CN104771368B - Cefpodoxime Proxetil quick releasing formulation and preparation method thereof - Google Patents
Cefpodoxime Proxetil quick releasing formulation and preparation method thereof Download PDFInfo
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- CN104771368B CN104771368B CN201510163430.XA CN201510163430A CN104771368B CN 104771368 B CN104771368 B CN 104771368B CN 201510163430 A CN201510163430 A CN 201510163430A CN 104771368 B CN104771368 B CN 104771368B
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- 239000000203 mixture Substances 0.000 title claims abstract description 89
- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 title claims abstract description 55
- 229960004797 cefpodoxime proxetil Drugs 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 238000009472 formulation Methods 0.000 title claims abstract description 30
- 239000007787 solid Substances 0.000 claims abstract description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- 239000004094 surface-active agent Substances 0.000 claims abstract description 20
- 238000012856 packing Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 9
- 239000003085 diluting agent Substances 0.000 claims abstract description 8
- 239000007884 disintegrant Substances 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 239000000375 suspending agent Substances 0.000 claims abstract description 8
- 238000005550 wet granulation Methods 0.000 claims abstract description 6
- 239000012530 fluid Substances 0.000 claims description 16
- 229930006000 Sucrose Natural products 0.000 claims description 11
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 239000005720 sucrose Substances 0.000 claims description 11
- 229920001285 xanthan gum Polymers 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 9
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical group O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 9
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 8
- 206010013786 Dry skin Diseases 0.000 claims description 8
- 239000011575 calcium Substances 0.000 claims description 8
- 229910052791 calcium Inorganic materials 0.000 claims description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 8
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 8
- 229960005090 cefpodoxime Drugs 0.000 claims description 7
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000796 flavoring agent Substances 0.000 claims description 4
- 235000019634 flavors Nutrition 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 235000009434 Actinidia chinensis Nutrition 0.000 claims description 2
- 244000298697 Actinidia deliciosa Species 0.000 claims description 2
- 235000009436 Actinidia deliciosa Nutrition 0.000 claims description 2
- 244000144730 Amygdalus persica Species 0.000 claims description 2
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- 244000241235 Citrullus lanatus Species 0.000 claims description 2
- 235000012828 Citrullus lanatus var citroides Nutrition 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims description 2
- 244000131522 Citrus pyriformis Species 0.000 claims description 2
- 244000241257 Cucumis melo Species 0.000 claims description 2
- 235000015510 Cucumis melo subsp melo Nutrition 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 2
- 240000009088 Fragaria x ananassa Species 0.000 claims description 2
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 2
- XINCECQTMHSORG-UHFFFAOYSA-N Isoamyl isovalerate Chemical compound CC(C)CCOC(=O)CC(C)C XINCECQTMHSORG-UHFFFAOYSA-N 0.000 claims description 2
- 240000008790 Musa x paradisiaca Species 0.000 claims description 2
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000009754 Vitis X bourquina Nutrition 0.000 claims description 2
- 235000012333 Vitis X labruscana Nutrition 0.000 claims description 2
- 240000006365 Vitis vinifera Species 0.000 claims description 2
- 235000014787 Vitis vinifera Nutrition 0.000 claims description 2
- FJJCIZWZNKZHII-UHFFFAOYSA-N [4,6-bis(cyanoamino)-1,3,5-triazin-2-yl]cyanamide Chemical compound N#CNC1=NC(NC#N)=NC(NC#N)=N1 FJJCIZWZNKZHII-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000014121 butter Nutrition 0.000 claims description 2
- 235000019219 chocolate Nutrition 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 235000002710 Ilex cornuta Nutrition 0.000 claims 1
- 241001310146 Ilex cornuta Species 0.000 claims 1
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 239000002994 raw material Substances 0.000 abstract description 9
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- 238000009434 installation Methods 0.000 abstract description 3
- 238000001879 gelation Methods 0.000 abstract description 2
- 238000012986 modification Methods 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 238000004090 dissolution Methods 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 235000015165 citric acid Nutrition 0.000 description 8
- 229940105329 carboxymethylcellulose Drugs 0.000 description 7
- 238000005469 granulation Methods 0.000 description 7
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- 239000000463 material Substances 0.000 description 7
- 239000008213 purified water Substances 0.000 description 7
- 238000010586 diagram Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- -1 oxime ester Chemical class 0.000 description 6
- 239000013558 reference substance Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 description 2
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- 239000008351 acetate buffer Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940065110 cefpodoxime 100 mg Drugs 0.000 description 2
- 229940124587 cephalosporin Drugs 0.000 description 2
- 150000001780 cephalosporins Chemical class 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 description 1
- HVUMOYIDDBPOLL-UHFFFAOYSA-N 2-(3,4-Dihydroxyoxolan-2-yl)-2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)C1OCC(O)C1O HVUMOYIDDBPOLL-UHFFFAOYSA-N 0.000 description 1
- ILPBINAXDRFYPL-UHFFFAOYSA-N 2-octene Chemical compound CCCCCC=CC ILPBINAXDRFYPL-UHFFFAOYSA-N 0.000 description 1
- 108010051152 Carboxylesterase Proteins 0.000 description 1
- 102000013392 Carboxylesterase Human genes 0.000 description 1
- 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 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 101710120757 Pheromone-binding protein 1 Proteins 0.000 description 1
- 101710181935 Phosphate-binding protein PstS 1 Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 229920002651 Polysorbate 85 Polymers 0.000 description 1
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 1
- NWGKJDSIEKMTRX-MDZDMXLPSA-N Sorbitan oleate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OCC(O)C1OCC(O)C1O NWGKJDSIEKMTRX-MDZDMXLPSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- 230000001133 acceleration Effects 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
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
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- 239000002736 nonionic surfactant Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of Cefpodoxime Proxetil fast release solid formulation and preparation method thereof, the Cefpodoxime Proxetil fast release solid formulation includes：The 15wt% of said preparation gross weight 2.5 Cefpodoxime Proxetil is accounted for, accounts for the 15.0wt% of said preparation gross weight 0.8 surfactant.The method for preparing the fast release solid formulation is wet granulation, and specific preparation technology is：(1) Cefpodoxime Proxetil and surfactant are dissolved in absolute ethyl alcohol, obtain mixture one, (2) after diluent and disintegrant being well mixed, mixture one is slowly added into or sprayed into, is pelletized, fluidized bed drying, obtain mixture two, (3) suspending agent, flavouring and lubricant are added into mixture two, total mixed, packing.The fast release solid formulation meets water energy Fast Stripping, will not produce gelation, while uses process modification, avoids the process of raw material crushing and micronization processes, it is not required that using special installations such as dry granulating machines, ensures product stability while simplifying production operation.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly to a kind of Cefpodoxime Proxetil fast release solid formulation and its preparation side
Method.
Background technology
Cefpodoxime Proxetil chemical name：(6R, 7R) -7- [2- (thiazolamine -4- bases) -2- (Z)-(methoxyimino) -
Acetamido] -3- methoxyl methyl -8- oxo -5- sulphur -1- azabicyclos-[4,2,0] oct-2-ene -2- formic acid isopropyl oxygen carbonyl oxygen second
Base ester, its structural formula are：
Molecular formula：C21H27N5O9S2
CAS：87239-81-4
Cefpodoxime Proxetil trade name：VANTIN, be Japan exploitation the oral broad-spectrum cephalosporin of the third generation, 1992 8
Month Cefpodoxime Proxetil tablets on the 7th and dry suspensoid agent have passed through FDA application for quotation, are listed in the U.S..Cefpodoxime Proxetil is that possess
Has a broad antifungal spectrum, long half time, the third generation cephalosporin for the advantages that easy to use, cross resistance is smaller, dosage is few, face
Bed, which is mainly used in treating caused by sensitive bacteria, to be infected.
Cefpodoxime Proxetil is the pro-drug of Cefpodoxime, itself without antibacterial activity, it is oral after through intestinal absorption, in intestinal wall
Antibacterial activity is played into Cefpodoxime by nonspecific esterase hydrolyzed.Cefpodoxime to specific PBP 1,
3 have very high compatibility.Cefpodoxime with antibacterial activity, bacteria cell wall synthesis can be influenceed, causes cell to dissolve.
Cefpodoxime Proxetil is white or pale yellow powder, odorless or micro- have special odor.It is easily molten in acetonitrile or methanol
Solution, it is readily soluble in absolute ethyl alcohol, it is almost insoluble in water, water unstable and be in gel is met, has a strong impact on that the dissolving of medicine is fast
Degree.According to Biopharmaceutics Classification system, belong to the classes of BCS IV.
Cefpodoxime proxetil suspension Yuan Yan producers are common pharmaceutical Co. Ltd of Japan the one or three, and it is in water, pH1.2 hydrochloric acid
15 minutes dissolution rates are more than 85% in medium, pH4.0 acetate buffers and pH6.8 phosphate buffers.Domestic listing at present
Dissolution rate of the Cefpodoxime proxetil suspension in above-mentioned four kinds of dissolution mediums it is inconsistent, it is most of can not reach developed with former
The consistent result of extraction of agent, therefore there is an urgent need to a kind of Cefpodoxime Proxetil fast release solid formulation in the market.
The patent CN1681497 of Ranbaxy Lboratories Ltd. of India application discloses a kind of beta-Lactam antibiotic
The preparation method of oral disnitegration tablet, it is that using the method for aqueous granulation prepared by medicine and disintegrant into oral disnitegration tablet.
The patent CN1505515 of Ranbaxy Lboratories Ltd. of India application discloses a kind of cephalo of oral medication
The stabilizing pharmaceutical composition of oxime ester is moored, it is particle diameter and specific surface area will to be controlled after drug micronization, then passes through special equipment
Make Drug absorbability on particular polymers surface, so as to improve the dissolution rate of medicine.
The patent CN 102525948 of SHANDONG LUOXIN PHARMACY STOCK Co., LTD.'s application discloses a kind of Cefpodoxime proxetil
Supensoid agent and preparation method thereof, this method first mix raw material with remaining auxiliary material, then are pelletized by the use of 95% ethanol as wetting agent, keep away
Exempt from medicine caking.
The patent CN 103230367 of SHANDONG LUOXIN PHARMACY STOCK Co., LTD.'s application discloses a kind of Cefpodoxime proxetil
Supensoid agent and preparation method thereof, this method first mix raw material with remaining auxiliary material, then are pelletized by the use of starch slurry as adhesive, avoid
Medicine lumps, and strengthens the antibacterial effect of Cefpodoxime Proxetil.
The patent CN100571683 of Shenzhen Zhijun Pharmaceutical Co., Ltd's application discloses a kind of dry suspensoid agent and its preparation side
Excipient is added to the water to obtain suspending medium by method, the preparation method, adds active component and prepares medicine suspension solution, purpose
It is to avoid luming, reduces production cost.
Although prior art improves medicine caking phenomenon, but it is relatively low to still suffer from preparation dissolution rate, and raw material needs special place
The problem of reason or production process are cumbersome, it is therefore desirable to one or more of auxiliary materials are found, using a kind of simple and easy preparation work
Skill, overcome prior art insufficient, to increase drug dissolution and dissolution rate, ensure that product is stable while simplifying production operation
Property.
The content of the invention
It is an object of the invention to provide a kind of Cefpodoxime Proxetil fast release solid formulation and preparation method thereof, to solve existing head
It is in gel state that raw material, which meets water, in spore pool oxime ester fast release solid formulation technology, and preparation dissolution rate is relatively low；Raw material need specially treated and
The problem of dry granulation is high to equipment requirement, and production process is cumbersome.
Contain Cefpodoxime Proxetil in Cefpodoxime Proxetil fast release solid formulation of the present invention, also contain to reach the present invention
Surfactant, diluent, disintegrant, suspending agent and lubricant necessary to purpose, it is characterised in that each composition is total by preparation
Weight meter：
Wherein each component content sum is equal to 100%；
Preferably, fast release solid formulation of the present invention, each composition press total formulation weight gauge：
Wherein each component content sum is equal to 100%；
The weight of surfactant and Cefpodoxime Proxetil ratio is 1 in fast release solid formulation of the present invention:1~1:3, it is excellent
Select 1:2~1:3, more preferably 1:2.
Surfactant is nonionic surfactant in fast release solid formulation of the present invention, selected from Tweens, sapn
One or more of mixtures in class, polyoxyethylene, can be polysorbas20, polysorbate40, polysorbate60, Tween 80, polysorbate85,
Span 20, span 40, sorbester p18, sorbester p17, sorbester p37, Emulsifier EL-60, Crodaret and pool Lip river are husky
One or both is mixed in one or more of mixture in nurse, preferably Emulsifier EL-60 and Crodaret
Compound, more preferably Crodaret.
Diluent mixture one or more of in sucrose, Lactis Anhydrous, mannitol, soluble starch, preferably without
One or two kinds of mixture in water and milk sugar and sucrose；
Disintegrant is selected from low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, carboxymethyl cellulose
One or more of mixture in calcium, preferably carboxymethyl cellulose calcium；
Suspending agent is a kind of in hydroxypropylcellulose, hydroxypropyl methylcellulose, PVP, sodium carboxymethylcellulose and xanthans
Or several mixtures, preferred xanthans；
Lubricant agent is selected from silica, talcum powder, magnesium stearate, stearic acid, polyethylene glycol, sodium stearyl fumarate, mountain
One or more of mixtures in Yu acid glycerides and hydrogenated vegetable oil, preferably talc powder.
Also contain flavouring in fast release solid formulation of the present invention, flavouring is the mixing of acidity regulator and essence
Thing.One or more of mixtures of the acidity regulator in citric acid, malic acid, tartaric acid, preferably citric acid；Essence selects
It is fragrant from flavoring banana essence, flavoring orange essence, lemon extract, peach flavor, butter essence, chocolate essence, strawberry essence, pineapple
One or more of mixtures in essence, flavoring apple essence, kiwi flavor, grape essence, watermelon essence, Hami melon essence, it is excellent
Select flavoring orange essence.
Another object of the present invention is to provide a kind of preparation method of Cefpodoxime Proxetil fast release solid formulation, it prepares work
Skill is wet granulation, and the equipment used is wet mixing pelletizer or fluid bed.Concrete operations are：
(1) Cefpodoxime Proxetil and surfactant are dissolved in absolute ethyl alcohol, obtain mixture one；
(2) after being well mixed diluent and disintegrant, mixture one is slowly added into or sprayed into, is pelletized, 30 DEG C of fluid bed
Dry, obtain mixture two；
(3) suspending agent, flavouring and lubricant are added into mixture two, total mixed, packing.
The fast release solid formulation of the present invention is adapted to oral drug preparation, can be Oral Dry Suspensions and granule etc..It is former
Material and surfactant are codissolved in absolute ethyl alcohol, and Cefpodoxime Proxetil and surfactant are dispersed in after granulation is dried
Grain surface and inside, when the pharmaceutical preparation is added to water-based dissolution medium, water soluble adjuvant and part Cefpodoxime Proxetil are quick
Dissolving, surfactant can then be distributed in the surface of remaining undissolved medicine rapidly, and its distinctive hydrophilic radical flexes outward knot
Heshui molecule, hydrophobic grouping are enclosed in Cefpodoxime Proxetil molecular surface, drug molecule are separated one by one, so as to effectively avoid
Medicine produces the trend of gelation, accelerates the dissolving of Cefpodoxime Proxetil.
The present invention eliminates by the way that Cefpodoxime Proxetil is dissolved in into absolute ethyl alcohol and uses special installation in the prior art by raw material
Micronizing, then raw material is adsorbed in special installation to the troublesome operation on auxiliary material surface again；Wetting is used as using absolute ethyl alcohol
Agent, whole preparation process avoid the introducing of moisture, ensure the stability of medicine.The use of surfactant, effectively prevent head
Spore pool oxime ester meets aqueous gelled trend, substantially increases the dissolution rate of preparation.
Brief description of the drawings
Preparation (embodiment 1~3 and comparative example 2~3) stripping curve in purified water of Fig. 1 different surfaces activating agent dosages
Comparison diagram.
Fig. 2 uses preparation (embodiment 2 and 4) stripping curve comparison diagram in purified water of different wet granulation equipment.
Fig. 3 embodiments 2 and the stripping curve comparison diagram in purified water of comparative example 1.
Fig. 4 embodiments 2 and the stripping curve comparison diagram in pH1.2 hydrochloric acid mediums of comparative example 1.
Fig. 5 embodiments 2 and the stripping curve comparison diagram in pH4.0 acetate medias of comparative example 1.
Fig. 6 embodiments 2 and the stripping curve comparison diagram in pH6.8 phosphoric acid salt mediums of comparative example 1.
The accelerated test comparing result of 1 embodiment of table 2.
Embodiment
The present invention is described in further detail by the following examples.But the present invention is not limited to these examples.
Embodiment 1 (1000 bags of amounts)
Preparation process：
(1) take recipe quantity Cefpodoxime Proxetil and Crodaret to be dissolved in absolute ethyl alcohol, obtain mixture one.
(2) Lactis Anhydrous, sucrose and calcium carboxymethylcellulose is put after being well mixed in fluid bed, slowly sprays into mixture
One, granulation, 30 DEG C of dryings of fluid bed, obtain mixture two.
(3) xanthans, citric acid, talcum powder and flavoring orange essence are added into mixture two, total mixed, packing.
Embodiment 2 (1000 bags of amounts)
Preparation process：
(1) take recipe quantity Cefpodoxime Proxetil and Crodaret to be dissolved in absolute ethyl alcohol, obtain mixture one.
(2) Lactis Anhydrous, sucrose and calcium carboxymethylcellulose is put after being well mixed in fluid bed, slowly sprays into mixture
One, granulation, 30 DEG C of dryings of fluid bed, obtain mixture two.
(3) xanthans, citric acid, talcum powder and flavoring orange essence are added into mixture two, total mixed, packing.
Embodiment 3 (1000 bags of amounts)
Preparation process：
(1) take recipe quantity Cefpodoxime Proxetil and Crodaret to be dissolved in absolute ethyl alcohol, obtain mixture one.
(2) Lactis Anhydrous, sucrose and calcium carboxymethylcellulose is put after being well mixed in fluid bed, slowly sprays into mixture
One, granulation, 30 DEG C of dryings of fluid bed, obtain mixture two.
(3) xanthans, citric acid, talcum powder and flavoring orange essence are added into mixture two, total mixed, packing.
Embodiment 4 (1000 bags of amounts)
Preparation process：
(1) take recipe quantity Cefpodoxime Proxetil and Crodaret to be dissolved in absolute ethyl alcohol, obtain mixture one.
(2) Lactis Anhydrous, sucrose and calcium carboxymethylcellulose is put after being well mixed in wet mixing pelletizer, slowly added
Enter mixture one, pelletize, 30 DEG C of dryings of fluid bed, obtain mixture two.
(3) xanthans, citric acid, talcum powder and flavoring orange essence are added into mixture two, total mixed, packing.
Contrasted for convenience of with embodiment, spy enumerates following comparative example, carries out comparative study.
Comparative example 1 (1000 bags of amounts)
Preparation process：
Take Cefpodoxime Proxetil and sucrose to cross 100 mesh sieves respectively, take hydroxypropyl methylcellulose, xanthans to cross 120 mesh sieves respectively standby
With；The sucrose 660g for taking the Cefpodoxime Proxetil 50g of crushing and crushing is well mixed, and adds 95% ethanol 200g softwoods, then
40 mesh sieves are pelletized, and obtained wet granular is dried 30 minutes at 45~50 DEG C, cross 40 mesh sieve whole grains；By obtained dry particl and crushing
Hydroxypropyl methylcellulose 71g and the xanthans 71g mixing crushed, are produced.
Comparative example 2 (1000 bags of amounts)
Preparation process：
(1) take recipe quantity Cefpodoxime Proxetil and Crodaret to be dissolved in absolute ethyl alcohol, obtain mixture one.
(2) Lactis Anhydrous, sucrose and calcium carboxymethylcellulose is put after being well mixed in fluid bed, slowly sprays into mixture
One, granulation, 30 DEG C of dryings of fluid bed, obtain mixture two.
(3) xanthans, citric acid, talcum powder and flavoring orange essence are added into mixture two, total mixed, packing.
Comparative example 3 (1000 bags of amounts)
Preparation process：
(1) take recipe quantity Cefpodoxime Proxetil and Crodaret to be dissolved in absolute ethyl alcohol, obtain mixture one.
(2) Lactis Anhydrous, sucrose and calcium carboxymethylcellulose is put after being well mixed in fluid bed, slowly sprays into mixture
One, granulation, 30 DEG C of dryings of fluid bed, obtain mixture two.
(3) xanthans, citric acid, talcum powder and flavoring orange essence are added into mixture two, total mixed, packing.
Stripping curve assay method：
The dry suspensoid agent for weighing embodiment 1~4 and the gained of comparative example 1~3 respectively carries out stripping curve test.Dissolution medium
For：PH1.2 hydrochloric acid solution, pH4.0 Acetate Solution, pH6.8 phosphate solution and purified water, medium volume：
900mL.Slurry processes, rotating speed：50 revs/min.Test solution temperature：37±0.5℃.UV Detection wavelengths：240nm.Respectively at 5 points
Clock, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes and the 5 milliliters of tests of sampling in 120 minutes, together
When add synthermal isometric dissolution medium.As a result accompanying drawing 1~6 is seen.
PH value assay method：
Measuring instrument：PH value analyzer (Mettler-Toledo, Inc.)
Measurement process：Take sample appropriate (containing about Cefpodoxime 100mg), add purified water 10ml, it is continuous to survey after shake well
Fixed pH value three times, averages.
Determination of moisture method：
Measuring instrument：Karl Fischer formula moisture teller (Wan Tong Instrument Ltd. of Switzerland)
Measurement process：Take sample appropriate (about moisture content 1mg), it is accurately weighed.Added from injection port in titration vessel, wait to drip
After the completion of fixed, moisture value is recorded, METHOD FOR CONTINUOUS DETERMINATION twice, is averaged.
Content assaying method：
Tester：High performance liquid chromatograph.Chromatographic condition：Chromatographic column：Agilent Zorbax ODS posts (4.6mm ×
250mm, 5um), mobile phase：Methanol：Water (60:40), Detection wavelength：240nm, column temperature：40℃.
Continuous mode：Take Cefpodoxime Proxetil reference substance appropriate, add proper amount of methanol to dissolve, then every 1ml is diluted to mobile phase
Containing about Cefpodoxime Proxetil 1mg solution, as reference substance solution.It is another to take this product appropriate (being approximately equivalent to Cefpodoxime 30mg), essence
It is close weighed, put in 100ml volumetric flasks, add proper amount of methanol to dissolve, then with mobile phase constant volume, shake up, filtration is need testing solution.
Reference substance solution and each 20ul injections liquid chromatograph of need testing solution are taken, chromatogram is recorded, Cefpodoxime is calculated by external standard method
Ester content.
Relevant substance-measuring method：
Tester：High performance liquid chromatograph.Chromatographic condition：Chromatographic column：Agilent Zorbax ODS posts (4.6mm ×
250mm, 5um), mobile phase：Methanol：Water (60:40), Detection wavelength：240nm, column temperature：40℃.
Continuous mode：Take this product appropriate (being approximately equivalent to Cefpodoxime 100mg), it is accurately weighed, put in 100ml volumetric flasks,
Add proper amount of methanol to dissolve, then with mobile phase constant volume, shake up, filter, as need testing solution.Precision measures need testing solution 1ml,
Put in 100ml volumetric flasks, with mobile phase constant volume, shake up, as reference substance solution.Take reference substance solution and need testing solution each
20ul injects liquid chromatograph, and record chromatogram is appointed in need testing solution chromatogram to 2 times of Second principal component, peak retention time
What is less than the main peak area of contrast solution two and 0.1 times of peak can be neglected.
Accelerated test method：
Sample after packaging is put into medicine stability to investigate in chamber, sets investigation condition as 40 DEG C of temperature, it is relatively wet
Degree 75%, sampled respectively at January, 2 months, March and June, detection character, pH value, moisture, content and relevant material.
Experimental result：
As shown in Figure 1, with the increase of raw material and Surfactant Ratio, comparative example 2, embodiment 1~3 and comparative example 3
The dissolution rate at each time point gradually reduces.5 minutes Dissolution Values of embodiment 1 and comparative example 2 continue to increase surface close to 90%
Activating agent dosage has little significance, and 15 minutes Dissolution Values of embodiment 3 are close to 85%, and 15 minutes Dissolution Values of comparative example 3 are not
Foot 75%, therefore be 1 by the ratio-dependent of Cefpodoxime Proxetil and surfactant:1~3:1, to improving the fast release solid formulation
Dissolution rate there is significant beneficial effect.It is real although the 15min dissolution rates both greater than 85% of embodiment 1,2 and comparative example 2
The dosage of surfactant minimum of example 2 is applied, the used time is also minimum that this drops when commercially producing when being dissolved in absolute ethyl alcohol
It is highly beneficial in terms of low production cost and raising production efficiency, therefore the preferably ratio of Cefpodoxime Proxetil and surfactant
For 1:2.
As shown in Figure 2, stripping curve of the embodiment 2 with embodiment 4 in purified water is almost consistent, therefore draws a conclusion：
The result of extraction of the present invention is had not significant impact using different wet granulation equipment.
From Fig. 3~6, stripping curve of the embodiment 2 in four kinds of different dissolution mediums is almost consistent, and 15 minutes
Dissolution rate is all higher than 85%.Stripping curve of the comparative example 1 in four kinds of different dissolution mediums is completely inconsistent, can only ensure
15 minutes dissolution rates are more than 85% in pH1.2 hydrochloric acid mediums, and pH4.0 acetate buffers, pH6.8 phosphate buffers and
15 minutes dissolution rates only have 50% or so in purifying aqueous medium, are differed greatly with the result of extraction of the embodiment of the present invention, illustrate this
The beneficial effect that the prescription and technique that invention uses are brought to the dissolution rate for improving the Cefpodoxime Proxetil fast release solid formulation.
The accelerated test result of 1 embodiment of table 2
*：Dissolution medium is：Purified water, sample time are 30 minutes.
As seen from the above table, the sample of embodiment 2 is placed 6 months under the conditions of Acceleration study, character, pH value, moisture, dissolution
Degree and content have no significant change, and relevant material is increased slightly trend, but changes unobvious, and sample stability is good.
Claims (7)
1. a kind of Cefpodoxime Proxetil fast release solid formulation, in said preparation containing Cefpodoxime Proxetil, surfactant, diluent, collapse
Solve agent, suspending agent and lubricant, it is characterised in that each composition presses total formulation weight gauge：
Wherein each component content sum is equal to 100%；
The weight ratio of the surfactant and Cefpodoxime Proxetil is 1:1~1:3；
The surfactant is Crodaret；
The diluent is selected from the mixture of both sucrose and Lactis Anhydrous；
The disintegrant is selected from calcium carboxymethylcellulose；
The suspending agent is selected from xanthans；
The lubricant is selected from talcum powder；
Contain flavouring in the fast release solid formulation, the flavouring is the mixture of acidity regulator and essence；
It uses wet granulation to prepare, and concrete operations are：
(1) Cefpodoxime Proxetil and surfactant are dissolved in absolute ethyl alcohol, obtain mixture one；
(2) after being well mixed diluent and disintegrant, mixture one is slowly added into or sprayed into, is pelletized, 30 DEG C of dryings of fluid bed,
Obtain mixture two；
(3) suspending agent, flavouring and lubricant are added into mixture two, total mixed, packing.
2. Cefpodoxime Proxetil fast release solid formulation as claimed in claim 1, it is characterised in that each composition presses total formulation weight
Meter：
3. Cefpodoxime Proxetil fast release solid formulation as claimed in claim 1, it is characterised in that said preparation be dry suspensoid agent or
Granula.
4. Cefpodoxime Proxetil fast release solid formulation as claimed in claim 1, it is characterised in that surfactant and Cefpodoxime
The weight ratio of ester is 1:2.
5. Cefpodoxime Proxetil fast release solid formulation as claimed in claim 4, it is characterised in that the acidity regulator is selected from Chinese holly
One or more of mixtures in rafter acid, malic acid, tartaric acid；Essence be selected from flavoring banana essence, flavoring orange essence, lemon extract,
Peach flavor, butter essence, chocolate essence, strawberry essence, flavoring pineapple essence, flavoring apple essence, kiwi flavor, grape are fragrant
One or more of mixtures in essence, watermelon essence, Hami melon essence.
6. prepare the method for the Cefpodoxime Proxetil fast release solid formulation of any one in Claims 1 to 5, it is characterised in that system
Standby technique is wet granulation, and concrete operations are：
(1) Cefpodoxime Proxetil and surfactant are dissolved in absolute ethyl alcohol, obtain mixture one；
(2) after being well mixed diluent and disintegrant, mixture one is slowly added into or sprayed into, is pelletized, 30 DEG C of dryings of fluid bed,
Obtain mixture two；
(3) suspending agent, flavouring and lubricant are added into mixture two, total mixed, packing.
7. the method as claimed in claim 6 for preparing fast release solid formulation, what wherein the married operation in step (2) used sets
Standby is wet mixing pelletizer or fluid bed.
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| CN113817440B (en) * | 2020-06-18 | 2022-11-08 | 中国石油化工股份有限公司 | Compound hydrate accelerant, application and gas storage and transportation method |
| CN116392447A (en) * | 2021-12-28 | 2023-07-07 | 通化万通药业股份有限公司 | Irbesartan dry suspension and preparation method thereof |
| CN115813868B (en) * | 2022-12-06 | 2024-06-28 | 江西省保灵动物保健品有限公司 | High-dissolution cefpodoxime proxetil tablet and preparation method thereof |
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| CN1505515A (en) * | 2001-02-27 | 2004-06-16 | ʵ | Oral pharmaceutical composition of cefpodoxime proxetil |
| CN101011360A (en) * | 2007-02-05 | 2007-08-08 | 深圳致君制药有限公司 | Recipe composition of dry turbid agent and its preparation process |
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| CN103230367A (en) * | 2013-05-07 | 2013-08-07 | 山东罗欣药业股份有限公司 | Cefpodoxime proxetil composition dry suspension and preparation method thereof |
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| CN1505515A (en) * | 2001-02-27 | 2004-06-16 | ʵ | Oral pharmaceutical composition of cefpodoxime proxetil |
| CN101011360A (en) * | 2007-02-05 | 2007-08-08 | 深圳致君制药有限公司 | Recipe composition of dry turbid agent and its preparation process |
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