CN104352478B - Preparation method of furazolidone preparation - Google Patents
Preparation method of furazolidone preparation Download PDFInfo
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- CN104352478B CN104352478B CN201410654701.7A CN201410654701A CN104352478B CN 104352478 B CN104352478 B CN 104352478B CN 201410654701 A CN201410654701 A CN 201410654701A CN 104352478 B CN104352478 B CN 104352478B
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- furazolidone
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- PLHJDBGFXBMTGZ-WEVVVXLNSA-N furazolidone Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)OCC1 PLHJDBGFXBMTGZ-WEVVVXLNSA-N 0.000 title claims abstract description 78
- 229960001625 furazolidone Drugs 0.000 title claims abstract description 78
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000002775 capsule Substances 0.000 claims abstract description 36
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 33
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 29
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 27
- 229920002472 Starch Polymers 0.000 claims abstract description 22
- 239000008107 starch Substances 0.000 claims abstract description 22
- 235000019698 starch Nutrition 0.000 claims abstract description 22
- 239000011734 sodium Substances 0.000 claims abstract description 18
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 239000000945 filler Substances 0.000 claims abstract description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 13
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 13
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 13
- 239000007779 soft material Substances 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 239000008187 granular material Substances 0.000 claims description 33
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 14
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 13
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 12
- 239000012467 final product Substances 0.000 claims description 12
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 12
- 229920000858 Cyclodextrin Polymers 0.000 claims description 8
- 206010013786 Dry skin Diseases 0.000 claims description 7
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 7
- -1 hydroxypropyl cyclodextrin Chemical compound 0.000 claims description 7
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 6
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 6
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 6
- 229960000502 poloxamer Drugs 0.000 claims description 6
- 229920001983 poloxamer Polymers 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 5
- 239000008101 lactose Substances 0.000 claims description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 claims description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 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
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 19
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 208000015181 infectious disease Diseases 0.000 abstract description 3
- 238000005453 pelletization Methods 0.000 abstract description 3
- 230000001954 sterilising effect Effects 0.000 abstract description 2
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 abstract 4
- 229940069328 povidone Drugs 0.000 abstract 4
- 238000002156 mixing Methods 0.000 abstract 3
- 235000015424 sodium Nutrition 0.000 abstract 2
- 208000035473 Communicable disease Diseases 0.000 abstract 1
- 239000011361 granulated particle Substances 0.000 abstract 1
- 210000000936 intestine Anatomy 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- 238000004090 dissolution Methods 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000012216 screening Methods 0.000 description 10
- 230000000968 intestinal effect Effects 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 230000009286 beneficial effect Effects 0.000 description 5
- 229940035423 ethyl ether Drugs 0.000 description 5
- 239000004744 fabric Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000011835 investigation Methods 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000000337 buffer salt Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003292 glue Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000005063 solubilization Methods 0.000 description 3
- 230000007928 solubilization Effects 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 208000001848 dysentery Diseases 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000013505 freshwater Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 208000028774 intestinal disease Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- XWBADQOPXPRKBX-FMIVXFBMSA-N 1-n,1-n-diethyl-4-n-[6-methoxy-2-[(e)-2-(4-nitrophenyl)ethenyl]quinolin-4-yl]pentane-1,4-diamine Chemical compound N=1C2=CC=C(OC)C=C2C(NC(C)CCCN(CC)CC)=CC=1\C=C\C1=CC=C([N+]([O-])=O)C=C1 XWBADQOPXPRKBX-FMIVXFBMSA-N 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- 241000224467 Giardia intestinalis Species 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- XFOFGOKRBIMQBI-UHFFFAOYSA-N O1C(NC=C1)=O.O1C=CC=C1 Chemical compound O1C(NC=C1)=O.O1C=CC=C1 XFOFGOKRBIMQBI-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 241000607626 Vibrio cholerae Species 0.000 description 1
- 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 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003716 antitrichomonal agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229940032049 enterococcus faecalis Drugs 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 238000005429 filling process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960003883 furosemide Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 229940085435 giardia lamblia Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003578 releasing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 201000005113 shigellosis Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a furazolidone preparation. The furazolidone preparation comprises the following raw materials in parts by weight: 100-300 parts of furazolidone, 4-100 parts of a filler, 4-20 parts of povidone, 0.5-10 parts of a solubilizer, 2-15 parts of sodium carboxymethyl starch, 0.5-3 parts of magnesium stearate and 0.5-3 parts of silicon dioxide. The preparation method comprises the following steps: adding water to povidone, and preparing a water solution of which the mass concentration is 10-35%; pouring the solubilizer into a povidone water solution and mixing evenly; mixing furazolidone with the filler, adding the povidone water solution containing the solubilizer to prepare a soft material; pelletizing, drying, and granulating; adding magnesium stearate, silicon dioxide and sodium carboxymethyl starch to the granulated particles; and mixing evenly, and filling an enteric capsule, so as to prepare the furazolidone preparation. The treatment concentration of the medicine can be enhanced by target drug release in human intestines, thus the sterilization effect of the medicine can be enhanced; the treatment effect of the furazolidone on the enteric infectious disease can also be improved; and the furazolidone preparation has relatively strong application value.
Description
Technical field
The present invention relates to pharmaceutical technology field, specifically a kind of preparation method of furazolidone enteric coated capsule preparation.
Background technology
Furazolidone, chemical entitled 3- (5- furosemide feeding methylamino) -2- oxazolidone.This product is itrofurans antimicrobial drug.
All there is certain antibacterial action to Grain-positive and negative bacterium, including Salmonella, Shigella, escherichia coli, kerekou pneumonia primary
Bacterium, Enterobacter, S. aureus L-forms, enterococcus faecalis, micrococcus scarlatinae, vibrio cholera, Campylobacter, Bacteroidess etc., certain
Also active to trichomonacide, giardia lamblia stiles under concentration.Its mechanism of action is interference bacterial oxidation reductase thus blocking antibacterial
Homergy.
Furazolidone is atomic to be dissolved in water and ethanol, is slightly soluble in chloroform, insoluble in ether, is soluble in dimethylformamide and nitre
In methylmethane.Bioavailability in vivo is relatively low.Furazolidone tablet is called as furaxone, is domestic at present unique listing
Furazolidone single preparations of ephedrine.The quality standard that state-promulgated pharmacopoeia is 2010 editions improves this kind dissolution in vitro to 70%, and domestic
The tablet dissolution in vitro that the production technology of this kind existing obtains is mostly 50-60%, does not far reach quality standard qualified
The requirement of limit.The patent of our company's application《A kind of preparation technology of Furazolidone tablet》In (application number 201310225487.9)
Furazolidone tablet is improved to more than 85% according to dissolution specification, higher than commercially available dissolution.Furazolidone tablet is mainly in stomach
Portion absorbs, the campylobacter pyloridises on suppression gastric mucosa, and clinical multiplex its treats chronic gastritiss and peptic ulcer, and therefore domestic have
People is even made into gastric endocopy, improves its absorption in stomach.But modern pharmacy finds furazolidone, and it is tangible
Drug level in intestinal in human body is higher, and most of enteric infection pathogenic bacterias such as dysentery bacterium, salmonella that it can be killed
Genus, escherichia coli etc. all exist in intestinal, according in the drug sensitive experiment group of certain hospital find, furazolidone compare other antibiotic,
Antibiotics are the strongest to the sensitivity of dysentery bacterium, are the choice drugs for the treatment of bacillary dysentery.And furazolidone stomach absorption undoubtedly
Limit the effect of its suppression pathogenic entero becteria.At present, the domestic formulation products that furazolidone is used in intestinal release still belong to
Blank, targeting drug release in human body intestinal canal for the furazolidone not only can strengthen the sterilization effect of medicine moreover it is possible to improve furan azoles
Ketone treats the therapeutic effect of infectious intestinal disease, has stronger using value.The present invention provides a kind of furazolidone enteric coated capsule, phase
The original Tabuleses of ratio, process is simple, drug release rate is fast, release amount is higher moreover it is possible to by furazolidone targeting drug release in intestinal,
It is more conducive to improve the absorption of medicine and the performance of curative effect.
Content of the invention
It is an object of the invention to provide a kind of be different from traditional, process is simple, low cost, dissolution is high, biological utilisation
Degree is high, the preparation method of the furazolidone enteric coated capsule of targeting drug release.
The preparation method of the furazolidone enteric coated capsule of the present invention is as follows：
The weight proportion of raw material is：
Preparation method：
1) take polyvidone, add water, be made into 10～35% mass concentration aqueous solution；
2) solubilizing agent is poured in above-mentioned polyvidone aqueous solution, mix；
3) take furazolidone and filler mix homogeneously, add the above-mentioned polyvidone aqueous solution soft material containing solubilizing agent,
16～20 mesh are pelletized, 55～70 DEG C of dryings, 16～40 mesh granulate；
4) add magnesium stearate, silicon dioxide and carboxymethyl starch sodium, mix homogeneously in the granule after granulate, fill enteric
Capsule obtains final product；
Described filler be starch, Pregelatinized Starch, Lactose, cyclodextrin, hydroxypropyl cyclodextrin, Macrogol 4000,
One or more of polyethylene glycol 6000；
Described solubilizing agent is sodium lauryl sulphate, poloxamer, Caprylocaproyl Macrogolglycerides, diethylene glycol
One or more of single ethylether, PEG400.
Present invention advantage compared to existing technology is：
1st, fill up domestic furazolidone in intestinal-specific release, the formulation blank of rapid delivery of pharmaceuticals.Furazolidone is in people
Targeting drug release in body intestinal can strengthen the treatment concentration of medicine, and then strengthens the bactericidal effect of medicine moreover it is possible to improve furan
Oxazolone treats the therapeutic effect of infectious intestinal disease, has stronger using value.
2nd, the present invention compares original Tabuleses, process is simple, and drug release rate is fast, release amount is higher.1.3% 12
Drug-eluting amount during in sodium alkyl sulfate solution dissolution medium 60 minutes reaches more than 93%, far above the fresh water (FW) of tablet
Flat.Also reach more than 76% according to enteric coated capsule in the burst size in the buffer salt of PH6.8.
The technical study of the furazolidone enteric coated capsule of the present invention
1st, experiment purpose：By experiment screening can make furazolidone enteric coated capsule satisfactory quality supplementary product kind,
Consumption and process conditions.
2nd, experimental technique：Screening filler, solubilizing agent, binding agent, lubricant, technological parameter affect on the quality of product.
3rd, prescription：But require according to 2010 editions two annex XD of Chinese Pharmacopoeia, furazolidone enteric coated capsule should be insoluble
In 0.1mol/L hydrochloric acid solution, and there is a certain amount of burst size in the phosphate buffered saline(PBS) of PH6.8.In view of furazolidone is difficult
It is dissolved in water, and dissolution medium 1.3% sodium lauryl sulphate using during the dissolution determination of Related product Furazolidone tablet
Solution is the alkaline solution of more than PH7, and dissolution limit is 70%, therefore, with reference to the regulation of this standard and Chinese Pharmacopoeia, furan
Burst size in the phosphate-buffered salt of PH6.8 for the oxazolone enteric coated capsule must not be less than 70%.
4th, detection method：
4.1 assay：Precision weighs each sample and reference substance to 200ml volumetric flask, adds dimethylformamide
32ml, dissolving is complete, ultrasonic 5 minutes of sample sets.It is diluted with water to scale, shake up, filtration, precision measures filtrate 10ml extremely
In 100ml measuring bottle, it is diluted with water to scale, shake up.Ultraviolet absorptivity is measured at 367nm.Calculate.
4.2 capsule particles and the dissolution study of capsule
Precision takes the sign sample particle of content 100mg or the enteric coated capsule equipped with sample particle.By Chinese Pharmacopoeia 2010
Year two annex XC dissolution determination methods of version, with 1.3% sodium dodecyl sulfate solution 1000mL as dissolution medium, rotating speed is
120r/min, operates in accordance with the law.Solution 10mL is taken, microporous filter membrane filters, precision measures subsequent filtrate 5mL and puts 50mL measuring bottle during 60min
In, it is diluted with water to scale, shakes up, obtain final product need testing solution；
Take furazolidone reference substance about 20mg, accurately weighed, put in 200mL measuring bottle, plus dimethylformamide 20mL dissolving
Afterwards, it is diluted with water to scale, shakes up, precision measures 5mL, put in 50mL measuring bottle, be diluted with water to scale, shake up, as comparison
Product solution.Take above-mentioned 2 kinds of solution, difference mensuration absorbance at the wavelength of 367nm.Calculate sample stripping quantity.
The release research of 4.3 enteric coated capsulees
Take the enteric coated capsule sample equipped with granule, according to two annex XD release degree mensure sides of Chinese Pharmacopoeia version in 2010
Method, measures 0.1mol/L hydrochloric acid solution 750ml, injects each stripping rotor, treats dissolution medium temperature constant at 37 DEG C ± 0.5 DEG C,
Take 6 to put into respectively and turn in basket, rotating speed is 120r/min, after 2 hours, sample 10mL, supplement 0.1mol/L hydrochloric acid solution simultaneously
10mL.Sample is filtered with microporous filter membrane, and precision measures subsequent filtrate 5mL and puts in 50mL measuring bottle, is diluted with water to scale, shakes up, that is,
Obtain need testing solution 1；Add the 0.2mol/L sodium radio-phosphate,P-32 solution 250ml that temperature is 37 DEG C ± 0.5 DEG C (necessary in above-mentioned acid solution
When adjust pH value to 6.8 with 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution), remain in operation 60 minutes, take solution
10mL, microporous filter membrane filters, and precision measures subsequent filtrate 5mL and puts in 50mL measuring bottle, is diluted with water to scale, shakes up, and obtains final product for examination
Product solution 2；
Take furazolidone reference substance about 20mg, accurately weighed, put in 200mL measuring bottle, plus dimethylformamide 20mL dissolving
Afterwards, it is diluted with water to scale, shake up.Precision measures 5mL, puts in 50mL measuring bottle, is diluted with water to scale, shake up, as comparison
Product solution.
Take above-mentioned 3 kinds of solution, difference mensuration absorbance at the wavelength of 367nm.Calculate burst size.
Burst size in acid：In 6, the burst size of every no more than the 10% of labelled amount, 6 in have 1～2 to be more than
10%, but its mean release is not more than 10%.
Burst size in buffer：In 6, the burst size of every is calculated by labelled amount and is all not less than 70%.
5th, the investigation of different filleies
Take 100g furazolidone, be separately added into different filleies, mix, add 50% ethanol solution to be pelletized, be dried,
Granulate.Investigate the impact to furazolidone, screening is beneficial to the adjuvant of furazolidone dissolution.
Table 1
Matched group is the group not adding filler.
From result above：Starch, Pregelatinized Starch, Lactose, cyclodextrin, hydroxypropyl cyclodextrin, Macrogol 4000,
Macrogol 600 has more than 7% solubilization to furazolidone, is also obviously improved the effect of the mobility of furazolidone
(comparing matched group to diminish angle of repose, the rate of outflow becomes big), therefore may select for filler.Above filler is in consumption 4g
When have an obvious solubilizing effect, experiment also confirms that and also can guarantee that the solubilising work having more than 7% to furazolidone in consumption 100g
With therefore, selecting the amount ranges that 4g～100g is filler.
6th, the investigation of different binding agents
Take 100g furazolidone, mix with filler respectively, add different binding agents to be pelletized, be dried, granulate.Examine
Examine the impact to furazolidone, screening is beneficial to the adjuvant of furazolidone dissolution.
Table 2
From result above：In typical binders, polyvidone aqueous solution is the most obvious to furazolidone solubilization, improves
The effect of mobility the most substantially (is compared matched group to diminish, the rate of outflow becomes big) angle of repose.Therefore, select polyvidone as bonding
Agent.Also confirm all to can guarantee that there is obvious solubilising to furazolidone when concentration 10%～30%, consumption 4g～20g by experiment
Effect, when concentration is higher than 35%, granule glues excessively it is difficult to pelletize.When concentration is less than 10%, solubilizing effect is inconspicuous.Therefore, select
Concentration 10%～30%, consumption 4g～20g is concentration and the amount ranges of polyvidone.
7th, the investigation of different solubilizing agents
Take 100g furazolidone, be separately added into the 10% polyvidone aqueous solution containing different cosolvents and pelletized, be dried,
Granulate.Investigate the impact to furazolidone, screening is beneficial to the adjuvant of furazolidone dissolution.
Table 3
Reference substance does not add solubilizing agent group.
From result above：Sodium lauryl sulphate, poloxamer, Caprylocaproyl Macrogolglycerides, diethyl two
Alcohol list ethylether, PEG400 have more than 4% solubilization to furazolidone, compare other streams to material for adjuvant group
Dynamic property is improved more obvious.It is thereby possible to select as solubilizing agent.
8th, the investigation of different disintegrating agents：Investigate the impact to furazolidone, screening is beneficial to the disintegrating agent of furazolidone dissolution
Adjuvant.
Table 4
Significantly solubilising is not made to furazolidone for superdisintegrantes cross-linked pvp, cross-linking sodium carboxymethyl cellulose, Extra Sodium Carboxylmethyl Starch
With.The disintegrate of the outer addition of carboxymethyl starch sodium is the fastest, and release is slightly higher.Carboxymethyl starch sodium is therefore selected to be main disintegrating agent, outward
Add mode.
9th, the influence degree of the dissolution to furazolidone for the lubricant is investigated
Need granule to have certain mobility in filling process, therefore, investigate the impact to furazolidone, screening is beneficial to work
The adjuvant of skill.
Table 5
Reference substance does not add lubricant group.
Mobility by micropowder silica gel knowable to result above and magnesium stearate group is preferable, and hydrophilic micropowder silica gel has
Faint dissolution effect, and the hydrophobic magnesium stearate not dissolution to impact furazolidone, have slight dissolution to imitate on the contrary
Fruit, it is contemplated that the mobility of material, therefore selects micropowder silica gel, magnesium stearate to be combined together as lubricant, flows after combination
Property be remarkably reinforced, angle of repose be 29., rate of outflow 10.9g/min.
10th, the screening of different granulation sieve numbers
Furazolidone is mixed with filler, adds the polyvidone aqueous solution soft material containing solubilizing agent, respectively using not
Pelletize with mesh number screen cloth, investigate the impact that different-grain diameter particle discharges to furazolidone.
Table 6
From result：The impact pelletized to dissolution between 16 mesh～30 mesh is not very big, and 16 mesh are with lower screen cloth system
During grain, granule is more thick and stiff, and release is slightly impacted.When more than 20 mesh pelletizing, because screen cloth is meticulous, and material has certain gluing
Property, sieve operating difficultiess, therefore selects 16～20 mesh as the technological parameter pelletized.
11st, the screening of different granulate sieve numbers
By dried granule, the screen cloth with 10 mesh, 16 mesh, 18 mesh, 24 mesh, 30 mesh, 40 mesh, 50 mesh and 60 mesh is whole respectively
Grain, investigates the impact to filling mobility for the different-grain diameter particle.
Table 7
From result：40 mesh are more with particle powder after upper screen cloth granulate, become angle of repose big, the rate of outflow diminishes, thing
Material mobility is deteriorated.During 14 mesh following granulate, coarse granule is larger, and the RSD value of the filling difference of material, more than 2%, compares other mesh
Number is slightly larger.After granule is excessively thick, release and dissolution slightly delay.Mobility of particle between 16 mesh～40 mesh is good, and RSD value is little, symbol
Close the requirement of filling, drug release rate is stable, is therefore selected as the technological parameter of granulate.
12nd, the screening of different baking temperatures
By the granule after pelletizing, it is dried at different temperatures respectively, every part of 1kg, is dried to the moisture of suitable tabletting,
It is about 3.5%, the record time investigates the impact to filling mobility for the temperature.
Table 8
From result：45～80 DEG C of releases on medicine and dissolution impact less, but less than 55 DEG C when being dried,
The spent time is longer, and more than 70 DEG C when being dried, and particle appearance has the sign of variable color.Therefore, 55～70 DEG C are selected as dry
Dry technological parameter.
Brief description
Fig. 1 be furazolidone enteric coated capsule and granule 1.3% sodium dodecyl sulfate solution molten in stripping curve
Figure.
Fig. 2 is release curve chart in the phosphoric acid buffer salt solvent liquid of PH6.8 for the furazolidone enteric coated capsule.
Specific embodiment
Embodiment：1
Take furazolidone 100g and starch 10g mix homogeneously, add and gather containing sodium lauryl sulphate 0.4g, caprylic capric
The polyvidone aqueous solution soft material of 20% mass concentration of glycol glycerin ester 0.8g, polyvidone consumption 6g.16 mesh are pelletized, 70 DEG C
It is dried, 20 mesh granulate, adds 1.5g magnesium stearate, 1.0g silicon dioxide and 4g carboxymethyl starch sodium mix homogeneously, fill enteric
Capsule obtains final product.
Embodiment：2
Take furazolidone 100g and Pregelatinized Starch 4g mix homogeneously, add and contain poloxamer 0.5g, diethylene glycol list
The polyvidone aqueous solution soft material of 10% mass concentration of ethylether 0.5g, polyvidone consumption 20g.18 mesh are pelletized, 60 DEG C of dryings,
16 mesh granulate, add 0.5g magnesium stearate, 0.5g silicon dioxide and 2g carboxymethyl starch sodium mix homogeneously, and filling enteric coated capsule is
?.
Embodiment：3
Take furazolidone 100g and Macrogol 4000 100g mix homogeneously, add 35% containing PEG400 10g
The polyvidone aqueous solution soft material of mass concentration, polyvidone consumption 4g.20 mesh are pelletized, 65 DEG C of dryings, 40 mesh granulate, add 3g hard
Fatty acid magnesium, 3g silicon dioxide and 15g carboxymethyl starch sodium mix homogeneously, filling enteric coated capsule obtains final product.
Embodiment：4
Take furazolidone 200g and cyclodextrin 10g mix homogeneously, add and contain sodium lauryl sulphate 0.4g, caprylic capric
The polyvidone aqueous solution soft material of 20% mass concentration of polyethyleneglycol glyceride 0.8g, polyvidone consumption 6g.16 mesh are pelletized, and 55
DEG C drying, 20 mesh granulate, add 1.5g magnesium stearate, 1.5g silicon dioxide and 6g carboxymethyl starch sodium mix homogeneously, fill intestinal
Colloidal sol capsule obtains final product.
Embodiment：5
Take furazolidone 200g and hydroxypropyl cyclodextrin 4g mix homogeneously, add and contain poloxamer 0.5g, diethylene glycol
The polyvidone aqueous solution soft material of 10% mass concentration of single ethylether 0.5g, polyvidone consumption 20g.16 mesh are pelletized, and do for 60 DEG C
Dry, 24 mesh granulate, add 0.5g magnesium stearate, 0.5g silicon dioxide and 2g carboxymethyl starch sodium mix homogeneously, fill enteric glue
Capsule obtains final product.
Embodiment：6
Take furazolidone 200g and Lactose 50g, starch 50g mix homogeneously, add 35% containing PEG400 10g
The polyvidone aqueous solution soft material of mass concentration, polyvidone consumption 6g.20 mesh are pelletized, 65 DEG C of dryings, 40 mesh granulate, add 3g hard
Fatty acid magnesium, 3g silicon dioxide and 15g carboxymethyl starch sodium mix homogeneously, filling enteric coated capsule obtains final product.
Embodiment：7
Take furazolidone 300g and Lactose 10g mix homogeneously, add and contain sodium lauryl sulphate 0.4g, Polyethylene Glycol
4000.4g, the polyvidone aqueous solution soft material of 20% mass concentration of Caprylocaproyl Macrogolglycerides 1.0g, polyvidone is used
Amount 6g.16 mesh are pelletized, 70 DEG C of dryings, 20 mesh granulate, add 1.5g magnesium stearate, 1.5g silicon dioxide and 6g carboxymethyl starch sodium
Mix homogeneously, filling enteric coated capsule obtains final product.
Embodiment：8
Take furazolidone 300g and polyethylene glycol 6000 100g mix homogeneously, add and contain poloxamer 0.5g, diethyl two
The polyvidone aqueous solution soft material of 10% mass concentration of alcohol list ethylether 0.5g, polyvidone consumption 10g.10 mesh are pelletized, 60 DEG C
It is dried, 40 mesh granulate, adds 0.5g magnesium stearate, 0.5g silicon dioxide and 2g carboxymethyl starch sodium mix homogeneously, fill enteric
Capsule obtains final product.
Embodiment：9
Take furazolidone 300g and starch 50g mix homogeneously, add 35% mass concentration containing PEG400 10g
Polyvidone aqueous solution soft material, polyvidone consumption 15g.20 mesh are pelletized, 65 DEG C of dryings, 40 mesh granulate, addition 3g magnesium stearate,
3g silicon dioxide and 15g carboxymethyl starch sodium mix homogeneously, filling enteric coated capsule obtains final product.
The detection data such as following table of the furazolidone enteric coated capsule of table 9 embodiment 1～9：
According to the dissolution in 1.3% sodium dodecyl sulfate solution in enteric coated capsule technical study the 4th point and
Detection method in the phosphate buffer of PH6.8.Respectively when 5,10,15,30,45,60,90min, take solution 10mL (simultaneously
Supplement the dissolution medium of same volume), calculate each time point stripping quantity.With the time as abscissa, stripping quantity is vertical coordinate, draws
Stripping curve, is shown in Fig. 1, Fig. 2.
Obtain dissolution in furazolidone enteric coated capsule and its granule under 1.3% sodium dodecyl sulfate solution dissolution medium
Can be seen that in curve Fig. 1：Enteric coated capsule is in PH>When 7, capsule shells disintegrate needs 5 minutes, therefore in drug-eluting initial stage, glue
The stripping quantity of capsule can be fewer than granule, and dissolution rate is slow, and after capsule shells dissolving rupture, after 15 minutes, both is molten
Output is identical, and after 60 minutes, stripping quantity reaches more than 93%.
Release according to the enteric coated preparation in 2010 editions two annex of Chinese Pharmacopoeia requires, and furazolidone enteric coated capsule exists
Insoluble in hydrochloric acid, meet States Pharmacopoeia specifications.Releasing effect in the phosphoric acid buffer salt solvent liquid of PH6.8 for the furazolidone enteric coated capsule
Although not good in 1.3% sodium dodecyl sulfate solution, also when 5 minutes release 40% furazolidone, 60
When during minute more than 76%, 90 minute, cumulative release amount reaches more than 80%, sees Fig. 2.
Claims (1)
1. a kind of preparation method of furazolidone preparation is it is characterised in that be carried out as follows：
The weight proportion of raw material is：
Preparation method：
1) take polyvidone, add water, be made into 10～35% mass concentration aqueous solution；
2) solubilizing agent is poured in above-mentioned polyvidone aqueous solution, mix；
3) take furazolidone and filler mix homogeneously, add the above-mentioned polyvidone aqueous solution soft material containing solubilizing agent, 16～
20 mesh are pelletized, 55～70 DEG C of dryings, 16～40 mesh granulate；
4) add magnesium stearate, silicon dioxide and carboxymethyl starch sodium, mix homogeneously in the granule after granulate, fill enteric coated capsule
Obtain final product；
Described filler is starch, Pregelatinized Starch, Lactose, cyclodextrin, hydroxypropyl cyclodextrin, Macrogol 4000, poly- second
One or more of glycol 6000；
Described solubilizing agent is sodium lauryl sulphate, poloxamer, Caprylocaproyl Macrogolglycerides, diethylene glycol list second
One or more of base ether, PEG400.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4668517A (en) * | 1985-04-04 | 1987-05-26 | Norwich Eaton Pharmaceuticals, Inc. | Furazolidone dosage form |
| CN103271887A (en) * | 2013-06-07 | 2013-09-04 | 昆明振华制药厂有限公司 | Furazolidone tablet preparation method |
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2014
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4668517A (en) * | 1985-04-04 | 1987-05-26 | Norwich Eaton Pharmaceuticals, Inc. | Furazolidone dosage form |
| CN103271887A (en) * | 2013-06-07 | 2013-09-04 | 昆明振华制药厂有限公司 | Furazolidone tablet preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 10 天与 14 天含呋喃唑酮四联疗法补救治疗幽门螺杆菌的疗效比较;郑小丽，许乐;《中国新药杂志》;20131231;第22卷(第23期);第2786-2788页 * |
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