CN106074423A - Diabecron sustained-release tablet agent and preparation method thereof - Google Patents
Diabecron sustained-release tablet agent and preparation method thereof Download PDFInfo
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- CN106074423A CN106074423A CN201610404666.2A CN201610404666A CN106074423A CN 106074423 A CN106074423 A CN 106074423A CN 201610404666 A CN201610404666 A CN 201610404666A CN 106074423 A CN106074423 A CN 106074423A
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- Prior art keywords
- metformin hydrochloride
- release
- sustained
- solution
- agent
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- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 20
- 239000003795 chemical substances by application Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 16
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical class Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 57
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 55
- 239000011248 coating agent Substances 0.000 claims abstract description 18
- 238000000576 coating method Methods 0.000 claims abstract description 18
- 238000013268 sustained release Methods 0.000 claims abstract description 15
- 239000012730 sustained-release form Substances 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 15
- 239000004088 foaming agent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 239000000853 adhesive Substances 0.000 claims description 10
- 230000001070 adhesive effect Effects 0.000 claims description 10
- 229920000058 polyacrylate Polymers 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 9
- 239000002245 particle Substances 0.000 claims description 9
- 239000003826 tablet Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 239000004014 plasticizer Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 7
- -1 sorbefacient Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000005507 spraying Methods 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group 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 5
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000001757 thermogravimetry curve Methods 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 238000001228 spectrum Methods 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 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 3
- 206010013786 Dry skin Diseases 0.000 claims description 3
- 229920003135 Eudragit® L 100-55 Polymers 0.000 claims description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical group CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 3
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical group CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- RRLOOYQHUHGIRJ-UHFFFAOYSA-M sodium;ethyl sulfate Chemical compound [Na+].CCOS([O-])(=O)=O RRLOOYQHUHGIRJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000011122 softwood Substances 0.000 claims description 3
- 235000020985 whole grains Nutrition 0.000 claims description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical group CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 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 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 229940084106 spermaceti Drugs 0.000 claims description 2
- 239000012177 spermaceti Substances 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 abstract description 11
- 238000005516 engineering process Methods 0.000 abstract description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 5
- 239000000047 product Substances 0.000 description 25
- 239000003814 drug Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 210000000813 small intestine Anatomy 0.000 description 8
- 229940123208 Biguanide Drugs 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 150000004283 biguanides Chemical group 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- NLMKTBGFQGKQEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hexadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical group CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO NLMKTBGFQGKQEV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229940056318 ceteth-20 Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000010603 pastilles Nutrition 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical compound [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- 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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of diabecron sustained-release tablet agent and preparation method thereof, belong to pharmaceutical technology field.This metformin hydrochloride slow release preparation consists of and is made up of the piece heart and sustained release coating.Diabecron sustained-release tablet agent prepared by the present invention can solve Metformin hydrochloride portion on the gastrointestinal tract and dash forward and release and problem that absorption window is narrow, slowly discharges in 10 hours, and release steadily, and can effectively absorb.
Description
Technical field
The present invention relates to a kind of sustained-release tablet and preparation method thereof, be specifically related to a kind of diabecron sustained-release tablet agent
And preparation method thereof, belong to pharmaceutical technology field.
Background technology
Metformin hydrochloride (Metformin hydrochloride), chemical entitled 1,1-Dimethylbiguanide hydrochloride, point
Minor C4H11N5HCl, molecular weight is 165.63；White crystals or crystalline powder, odorless；In water readily soluble, in methyl alcohol
Dissolve, slightly soluble in ethanol, insoluble in ether or chloroform.Metformin hydrochloride is biguanides hypoglycemic agent, due to medicine
Thing bad reaction is less, is widely used in the treatment of diabetes B.Metformin hydrochloride is that easily water soluble drug is (at 25 DEG C
Under, dissolve ＞ 300mg/mL), conventional tablet needs daily 2～3 times, applies melbine to need clinically heavy dose of anti-
Multiplexing medicine, to maintain effective blood drug concentration (three times a day, each 500mg), easily causes internal blood concentration fluctuation big, causes bad
Reaction, simultaneously as Metformin hydrochloride is very poor to the penetration capacity of small intestine hypomere and large intestine, absorption site is concentrated mainly on little
Intestines epimere, causes bioavilability low, and the absolute bioavailability of Metformin hydrochloride conventional tablet is 40～60%, and with
The increase of dosage and decline.
The problem low for solving Metformin hydrochloride absolute bioavailability, needs to design a kind of medicinal tablet, and it needs
To solve problems with simultaneously, first, Metformin hydrochloride runs in the environment of a large amount of water at stomach, not because of its high-dissolvability
There is release rapidly；Second, Metformin hydrochloride can retain the long period fully to inhale at the upper part of small intestine being suitable to absorb
Receive；3rd, promote the absorption in small intestine middle and lower part for the Metformin hydrochloride, extend soak time, increase Metformin hydrochloride at stomach
The absorption window of enteron aisle.
Prior art has occurred in that the technical scheme of multiple Metformin hydrochloride slow-release tablet agent.CN1295467A is open
The biphasic controlled release delivery system of a kind of high solubility pharmaceuticals, it comprises (1) solid particles inside phase, and (2) outer solid is even
Continuous phase, wherein the particle of solid particles inside phase disperses and is embedded in described outer solid continuous phase, described internal solids
Grain comprises the medicine that (a) has high water solubility mutually；(b) slow-release material, outer solid continuous phase comprises slow-release material.This piece
Agent slowly can discharge in 6 hours, is administered once daily, and commercialized product is i.e. prepared from according to the technical scheme of this patent.
CN103239424A discloses a kind of diabecron sustained-release micro pill capsule, its by the Metformin hydrochloride capsule heart,
Coating of pellets, enteric capsule shell composition, wherein the excipient of the capsule heart be microcrystalline cellulose, lactose, xylitol, mannitol, in water
One of which or several, use acrylic resin family macromolecule, talcum powder etc. make sustained release coating.
CN103040761A also discloses a kind of Metformin hydrochloride micro pill capsule, and wherein slow-release pill is by the pastille ball heart
Making with sustained-release coating layer, wherein pastille ball pericardium is containing main ingredient, filler, adhesive, wetting agent and antiplastering aid, sustained-release coating layer
Comprising matrix material and pore-foaming agent, described pore-foaming agent is selected from methylcellulose, polyethylene glycol, polyvinylpyrrolidone, sucrose, hydroxyl
Third first fiber, polymethacrylate, any or two or more mixture of cellulose phthalate element class.
CN101785763 discloses a kind of diabecron sustained-release tablet, by Metformin hydrochloride, carboxymethylcellulose calcium
Sodium, Hydroxypropyl methylcellulose and polyvinylpyrrolidone, be prepared from the ethanol solution of resin for adhesive.Wherein, polypropylene
Acid resin is enteric coating liquid.
Above-mentioned tablet solves Metformin hydrochloride and meets the problem that water environment quickly discharges, but still can not solve hydrochloride
Biguanides is only capable of absorbing at upper part of small intestine, and the problem of absorption site narrow range, bioavilability still can not significantly improve.
CN103622930A discloses a kind of metformin hydrochloride slow release preparation and preparation method thereof, and described hydrochloride is double
Guanidine sustained release preparation consists of (1) piece heart: Metformin hydrochloride 50～60%, filler 23～25%, adhesive 4.5～8%, inhales
Receive accelerator 11～16%, lubricant 0～1%；(2) sustained release coating: the part by weight accounting for the piece heart is 8～12%, by acrylic acid
Family macromolecule, plasticizer, antiplastering aid, pore-foaming agent composition, its part by weight is 5:0.15:0.45:1.This patent document provides
Metformin hydrochloride slow release preparation can solve Metformin hydrochloride portion on the gastrointestinal tract and dash forward and release and problem that absorption window is narrow, 6
Slowly release in hour, release steadily, and can effectively absorb.
For expanding the application of Metformin hydrochloride further, promoting the innovation of drug preparation technique, pharmaceutical manufacturer is necessary
Develop new diabecron sustained-release technology to realize object defined above.
Content of the invention
It is an object of the invention to solve Metformin hydrochloride portion on the gastrointestinal tract and discharge too fast causing under bioavilability
Fall, and in gastrointestinal absorption narrow range, in the non-absorbent problem in small intestine middle and lower part, provide one can effectively improve hydrochloride
The diabecron sustained-release tablet agent of biguanides bioavilability.
For solving the problems referred to above, the technical scheme is that
A kind of diabecron sustained-release tablet agent, is made up of label and sustained release coating, consisting of:
(1) label: Metformin hydrochloride 50～60%, filler 23～25%, adhesive 4.5～8%, sorbefacient
11～16%, lubricant 0～1%；
(2) sustained release coating: the part by weight accounting for label is 8～12%, by acrylic polymer, plasticizer, antiplastering aid,
Pore-foaming agent forms, and its part by weight is 5:0.15:0.45:1；
Wherein, the XRPD collection of illustrative plates of described Metformin hydrochloride 2 θ be 8.818 ± 0.2,10.442 ± 0.2,12.901 ±
0.2、14.901±0.2、16.076±0.2、16.88±0.2、17.54±0.2、18.677±0.2、19.12±0.2、
19.44±0.2、20.596±0.2、21.699±0.2、22.422±0.2、23.181±0.2、24.539±0.2、25.779
There is diffraction maximum at ± 0.2,27.013 ± 0.2,28.461 ± 0.2；The differential scanning calorimetric thermogram of described Metformin hydrochloride
Spectrum has feature melting peak at 208.2 ± 0.2 DEG C；Described sorbefacient is laureth sodium sulfovinate；Described pore-foaming agent is
Ceteth-20；Described acrylic polymer is EUDRAGIT L100-55；Described filler is selected from
One or more in microcrystalline cellulose, mannitol or lactose；Described adhesive is selected from polyvinylpyrrolidone or hydroxypropyl first is fine
Dimension element in one or both；Described lubricant is selected from talcum powder or magnesium stearate；Described plasticizer is triethyl citrate；Institute
Stating antiplastering aid is talcum powder.
The present invention also aims to provide the preparation method of above-mentioned diabecron sustained-release tablet agent.
Above-mentioned purpose is achieved through the following technical solutions:
(1) Metformin hydrochloride crude product is added to the water, is heated to backflow and dissolves, then in solution, add certain proportioning
Oxolane and the tert-butyl alcohol and then formation mixed solvent system, then cooling down crystallization, filter, washing, vacuum drying, obtain
Metformin hydrochloride；Weight g of described Metformin hydrochloride crude product and water: volume ml ratio is for 1:8；Described mixed solvent system
The volume ml of middle water, oxolane and the tert-butyl alcohol is than for 10:3:7；Described cooling down crystallization, its temperature reduces to 4 DEG C；Described
Washing, its use solvent be ether；Described vacuum drying, it is dried used temperature 90 DEG C；
(2) Metformin hydrochloride of step (1) gained is mixed standby with filler, sorbefacient, adhesive is joined
Make the aqueous solution of 5%, prepared binder solution is joined mixed material mixes softwood processed, cross 18 mesh sieve systems
Grain；
(3) particle obtaining step (2) is at 40 DEG C of dryings 0.5 hour, whole grain；
(4) adding lubricant in the particle that step (3) obtains, mixing, label made by compressing tablet；
(5) by acrylic polymer, plasticizer, antiplastering aid and with the water of two times of weight of acrylic polymer in proportion
Mixing and forming solution, add pore-foaming agent in solution, stirring, it is standby that coating solution is made in mixing；
(6) coating solution that step (5) obtains uniformly is sprayed onto the prepared piece wicking surface of step (4) to be coated, spray coating
Liquid operation is carried out at 30 DEG C, and spray coating solution process should continue to complete for 1 hour, is dried 0.5 hour, obtains hydrochloric acid two at 65 DEG C
First biguanides sustained-release tablet.
EUDRAGIT L100-55 of the present invention is commercially available prod, mol ratio 1:1, and trade name is outstanding
Special strange L 30D-55.
The present invention preparation-obtained Metformin hydrochloride hygroscopicity is little, good fluidity, more can meet pharmaceutics
Require, be more suitable for preparing various pharmaceutical preparation.The present invention adds pore-foaming agent ceteth-20 in sustained release coating film, permissible
Change Metformin hydrochloride in the middle part of small intestine and the situation of the inconspicuous absorption in bottom, hence it is evident that increase the absorption of Metformin hydrochloride
Window, extends Metformin hydrochloride at GI soak time, meanwhile, in conjunction with the slow releasing function of sustained release coating film, it is to avoid salt
Acid the prominent of melbine portion on the gastrointestinal tract releases effect, and adding Metformin hydrochloride can be in the release of effective uptake zone small intestine
Amount, improves bioavilability further.Pore-foaming agent of the present invention be chosen as key factor, through lot of experiments screening, select spermaceti
Alcohol polyethers-20, as pore-foaming agent, can regulate corrosion speed in different gastrointestinal tract environments for the sustained release coating, make hydrochloride
Biguanides is from upper part of small intestine until bottom can continue at the uniform velocity to discharge.Another key technology of the present invention is, matches with sustained release coating
Closing, the present invention also adds sorbefacient, i.e. laureth sodium sulfovinate, the addition of above composition in label, can make
Metformin hydrochloride increases in the permeability of small bowel, is allowed to be more readily absorbed.
Brief description
The XRPD collection of illustrative plates of the Metformin hydrochloride obtained by Fig. 1 embodiment of the present invention 1 step (1)
The differential scanning calorimetric thermogram spectrum of the Metformin hydrochloride obtained by Fig. 2 embodiment of the present invention 1 step (1)
Detailed description of the invention
The present invention is embodied as by following example, and following example may be used for explaining the present invention but not as this
The restriction of bright protection domain.
Embodiment 1
Prescription, is shown in Table 1:
Table 1 embodiment 1 prescription component list
Preparation method:
(1) reactor used, filter, apparatus etc. are carried out aseptic process.Metformin hydrochloride crude product 1000g is added
In 15L there-necked flask, add water 8000mL, stir, be heated to backflow dissolve, then in solution add 2400mL oxolane and
The 5600mL tert-butyl alcohol, then slow cooling is cooled to 4 DEG C, stirring and crystallizing, filters, and ether washs, and 90 DEG C of vacuum drying obtain salt
Acid melbine dry product 953g, yield 95.3%；
(2) Metformin hydrochloride of step (1) gained is mixed standby with filler, sorbefacient, adhesive is joined
Make the aqueous solution of 5%, prepared binder solution is joined mixed material mixes softwood processed, cross 18 mesh sieve systems
Grain；
(3) particle obtaining step (2) is at 40 DEG C of dryings 0.5 hour, whole grain；
(4) adding lubricant in the particle that step (3) obtains, mixing, label made by compressing tablet；
(5) by acrylic polymer, plasticizer, antiplastering aid and with the water of two times of weight of acrylic polymer in proportion
Mixing and forming solution, add pore-foaming agent in solution, stirring, it is standby that coating solution is made in mixing；
(6) coating solution that step (5) obtains uniformly is sprayed onto the prepared piece wicking surface of step (4) to be coated, spray coating
Liquid operation is carried out at 30 DEG C, and spray coating solution process should continue to complete for 1 hour, is dried 0.5 hour, obtains hydrochloric acid two at 65 DEG C
First biguanides sustained-release tablet.
Wherein, the Metformin hydrochloride obtained by step (1), is tested:
First, XRPD collection of illustrative plates
The XRPD collection of illustrative plates of the Metformin hydrochloride obtained by step (1) 2 θ be 8.818 ± 0.2,10.442 ± 0.2,
12.901±0.2、14.901±0.2、16.076±0.2、16.88±0.2、17.54±0.2、18.677±0.2、19.12±
0.2、19.44±0.2、20.596±0.2、21.699±0.2、22.422±0.2、23.181±0.2、24.539±0.2、
There is diffraction maximum, as shown in Figure 1 at 25.779 ± 0.2,27.013 ± 0.2,28.461 ± 0.2.
2nd, differential scanning calorimetric thermogram
The differential scanning calorimetric thermogram spectrum of the Metformin hydrochloride obtained by step (1) has feature at 208.2 ± 0.2 DEG C
Melting peak, as shown in Figure 2.
3rd, moist test is drawn
Intend increasing revision annex Ⅹ Ⅸ J medicine with reference to " Chinese Pharmacopoeia " version two in 2010 to draw in moist test direction principle
Test method, Metformin hydrochloride three batch sample preparing step of the present invention (1) is entered with commercially available product the 1st, commercially available product the 2nd, commercially available product 3
Row medicine draws moist test.Result of the test Metformin hydrochloride prepared by the present invention for the display draws and moist is below 1%, is better than city
Sell product, the results are shown in Table 2.
Table 2 draws moist measurement result
| Sample 1 | Sample 2 | Sample 3 | Commercially available product 1 | Commercially available product 2 | Commercially available product 3 | |
| Draw moist | 0.71% | 0.72% | 0.66% | 2.93% | 3.30% | 3.35% |
4th, mobility compares
Angle of repose is the method the easiest of inspection powder fluidity quality, and angle of repose is less, illustrates that frictional force is less, stream
Dynamic property is better.This test uses injection method (fixed funnel method) to measure Metformin hydrochloride three batches prepared by step (1) of the present invention
Sample and the angle of repose of commercially available product the 1st, commercially available product the 2nd, commercially available product 3.Pour testing sample into funnel so that it is lightly, fall equably
Enter disc centre, form a cone, stop charging, consumption when material freely falls from powder hypotenuse along disk border
Angle device measures angle of repose, and measurement result is shown in Table 3.Metformin hydrochloride mobility prepared by the result display present invention is more preferable, is better than
Commercially available product 1-3.
Table 3 angle of repose measurement result
| Sample | Outward appearance | Angle of repose |
| Sample 1 | White crystalline powder | 22.3 |
| Sample 2 | White crystalline powder | 22.4 |
| Sample 3 | White crystalline powder | 22.1 |
| Commercially available product 1 | White is to pale yellow crystals adhesion powder | 47.6 |
| Commercially available product 2 | White is to pale yellow crystals adhesion powder | 50.5 |
| Commercially available product 3 | White is to pale yellow crystals adhesion powder | 48.7 |
Embodiment 2
Adjust prescription according to such as following table ratio, be prepared embodiment 2～5 product with method.
Table 4 embodiment 2～5 prescription forms list
Preparation method is with embodiment 1, and only wherein auxiliary material is replaced according to actual conditions in table 2.
Test example 1
According to diabecron sustained-release tablet standard to embodiment the 1st, the 2nd, the 3rd, the 4th, the 5 diabecron sustained-release tablet agent prepared
Vitro release be measured, result such as table 5:
Table 5 embodiment the 1st, the 2nd, the 3rd, the 4th, 5 product release
| Time (h) | 1 | 2 | 3 | 5 | 7 | 10 |
| Embodiment 1 | 18% | 31% | 47% | 69% | 87% | 96% |
| Embodiment 2 | 16% | 32% | 45% | 67% | 85% | 93% |
| Embodiment 3 | 15% | 29% | 42% | 65% | 85% | 94% |
| Embodiment 4 | 16% | 31% | 46% | 66% | 88% | 95% |
| Embodiment 5 | 17% | 27% | 48% | 68% | 86% | 97% |
As seen from the above table, the release of the present embodiment products obtained therefrom is mild, without phenomenon of burst release, can discharge gently in 10 hours.
Test example 2
Use the diabecron sustained-release tablet agent of embodiment 1 preparation, reproduce patent CN201310704959.9 embodiment 1
Metformin Extended-release Tablets agent prepared by technical scheme is comparative example 1, is right with commercialized product (sustained release tablets GLUCOPHAGE XR)
According to employing double-blind, randomized controlled clinical study method carries out human bioavailability test to 24 case health volunteers, the results are shown in Table 6.
The bioavilability of table 6 embodiment the 1st, comparative example the 1st, the relative commercialized product of comparative example 2
The diabecron sustained-release tablet agent of embodiment 1 preparation relative to the relative bioavailability of commercialized product is
142%, illustrate embodiment 1 compared with commercialized product, bioavilability significantly improves, illustrate in the present invention add absorption enhancement
Agent and special pore material play a key effect.Comparative example 1 is 137% relative to the relative bioavailability of commercialized product,
Illustrate that comparative example 1 bioavilability compared with commercialized product is also to significantly improve, but the Metformin hydrochloride of embodiment 1 preparation delays
Release tablet formulations relative bioavailability compared with comparative example 1 is higher, and exceeding is 3.6%, illustrates that technical solution of the present invention more can be obvious
Improve absorption level.
Above-described embodiment is only technology design and the advantage that the present invention is described, the present invention also can have other form and become
Changing, as well known to the skilled person, above-described embodiment functions only as to the exemplary role in foregoing invention protection domain, right
For those of ordinary skill in the art, in the protection domain that the present invention is limited, also has a lot of conventional deformation and other enforcement
Example, within the protection domain that these deformation and embodiment all will await the reply in the present invention.
Claims (2)
1. diabecron sustained-release tablet agent, is made up of label and sustained release coating, it is characterised in that consisting of:
(1) label: Metformin hydrochloride 50～60%, filler 23～25%, adhesive 4.5～8%, sorbefacient 11～
16%, lubricant 0～1%；
(2) sustained release coating: the part by weight accounting for label is 8～12%, by acrylic polymer, plasticizer, antiplastering aid, pore
Agent forms, and its part by weight is 5:0.15:0.45:1；
Wherein, the XRPD collection of illustrative plates of described Metformin hydrochloride 2 θ be 8.818 ± 0.2,10.442 ± 0.2,12.901 ± 0.2,
14.901±0.2、16.076±0.2、16.88±0.2、17.54±0.2、18.677±0.2、19.12±0.2、19.44±
0.2、20.596±0.2、21.699±0.2、22.422±0.2、23.181±0.2、24.539±0.2、25.779±0.2、
There is diffraction maximum at 27.013 ± 0.2,28.461 ± 0.2；The differential scanning calorimetric thermogram spectrum of described Metformin hydrochloride exists
208.2 ± 0.2 DEG C have feature melting peak；Described sorbefacient is laureth sodium sulfovinate；Described pore-foaming agent is spermaceti
Alcohol polyethers-20；Described acrylic polymer is EUDRAGIT L100-55；Described filler is selected from crystallite
One or more in cellulose, mannitol or lactose；Described adhesive is selected from polyvinylpyrrolidone or Hydroxypropyl methylcellulose
In one or both；Described lubricant is selected from talcum powder or magnesium stearate；Described plasticizer is triethyl citrate；Described anti-
Stick is talcum powder.
2. the method preparing diabecron sustained-release tablet agent according to claim 1, it is characterised in that comprise following step
Rapid:
(1) Metformin hydrochloride crude product is added to the water, is heated to backflow and dissolves, then in solution, add the tetrahydrochysene of certain proportioning
Furans and the tert-butyl alcohol and then formation mixed solvent system, then cooling down crystallization, filter, washing, vacuum drying, obtain hydrochloric acid
Melbine；Weight g of described Metformin hydrochloride crude product and water: volume ml ratio is for 1:8；In described mixed solvent system
The volume ml of water, oxolane and the tert-butyl alcohol is than for 10:3:7；Described cooling down crystallization, its temperature reduces to 4 DEG C；Described
Washing, its solvent using is ether；Described vacuum drying, it is dried used temperature 90 DEG C；
(2) Metformin hydrochloride of step (1) gained is mixed standby with filler, sorbefacient, adhesive is configured to
Prepared binder solution is joined and mixes softwood processed in mixed material by the aqueous solution of 5%, crosses 18 mesh sieves and pelletizes；
(3) particle obtaining step (2) is at 40 DEG C of dryings 1～3 hour, whole grain；
(4) adding lubricant in the particle that step (3) obtains, mixing, label made by compressing tablet；
(5) acrylic polymer, plasticizer, antiplastering aid and the water with two times of weight of acrylic polymer are mixed in proportion
Forming solution, adding pore-foaming agent in solution, stirring, it is standby that coating solution is made in mixing；
(6) coating solution that step (5) obtains uniformly is sprayed onto the prepared piece wicking surface of step (4) to be coated, spray coating solution behaviour
Making to carry out at 38～40 DEG C, spray coating solution process should continue to complete for 2～4 hours, drying 1～2 hour at 75～80 DEG C, i.e.
Obtain diabecron sustained-release tablet agent.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108125930A (en) * | 2018-02-28 | 2018-06-08 | 河北爱尔海泰制药有限公司 | Diabecron sustained-release capsule composition and preparation method thereof |
| CN110256300A (en) * | 2019-06-26 | 2019-09-20 | 武汉大学 | A kind of Metformin hydrochloride compound and metformin hydrochloride tablet composition |
| CN110354090A (en) * | 2019-07-29 | 2019-10-22 | 石药集团欧意药业有限公司 | A kind of diabecron sustained-release tablet and preparation method thereof |
| CN111388438A (en) * | 2020-05-08 | 2020-07-10 | 福建东瑞制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060096728A (en) * | 2005-03-02 | 2006-09-13 | 씨제이 주식회사 | Sustained release formulations and sustained release tablets comprising sustained release pellets |
| CN103622930A (en) * | 2013-12-19 | 2014-03-12 | 石家庄市华新药业有限责任公司 | Metformin hydrochloride slow release preparation and preparation method thereof |
| CN105601635A (en) * | 2016-02-01 | 2016-05-25 | 上海宣创生物科技有限公司 | A crystal form, H crystal form and I crystal form of baricitinib phosphate and preparation method thereof |
-
2016
- 2016-06-08 CN CN201610404666.2A patent/CN106074423A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060096728A (en) * | 2005-03-02 | 2006-09-13 | 씨제이 주식회사 | Sustained release formulations and sustained release tablets comprising sustained release pellets |
| CN103622930A (en) * | 2013-12-19 | 2014-03-12 | 石家庄市华新药业有限责任公司 | Metformin hydrochloride slow release preparation and preparation method thereof |
| CN105601635A (en) * | 2016-02-01 | 2016-05-25 | 上海宣创生物科技有限公司 | A crystal form, H crystal form and I crystal form of baricitinib phosphate and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 赵临襄: "《化学制药工艺学》", 31 August 2015 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108125930A (en) * | 2018-02-28 | 2018-06-08 | 河北爱尔海泰制药有限公司 | Diabecron sustained-release capsule composition and preparation method thereof |
| CN108125930B (en) * | 2018-02-28 | 2020-07-31 | 河北爱尔海泰制药有限公司 | Metformin hydrochloride sustained-release capsule composition and preparation method thereof |
| CN110256300A (en) * | 2019-06-26 | 2019-09-20 | 武汉大学 | A kind of Metformin hydrochloride compound and metformin hydrochloride tablet composition |
| CN110256300B (en) * | 2019-06-26 | 2022-04-05 | 武汉大学 | A kind of metformin hydrochloride compound and metformin hydrochloride tablet composition |
| CN110354090A (en) * | 2019-07-29 | 2019-10-22 | 石药集团欧意药业有限公司 | A kind of diabecron sustained-release tablet and preparation method thereof |
| CN110354090B (en) * | 2019-07-29 | 2021-10-01 | 石药集团欧意药业有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
| CN111388438A (en) * | 2020-05-08 | 2020-07-10 | 福建东瑞制药有限公司 | Metformin hydrochloride sustained release tablet and preparation method thereof |
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