NO130844B - - Google Patents
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- Publication number
- NO130844B NO130844B NO00640/70A NO64070A NO130844B NO 130844 B NO130844 B NO 130844B NO 00640/70 A NO00640/70 A NO 00640/70A NO 64070 A NO64070 A NO 64070A NO 130844 B NO130844 B NO 130844B
- Authority
- NO
- Norway
- Prior art keywords
- coating
- intestinal juice
- approx
- sensitive
- tablets
- Prior art date
Links
- 238000000576 coating method Methods 0.000 claims description 45
- 239000011248 coating agent Substances 0.000 claims description 35
- 230000000968 intestinal effect Effects 0.000 claims description 29
- 235000011389 fruit/vegetable juice Nutrition 0.000 claims description 28
- 239000000463 material Substances 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000006116 polymerization reaction Methods 0.000 claims description 7
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 6
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 5
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 210000004051 gastric juice Anatomy 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 4
- 239000011928 denatured alcohol Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 229920002689 polyvinyl acetate Polymers 0.000 description 3
- 239000011118 polyvinyl acetate Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 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 2
- 239000012530 fluid Substances 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229960003966 nicotinamide Drugs 0.000 description 2
- 235000005152 nicotinamide Nutrition 0.000 description 2
- 239000011570 nicotinamide Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000009495 sugar coating Methods 0.000 description 2
- 235000019166 vitamin D Nutrition 0.000 description 2
- 239000011710 vitamin D Substances 0.000 description 2
- 150000003710 vitamin D derivatives Chemical group 0.000 description 2
- 229940046008 vitamin d Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- AEDORKVKMIVLBW-BLDDREHASA-N 3-oxo-3-[[(2r,3s,4s,5r,6r)-3,4,5-trihydroxy-6-[[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methoxy]oxan-2-yl]methoxy]propanoic acid Chemical compound OCC1=C(O)C(C)=NC=C1CO[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(=O)CC(O)=O)O1 AEDORKVKMIVLBW-BLDDREHASA-N 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229940036811 bone meal Drugs 0.000 description 1
- 239000002374 bone meal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- -1 phthalic acid ester Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960000342 retinol acetate Drugs 0.000 description 1
- 235000019173 retinyl acetate Nutrition 0.000 description 1
- 239000011770 retinyl acetate Substances 0.000 description 1
- QGNJRVVDBSJHIZ-QHLGVNSISA-N retinyl acetate Chemical group CC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C QGNJRVVDBSJHIZ-QHLGVNSISA-N 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F42—AMMUNITION; BLASTING
- F42B—EXPLOSIVE CHARGES, e.g. FOR BLASTING, FIREWORKS, AMMUNITION
- F42B5/00—Cartridge ammunition, e.g. separately-loaded propellant charges
- F42B5/02—Cartridges, i.e. cases with charge and missile
- F42B5/03—Cartridges, i.e. cases with charge and missile containing more than one missile
- F42B5/035—Cartridges, i.e. cases with charge and missile containing more than one missile the cartridge or barrel assembly having a plurality of axially stacked projectiles each having a separate propellant charge
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F42—AMMUNITION; BLASTING
- F42B—EXPLOSIVE CHARGES, e.g. FOR BLASTING, FIREWORKS, AMMUNITION
- F42B12/00—Projectiles, missiles or mines characterised by the warhead, the intended effect, or the material
- F42B12/02—Projectiles, missiles or mines characterised by the warhead, the intended effect, or the material characterised by the warhead or the intended effect
- F42B12/36—Projectiles, missiles or mines characterised by the warhead, the intended effect, or the material characterised by the warhead or the intended effect for dispensing materials; for producing chemical or physical reaction; for signalling ; for transmitting information
- F42B12/56—Projectiles, missiles or mines characterised by the warhead, the intended effect, or the material characterised by the warhead or the intended effect for dispensing materials; for producing chemical or physical reaction; for signalling ; for transmitting information for dispensing discrete solid bodies
- F42B12/58—Cluster or cargo ammunition, i.e. projectiles containing one or more submissiles
Landscapes
- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Combustion & Propulsion (AREA)
- Aiming, Guidance, Guns With A Light Source, Armor, Camouflage, And Targets (AREA)
- Medicinal Preparation (AREA)
- Air Bags (AREA)
- Automotive Seat Belt Assembly (AREA)
Description
Fremstilling av medisinske preparater med tarmsaftfølsomt belegg. Production of medical preparations with intestinal juice-sensitive coating.
Oppfinnelsen angĂĄr fremstilling av The invention relates to the production of
nye farmasøytiske preparater, nærmere be-stemt doseringsenheter i fast form og for-synt med tarmsaftfølsomt belegg. new pharmaceutical preparations, more specifically dosage units in solid form and provided with a coating sensitive to intestinal juice.
Det har vært godtatt praksis ved fremstilling av farmasøytiske tabletter å for-syne visse typer av tabletter med et såkalt It has been accepted practice in the manufacture of pharmaceutical tablets to provide certain types of tablets with a so-called
tarmsaftfølsomt belegg, på engelsk gjerne coating sensitive to intestinal juice, preferably in English
kalt «enteric coating». Det tarmsaftføl-somme belegg er et belegg som motstår called "enteric coating". The intestinal juice-sensitive coating is a coating that resists
virkningen av mavesaften og ikke blir opp-løst i eller på annen måte influert av den, the effect of the gastric juice and is not dissolved in or otherwise influenced by it,
sĂĄ det virksomme stoff i tabletten vil pas-sere maven og komme inn i tarmen. Det so the active substance in the tablet will pass through the stomach and enter the intestine. The
tarmsaftfølsomme belegg er av en slik art coatings sensitive to intestinal juice are of such a nature
at det meget lett oppløses i tarmvæskene, that it dissolves very easily in the intestinal fluids,
sĂĄ det virksomme stoff som var innesluttet then the active substance that was contained
i belegget, vil komme til virkning i tarmen in the coating, will have an effect in the intestine
istedenfor i maven. Innen medisinen er der instead of in the stomach. Within the medicine is there
i virkeligheten et betydelig antall av be-handlingstyper hvor tarmsaftfølsomme belegg anses som ytterst nyttige. in fact, a significant number of treatment types where intestinal juice-sensitive coatings are considered extremely useful.
Utførte undersøkelser in vitro på be-leggstoffer har vist at celluloseacetat-fthalat er et av de mest effektive stoffer In vitro studies on coating substances have shown that cellulose acetate phthalate is one of the most effective substances
som er kjent for tarmsaftfølsomme belegg which is known for intestinal juice-sensitive coatings
av denne type. of this type.
Skjønt dette stoff er anerkjent som Although this substance is recognized as
ytterst effektivt for et tarmsaftfølsomt belegg, er det undergitt alvorlige begrens-ninger med hensyn til sin praktiske anvendelse i produksjonsmålestokk. En ulempe man har iakttatt, er at stoffet må på-føres i sterkt fortynnet tilstand og der extremely effective for an intestinal juice-sensitive coating, it is subject to serious limitations with regard to its practical application on a production scale. A disadvantage that has been observed is that the substance must be applied in a highly diluted state and there
kreves mange adskilte påføringsoperasjo-ner for å bygge opp et tilfredsstillende, tørt many separate application operations are required to build up a satisfactory, dry
belegg av tilstrekkelig tykkelse. Det er ogsĂĄ coating of sufficient thickness. It is also
kjent at det er vanskelig ĂĄ oppnĂĄ glatte known that it is difficult to achieve smooth
belegg. Enda en ulempe når det gjelder anvendelsen av celluloseacetat-fthalat, er det forhold at oppløsningsmidlene for stoffet enten er farlige og eksplosive, f. eks. lavere ketoner, eller danner sterkt giftige damper, f. eks. blandinger av methylalkohol og ethylendiklorid. coating. Another disadvantage when it comes to the use of cellulose acetate phthalate is the fact that the solvents for the substance are either dangerous and explosive, e.g. lower ketones, or form highly toxic fumes, e.g. mixtures of methyl alcohol and ethylene dichloride.
I henhold til den foreliggende oppfin-nelse er det nu lykkes å skaffe et forbedret tarmsaftfølsomt beleggmateriale og å fremstille en medisinsk doseringsenhet i fast form for oral inngift og belagt med dette tarmsaftfølsomme stoff. According to the present invention, it has now been possible to obtain an improved intestinal juice-sensitive coating material and to produce a medical dosage unit in solid form for oral administration and coated with this intestinal juice-sensitive substance.
Det tarmsaftfølsomme beleggmateriale som anvendes ifølge oppfinnelsen er en fthalsyre-ester av delvis forestret polyvinylalkohol, hvori vinylgrupppenes hydroxylgrupper er delvis forestret med fthalsyre, delvis acetylert og delvis frie (unreplaced). Polyvinylacetat-fthalatet som anvendes ifølge oppfinnelsen, er karakterisert ved at det har en polymerisasjonsgrad fra 600-800, et fthalylinnhold i området 60'—70 % og et acetylinnhold i området 1,6—6,0 %, og fås fra et polyvinylacetat med en molekylarvekt i området 25 000—40 000, hvilket sva-rer til en polymerisasjonsgrad på 600—800. Polyvinylacetat-fthalatet er videre karakterisert ved at det er hovedsakelig uopp-løselig i et surt medium i likhet med mavesaften, hovedsakelig oppløselig i et svakt alkalisk medium, som tarmsaftene, og fullstendig oppløselig i en 90—95 %'s ethyl-alkoholoppløsning. Det er også karakterisert ved sin lave viskositet når det foreligger som 30 %'s oppløsning i alkohol. Som eksempel på polyvinylacetatfthalat som egner seg til å brukes som tarmsaftfølsomt beleggstoff, kan nevnes et polyvinylacetat-fthalat med en polymerisasjonsgrad på ca. 750, et fthalylinnhold på ca. 65 % og et acetylinnhold på ca. 3,7 %. The intestinal juice-sensitive coating material used according to the invention is a phthalic acid ester of partially esterified polyvinyl alcohol, in which the hydroxyl groups of the vinyl groups are partially esterified with phthalic acid, partially acetylated and partially free (unreplaced). The polyvinyl acetate phthalate used according to the invention is characterized in that it has a degree of polymerization of 600-800, a phthalyl content in the range 60'-70% and an acetyl content in the range 1.6-6.0%, and is obtained from a polyvinyl acetate with a molecular weight in the range 25,000-40,000, which corresponds to a degree of polymerization of 600-800. The polyvinyl acetate phthalate is further characterized in that it is mainly insoluble in an acidic medium such as gastric juice, mainly soluble in a weakly alkaline medium, such as intestinal juices, and completely soluble in a 90-95% ethyl alcohol solution. It is also characterized by its low viscosity when it is present as a 30% solution in alcohol. As an example of polyvinyl acetate phthalate which is suitable for use as a coating material sensitive to intestinal juice, mention may be made of a polyvinyl acetate phthalate with a degree of polymerization of approx. 750, a phthalyl content of approx. 65% and an acetyl content of approx. 3.7%.
Oppfinnelsen tar videre sikte på fremstilling av en medisinsk doseringsenhet i fast form for oral inngift og inneholdende minst ett fast medisinsk agens, samt om-fattende en formet kjerne som inneholder det medisinske agens, og som er omgitt av en hinne eller et lag av det tarmsaftføl-somme polyvinylacetat-fthalat ifølge oppfinnelsen. The invention further aims at the production of a medical dosage unit in solid form for oral administration and containing at least one solid medical agent, as well as comprising a shaped core that contains the medical agent, and which is surrounded by a membrane or a layer of the intestinal juice felt - some polyvinyl acetate phthalate according to the invention.
For fremstilling av det tarmsaftføl-somme beleggmateriale i henhold til oppfinnelsen kan man behandle en delvis hydrolysert polyvinylalkohol med et fthalsyre-anhydrid i et inert oppløsningsmiddel ved moderat forhøyet temperatur. Reak-sjonsblandingen helles så i en vandig mi-neralsyreoppløsning for utfelling av det ønskede polyvinylacetat-fthalat. For the production of the intestinal juice-sensitive coating material according to the invention, a partially hydrolyzed polyvinyl alcohol can be treated with a phthalic anhydride in an inert solvent at a moderately elevated temperature. The reaction mixture is then poured into an aqueous mineral acid solution to precipitate the desired polyvinyl acetate phthalate.
Den partielt hydrolyserte polyvinylalkohol der egner seg som utgangsmateri-ale, er en som har en polymerisasjonsgrad innenfor området 600—800, et acetylinnhold fra 5—15 % en viskositet fra 4—6 eps. og en molekylarvekt fra 25 000—40 000. Som eksempel på et foretrukket polyvinylacetat kan nevnes et produkt som mar-kedsføres under varemerket «ELVANOL» The partially hydrolyzed polyvinyl alcohol that is suitable as starting material is one that has a degree of polymerization in the range 600-800, an acetyl content of 5-15% and a viscosity of 4-6 eps. and a molecular weight from 25,000-40,000. As an example of a preferred polyvinyl acetate, a product marketed under the trademark "ELVANOL" can be mentioned
(51—05) av E. I DuPont de Nemours & Co. Inc., Wilmington, Del. U.S.A., og som har en polymerisasjonsgrad på ca. 750, en gjennomsnittlig molekylarvekt på 33 000 og en viskositet fra 4—6 eps., målt i en 4 %'s vannoppløsning ved 20° C, samt er 88 % hydrolysert og har et acetylinnhold På 12 %. (51—05) by E. In DuPont de Nemours & Co. Inc., Wilmington, Del. U.S.A., and which has a degree of polymerization of approx. 750, an average molecular weight of 33,000 and a viscosity of 4-6 eps., measured in a 4% water solution at 20° C, and is 88% hydrolysed and has an acetyl content of 12%.
Reaksjonen utføres i et inert oppløs-ningsmiddel. Som eksempler på egnede inerte oppløsningsmidler kan nevnes pyridin, picolin eller methyl-ethyl-keton. The reaction is carried out in an inert solvent. Examples of suitable inert solvents include pyridine, picoline or methyl ethyl ketone.
Reaksjonen utføres under tilbakeløps-kokning i et tidsrom av 1—3 timer, alt etter de anvendte reagenser. The reaction is carried out under reflux for a period of 1-3 hours, depending on the reagents used.
Anvendelsen av polyvinylacetat-fthalat i henhold til oppfinnelsen som tarm-saftfølsomt belegg har mange fordeler fremfor tidligere belegg til samme formål. Det er ganske uoppløselig i vandige fluider med pH under 3,5 og viser stigende opp-løselighet opp til pH 6 og er uten videre oppløselig i simulert tarmsaft inneholdende pancreatin med pH 7—7,5. The use of polyvinyl acetate phthalate according to the invention as an intestinal juice-sensitive coating has many advantages over previous coatings for the same purpose. It is quite insoluble in aqueous fluids with a pH below 3.5 and shows increasing solubility up to pH 6 and is readily soluble in simulated intestinal juice containing pancreatin with a pH of 7-7.5.
Det nye tarmsaftfølsomme belegnings-stoff er særlig egnet for å gi glatte belegg og gjør det unødvendig å bruke oppløs-ningsmidler som er forbundet med risiko, og ennvidere er det istand til å danne kon-sentrerte oppløsninger med lav viskositet hvorved den nødvendige mengde oppløs-ningsmiddel og dermed antallet av nød-vendige belegningsoperasjoner blir redu-sert i forhold til hva som normalt kreves ved tidligere kjente tarmsaftfølsomme be-leggstoffer. The new intestinal juice-sensitive coating substance is particularly suitable for providing smooth coatings and makes it unnecessary to use solvents which are associated with risk, and furthermore it is able to form concentrated solutions with low viscosity whereby the required amount of solvent coating agent and thus the number of necessary coating operations is reduced compared to what is normally required with previously known intestinal juice-sensitive coating materials.
For fremstilling av beleggene blir tablettene anbragt i en roterende belegningspanne av den standardtype som anvendes i industrien, og beleggmaterialet påføres i flytende form som en oppløsning i et egnet ikke-risikabelt oppløsningsmiddel, f. eks. ethanol. Belegningsoppløsningen påføres i flere etapper og hver gang med et volum som akkurat er tilstrekkelig til å fukte overflaten av alle tablettene i pannen. En varmluftstrøm blåses mot de roterende tabletter for å avdampe oppløsningsmidde-let, og når belegget tørker til et klebrig stadium, blir et egnet strøpulver tilsatt for å hindre tablettene i å klistre til hver-andre. To produce the coatings, the tablets are placed in a rotary coating pan of the standard type used in industry, and the coating material is applied in liquid form as a solution in a suitable non-hazardous solvent, e.g. ethanol. The coating solution is applied in several stages and each time with a volume that is just sufficient to wet the surface of all the tablets in the pan. A stream of hot air is blown against the rotating tablets to evaporate the solvent, and when the coating dries to a tacky stage, a suitable dusting powder is added to prevent the tablets from sticking to each other.
Denne prosess gjentas inntil der er bygget opp beleggmateriale i tilstrekkelig tykkelse til fullstendig å tette for tablet-tens overflate og motstå gj ennomtrengning av mavesekresjoner i et tidsrom av 2—6 timer. This process is repeated until a coating material of sufficient thickness has been built up to completely seal the tablet's surface and resist the penetration of gastric secretions for a period of 2-6 hours.
Den anvendte oppløsning kan ha en konsentrasjon av 20—40 %, regnet i vekt pr. volumenhet (w/v), med en foretrukken konsentrasjon av ca. 30 %. Som oppløs-ningsmiddel kan anvendes ketoner, lavere alkoholer eller blandinger av alkoholer og klorerte oppløsningsmidler. Fortrinnsvis benyttes 95 % ethanol. Antallet av beleg-ninger vil variere med konsentrasjonen av det tarmsaftfølsomme beleggmateriale. For praktiske formål anvendes 6—8 belegnin-ger når man bruker en 30 %'s oppløsning. The solution used can have a concentration of 20-40%, calculated by weight per volume unit (w/v), with a preferred concentration of approx. 30%. Ketones, lower alcohols or mixtures of alcohols and chlorinated solvents can be used as solvents. Preferably 95% ethanol is used. The number of coatings will vary with the concentration of the intestinal juice-sensitive coating material. For practical purposes, 6-8 coatings are used when using a 30% solution.
Det tarmsaftfølsomme belegg i henhold til oppfinnelsen kan benyttes til be-legning av en hvilken som helst farmasøyt-isk tablett som man ønsker skal ha «tarm-saftfølsomme» egenskaper. The intestinal juice-sensitive coating according to the invention can be used to coat any pharmaceutical tablet that you want to have "intestinal juice-sensitive" properties.
Oppfinnelsen vil bli forstått mer fullstendig fra de følgende eksempler som an-føres for å belyse oppfinnelsen. The invention will be understood more fully from the following examples given to illustrate the invention.
Eksempel 1: Example 1:
Fremstilling av polyvinylacetat- fthalat. Production of polyvinyl acetate phthalate.
Til en oppløsning av 9,5 g fthalsyre-anhydrid i 25 cm<3> pyridin ble der satt 5,0 g polyvinylacetat i form av den ovennevnte markedsvare «ELVANOL» (51—05) (12% acetyl, viskositet 4—6 eps., molekylarvekt ca. 33 000), og man varmet opp til 100— To a solution of 9.5 g of phthalic anhydride in 25 cm<3> pyridine was added 5.0 g of polyvinyl acetate in the form of the above-mentioned commercial product "ELVANOL" (51-05) (12% acetyl, viscosity 4-6 eps ., molecular weight approx. 33,000), and heated to 100—
110° C i en time. Etter fortynning med 100 cm<3> vann ble den klare oppløsning bragt til utfelling ved å renne inn i en 110° C for one hour. After dilution with 100 cm<3> of water, the clear solution was precipitated by running into a
oppløsning bestående av 200 cm<3> vann og 255 cm<3> konsentrert saltsyre under omrør-ing. Produktet ble filtrert, vasket med vann, tørket ved værelsestemperatur og malt til et ikke helt hvitt pulver. Utbytte 12,4 g. Fthalylinnhold 65 %. Acetylinnhold 3,7 %. En 25 %'s oppløsning egnet for be-legning ble tilberedt ved oppløsning i denaturert sprit (90—95 %). solution consisting of 200 cm<3> of water and 255 cm<3> of concentrated hydrochloric acid under stirring. The product was filtered, washed with water, dried at room temperature and ground to an off-white powder. Yield 12.4 g. Phthalyl content 65%. Acetyl content 3.7%. A 25% solution suitable for coating was prepared by dissolving in denatured alcohol (90-95%).
Eksempel 2: 240 000 tabletter hver med en vekt av 0,25 g og inneholdende 150 mg ølgjærkon-sentrat, 5 mg thiamin HC1, 3 mg riboflavin (vitamin B2), 12,5 mg niacinamid, 1 mg pyridoxin HC1, 1,5 mikrogram vitamin B12, 35 mg vitamin C (ascorbinsyre) og 500 In-ternationale enheter vitamin D ble anbragt i en roterende belegningspanne og behandlet med en oppløsning inneholdende 30 % regnet i vekt pr. volumenhet av polyvinylacetat-fthalat fremstilt som i eksempel 1, oppløst i 90 % denaturert sprit. Example 2: 240,000 tablets each weighing 0.25 g and containing 150 mg brewer's yeast concentrate, 5 mg thiamine HC1, 3 mg riboflavin (vitamin B2), 12.5 mg niacinamide, 1 mg pyridoxine HC1, 1.5 micrograms of vitamin B12, 35 mg of vitamin C (ascorbic acid) and 500 International Units of vitamin D were placed in a rotating coating pan and treated with a solution containing 30% by weight per unit volume of polyvinyl acetate phthalate prepared as in example 1, dissolved in 90% denatured alcohol.
Oppløsningen ble tilsatt i mengder av 1200 ml ad gangen og tablettene bestrødd med talkumpulver mellom påføringsopera-sj onene for å forhindre klistring. Tørke-tiden mellom belegningene var ca. 15 minutter, og der ble påført 8 belegg. Den sam-lede belegningstid var ca. 2y2 time, og tablettene fikk et glatt, ensartet belegg av ca. 35 mg belegningsmateriale pr. tablett. Et normalt sukkerovertrekk ble så påført over det tarmsaftfølsomme lag. The solution was added in amounts of 1200 ml at a time and the tablets sprinkled with talcum powder between application operations to prevent sticking. The drying time between coatings was approx. 15 minutes, and 8 coatings were applied. The total coating time was approx. 2y2 hours, and the tablets received a smooth, uniform coating of approx. 35 mg coating material per tablet. A normal sugar coating was then applied over the intestinal juice-sensitive layer.
Disintegreringsprøver på disse tabletter viste at de motstår virkningen av simulert mavesaft (pH 1,5) i minst 3 timer, og at de disintegrerer i simulert tarmsaft (pH 7,5) innen 20 minutter. Disintegration tests on these tablets showed that they resist the action of simulated gastric juice (pH 1.5) for at least 3 hours, and that they disintegrate in simulated intestinal juice (pH 7.5) within 20 minutes.
Noen tabletter som var fjernet fra be-legningspannen etter 6 påføringer av det tarmsaftfølsomme belegg, ble også under-søkt på disintegreringsegenskaper. Der ble funnet at de motstår den simulerte mavesaft i 2y2 time og disintegrerer i den simulerte tarmsaft i løpet av 15 minutter. Der foreligger således en tydelig proporsjonali-tet mellom mengden av påført tarmsaft-følsom harpiks og disintegreringstiden. Some tablets that had been removed from the coating pan after 6 applications of the gut-sensitive coating were also examined for disintegration properties. It was found that they resist the simulated gastric juice for 2y2 hours and disintegrate in the simulated intestinal juice within 15 minutes. There is thus a clear proportionality between the amount of applied intestinal juice-sensitive resin and the disintegration time.
Eksempel 3: En porsjon av 60 000 tabletter som hver veiet 0,725 g og inneholdt 325 mg f errosulf at B.P., 325 mg spiselig benmel, 1500 interna-tionale enheter vitamin A acetat, 500 in-ternationale enheter vitamin D, 1 mg vitamin Bi, 1 mg riboflavin, 5 mg niacinamid, 30 mg vitamin C (ascorbinsyre) og 0,2 mg natriumjodid, ble anbragt en roterende be legningspanne og behandlet med en opp-løsning inneholdende 30 %, regnet i vekt pr. volumenhet, polyvinylacetat-fthalat som fremstilt i eksempel 1, oppløst i 95 % denaturert sprit SDAG-1G (offisiell kana-disk standard for spesielt denaturert alkohol, første grad). Belegningsprosessen var som følger: 750 ml belegningsoppløsning ble helt over de roterende tabletter. Etter at oppløsnin-gen var grundig dispergert, og i det øye-blikk da tablettene begynte å klebe til pannen, ble 1 100 g talkumpulver påstrødd tablettene for å forhindre klistring. Omtrent 30 sek. senere ble kold luft blåst over tablettene for å fjerne overskytende talkum og fullføre avdampningen av alkoholen. Pannen fortsatte å rotere i 1 minutt til og ble så stanset. I de neste 15 minutter ble kold luft kontinuerlig blåst over tablettene og pannen dreiet en halv omgang hvert annet eller tredje minutt. Example 3: A portion of 60,000 tablets each weighing 0.725 g and containing 325 mg of ferrosulfate B.P., 325 mg of edible bone meal, 1500 international units of vitamin A acetate, 500 international units of vitamin D, 1 mg of vitamin Bi, 1 mg of riboflavin, 5 mg of niacinamide, 30 mg of vitamin C (ascorbic acid) and 0.2 mg of sodium iodide were placed in a rotating be laying pan and treated with a solution containing 30%, calculated by weight per unit volume, polyvinyl acetate phthalate as prepared in Example 1, dissolved in 95% denatured alcohol SDAG-1G (official Canadian standard for specially denatured alcohol, first degree). The coating process was as follows: 750 ml of coating solution was poured over the rotating tablets. After the solution was thoroughly dispersed, and at the moment when the tablets began to stick to the pan, 1,100 g of talcum powder was sprinkled on the tablets to prevent sticking. About 30 sec. later, cold air was blown over the tablets to remove excess talc and complete the evaporation of the alcohol. The pan continued to rotate for 1 more minute and then stopped. For the next 15 minutes, cold air was continuously blown over the tablets and the pan rotated half a revolution every two or three minutes.
Denne prosess ble så gjentatt syv gan-ger for å bygge opp overtrekkslaget. Tablettene ble tørket natten over, og den føl-gende dag ble sukkerovertrekk påført under anvendelse av standard teknikk. This process was then repeated seven times to build up the overcoat layer. The tablets were dried overnight and the following day sugar coating was applied using standard techniques.
Disintegreringsprøver på disse tabletter viste at de motstår virkningen av simulert mavesaft (pH 1,5) i minst tre timer, og at de disintegrerer i simulert tarmsaft (pH 7,5) innen 20 minutter. Disintegration tests on these tablets showed that they resist the effects of simulated gastric juice (pH 1.5) for at least three hours, and that they disintegrate in simulated intestinal juice (pH 7.5) within 20 minutes.
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR6905801A FR2036076A5 (en) | 1969-03-04 | 1969-03-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO130844B true NO130844B (en) | 1974-11-11 |
| NO130844C NO130844C (en) | 1975-02-19 |
Family
ID=9029997
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO640/70A NO130844C (en) | 1969-03-04 | 1970-02-23 |
Country Status (13)
| Country | Link |
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| US (1) | US3686999A (en) |
| JP (1) | JPS4942400B1 (en) |
| BE (1) | BE745987A (en) |
| CH (1) | CH524130A (en) |
| DE (1) | DE2010154C3 (en) |
| ES (1) | ES377443A1 (en) |
| FR (1) | FR2036076A5 (en) |
| GB (1) | GB1307692A (en) |
| IE (1) | IE33728B1 (en) |
| IL (1) | IL33919A (en) |
| NO (1) | NO130844C (en) |
| SE (1) | SE373657B (en) |
| ZA (1) | ZA701131B (en) |
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| DE3041149C2 (en) * | 1980-10-31 | 1986-10-02 | Dynamit Nobel Ag, 5210 Troisdorf | Submunition wiring |
| US4733597A (en) * | 1987-04-06 | 1988-03-29 | Sparton Corporation | Sequential launching system |
| US4969283A (en) * | 1989-10-12 | 1990-11-13 | The United States Of America As Represented By The United States Department Of Energy | Firearm equipped with live round inhibiting means and method of making same |
| WO2002027258A2 (en) * | 2000-08-24 | 2002-04-04 | Armalite, Inc. | Light weight weapon operating system and cartridge feed |
| US6643897B2 (en) | 2001-10-23 | 2003-11-11 | Trw Inc. | Retractable grab handle and coat hook |
| AUPS303702A0 (en) * | 2002-06-20 | 2002-07-11 | Metal Storm Limited | A cartridge assembly for multiple projectiles |
| DE10320731B4 (en) * | 2003-05-08 | 2005-07-21 | Nico-Pyrotechnik Hanns-JĂĽrgen Diederichs GmbH & Co. KG | Automatic weapon |
| WO2010088741A1 (en) * | 2009-02-06 | 2010-08-12 | Metal Storm Limited | Stacked projectile launcher and associated methods |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2845004A (en) * | 1954-07-07 | 1958-07-29 | Quinton C Johnson | Rocket launching system |
| US2930288A (en) * | 1955-05-09 | 1960-03-29 | Chance Vought Aircraft Inc | Tandem rocket launcher and firing system |
| US2937573A (en) * | 1956-06-28 | 1960-05-24 | Martin Co | Bombing apparatus |
| BE570008A (en) * | 1957-08-27 | |||
| US3421244A (en) * | 1962-03-02 | 1969-01-14 | Us Army | Firing mechanism for a rifle mounted auxiliary firearm |
| US3139795A (en) * | 1962-05-24 | 1964-07-07 | Altschuler Samuel | Tandem loaded firing tubes |
| US3451306A (en) * | 1967-01-26 | 1969-06-24 | Susquehanna Corp | Safe and arm ejection system |
-
1969
- 1969-03-04 FR FR6905801A patent/FR2036076A5/fr not_active Expired
-
1970
- 1970-02-13 CH CH207870A patent/CH524130A/en not_active IP Right Cessation
- 1970-02-13 BE BE745987D patent/BE745987A/en not_active IP Right Cessation
- 1970-02-17 IL IL33919A patent/IL33919A/en unknown
- 1970-02-17 IE IE202/70A patent/IE33728B1/en unknown
- 1970-02-20 ZA ZA701131A patent/ZA701131B/en unknown
- 1970-02-23 NO NO640/70A patent/NO130844C/no unknown
- 1970-02-23 GB GB862170A patent/GB1307692A/en not_active Expired
- 1970-02-25 SE SE7002437A patent/SE373657B/en unknown
- 1970-03-03 JP JP45018229A patent/JPS4942400B1/ja active Pending
- 1970-03-03 ES ES377443A patent/ES377443A1/en not_active Expired
- 1970-03-04 US US16302A patent/US3686999A/en not_active Expired - Lifetime
- 1970-03-04 DE DE2010154A patent/DE2010154C3/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IE33728L (en) | 1970-09-04 |
| CH524130A (en) | 1972-06-15 |
| DE2010154B2 (en) | 1973-10-25 |
| NO130844C (en) | 1975-02-19 |
| IL33919A (en) | 1974-07-31 |
| DE2010154A1 (en) | 1970-09-10 |
| IE33728B1 (en) | 1974-10-16 |
| BE745987A (en) | 1970-07-16 |
| ZA701131B (en) | 1971-04-28 |
| ES377443A1 (en) | 1972-07-01 |
| IL33919A0 (en) | 1970-11-30 |
| FR2036076A5 (en) | 1970-12-24 |
| US3686999A (en) | 1972-08-29 |
| DE2010154C3 (en) | 1974-05-30 |
| JPS4942400B1 (en) | 1974-11-14 |
| SE373657B (en) | 1975-02-10 |
| GB1307692A (en) | 1973-02-21 |
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