CN1586610A - Process for preparing granular powder for treating neurosism and quality control method - Google Patents
Process for preparing granular powder for treating neurosism and quality control method Download PDFInfo
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- CN1586610A CN1586610A CNA2004100780940A CN200410078094A CN1586610A CN 1586610 A CN1586610 A CN 1586610A CN A2004100780940 A CNA2004100780940 A CN A2004100780940A CN 200410078094 A CN200410078094 A CN 200410078094A CN 1586610 A CN1586610 A CN 1586610A
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- 239000000843 powder Substances 0.000 title claims description 8
- 238000003908 quality control method Methods 0.000 title abstract description 13
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 44
- 239000008187 granular material Substances 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 33
- 239000000341 volatile oil Substances 0.000 claims abstract description 28
- 229930003451 Vitamin B1 Natural products 0.000 claims abstract description 26
- 229960003495 thiamine Drugs 0.000 claims abstract description 26
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims abstract description 26
- 239000011691 vitamin B1 Substances 0.000 claims abstract description 26
- 235000010374 vitamin B1 Nutrition 0.000 claims abstract description 26
- TZJALUIVHRYQQB-XFDQAQKOSA-N Icariin Natural products O(C)c1ccc(C2=C(O[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O3)C(=O)c3c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O4)c(C/C=C(\C)/C)c3O2)cc1 TZJALUIVHRYQQB-XFDQAQKOSA-N 0.000 claims abstract description 25
- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 claims abstract description 25
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 claims abstract description 25
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 14
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 12
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 12
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 12
- 229960004853 betadex Drugs 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 11
- 238000001694 spray drying Methods 0.000 claims abstract description 7
- 229920001353 Dextrin Polymers 0.000 claims abstract description 6
- 239000004375 Dextrin Substances 0.000 claims abstract description 6
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims abstract description 6
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- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000019202 steviosides Nutrition 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 67
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- 238000012360 testing method Methods 0.000 claims description 26
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 17
- 239000013558 reference substance Substances 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
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- 229910019142 PO4 Inorganic materials 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 239000011230 binding agent Substances 0.000 claims description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 3
- 239000007766 cera flava Substances 0.000 claims description 3
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
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- OBAMWENTFIOOIT-UHFFFAOYSA-N butan-2-one;ethyl acetate Chemical compound CCC(C)=O.CCOC(C)=O OBAMWENTFIOOIT-UHFFFAOYSA-N 0.000 claims 1
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- 229940088594 vitamin Drugs 0.000 claims 1
- 229930003231 vitamin Natural products 0.000 claims 1
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- 150000003722 vitamin derivatives Chemical class 0.000 claims 1
- 241000893536 Epimedium Species 0.000 abstract 1
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- NLDDIKRKFXEWBK-AWEZNQCLSA-N gingerol Chemical compound CCCCC[C@H](O)CC(=O)CCC1=CC=C(O)C(OC)=C1 NLDDIKRKFXEWBK-AWEZNQCLSA-N 0.000 description 6
- JZLXEKNVCWMYHI-UHFFFAOYSA-N gingerol Natural products CCCCC(O)CC(=O)CCC1=CC=C(O)C(OC)=C1 JZLXEKNVCWMYHI-UHFFFAOYSA-N 0.000 description 6
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- 229930003944 flavone Natural products 0.000 description 4
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- 239000003921 oil Substances 0.000 description 4
- 206010019233 Headaches Diseases 0.000 description 3
- 208000007443 Neurasthenia Diseases 0.000 description 3
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- 238000004458 analytical method Methods 0.000 description 3
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- KKOXKGNSUHTUBV-UHFFFAOYSA-N racemic zingiberene Natural products CC(C)=CCCC(C)C1CC=C(C)C=C1 KKOXKGNSUHTUBV-UHFFFAOYSA-N 0.000 description 3
- 238000011003 system suitability test Methods 0.000 description 3
- KKOXKGNSUHTUBV-LSDHHAIUSA-N zingiberene Chemical compound CC(C)=CCC[C@H](C)[C@H]1CC=C(C)C=C1 KKOXKGNSUHTUBV-LSDHHAIUSA-N 0.000 description 3
- 229930001895 zingiberene Natural products 0.000 description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- QQXDYWHKPKEBJU-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCC[Na] Chemical compound CCCCCCCCCCCCCCCCCC[Na] QQXDYWHKPKEBJU-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 244000303040 Glycyrrhiza glabra Species 0.000 description 2
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229930003270 Vitamin B Natural products 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- KIBLEPZGKRYXBB-UHFFFAOYSA-N butan-2-one ethyl acetate formic acid hydrate Chemical compound O.OC=O.CCC(C)=O.CCOC(C)=O KIBLEPZGKRYXBB-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
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- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 2
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- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
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- 238000002844 melting Methods 0.000 description 2
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- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
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- 235000019156 vitamin B Nutrition 0.000 description 2
- 239000011720 vitamin B Substances 0.000 description 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
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- JZRWCGZRTZMZEH-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention relates to the preparation process and quality control method of medicine granule for treating neurosism. The medicine granule is prepared with pilose antler and other six kinds of Chinese medicinal materials and contains also dextrin, stevioside as corrective. The preparation process includes beta-cyclodextrin clathration of volatile oil, beta-cyclodextrin co-dissolution, spray drying and dry pelletizing and is favorable to maintaining the effective components and continuous GMP production. The medicine is stable, safe and accurate in dosage. The quality control method includes the thin layer identification of epimedium, and the measurement of icariin and vitamin B1 content to ensure the consistency and effectiveness of the preparation.
Description
(technical field)
The present invention relates to a kind of spermatogenesis benefit marrow that has, strengthen mental effect, the treatment neurasthenia, insomnia, forgetful, medicine of headache and preparation method thereof belongs to the field of Chinese medicines.
(background technology)
The neurasthenia, insomnia, forgetful, headache has become the commonly encountered diseases of society now, and the drug research for the treatment of this class disease is also more paid attention to, and uses also increasingly extensive.Ataractic use can bring pronounced side effects in the modern chemistry medicine, also do not have so far a kind of treat such disease safe, can be for the medicine taken for a long time.And develop the Chinese medicine traditional advantage, exploitation preparation stabilization, drug safety, dosage is accurate, quality controllable, the reliable Chinese medicine preparation of curative effect is significant.The Chinese medicine ANSHEN BUNAO YE is a kind of neurasthenia of being used for the treatment of, insomnia, and forgetful, the Chinese medicine patent medicine preparation of headache is made by main material medicine Cornu Cervi Pantotrichum, Radix Polygoni Multiflori Preparata, Herba Epimedii, Rhizoma Zingiberis, Radix Glycyrrhizae, Fructus Jujubae, vitamin B1.But this pharmaceutical preparation at present is liquid preparation, and dosage form falls behind, and medicine stability is poor; Contain ethanol, antiseptic and a large amount of simple syrup, the absorption of ethanol, antiseptic and too much sugar there is no benefit to human body, influences the safe handling of preparation; The patient who while ethanol autopath or some is avoided sugared disease also can produce untoward reaction such as allergy, hyperglycemia.
(summary of the invention)
One of purpose of the present invention provides a kind of Chinese medicine Anshenbunao granule, contain the harmful effect of ethanol, antiseptic and too much sugar to overcome liquid preparation to human body, and reaching the purpose of taking convenience, this preparation significantly improves than the medicine stability of former dosage form simultaneously.Two of purpose of the present invention provides the preparation method and the method for quality control of this Chinese medicine Anshenbunao granule.
Chinese medicine of the present invention " Anshenbunao granule " is made by 30 weight portion Cornu Cervi Pantotrichums, 625 weight portion Radix Polygoni Multiflori Preparatas, 500 weight portion Herba Epimedii, 125 weight portion Rhizoma Zingiberiss, 62.5 weight portion Radix Glycyrrhizaes, 125 weight portion Fructus Jujubaes, 5 weight portion vitamin B1 crude drug, and medicament also contains forming agent dextrin 900-1200 weight portion and correctives stevioside 100 weight portions.
Chinese medicine of the present invention " Anshenbunao granule " also uses beta-cyclodextrin inclusion compound volatile oil technology, and the retention rate of the effective ingredient zingiberene in the volatile oil is brought up to more than the twice, and the consumption of beta-schardinger dextrin-is the 6.8-13.6 weight portion.
Used ethanol with the relatively poor active component of dissolubility in the hydrotropy side in the former standard preparation, for improving the dissolubility of the relatively poor active component of these dissolubilities in water, increase the melting of granule, Chinese medicine of the present invention " Anshenbunao granule " uses the method for beta-cyclodextrin inclusion compound medicinal liquid with hydrotropy, [icariin has the cerebral tissue of delaying aging to make icariin in the Herba Epimedii and total flavones, suppress cholinesterase activity in aged mouse brain and the blood. Meng Xianli, Ceng Nan, Zhang Yi etc. CHINA JOURNAL OF CHINESE MATERIA MEDICA .1996,21 (11): 683; Herba Epimedii total flavones is to the influence of rabbit platelet function and mice tranquilizing soporific and endurance effect. Gao Qiming, Yuan Bingxiang, Li Shengzheng etc. and northwest pharmaceutical journal, 1992; (3): 15], 6-gingerol in the Rhizoma Zingiberis [the 6-gingerol has anticoagulant, removing free radical, antiinflammatory, analgesic effect. Chen Huifang. and the active components of plants dictionary, first, Beijing, Chinese Medicine science and technology publishing house, 2001:902], [lecithin can promote the growth promoter of blood cell to lecithin in the Radix Polygoni Multiflori Preparata, main component for its invigorating the liver and kidney, benefiting essence-blood. Xu Chujiang, the chief editor. the science of Chinese drug processing, Shanghai, the 1985:145 of Science and Technology of Shanghai publishing house] etc. the mass efficient composition kept, the consumption of beta-schardinger dextrin-is the 500-800 weight portion.
The preparation method of this Chinese medicine Anshenbunao granule is as follows:
Take by weighing 30 weight portion Cornu Cervi Pantotrichums, 625 weight portion Radix Polygoni Multiflori Preparatas, 500 weight portion Herba Epimedii, 125 weight portion Rhizoma Zingiberiss, 62.5 weight portion Radix Glycyrrhizaes, 125 weight portion Fructus Jujubaes, 5 weight portion vitamin B1s, standby;
More than seven flavors, Rhizoma Zingiberis adds 1000 weight parts waters and extracted volatile oil 4 hours, volatile oil is with 6.8-13.6 weight portion beta-cyclodextrin inclusion compound, enclose liquid is standby.Medicinal residues and Radix Polygoni Multiflori Preparata, Herba Epimedii, Fructus Jujubae, Radix Glycyrrhizae decoct with water three times, and 2 hours for the first time, amount of water was 14375 weight portions, second and third time each 1 hour, amount of water is 11500 weight portions, collecting decoction, filter, filtrate is concentrated into flowing soaking paste (about 1.30,50 ℃ of relative density), add ethanol to 70%, precipitation filters filtrate recycling ethanol, be concentrated into about 1.08～1.10 (50 ℃) of relative density, standby.The Cornu Cervi Pantotrichum coarse powder is decocted with water five times, and 4,4,3,3,2 hours successively time, amount of water is respectively 300,300,240,240,180 weight portions, and gradation filters, merging filtrate is concentrated into 1/2 of crude drug in whole, adds Cera Flava, leave standstill solidify fully to the wax layer after, remove the dewax layer, sucking filtration is to clear and bright.Adding 80% ethanol is 40% to containing the alcohol amount, and room temperature was placed 48 hours, filtered, filtrate recycling ethanol is to about 1.05～1.15 (50 ℃) of relative density, and adding ethanol is 60% to containing the alcohol amount, and room temperature was placed 24 hours, filter, filtrate recycling ethanol is to about 1.05～1.15 (50 ℃) of relative density.Above-mentioned medicinal liquid, inclusion essential oil liquid, Cornu Cervi Pantotrichum extracting solution are added beta-schardinger dextrin-500-800 weight portion hydrotropy, add-on type agent dextrin 900-1200 weight portion again, fully stir, filter, under atomize, feed hot-air, carry out spray drying, 180 ℃ of hot-air inlet temperature, 80 ℃ of leaving air temps, spray powder add and vitamin B1 mixes; Correctives stevioside 100 weight portions, mixing, material is dry granulation under 18-60 ℃ of temperature, and granulate gets granule, packing, every bag of 2g, promptly.
The method of quality control of Anshenbunao granule of the present invention comprises the discrimination method of Herba Epimedii in the preparation and the content assaying method of icariin and vitamin B1.
The method of quality control of Anshenbunao granule of the present invention, wherein the concrete steps of the discrimination method of Herba Epimedii are in the preparation:
Get this product 6g, porphyrize adds ethanol 20ml reflux, extract,, filters, and filtrate evaporate to dryness, residue add the 2ml dissolve with ethanol, as need testing solution.Other gets Herba Epimedii control medicinal material 0.5g, shines medical material solution in pairs with legal system.According to thin layer chromatography (" 2000 editions one appendix VI B of Chinese pharmacopoeia) test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel H lamellae of binding agent with the sodium carboxymethyl cellulose, with ethyl acetate-butanone-formic acid-water (10: 1: 1: 1) be developing solvent, take out, dry, spray 5% aluminum chloride test solution, 105 ℃ were dried by the fire 5 minutes, and put under the ultra-violet lamp (365nm) again and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
The method of quality control of Anshenbunao granule of the present invention, measure wherein that the concrete parameter of icariin content is in the preparation: with octadecylsilane chemically bonded silica is filler;
Mobile phase is
Acetonitrile 30 volumes
0.1% trifluoroacetic acid aqueous solution, 70 volumes
The detection wavelength is 270nm;
Number of theoretical plate calculates by the icariin peak should be not less than 3000.
Wherein mobile phase can also be: with methanol-0.1% phosphate aqueous solution (30: 70) (v/v) or methanol-0.1% trifluoroacetic acid aqueous solution (30: 70) (v/v).
The method of quality control of Anshenbunao granule of the present invention, measure wherein that the concrete parameter of vitamin B1 content is in the preparation: with octadecylsilane chemically bonded silica is filler;
Mobile phase is
Methanol 23 volumes
10mmol/L heptane Ji Huangsuannashui (containing 1% glacial acetic acid, 0.2% triethylamine) 77 volumes
The detection wavelength is 254nm;
Number of theoretical plate calculates by the vitamin B1 peak should be not less than 3000.
Mobile phase can also for
Methanol 23 volumes
10mmol/L octadecyl sodium sulfonate water (containing 1% glacial acetic acid, 0.2% triethylamine) 77 volumes
Anshenbunao granule of the present invention adopts the beta-cyclodextrin inclusion compound technology of Rhizoma Zingiberis volatile oil, thereby increase the stability of volatile oil, preparation of the present invention has also used beta-schardinger dextrin-hydrotropy technology simultaneously, and the effective ingredient in the preparation is better kept, and has improved the curative effect of preparation.
The present invention changes the Anshen Bunao oral liquid into granule (solid preparation), and medicine stability is good, easily storage, transportation.Said preparation does not contain ethanol, antiseptic and simple syrup, takes safer.
Preparation of the present invention also is prepared from by the new technique of spray drying, dry granulation.Effective ingredient is not destroyed and fully reservation in the spray drying technology side of making, and has overcome present syrup and has been aqueous solution state, and effective ingredient is easily degraded and unsettled drawback.Dry granulation is that medicine dry powder is added suitable amount of adhesive adjuvant PVP, and mechanical compaction, one-tenth are put in order and formed under the convection drying state, make stable effective ingredients such as icariin and vitamin B1 constant.The said method operating process is simple, is convenient to large-scale production under the seriality GMP condition.
The invention provides the content assaying method of icariin and vitamin B1 in the discrimination method of Herba Epimedii in the preparation and the preparation.Preparation increases quality control method, has improved the quality control of medicine, has guaranteed preparation homogeneity and effectiveness.
(specific embodiment)
The preparation of embodiment one Anshenbunao granule
Take by weighing raw material Cornu Cervi Pantotrichum 30g, Radix Polygoni Multiflori Preparata 625g, Herba Epimedii 500g, Rhizoma Zingiberis 125g, Radix Glycyrrhizae 62.5g, Fructus Jujubae 125g, vitamin B1 5g, standby;
More than seven the flavor, Rhizoma Zingiberis adds 1000g water extraction volatile oil 4 hours, volatile oil 10.2g beta-cyclodextrin inclusion compound, enclose liquid is standby.Medicinal residues and Radix Polygoni Multiflori Preparata, Herba Epimedii, Fructus Jujubae, Radix Glycyrrhizae decoct with water three times, and 2 hours for the first time, amount of water was 14375g, second and third time each 1 hour, amount of water is 11500g, collecting decoction, filter, filtrate is concentrated into flowing soaking paste (about 1.30,50 ℃ of relative density), add ethanol to 70%, precipitation filters filtrate recycling ethanol, be concentrated into about 1.08～1.10 (50 ℃) of relative density, standby.The Cornu Cervi Pantotrichum coarse powder is decocted with water five times, and 4,4,3,3,2 hours successively time, amount of water is respectively 300,300,240,240,180g, and gradation filters, merging filtrate is concentrated into 1/2 of crude drug in whole, adds Cera Flava, leave standstill solidify fully to the wax layer after, remove the dewax layer, sucking filtration is to clear and bright.Adding 80% ethanol is 40% to containing the alcohol amount, and room temperature was placed 48 hours, filtered, filtrate recycling ethanol is to about 1.05～1.15 (50 ℃) of relative density, and adding ethanol is 60% to containing the alcohol amount, and room temperature was placed 24 hours, filter, filtrate recycling ethanol is to about 1.05～1.15 (50 ℃) of relative density.Above-mentioned medicinal liquid, inclusion essential oil liquid, Cornu Cervi Pantotrichum extracting solution are added beta-schardinger dextrin-500g hydrotropy, add dextrin 1200g again, fully stir, filter, under atomize, feed hot-air, carry out spray drying, 180 ℃ of hot-air inlet temperature, 80 ℃ of leaving air temps, spray powder add and the vitamin B1 mixing adds stevioside 100g, mixing again, material is dry granulation under 18-60 ℃ of temperature, granulate gets brown particle 2000g, is distributed into bag by each dose 2g.
The selection of embodiment two Rhizoma Zingiberis volatile oil beta-cyclodextrin inclusion compound conditions
In order to increase the stability of volatile oil, guarantee the curative effect of preparation, we adopt saturated water solution method, and Rhizoma Zingiberis volatile oil carries out enclose in the general side, and screens best clathrate process condition with orthogonal experiment.
The saturated water solution method enclose: it is an amount of that precision takes by weighing beta-schardinger dextrin-, place 150ml tool plug triangular flask, add distilled water 100ml, heating in water bath makes dissolving, reduce to set point of temperature, add the equal amount of mixture of volatile oil and dehydrated alcohol, ultrasonic enclose certain hour was put refrigerator cold-storage 24 hours, sucking filtration, with petroleum ether (30～60 ℃) washing (10,5,5ml), to drain, 40 ℃ of dryings promptly got clathrate in 4 hours.
Set up beta-schardinger dextrin-and oily proportioning, the enclose temperature, ultrasonic time is three principal elements, respectively gets three levels, carries out orthogonal test.Test data and calculating thereof see Table 1, table 2.
Table 1 beta-cyclodextrin inclusion compound volatile oil orthogonal experiments
Table 2 beta-cyclodextrin inclusion compound volatile oil orthogonal test analysis of variance table
The mean square F significance of soruces of variation quadratic sum degree of freedom
β-CD: oil 87.41 2 43.70 9.79 is not remarkable
The enclose temperature (℃) 453.50 2 226.75 50.80 remarkable
Ultrasonic time (min) 24.25 2 12.12 2.72 is not remarkable
Error 8.93 2 4.46
By intuitive analysis as seen, the order that influences inclusion essential oil is: enclose temperature＞beta-schardinger dextrin-and oily proportioning＞time, and with enclose temperature effect maximum.By the variance analysis of table 2 as can be seen, the enclose temperature has the significance influence to inclusion essential oil, beta-schardinger dextrin-does not have the significance influence with the proportioning and the ultrasonic time of oil to inclusion essential oil, wherein β-CD is 4 with the proportioning of oil: 1-8: 1, the inclusion temperature is 30-40 ℃, and mixing time is 15-30min.Best clathrate process condition is: beta-schardinger dextrin-is 6: 1 with the proportioning of oil, and the enclose temperature is 40 ℃, and ultrasonic time is 45min.
Embodiment three beta-schardinger dextrin-s disperse the selection of hydrotropy condition
Owing to contain the relatively poor active component of water-soluble among the we,, increase the melting of granule so adopt beta-schardinger dextrin-to make its better dispersion.In order to select the dispersive optimum condition of beta-schardinger dextrin-, three comparative tests have been carried out.
Take by weighing raw material Cornu Cervi Pantotrichum 90g, Radix Polygoni Multiflori Preparata 1875g, Herba Epimedii 1500g, Rhizoma Zingiberis 375g, Radix Glycyrrhizae 187.5g, Fructus Jujubae 375g; Get the medicinal liquid behind concentrated medicament, Rhizoma Zingiberis volatile oil enclose liquid and the Cornu Cervi Pantotrichum extracting solution mixing of Rhizoma Zingiberis, Radix Polygoni Multiflori Preparata, Herba Epimedii, Fructus Jujubae, liquorice beverage decocting liquid, three parts of div in par aeq add not commensurability beta-schardinger dextrin-respectively, test after stirring evenly.With general gingerol, total flavones and icariin as investigating index, investigate its to and the influence of the retention rate of icariin, the results are shown in Table 3.
Table 3 beta-schardinger dextrin-consumption is to the influence of icariin retention rate
The result shows, solubilization-aid effect was undesirable when the beta-schardinger dextrin-consumption was 200g, when increasing to 500g, the retention rate of index components general gingerol, total flavones and icariin is higher, when increasing to 800g again as the beta-schardinger dextrin-consumption, the retention rate difference of index components is very little during with 500g, is 500-800g so select the consumption of beta-schardinger dextrin-, and the best is 500g.
Therefore, the consumption of the dispersion of the medicinal liquid beta-schardinger dextrin-behind the concentrated medicament of Rhizoma Zingiberis, Radix Polygoni Multiflori Preparata, Herba Epimedii, Fructus Jujubae, liquorice beverage decocting liquid, Rhizoma Zingiberis volatile oil enclose liquid, Cornu Cervi Pantotrichum extracting solution mixing hydrotropy is 500g.
The active constituent content of embodiment four Anshen Bunao oral liquids, Anshenbunao granule is (one) relatively
The active constituent content comparative test (one) of table 4 Anshen Bunao oral liquid, Anshenbunao granule
Sample zingiberene content (mg) 6-gingerol content (mg) lecithin content (mg)
0.177/ 0.064/ 2.67/ of Anshen Bunao oral liquid
0.372/ bag 0.12/ bag 4.83/ bag of Anshenbunao granule
Raising rate 110% 87.5% 80.9%
The result shows that behind the employing beta-cyclodextrin inclusion compound Rhizoma Zingiberis volatile oil, the content of volatile oil component zingiberene significantly improves than the content in the Anshen Bunao particulate oral liquid in the Anshenbunao granule preparation; After using beta-schardinger dextrin-hydrotropy technology, the effective ingredient 6-gingerol in the preparation, the dissolubility of lecithin are increased, guarantee the curative effect of preparation.
The active constituent content of embodiment five Anshen Bunao oral liquids, Anshenbunao granule is (two) relatively
The active constituent content comparative test (two) of table 5 Anshen Bunao oral liquid, Anshenbunao granule
Sample icariin content 2,2,5,4 '-tetrahydroxy hexichol second vitamin B1 content
(mg) alkene-2-O-glucoside content (mg) (mg)
1.72/ 2.12/ 3.41/ of Anshen Bunao oral liquid
2.14/ bag 3.23/ bag 4.72/ bag of Anshenbunao granule
1.94/ bag 2.73/ bag 4.37/ bag of wet granulation Anshenbunao granule
The result shows, adopt the new technique of spray drying, dry granulation, can pass through the wink-dry technology, make heat-labile effective ingredient as 2,2,5,4 '-tetrahydroxystilbene-2-O-glucoside is not destroyed and fully keeps, overcome present syrup and be aqueous solution state, the drawback of effective ingredient degraded.
The thin layer of Herba Epimedii is differentiated in embodiment six Anshenbunao granules
Get this product 6g, porphyrize adds ethanol 20ml reflux, extract,, filters, and filtrate evaporate to dryness, residue add the 2ml dissolve with ethanol, as need testing solution.Other gets control medicinal material 0.5g, shines medical material solution in pairs with legal system.According to thin layer chromatography (" 2000 editions one appendix VI B of Chinese pharmacopoeia) test, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel H lamellae of binding agent with the sodium carboxymethyl cellulose, with ethyl acetate-butanone-formic acid-water (10: 1: 1: 1) be developing solvent, take out, dry, spray 5% aluminum chloride test solution, 105 ℃ were dried by the fire 5 minutes, and put under the ultra-violet lamp (365nm) again and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
Icariin assay in embodiment seven Anshenbunao granules
Measure according to high performance liquid chromatography (" 2000 editions one appendix VI D of Chinese pharmacopoeia).
Wherein flow phase system test shows: with methanol-0.1% phosphate aqueous solution (30: 70) (v/v) or methanol-0.1% trifluoroacetic acid aqueous solution (30: 70) (v/v) (v/v) obtain similar analysis collection of illustrative plates when being mobile phase to methanol-0.1% trifluoroacetic acid aqueous solution (30: 70), but trifluoroacetic acid, acetic acid are organic acid, it is all little than phosphoric acid to the influence of chromatographic apparatus and chromatographic column, and it is preferably to make mobile phase pH reagent with trifluoroacetic acid.
Chromatographic condition and system suitability test: Waters 600 pumps, ultraviolet 486 detectors, Rheodyne injector.
With octadecylsilane chemically bonded silica is filler, and be 30: 70 acetonitrile with volume ratio: 0.1% trifluoroacetic acid aqueous solution is a mobile phase; The detection wavelength is 270nm.Number of theoretical plate calculates by the icariin peak should be not less than 3000.
The preparation of reference substance solution: precision takes by weighing in 60 ℃ of icariin reference substances that are dried to constant weight an amount of, makes the solution that every 1ml contains the 0.282mg icariin with mobile phase, promptly;
The preparation of need testing solution: get in this product 1g to 25ml measuring bottle, add mobile phase and be diluted to scale, shake up, membrane filtration, promptly;
Measure: accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, calculate with external standard method, promptly.
This product contains Herba Epimedii for every bag and is no less than 1.74mg in icariin.
Vitamin B1 assay (one) in embodiment eight Anshenbunao granules
Measure according to high performance liquid chromatography (" 2000 editions one appendix VI D of Chinese pharmacopoeia).
Chromatographic condition and system suitability test:
Waters 600 pumps, ultraviolet 486 detectors, Rheodyne injector.
With octadecylsilane chemically bonded silica is filler, is 23: 77 methanol with volume ratio: 10mmol/L heptane Ji Huangsuannashui (containing 1% glacial acetic acid, 0.2% triethylamine) is a mobile phase; The detection wavelength is 254nm; Flow velocity 1.0ml/min.Number of theoretical plate calculates by the vitamin B1 peak should be not less than 3000.
The preparation of reference substance solution: precision takes by weighing in 60 ℃ of vitamin B1 reference substances that are dried to constant weight an amount of, makes the solution that every 1ml contains the 0.254mg vitamin B1 with mobile phase, promptly;
The preparation of need testing solution: get this product 0.5g, the accurate title, decide, and puts in the 25ml measuring bottle, accurate 1% hydrochloric acid 20ml, the supersound extraction 15 minutes of adding, put coldly, add 1% hydrochloric acid, shake up, leave standstill to scale, it is an amount of to get supernatant, and centrifugal (per minute rotating speed 10000 changes) 10 minutes gets supernatant, promptly.
Measure: accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, calculate with external standard method, promptly.
This product contains vitamin B1 for every bag and is no less than 4.01mg.
Vitamin B1 assay (two) in embodiment nine Anshenbunao granules
Measure according to high performance liquid chromatography (" 2000 editions one appendix VI D of Chinese pharmacopoeia).
Chromatographic condition and system suitability test:
Waters 600 pumps, ultraviolet 486 detectors, Rheodyne injector.
With octadecylsilane chemically bonded silica is filler, is 23: 77 methanol with volume ratio: 10mmol/L octadecyl sodium sulfonate water (containing 1% glacial acetic acid, 0.2% triethylamine) is mobile phase; The detection wavelength is 254nm; Flow velocity 1.0ml/min.Number of theoretical plate calculates by the vitamin B1 peak should be not less than 3000.
The preparation of reference substance solution: precision takes by weighing in 60 ℃ of vitamin B1 reference substances that are dried to constant weight an amount of, makes the solution that every 1ml contains the 0.254mg vitamin B1 with mobile phase, promptly;
The preparation of need testing solution: get this product 0.5g, the accurate title, decide, and puts in the 25ml measuring bottle, accurate 1% hydrochloric acid 20ml, the supersound extraction 15 minutes of adding, put coldly, add 1% hydrochloric acid, shake up, leave standstill to scale, it is an amount of to get supernatant, and centrifugal (per minute rotating speed 10000 changes) 10 minutes gets supernatant, promptly.
Measure: accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, calculate with external standard method, promptly.
This product contains vitamin B1 for every bag and is no less than 4.0mg.
This Anshenbunao granule adopts said method to carry out quality control, compares with the standard of the existing quality control of Anshen Bunao oral liquid, and quality standard of the present invention has had significant raising, has more effectively controlled the quality of product, guarantees the curative effect of medicine.
Description of drawings
Fig. 1 lacks Herba Epimedii negative sample HPLC figure
Fig. 2 icariin reference substance HPLC figure
Fig. 3 Anshen Bunao particulate samples HPLC schemes (survey icariin)
Fig. 4 lacks vitamin B
1Negative sample HPLC figure
Fig. 5 vitamin B
1Reference substance HPLC figure
Fig. 6 Anshen Bunao particulate samples HPLC figure (surveys vitamin B
1)
Claims (7)
1. treat neurasthenic granule for one kind, by 30 weight portion Cornu Cervi Pantotrichums, 625 weight portion Radix Polygoni Multiflori Preparatas, 500 weight portion Herba Epimedii, 125 weight portion Rhizoma Zingiberiss, 62.5 weight portion Radix Glycyrrhizaes, 125 weight portion Fructus Jujubaes, 5 weight portion vitamin B1s is that crude drug is made, and it is characterized in that: contain inclusion essential oil agent beta-schardinger dextrin-6.8-13.6 weight portion; The cosolvent beta-schardinger dextrin-500-800 weight portion of liposoluble constituent; Contain correctives stevioside 100 weight portions; Contain forming agent dextrin 900-1200 weight portion.
2. a kind of preparation method for the treatment of neurasthenic granule according to claim 1 is as follows by concrete steps:
More than seven flavors, Rhizoma Zingiberis adds 1000 weight parts waters and extracted volatile oil 4 hours, volatile oil is with 10.2 weight portion beta-cyclodextrin inclusion compounds, enclose liquid is standby.Medicinal residues and Radix Polygoni Multiflori Preparata, Herba Epimedii, Fructus Jujubae, Radix Glycyrrhizae decocts with water three times, 2 hours for the first time, amount of water is 14375 weight portions, second, three times each 1 hour, amount of water was 11500 weight portions, collecting decoction, filter, filtrate is concentrated into flowing soaking paste, 1.30,50 ℃ of mensuration of relative density, add ethanol to 70%, precipitation filters filtrate recycling ethanol, be concentrated into relative density 1.08～1.10,50 ℃ of mensuration, standby, the Cornu Cervi Pantotrichum coarse powder is decocted with water five times, time successively 4,4,3,3,2 hours, amount of water is respectively 300,300,240,240,180 weight portions, gradation filters, merging filtrate, be concentrated into 1/2 of crude drug in whole, add Cera Flava, leave standstill solidify fully to the wax layer after, remove the dewax layer, sucking filtration is to clear and bright, adding 80% ethanol is 40% to containing the alcohol amount, and room temperature was placed 48 hours, filtered, filtrate recycling ethanol is to relative density 1.05～1.15,50 ℃ of mensuration, adding ethanol is 60% to containing the alcohol amount, room temperature was placed 24 hours, filter, filtrate recycling ethanol to relative density is 1.05～1.15,50 ℃ of mensuration, with above-mentioned medicinal liquid, inclusion essential oil liquid, the Cornu Cervi Pantotrichum extracting solution mixing; Add beta-schardinger dextrin-500～800 weight portion hydrotropies, add-on type agent dextrin 900-1200 weight portion fully stirs again, filters, under atomize, feed hot-air, carry out spray drying, 180 ℃ of hot-air inlet temperature, 80 ℃ of leaving air temps, spray powder adds correctives stevioside 100 weight portions and vitamin B1, mixing, material is dry granulation under 18-60 ℃ of temperature, granulate.
3. the neurasthenic granule of a kind of treatment according to claim 1, the discrimination method of its Herba Epimedii is:
Get this product 6g, porphyrize adds ethanol 20ml reflux, extract,, filters, and filtrate evaporate to dryness, residue add the 2ml dissolve with ethanol, as need testing solution; Other gets control medicinal material 0.5g, shine medical material solution in pairs with legal system, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel H lamellae of binding agent with the sodium carboxymethyl cellulose, with volume ratio is 10: 1: 1: ethyl acetate-butanone of 1-formic acid-water is developing solvent, take out, dry, spray 5% aluminum chloride test solution, 105 ℃ were dried by the fire 5 minutes, and put under the ultra-violet lamp again and inspect, wavelength is 365nm, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
4. the neurasthenic brain granule of a kind of treatment according to claim 1, its icariin content assaying method is:
The preparation of reference substance solution: precision takes by weighing in 60 ℃ of icariin reference substances that are dried to constant weight an amount of, makes the solution that every 1ml contains the 0.282mg icariin with mobile phase, promptly;
The preparation of need testing solution: get in this product 1g to 25ml measuring bottle, add mobile phase and be diluted to scale, shake up, membrane filtration, promptly;
Chromatographic condition: with octadecylsilane chemically bonded silica is filler;
Volume ratio is 30: 70 a acetonitrile: 0.1% trifluoroacetic acid aqueous solution is a mobile phase;
The detection wavelength is 270nm; Flow velocity 1ml/min;
Accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing inject hplc determination.
5. a kind of icariin content assaying method for the treatment of neurasthenic granule according to claim 4, it is characterized in that: volume ratio is 30: 70 a acetonitrile: 0.1% acetic acid aqueous solution is a mobile phase.
6. a kind of icariin content assaying method for the treatment of neurasthenic granule according to claim 4, it is characterized in that: volume ratio is 30: 70 a acetonitrile: 0.1% phosphate aqueous solution is a mobile phase.
7. the neurasthenic granule of a kind of treatment according to claim 1, its vitamin B1 content assaying method is:
The preparation of reference substance solution: precision takes by weighing in 60 ℃ of vitamin B1 reference substances that are dried to constant weight an amount of, makes the solution that every 1ml contains the 0.254mg vitamin B1 with mobile phase, promptly;
The preparation of need testing solution: get this product 0.5g, the accurate title, decide, and puts in the 25ml measuring bottle, accurate 1% hydrochloric acid 20ml, the supersound extraction 15 minutes of adding, put coldly, add 1% hydrochloric acid to scale, shake up, leave standstill, it is an amount of to get supernatant, centrifugal 10 minutes, per minute rotating speed 10000 changeed, and gets supernatant, promptly;
Chromatographic condition: with octadecylsilane chemically bonded silica is filler;
Mobile phase is
Methanol: 23 volumes
The 10mmol/L heptane Ji Huangsuannashui that contains 1% glacial acetic acid, 0.2% triethylamine: 77 volumes;
The detection wavelength is 254nm;
Accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing inject chromatograph of liquid.
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| CN101288483B (en) * | 2008-05-12 | 2011-06-22 | 江阴天江药业有限公司 | Preparation method of ginger and jujube granule |
| CN104198616A (en) * | 2014-09-17 | 2014-12-10 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Method for determining content of icariin in climacterium capsule |
| CN107789596A (en) * | 2016-08-31 | 2018-03-13 | 浙江康恩贝制药股份有限公司 | A kind of Anshen Bunao granule preparing process |
| CN115089685A (en) * | 2022-03-01 | 2022-09-23 | 江苏聚荣制药集团有限公司 | Sugar-free nerve-soothing and brain-nourishing liquid and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101288483B (en) * | 2008-05-12 | 2011-06-22 | 江阴天江药业有限公司 | Preparation method of ginger and jujube granule |
| CN104198616A (en) * | 2014-09-17 | 2014-12-10 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Method for determining content of icariin in climacterium capsule |
| CN107789596A (en) * | 2016-08-31 | 2018-03-13 | 浙江康恩贝制药股份有限公司 | A kind of Anshen Bunao granule preparing process |
| CN115089685A (en) * | 2022-03-01 | 2022-09-23 | 江苏聚荣制药集团有限公司 | Sugar-free nerve-soothing and brain-nourishing liquid and preparation method thereof |
| CN119310228A (en) * | 2024-12-17 | 2025-01-14 | 中国人民解放军总医院第六医学中心 | Granule fingerprint spectrum for treating debilitating syndrome and establishing method thereof |
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