CN106606502A - Doxylamine succinate-pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof - Google Patents
Doxylamine succinate-pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof Download PDFInfo
- Publication number
- CN106606502A CN106606502A CN201510705249.7A CN201510705249A CN106606502A CN 106606502 A CN106606502 A CN 106606502A CN 201510705249 A CN201510705249 A CN 201510705249A CN 106606502 A CN106606502 A CN 106606502A
- Authority
- CN
- China
- Prior art keywords
- added
- coating
- enteric
- pyridoxine hydrochloride
- doxylamine succinate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 229960005178 doxylamine Drugs 0.000 title abstract description 7
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 title abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 5
- 239000002662 enteric coated tablet Substances 0.000 title abstract description 3
- SBYPAUKLAVADFN-UHFFFAOYSA-N Cl.OC(=O)CCC(O)=O.Cc1ncc(CO)c(CO)c1O Chemical compound Cl.OC(=O)CCC(O)=O.Cc1ncc(CO)c(CO)c1O SBYPAUKLAVADFN-UHFFFAOYSA-N 0.000 title abstract 2
- 239000011248 coating agent Substances 0.000 claims abstract description 80
- 238000000576 coating method Methods 0.000 claims abstract description 80
- 239000000203 mixture Substances 0.000 claims abstract description 54
- KBAUFVUYFNWQFM-UHFFFAOYSA-N Doxylamine succinate Chemical compound OC(=O)CCC(O)=O.C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KBAUFVUYFNWQFM-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960005008 doxylamine succinate Drugs 0.000 claims abstract description 50
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 claims abstract description 49
- 239000011764 pyridoxine hydrochloride Substances 0.000 claims abstract description 47
- 229960004172 pyridoxine hydrochloride Drugs 0.000 claims abstract description 47
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000463 material Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000002702 enteric coating Substances 0.000 claims abstract description 7
- 238000009505 enteric coating Methods 0.000 claims abstract description 7
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 42
- 238000002156 mixing Methods 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000012467 final product Substances 0.000 claims description 22
- 239000007788 liquid Substances 0.000 claims description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 230000004584 weight gain Effects 0.000 claims description 18
- 235000019786 weight gain Nutrition 0.000 claims description 18
- 238000013019 agitation Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 239000000843 powder Substances 0.000 claims description 13
- 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 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 239000000945 filler Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 239000000377 silicon dioxide Substances 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 8
- 235000012239 silicon dioxide Nutrition 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 7
- 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 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 239000013530 defoamer Substances 0.000 claims description 6
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 6
- 238000003113 dilution method Methods 0.000 claims description 6
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000004014 plasticizer Substances 0.000 claims description 6
- 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 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 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
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920003148 Eudragit® E polymer Polymers 0.000 claims description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 3
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 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
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 229940008099 dimethicone Drugs 0.000 claims description 3
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000013769 triethyl citrate Nutrition 0.000 claims description 3
- 239000004925 Acrylic resin Substances 0.000 claims description 2
- 229920000178 Acrylic resin Polymers 0.000 claims description 2
- 239000008118 PEG 6000 Substances 0.000 claims description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 2
- 229940083542 sodium Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 abstract description 24
- 230000008569 process Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 210000004211 gastric acid Anatomy 0.000 abstract description 3
- 230000007935 neutral effect Effects 0.000 abstract description 3
- 210000000936 intestine Anatomy 0.000 abstract 1
- 238000002955 isolation Methods 0.000 abstract 1
- 210000002784 stomach Anatomy 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000002994 raw material Substances 0.000 description 17
- 238000004090 dissolution Methods 0.000 description 13
- 239000002253 acid Substances 0.000 description 12
- 239000003513 alkali Substances 0.000 description 12
- 238000011017 operating method Methods 0.000 description 12
- 239000008363 phosphate buffer Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 9
- 208000009233 Morning Sickness Diseases 0.000 description 7
- 208000034850 Vomiting in pregnancy Diseases 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000009472 formulation Methods 0.000 description 5
- 230000035935 pregnancy Effects 0.000 description 5
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 208000007502 anemia Diseases 0.000 description 4
- 230000001387 anti-histamine Effects 0.000 description 4
- 239000000739 antihistaminic agent Substances 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 235000019158 vitamin B6 Nutrition 0.000 description 4
- 239000011726 vitamin B6 Substances 0.000 description 4
- 229940011671 vitamin b6 Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960001340 histamine Drugs 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 2
- 102000004506 Blood Proteins Human genes 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000003834 Histamine H1 Receptors Human genes 0.000 description 2
- 108090000110 Histamine H1 Receptors Proteins 0.000 description 2
- 102000000543 Histamine Receptors Human genes 0.000 description 2
- 108010002059 Histamine Receptors Proteins 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 2
- 208000003056 Vitamin B6 deficiency Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000008484 agonism Effects 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 230000036528 appetite Effects 0.000 description 2
- 235000019789 appetite Nutrition 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 239000003595 mist Substances 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 2
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 2
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 2
- 229960001327 pyridoxal phosphate Drugs 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 208000008742 seborrheic dermatitis Diseases 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- LFDGRWDETVOGDT-UHFFFAOYSA-N 1h-pyrrole;hydrochloride Chemical compound Cl.C=1C=CNC=1 LFDGRWDETVOGDT-UHFFFAOYSA-N 0.000 description 1
- 208000019932 Aciduria Diseases 0.000 description 1
- 206010008418 Cheilosis Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 229920003159 Eudragit® RS 100 Polymers 0.000 description 1
- 101150056637 Hrh2 gene Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 206010067171 Regurgitation Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- -1 alcohol hydrochlorides Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 208000002296 eclampsia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 210000001630 jejunum Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 210000001711 oxyntic cell Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a compound doxylamine succinate-pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and a preparation method thereof. The composition comprises a tablet core containing doxylamine succinate and pyridoxine hydrochloride, an isolation coating, an enteric coating and other medicinal auxiliary materials. The preparation method has simple processes. The pharmaceutical composition has good stability, is insoluble in the stomach and can be fast released in the intestine so that the problem that the existing pharmaceutical composition has a reduced release rate when entering into an intra-intestinal neutral environment from a gastric acid environment.
Description
Technical field
The present invention relates to a kind of doxylamine succinate pyridoxine hydrochloride enteric tablet medicament composition and preparation method thereof, belongs to medicine
Technical field.
Background technology
Morning sickness is a kind of natural reaction of period of gestation, and cardinal symptom shows as weak all over, and mood is gloomy, dizzy, regurgitation,
Nausea, appetite be not good enough, or strong reaction more sensitive to abnormal flavour, becomes apparent from when especially having slept in the morning or just.These symptoms
Typically occur in the pregnant initial stage the 5th week or so, to the 16th week after, the morning sickness of most people reaction can mitigate gradually until
Lock-out, but also have the whole period of gestation of minority anemia of pregnant woman to have morning sickness reaction, this is that comparison is painful.Morning sickness reaction is not only not
Beneficial to the recuperation of anemia of pregnant woman itself, due also to most people are affected in gestation appetite, and the nutrition of fetus all from
Parent, therefore, morning sickness how is tackled, morning sickness how is reduced as far as possible and particularly heavy is just seemed to the adverse effect of anemia of pregnant woman and fetus
Want.
Doxylamine succinate its chemical entitled N, N- dimethyl -2- [1- phenyl -1- (2- pyridines) ethyoxyl] ethamine succinate, is white
Color or off-white powder, soluble in water and ethanol and chloroform, it is atomic to be dissolved in ether and benzene.This product has antihistamine effect, anti-gallbladder
Alkali is acted on and significant sedation, and intestinal side effect is relatively low.Antihistaminic is that the various pathology that a class can cause to antihistamine are anti-
The medicine answered.This class medicine reversibility captures histamine receptor, competitive blocking histamine and receptor binding, so as to show antihistamine work
With.Histamine receptor has H1 and H2 two types, and different effects are produced when exciting.Bronchus can be caused during H1 receptor agonisms
And gastrointestinal smooth muscle shrinks, relaxing the VSM, heart muscle shrinks to be strengthened, and Atrioventricular Conduction slows down.During H2 receptor agonisms
Parietal cell secretion gastric acid can be caused to increase etc..This two classes effect is respectively by different medicine institute antagonisms.H1 receptor antagonists instead of
Histamine in body, competitive antagonism its effect, it can not inactivate histamine, do not suppress yet its synthesis with release.Therefore be mainly used in
The symptom of Reduce allergy reaction.
Benadon is vitamin B6, its chemical entitled 5- hydroxyls -6- methyl -3,4- pyridine diformazan alcohol hydrochlorides, is white or class
The crystalline powder of white, it is soluble in water, ethanol is slightly soluble in, ether is practically insoluble in.Stable in the air, thermostability is preferable,
But slow in the sun to decompose, then accelerated decomposition in aqueous solution, about 206 DEG C of fusing point simultaneously can decomposeds.It is a kind of water solublity
Vitamin, stable in acid solution, the destructible in alkali liquor.It is a kind of vitamin B group containing pyridoxol or 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine. or pyridoxamine.
Vitamin B6 is converted into pyridoxal 5-phosphate in erythrocyte, as coenzyme to protein, carbohydrate, lipid various generations
Thank to function to work.Vitamin B6 also participates in tryptophan and changes into nicotinic acid or 5-hydroxy tryptamine.It is main to absorb in jejunum.Vitamin
B6 is not combined with plasma protein, and pyridoxal 5-phosphate is combined with plasma protein completely.Long half time was up to 15～20 days.Intrahepatic metabolism,
Jing renal excretion.Benadon is applied to Vitamin B6 deficiency, and (Vitamin B6 deficiency can cause xanthine aciduria, abrasive grit children
Cell anemia, nervous system lesion, seborrheic dermatitis and cheilosis) prevention and treatment, prevent and treat poisoning by isoniazid；Also can use
Vomiting, seborrheic dermatitis caused by gestation, radiation sickness and anticarcinogen；Treatment eclampsia infantum is used to maternity dress in case baby is frightened
Faint.
Canadian Duchesnay Inc (Duchesnay Inc.) have developed doxylamine succinate pyridoxine hydrochloride compound recipe earliest to be used for
The treatment of vomiting, its nineteen ninety-five patent CA2139896 disclose doxylamine succinate and pyridoxine hydrochloride by roughly equal
Weight than combination, for preventing and suppressing the symptoms of emesis of nausea and incuarable, be related to oral formulations, rectal suppository,
The dosage forms such as intravenous injection.
Duchesnay Inc's patent ZL01814548.5 (publication number：CN1447694A) there is provided a kind of salt of enteric coating coating
The rapid onset formulation of sour Benadon and doxylamine succinate, comprising disintegrating agent, so that at 37 DEG C, 1000ml pH6.8's
In phosphate buffer, when being determined with 100rpm with 2 type dissolving devices, said preparation meets following dissolution characteristic：A () determines 30
After minute, pyridoxine hydrochloride and doxylamine succinate are with least about 40% dissolution of respective total amount；B () determines 60 minutes after,
Pyridoxine hydrochloride and doxylamine succinate are with least about 70% dissolution of respective total amount；C () determines 90 minutes after, hydrochloric acid pyrrole is trembled
Pungent and doxylamine succinate is with least about 80% dissolution of respective total amount；D () determines 120 minutes after, pyridoxine hydrochloride and succinum
Sour doxylamine is with least about 90% dissolution of respective total amount.Preferably, said preparation includes the core with least one of which enteric coating coating
Core, the core include pyridoxine hydrochloride, doxylamine succinate and following inactive excipient：Filler or binding agent, collapse
Solution agent, lubricant, silica flow conditioner and stabilizer.
Duchesnay Inc patent application CN104136004A discloses a kind of while with rapid release and the dual release action of slow release
Doxylamine succinate pyridoxine hydrochloride oral formulations, embodiment tablet composition include：Slow release label succinic acid containing 7.5mg is more
Hila is quick, 7.5mg pyridoxine hydrochlorides, rapid release label doxylamine succinate containing 2.5mg, 2.5mg pyridoxine hydrochlorides.
CN103432126A discloses a kind of pharmaceutical composition for treating morning sickness, containing doxylamine succinate (1-50mg/ grains) or
Further contain benadon, oral formulations, including enteric coated tablet, capsule are made together with pharmaceutically acceptable adjuvant.
WO2013082706 discloses a kind of oral sustained release compositionss without disintegrating agent, including label and enteric coat layer, uses
II devices of USP Type are determined under the conditions of stir speed (S.S.) 100rpm, pH6.5 phosphate buffered solution 900mL, in 20 minutes
Drug-eluting rate about 95%；Active component includes：Doxylamine and/or pyridoxine hydrochloride, content are each 10mg.
Inventor has found that the doxylamine succinate pyridoxine hydrochloride enteric coatel tablets of above-mentioned prior art are carrying out first 0.1N HCl (acid
Stage) when the dissolution of pH6.8 phosphate buffers (alkali stage) is tested afterwards, which discharges very slow in the alkali stage, the release of 1h
Degree can only achieve 50% or so, and when the dissolution test in alkali stage is directly carried out without acid phase, then normally comparatively fast can discharge,
The release of 1h can reach more than 70%；But tablet first must enter back into the neutral environment of small intestinal, class in vivo Jing after gastric acid environment
The dissolution test process in alkali stage after first acid phase above is similar to, if enteric coatel tablets can not be in alkali rank after formerly experiencing sour environment
Section dissolution well, will necessarily affect the fast onset of drug effect.Occur such case may the reason for be, some medicines and enteric
The carboxyl of material can occur complexation, and in acid in the immersion process of 2 hours, the infiltration of moisture content makes the raw material and enteric of piece core inner
Material complexation forms the material for not readily dissolving, so as to affect release.
The content of the invention
In order to solve the above-mentioned deficiency of the prior art of doxylamine succinate pyridoxine hydrochloride enteric coatel tablets, it is an object of the invention to
Quick release, process is simple, good stability compound recipe amber is remained in alkali stage dissolution medium after a kind of experience acid phase is provided
Amber acid doxylamine pyridoxine hydrochloride enteric tablet medicament composition and preparation method thereof.
The present invention is realized by following technological means：
The doxylamine succinate pyridoxine hydrochloride enteric tablet medicament composition that the present invention is provided, its described enteric coatel tablets are by containing succinum
The label of sour doxylamine, pyridoxine hydrochloride and pharmaceutic adjuvant and the first contagion gown being wrapped in outside label, enteric coating and
Tablet made by two contagion gown layers；
In the label, the weight ratio of components of each component is：Doxylamine succinate:Pyridoxine hydrochloride:Filler:Disintegrating agent:
Lubricant:Fluidizer=5～20:5～20:80～160:1～6:2～6:0.5～2；
In first contagion gown and the second contagion gown, the weight ratio of components of each component is：Isolated material:Antiplastering aid:Disperse medium
=1～50:1～15:50～500；First contagion gown and the second contagion gown or be Ka Lekang coating powders YS-1-7472 or
8～20% aqueous solutions of YS-1-7003；
In the enteric coating, the weight ratio of components of each component is：Enteric material:Plasticizer:Antiplastering aid:Defoamer:PH regulator
Agent:Disperse medium=30～50:0.8～2:4～10:0.1～1:0.1～0.3:15～50.
Further, one or more in Microcrystalline Cellulose, Lactose, starch, Mannitol of the filler.
Further, the disintegrating agent is selected from carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, Croscarmellose Sodium
With one or more in polyvinylpolypyrrolidone.
Further, the lubricant is magnesium stearate.
Further, the fluidizer is silicon dioxide or Pulvis Talci.
Further, one or more in PVP, HPMC and PEG4000 of the isolated material.
Further, the enteric material is selected from Eudragit E udragit L, hydroxypropylmethyl cellulose phthalate
(HPMCP), one or more in acrylic resin Kollicoat MAE 100P and Ya Ke suitable 930；The plasticizer choosing
One or more from diethyl phthalate, PEG6000, PEG400 and triethyl citrate；The defoamer is two
Methyl-silicone oil；The pH adjusting agent is sodium hydroxide or sodium bicarbonate.
Further, the antiplastering aid is Pulvis Talci；Mixture of the disperse medium for water or ethanol or both.
The present invention also provides the preparation method of the doxylamine succinate pyridoxine hydrochloride enteric tablet medicament composition, including following step
Suddenly：
It is prepared by step 1. label：
(1) filler drying to moisture is less than into 4%～6% less than 1%～4%, fluidizer drying to moisture respectively at 80 DEG C；
(2) doxylamine succinate, pyridoxine hydrochloride are crushed, crosses 100 mesh sieves, it is standby；
(3) doxylamine succinate is mixed with fluidizer, crosses the dispersion of 40 mesh sieves, 1. mixing obtains mixture；
(4), in 1. pyridoxine hydrochloride being added to mixture, 2. mixing obtains mixture；
(5), in being added to mixture 2. after disintegrating agent filler equivalent dilution method being mixed 2 times, 3. mixing obtains mixture；
(6) 3. remaining filler, mixture is added in Mixers with Multi-direction Movement, rotating speed 10rpm, mixes 20min；
(7) lubricant is added to continue mixing 5min；
(8) tabletting.
Step 2. wraps the first contagion gown：
(1) weigh the isolated material of recipe quantity, antiplastering aid to be dissolved or dispersed in disperse medium, or by Ka Lekang coating powders
YS-1-7472 or YS-1-7003 are configured to the aqueous solution that concentration is 12%, more than electromagnetic agitation 2h, are allowed to fully dispersed and are obtained
Coating solution；
(2) label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomizing pressure
For 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and obtains final product bag
There are the label of contagion gown, coating weight gain 4%～5% ± 0.5%.
Step 3. is enteric coated：
(1) sodium hydroxide solution or sodium bicarbonate solution are added in enteric material under agitation, dispersed with stirring is uniform；
(2) disperse medium is added in beaker, adds plasticizer, antiplastering aid and defoamer, homogenizing 20min, gentle
The suspension is added in enteric material solution under stirring, uses；
(3) label for being surrounded by contagion gown is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C,
Atomizing pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product ECT, coating weight gain 10%～15% ± 0.5%.
Step 4. wraps the second contagion gown：
(1) weigh the isolated material of recipe quantity, antiplastering aid to be dissolved or dispersed in disperse medium, or by Ka Lekang coating powders
YS-1-7472 or YS-1-7003 are configured to the aqueous solution that concentration is 12%, more than electromagnetic agitation 2h, are allowed to fully dispersed and are obtained
Coating solution；
(2) ECT is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomization
Pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and is obtained final product
State doxylamine succinate pyridoxine hydrochloride enteric coatel tablets, coating weight gain 2.5%～4% ± 0.5%.
According to doxylamine succinate pyridoxine hydrochloride enteric tablet medicament composition made by inventive formulation and preparation method, in acid
Stage not discharge active component, after experience acid phase in the dissolution medium in alkali stage can rapid release of active composition, reached
Gastric is insoluble, and in the effect of the rapid discharge active component of enteral, overcome prior art doxylamine succinate pyridoxine hydrochloride
The defect of enteric coatel tablets；Enteric coatel tablets adjuvant of the present invention is constituted less, low cost, process is simple, using conventional tablet production equipment；
Enteric coatel tablets medicine stability of the present invention is good；It is bad anti-that enteric coatel tablets of the present invention avoid that stimulation of the doxylamine to upper digestive tract bring
Should, patient compliance is good.
Specific embodiment
Detailed description below is that the present invention is further illustrated, and is not considered as the restriction of the scope of the present invention.
The preparation of 1 doxylamine succinate pyridoxine hydrochloride piece of the present invention of embodiment
1. prepared by label：
(1000) are got the raw materials ready according to following formula：
Preparation process：
(1) starch drying to moisture is less than into 5% less than 1.5%, Pulvis Talci drying to moisture respectively at 80 DEG C；
(2) doxylamine succinate, pyridoxine hydrochloride are crushed, crosses 100 mesh sieves, it is standby；
(3) doxylamine succinate is mixed with Pulvis Talci, crosses the dispersion of 40 mesh sieves, 1. mixing obtains mixture；
(4), in 1. pyridoxine hydrochloride being added to mixture, 2. mixing obtains mixture；
(5), in being added to mixture 2. after low-substituted hydroxypropyl cellulose starch equivalent dilution method being mixed 2 times, mixing is obtained
Mixture is 3.；
(6) 3. remaining starch, mixture is added in Mixers with Multi-direction Movement, rotating speed 10rpm, mixes 20min；
(7) magnesium stearate is added to continue mixing 5min；
(8) tabletting, obtains final product label.
2. the first contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) PVP, Pulvis Talci are weighed by above-mentioned recipe quantity to be scattered in ethanol water, more than electromagnetic agitation 2h, is allowed to fill
Dispersion is obtained coating solution；
(2) label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomizing pressure
For 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and obtains final product bag
There are the label of contagion gown, coating weight gain 4.5% ± 0.5%.
3. enteric coated
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) 4% sodium hydroxide solution 5g is added in Kollicoat MAE 100P under agitation, dispersed with stirring is uniform；
(2) 33mL water is added in beaker, addition diethyl phthalate, Pulvis Talci and dimethicone, homogenizing 20min,
The suspension is added in Kollicoat MAE 100P solution under gentle stirring, uses；
(3) label for being surrounded by contagion gown is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C,
Atomizing pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product ECT, coating weight gain 13% ± 0.5%.
4. the second contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) weigh the HPMC of recipe quantity, be dissolved in ethanol water, more than electromagnetic agitation 2h, be allowed to fully dispersed system
Obtain coating solution；
(2) ECT is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, mist
Change pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product and state doxylamine succinate pyridoxine hydrochloride enteric coatel tablets, coating weight gain 3% ± 0.5%.
The preparation of 2 doxylamine succinate pyridoxine hydrochloride piece of the present invention of embodiment
1. prepared by label：
(1000) are got the raw materials ready according to following formula：
Preparation process：
(1) respectively Microcrystalline Cellulose PH102 is dried to moisture at 80 DEG C and is less than to moisture less than 3%, silicon dioxide drying
5%；
(2) doxylamine succinate, pyridoxine hydrochloride are crushed, crosses 100 mesh sieves, it is standby；
(3) doxylamine succinate is mixed with silicon dioxide, crosses the dispersion of 40 mesh sieves, 1. mixing obtains mixture；
(4), in 1. pyridoxine hydrochloride being added to mixture, 2. mixing obtains mixture；
(5), in being added to mixture 2. after carboxymethyl starch sodium Mannitol equivalent dilution method being mixed 2 times, mixing must mix
Thing is 3.；
(6) by remaining Mannitol, mixture 3., Microcrystalline Cellulose PH102 be added in Mixers with Multi-direction Movement, rotating speed 10rpm,
Mixing 20min；
(7) magnesium stearate is added to continue mixing 5min；
(8) tabletting, obtains final product label.
2. the first contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) HPMC, Pulvis Talci are weighed by above-mentioned recipe quantity to be scattered in ethanol water, more than electromagnetic agitation 2h, is allowed to
Fully dispersed prepared coating solution；
(2) label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomizing pressure
For 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and obtains final product bag
There are the label of contagion gown, coating weight gain 4% ± 0.5%.
3. enteric coated
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) 4% sodium hydroxide solution 1.3g is added in HPMCP under agitation, dispersed with stirring is uniform；
(2) 34mL ethanol waters are added in beaker, addition PEG400, Pulvis Talci and dimethicone, homogenizing 20min,
The suspension is added in HPMCP under gentle stirring, uses；
(3) label for being surrounded by contagion gown is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C,
Atomizing pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product ECT, coating weight gain 10% ± 0.5%.
4. the second contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) weigh the PEG4000 of recipe quantity, be dissolved in ethanol water, more than electromagnetic agitation 2h, be allowed to fully dispersed
Prepared coating solution；
(2) ECT is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, mist
Change pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product and state doxylamine succinate pyridoxine hydrochloride enteric coatel tablets, coating weight gain 2.5% ± 0.5%.
The preparation of 3 doxylamine succinate pyridoxine hydrochloride piece of the present invention of embodiment
1. prepared by label：
(1000) are got the raw materials ready according to following formula：
Preparation process：
(1) at 80 DEG C respectively by Microcrystalline Cellulose PH102 be dried to moisture less than 3%, Lactose drying to moisture less than 1.5%,
Silicon dioxide drying is less than 5% to moisture；
(2) doxylamine succinate, pyridoxine hydrochloride are crushed, crosses 100 mesh sieves, it is standby；
(3) doxylamine succinate is mixed with silicon dioxide, crosses the dispersion of 40 mesh sieves, 1. mixing obtains mixture；
(4), in 1. pyridoxine hydrochloride being added to mixture, 2. mixing obtains mixture；
(5), in being added to mixture 2. after Croscarmellose Sodium Lactose equivalent dilution method being mixed 2 times, mixing is obtained
Mixture is 3.；
(6) by remaining Lactose, mixture 3., Microcrystalline Cellulose PH102 be added in Mixers with Multi-direction Movement, rotating speed 10rpm,
Mixing 20min；
(7) magnesium stearate is added to continue mixing 5min；
(8) tabletting, obtains final product label.
2. the first contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Ka Lekang coating powder YS-1-7472 7.5g
Water 55mL
Operating procedure：
(1) Ka Lekang coating powder YS-1-7472 are weighed by recipe quantity and is configured to the aqueous solution that concentration is 12%, electromagnetic agitation 2h
More than, it is allowed to fully dispersed prepared coating solution；
(2) label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomizing pressure
For 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and obtains final product bag
There are the label of contagion gown, coating weight gain 4.5% ± 0.5%.
3. enteric coated
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) by 4% sodium hydroxide in the case of stirring, it is added in Eudragit E udragit L30D-55；
(2) add water in beaker, add triethyl citrate and Pulvis Talci, simethicone, homogenizing 20min, gentle
Stirring under the suspension is added in Eudragit RS 100, with before cross 60 mesh sieves；
(3) label for being surrounded by contagion gown is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C,
Atomizing pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product ECT, coating weight gain 12.5% ± 0.5%.
4. the second contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Ka Lekang coating powder YS-1-7003 8.5g
Water 62.5mL
Operating procedure：
(1) Ka Lekang coating powder YS-1-7003 are weighed by recipe quantity and is configured to the aqueous solution that concentration is 12%, electromagnetic agitation 2h
More than, it is allowed to fully dispersed prepared coating solution；
(2) label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, and atomizing pressure is
0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid to be coated charging is finished, obtain final product be surrounded by every
From the label of clothing, coating weight gain 3% ± 0.5%.
The preparation of 4 doxylamine succinate pyridoxine hydrochloride piece of the present invention of embodiment
1. prepared by label：
(1000) are got the raw materials ready according to following formula：
Preparation process：
(1) starch drying to moisture is less than into 5% less than 1.5%, silicon dioxide drying to moisture respectively at 80 DEG C；
(2) doxylamine succinate, pyridoxine hydrochloride are crushed, crosses 100 mesh sieves, it is standby；
(3) doxylamine succinate is mixed with silicon dioxide, crosses the dispersion of 40 mesh sieves, 1. mixing obtains mixture；
(4), in 1. pyridoxine hydrochloride being added to mixture, 2. mixing obtains mixture；
(5), in being added to mixture 2. after polyvinylpolypyrrolidone Mannitol equivalent dilution method being mixed 2 times, mixing obtains mixture
③；
(6) by remaining Mannitol, mixture 3., starch be added in Mixers with Multi-direction Movement, rotating speed 10rpm, mix 20min；
(7) magnesium stearate is added to continue mixing 5min；
(8) tabletting, obtains final product label.
2. the first contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) PVP, Pulvis Talci are weighed by above-mentioned recipe quantity to be scattered in ethanol water, more than electromagnetic agitation 2h, is allowed to fill
Dispersion is obtained coating solution；
(2) label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomizing pressure
For 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and obtains final product bag
There are the label of contagion gown, coating weight gain 5% ± 0.5%.
3. enteric coated
(1000) are got the raw materials ready according to following formula：
Suitable 930 50g of Ya Ke
Water 50ml
Operating procedure：
(1) refined gram suitable 930 is weighed by above-mentioned recipe quantity to be dispersed in water, more than electromagnetic agitation 2h, be allowed to fully dispersed and be obtained
Coating solution, uses；
(3) label for being surrounded by contagion gown is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C,
Atomizing pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished,
Obtain final product ECT, coating weight gain 15% ± 0.5%.
4. the second contagion gown is wrapped
(1000) are got the raw materials ready according to following formula：
Operating procedure：
(1) weigh the HPMC of recipe quantity, be dissolved in ethanol water, more than electromagnetic agitation 2h, be allowed to fully dispersed system
Obtain coating solution；
(2) ECT is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomization
Pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, and is obtained final product
State doxylamine succinate pyridoxine hydrochloride enteric coatel tablets, coating weight gain 4% ± 0.5%.
5 vitro release of embodiment is tested
In order to investigate the enteric effect of the present invention, according to《2010 editions second annex XD drug release determination methods of Chinese Pharmacopoeia》In
The second method (be used for enteric coated preparation), studied as follows：
This product is taken, is respectively placed in the glass tubing of lift disintegration tester, checked in 0.1mol/L hydrochloric acid solutions, stop after 120 minutes
Only, this product, observation are taken out.Then hanging basket is taken out, after being washed with a small amount, often pipe adds 1 piece of plate washer, then slow in phosphate
Rush and checked in liquid (pH6.8).Disintegration inspection result such as table 1 of the embodiment sample in hydrochloric acid solution and phosphate buffer
It is shown：
Disintegration inspection result of 1 embodiment sample of table in hydrochloric acid solution and phosphate buffer
| Medium | Hydrochloric acid solution (after 120 minutes) | Phosphate buffer |
| Embodiment 1 | Without crack, disintegrate or ruckbildung | Whole disintegrates after 12 minutes |
| Embodiment 2 | Without crack, disintegrate or ruckbildung | Whole disintegrates after 11 minutes |
| Embodiment 3 | Without crack, disintegrate or ruckbildung | Whole disintegrates after 12 minutes |
| Embodiment 4 | Without crack, disintegrate or ruckbildung | Whole disintegrates after 15 minutes |
In order to further investigate the enteric effect of the present invention, according to two annex XC drug release determinations methods of Chinese Pharmacopoeia version in 2010 the
Two methods (paddle method), the release with doxylamine succinate are studied as follows as index：
Take this product, be respectively placed in turning in basket for digestion instrument, with 0.1mol/L hydrochloric acid solution 750mL as dissolution medium, rotating speed be per point
100 turns of clock, is operated in accordance with the law, and solution was taken in the 120th minute in right amount, filtration, and subsequent filtrate is used as need testing solution；Immediately above-mentioned
0.2mol/L sodium radio-phosphate,P-32 solution 250mL are added in acid solution, and pH are adjusted to 6.8 with 2mol/L hydrochloric acid or 2mol/L sodium hydroxide solutions,
Remain in operation 45 minutes, take solution in right amount, filtration, subsequent filtrate is used as need testing solution.Separately take this product appropriate, grind, it is accurate
Hunan is weighed when in the fine powder of average loading amount, above-mentioned hydrochloric acid solution and phosphate buffer is separately added into, ultrasound makes succinic acid how western
Stretching-sensitive is fully dissolved out, filtration, takes subsequent filtrate as contrast solution.Operate by quality standard.Embodiment sample in hydrochloric acid solution and
Dissolution result in phosphate buffer is as shown in table 2：
Dissolution result of 2 embodiment sample of table in hydrochloric acid solution and phosphate buffer
| Dissolution medium | Hydrochloric acid solution | Phosphate buffer |
| Dissolution time | 120 minutes | 45 minutes |
| Embodiment 1 | 1.36% | 92.73% |
| Embodiment 2 | 0.79% | 90.80% |
| Embodiment 3 | 1.05% | 93.09% |
| Embodiment 4 | 0.42% | 92.28% |
| Embodiment 5 | 0.99% | 90.40% |
In Tables 1 and 2, each embodiment is respectively provided with significant enteric feature：In hydrochloric acid solution, after 120 minutes without crack, disintegrate or
Ruckbildung, the amount for discharging doxylamine succinate are less than 10%；In phosphate buffer, whole disintegrates after 11～15 minutes,
When 45 minutes, release is more than 70%, meets requirement of the Chinese Pharmacopoeia version in 2010 to enteric coated preparation disintegration and release.
Inventor is also by carrying in CN1447694A, CN104136004A, CN103432126A, WO2013082706 description
For method be prepared for wherein each embodiment doxylamine succinate pyridoxine hydrochloride enteric coatel tablets sample, carry out together with commercially available product
Vitro release test, first directly carries out release test in pH6.8 phosphate buffers, and each sample can normally compared with quick release
Put, the release of 1h can reach more than 70% (sample of WO2013082706 can reach more than 90% in 20 minutes)；Then will
Each sample carry out first 0.1N HCl (acid phase) afterwards pH6.8 phosphate buffers (alkali stage) release test, as a result show,
They are slight in acid phase not disintegrate substantially or disintegrate, substantially not discharge active component, and after going to the alkali stage, release is slow, 1h
Release can only achieve 50% or so, with the growth of dissolution time, again can dissolution gradually, it is final after 6～8 hours about can be molten
Go out 90%.
As can be seen here, doxylamine succinate pyridoxine hydrochloride enteric coatel tablets of the present invention formerly experience after sour environment (acid phase)
Neutral environment remains to rapidly discharge active component in (alkali stage), it is ensured that the rapid performance of drug effect, its dissolution characteristic are relative
There is remarkable advantage in prior art.
Claims (9)
1. a kind of doxylamine succinate pyridoxine hydrochloride enteric tablet medicament composition, characterized in that, the enteric coatel tablets are by the label containing doxylamine succinate, pyridoxine hydrochloride and pharmaceutic adjuvant and the first contagion gown being wrapped in outside label, enteric coating and tablet made by the second contagion gown layer；
In the label, the weight ratio of components of each component is：Doxylamine succinate:Pyridoxine hydrochloride:Filler:Disintegrating agent:Lubricant:Fluidizer=5～20:5～20:80～160:1～6:2～6:0.5～2；
In first contagion gown and the second contagion gown, the weight ratio of components of each component is：Isolated material:Antiplastering aid:Disperse medium=1～50:1～15:50～500；First contagion gown and the second contagion gown or 8～20% aqueous solutions for Ka Lekang coating powder YS-1-7472 or YS-1-7003；
In the enteric coating, the weight ratio of components of each component is：Enteric material:Plasticizer:Antiplastering aid:Defoamer:PH adjusting agent:Disperse medium=30～50:0.8～2:4～10:0.1～1:0.1～0.3:15～50.
2. compositionss as claimed in claim 1, it is characterised in that one or more in Microcrystalline Cellulose, Lactose, starch, Mannitol of the filler.
3. compositionss as claimed in claim 1, it is characterised in that one or more in carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, Croscarmellose Sodium and polyvinylpolypyrrolidone of the disintegrating agent.
4. compositionss as claimed in claim 1, it is characterised in that the lubricant is magnesium stearate.
5. compositionss as claimed in claim 1, it is characterised in that the fluidizer is silicon dioxide or Pulvis Talci.
6. compositionss as claimed in claim 1, it is characterised in that one or more in PVP, HPMC and PEG4000 of the isolated material.
7. compositionss as claimed in claim 1, it is characterised in that the enteric material is selected from Eudragit E udragit L, hydroxypropylmethyl cellulose phthalate（HPMCP）, acrylic resin Kollicoat
One or more in MAE 100P and Ya Ke suitable 930；One or more in diethyl phthalate, PEG6000, PEG400 and triethyl citrate of the plasticizer；The defoamer is dimethicone；The pH adjusting agent is sodium hydroxide or sodium bicarbonate.
8. compositionss as claimed in claim 1, it is characterised in that the antiplastering aid is Pulvis Talci；Mixture of the disperse medium for water or ethanol or both.
9. the method for preparing the doxylamine succinate pyridoxine hydrochloride enteric tablet medicament composition as any one of claim 1～8, it is characterised in that comprise the following steps：
（1）It is prepared by label：
（1.1）Filler drying to moisture is less than into 4%～6% less than 1%～4%, fluidizer drying to moisture respectively at 80 DEG C；
（1.2）Doxylamine succinate, pyridoxine hydrochloride are crushed, 100 mesh sieves are crossed, it is standby；
（1.3）Doxylamine succinate is mixed with fluidizer, the dispersion of 40 mesh sieves is crossed, 1. mixing obtains mixture；
（1.4）During 1. pyridoxine hydrochloride is added to mixture, 2. mixing obtains mixture；
（1.5）In being added to mixture 2. after disintegrating agent filler equivalent dilution method is mixed 2 times, 3. mixing obtains mixture；
（1.6）3. remaining filler, mixture is added in Mixers with Multi-direction Movement, rotating speed 10rpm, mixes 20min；
（1.7）Lubricant is added to continue mixing 5min；
（1.8）Tabletting；
（2）Wrap the first contagion gown：
（2.1）Weigh the isolated material of recipe quantity, antiplastering aid to be dissolved or dispersed in disperse medium, or Ka Lekang coating powder YS-1-7472 or YS-1-7003 are configured to into the aqueous solution that concentration is 12%, more than electromagnetic agitation 2h, be allowed to fully dispersed prepared coating solution；
（2.2）Label is added in coating pan, it is 60 DEG C to adjust inlet temperature, and piece bed tempertaure is 30～35 DEG C, atomizing pressure is 0.25MPa, and coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, liquid charging to be coated is finished, and obtains final product the label for being surrounded by contagion gown, coating weight gain 4%～5% ± 0.5%；
（3）It is enteric coated：
（3.1）Sodium hydroxide solution or sodium bicarbonate solution are added in enteric material under agitation, dispersed with stirring is uniform；
（3.2）Disperse medium is added in beaker, plasticizer, antiplastering aid and defoamer, homogenizing 20min is added, the suspension is added in enteric material solution under gentle stirring, used；
（3.3）The label for being surrounded by contagion gown is added in coating pan, it is 60 DEG C to adjust inlet temperature, piece bed tempertaure is 30～35 DEG C, atomizing pressure is 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, obtain final product ECT, coating weight gain 10%～15% ± 0.5%；
（4）Wrap the second contagion gown：
（4.1）Weigh the isolated material of recipe quantity, antiplastering aid to be dissolved or dispersed in disperse medium, or Ka Lekang coating powder YS-1-7472 or YS-1-7003 are configured to into the aqueous solution that concentration is 12%, more than electromagnetic agitation 2h, be allowed to fully dispersed prepared coating solution；
（4.2）ECT is added in coating pan, it is 60 DEG C to adjust inlet temperature, piece bed tempertaure is 30～35 DEG C, atomizing pressure is 0.25MPa, coating pan rotating speed is 10～30rph, and sample introduction flow velocity is 3～8g/min, and liquid charging to be coated is finished, obtain final product and state doxylamine succinate pyridoxine hydrochloride enteric coatel tablets, coating weight gain 2.5%～4% ± 0.5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510705249.7A CN106606502B (en) | 2015-10-27 | 2015-10-27 | Doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510705249.7A CN106606502B (en) | 2015-10-27 | 2015-10-27 | Doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106606502A true CN106606502A (en) | 2017-05-03 |
| CN106606502B CN106606502B (en) | 2019-12-31 |
Family
ID=58615197
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510705249.7A Active CN106606502B (en) | 2015-10-27 | 2015-10-27 | Doxylamine succinate and pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106606502B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112839638A (en) * | 2018-09-27 | 2021-05-25 | 益利巴萨妇科股份公司 | Method for preparing a sustained release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride |
| CN115078556A (en) * | 2021-03-11 | 2022-09-20 | 远大生命科学(武汉)有限公司 | Method for simultaneously determining content of doxylamine and content of pyridoxine |
| WO2022254277A1 (en) * | 2021-05-31 | 2022-12-08 | Maneesh Pharmaceuticals Ltd | Extended release composition and its process for the preparation |
| CN115697311A (en) * | 2020-03-25 | 2023-02-03 | 意大发马克股份公司 | Modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406656A (en) * | 2011-11-21 | 2012-04-11 | 南开大学 | Sodium bicarbonate enteric-coated tablet and preparation method thereof |
| CN103432126A (en) * | 2013-08-05 | 2013-12-11 | 北京阜康仁生物制药科技有限公司 | Drug composition for treating vomiting during pregnancy |
-
2015
- 2015-10-27 CN CN201510705249.7A patent/CN106606502B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406656A (en) * | 2011-11-21 | 2012-04-11 | 南开大学 | Sodium bicarbonate enteric-coated tablet and preparation method thereof |
| CN103432126A (en) * | 2013-08-05 | 2013-12-11 | 北京阜康仁生物制药科技有限公司 | Drug composition for treating vomiting during pregnancy |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112839638A (en) * | 2018-09-27 | 2021-05-25 | 益利巴萨妇科股份公司 | Method for preparing a sustained release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride |
| CN112839638B (en) * | 2018-09-27 | 2023-12-19 | 意大发马克股份公司 | Method for preparing sustained release multi-unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride |
| CN115697311A (en) * | 2020-03-25 | 2023-02-03 | 意大发马克股份公司 | Modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and preparation method thereof |
| CN115078556A (en) * | 2021-03-11 | 2022-09-20 | 远大生命科学(武汉)有限公司 | Method for simultaneously determining content of doxylamine and content of pyridoxine |
| CN115078556B (en) * | 2021-03-11 | 2023-10-24 | 远大生命科学(武汉)有限公司 | Method for simultaneously measuring content of doxylamine and pyridoxine |
| WO2022254277A1 (en) * | 2021-05-31 | 2022-12-08 | Maneesh Pharmaceuticals Ltd | Extended release composition and its process for the preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106606502B (en) | 2019-12-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11975105B2 (en) | Modified release composition of orlistat and acarbose for the treatment of obesity and related metabolic disorders | |
| JP2021167343A (en) | Palbociclib solid dosage form | |
| EP1239857B1 (en) | Dual-release compositions of a cyclooxygenase-2- inhibitor | |
| CN105263498B (en) | Xenicviro compositions and methods of making and using the same | |
| JP2020063292A (en) | Capsule and powder formulations containing lanthanum compounds | |
| SK9022002A3 (en) | Sustained-release formulation of a cyclooxygenase-2 inhibitor | |
| MX2010009704A (en) | Modified release pharmaceutical compositions comprising mycophenolate and processes thereof. | |
| JP2004501099A (en) | Aldosterone antagonist composition for release during aldosterone vertex phase | |
| CN106606502A (en) | Doxylamine succinate-pyridoxine hydrochloride enteric-coated tablet pharmaceutical composition and preparation method thereof | |
| WO2021041608A1 (en) | System and method of multi-drug delivery | |
| CN112618505B (en) | Compound pharmaceutical composition containing benazepril and pimobendan for pets and preparation method thereof | |
| CN102008449B (en) | Lansoprazole enteric pellet and preparation method thereof | |
| CN102283816B (en) | Silodosin sustained-release tablet and preparation method thereof | |
| CN106456611A (en) | Ondansetron extended release solid dosage forms for treating either nausea, vomiting or diarrhea symptoms | |
| CN108125918A (en) | Everolimus pharmaceutical composition | |
| EP4193991A1 (en) | Obizidine fumarate enteric-coated pill, preparation method therefor and use thereof | |
| CN103432126A (en) | Drug composition for treating vomiting during pregnancy | |
| CN102579453A (en) | Compound preparation for treating gastric ulcer and preparation method of same | |
| CN102846571A (en) | Esomeprazole magnesium micro-tablet | |
| US20070202170A1 (en) | Dual-release compositions of a cyclooxygenase-2 inhibitor | |
| KR20120137998A (en) | A dosage form with increased stability comprising tamsulosin and finasteride | |
| CN106983752A (en) | A kind of preparation method of valsartan and Hydrochlorothiade capsule | |
| CN106822047A (en) | A kind of microporous barrier controlled release coat Desloratadine micropill and preparation method thereof | |
| CN115887399A (en) | Selipacard tablet and preparation method thereof | |
| CN107510696A (en) | For treating the pharmaceutical composition of NASH |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |