CN104840437B - A kind of pharmaceutical composition containing Repaglinide - Google Patents
A kind of pharmaceutical composition containing Repaglinide Download PDFInfo
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- CN104840437B CN104840437B CN201410049868.0A CN201410049868A CN104840437B CN 104840437 B CN104840437 B CN 104840437B CN 201410049868 A CN201410049868 A CN 201410049868A CN 104840437 B CN104840437 B CN 104840437B
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- China
- Prior art keywords
- repaglinide
- pharmaceutical composition
- rapeseed oil
- vitwas
- starch
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- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 title claims abstract description 78
- 229960002354 repaglinide Drugs 0.000 title claims abstract description 77
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 235000019484 Rapeseed oil Nutrition 0.000 claims abstract description 26
- 239000000945 filler Substances 0.000 claims abstract description 9
- 239000007884 disintegrant Substances 0.000 claims abstract description 7
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- 229920002472 Starch Polymers 0.000 claims description 18
- 239000008107 starch Substances 0.000 claims description 18
- 235000019698 starch Nutrition 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 15
- 239000000843 powder Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- 239000011259 mixed solution Substances 0.000 claims description 13
- 239000000741 silica gel Substances 0.000 claims description 13
- 229910002027 silica gel Inorganic materials 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 12
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 10
- 238000007908 dry granulation Methods 0.000 claims description 9
- 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 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 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 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000000346 sugar Nutrition 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000012535 impurity Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 239000013558 reference substance Substances 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- BXWLVQXAFBWKSR-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(O)=O BXWLVQXAFBWKSR-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 3
- 235000019796 monopotassium phosphate Nutrition 0.000 description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- -1 di(2-ethylhexyl)phosphate Hydrogen ammonium salt Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229960003424 phenylacetic acid Drugs 0.000 description 2
- 239000003279 phenylacetic acid Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical group OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- 210000004128 D cell Anatomy 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N N-butylamine Natural products CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000004703 cross-linked polyethylene Substances 0.000 description 1
- 229920003020 cross-linked polyethylene Polymers 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- KDQPSPMLNJTZAL-UHFFFAOYSA-L disodium hydrogenphosphate dihydrate Chemical compound O.O.[Na+].[Na+].OP([O-])([O-])=O KDQPSPMLNJTZAL-UHFFFAOYSA-L 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- BNYHRGTXRPWASY-UHFFFAOYSA-N nonylsulfonylurea Chemical compound CCCCCCCCCS(=O)(=O)NC(N)=O BNYHRGTXRPWASY-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940103180 repaglinide 1 mg Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of pharmaceutical composition containing Repaglinide, described pharmaceutical composition contain Repaglinide, filler, disintegrant, lubricant, rapeseed oil and Vitwas E.The product stability of the invention of the present invention is good, and dissolution is complete, has more outstanding product quality；Operation is simple for the production of the present invention, is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of pharmaceutical composition containing Repaglinide and its tablet
Preparation method.
Background technology
Repaglinide（English name Repaglinide）, its chemical name is：S (+) -2- ethyoxyls -4- 2- [(3- methyl -
1- (2- (1- piperidyls) phenyl) butyl) amino] -2- oxoethyls } benzoic acid.Molecular formula：C27H36N2O4, molecular weight：
452.59 its structural formula is as follows：
Repaglinide is benzoic acid derivative, non-sulfonylurea Drugs Promoting Insulin Secretion, is that a kind of effect is rapidly new
Oral hypoglycemic drug, combined with the 36KDA protein-specifics outside d cell film on the potassium-channel of dependency ATP, lead to potassium
Road is closed, D cell depolarizations, and calcium channel opens, flow of calcium ions, promotes insulin secretion, and its effect is faster than sulfonylurea, therefore
Postprandial hypoglycemic effect is fast.
Repaglinide is white or off-white color crystalline powder, odorless.This product is readily soluble in chloroform, in ethanol or acetone
It is slightly molten, almost insoluble in water, the slightly soluble in 0.1mol/L hydrochloric acid solutions；The poor dissolubility of Repaglinide is to influence to face
The key factor of bed Different therapeutical effect.To oxygen, damp and hot unstable ether fracture, degraded can occur on this condition for Repaglinide
Product increase, so as to further produce toxic impurities.Foreign countries carry out compatibility using polacrilin potassium and Repaglinide, are drawn using ripple
Crin potassium and the intermolecular network of Repaglinide and, add the stability of Repaglinide；It is domestic to be produced and storage using control
Condition delays the degraded of Repaglinide, but two methods fail the problem that fundamentally solves Repaglinide degraded.Therefore
A kind of good and steady in a long-term repaglinide of dissolution in vitro is developed to be imminent.
The content of the invention
, should the medicine containing Repaglinide it is an object of the invention to provide a kind of new pharmaceutical composition containing Repaglinide
The stability of compositions is good, and dissolution is good.
It is another object of the present invention to provide a kind of preparation method of the pharmaceutical composition containing Repaglinide, the party
Method is adapted to industrial production.
Specifically, the invention provides：
A kind of pharmaceutical composition containing Repaglinide, contains：Repaglinide, filler, disintegrant, lubricant, vegetable seed
Oil and Vitwas E.
The described pharmaceutical composition containing Repaglinide is tablet.
The described pharmaceutical composition containing Repaglinide, the weight ratio of each component are：
The parts by weight of Repaglinide 0.5 ~ 5
The parts by weight of rapeseed oil 3 ~ 8
The parts by weight of Vitwas E 1 ~ 5
The parts by weight of filler 30 ~ 60
The parts by weight of disintegrant 4 ~ 10
The parts by weight of lubricant 1 ~ 5.
One kind in starch, lactose, Icing Sugar, mannitol, microcrystalline cellulose, pregelatinized starch of described filler or
It is several.
Described disintegrant is selected from dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyethylene pyrroles
One or more in alkanone, Ac-Di-Sol.
One or more of the described lubricant in superfine silica gel powder, talcum powder, magnesium stearate.
The described pharmaceutical composition containing Repaglinide prepares piece agent, and its preparation method comprises the following steps：
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) filler, disintegrant and mix lubricant are uniformly added in step (1) resulting material afterwards, using dry method system
Tabletting after grain, obtains Repaglinide tablet.
The present invention has the advantages that compared with prior art：
1st, product stability of the invention is good, and dissolution is complete.
2nd, operation is simple for production of the invention, is suitable for industrial production.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art according to the present invention basic thought, various modifications may be made or improve, but without departing from this
The basic thought of invention, within the scope of the present invention.
Test method
Relevant material takes this product fine powder（It is approximately equivalent to Repaglinide 10mg）, put in 10ml measuring bottles, add Mobile phase B appropriate,
Shaking makes dissolving in 10 minutes, is diluted to scale with Mobile phase B, shakes up, and centrifuges 20 minutes, takes supernatant as need testing solution；
Precision measures 1ml, puts in 100ml measuring bottles, is diluted to scale with Mobile phase B, shakes up.Precision measures 5ml, puts in 25ml measuring bottles,
Scale is diluted to Mobile phase B, is shaken up, as contrast solution.It is another take impurity I, impurity II, impurity III, the reference substance of impurity IV and
Repaglinide reference substance is each appropriate, adds methanol dissolve and dilutes impure I 20 μ g of every 1ml difference, μ g of impurity II 2, impurity is made
III 2 μ g, the μ g of impurity IV 2 and Repaglinide 1mg mixed solution, as system suitability solution.According to high performance liquid chromatography
Method（Two annex V D of Chinese Pharmacopoeia version in 2010）Measure.It is filler with octadecylsilane chemically bonded silica；With phosphoric acid
Dihydro potassium solution（Potassium dihydrogen phosphate 4.0g is taken, after adding water about 900ml to dissolve, adjusts pH value to be added water to 3.2 with the phosphoric acid of dilution
To 1000ml）- acetonitrile（9:1）For mobile phase A, with potassium dihydrogen phosphate（Potassium dihydrogen phosphate 4.0g is taken, adds water about 900ml molten
Xie Hou, pH value is adjusted to be added water to 3.2 to 1000ml with the phosphoric acid of dilution）- acetonitrile（3:7）For Mobile phase B, according to the form below enters line
Property gradient elution；Detection wavelength is 240nm；Column temperature is 45 DEG C；Flow velocity is 0.8ml per minute.Take system suitability solution
20 μ 1 inject liquid chromatograph, record chromatogram, and peak sequence is followed successively by impurity II, impurity III, impurity I, impurity IV and auspicious lattice
Row how peak, the separating degree at impurity IV and Repaglinide peak should meet the requirements.The μ l of contrast solution 20 are taken to inject liquid chromatograph, regulation
Detection sensitivity, the peak height for making principal component chromatographic peak are about the 10%~20% of full scale；Precision measures contrast solution and for examination again
Each 20 μ l of product solution, liquid chromatograph is injected separately into, records chromatogram.
Dissolution rate takes this product, according to dissolution method (two methods of annex XC second of Chinese Pharmacopoeia version in 2010), with
PH5.0 citric acids-phosphate buffer (take citric acid 10.30g, disodium phosphate dihydrate 18.16g, are dissolved in water and dilute
Releasing to 1000ml, shake up, produce) 900ml is dissolution medium, rotating speed is 75 turns per minute, is operated in accordance with the law, during through 30 minutes, is taken
Solution 10ml, filtration, filtrate is as need testing solution；It is another to take Repaglinide reference substance about 11mg, it is accurately weighed, put 100ml amounts
In bottle, add methanol to dissolve and be diluted to scale, shake up, precision measures 1ml, puts in 100ml measuring bottles, with pH5.0 citric acids-phosphoric acid
Salt buffer is diluted to scale, shakes up, as reference substance solution.According to the chromatographic condition under assay item, precision is measured for examination
Product solution and each 100 μ 1 of reference substance solution, liquid chromatograph is injected separately into, records chromatogram.By external standard method with calculated by peak area
The stripping quantity of every.
Uniformity of dosage units takes this product 1, puts in 20ml measuring bottles, adds mobile phase appropriate, and shaking makes dissolving and is diluted to quarter
Degree, shakes up, and filters, takes subsequent filtrate as need testing solution.It is another to take Repaglinide reference substance about 12.5mg, it is accurately weighed, put
In 25ml measuring bottles, add methanol to dissolve and be diluted to scale, shake up, precision measures 5ml, puts in 50ml measuring bottles, with flowing phase dilution
To scale, shake up, as reference substance solution.Determined according to the method under assay item.
Assay shines high performance liquid chromatography（Two annex V D of Chinese Pharmacopoeia version in 2010）Measure.
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability；With 0.2% di(2-ethylhexyl)phosphate
Hydrogen ammonium salt solution (with phosphorus acid for adjusting pH value to 2.5)-methanol (30:70) it is mobile phase；Detection wavelength is 245nm；40 DEG C of column temperature.
Repaglinide reference substance solution is taken to repeat sample introduction 6 times, the relative standard deviation of its peak area should be not more than 2.0%.
Determination method takes this product 20, accurately weighed, and finely ground, precision weighs in right amount（It is approximately equivalent to Repaglinide 8.0mg）,
Put in 100ml measuring bottles, add mobile phase appropriate, shaking makes dissolving and be diluted to scale for 10 minutes, shakes up, and filters, precision measures continuous
The μ 1 of filtrate 20 injects liquid chromatograph, records chromatogram；It is another to take Repaglinide reference substance about 20mg, it is accurately weighed, put 25ml amounts
In bottle, adding methanol to dissolve and be diluted to scale, shake up, precision measures 5ml, puts in 50ml measuring bottles, and scale is diluted to mobile phase,
Shake up, be measured in the same method.By external standard method with calculated by peak area, produce.
Impurity I：
Chinese name：（s）- 3- methyl isophthalic acids-（2- piperidinyl-phenyls）- 1- butylamine N- acetyl-Pidolidone salt
Impurity II：
Chinese name：3- ethyoxyls -4- carboxyls-phenylacetic acid
Impurity III：
Chinese name：[3- ethyoxyls -4- (ethoxycarboxy)] phenylacetic acid
Impurity IV：
Chinese name：((s) -2- ethyoxyls -4- [2- [[2- phenyl -1- [2- (1- piperidyls) phenyl] ethylamino] -2-
Oxoethyl]
Benzoic acid)
Test example 1：Prescription screening is tested
Repaglinide 1g is taken respectively（Content 99.9%, total miscellaneous 0.09%）, starch 35g, dried starch 4g, superfine silica gel powder 1.8g,
The tablet containing Repaglinide is made by following prescriptions, detects relevant material and dissolution rate, the results are shown in Table 2：
The prescription screening of table 1
Table 2 is about substances test result
Result of the test shows：
Repaglinide and rapeseed oil are dissolved in relevant material and dissolution rate made from Vitwas E
Better than other method.
Test example 2：Influence factor is tested
The product of Example 3,5,6,8 and the product as made from the method for 201210266520.8 embodiments of ZL 1 are influenceed
Factorial experiments, it the results are shown in Table 3.
The influence factor test data of table 3
Conclusion：Road as seen from the above table, the product prepared by the inventive method, stability under high temperature and illumination better than pair
Ratio.
Test example 3：Accelerated test
The product of Example 5,6,8 and the product as made from the method for 201210266520.8 embodiments of ZL 1 carry out acceleration examination
Test, the results are shown in Table 4.
The accelerated test data of table 4
Packaging：Commercially available back, investigate condition：40 DEG C of temperature, humidity 75%
Conclusion：Road as seen from the above table, the product prepared by the inventive method, stability under high temperature and illumination better than pair
Ratio.
Embodiment 1
Prescription
Repaglinide 1.0g
Rapeseed oil 5g
Vitwas E 3.6g
Starch 35g
Dried starch 4g
Superfine silica gel powder 1.8g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) added after being well mixed starch, dried starch and superfine silica gel powder in step (1) resulting material, using dry method system
Tabletting after grain, obtains Repaglinide tablet.
Embodiment 2
Prescription
Repaglinide 0.5g
Rapeseed oil 4.5g
Vitwas E 2g
Lactose 38g
Sodium carboxymethyl starch 8g
Talcum powder 2.8g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) added after being well mixed lactose, sodium carboxymethyl starch and talcum powder in step (1) resulting material, using dry
Tabletting after method granulation, obtains Repaglinide tablet.
Embodiment 3
Prescription
Repaglinide 2.0g
Rapeseed oil 4.0g
Vitwas E 2.8g
Icing Sugar 45g
Low-substituted hydroxypropyl cellulose 10g
Superfine silica gel powder 2.5g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) step (1) resulting material is added after being well mixed Icing Sugar, low-substituted hydroxypropyl cellulose and superfine silica gel powder
In, using tabletting after dry granulation, obtain Repaglinide tablet.
Embodiment 4
Prescription
Repaglinide 2.5g
Rapeseed oil 7.5g
Vitwas E 4.3g
Mannitol 54g
PVPP 5g
Magnesium stearate 2.5g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) step (1) gains are added after being well mixed mannitol, PVPP and magnesium stearate
In material, using tabletting after dry granulation, Repaglinide tablet is obtained.
Embodiment 5
Prescription
Repaglinide 3g
Rapeseed oil 8g
Vitwas E 3.2g
Microcrystalline cellulose 37g
Ac-Di-Sol 6g
Magnesium stearate 1.5g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) step (1) institute is added after being well mixed microcrystalline cellulose, Ac-Di-Sol and magnesium stearate
Obtain in material, using tabletting after dry granulation, obtain Repaglinide tablet.
Embodiment 6
Prescription
Repaglinide 3.5g
Rapeseed oil 4g
Vitwas E 5g
Microcrystalline cellulose 55g
Dried starch 6g
Sodium carboxymethyl starch 4g
Talcum powder 0.8g
Magnesium stearate 0.5g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) add and walk after being well mixed microcrystalline cellulose, dried starch, sodium carboxymethyl starch, talcum powder, magnesium stearate
Suddenly in (1) resulting material, using tabletting after dry granulation, Repaglinide tablet is obtained.
Embodiment 7
Prescription
Repaglinide 4.0g
Rapeseed oil 6.1g
Vitwas E 4.2g
Pregelatinized starch 53g
Low-substituted hydroxypropyl cellulose 5g
Ac-Di-Sol 5g
Superfine silica gel powder 4g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) pregelatinized starch, low-substituted hydroxypropyl cellulose, Ac-Di-Sol, superfine silica gel powder are mixed equal
Added after even in step (1) resulting material, using tabletting after dry granulation, obtain Repaglinide tablet.
Embodiment 8
Prescription
Repaglinide 1.0g
Rapeseed oil 3.5g
Vitwas E 2.3g
Microcrystalline cellulose 48g
Low-substituted hydroxypropyl cellulose 9.2g
Superfine silica gel powder 1.5g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) step (1) gains are added after being well mixed crystalline cellulose, low-substituted hydroxypropyl cellulose, superfine silica gel powder
In material, using tabletting after dry granulation, Repaglinide tablet is obtained.
Embodiment 9
Prescription
Repaglinide 2.0g
Rapeseed oil 3.5g
Vitwas E 1.2g
Mannitol 60g
Ac-Di-Sol 4g
Talcum powder 3g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) step (1) resulting material is added after being well mixed mannitol, Ac-Di-Sol, talcum powder
In, using tabletting after dry granulation, obtain Repaglinide tablet.
Embodiment 10
Prescription
Repaglinide 4.0g
Rapeseed oil 7.1g
Vitwas E 2.1g
Mannitol 50g
Low-substituted hydroxypropyl cellulose 9g
Superfine silica gel powder 5g.
Preparation method
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) step (1) resulting material is added after being well mixed mannitol, low-substituted hydroxypropyl cellulose, superfine silica gel powder
In, using tabletting after dry granulation, obtain Repaglinide tablet.
Claims (6)
1. a kind of pharmaceutical composition containing Repaglinide, it is characterised in that the weight ratio of pharmaceutical composition each component is：
2. the pharmaceutical composition according to claim 1 containing Repaglinide, it is characterised in that：The rapeseed oil is given birth to dimension
The weight ratio of plain E acetates is 2:1.
3. the pharmaceutical composition according to claim 1 containing Repaglinide, it is characterised in that described filler is selected from
One or more in starch, lactose, Icing Sugar, mannitol, microcrystalline cellulose, pregelatinized starch.
4. the pharmaceutical composition according to claim 1 containing Repaglinide, it is characterised in that described disintegrant is selected from
Dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol
In one or more.
5. the pharmaceutical composition according to claim 1 containing Repaglinide, it is characterised in that described lubricant is selected from
One or more in superfine silica gel powder, talcum powder, magnesium stearate.
6. the pharmaceutical composition according to claim 1 containing Repaglinide, it is characterised in that pharmaceutical composition is prepared into
Tablet, its preparation method are：
(1) by the mixed solution of Repaglinide, rapeseed oil and Vitwas E, stir；
(2) filler, disintegrant and mix lubricant are uniformly added in step (1) resulting material afterwards, after dry granulation
Tabletting, obtain Repaglinide tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410049868.0A CN104840437B (en) | 2014-02-13 | 2014-02-13 | A kind of pharmaceutical composition containing Repaglinide |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410049868.0A CN104840437B (en) | 2014-02-13 | 2014-02-13 | A kind of pharmaceutical composition containing Repaglinide |
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| Publication Number | Publication Date |
|---|---|
| CN104840437A CN104840437A (en) | 2015-08-19 |
| CN104840437B true CN104840437B (en) | 2018-04-03 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189029A (en) * | 2005-04-28 | 2008-05-28 | 盖伦尼卡技术股份公司 | Pharmaceutical dosage forms comprising a lipid phase |
| CN102552258A (en) * | 2012-02-24 | 2012-07-11 | 北京协和药厂 | Pharmaceutical composition containing repaglinide and preparation method of same |
| CN102743354A (en) * | 2012-07-31 | 2012-10-24 | 南京正科制药有限公司 | Repaglinide tablet and preparation method thereof |
-
2014
- 2014-02-13 CN CN201410049868.0A patent/CN104840437B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101189029A (en) * | 2005-04-28 | 2008-05-28 | 盖伦尼卡技术股份公司 | Pharmaceutical dosage forms comprising a lipid phase |
| CN102552258A (en) * | 2012-02-24 | 2012-07-11 | 北京协和药厂 | Pharmaceutical composition containing repaglinide and preparation method of same |
| CN102743354A (en) * | 2012-07-31 | 2012-10-24 | 南京正科制药有限公司 | Repaglinide tablet and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN104840437A (en) | 2015-08-19 |
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Denomination of invention: A drug combination containing regagliflozone Effective date of registration: 20231226 Granted publication date: 20180403 Pledgee: China Construction Bank Co.,Ltd. Changchun Science and Technology Sub branch Pledgor: CHANGCHUN HAIYUE PHARMACEUTICAL Co.,Ltd. Registration number: Y2023220000149 |
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