CN117398360B - Compound preparation capsule for treating helicobacter pylori and preparation method thereof - Google Patents
Compound preparation capsule for treating helicobacter pylori and preparation method thereof Download PDFInfo
- Publication number
- CN117398360B CN117398360B CN202311713149.XA CN202311713149A CN117398360B CN 117398360 B CN117398360 B CN 117398360B CN 202311713149 A CN202311713149 A CN 202311713149A CN 117398360 B CN117398360 B CN 117398360B
- Authority
- CN
- China
- Prior art keywords
- parts
- micro
- rifabutin
- adhesive
- amoxicillin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 57
- 239000002775 capsule Substances 0.000 title claims abstract description 40
- 241000590002 Helicobacter pylori Species 0.000 title claims abstract description 37
- 229940037467 helicobacter pylori Drugs 0.000 title claims abstract description 37
- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- MQEUGMWHWPYFDD-UHFFFAOYSA-N magnesium;6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1h-benzimidazole Chemical compound [Mg].N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C MQEUGMWHWPYFDD-UHFFFAOYSA-N 0.000 claims abstract description 75
- 229960003117 omeprazole magnesium Drugs 0.000 claims abstract description 75
- 229960000885 rifabutin Drugs 0.000 claims abstract description 74
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 claims abstract description 73
- 229960003022 amoxicillin Drugs 0.000 claims abstract description 66
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims abstract description 65
- 239000000853 adhesive Substances 0.000 claims abstract description 64
- 230000001070 adhesive effect Effects 0.000 claims abstract description 64
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 28
- 229920000881 Modified starch Polymers 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 25
- 239000000314 lubricant Substances 0.000 claims abstract description 22
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 14
- 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 abstract description 13
- 229930195725 Mannitol Natural products 0.000 claims abstract description 13
- 239000000594 mannitol Substances 0.000 claims abstract description 13
- 235000010355 mannitol Nutrition 0.000 claims abstract description 13
- 230000003113 alkalizing effect Effects 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- 239000011248 coating agent Substances 0.000 claims description 57
- 238000000576 coating method Methods 0.000 claims description 57
- 239000002245 particle Substances 0.000 claims description 28
- 239000000463 material Substances 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 21
- 238000002955 isolation Methods 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- 238000005507 spraying Methods 0.000 claims description 17
- 238000009826 distribution Methods 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 230000004584 weight gain Effects 0.000 claims description 12
- 235000019786 weight gain Nutrition 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 11
- 239000007888 film coating Substances 0.000 claims description 9
- 238000009501 film coating Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 239000012055 enteric layer Substances 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical group CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 229960003194 meglumine Drugs 0.000 claims description 7
- 238000000889 atomisation Methods 0.000 claims description 6
- 238000007599 discharging Methods 0.000 claims description 6
- 238000003825 pressing Methods 0.000 claims description 6
- 238000007873 sieving Methods 0.000 claims description 6
- 235000020985 whole grains Nutrition 0.000 claims description 6
- 108010010803 Gelatin Proteins 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 229920000159 gelatin Polymers 0.000 claims description 5
- 239000008273 gelatin Substances 0.000 claims description 5
- 235000019322 gelatine Nutrition 0.000 claims description 5
- 235000011852 gelatine desserts Nutrition 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 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 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000004090 dissolution Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 239000011230 binding agent Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 239000006160 differential media Substances 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 3
- 229910052797 bismuth Inorganic materials 0.000 description 3
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 230000008029 eradication Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940126409 proton pump inhibitor Drugs 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229960000282 metronidazole Drugs 0.000 description 2
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 2
- 229940106827 pylera Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- -1 amoxicillin rifabutin compound Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- KWORUUGOSLYAGD-UHFFFAOYSA-N magnesium 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]benzimidazol-1-ide Chemical compound [Mg+2].N=1C2=CC(OC)=CC=C2[N-]C=1S(=O)CC1=NC=C(C)C(OC)=C1C.N=1C2=CC(OC)=CC=C2[N-]C=1S(=O)CC1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-UHFFFAOYSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229940083575 sodium dodecyl sulfate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of helicobacter pylori treatment medicines, in particular to a compound preparation capsule for treating helicobacter pylori and a preparation method thereof. The invention comprises amoxicillin rifabutin micro-tablets and omeprazole magnesium enteric-coated micro-tablets, wherein the amoxicillin rifabutin micro-tablets comprise 250-330 parts of amoxicillin, 9-15 parts of rifabutin, 10-25 parts of pregelatinized starch, 6-18 parts of adhesive and 1-6 parts of lubricant; the omeprazole magnesium enteric coated micro-tablet comprises 7-13 parts of omeprazole magnesium, 70-90 parts of mannitol, 70-90 parts of pregelatinized starch, 5-15 parts of adhesive, 5-15 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant. The preparation method solves the problems of insufficient content and low uniformity of the raw materials of the microchip, obviously improves the quality of the compound preparation capsule, is simple to operate, has stable process and is easy to amplify, convert and produce.
Description
Technical Field
The invention relates to the field of helicobacter pylori treatment medicines, in particular to a compound preparation capsule for treating helicobacter pylori and a preparation method thereof.
Background
Helicobacter pylori is a gram-negative bacterium and is often parasitized in gastric mucosal tissues, and researches prove that helicobacter pylori is a main cause of chronic gastritis, peptic gastric ulcer, gastric cancer and gastric mucosa-related lymphoid tissue lymphoma. In 2017, the world health organization International cancer research Institute (IARC) has listed helicobacter pylori in a list of carcinogens, and related reports have shown that the risk of developing gastric cancer for helicobacter pylori infected persons can be increased 2 to 3 times over normal persons. It follows that there is a great hazard from helicobacter pylori infection, which is becoming more of a concern as public attention is paid to health care.
The accepted standard of care for eradicating H.pylori is clarithromycin-based triple therapy or bismuth-agent-based quadruple therapy. Triple therapy has been largely abandoned due to its resistance. Bismuth-based tetrad therapy comprises proton pump inhibitor + bismuth agent + two antibiotics, and the current global latest formulation is a united package drug of Pylera (bismuth agent + metronidazole + tetracycline hydrochloride capsule) obtained in the united states, which contains metronidazole, also has drug resistance risk, and has reduced curative effect over time, and the Pylera + proton pump inhibitor needs to be taken simultaneously, so that the medical cost is high and the patient compliance is poor; the medicine used in the disease treatment field increases with the medicine resistance, the curative effect is reduced, the patient faces the risk of medicine free and medical treatment, and the helicobacter pylori patient needs a new medicine with low medicine resistance rate and good curative effect for treatment.
Omeprazole magnesium amoxicillin rifabutin enteric capsule, the first helicobacter pylori therapy using the antibiotic rifabutin, combined with two antibiotics rifabutin and amoxicillin, and Proton Pump Inhibitor (PPI) omeprazole. First developed by REDHILL BIOPHARMA LTD (trade name TALICIA), first obtained in FDA at 11 in 2019 and marketed in the united states at 3 in 2020. Clinical study in patients following strictly course of treatment without skip of administration, the eradication rate of TALICIA H.pylori was 90.3% (95% CI: 85.5-93.7), and the resistance to rifabutin was 0%. The invention patent CN109893516A discloses a pharmaceutical composition for treating helicobacter pylori, and relates to a preparation method of a prescription of amoxicillin rifabutin micro-tablets, and experiments in the early stage of the invention find that the content uniformity of amoxicillin and rifabutin in pressed micro-tablets is not up to standard and the content uniformity of omeprazole magnesium enteric-coated micro-tablets is not up to standard because of wider particle size distribution; the diameter of the microchip is 2mm, the compression of the microchip has extremely high requirements on the powder properties of materials, and compared with the common tablet, the microchip belongs to the non-conventional material properties, the flowability, the compressibility and the particle size distribution range of the materials directly determine the quality of the microchip and the feasibility of industrial production, and the amoxicillin in the variety is larger, the granulating is difficult, and the prescription process difficulty is larger.
Disclosure of Invention
The invention aims to solve the technical problems of providing a compound preparation capsule for treating helicobacter pylori and a preparation method thereof, and solves the problems of insufficient content and low uniformity of microchip medicine raw materials in the capsule by improving the preparation process on the basis of ensuring high helicobacter pylori eradication rate and low drug resistance, thereby remarkably improving the quality of the compound preparation capsule.
The invention is realized by the following technical scheme:
the compound preparation capsule for treating helicobacter pylori comprises amoxicillin rifabutin micro tablets and omeprazole magnesium enteric micro tablets, wherein the amoxicillin rifabutin micro tablets comprise the following raw materials in parts by weight: 250-330 parts of amoxicillin, 9-15 parts of rifabutin, 10-25 parts of pregelatinized starch, 6-18 parts of adhesive and 1-6 parts of lubricant;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 7-13 parts of omeprazole magnesium, 70-90 parts of mannitol, 70-90 parts of pregelatinized starch, 5-15 parts of adhesive, 5-15 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant;
the particle size distribution D90 of rifabutin in the amoxicillin rifabutin micro-tablet is 10-50 mu m, and the particle size distribution D90 of omeprazole magnesium in the omeprazole magnesium enteric-coated micro-tablet is 0.1-20 mu m.
Preferably, the amoxicillin rifabutin micro-tablet comprises the following raw materials in parts by weight: 260-320 parts of amoxicillin, 10-14 parts of rifabutin, 10-25 parts of pregelatinized starch, 6-18 parts of adhesive and 1-6 parts of lubricant;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 7.5-12.5 parts of omeprazole magnesium, 70-90 parts of mannitol, 70-90 parts of pregelatinized starch, 5-15 parts of adhesive, 5-15 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant;
the particle size distribution D90 of rifabutin in the amoxicillin rifabutin micro-tablet is 12-48 mu m, and the particle size D90 of omeprazole magnesium in the omeprazole magnesium enteric-coated micro-tablet is 0.5-19.5 mu m.
Preferably, the amoxicillin rifabutin micro-tablet comprises the following raw materials in parts by weight: 287 parts of amoxicillin, 12.5 parts of rifabutin, 12-23 parts of pregelatinized starch, 7-17 parts of adhesive and 1.5-5.5 parts of lubricant;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 10.3 parts of omeprazole magnesium, 73-87 parts of mannitol, 73-87 parts of pregelatinized starch, 6-14 parts of adhesive, 6-14 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant.
Preferably, the omeprazole magnesium enteric micro-tablet further comprises an inner barrier coating, an enteric layer coating and an outer barrier coating; based on the weight of the micro tablet, the weight of the inner isolation coating is increased by 6-10 wt%, the weight of the enteric coating is increased by 20-26 wt%, and the weight of the outer isolation coating is increased by 5-9 wt%.
Preferably, the binder is a cellulosic binder, preferably hydroxypropyl cellulose or hypromellose, further preferably hydroxypropyl cellulose; and/or
The disintegrating agent is at least one of crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose, preferably crospovidone; and/or
The alkalizing agent is at least one of meglumine and sodium bicarbonate, preferably meglumine; and/or
The lubricant is at least one of talcum powder, stearic acid, sodium stearate and magnesium stearate, preferably magnesium stearate.
Preferably, the amoxicillin rifabutin micro-tablet comprises the following raw materials in parts by weight: 287 parts of amoxicillin, 12.5 parts of rifabutin, 20 parts of pregelatinized starch, 10 parts of hydroxypropyl cellulose and 3.5 parts of magnesium stearate;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 10.3 parts of omeprazole magnesium, 80 parts of mannitol, 80 parts of pregelatinized starch, 10 parts of hydroxypropyl cellulose, 10 parts of crospovidone, 5 parts of sodium dodecyl sulfate, 7 parts of meglumine and 3 parts of magnesium stearate; the omeprazole magnesium enteric-coated micro-tablet further comprises an inner isolation coating, an enteric layer coating and an outer isolation coating, wherein the inner isolation coating is increased by 8 wt%, the enteric layer coating is increased by 23 wt%, and the outer isolation coating is increased by 7 wt%, based on the mass of the micro-tablet.
The preparation method of the compound preparation capsule for treating helicobacter pylori comprises the following steps of:
the preparation method of the amoxicillin rifabutin micro-tablet comprises the following specific steps:
(1) And (3) pretreatment of an adhesive: adding water into the adhesive to prepare an adhesive water solution with the concentration of 3-5 wt.% for later use;
(2) Wet granulation: adding amoxicillin and rifabutin into a wet granulator, uniformly mixing, spraying the aqueous solution of the adhesive prepared in the step (1), and pre-granulating;
preferably, spraying the adhesive aqueous solution with the weight of 8-12 wt.% of the total weight of the adhesive aqueous solution;
(3) Granulating by a fluidized bed: transferring the preformed particles obtained in the step (2) into a fluidized bed boiler body, adjusting the air inlet quantity to keep the materials in a fluidized state, and granulating by spraying the residual adhesive aqueous solution on the top of the fluidized bed;
(4) Finishing: sieving the material obtained in the step (3) through a No. 3 pharmacopoeia sieve to obtain whole grains;
(5) Total mixing: uniformly mixing pregelatinized starch and a lubricant with the particles prepared in the step (4), and discharging;
(6) Tabletting: pressing by adopting a punch with the diameter of 1-3 mm to obtain the amoxicillin rifabutin microchip, preferably 2mm;
the preparation method of the omeprazole magnesium enteric-coated microchip comprises the following specific steps:
s1, adhesive pretreatment: dissolving omeprazole magnesium, sodium dodecyl sulfate, an alkalizing agent and an adhesive in water to obtain an adhesive mixed solution for later use;
in the adhesive mixed solution, the mass percent of the adhesive is 3-5 wt%;
s2, granulating by a fluidized bed: mannitol and pregelatinized starch are put into a fluidized bed pot body, the air inlet quantity is adjusted to keep the materials in a fluidized state, and the fluidized bed top-spraying adhesive mixed solution is granulated;
s3, finishing: sieving the material obtained in the step S2 through a No. 3 pharmacopoeia sieve to obtain whole grains;
s4, total mixing: uniformly mixing the disintegrating agent, the lubricant and the granules prepared in the step S3, and then discharging;
s5, tabletting: pressing by adopting a punch with the diameter of 1-3 mm, preferably 2mm;
s6, inner isolation coating: coating by adopting a coating solution prepared by using a Ka Le Kangou Barbary gastric-soluble film coating premix with the solid content of 8-12 wt.%, wherein the coating weight gain is 6-10 wt.% of the weight of the 1-3 mm micro tablet prepared in the step S5;
s7, coating an enteric layer: coating by adopting a coating solution with 18-22wt.% of solid content prepared by adopting a Kalercanic-Jack series enteric film coating premix, wherein the coating weight gain is 20-26wt.% of the weight of the 1-3 mm micro tablet prepared in the step S5;
s8, external isolation coating: coating by adopting a coating solution prepared from a Ka Le Kangou Barbary gastric-soluble film coating premix with the solid content of 10wt.%, wherein the coating weight is 5-9 wt.% of the weight of the 1-3 mm micro tablet prepared in the step S5, so as to obtain the omeprazole magnesium enteric-coated micro tablet;
filling 36-40 amoxicillin rifabutin micro-tablets and 32-36 omeprazole magnesium enteric micro-tablets obtained by the method into a gelatin hollow capsule of No. 00, thus obtaining the compound preparation capsule for treating helicobacter pylori;
preferably amoxicillin rifabutin micro-tablet 38 and omeprazole magnesium enteric-coated micro-tablet 34.
Preferably, the air inlet quantity of the fluidized bed is 30m 3 /h~50m 3 And/h, the air inlet temperature is 60-80 ℃, the atomization pressure is 1.0-1.5 bar, the liquid spraying amount is 6-8 mL/min, and the material temperature is 30-35 ℃.
Preferably, in the total mixing process, a hopper mixer is used for mixing, the mixing speed is 12rpm, and the mixing time is 5min.
Compared with the prior art, the invention has the following beneficial effects:
1. the amoxicillin and rifabutin micro-tablets have the advantages that the prescription ratio of amoxicillin in the amoxicillin and rifabutin micro-tablets is more than 80%, amoxicillin BCS is classified into 1 class, granules meeting the requirements of micro-tablet compression are difficult to obtain by a common granulation process, a fluidized bed granulation process is adopted, but because the amoxicillin specification is limited greatly, the prescription ratio of amoxicillin and rifabutin is relatively high, the rifabutin electrostatic adsorption is strong, the content reduction condition is easy to occur, and the problem of low raw material content can be solved by adopting a wet granulator pre-granulation mode.
2. The omeprazole magnesium enteric-coated micro-tablets are usually smaller in diameter, extremely high in requirement on particle size distribution of micro-tablet intermediate particles, difficult to meet the requirement on general dry granulation, and strong in operability of a conventional wet granulation laboratory, but difficult to produce and transfer, and often difficult to obtain particles meeting the requirements of micro-tablet compression.
3. In the preparation method of the capsule, prescription auxiliary materials are easy to obtain and low in cost, and the dissolution curve of the product is similar to that of the original developing agent, so that the success rate of bioequivalence is greatly improved; solves the problems of difficult granulation and easy degradation of the amoxicillin rifabutin compound micro-tablet and the omeprazole magnesium enteric-coated micro-tablet by wet granulation, and has the characteristics of simple process, stable finished product property and suitability for micro-tablet mass production; the required production equipment is conventional equipment, so that the cost is saved, and the production possibility is improved.
4. The compound preparation capsule for treating helicobacter pylori overcomes the difficulty of antibiotic drug resistance, improves the eradication rate of helicobacter pylori, provides a new choice for clinical patients to radically treat diseases caused by helicobacter pylori, and improves the administration compliance of patients by taking only one drug.
Drawings
FIG. 1, example 6, compared with the original developer, shows that amoxicillin dissolves in a differential medium;
FIG. 2, example 6, compared to the original formulation, the dissolution of rifabutin in a differential medium;
FIG. 3, example 6, shows the dissolution of omeprazole magnesium in a medium at pH1.0+ pH6.0 in comparison with the original formulation;
FIG. 4, example 6, shows the dissolution of omeprazole magnesium in a medium at pH1.0+pH6.8, compared to the original formulation.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. The original formulation was developed by REDHILL BIOPHARMA LTD company as TALICIA, approved by the FDA in 2019.
Example 1
The compound preparation capsule for treating helicobacter pylori comprises amoxicillin rifabutin micro-tablets and omeprazole magnesium enteric-coated micro-tablets, and the raw materials of the compound preparation capsule comprise the following raw materials in parts by weight, and the raw materials are shown in a table 1.
The particle size distribution D90 of the rifabutin is 10-50 mu m, and the particle size D90 of the omeprazole magnesium is 0.1-20 mu m.
The preparation method of the compound preparation capsule for treating helicobacter pylori comprises the following steps of:
the preparation method of the amoxicillin rifabutin micro-tablet comprises the following specific steps:
(1) And (3) pretreatment of an adhesive: adding water into the adhesive to prepare an adhesive water solution with the mass percent of 4wt.% for later use;
(2) Wet granulation: adding amoxicillin and rifabutin into a wet granulator, uniformly mixing, spraying the aqueous solution of the adhesive prepared in the step (1), and pre-granulating;
spraying an aqueous binder solution in an amount of 10wt.% based on the total weight of the aqueous binder solution;
(3) Granulating by a fluidized bed: transferring the preformed particles obtained in the step (2) into a fluidized bed boiler body, adjusting the air inlet quantity to keep the materials in a fluidized state, and granulating by spraying the residual adhesive aqueous solution on the top of the fluidized bed;
the air inlet quantity of the fluidized bed is 40m 3 The inlet air temperature is 70 ℃, the atomization pressure is 1.25bar, the spray amount is 7mL/min, and the material temperature is 32.5 ℃;
(4) Finishing: sieving the material obtained in the step (3) through a No. 3 pharmacopoeia sieve to obtain whole grains;
(5) Total mixing: uniformly mixing pregelatinized starch, a lubricant and the particles prepared in the step (4) in a hopper mixer, discharging, and mixing at a speed of 12rpm for 5min;
(6) Tabletting: and pressing by adopting a punch with the diameter of 2mm to obtain the amoxicillin rifabutin micro-tablet.
The preparation method of the omeprazole magnesium enteric-coated microchip comprises the following specific steps:
s1, adhesive pretreatment: dissolving omeprazole magnesium, sodium dodecyl sulfate, an alkalizing agent and an adhesive in water to obtain an adhesive mixed solution for later use;
in the adhesive mixed solution, the mass percent of the adhesive is 4wt.%;
s2, granulating by a fluidized bed: mannitol and pregelatinized starch are put into a fluidized bed pot body, the air inlet quantity is adjusted to keep the materials in a fluidized state, and the fluidized bed top-spraying adhesive mixed solution is granulated;
the air inlet quantity of the fluidized bed is 40m 3 The inlet air temperature is 70 ℃, the atomization pressure is 1.25bar, the spray amount is 7mL/min, and the material temperature is 32.5 ℃;
s3, finishing: sieving the material obtained in the step S2 through a No. 3 pharmacopoeia sieve to obtain whole grains;
s4, total mixing: uniformly mixing the disintegrating agent, the lubricant and the granules prepared in the step S3 in a hopper mixer, discharging, and mixing at a speed of 12rpm for 5min;
s5, tabletting: pressing by adopting a punch with the diameter of 2mm;
s6, inner isolation coating: coating by adopting a coating solution prepared by using a Ka Le Kangou Barbary gastric-soluble film coating premix with the solid content of 10wt.%, wherein the coating weight gain is 8wt.% of the weight of the 2mm micro tablet prepared in the step S5;
s7, coating an enteric layer: coating by adopting a coating solution with 20wt.% of solid content prepared by a Kalercanic-Jack series enteric film coating premix, wherein the coating weight gain is 23wt.% of the weight of the 2mm micro tablet prepared in the step S5;
s8, external isolation coating: coating by adopting a coating solution prepared by adopting a Ka Le Kangou Barbary gastric-soluble film coating premix with the solid content of 10wt.%, wherein the coating weight gain is 7wt.% of the weight of the 2mm micro-tablet prepared in the step S5, and thus the omeprazole magnesium enteric-coated micro-tablet can be obtained.
And filling the amoxicillin rifabutin micro-tablet 38 and omeprazole magnesium enteric micro-tablet 34 obtained in the above way into a gelatin hollow capsule of No. 00, thus obtaining the compound preparation capsule for treating helicobacter pylori.
TABLE 1
Examples 2 to 6
The preparation method of the compound preparation capsule for treating helicobacter pylori of the invention refers to the example 1, except that: the raw material compositions of the amoxicillin rifabutin micro-tablet and the omeprazole magnesium enteric micro-tablet are shown in table 2 in parts by weight.
TABLE 2
Further, the quality of the amoxicillin rifabutin micro-tablet and the omeprazole magnesium enteric-coated micro-tablet prepared in example 6 is evaluated, and the results are shown in table 3 and table 4 respectively; example 6 is compared with the original developer, and the dissolution condition in the medium is distinguished, as shown in fig. 1-4, and fig. 1 is the dissolution condition of amoxicillin in the medium is distinguished in comparison of example 6 with the original developer; FIG. 2 is a graph showing the dissolution of rifabutin in a differential medium as compared to the original formulation of example 6; FIG. 3 shows the dissolution of magnesium omeprazole in a medium at pH1.0+ pH6.0 in comparison with the original formulation of example 6; FIG. 4 shows the dissolution of omeprazole magnesium in a medium at pH1.0+ pH6.8, in comparison to the original formulation of example 6.
Table 3 example 6 amoxicillin rifabutin microtablet quality evaluation
Table 4 example 6 evaluation of quality of omeprazole magnesium enteric-coated micro-tablets
Examples 7 to 9
With reference to example 6, the difference is: the particle size distribution of rifabutin and omeprazole magnesium is shown in table 5.
TABLE 5
Omeprazole magnesium and rifabutin are classified as BCS class 2, and the particle size influences the solubility of the bulk drug and further influences the release and absorption in vivo; the particle size ranges of the rifabutin and the omeprazole magnesium are obtained through experiments, the particle size D90 of the omeprazole magnesium is 0.1-20 mu m, the particle size distribution D90 of the rifabutin is 10-50 mu m, and the in vitro dissolution curve is similar to that of the original preparation.
Examples 10 to 13
Reference example 6, except that the enteric coated microtablets of omeprazole magnesium had a weight gain as shown in table 6.
TABLE 6
The weight gain of the inner isolation coating, the enteric coating and the outer isolation coating can influence the acid resistance of the omeprazole magnesium enteric micro-tablet in a pH1.0 medium, further influence the dissolution condition in a differential medium, and the weight gain of the inner isolation coating, the weight gain of the enteric coating and the weight gain of the outer isolation coating are 5-10 wt.%, 20-25 wt.% and 5-10 wt.% respectively, so that the dissolution curve of the self-product is similar to that of the original developer.
Examples 14 to 17
The preparation method of the compound preparation capsule for treating helicobacter pylori of the invention refers to the example 1, except that: the preparation process parameters, the raw material compositions of the amoxicillin rifabutin micro-tablet and the omeprazole magnesium enteric micro-tablet are shown in table 7 in parts by weight.
TABLE 7
In examples 14-15, in the preparation step (2) of amoxicillin rifabutin micro-tablets, spraying an aqueous binder solution with a weight of 8wt.% of the total weight of the aqueous binder solution; in the preparation step S1 of the omeprazole magnesium enteric-coated microchip, the mass percentage of the adhesive in the adhesive mixed solution is 3 wt%;
the air inlet quantity of the fluidized bed is 50m 3 The air inlet temperature is 80 ℃, the atomization pressure is 1.5bar, the liquid spraying amount is 8mL/min, and the material temperature is 35 ℃;
and filling the obtained 36 pieces of amoxicillin rifabutin micro-tablets with the size of 1mm and 32 pieces of omeprazole magnesium enteric micro-tablets with the size of 1mm into a gelatin hollow capsule with the size of 00, thus obtaining the compound preparation capsule for treating helicobacter pylori.
In examples 16-17, in the preparation step (2) of amoxicillin rifabutin micro-tablets, spraying an aqueous binder solution with a weight of 12wt.% of the total weight of the aqueous binder solution; in the preparation step S1 of the omeprazole magnesium enteric-coated microchip, the mass percentage of the adhesive in the adhesive mixed solution is 5 wt%;
the air inlet quantity of the fluidized bed is 30m 3 The inlet air temperature is 60 ℃, the atomization pressure is 1.0bar, the spray amount is 6mL/min, and the material temperature is 30 ℃;
and filling the obtained 40 pieces of the 3mm amoxicillin rifabutin micro-tablets and 36 pieces of the 3mm omeprazole magnesium enteric micro-tablets into a No. 00 gelatin hollow capsule to obtain the compound preparation capsule for treating helicobacter pylori.
Comparative example 1
With reference to example 1, the difference is:
the raw material compositions of the amoxicillin rifabutin micro-tablet and the omeprazole magnesium enteric micro-tablet are shown in table 1 in parts by weight;
b in the preparation of amoxicillin rifabutin micro-tablets, amoxicillin He Lifu statin is not uniformly mixed in a wet granulator, and is sprayed with an aqueous solution of an adhesive for pre-granulation, but amoxicillin He Lifu statin is directly put into a fluidized bed pan body, and is sprayed with the aqueous solution of the adhesive for granulation;
in the preparation of the omeprazole magnesium enteric-coated microchip, the adhesive is pretreated, the omeprazole magnesium, sodium dodecyl sulfate and meglumine are not mixed with the adhesive for pretreatment, but the adhesive is added with water to prepare an adhesive water solution with the mass percent of 4 wt%, mannitol, the omeprazole magnesium, sodium dodecyl sulfate, the meglumine and pregelatinized starch are put into a fluidized bed pot body, and the adhesive water solution is sprayed on the top for granulation.
Comparative example 2
Reference examples 7-9, except: particle size distribution of rifabutin and omeprazole magnesium.
Comparative example 3
Reference examples 7-9, except: particle size distribution of rifabutin and omeprazole magnesium.
Claims (8)
1. A compound preparation capsule for treating helicobacter pylori is characterized in that: the capsule comprises amoxicillin rifabutin micro-tablets and omeprazole magnesium enteric-coated micro-tablets, wherein the amoxicillin rifabutin micro-tablets comprise the following raw materials in parts by weight: 250-330 parts of amoxicillin, 9-15 parts of rifabutin, 10-25 parts of pregelatinized starch, 6-18 parts of adhesive and 1-6 parts of lubricant;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 7-13 parts of omeprazole magnesium, 70-90 parts of mannitol, 70-90 parts of pregelatinized starch, 5-15 parts of adhesive, 5-15 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant;
the particle size distribution D90 of rifabutin in the amoxicillin rifabutin micro-tablet is 10-50 mu m, and the particle size distribution D90 of omeprazole magnesium in the omeprazole magnesium enteric micro-tablet is 0.1-20 mu m;
the alkalizing agent is meglumine;
the preparation method of the compound preparation capsule for treating helicobacter pylori comprises the following steps of:
the preparation method of the amoxicillin rifabutin micro-tablet comprises the following specific steps:
(1) And (3) pretreatment of an adhesive: adding water into the adhesive to prepare an adhesive water solution with the concentration of 3-5 wt.% for later use;
(2) Wet granulation: adding amoxicillin and rifabutin into a wet granulator, uniformly mixing, spraying the aqueous solution of the adhesive prepared in the step (1), and pre-granulating;
(3) Granulating by a fluidized bed: transferring the preformed particles obtained in the step (2) into a fluidized bed boiler body, adjusting the air inlet quantity to keep the materials in a fluidized state, and granulating by spraying the residual adhesive aqueous solution on the top of the fluidized bed;
(4) Finishing: sieving the material obtained in the step (3) through a No. 3 pharmacopoeia sieve to obtain whole grains;
(5) Total mixing: uniformly mixing pregelatinized starch and a lubricant with the particles prepared in the step (4), and discharging;
(6) Tabletting: pressing by adopting a punch with the diameter of 1-3 mm to obtain the amoxicillin rifabutin micro-tablet;
the preparation method of the omeprazole magnesium enteric-coated microchip comprises the following specific steps:
s1, adhesive pretreatment: dissolving omeprazole magnesium, sodium dodecyl sulfate, an alkalizing agent and an adhesive in water to obtain an adhesive mixed solution for later use;
s2, granulating by a fluidized bed: mannitol and pregelatinized starch are put into a fluidized bed pot body, the air inlet quantity is adjusted to keep the materials in a fluidized state, and the fluidized bed top-spraying adhesive mixed solution is granulated;
s3, finishing: sieving the material obtained in the step S2 through a No. 3 pharmacopoeia sieve to obtain whole grains;
s4, total mixing: uniformly mixing the disintegrating agent, the lubricant and the granules prepared in the step S3, and then discharging;
s5, tabletting: pressing by adopting a punch with the diameter of 1-3 mm;
s6, inner isolation coating: coating by adopting a coating solution prepared by using a Ka Le Kangou Barbary gastric-soluble film coating premix with the solid content of 8-12 wt.%, wherein the coating weight gain is 6-10 wt.% of the weight of the 1-3 mm micro tablet prepared in the step S5;
s7, coating an enteric layer: coating by adopting a coating solution with 18-22wt.% of solid content prepared by adopting a Kalercanic-Jack series enteric film coating premix, wherein the coating weight gain is 20-26wt.% of the weight of the 1-3 mm micro tablet prepared in the step S5;
s8, external isolation coating: coating by adopting a coating solution prepared from a Ka Le Kangou Barbary gastric-soluble film coating premix with the solid content of 10wt.%, wherein the coating weight is 5-9 wt.% of the weight of the 1-3 mm micro tablet prepared in the step S5, so as to obtain the omeprazole magnesium enteric-coated micro tablet;
and filling 36-40 amoxicillin rifabutin micro-tablets and 32-36 omeprazole magnesium enteric micro-tablets obtained by the method into a gelatin hollow capsule of No. 00, thus obtaining the compound preparation capsule for treating helicobacter pylori.
2. The compound preparation capsule for treating helicobacter pylori according to claim 1, characterized in that: the amoxicillin rifabutin micro-tablet comprises the following raw materials in parts by weight: 260-320 parts of amoxicillin, 10-14 parts of rifabutin, 10-25 parts of pregelatinized starch, 6-18 parts of adhesive and 1-6 parts of lubricant;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 7.5-12.5 parts of omeprazole magnesium, 70-90 parts of mannitol, 70-90 parts of pregelatinized starch, 5-15 parts of adhesive, 5-15 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant;
the particle size distribution D90 of rifabutin in the amoxicillin rifabutin micro-tablet is 12-48 mu m, and the particle size D90 of omeprazole magnesium in the omeprazole magnesium enteric-coated micro-tablet is 0.5-19.5 mu m.
3. The compound preparation capsule for treating helicobacter pylori according to claim 2, characterized in that: the amoxicillin rifabutin micro-tablet comprises the following raw materials in parts by weight: 287 parts of amoxicillin, 12.5 parts of rifabutin, 12-23 parts of pregelatinized starch, 7-17 parts of adhesive and 1.5-5.5 parts of lubricant;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 10.3 parts of omeprazole magnesium, 73-87 parts of mannitol, 73-87 parts of pregelatinized starch, 6-14 parts of adhesive, 6-14 parts of disintegrating agent, 3-6 parts of sodium dodecyl sulfate, 5-10 parts of alkalizing agent and 2-5 parts of lubricant.
4. A compound capsule for treating helicobacter pylori according to any one of claims 1 to 3, characterized in that: the adhesive is hydroxypropyl cellulose or hypromellose; and/or
The disintegrating agent is at least one of crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; and/or
The lubricant is at least one of talcum powder, stearic acid, sodium stearate and magnesium stearate.
5. The capsule of claim 4, wherein the capsule comprises:
the amoxicillin rifabutin micro-tablet comprises the following raw materials in parts by weight: 287 parts of amoxicillin, 12.5 parts of rifabutin, 20 parts of pregelatinized starch, 10 parts of hydroxypropyl cellulose and 3.5 parts of magnesium stearate;
the omeprazole magnesium enteric-coated micro-tablet comprises the following raw materials in parts by weight: 10.3 parts of omeprazole magnesium, 80 parts of mannitol, 80 parts of pregelatinized starch, 10 parts of hydroxypropyl cellulose, 10 parts of crospovidone, 5 parts of sodium dodecyl sulfate, 7 parts of meglumine and 3 parts of magnesium stearate; the omeprazole magnesium enteric-coated micro-tablet further comprises an inner isolation coating, an enteric layer coating and an outer isolation coating, wherein the inner isolation coating is increased by 8 wt%, the enteric layer coating is increased by 23 wt%, and the outer isolation coating is increased by 7 wt%, based on the mass of the micro-tablet.
6. The compound preparation capsule for treating helicobacter pylori according to claim 1, characterized in that: the air inlet quantity of the fluidized bed is 30m 3 /h~50m 3 And/h, the air inlet temperature is 60-80 ℃, the atomization pressure is 1.0-1.5 bar, the liquid spraying amount is 6-8 mL/min, and the material temperature is 30-35 ℃.
7. The compound preparation capsule for treating helicobacter pylori according to claim 1, characterized in that: in the preparation step (2) of the amoxicillin rifabutin micro-tablet, spraying an aqueous solution of an adhesive, wherein the weight of the aqueous solution of the adhesive is 8-12 wt.% of the total weight of the aqueous solution of the adhesive.
8. The compound preparation capsule for treating helicobacter pylori according to claim 1, characterized in that: in the preparation step S1 of the omeprazole magnesium enteric-coated microchip, the mass percentage of the adhesive in the adhesive mixed solution is 3-5 wt%.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6489317B1 (en) * | 1998-04-30 | 2002-12-03 | Thomas Julius Borody | Method for eradication of Helicobacter pylori |
| CN101036633A (en) * | 2007-04-28 | 2007-09-19 | 杭州民生药业集团有限公司 | Enteric coated omeprazole pellets capsule and the preparing method thereof |
| CN102949369A (en) * | 2012-10-30 | 2013-03-06 | 丽珠医药集团股份有限公司 | Preparation method of gemifloxacin mesylate medicinal composition |
| CN105163743A (en) * | 2013-02-13 | 2015-12-16 | 红山生物医药有限公司 | Pharmaceutical compositions for the treatment of helicobacter pylori |
| CN110366415A (en) * | 2017-10-15 | 2019-10-22 | 消化系统疾病中心 | For treating, mitigating and preventing the composition and method of helicobacter pylori infections |
| US20210346362A1 (en) * | 2020-05-07 | 2021-11-11 | Redhill Biopharma Ltd. | Method for eradicating helicobacter pylori infection in patients regardless of body mass index |
| CN116036123A (en) * | 2023-02-14 | 2023-05-02 | 山东齐都药业有限公司 | Compound montmorillonite granule for treating helicobacter pylori infection and preparation method thereof |
-
2023
- 2023-12-14 CN CN202311713149.XA patent/CN117398360B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6489317B1 (en) * | 1998-04-30 | 2002-12-03 | Thomas Julius Borody | Method for eradication of Helicobacter pylori |
| CN101036633A (en) * | 2007-04-28 | 2007-09-19 | 杭州民生药业集团有限公司 | Enteric coated omeprazole pellets capsule and the preparing method thereof |
| CN102949369A (en) * | 2012-10-30 | 2013-03-06 | 丽珠医药集团股份有限公司 | Preparation method of gemifloxacin mesylate medicinal composition |
| CN105163743A (en) * | 2013-02-13 | 2015-12-16 | 红山生物医药有限公司 | Pharmaceutical compositions for the treatment of helicobacter pylori |
| CN110366415A (en) * | 2017-10-15 | 2019-10-22 | 消化系统疾病中心 | For treating, mitigating and preventing the composition and method of helicobacter pylori infections |
| US20210346362A1 (en) * | 2020-05-07 | 2021-11-11 | Redhill Biopharma Ltd. | Method for eradicating helicobacter pylori infection in patients regardless of body mass index |
| CN116036123A (en) * | 2023-02-14 | 2023-05-02 | 山东齐都药业有限公司 | Compound montmorillonite granule for treating helicobacter pylori infection and preparation method thereof |
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| CN117398360A (en) | 2024-01-16 |
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