CN101321514A - Finely dispersed cross-linked polyvinylpyrrolidone for use as tablet disintegrant - Google Patents
Finely dispersed cross-linked polyvinylpyrrolidone for use as tablet disintegrant Download PDFInfo
- Publication number
- CN101321514A CN101321514A CNA2006800452731A CN200680045273A CN101321514A CN 101321514 A CN101321514 A CN 101321514A CN A2006800452731 A CNA2006800452731 A CN A2006800452731A CN 200680045273 A CN200680045273 A CN 200680045273A CN 101321514 A CN101321514 A CN 101321514A
- Authority
- CN
- China
- Prior art keywords
- tablet
- polymer
- polymerization
- disintegrating agent
- popcorn
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000007885 tablet disintegrant Substances 0.000 title claims abstract description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 title abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 title abstract description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 title abstract description 6
- 230000036571 hydration Effects 0.000 claims abstract description 11
- 238000006703 hydration reaction Methods 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims abstract description 8
- 150000005846 sugar alcohols Chemical class 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 45
- 229920000642 polymer Polymers 0.000 description 29
- 239000000203 mixture Substances 0.000 description 26
- 239000003795 chemical substances by application Substances 0.000 description 25
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 24
- 241000482268 Zea mays subsp. mays Species 0.000 description 24
- 238000006116 polymerization reaction Methods 0.000 description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000178 monomer Substances 0.000 description 9
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 229920003085 Kollidon® CL Polymers 0.000 description 8
- 239000003431 cross linking reagent Substances 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 229910052756 noble gas Inorganic materials 0.000 description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 239000011261 inert gas Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- -1 (methyl) acrylic acid alkylidene diol ester Chemical class 0.000 description 5
- 238000007906 compression Methods 0.000 description 5
- 230000006835 compression Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000001788 irregular Effects 0.000 description 3
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 3
- 229960003088 loratadine Drugs 0.000 description 3
- 238000012673 precipitation polymerization Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- MYRTYDVEIRVNKP-UHFFFAOYSA-N 1,2-Divinylbenzene Chemical compound C=CC1=CC=CC=C1C=C MYRTYDVEIRVNKP-UHFFFAOYSA-N 0.000 description 2
- KUDUQBURMYMBIJ-UHFFFAOYSA-N 2-prop-2-enoyloxyethyl prop-2-enoate Chemical compound C=CC(=O)OCCOC(=O)C=C KUDUQBURMYMBIJ-UHFFFAOYSA-N 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 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 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000009849 deactivation Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 2
- 229940075931 sodium dithionate Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- ALDLWNVQGSGVDF-UHFFFAOYSA-N 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CC(=C)C(O)=O.OCCOCCOCCOCCO ALDLWNVQGSGVDF-UHFFFAOYSA-N 0.000 description 1
- YDOVPVLKADMTFE-UHFFFAOYSA-N 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol;prop-2-enoic acid Chemical compound OC(=O)C=C.OCCOCCOCCOCCO YDOVPVLKADMTFE-UHFFFAOYSA-N 0.000 description 1
- FYRWKWGEFZTOQI-UHFFFAOYSA-N 3-prop-2-enoxy-2,2-bis(prop-2-enoxymethyl)propan-1-ol Chemical compound C=CCOCC(CO)(COCC=C)COCC=C FYRWKWGEFZTOQI-UHFFFAOYSA-N 0.000 description 1
- DBCAQXHNJOFNGC-UHFFFAOYSA-N 4-bromo-1,1,1-trifluorobutane Chemical compound FC(F)(F)CCCBr DBCAQXHNJOFNGC-UHFFFAOYSA-N 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 206010009866 Cold sweat Diseases 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N alpha-methacrylic acid Natural products CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- BLCTWBJQROOONQ-UHFFFAOYSA-N ethenyl prop-2-enoate Chemical compound C=COC(=O)C=C BLCTWBJQROOONQ-UHFFFAOYSA-N 0.000 description 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Substances CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- XXQBGBUZLWZPKT-UHFFFAOYSA-N n-prop-2-enoylbuta-2,3-dienamide Chemical compound C=CC(=O)NC(=O)C=C=C XXQBGBUZLWZPKT-UHFFFAOYSA-N 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 150000002835 noble gases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- DBSDMAPJGHBWAL-UHFFFAOYSA-N penta-1,4-dien-3-ylbenzene Chemical compound C=CC(C=C)C1=CC=CC=C1 DBSDMAPJGHBWAL-UHFFFAOYSA-N 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- FBCQUCJYYPMKRO-UHFFFAOYSA-N prop-2-enyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCC=C FBCQUCJYYPMKRO-UHFFFAOYSA-N 0.000 description 1
- QTECDUFMBMSHKR-UHFFFAOYSA-N prop-2-enyl prop-2-enoate Chemical compound C=CCOC(=O)C=C QTECDUFMBMSHKR-UHFFFAOYSA-N 0.000 description 1
- 239000007898 rapid-disintegration tablet Substances 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000006228 supernatant 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
- 238000001291 vacuum drying Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
The invention relates to the use of cross-linked polyvinylpyrrolidone of an average particle size of from 5 - 60 [mu]m and a hydration capacity of more than 7 g/g as tablet disintegrant.
Description
The present invention relates to particle mean size is that 5～60 μ m and hydration capability are higher than the purposes of the finely dispersed cross-linked polyvinylpyrrolidonefor of 7g/g as tablet disintegrant.
The disintegration rate and the rate of dissolution that use disintegrating agent to improve tablet are generally approved already.
About this point, the most frequently used a kind of disintegrating agent is a crospolyvinylpyrrolidone.Such crospolyvinylpyrrolidone is commercially available, for example from BASF Aktiengesellschaft's
The CL type, or from ISP Investments Inc.'s
The XL type.
Crospolyvinylpyrrolidone mainly with particle mean size greater than the thick form of 100 μ m as tablet disintegrant (Kollidon CL is about 120 μ m, and Polyplasdone XL is about 130 μ m).Although the big disintegrate of granularity is effective, but granularity greatly also has many shortcomings, and tablet surface is more coarse when for example storing under wet condition, resistance to crushing is low, resistance to crushing reduces when storing under wet condition, tablet mixes inhomogeneous and isolating tendency takes place in tablet mixture.Other shortcoming is that thick disintegrating agent granule causes uncomfortable gritty mouthfeel.
At present, generally believe that always the disintegrate effect is relevant with granularity.Therefore, and the disintegrate effect that smaller particles should always can be significantly reduced (referring to V.Buehler, " medicine polyvinylpyrrolidone excipient ", the 128th page reaches each page subsequently, Springer Verlag Berlin Heidelberg, 2005).Therefore, Polyplasdone XL 10 (granularity is about 30 μ m) is on duty mutually with the disintegrate effect of Kollidon CL-M (granularity is about 5 μ m).Therefore, given play to specific disintegrate effect in order to make these granule products, needed much higher concentration, this causes cost, and higher more humidification is quick with tablet, thereby is disadvantageous.Usually, also can not reach fast disintegrate as using the crospolyvinylpyrrolidone coarse granule even improve concentration.
US 6,677, and 417 disclose granularity is the crospolyvinylpyrrolidone of＞400 μ m to the 1500 μ m purposes as tablet disintegrant.
The objective of the invention is to seek the tablet disintegrant that helps avoid above-mentioned shortcoming.
Therefore, found the defined purposes of beginning.The particle mean size of the crospolyvinylpyrrolidone disintegrating agent that the present invention is used is 5-60 μ m, preferred 10-50 μ m, especially preferred 15-40 μ m.Hydration capability is higher than 7.0g/g, preferably is higher than 7.5g/g, especially preferably is higher than 8.0g/g, and can be up to 12.0g/g.
Hydration capability is measured by following method:
Take by weighing the 2g polymer to centrifuge tube, and expanded 15 minutes with 40ml is water-soluble.Subsequently, with 2000rpm centrifugal 15 minutes, pour out supernatant, sample is weighed once more.
(also referring to V.Buehler, " medicine polyvinylpyrrolidone excipient ", the 132nd page reaches with the reserve page or leaf Springer Verlag Berlin Heidelberg, 2005).
Such crospolyvinylpyrrolidone is can be by itself known and be called the polymerization preparation of popcorn polymerization.For example precipitation polymerization or polymerisation in bulk are carried out by known method in described popcorn polymerization.Example of known method such as a kind of method described in the EP-B-0 177 812, wherein by under oxygen and the non-existent condition of polymerization initiator, heating 99.6～98.8wt%N-vinyl pyrrolidone and 0.4～1.2wt% begin described popcorn polymerization as the temperature of mixture to 100～150 of the chemical compound with at least two ethylenic unsaturated double-bonds of cross-linking agent ℃.
Comprise at least two ethylenic unsaturated double-bonds in the molecule as the described chemical compound of cross-linking agent.Especially suitable example is alkylidene diacrylamine such as methylene diacrylamine and N; N '-acryloyl group ethylenediamine, N; N '-divinyl ethylidene-urea, N; N '-divinyl propylidene urea, ethylene-3-(N-vinyl pyrrolidone), N; N '-divinyl diimidazole base (2,2 ') butane and 1,1 '-two (3; 3 '-vinyl benzo imidazole radicals-2-ketone)-1, the 4-butane.The example of other suitable crosslinking agent is two (methyl) acrylic acid alkylidene diol ester such as ethylene glycol diacrylate, Ethylene glycol dimethacrylate, acrylic acid tetraethylene glycol (TEG) ester, dimethacrylate tetraethylene glycol (TEG) ester, acrylic acid diethylene glycol ester, methacrylic acid diethylene glycol ester; Aromatic divinyl compound such as divinylbenzene and divinyl toluene; With vinyl acrylate, allyl acrylate, allyl methacrylate, divinyl diox, pentaerythritol triallyl ether, and the mixture of described cross-linking agent.The preferred cross-linking agent that uses is N, N '-divinyl ethylidene-urea.
The consumption of cross-linking agent is 0.1～10wt% based on amount of monomer used in the polymerization, preferred 1～4wt%.
This polymerization can be initiated in the presence of small amounts of sodium hydroxide solution or potassium hydroxide solution.Form polymerisable popcorn polymer at short notice, this polymerisable popcorn polymer is when adding the N-vinyl pyrrolidone in addition and continuing to add cross-linking agent, the popcorn polymerization that does not have induction period is also finished in beginning, wherein according to the present invention even before popcorn polymerization begins by feeding the granularity that inert gas is controlled the gained popcorn polymer in the preferred monomer in being incorporated into aggregation container.But, during induction period in polymerization, begin to feed inert gas at the latest, and make inert gas during whole popcorn polymerization, pass through reactant mixture.
In order to carry out solvent-free popcorn polymerization reaction, i.e. polymerisation in bulk makes the monomer deactivation of introducing by feeding nitrogen, is heated to 100～200 ℃ then, preferred 150～180 ℃ temperature.Advantageously even between polymerization period, all continue to make gentle nitrogen current to pass through monomer.Also realized the eliminating of oxygen by polyblend under monomer boiling and pressure below atmospheric pressure.But, can under reduced pressure feed noble gas simultaneously and carry out popcorn polymerization.Depend on monomeric consumption and selected temperature, mixture polymerization in 1～20 hour.Obtain the popcorn polymer of powder type thus, productive rate is higher than 90%.
Yet for the preparation popcorn polymer, the precipitation polymerization in water is preferred.In this case, select monomeric concentration rightly, make reactant mixture during entire reaction, can both obtain satisfactory stirring.If monomeric concentration is too high in the water, 95wt% for example, then polymer beads becomes and is clamminess, thereby than more difficult stirring in rarer aqueous solution.In order in conventional stirred vessel, to react, select based on for example about 5～30wt% of aqueous mixture, the monomer concentration of preferred 10～20wt%.If use more strong agitator, the monomer concentration of aqueous solution also can be brought up to 50wt%, and suitable words concentration can be higher.Maybe advantageously begin popcorn polymerization with dense relatively solution in some cases, then thin up during reaction.
Preferably carry out popcorn polymerization to avoid any possible monomer hydrolysis being higher than under 6 the pH value.Can be by adding a spot of alkali such as sodium hydroxide or ammonia or adding a spot of commonly used buffer salt such as sodium carbonate, sodium bicarbonate or sodium phosphate are regulated pH value.If suitable, could be by would treating that polymeric mixture heated is to seething with excitement and making inert gas realize the eliminating of oxygen with the granularity of control popcorn polymer by reactant mixture in addition.
In this case, control the granularity of popcorn polymer by the amount of the inert gas by polymeric solution.If provide a spot of noble gas to reactant mixture, then obtain the flower-shaped polymer of unpolished rice usually, and if make a large amount of noble gases by polymeric solution, then obtain thinner popcorn polymer.Based on various restrictive conditions such as container dimensional, temperature and pressure, can not point out to regulate the accurate condition of the concrete granularity of popcorn polymer to each concrete condition.Just can easily find the exact amount that to pass through the noble gas of reactant mixture under the concrete condition by simple test several times.Point out that as top the amount of the noble gas by reactant mixture is 0.01～100, preferred 0.1～30 liter of noble gas/rise reactant mixture/hour.
Can use rare gas such as helium, neon or argon as noble gas.Carbon dioxide also is suitable.The preferred nitrogen that uses.
In order to remove dissolved oxygen fully, also can be with a small amount of, be that Reducing agent such as sodium sulfite, sodium pyrosulfite, sodium dithionate, ascorbic acid or the Reducing agent mixture of 0.1～1wt% joins in the reactant mixture for example based on monomer mixture.In preferred embodiments, popcorn polymerization takes place in the presence of as the sodium dithionate of Reducing agent.
Can in wide region, change polymerization temperature, for example about 20～200 ℃, preferred 50～150 ℃.
In especially preferred precipitation polymerization embodiment, if in inert gas, add hot water soluble comonomer, partial cross-linked dose, water and suitable buffer agent and Reducing agent, up to first polymer beads occurring.If desired, if added the mixture of one or more above-mentioned comonomers and residue cross-linking agent and suitable water as diluent then in 0.2～5 hour, this mixture is the deactivation by being blown into nitrogen in advance.The advantage of this method is that popcorn polymerization only need be used the short time.
Usually about 90% to＞99% the productive rate with theoretical yield obtains popcorn polymer.They can be by filtering or centrifugally separating with aqueous suspension, with after washing and dry in conventional drying device such as heated-air circulation oven (circulating air drying oven) or vacuum drying oven, slurry formula exsiccator, revolver drier, fluidized bed dryer or pneumatic conveyer dryer.Not only water insoluble and all solvents of this popcorn polymer, and slight swelling is only arranged therein.Swelling volume in water is 8～10L/kg.
It is commercially available being suitable for popcorn polymer of the present invention, as BASF Aktiengesellschaft
Type.
Control described method, make that the particle mean size of dry polymer is that 5 μ m～60 μ m and hydration capability are higher than 7g/g.Granularity can utilize Malvern Mastersizer to measure by light scattering.
These polymer can be blended in the tablet mixture very equably, thereby make the standard deviation of disintegration of tablet time significantly reduce.The surface of this tablet is obviously Paint Gloss, even also is like this when storing under wet condition.
Polymer of the present invention is particularly suited for quickly disintegrated tablet in mouth, and this tablet is called quick dispersible tablet or melts sheet fast, and reason is opposite with thick disintegrating agent, and polymer of the present invention does not have gritty mouthfeel, and in fact mouthfeel is very soft comfortable.
They are same favourable for the tablet that is placed on disintegrate in one glass of water before taking.In this case, there is not the graininess precipitate to form; On the contrary, obtained the fine grained suspended substance.
Another characteristics are that they can mix with extremely a large amount of water or organic solvent and constant tide or do not become pastel or slurry.This character is especially favourable for wet granulation in blender, also is like this when particularly adopting high relatively disintegrating agent concentration with relative high agglomerant concentration.Unexpectedly, polymer of the present invention does not lose its disintegrate effect through moistening and drying, and promptly they can be introduced in the pelletize, and the quick disintegrate of tablet.Also be that they are particularly suitable for wet granulation for this reason.
The consumption of the used disintegrating agent of the present invention is 0.5～50wt% based on the weight of tablet usually, preferred 1～10wt%.
The used disintegrating agent of the present invention is suitable for preparing all types of active constituents of medicine tablets in principle.In addition, they also are suitable for preparing the nutritional supplement of tablet form.
The used disintegrating agent of the present invention preferably is suitable for preparing rapid disintegration tablet.The quickly disintegrated meaning is tablet disintegrate fully in 10～120 seconds under 20 ℃ in water.
The used disintegrating agent of the present invention is particularly suited for preparation quickly disintegrated tablet in mouth.
The character of the used polymer of the present invention (polymer 1,2) and the character of contrast product:
| Kollidon CL | Kollidon CL-M | Polyplasdone XL 10 | Polymer 1 | Polymer 2 | |
| Hydration capability [g/g] | 4.4 | 4.0 | 4.6 | 8.0 | 8.1 |
| Particle mean size [μ m] | 120 | 5 | 29 | 19 | 21 |
Application Example
The blank tablet
Disintegrating agent concentration is the composition of 6% tablet:
Ludipress LCE 467.50mg
Disintegrating agent 30.00mg
Magnesium stearate 2.50mg
Tablet weight 500.00mg
Make all the components pass through the sieve of 0.8mm, and in Turbula blender (available from Bachofen, Switzerland), mixed 10 minutes.Use 12mm stamping machine (bevelled) to impact for 30 times/tabletting minute in eccentric press (Korsch EKO, available from Korsch, Berlin).Compression stress is 18kN.
Obtain following tablet character:
| No disintegrating agent | Kollidon CL | Kollidon CL-M | Polyplasdone XL | Polyplasdone XL 10 | Polymer 1 | |
| Disintegrate | 433 | 70 | 291 | 73 | 127 | 67 |
| The relative standard deviation of disintegrate (%) | 15.7 | 14.5 | 13.9 | 14.0 | 6.3 | 6.5 |
| Resistance to crushing (N) | 165 | 145 | 194 | 148 | 161 | 178 |
| Fragility (%) | 0.19 | 0.11 | 0.05 | 0.16 | 0.12 | 0.05 |
The stability of test tablet under 23 ℃, 65% relative humidity, 7 days condition:
The tablet that contains Kollidon CL: 6.5
The stability of test tablet under 23 ℃, 65% relative humidity, 7 days condition:
The tablet that contains Kollidon CL: 6.5
The tablet that contains embodiment 1 polymer: 4
The tablet surface evaluation criterion:
1 is smooth
There is a little irregular on 2 tablet surface
3 a little irregular/coarse tablet surface
4 significantly irregular/as to begin to occur pit
5 slight pits
6 moderate pits
7 severe pits
Frangible and the porous of 8 severe pit/tablets
Tablet for alleviating pain
Disintegrating agent concentration is the composition of the tablet of 2.7wt%:
Aspirin powder 250.00mg
Acetaminophen crystal 2 50.00mg
Caffeine granule 0.2-0.550.00mg
Kollidon 30 27.50mg
Disintegrating agent 16.00mg
Magnesium stearate 5.00mg
Tablet weight 598.50mg
At first, three kinds of active component are mixed in the Diosna blender, and with 20% Kollidon 30 aqueous solution moistenings.The compositions that makes this moistening then is by the sieve of the wide 0.8mm of sieve aperture, and on pallet at room temperature with dry 24 hours of thin layer form.These granules and disintegrating agent and the magnesium stearate of having passed through the 0.8mm sieve and mixed in Turbula blender (available from Bachofen, Switzerland) 10 minutes are mixed.Use 12mm stamping machine (bevelled) to impact for 30 times/tabletting minute in eccentric press (KorschEKO, available from Korsch, Berlin).Compression stress is 18kN.
Obtain following tablet character:
| No disintegrating agent | Kollidon CL | Kollidon CL-M | Polyplasdone XL | Polyplasdone XL 10 | The polymer of embodiment 1 | |
| Disintegrate (divide: second) | 70:40 | 9:13 | 18:15 | 13:03 | 19:04 | 7:36 |
| Resistance to crushing (N) | 165 | 93 | 120 | 97 | 106 | 149 |
| Fragility (%) | 0.38 | 0.38 | 0.20 | 0.41 | 0.42 | 0.25 |
The stability of test tablet under 23 ℃, 85% relative humidity, 7 days condition:
Kollidon CL： 6.5
No. 1 polyvinylpyrrolidone (Crospovidone) 3
Hydration capability 8.0g/g
Vitamin C tablet
Disintegrating agent concentration is the composition of the tablet of 3.2wt%:
Vitamin C 90 (Roche) 480.00mg
Avicel PH 102 96.06mg
Disintegrating agent 19.20mg
Magnesium stearate 4.32mg
Tablet weight 599.58mg
Make all the components pass through the sieve of 1.0mm, and in Turbula blender (available from Bachofen, Switzerland), mixed 10 minutes.Use 12mm stamping machine (bevelled) with 40rpm tabletting in rotary press (Korsch PH 106, available from Korsch, Berlin).Compression stress is 18kN.
Obtain following tablet character:
| No disintegrating agent | Kollidon CL | Kollidon CL-M | Polyplasdone XL | Polyplasdone XL 10 | The polymer of embodiment 1 | |
| Disintegrate (divide: second) | 11:2 9 | 3:57 | 6:12 | 4:53 | 6:00 | 4:54 |
| Resistance to crushing (N) | 141 | 114 | 207 | 131 | 144 | 200 |
| Fragility (%) | 0.21 | 0.21 | 0.12 | 0.14 | 0.15 | 0.11 |
KollidonCL： 6
No. 1 polyvinylpyrrolidone 2.5
Hydration capability 8.0g/g
Oral disintegrate loratadine (Loratadine) sheet
Disintegrating agent concentration is the composition of 8.0% tablet:
Loratadine 10.0mg
Mannitol 100.0mg
Erithritol 73.0mg
Disintegrating agent 16.0mg
Magnesium stearate 1.0mg
Tablet weight 200.0mg
Make all the components pass through the sieve of 0.8mm, and in Turbula blender (available from Bachofen, Switzerland), mixed 10 minutes.Use 8mm stamping machine (bevelled) with 40rpm tabletting in rotary press (Korsch PH 106, available from Korsch, Berlin).Compression stress is 15kN.
Obtain following tablet character:
Disintegrate in mouth: 40s
Mouthfeel: as snug as a bug in a rug, refrigerant slightly, no granule
Resistance to crushing: 50N
Quickly disintegrated Basa
Disintegrating agent concentration is the composition of the tablet of 8.0wt%:
Aspirin 100.0mg
Mannitol 60.0mg
Avicel PH 101 53.5mg
Disintegrating agent 35.0mg
Magnesium stearate 1.5mg
Tablet weight 250.0mg
Make all the components pass through the sieve of 0.8mm, and ploughshear mixer (available from
) the middle mixing 5 minutes.Use 10mm stamping machine (bevelled) with 30rpm tabletting in rotary press (Korsch PH 106, available from Korsch, Berlin).Compression stress is 16kN.
Obtain following tablet character:
Resistance to crushing: 70N
Disintegrate in one glass of water (200ml): 60s, outward appearance: thin suspended substance
Claims (9)
1. particle mean size is that 5～60 μ m and hydration capability are higher than the purposes of the crospolyvinylpyrrolidone of 7g/g as tablet disintegrant.
2. the described purposes of claim 1, wherein said granularity is 10～50 μ m.
3. the described purposes of claim 1, wherein said granularity is 15～40 μ m.
4. each described purposes of claim 1～3, wherein said hydration capability is higher than 7.5g/g.
5. each described purposes of claim 1～3, wherein said hydration capability is higher than 8.0g/g
6. tablet comprises each described crospolyvinylpyrrolidone of claim 1～5 based on the gross weight of described tablet with the concentration of 0.5～50wt%.
7. the described tablet of claim 6 comprises crospolyvinylpyrrolidone with the concentration of 1.0～10wt%.
8. quickly disintegrated tablet in mouth comprises each described crospolyvinylpyrrolidone of claim 1～5 with the concentration of 1.0～10wt%.
Claim 8 described in mouth quickly disintegrated tablet, comprise the sugar alcohol of 20～95wt%.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05112607.6 | 2005-12-21 | ||
| EP05112607 | 2005-12-21 | ||
| EP05112963.3 | 2005-12-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101321514A true CN101321514A (en) | 2008-12-10 |
Family
ID=40181196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800452731A Pending CN101321514A (en) | 2005-12-21 | 2006-12-11 | Finely dispersed cross-linked polyvinylpyrrolidone for use as tablet disintegrant |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101321514A (en) |
-
2006
- 2006-12-11 CN CNA2006800452731A patent/CN101321514A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4595587A (en) | Divisible pharmaceutical tablet with delayed active ingredient release | |
| US20060093668A1 (en) | Melt granulated composition and modified release dosage form prepared from said composition | |
| WO1983003353A1 (en) | Psyllium compositions | |
| US8597679B2 (en) | Fine-particle crosslinked polyvinylpyrrolidone as tablet disintegrant | |
| CN101612135A (en) | A kind of levetiracetam composition and method of making the same that is used for direct compression | |
| TWI284541B (en) | Process for preparing direct tabletting formulations or aids | |
| PL168605B1 (en) | Method of making solid dosage units of controllable release | |
| CN103356498B (en) | Mosapride citrate sustained-release tablet | |
| TW201023894A (en) | Directly compressible high functionality granular dibasic calcium phosphate based co-processed excipient | |
| KR101519612B1 (en) | Process for the preparation of controlled-release solid formulations containing oxcarbazepine, and formulations obtainable by said process | |
| CN109745295B (en) | Rivaroxaban oral solid preparation and preparation method thereof | |
| CN1172660C (en) | Low-dose tablets and preparation method | |
| CN101321514A (en) | Finely dispersed cross-linked polyvinylpyrrolidone for use as tablet disintegrant | |
| CN102755300A (en) | Voriconazole composition and preparation method thereof | |
| CN101843598A (en) | Preparation method of felodipine sustained release tablets | |
| CN111467317B (en) | Pharmaceutical composition containing atorvastatin calcium and preparation method thereof | |
| EP1020184A1 (en) | Sustained release tablets containing bupropion hydrochloride | |
| CN115998700A (en) | Pharmaceutical composition containing glucosamine hydrochloride and preparation method thereof | |
| RU2445118C2 (en) | Method for producing carrier of biologically active compounds of interpolyelectrolyte complex | |
| CN113750067A (en) | Preparation process of levofloxacin tablets | |
| CN111053753A (en) | Rivaroxaban pharmaceutical composition and preparation method thereof | |
| CN117835971A (en) | Adjuvant composition for direct compression | |
| TW200302111A (en) | Increased-dosage nelfinavir tablet and method of making same | |
| CN117064860A (en) | Preparation method of riocigua tablet | |
| CN115381834A (en) | Ticagrelor sustained-release solid composition and capsule preparation containing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20081210 |