CN111686084A - Application of berberine hydrochloride oryzanol tablets in treating diabetes - Google Patents
Application of berberine hydrochloride oryzanol tablets in treating diabetes Download PDFInfo
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- CN111686084A CN111686084A CN202010588304.XA CN202010588304A CN111686084A CN 111686084 A CN111686084 A CN 111686084A CN 202010588304 A CN202010588304 A CN 202010588304A CN 111686084 A CN111686084 A CN 111686084A
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- China
- Prior art keywords
- oryzanol
- berberine hydrochloride
- berberine
- granules
- hydrochloride
- 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.)
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- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 title claims abstract description 91
- 206010012601 diabetes mellitus Diseases 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- 239000008187 granular material Substances 0.000 claims abstract description 26
- 238000002156 mixing Methods 0.000 claims abstract description 19
- 239000002245 particle Substances 0.000 claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 12
- 239000011248 coating agent Substances 0.000 claims description 30
- 238000000576 coating method Methods 0.000 claims description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 239000002270 dispersing agent Substances 0.000 claims description 19
- 239000004094 surface-active agent Substances 0.000 claims description 19
- 238000005507 spraying Methods 0.000 claims description 16
- 238000010902 jet-milling Methods 0.000 claims description 14
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 13
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 13
- 229920000053 polysorbate 80 Polymers 0.000 claims description 13
- 229940068968 polysorbate 80 Drugs 0.000 claims description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 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 10
- 239000008101 lactose Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 8
- 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 8
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 8
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 6
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920001983 poloxamer Polymers 0.000 claims description 6
- 229960000502 poloxamer Drugs 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 5
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- 230000004584 weight gain Effects 0.000 claims description 3
- 235000019786 weight gain Nutrition 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 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 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 18
- 238000004090 dissolution Methods 0.000 abstract description 13
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 abstract description 3
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 abstract description 3
- 229940093265 berberine Drugs 0.000 abstract description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- 239000008280 blood Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 9
- 229960001375 lactose Drugs 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 229940057948 magnesium stearate Drugs 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 6
- 229960003943 hypromellose Drugs 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000011361 granulated particle Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- HIMXGTXNXJYFGB-UHFFFAOYSA-N alloxan Chemical compound O=C1NC(=O)C(=O)C(=O)N1 HIMXGTXNXJYFGB-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- -1 2, 4-methylene cycloartenyl ferulate Chemical compound 0.000 description 3
- 235000020828 fasting Nutrition 0.000 description 3
- 230000003345 hyperglycaemic effect Effects 0.000 description 3
- QVZGAIWUSYVGBJ-UHFFFAOYSA-N Cycloartenyl ferulate Natural products CCC12CCC3(C)C(C(C)CCC=C(C)C)CCC3(C)C1CCC(C1(C)C)C2CCC1OC(=O)C=CC1=CC=C(O)C(OC)=C1 QVZGAIWUSYVGBJ-UHFFFAOYSA-N 0.000 description 2
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- FODTZLFLDFKIQH-UHFFFAOYSA-N cycloartenol trans-ferulate Natural products C1=C(O)C(OC)=CC(C=CC(=O)OC2C(C3CCC4C5(C)CCC(C5(C)CCC54CC53CC2)C(C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-UHFFFAOYSA-N 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 238000012417 linear regression Methods 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 235000020927 12-h fasting Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019774 Rice Bran oil Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- FODTZLFLDFKIQH-FSVGXZBPSA-N gamma-Oryzanol (TN) Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)O[C@@H]2C([C@@H]3CC[C@H]4[C@]5(C)CC[C@@H]([C@@]5(C)CC[C@@]54C[C@@]53CC2)[C@H](C)CCC=C(C)C)(C)C)=C1 FODTZLFLDFKIQH-FSVGXZBPSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000008165 rice bran oil Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 239000011782 vitamin Substances 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
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a berberine hydrochloride oryzanol tablet and application thereof in treating diabetes, wherein the berberine hydrochloride oryzanol tablet is prepared by mixing and tabletting modified berberine hydrochloride oryzanol particles and other auxiliary materials according to a certain proportion, and the modified berberine hydrochloride oryzanol particles are mixed and tableted with other auxiliary materialsThe modified granule can improve the solubility of berberine hydrochloride and oryzanol, and improve the dissolution rate and bioavailability of the medicine. The tablet achieves good effect of treating diabetes through compatibility of medicines, a reasonable prescription and a preparation process.
Description
Technical Field
The invention belongs to the field of medicines, and relates to a prescription of a berberine hydrochloride oryzanol tablet, a preparation process of the berberine hydrochloride oryzanol tablet, and application of the tablet in medicines for treating diabetes.
Background
Berberine hydrochloride (Berberine) is an isoquinoline alkaloid separated from Chinese medicinal rhizoma Coptidis, and is the main antibacterial active ingredient of rhizoma Coptidis. It is yellow needle-like crystal and bitter in taste. It is widely distributed in the plant kingdom. Berberine hydrochloride is commonly used for intestinal tract infection,
oryzanol (OZ) is a vitamin medicine extracted from rice bran oil, and its main ingredients are cycloartenyl ferulate and 2, 4-methylene cycloartenyl ferulate. China is a world large country for rice production, and raw materials for extracting oryzanol are abundant in sources. Oryzanol is mainly used for improving autonomic nerve function, reducing endocrine disturbance and improving mental and neurological disorder symptoms.
The prior art proves that berberine hydrochloride and oryzanol both have obvious effects of reducing blood sugar, regulating lipid, losing weight and reducing blood sugar, and the combination of the berberine hydrochloride and the oryzanol has synergistic action. In the prior art, the prior oryzanol preparation and berberine hydrochloride preparation are combined to treat related diseases. If a compound preparation can be developed, the compliance of patients can be greatly improved.
However, oryzanol is a poorly soluble drug, is almost insoluble in water, and has low bioavailability. Berberine hydrochloride has poor absorption in vivo and very low bioavailability. The two medicines are prepared into a compound preparation, so that the problems of low dissolution rate and low bioavailability of the medicines are solved, and meanwhile, the technical difficulties of auxiliary material selection and the like are inevitably encountered when the raw materials of different medicines are different in properties. Therefore, the berberine hydrochloride oryzanol compound preparation which has simple prescription process and high drug solubility and bioavailability has good market prospect.
Disclosure of Invention
The invention aims to provide a berberine hydrochloride and oryzanol compound preparation which has simple preparation process, convenient use and obviously improved bioavailability.
The invention mixes the surface active agent, the dispersing agent and the medicine, then carries out gas flow crushing, and carries out dry granulation to disperse the medicine in the surface active agent and the dispersing agent, thereby improving the specific surface area and the dispersibility of the medicine. Further coating the coating liquid containing a surfactant, a dispersant and a hydrophilic film coating material to form a hydrophilic coating layer on the surface of the drug particles, further improving the dispersibility and dissolution rate of the drug, and greatly improving the bioavailability of berberine hydrochloride and oryzanol.
The invention provides a berberine hydrochloride oryzanol tablet, which comprises berberine hydrochloride oryzanol particles, a filler, a disintegrant and a lubricant.
The berberine hydrochloride oryzanol particles are composed of berberine hydrochloride, oryzanol, a surfactant, a dispersant and a hydrophilic film coating material, wherein the weight ratio of the berberine hydrochloride to the oryzanol is 1: 0.2-0.8.
Preferably, the weight ratio of the berberine hydrochloride to the oryzanol is 1: 0.2-0.6.
The surfactant is selected from one or a combination of two of sodium dodecyl sulfate and polysorbate 80.
The dispersing agent is selected from one or more of microcrystalline cellulose, hydroxypropyl methylcellulose and poloxamer.
The hydrophilic film coating material is selected from one or more of hydroxyethyl cellulose and hydroxyethyl methyl cellulose.
The filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch and mannitol.
The disintegrant is one or more of croscarmellose sodium, crospovidone, hypromellose, and corn starch.
The lubricant is one or more of magnesium stearate and silicon dioxide.
The invention also aims to provide a preparation method of the oryzanol berberine hydrochloride tablet, which comprises the following steps:
(1) preparation of berberine hydrochloride oryzanol granules: mixing berberine hydrochloride, oryzanol, part of surfactant and dispersant, jet milling, and dry granulating to obtain granule;
(2) dissolving the residual surfactant and dispersant in the hydrophilic film coating material solution, and stirring until the residual surfactant and dispersant are dissolved to obtain a coating solution; spraying the coating solution onto the granules by fluidized bed spraying to obtain modified berberine hydrochloride oryzanol granules;
(3) mixing the modified berberine hydrochloride oryzanol granules with a filler, a disintegrant and a lubricant according to a certain proportion, and tabletting.
Preferably, the particle size of the mixture after jet milling is D90 ≤ 20 μm.
Preferably, the weight gain of the coating is 3% -5%.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the surfactant with solubilization and the dispersant with strong hydrophilicity are selected, so that the dispersibility and dissolution rate of berberine hydrochloride and oryzanol can be remarkably improved.
(2) The surfactant and the dispersant are mixed with the berberine hydrochloride and the oryzanol, and then the mixture is subjected to jet milling and dry granulation, so that the berberine hydrochloride and the oryzanol can be well dispersed in the surfactant and the dispersant, and the specific surface area and the dispersibility of the berberine hydrochloride or the oryzanol are improved.
(3) The surfactant and the dispersant are dissolved in the hydrophilic film coating material solution, and the berberine hydrochloride oryzanol particles are coated by adopting a fluidized bed spraying method, so that a hydrophilic coating layer can be formed on the surfaces of the particles, and the surfactant and the dispersant are quickly dissolved after meeting water, so that the hydrophilicity and the dissolution rate are further improved, and the bioavailability of the medicine is further improved.
(4) The prescription and the preparation process are simple, the combined application of the berberine hydrochloride and the oryzanol has the effect of synergistically treating the diabetes, the prescription composition is simple, and the compliance of patients is greatly improved.
Detailed Description
The present invention is further described in detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The test methods in the following examples are all conventional methods unless otherwise specified, and the raw materials, reagent materials and the like used in the following examples are all commercially available products unless otherwise specified. The amount used in each example is weight percent.
Example 1
A berberine hydrochloride oryzanol tablet comprises the following components:
the preparation method comprises the following steps:
(1) preparation of berberine hydrochloride oryzanol granules
Mixing berberine hydrochloride, oryzanol, polysorbate 80, and hypromellose, jet milling, and dry granulating. And (3) adding polysorbate 80 and hydroxypropyl methylcellulose into a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution. Spraying the coating solution onto the dry-granulated particles by using a fluidized bed spraying mode, wherein the coating weight is increased by 3 percent, and thus obtaining the berberine hydrochloride oryzanol modified particles.
(2) Preparation of tablets
Mixing the berberine hydrochloride and oryzanol modified granules with lactose, croscarmellose sodium and magnesium stearate, and tabletting.
Example 2:
a berberine hydrochloride oryzanol tablet comprises the following components:
the preparation method comprises the following steps:
(1) preparation of berberine hydrochloride oryzanol granules
Mixing berberine hydrochloride, oryzanol, sodium laurylsulfate and poloxamer, jet-milling, and dry granulating. And (3) dissolving the added lauryl sodium sulfate and the added poloxamer into 5% hydroxyethyl methyl cellulose aqueous solution to obtain a coating solution. Spraying the coating solution onto the dry-granulated particles by using a fluidized bed spraying mode, wherein the coating weight is increased by 3 percent, and thus obtaining the berberine hydrochloride oryzanol modified particles.
(2) Preparation of tablets
Mixing the berberine hydrochloride and oryzanol modified granules with lactose, croscarmellose sodium and magnesium stearate, and tabletting.
Example 3:
a berberine hydrochloride oryzanol tablet comprises the following components:
the preparation method comprises the following steps:
(1) preparation of berberine hydrochloride oryzanol granules
Mixing berberine hydrochloride, oryzanol, sodium laurylsulfate and hypromellose, jet milling, and dry granulating. And (3) dissolving the added lauryl sodium sulfate and the added hydroxypropyl methylcellulose into a 3% hydroxyethyl methyl cellulose aqueous solution to obtain a coating solution. Spraying the coating solution onto the dry-granulated particles by using a fluidized bed spraying mode, wherein the coating weight is increased by 3 percent, and thus obtaining the berberine hydrochloride oryzanol modified particles.
(2) Preparation of tablets
Mixing the berberine hydrochloride oryzanol modified granules with microcrystalline cellulose, lactose, crospovidone and magnesium stearate, and tabletting.
Example 4:
a berberine hydrochloride oryzanol tablet comprises the following components:
the preparation method comprises the following steps:
(2) preparation of berberine hydrochloride oryzanol granules
Mixing berberine hydrochloride, oryzanol, polysorbate 80 and microcrystalline cellulose, jet milling, and dry granulating. And (3) dissolving additional polysorbate 80 and additional microcrystalline cellulose in a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution. Spraying the coating solution onto the dry-granulated particles by using a fluidized bed spraying mode, wherein the coating weight is increased by 3 percent, and thus obtaining the berberine hydrochloride oryzanol modified particles.
(2) Preparation of tablets
Mixing the berberine hydrochloride and oryzanol modified granules with lactose, crospovidone and magnesium stearate, and tabletting.
Example 5:
a berberine hydrochloride oryzanol tablet comprises the following components:
the preparation method comprises the following steps:
(1) preparation of berberine hydrochloride oryzanol granules
Mixing berberine hydrochloride, oryzanol, polysorbate 80 and poloxamer, jet-milling, and dry granulating. And (3) dissolving the additional polysorbate 80 and the additional poloxamer in a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution. Spraying the coating solution onto the dry-granulated particles by using a fluidized bed spraying mode, wherein the coating weight is increased by 3 percent, and thus obtaining the berberine hydrochloride oryzanol modified particles.
(2) Preparation of tablets
Mixing the berberine hydrochloride and oryzanol modified granules with lactose, croscarmellose sodium and magnesium stearate, and tabletting.
Comparative example 1: directly mixing and tabletting.
The formulation is the same as example 1, and the preparation method is as follows: mixing berberine hydrochloride, oryzanol, polysorbate 80, hypromellose, lactose, croscarmellose sodium, and magnesium stearate, and directly tabletting.
Comparative example 2: and (4) tabletting without coating.
The formulation is the same as example 1, and the preparation method is as follows: mixing berberine hydrochloride, oryzanol, polysorbate 80 and hypromellose, jet milling, and dry granulating. The granules were mixed with lactose, croscarmellose sodium and magnesium stearate and compressed into tablets.
Comparative example 3: tabletting without jet milling
The formulation is the same as example 1, and the preparation method is as follows: mixing berberine hydrochloride, oryzanol, polysorbate 80 and hypromellose, and granulating by dry method. And (3) adding polysorbate 80 and hydroxypropyl methylcellulose into a 3% hydroxyethyl cellulose aqueous solution to obtain a coating solution. The coating solution is sprayed on the particles obtained by dry granulation by adopting a fluidized bed spraying mode, and the weight gain of the coating is 3 percent. The granules were mixed with lactose, croscarmellose sodium and magnesium stearate and compressed into tablets.
Comparative example 4: berberine hydrochloride single tablet
The formulation and preparation were the same as in example 1 except that oryzanol was not contained.
Comparative example 5: oryzanol single tablet
The formulation and preparation method are the same as example 1 except that berberine hydrochloride is not contained, and the preparation method is as follows:
experimental example 1:
drawing of standard curve
1. Drawing of oryzanol standard curve
Precisely weighing 20mg of oryzanol raw material medicine, placing the oryzanol raw material medicine into a 100mL measuring flask, adding a proper amount of n-heptane, heating in a water bath at 70 ℃ for 10min to dissolve, cooling, adding n-heptane to scale, shaking up, and preparing into a standard stock solution with the concentration of 0.2 mg/mL. 1, 2, 3, 4, 5ml are precisely measured, respectively placed in a 50ml measuring flask, diluted to the scale with n-heptane, shaken well and measured for absorbance (A) at 315nm wavelength. And (D) performing linear regression on the concentration C (X, mu g/mL) by using A (Y) to obtain a regression equation and a standard curve of the absorbance and the concentration of the oryzanol.
2. Drawing standard curve of berberine hydrochloride
Accurately weighing 20mg of berberine hydrochloride, placing into a 50ml measuring flask, dissolving with appropriate amount of 80% ethanol, and fixing volume. Accurately sucking 1, 2, 3, 4, 5mL of the above standard solution, diluting with 80% ethanol and diluting to 50mL, measuring absorbance (A) at 348nm, and performing linear regression on concentration C (X, μ g/mL) with A (Y) to obtain regression equation and standard curve of berberine hydrochloride absorbance and concentration.
Experimental example 2:
content uniformity determination
The tablets of examples 1 to 5 and comparative examples 1 to 3 were measured for the content uniformity of oryzanol. 6 tablets prepared in examples 1 to 5 and comparative examples 1 to 3 were each ground with about 30ml of n-heptane, transferred to a 50ml measuring flask, heated in a water bath at 70 ℃ for 10min to dissolve, allowed to cool, diluted to the mark with n-heptane, shaken up, 1ml of the subsequent filtrate was taken, placed in a 10ml measuring flask, added to the mark with n-heptane, shaken up, and the absorbance was measured at a wavelength of 315nm and calculated by substituting the regression equation, and the results are shown in Table 1.
TABLE 1 content uniformity of tablets
As can be seen from the above table: the berberine hydrochloride oryzanol tablets prepared in the examples 1-5 of the invention have uniform content, however, the tablets prepared in the comparative examples 1-3 have great difference among different tablets. The main reason is that comparative example 1 is directly mixed, comparative example 3 is dry granulated without jet milling, oryzanol is poor in solubility and dispersibility, and is not uniformly mixed with the surfactant and the dispersant. Comparative example 2 does not include a hydrophilic material coating step and a hydrophilic coating is not formed on the surface of the granules, resulting in poor roundness and hydrophilicity of the granules as in the examples of the present application, poor friability and thus poor content uniformity of the tablets.
Experimental example 2
Determination of dissolution of tablets
Referring to the second method XC in the appendix of the second part of the Chinese pharmacopoeia 2010, in-vitro dissolution curves of berberine hydrochloride and oryzanol in the examples 1 to 6 and the comparative examples 1 and 4 of the invention are respectively measured at the temperature (37 +/-0.5) and the rotating speed of 100 r/min. In order to improve the solubility of oryzanol in the dissolution medium, 500mL of phosphate buffered saline (pH 7.4) containing 0.5% polysorbate-80 is selected as the dissolution medium, the test is carried out in a rotating basket, 5mL of the dissolution medium is sampled at 0, 15, 30, 45, 60, 90 and 120min, and 5mL of fresh dissolution medium with the same temperature is supplemented. After the sample is filtered by a filter membrane of 0.22 mu m, the dissolution amount of berberine hydrochloride and oryzanol is measured, and the cumulative dissolution percentage is calculated.
TABLE 1 cumulative percent dissolution of tablets prepared in examples 1-5
As can be seen from the table above, the tablets prepared in examples 1-5 of the present invention have good dissolution rates, all of which reach more than 80% within 120 min. The dissolution rates of the tablets prepared in comparative examples 1-3 are below 65% within 120 min. The reason is that: comparative example 1 in which the mixture was directly mixed, comparative example 2 in which the hydrophilic coating was not included, and comparative example 3 in which dry granulation was performed without jet milling, berberine hydrochloride and oryzanol were poorly dispersed in the tablets, and content uniformity was poor, resulting in a low dissolution rate. The bioavailability is low, and the preparation method has the advantages of low bioavailability,
experimental example 3:
pharmacodynamic experiment
Experimental animals: SPF grade mice, male, between 4-6 weeks of age, weigh 18-22 g.
1. And (3) establishing a diabetes model of a mouse induced by alloxan.
After the mice are adaptively fed for 7 days, the mice are fasted without water prohibition for 24 hours, 10 mice are randomly selected as a normal control group, the same amount of normal saline is injected into the abdominal cavity, 200mg/kg of alloxan is injected into the abdominal cavity of each of the other mice, a 2% solution is prepared by the normal saline before use, and normal feeding is recovered after injection. And after 72h, cutting the tail tip of the mouse to take blood, measuring the fasting blood sugar value by a glucometer, and fasting for 12h before measurement, wherein the mouse with the fasting blood sugar value more than 11.1mmol/L is a hyperglycemic mouse successfully modeled.
2. Experimental groups
First group (negative control group): normal mice were gavaged with normal saline;
second group (diabetes model group): normal saline for gavage of hyperglycaemic mice
Third group (positive control group): glimepiride, 5mg/kg
Experimental groups: berberine hydrochloride oryzanol tablets of embodiments 1-5 of the invention;
control group: berberine hydrochloride tablets of comparative example 4, oryzanol tablets of comparative example 5;
each group had 8.
3. Blood sugar lowering experiment
The administration mode comprises the following steps: gavage is performed 2 times a day with 12-hour intervals. The administration is continued for 14 days, each group is fed with basal feed and free drinking water, and the fasting blood glucose value of the mice is measured 7 days and 14 days after the administration. The experimental results are as follows:
TABLE 2 Effect of tablets prepared in examples 1-5 on blood glucose concentration in hyperglycemic model mice
As can be seen from the above table, examples 1-5 of the present invention were able to significantly reduce the blood glucose level in experimental animals after administration, similar to the positive control glibenclamide at low doses, and significantly reduce the blood glucose level in animals at high doses. And when the berberine hydrochloride or the oryzanol are singly used, the effect of reducing blood sugar is not better than that of combining the berberine hydrochloride and the oryzanol, which shows that the combination of the berberine hydrochloride and the oryzanol achieves the synergistic effect.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention.
Claims (7)
1. The berberine hydrochloride oryzanol tablet is characterized by comprising the following components in parts by weight: berberine hydrochloride oryzanol granules, a filler, a disintegrant and a lubricant;
the berberine hydrochloride oryzanol particles are composed of berberine hydrochloride, oryzanol, a surfactant, a dispersant and a hydrophilic film coating material, wherein the weight ratio of the berberine hydrochloride to the oryzanol is 1: 0.2-0.8.
2. The oryzanol berberine hydrochloride tablet of claim 1, wherein the surfactant is selected from one or a combination of two of sodium lauryl sulfate, polysorbate 80; the dispersing agent is selected from one or more of microcrystalline cellulose, hydroxypropyl methylcellulose and poloxamer; the hydrophilic film coating material is selected from one or more of hydroxyethyl cellulose and hydroxyethyl methyl cellulose.
3. The oryzanol berberine hydrochloride tablet of claim 1, wherein the filler is one or more of microcrystalline cellulose, lactose, pregelatinized starch, mannitol; the disintegrating agent is one or more of croscarmellose sodium, crospovidone, hydroxypropyl methylcellulose and corn starch; the lubricant is one or more of magnesium stearate and silicon dioxide.
4. The oryzanol berberine hydrochloride tablet of claim 1, wherein the weight ratio of the oryzanol hydrochloride to the berberine hydrochloride is 1: 0.2-0.6.
5. A process for the preparation of oryzanol berberine hydrochloride tablets as defined in claims 1-4, characterized in that:
preparation of berberine hydrochloride oryzanol granules: mixing berberine hydrochloride, oryzanol, internal surfactant and dispersant, jet-milling, and dry-granulating to obtain granule;
dissolving an additional surfactant and an additional dispersant in the hydrophilic film coating material solution, and stirring until the additional surfactant and the additional dispersant are dissolved to obtain a coating solution; spraying the coating solution onto the granules by fluidized bed spraying to obtain modified berberine hydrochloride oryzanol granules;
(3) mixing the modified berberine hydrochloride oryzanol granules with a filler, a disintegrant and a lubricant according to a certain proportion, and tabletting.
6. The method of claim 7, wherein the mixture after jet milling has a particle size of D90 ≤ 20 μm.
7. The method of claim 7, wherein the coating weight gain in step (2) is 3-5%.
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