CN100553622C - A kind of enteric coated mini-pill of pantoprazole sodium - Google Patents
A kind of enteric coated mini-pill of pantoprazole sodium Download PDFInfo
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- CN100553622C CN100553622C CNB2006100852276A CN200610085227A CN100553622C CN 100553622 C CN100553622 C CN 100553622C CN B2006100852276 A CNB2006100852276 A CN B2006100852276A CN 200610085227 A CN200610085227 A CN 200610085227A CN 100553622 C CN100553622 C CN 100553622C
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- pantoprazole sodium
- pill
- ball core
- pantoprazole
- enteric coated
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- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960004048 pantoprazole sodium Drugs 0.000 title claims abstract description 34
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 claims abstract description 33
- 239000002702 enteric coating Substances 0.000 claims abstract description 23
- 238000009505 enteric coating Methods 0.000 claims abstract description 23
- 239000000126 substance Substances 0.000 claims abstract description 11
- 229920002678 cellulose Polymers 0.000 claims abstract description 7
- 239000001913 cellulose Substances 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims description 22
- 230000001458 anti-acid effect Effects 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 12
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims description 8
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 8
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 8
- 229960005019 pantoprazole Drugs 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 6
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 5
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- 235000015424 sodium Nutrition 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000005516 engineering process Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000000576 coating method Methods 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 239000011248 coating agent Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- 235000010980 cellulose Nutrition 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000002572 peristaltic effect Effects 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229920002301 cellulose acetate Polymers 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- -1 hydroxypropyl Chemical group 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 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 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000001384 succinic acid Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 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
- 241001676635 Lepidorhombus whiffiagonis Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 208000031320 Teratogenesis Diseases 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of enteric coated mini-pill of pantoprazole sodium, comprise ball core that contains Pantoprazole Sodium and the enteric coating that contains cellulose substances.The invention also discloses a kind of preparation method of ball core.Prescription provided by the present invention and technology make that the Pantoprazole Sodium stability of formulation is higher, and are more suitable for suitability for industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, more particularly relate to enteric coated mini-pill of pantoprazole sodium.
Background technology
Pantoprazole Sodium (pantoprazole sodium) is the proton pump inhibitor that German hectogram is paused the pharmaceutical factory development and gone on the market, be widely used for the disease relevant with various acid, as duodenal ulcer, gastric ulcer, in, severe reflux esophagitis etc., and have curative effect height, short treating period, advantage such as better tolerance and relapse rate are low.
Present domestic extensive use enteric coatel tablets, common enteric coated capsule arranged, all be single dose of drug, the repeatability of its enteric effect is bad, and causes local concentration too high to gastric stimulation easily.And enteric coated micropill can improve medicine and gastrointestinal contact area, makes drug absorption complete, thereby improves bioavailability, avoids the untoward reaction such as stimulation to gastric mucosa simultaneously.Its drug release behavior is the compound recipe influence of forming a plurality of pillers compositions of a dosage, and seldom is subjected to the influence that gastric emptying changes, and absorption in vivo has good repeatability.At Chinese patent " enteric coated mini-pill of pantoprazole sodium " (application number: 2003101260.7, the applying date: on December 12nd, 2003, open day on November 17th, 2004) a kind of enteric coated micropill is disclosed in, prepare enteric coated mini-pill of pantoprazole sodium as enteric coating with the preparation method of routine with crylic acid resin material and other excipient, the more common enteric coated capsule of stability or the tablet of the enteric coated micropill that makes with this technical scheme increase, but await further to improve; And it prepares micropill because of prolonging with common process, and operation is more, and the suitability for industrialized production difficulty is big.
Summary of the invention
The stability that the objective of the invention is to overcome micropill in the prior art is not high, and preparation technology is difficult to industrialized deficiency, and a kind of more stable enteric coated mini-pill of pantoprazole sodium is provided, and a kind of preparation method capable of being industrialized is provided simultaneously.
The invention provides a kind of enteric coated mini-pill of pantoprazole sodium, comprise ball core that contains Pantoprazole Sodium and the enteric coating that contains cellulose substances.In file of the present invention, said " ball core " all refers to wrap up the pill core that carries of Pantoprazole Sodium, represents with " celphere " before packaging medicine, to show difference.
For improving the stability of micropill, the present invention has adopted multiple means to realize, at first the present invention improves enteric coating.Enteric coating of the present invention is selected from cellulose substances, as cellulose acetate-phthalate (CAP), hydroxypropylmethyl cellulose phthalate (HPMCP), 1,2,4-benzenetricarboxylic acid cellulose acetate (CAT), 1,2,4-benzenetricarboxylic acid hydroxypropyl emthylcellulose (HPMCT), succinic acid cellulose acetate (CAS), succinic acid hydroxypropyl emthylcellulose (HPMCAS) etc.Cellulose substances has many excellent characteristic, and such as plasticity, good film-forming property, safe, nontoxic, no teratogenesis etc. is suitable for enteric coating.Particularly the neighbour Cellulose Acetate Phthalate of hydroxypropylmethyl cellulose phthalate effect is good, and because of not containing acetoxy group in the chemical constitution, at duration of storage, can not dissociate acetic acid as CAP and causes that medicine is rotten.So preferred hydroxypropylmethyl cellulose phthalate of the present invention.
Through enteric coating consumption screening experiment (experimental result is as follows), enteric coating weight of the present invention is that the 15-30% of ball core weight is advisable.
Soak after 2 hours in the ☆ acid, micropill is kermesinus, and is orange.
★ changes in the basket the residue of dissolving.With detecting behind the Ph6.8 buffer dissolution filter, absorption is arranged at 288nm.
By last table result as can be seen two kinds of coating materials all principal agent is not had influence, micropill does not have metachromatism behind the coating, related substance does not have significant change.In the enteric coating liquid consumption screening experiment in sample 5 acid burst size defective, sample 1, sample 5 have metachromatism after soaking in acid solution, illustrate that the enteric coating film is not sufficiently complete, the part principal agent is destroyed by acid, and then influences the release in the buffer.Sample 4,8 every testing results are qualified, but still have part principal agent remnants in the buffer behind the drug release determination, the thickness effect of coating membrane the release of principal agent.Sample 2,3,6,7 every testing results are all qualified, comprehensive every index and cost, preferred sample 2, i.e. hydroxypropylmethyl cellulose phthalate (HPMCP) weightening finish 20%.
Enteric coating of the present invention also comprises other adjuvants such as triethyl citrate, Pulvis Talci etc. except comprising cellulose substances, with alkaline matter as solvent.Enteric coating prepares with conventional method.
Enteric coated mini-pill of pantoprazole sodium provided by the present invention also has one deck acid-resisting contagion gown between ball core and enteric coating.Contain hydroxypropyl emthylcellulose, propylene glycol, titanium dioxide and Pulvis Talci in the antiacid contagion gown, be added with one or more basifiers such as sodium hydroxide, natrium carbonicum calcinatum, sodium phosphate, magnesium oxide in the antiacid in addition contagion gown with any mixed.Wherein hydroxypropyl emthylcellulose is inert, and what rise is buffer action, prevents that enteric coating from exerting an influence to medicine stability.The clothing film thickness of antiacid contagion gown adopts in the antiacid contagion gown liquid HPMC weight and ball core percentage by weight to represent, result of the test shows, it is fine to isolate effect when ingredient proportion is 8%.Propylene glycol mainly plays plasticization, presses 10% of HPMC weight and adds, and the HPMC film property is good.Titanium dioxide plays interception, presses 20% of HPMC weight and adds, and can play shaded effect preferably.What basifier play is antiacid effect, and it can neutralize through the gastric acid of enteric coating, and preferred basifier is a natrium carbonicum calcinatum, and when pressing 10% interpolation of HPMC weight, its antiacid effect is better.Pulvis Talci can fluidizer in the coating process, eliminate static, and its adding proportion is the 10%-30% of HPMC weight.
The preparation by the following method of antiacid contagion gown of the present invention: slowly add the hot purified water of half amount among the HPMC, the limit edged stirs, after treating that it disperses fully, the purified water that adds surplus again, after treating its dissolving, add other adjuvant, the limit edged stirs, continue to stir 30 minutes, gained liquid is crossed 60 mesh sieves.The concentration of HPMC finally is controlled between the 5%-10%, and preferred 8%.
Technical scheme provided by the present invention is with antiacid, two-layer one deck of merging into of isolation, plays antiacid, isolated two effects simultaneously.Do so on the one hand and simplified production technology, improved the feasibility of its preparation; On the other hand basifier is joined in the contagion gown material, basifier more is evenly distributed in the ball wicking surface along with the film forming of HPMC like this, thereby can better play antiacid effect, more helps the stable of medicine.Wrap antiacid contagion gown and ensuingly enteric coatedly look like two processing steps, but in fact this two procedures is continuous, continual, thereby simplified production, improved efficient.
The present invention also provides a kind of preparation method that contains the ball core of Pantoprazole Sodium.Briefly the ball core prepares by the following method: pantoprazole and pharmaceutically acceptable auxiliaries are dispersed in the liquid, the liquid of gained are wrapped on the celphere make again.The popular employing of saying so " liquid medicine-feeding method " just is dispersed in Pantoprazole Sodium and pharmaceutically acceptable auxiliaries in the liquid earlier, transfers concentration to 15-50%, behind the PH to 11-13, the liquid of gained is wrapped on the celphere makes again.Wherein said liquid is the good solvent of pantoprazole such as water, ethanol, isopropyl alcohol, can select for use wherein one or more with the mixed liquor of any ratio, preferred water of the present invention, ethanol.Wherein said dispersion can also can be forms such as suspendible for dissolving.Can use NaOH, natrium carbonicum calcinatum etc. to transfer PH.
With " liquid medicine-feeding " legal system be equipped with the ball core with other the coating pan method, extrude spheronization and in patent documentation " enteric coated mini-pill of pantoprazole sodium " disclosed preparation method compare, have many advantages: the micropill particle size distribution that makes such as " liquid medicine-feeding " method is little, and the micropill in the particle diameter claimed range accounts for more than 95%; Medicine-feeding yield height can reach more than 95%; Uniform content, RSD is below 1%; Ball core mechanical strength height, proper sphere degree height, smooth surface are fit to further coating, particularly aqueous coatings; Operation is to carry out in airtight environment, reduces the contaminated chance of medicine, more helps the stable of medicine, meets the requirement of GMP simultaneously more.Because product dirt is few, more help labor protection in addition.And " powder medicine-feeding " method that patent documentation " enteric coated mini-pill of pantoprazole sodium " adopts is put the ball core on the rotation disc, binder solution is sprayed on the ball nuclear, add medicine or excipient powder subsequently, moist ball nuclear is under the liquid capillary effect, the powder particle is sticked to the surface, form fine-powder bed, along with constantly spraying into of slurry, more powder sticks on the ball nuclear, until the micropill that makes suitable size.The difficult control of the input of this method material, poor reproducibility between batch, drying efficiency is low, and dust pollution is big, and product yield is low, the micropill micropill content heterogeneity that makes.And the surface is more coarse, when coating, is unfavorable for forming complete film.In addition, the micropill mechanical strength that makes is low, is easy to fragmentation in the coating process, directly influences coating effect.As can be seen from the figure the micropill outward appearance of the present invention's preparation is with open source literature prepared micropill smooth surface, rounding.
The proportioning of said pantoprazole and pharmaceutically acceptable auxiliaries is as follows by weight in the preparation process of ball core:
100 parts of Pantoprazole Sodiums,
Diluent 0-200 part,
Binding agent 5-30 part.
Be preferably:
100 parts of Pantoprazole Sodiums,
Diluent 50-150 part,
Binding agent 7-15 part;
Wherein said diluent is starch, lactose, Icing Sugar, microcrystalline Cellulose, mannitol etc., preferred starch.Binding agent is PVP, HPMC, syrup, gelatin, starch slurry etc., preferred PVP.
In preparation process, control temperature of charge in the equipment at the ball core well, temperature is advisable to be controlled between 15 ℃-45 ℃.This temperature control is very important, can the stability of Pantoprazole Sodium be impacted if be higher than 45 ℃, makes its variable color, and related substance raises; If be lower than 15 ℃, the drying efficiency in the equipment can reduce, and the material moisture content in the equipment raises like this, will cause between the ball core to be sticked together, and makes yield reduce; As if the parcel speed of the liquid that slows down this moment, whole process of preparation is prolonged, also be unfavorable for the stable of Pantoprazole Sodium on the one hand, equipment, the reduction of personnel's utilization rate, production cost are raise.
Temperature controlling can be controlled by following measure: control temperature of charge by the control inlet temperature 1.; 2. by controlling liquid feed speed control temperature of charge; 3. by control air intake feed speed control temperature of charge; 4. by control air intake humidity control temperature of charge.
In the time of the control inlet temperature, can not ignore air intake humidity, because the height of air intake humidity has directly determined the drying efficiency of material.Air intake humidity is too high, if want to reach drying effect preferably, certainly will want elevated temperature, like this stable unfavorable to Pantoprazole Sodium; Air intake humidity is low excessively, can cause in the equipment very dryly, makes medicine and the adjuvant be wrapped on the ball core split away off, and directly influences yield; Medicine and the adjuvant that partly splits away off probably is bonded in the ball wicking surface with form of powder in addition, and the not enough rounding of ball wicking surface that makes like this influences ensuing coating effect probably.
Each parameter is not isolated in the whole process of preparation, but connect each other, interactional.In the preparation process, temperature, humidity and the air quantity of control air intake that must be meticulous and the feed speed of liquid, make it reach a dynamic equilibrium, temperature of charge and moisture content just can reach a better level like this, and the ball core quality and the yield that make just can reach better level.
Stable every index to the micropill of the present invention preparation is investigated, comprise accelerated tests, room temperature keep sample the experiment etc., experimental result shows: in character, related substance, sign content, the acid in release, the alkali every indexs such as release, health examination all normal, show that the micropill that the present invention prepares has good stability.
The write out a prescription micropill of preparation and the micropill of the disclosed document of patent preparation of the present invention carried out study on the stability, and the result shows that micropill stability of the present invention is better than the micropill in the open source literature, and the result is as follows:
A: burst size in the acid (%) B: burst size in the buffer (%)
Enteric coated mini-pill of pantoprazole sodium disclosed in this invention can further be prepared into various solid preparations.Look concrete needs and can make capsule that common gelatin seals, granule, dry suspension etc.
The present invention preferred by to each adjuvant in the prescription, to the optimization of technology in each operation, the micropill that makes the present invention prepare has had higher stability in preparation.The present invention had simultaneously both simplified preparation technology from the suitable for producing angle, had improved the quality of product again.
Description of drawings
Fig. 1 is the micropill outside drawing of prior art for preparing; Fig. 2 is the micropill outside drawing that the present invention prepares.
The specific embodiment
One. the preparation of ball core
1. the preparation of medicine-feeding liquid,
Embodiment 1
Take by weighing about 340g ethanol with a clean stainless steel cask precision, add 25gPVP, the limit edged stirs, and dissolves fully up to PVP, till the solution becomes clear.The about 440g of the former powder of Pantoprazole Sodium is added in the PVP solution for preparing, the limit edged stirs again, and continues to stir 10 minutes, crosses 60 mesh sieves, removes greater than 60 purpose solid matters.To install with another clean stainless steel cask less than 60 purpose solution, use Na
2CO3 transfers its pH value 11, and is standby.Solution materials concentration is 50%.
Embodiment 2
Pantoprazole Sodium 440g
HPMC 120g
Lactose 800g
Purified water 1310g
Transfer pH13 with 4%NaOH, solution concentration is 15%.
Preparation method is identical with embodiment 1.
Implement 3
Pantoprazole Sodium 440g
PVP 48g
Starch 400g
Purified water: ethanol (1: 1) 712g
4%NaOH transfers pH12, and solution concentration is 25%.
Preparation method is identical with embodiment 1.
2. liquid medicine-feeding
Embodiment 4
Celphere is placed fluid bed side spray rotating disk, adjust air-introduced machine frequency 25Hz, 55 ℃ of inlet temperature, 35 ℃ of temperature of charge, start blower fan, program and heat button, adjust 2-4 scale of turntable clearance, rotating disk frequency 8-14Hz starts rotating disk, adjust atomizing pressure 0.3-0.5MPa, 0.8-1.5 scale of peristaltic pump rotating speed will be gone up medicinal liquid spray and wrap on the celphere, on one side hydrojet be dried to ball on one side.
Embodiment 5
Celphere is placed the coating pelletizing machine; adjust air blast flux 4-8L/min; 35 ℃ of inlet temperature; 25 ℃ of temperature of charge; 160-220 rev/min of main frame revolution adjusted atomizing pressure 0.08-0.12MPa, 0.8-1.5 scale of peristaltic pump rotating speed; to go up medicinal liquid spray and wrap on the celphere, on one side hydrojet be dried to ball on one side.
Two. the preparation of antiacid sealing coat
Embodiment 6
Antiacid contagion gown is pressed the ratio preparation:
HPMC 135.0g
Propylene glycol 13.5g
Na
2CO3 13.5g
Titanium dioxide 27.0g
Pulvis Talci 40.5g
Water 1458g
The preparation of antiacid contagion gown: the hot water of 700g is slowly added among the HPMC, and the limit edged stirs, treat that it disperses fully after, add the water of surplus again, after treating its dissolving, add other adjuvant, the limit edged stirs, continue to stir 30 minutes, gained liquid is crossed 60 mesh sieves, the concentration of HPMC is 8%.
Wrap antiacid contagion gown: the ball core is poured into put into spray at the bottom of the fluid bed, pour load weighted ball core into end spray moving bed, push moving bed then, rise moving bed.Adjust spouted bed and moving bed gap 4-10 circle, adjust air blast flux 38-48Hz, inlet temperature 35-55 ℃, temperature of charge 25-35 ℃, adjust whiff pressure 0.3-0.5MPa, 1.0-2.5 scale of peristaltic pump rotating speed begins bag and isolates antiacid clothing.
Three. the preparation of micropill
Embodiment 7
The preparation enteric coating
HPMCP 337.6 grams
Triethyl citrate 84.4 grams
Pulvis Talci 67.52 grams
Ammonia 3376 grams of PH9
Prepare enteric coating by above charge ratio and with conventional method.
The preparation technology of continuity embodiment 6 sprays into moving bed with enteric coating by peristaltic pump, begins enteric coatedly outside wrapping the ball core of antiacid contagion gown, makes micropill.
Four. the preparation of dry suspension
Embodiment 8
Micropill 1700g
Microcrystalline Cellulose (RC-591) 500g
Icing Sugar 1200g
Be distributed into 10000 pouches, contain 40mg for every bag in pantoprazole.
Claims (5)
1. an enteric coated mini-pill of pantoprazole sodium comprises ball core that contains Pantoprazole Sodium and the enteric coating that contains cellulose substances, and it is characterized in that has the antiacid contagion gown of one deck between described ball core and enteric coating; Wherein said ball core prepares by the following method: earlier Pantoprazole Sodium and pharmaceutically acceptable auxiliaries are dispersed in the liquid, the liquid of gained are wrapped on the celphere make again, described enteric coating weight is the 20-25% of ball core; Wherein said enteric coating with alkaline matter as solvent; Wherein said cellulose substances enteric coating is hydroxypropylmethyl cellulose phthalate or cellulose acetate-phthalate.
2. enteric coated mini-pill of pantoprazole sodium as claimed in claim 1 is characterized in that described Pantoprazole Sodium and pharmaceutically acceptable auxiliaries in weight ratio, are following component:
100 parts of Pantoprazole Sodiums,
Diluent 0-200 part,
Binding agent 5-30 part.
3. enteric coated mini-pill of pantoprazole sodium as claimed in claim 2 is characterized in that described Pantoprazole Sodium and pharmaceutically acceptable auxiliaries in weight ratio, are following component:
100 parts of Pantoprazole Sodiums,
Diluent 50-150 part,
Binding agent 7-15 part.
4. enteric coated mini-pill of pantoprazole sodium as claimed in claim 1 is characterized in that described ball core in preparation process, and temperature is 15-25 ℃.
5. the solid preparation that is prepared from by the described enteric coated mini-pill of pantoprazole sodium of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNB2006100852276A CN100553622C (en) | 2006-06-06 | 2006-06-06 | A kind of enteric coated mini-pill of pantoprazole sodium |
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| CNB2006100852276A CN100553622C (en) | 2006-06-06 | 2006-06-06 | A kind of enteric coated mini-pill of pantoprazole sodium |
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| CN1883460A CN1883460A (en) | 2006-12-27 |
| CN100553622C true CN100553622C (en) | 2009-10-28 |
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| CN101836985A (en) * | 2009-03-17 | 2010-09-22 | 北京利乐生制药科技有限公司 | L-pantoprazole magnesium-containing pharmaceutical preparation and preparation method |
| CN104161807A (en) * | 2013-05-20 | 2014-11-26 | 陕西雪龙海姆普德药业股份有限公司 | Preparation method for medicine used for treating acute and chronic nasosinusitis and rhinitis |
| CN105534935B (en) * | 2015-12-30 | 2018-09-18 | 广州共禾医药科技有限公司 | Pantoprazole microplate, preparation method, multiple unit type Pantoprazole enteric sustained-release preparation and preparation method thereof |
| CN105651003B (en) * | 2016-01-22 | 2018-10-19 | 青岛华仁太医药业有限公司 | A kind of fluidized drying technique of Pu Yuan and capsule for treating gastropathy particle |
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Application publication date: 20061227 Assignee: HUADONG MEDICINE Co.,Ltd. Assignor: HANGZHOU ZHONGMEIHUADONG PHARMACEUTICAL Co.,Ltd. Contract record no.: X2021330000109 Denomination of invention: Pantoprazole sodium enteric coated pellets Granted publication date: 20091028 License type: Common License Record date: 20210820 |
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