011866 long-term treatment Methods 0.000 description 1
  • 235000019796 monopotassium phosphate Nutrition 0.000 description 1
  • YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
  • 238000005453 pelletization Methods 0.000 description 1
  • 239000008363 phosphate buffer Substances 0.000 description 1
  • 229920003023 plastic Polymers 0.000 description 1
  • 239000004033 plastic Substances 0.000 description 1
  • 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
  • 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
  • 229910052700 potassium Inorganic materials 0.000 description 1
  • 239000011591 potassium Substances 0.000 description 1
  • GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
  • 229940069328 povidone Drugs 0.000 description 1
  • 230000029058 respiratory gaseous exchange Effects 0.000 description 1
  • 230000033764 rhythmic process Effects 0.000 description 1
  • 238000005096 rolling process Methods 0.000 description 1
  • 238000007789 sealing Methods 0.000 description 1
  • 238000005063 solubilization Methods 0.000 description 1
  • 230000007928 solubilization Effects 0.000 description 1
  • 238000001694 spray drying Methods 0.000 description 1
  • 238000006467 substitution reaction Methods 0.000 description 1
  • 238000002604 ultrasonography Methods 0.000 description 1
  • XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
  • 235000020985 whole grains Nutrition 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to technical field of medicine, Montelukast Sodium enteric-coated pellet capsule more particularly to a kind of stabilization and preparation method thereof, the enteric-coated pellet capsule is made of the coating of pellet core, separation layer and enteric layer from the inside to the outside, wherein, pellet core accounts for the 50 65% of enteric-coated pellet capsule, separation layer accounts for the 10 20% of enteric-coated pellet capsule, and enteric layer coating accounts for the 25 30% of enteric-coated pellet capsule；Wherein, pellet core is made of Montelukast Sodium, sodium carboxymethylcellulose, filler, disintegrant and basifier；Separation layer is made of retarding agent, adhesive, antiplastering aid and opacifier；Enteric layer coating is made of enteric high molecular material, plasticizer, antiplastering aid and opacifier；Enteric-coated pellet capsule provided by the present invention simplifies preparation process, reduces production cost, improves product quality and stability, security and clinical efficacy are more preferable, is worth of widely use.

Description

A kind of Montelukast Sodium enteric-coated pellet capsule of stabilization and preparation method thereof

Technical field

The present invention relates to technical field of medicine, and in particular to a kind of Montelukast Sodium enteric-coated pellet capsule of stabilization and Its preparation method.

Background technology

Pellet is a kind of spherical or spherical preparation of diameter in 0.5-1.5mm, can improve medicine and be contacted in intestines and stomach Area, improves bioavilability；Can be needed that slow-release controlled-release and compound preparation is made according to clinic；Drug release is stablized, drug release rule tool There is reappearance；Medicine conveys the influence of the food rhythm and pace of moving things from alimentary canal；Good appearance, good fluidity are non-breakable；The system of pellet Standby technology mainly have rolling pelletization method, extrusion spheronization method, Centrifugal fluidized pellet method, melted high speed shear method, congealing spray, Pill etc. in spray drying process and liquid medium.

Preparation method directly prepares pellet core using extrusion spheronization in the present invention, by using bottom to spray after fluidized bed drying Bag barrier gown, then bag enteric layer, simplify operating procedure compared with existing process, shorten man-hour, improve product yield, avoid The shortcomings that time-consuming by existing preparation process, yield is low, substantially increases production efficiency.

Montelukast Sodium is suitable for the prevention and long-term treatment of adult and childhood asthma, includes the heavy breathing at prevention daytime and night Asthma shape, is treated to bronchoconstriction caused by the asthmatic patient of aspirin sensitive and prevention movement.

Enteric-coated pellet capsule, which has listed ordinary tablet, chewable tablets and granule, has following advantage：1. domestic ordinary tablet and Particle discharged in stomach easily lead to drug degradation lose it is amount of activated, that is to say, that：What patient may take be one it is invalid or The medicine of partial failure；It is multicomponent system and enteric-coated pellet capsule every is made of more than 100 small pellets, the mistake of indivedual pellets By mistake or defect will not have an impact the drug release behavior of preparation entirety, therefore the stability of medicine is improved.2. conventional capsule, Tablet disperse limited area, drug absorption is slower, and blood concentration easily fluctuates, and bioavilability is relatively low, and local mucous membrane stimulates Also it is big；And enteric-coated pellet capsule is big in intestines and stomach disperse area, good absorbing, bioavilability is high, and blood concentration is steady, mucous membrane thorn It is small to swash property.3. due to there is enteric coating outside each pellet, enteric-coated pellet capsule can whole grain swallow or also open glue Capsule directly takes pellet, and the patient for being very suitable for children and dysphagia takes.4. enteric coatel tablets or common capsulae enterosolubilis, due to grain Footpath is big, not easily passs through pylorus, is easily influenced by food rhythmicity；Pellet is since particle diameter is small, in the case of the closing of such as pylorus It can continue, uniformly across pylorus, be influenced by food rhythmicity small.

This product in an acidic solution with it is unstable under illumination condition, it is degradable to produce a large amount of impurity, after oral absorption Also degradation impurity is also easy to produce in gastric juice, reduces curative effect.Be conducive to improve this product quality stability after making enteric coated pellets formulation And clinical efficacy.Patent " a kind of montelukast sodium enteric-coated pellet of stabilization " (CN201610916676.4, Jiangsu Alpha is reported Medicine company) using Blank Pellets coating, upper drug-loaded layer (this technique drug loss is larger), separation layer and enteric layer；This product prepares work Skill flow is pellet core (extrusion spheronization), bag separation layer and enteric layer, and technical process reduction, reduces production cost, and medicine Thing almost free of losses, has reported patent to have more advantage.Separately the Montelukast Sodium figuration coated in patent in blank capsule core is reported Agent neutralizes contains the povidone incompatible with main ingredient and copolyvidone auxiliary material respectively in separation layer, supplementary material compatibility experiments are found This two kinds of auxiliary materials easily make main ingredient produce a large amount of degradation impurities and make main ingredient yellowish.Auxiliary material and Meng Lusi used in this product prescription Special sodium compatibility is preferable, and pellet core is non-discolouring under high temperature, high humidity and illumination condition, improves product quality and stabilization Property.

The content of the invention

For the enteric-coated pellet capsule that the prior art is provided there are the problem of, the present invention propose a kind of Meng Lu of stabilization Special sodium enteric-coated pellet capsule of department and preparation method thereof.The present invention provides enteric-coated pellet capsule cost existing for enteric-coated pellet capsule It is low, security is good, drug effect is notable.

In order to realize above-mentioned purpose, it is achieved by the following technical programs：

A kind of Montelukast Sodium enteric-coated pellet capsule of stabilization, the enteric-coated pellet capsule from the inside to the outside by pellet core, every Absciss layer and enteric layer coating composition, wherein, the pellet core accounts for the 50-65% of enteric-coated pellet capsule, and the separation layer accounts for intestines The 10-20% of molten micro pill capsule, the enteric layer coating account for the 25-30% of enteric-coated pellet capsule；

The pellet core is made of Montelukast Sodium, sodium carboxymethylcellulose, filler, disintegrant and basifier, institute The weight ratio for stating Montelukast Sodium is 7-10%, and the weight ratio of the sodium carboxymethylcellulose is 2-8%, the weight of the filler It is 60-70% to measure ratio, and the weight ratio of the disintegrant is 5-8%, and the weight ratio of the basifier is 10-15%；

Preferably, the filler is selected from mannitol or lactose；The disintegrant is selected from crospovidone or crosslinking carboxylic first Base sodium cellulosate；The one kind or more of the basifier in natrium carbonicum calcinatum, disodium hydrogen phosphate, zinc oxide and sodium hydroxide Kind；

The separation layer is made of retarding agent, adhesive, antiplastering aid and opacifier, and the weight ratio of the retarding agent is 20- 35%, the weight ratio of described adhesive is 50-65%, and the weight ratio of the antiplastering aid is 6-11%, the weight of the opacifier Than for 2-5%；

Preferably, the retarding agent is selected from ethyl cellulose, and described adhesive is selected from hypromellose, described anti-stick Agent is selected from talcum powder or superfine silica gel powder, and the opacifier is selected from titanium dioxide or iron oxide red；

The enteric layer coating is made of enteric high molecular material, plasticizer, antiplastering aid and opacifier, the enteric high score The weight ratio of sub- material is 70-75%, and the weight ratio of the plasticizer is 5-7%, and the weight ratio of the antiplastering aid is 15- 20%th, the weight ratio of the opacifier is 2-5%；

Preferably, the enteric high molecular material is selected from hypromellose phthalate, and the plasticizer is selected from One or more in triethyl citrate, glycerine, Macrogol 6000, the antiplastering aid is selected from talcum powder or monostearate is sweet Grease, the opacifier are selected from titanium dioxide or iron oxide red；

The preparation method of the enteric-coated pellet capsule includes the following steps：

(1) preparation of pellet core

Sodium carboxymethylcellulose, filler, disintegrant and the basifier for crossing 80 mesh sieves, montelukast sodium raw materials are taken respectively 200 mesh sieves are crossed, puts in mixer and is uniformly mixed altogether, dry powder in wet mixing pelletizer is put and mixes, are added with wetting agent using spraying The mode softwood of liquid, puts pill in extrusion spheronization pellet processing machine, and mesh size is 24 mesh, collects wet ball and puts fluid bed in a constant temperature It is dry under the conditions of degree, collect the drying capsule core of certain mesh sieve；

(2) preparation of separation layer

Retarding agent, adhesive are weighed, the ethanol that appropriate concentration is 85% is added, stirs evenly, add until completely dissolved Antiplastering aid and opacifier, add the ethanol that remaining concentration is 85%, after stirring evenly, 80 mesh sieves are crossed, up to isolation coat Liquid, dry capsule core is put in fluid bed, opens power supply, adjusting parameter carries out bag barrier gown；

(3) preparation of enteric layer

Retarding agent, adhesive are weighed, the ethanol that appropriate concentration is 85% is added, stirs evenly, add until completely dissolved Antiplastering aid and opacifier, add the ethanol that remaining concentration is 85%, after stirring evenly, 80 mesh sieves are crossed, up to isolation coat Liquid, dry capsule core is put in fluid bed, opens power supply, adjusting parameter carries out bag barrier gown.

Preferably, enteric-coated pellet capsule composition is as follows：60% pellet core, 10% separation layer, 30% enteric layer.

Preferably, temperature is 50~60 DEG C in fluid bed in step (1).

Preferably, dry capsule core particle diameter is 20~30 mesh in step (1).

Preferably, when standing time is small more than or equal to 12 in step (3).

It is as follows using above-mentioned technical solution, beneficial effects of the present invention：

1st, be made enteric-coated micro-pill solve existing formulation (tablet, chewable tablets, granule etc.) it is unstable in gastric acid environment, Degradable situation；

2nd, this product is shown in that light easily decomposes, which improves stability of the product under illumination condition；

3rd, the present invention directly prepares pellet core using extrusion spheronization method, by using spray bag isolation in bottom after fluidized bed drying Clothing, then bag enteric layer, simplify operating procedure compared with existing process, shorten man-hour, improve product yield, avoid existing system The shortcomings that time-consuming, yield is low for technique, substantially increases production efficiency；

4th, this product preparation process flow is pellet core (extrusion spheronization), bag separation layer and enteric layer, and technical process is reduced, And medicine almost free of losses, report patent to have more advantage, be conducive to industrialized production.

Brief description of the drawings：

Fig. 1 dissolution and the HPLC contrasts of degraded situation in pH1.2 and pH6.8 media for ordinary tablet, granule and embodiment Figure, wherein：

Scheme a and detect HPLC collection of illustrative plates in simulate the gastric juice (pH1.2) solubility for granule, degrade 20.203%, tR=8.536 For acid degradation product；

Scheme b and detect HPLC collection of illustrative plates in simulate the gastric juice (pH1.2) solubility for ordinary tablet, degrade 16.995%, tR=8.540 For acid degradation product；

Figure c is 1 attached drawing of embodiment, represents enteric-coated micro-pill and dissolves detection HPLC collection of illustrative plates, degraded in simulated intestinal fluid (pH6.8) 0.754% (light degradation, anacidity catabolite)；

Figure d is 2 attached drawing of embodiment, represents enteric-coated micro-pill and dissolves detection HPLC collection of illustrative plates, degraded in simulated intestinal fluid (pH6.8) 0.812% (light degradation, anacidity catabolite)；

Figure e is 3 attached drawing of embodiment, represents enteric-coated micro-pill and dissolves detection HPLC collection of illustrative plates, degraded in simulated intestinal fluid (pH6.8) 0.521% (light degradation, anacidity catabolite)；

Fig. 2 places related material detection HPLC contrasts in 7 days for ordinary tablet, granule and embodiment are exposed under illumination condition Figure, wherein：

It is that ordinary tablet exposed related material for placing 7 days under illumination condition detects HPLC figures to scheme a；

It is that granule exposed related material for placing 7 days under illumination condition detects HPLC figures to scheme b；

Figure c is 1 attached drawing of embodiment, represents enteric-coated micro-pill exposed related material detection for placing 7 days under illumination condition HPLC schemes；

Figure d is 2 attached drawing of embodiment, represents enteric-coated micro-pill exposed related material detection for placing 7 days under illumination condition HPLC schemes；

Figure e is 3 attached drawing of embodiment, and enteric-coated micro-pill exposed related material detection HPLC for placing 7 days under illumination condition schemes；

Embodiment

To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention, Technical solution in the embodiment of the present invention is clearly and completely described.Based on the embodiment of the present invention, the common skill in this area Art personnel all other embodiments obtained without creative efforts, belong to the model that the present invention protects Enclose.

Embodiment 1：

Pellet core
Montelukast Sodium 100g
Mannitol 800g
Crospovidone 80g
Sodium carboxymethylcellulose 35g
Natrium carbonicum calcinatum 180g
50% ethanol solution (contains 0.1MNaOH) 1L
Spacer layer coating
Ethyl cellulose 85g
Hydroxypropyl methylcellulose (E5) 160g
Talcum powder 25g
Titanium dioxide 20g
85% ethanol 5L
Enteric layer is coated
Hypromellose phthalate 500g
Triethyl citrate 45g
Talcum powder 125g
Titanium dioxide 20g
85% ethanol 8L

The preparation method of the enteric-coated pellet capsule includes the following steps：

(1) preparation of pellet core

Take respectively and cross the auxiliary materials such as natrium carbonicum calcinatum, mannitol, crospovidone and the sodium carboxymethylcellulose of 80 mesh sieves, Montelukast sodium raw materials cross 200 mesh sieves, put in mixer and are uniformly mixed altogether, put dry powder in wet mixing pelletizer and mix, use The wetting agent stated softwood processed by the way of liquid feeding of spraying, puts pill in extrusion spheronization pellet processing machine, and sieve screen apertures are collected through being 24 mesh Wet ball puts fluid bed in 50~60 DEG C of dryings, collects the drying capsule core between 20~30 mesh；

(2) preparation of separation layer

Ethyl cellulose and hydroxypropyl methylcellulose are weighed, the ethanol that appropriate concentration is 85% is added, stirs evenly, treat completely Talcum powder and titanium dioxide are added after dissolving, adds the ethanol that remaining concentration is 85%, after stirring evenly, crosses 80 mesh sieves, Up to isolation coat liquid, dry capsule core is put in fluid bed, opens power supply, adjusting parameter carries out bag barrier gown；

(3) preparation of enteric layer

Hypromellose phthalate is weighed to be dissolved in appropriate 85% ethanol, place 12 it is small when more than treat completely After dissolving, triethyl citrate, talcum powder and titanium dioxide are added, then adds 85% ethanol after stirring evenly, to cross 80 to full dose Mesh sieve, up to enteric coating liquid, the base ball for wrapping barrier gown is put in fluid bed or coating pan, open power supply, adjusting parameter into Row is enteric coated.

Embodiment 2：

Preparation method is the same as embodiment 1.

Embodiment 3：

Pellet core
Montelukast Sodium 100g
Lactose 790g
Crospovidone 85g
Sodium carboxymethylcellulose 30g
Natrium carbonicum calcinatum 175g
50% ethanol solution (contains 0.1MNaOH) 1L
Spacer layer coating
Methylcellulose 90g
Hydroxypropyl methylcellulose (E5) 150g
Superfine silica gel powder 30g
Iron oxide red 10g
85% ethanol 5L
Enteric layer is coated
Hypromellose phthalate 510g
Macrogol 6000 40g
Talcum powder 130g
Titanium dioxide 20g
85% ethanol 8L

Preparation method is the same as embodiment 1.

1st, the related check data of enteric-coated pellet capsule

As can be seen from the above table, the Montelukast Sodium enteric-coated pellet capsule indices obtained by the present invention meet rule It is fixed.

2nd, study on the stability

The montelukast sodium enteric-coated pellet of the present embodiment one~tri- is calculated into loading amount by intermediates content, is used after encapsulated Aluminium-plastic sealing is packed, and in 40 DEG C ± 2 DEG C of high temperature, carries out accelerating the stability of 6 months to examine under conditions of relative humidity 75% ± 5% Examine, as a result see the table below：

As can be seen from the above table, the Montelukast Sodium enteric-coated pellet capsule obtained by the present invention is in 40 DEG C of ± 2 DEG C of bars of high temperature Investigated 6 months under part, every Index for examination meets regulation.

3rd, illumination condition stability inferior detects

The present invention obtains product compared with conventional tablet and granule, exposed under the conditions of illumination (4500LX ± 500LX) The stability of 7 days is placed, it is as a result as follows：

Wherein, drug release determination method is as follows in buffer solution：

Lucifuge operates.This product is taken, according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method), with Phosphate buffer (0.5% lauryl sodium sulfate) 900ml of pH6.8 is dissolution medium, and rotating speed is 50 turns per minute, in accordance with the law Measure, during through 30 minutes, takes solution about 10ml, filters, discards primary filtrate, take subsequent filtrate as test solution；Separately take Meng Lu Department special dicyclohexylamine salt reference substance about 15mg, it is accurately weighed, to put in 50ml brown measuring bottles, add methanol about 40ml, ultrasound makes dissolving, With methanol dilution to scale, shaking up, precision measures 1ml into 50ml brown measuring bottles, and solubilization goes out medium to scale, shakes up, As reference substance solution.Tested according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).With octadecyl Silane group silica gel is filler (150 × 4.6mm, 5 μm), and (6.8g di(2-ethylhexyl)phosphates are weighed with 0.05mol/L potassium dihydrogen phosphates Hydrogen potassium, is dissolved in water to 1000ml, adds 1ml triethylamines, with phosphoric acid tune pH value to 5.6)-acetonitrile (25:75) it is mobile phase； Detection wavelength：345nm；Column temperature：40℃；Flow velocity：1.0ml/min.Precision measures test solution and each 25 μ l of reference substance solution, It is injected separately into chromatograph, records chromatogram, by external standard method with the stripping quantity of every bag of calculated by peak area, and result is multiplied by 0.764, Limit is the 85% of labelled amount, should meet regulation.

Above example is only to illustrate the technical solution of type of the present invention, rather than its limitations；Although with reference to foregoing implementation Type of the present invention is described in detail in example, it will be understood by those of ordinary skill in the art that：It still can be to foregoing each Technical solution described in embodiment is modified, or carries out equivalent substitution to which part technical characteristic；And these are changed Or replace, the essence of appropriate technical solution is departed from the spirit and scope of each embodiment technical solution of type of the present invention.

Claims (6)

  1. A kind of 1. Montelukast Sodium enteric-coated pellet capsule of stabilization, it is characterised in that the enteric-coated pellet capsule from the inside to the outside by containing Pill core, separation layer and enteric layer coating composition, wherein, the pellet core accounts for the 50-65% of enteric-coated pellet capsule, it is described every Absciss layer accounts for the 10-20% of enteric-coated pellet capsule, and the enteric layer coating accounts for the 25-30% of enteric-coated pellet capsule；

    Wherein, the pellet core is made of Montelukast Sodium, sodium carboxymethylcellulose, filler, disintegrant and basifier, institute The weight ratio for stating Montelukast Sodium is 7-10%, and the weight ratio of the sodium carboxymethylcellulose is 2-8%, the weight of the filler It is 60-70% to measure ratio, and the weight ratio of the disintegrant is 5-8%, and the weight ratio of the basifier is 10-15%；

    Wherein, the filler is selected from mannitol or lactose；The disintegrant is selected from crospovidone or cross-linked carboxymethyl fiber Plain sodium；One or more of the basifier in natrium carbonicum calcinatum, zinc oxide, sodium hydroxide and disodium hydrogen phosphate；

    Wherein, the separation layer is made of retarding agent, adhesive, antiplastering aid and opacifier, and the weight ratio of the retarding agent is 20- 35%, the weight ratio of described adhesive is 50-65%, and the weight ratio of the antiplastering aid is 6-11%, the weight of the opacifier Than for 2-5%；

    Wherein, the retarding agent is selected from ethyl cellulose or methylcellulose, described adhesive be selected from the third methylcellulose of carboxylic or PVP K30, the antiplastering aid are selected from talcum powder or superfine silica gel powder, and the opacifier is selected from titanium dioxide or iron oxide red；

    Wherein, the enteric layer coating is made of enteric high molecular material, plasticizer, antiplastering aid and opacifier, and the enteric is high The weight ratio of molecular material is 70-75%, and the weight ratio of the plasticizer is 5-7%, and the weight ratio of the antiplastering aid is 15- 20%th, the weight ratio of the opacifier is 2-5%；

    Wherein, the enteric high molecular material is selected from hypromellose phthalate, and the plasticizer is selected from citric acid One or more in triethyl, glycerine, Macrogol 6000, the antiplastering aid are selected from talcum powder or glycerin monostearate, The opacifier is selected from titanium dioxide or iron oxide red.

  2. 2. the Montelukast Sodium enteric-coated pellet capsule of stabilization according to claim 1, it is characterised in that the enteric-coated micro-pill glue The preparation method of capsule includes the following steps：

    (1) preparation of pellet core

    Sodium carboxymethylcellulose, filler, disintegrant and the basifier for crossing 80 mesh sieves, montelukast sodium raw materials mistake are taken respectively 200 mesh sieves, put in mixer and are uniformly mixed altogether, put dry powder in wet mixing pelletizer and mix, with wetting agent using spraying liquid feeding Mode softwood, put pill in extrusion spheronization pellet processing machine, mesh size is 24 mesh, collects wet ball and puts fluid bed in certain temperature Under the conditions of it is dry, collect the drying capsule core of certain sieve mesh number；

    (2) preparation of separation layer

    Retarding agent, adhesive are weighed, the ethanol that appropriate concentration is 85% is added, stirs evenly, add until completely dissolved anti-stick Agent and opacifier, add the ethanol that remaining concentration is 85%, after stirring evenly, cross 80 mesh sieves, will up to isolation coat liquid Dry capsule core is put in fluid bed, opens power supply, and adjusting parameter carries out bag barrier gown；

    (3) preparation of enteric layer

    Weigh enteric high molecular material to be dissolved in appropriate 85% ethanol, place a period of time until completely dissolved, add plasticising Agent, antiplastering aid and opacifier, then add 85% ethanol after stirring evenly, to cross 80 mesh sieves to full dose, will up to enteric coating liquid The base ball for wrapping barrier gown is put in fluid bed or coating pan, opens power supply, and adjusting parameter carries out enteric coated.

  3. 3. the Montelukast Sodium enteric-coated pellet capsule of stabilization according to claim 1, it is characterised in that the enteric-coated micro-pill glue Capsule composition is as follows：60% pellet core, 10% separation layer, 30% enteric layer.

  4. 4. the preparation method of the Montelukast Sodium enteric-coated pellet capsule of stabilization according to claim 2, it is characterised in that institute It is 50~60 DEG C to state in step (1) temperature in fluid bed.

  5. 5. the preparation method of the Montelukast Sodium enteric-coated pellet capsule of stabilization according to claim 2, it is characterised in that institute It is 20~30 mesh to state dry capsule core particle diameter in step (1).

  6. 6. the preparation method of the Montelukast Sodium enteric-coated pellet capsule of stabilization according to claim 2, it is characterised in that institute State in step (3) standing time be more than or equal to 12 it is small when.

CN201711328786.XA 2017-12-13 2017-12-13 A kind of Montelukast Sodium enteric-coated pellet capsule of stabilization and preparation method thereof Withdrawn CN108014089A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103142541A (en) * 2012-09-05 2013-06-12 北京万全阳光医学技术有限公司 Stable montelukast sodium capsule
CN106491556A (en) * 2016-10-21 2017-03-15 江苏阿尔法药业有限公司 A kind of stable montelukast sodium enteric-coated pellet

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103142541A (en) * 2012-09-05 2013-06-12 北京万全阳光医学技术有限公司 Stable montelukast sodium capsule
CN106491556A (en) * 2016-10-21 2017-03-15 江苏阿尔法药业有限公司 A kind of stable montelukast sodium enteric-coated pellet

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