NO152634B - PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION comprising a cardiac glycoside in combination with a polymer - Google Patents
PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION comprising a cardiac glycoside in combination with a polymer Download PDFInfo
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- NO152634B NO152634B NO794251A NO794251A NO152634B NO 152634 B NO152634 B NO 152634B NO 794251 A NO794251 A NO 794251A NO 794251 A NO794251 A NO 794251A NO 152634 B NO152634 B NO 152634B
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- Prior art keywords
- preparation
- polymer
- cardiac glycoside
- pharmaceutical preparation
- combination
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- 229920000642 polymer Polymers 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 14
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 13
- 229940097217 cardiac glycoside Drugs 0.000 title claims description 19
- 239000002368 cardiac glycoside Substances 0.000 title claims description 19
- 229930002534 steroid glycoside Natural products 0.000 title claims description 19
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title description 17
- 239000000463 material Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000011162 core material Substances 0.000 description 11
- 150000008143 steroidal glycosides Chemical class 0.000 description 10
- 239000013543 active substance Substances 0.000 description 7
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 6
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 5
- 229960005156 digoxin Drugs 0.000 description 5
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
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- JAYAGJDXJIDEKI-PTGWOZRBSA-N Lanatoside C Chemical compound O([C@H]1[C@@H](OC(C)=O)C[C@@H](O[C@@H]1C)O[C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@@H]1C[C@@H]2[C@]([C@@H]3[C@H]([C@]4(CC[C@@H]([C@@]4(C)[C@H](O)C3)C=3COC(=O)C=3)O)CC2)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JAYAGJDXJIDEKI-PTGWOZRBSA-N 0.000 description 2
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- 206010003119 arrhythmia Diseases 0.000 description 2
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- 239000007931 coated granule Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000001079 digestive effect Effects 0.000 description 2
- 229940082657 digitalis glycosides Drugs 0.000 description 2
- 229960000648 digitoxin Drugs 0.000 description 2
- WDJUZGPOPHTGOT-XUDUSOBPSA-N digitoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)CC5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O WDJUZGPOPHTGOT-XUDUSOBPSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
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- 206010019280 Heart failures Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
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- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- MYEJFUXQJGHEQK-ALRJYLEOSA-N Proscillaridin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C=C2CC[C@H]3[C@@]4(O)CC[C@H](C5=COC(=O)C=C5)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1 MYEJFUXQJGHEQK-ALRJYLEOSA-N 0.000 description 1
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- XZTUSOXSLKTKJQ-UHFFFAOYSA-N Uzarigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C1(O)CCC2C1=CC(=O)OC1 XZTUSOXSLKTKJQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
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- HWKJSYYYURVNQU-DXJNJSHLSA-N acetyldigoxin Chemical compound C1[C@H](OC(C)=O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O HWKJSYYYURVNQU-DXJNJSHLSA-N 0.000 description 1
- ACLJAFRNPZVVIW-ADFGDECNSA-N actodigin Chemical compound O([C@@H]1C[C@H]2CC[C@@H]3[C@@H]([C@]2(CC1)C)CC[C@]1([C@]3(O)CC[C@@H]1C=1C(OCC=1)=O)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O ACLJAFRNPZVVIW-ADFGDECNSA-N 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
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- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical class CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XZTUSOXSLKTKJQ-CESUGQOBSA-N digitoxigenin Chemical compound C1([C@H]2CC[C@]3(O)[C@H]4[C@@H]([C@]5(CC[C@H](O)C[C@H]5CC4)C)CC[C@@]32C)=CC(=O)OC1 XZTUSOXSLKTKJQ-CESUGQOBSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
FREMGANGSMÅTE FOR FREMSTILLING AV ET. FARMASØYTISK PREPARAT OMFATTENDE ET. HJERTEGLYKOSID I KOMBINASJON MED EN POLYMER.PROCEDURE FOR PREPARING A. PHARMACEUTICAL PREPARATION INCLUDING ONE. HEART GLYCOSID IN COMBINATION WITH A POLYMER.
Description
Oppfinnelsen vedrører en fremgangsmåte for frem- The invention relates to a method for
stilling av et farmasøytisk preparat omfattende et hjerte- position of a pharmaceutical preparation comprising a cardiac
glykosid i kombinasjon med en polymer. glycoside in combination with a polymer.
En hensikt med oppfinnelsen er å tilveiebringe et farmasøytisk preparat, hvori et hjerteglykosid inneholdt deri er beskyttet mot vesentlig nedbrytning i sure omgivelser i maven hos pattedyr - omfattende mennesker - uten tap av bioaktivitet ved frigjøring og fordøyelsesabsorbsjon. One purpose of the invention is to provide a pharmaceutical preparation, in which a cardiac glycoside contained therein is protected against substantial degradation in acidic environments in the stomach of mammals - including humans - without loss of bioactivity upon release and digestive absorption.
En ytterligere hensikt er å tilveiebringe et A further object is to provide a
farmasøytisk preparat som gir en forsinket eller kontrollert frigjøring av et hjerteglykosid omfattet deri uten tap av bioaktivitet . pharmaceutical preparation which provides a delayed or controlled release of a cardiac glycoside included therein without loss of bioactivity.
Digitalis glykosider eller hjerteglykosider ut- Digitalis glycosides or cardiac glycosides
gjør en klasse med farmasøytika, hvorblandt det er. noen få do a class of pharmaceuticals, among which it is. a few
av de eldste farmasøytika i tidligere bruk. Hovedanvendeligheten er i behandling av hjertesykdommer som hjerteinsuffisiens og hjertearrytmi. Uttrykket "hjerteglykosider" slik det benyttes her innbefatter terapeutisk effektive naturlige opptredende digitalis glukosider og tilsvarende forbindelser av forskjellig opprinnelse innbefattende forbindelser fremstillbare som halv-syntetiske derivater av naturlig opptredende forbindelser uansett måten de er oppnådd på. Nedenfor er hjerteglykosidene under tiden referert til som "det aktive stoff". of the oldest pharmaceuticals in previous use. The main application is in the treatment of heart diseases such as heart insufficiency and cardiac arrhythmia. The term "cardiac glycosides" as used herein includes therapeutically effective naturally occurring digitalis glucosides and corresponding compounds of various origins including compounds prepareable as semi-synthetic derivatives of naturally occurring compounds regardless of the manner in which they are obtained. Below, the cardiac glycosides are currently referred to as "the active substance".
Hjerteglykosider nedbrytes i sur omgivelse. Cardiac glycosides are broken down in an acidic environment.
Denne virkning sees spesielt med digoxin, lanatosid C, digitoxin This effect is seen especially with digoxin, lanatoside C, digitoxin
og proscillaridin. and proscillaridine.
Således hydrolyseres digoxin meget hurtig i en pufferoppløsning med pH 1 og etterlater bare 10 % derav etter å Thus, digoxin is hydrolysed very quickly in a buffer solution with pH 1, leaving only 10% of it after
ha vært utsatt for dette en time. Slik nedbrytning finner altså having been exposed to this for an hour. Thus, such decomposition finds
sted in vivo, således er det foreskrevet at 40 % av en gitt place in vivo, thus it is prescribed that 40% of a given
dose må nedbrytes. Da noen av hydrolyseoroduktene har en vesentlig lavere biologisk aktivitet enn moderstoffet, betyr dette at det terapeutiske svar på en gitt dose av hjerteglykosider kan variere mellom administrasjonsøyeblikket, avhengig av hvor preparatet befinner seg i maven og hvilken pH som hersker ved passerings- dose must be broken down. As some of the hydrolysis products have a significantly lower biological activity than the parent substance, this means that the therapeutic response to a given dose of cardiac glycosides can vary between the moments of administration, depending on where the preparation is located in the stomach and which pH prevails at the time of passage.
tiden . the time.
Det er imidlertid fra litteraturen kjent at However, it is known from the literature that
vanlig mavesaft-motstandsdyktige preparater av digitalis glukosider som tabletter utstyrt med et vanlig enterisk belegg gir en forbedret biologisk aktivitet av glykosidet. normal gastric juice-resistant preparations of digitalis glucosides as tablets equipped with a normal enteric coating provide an improved biological activity of the glycoside.
Det faktum at digitalis glukosider er vanskelig oppløselige The fact that digitalis glucosides are difficult to dissolve
i vandige medium gjør dem ytterligere vanskelig å innbefatte i farmasøytiske preparater og å oppnå en tilfredsstillende bioaktivitet. in an aqueous medium makes them even more difficult to include in pharmaceutical preparations and to achieve a satisfactory bioactivity.
Digitalis glykosider generelt har en snever teraoeutisk indeks, dvs. dosen herav som danner toksisk eller andre uønskede bivirkninger er ikke meget større enn den terapeutiske effektive dose. Mange bivirkninger f. eks. nausea og arrythmia som opptrer i behandling med hjerteglykosider for-bundet med en topp i plasmakonsentrasjonen som ofte opptrer få timer etter administrering av en dose. Av denne grunn er det meget ønskelig å fremstille sammensetninger som gir en forsinket frigjøring av hjerteglykosidene. Biofarmasøytiske studier har imidlertid vist at hittil kjente forsinket frigjørende preparater har den ulempe å gi en svekket bioaktivitet av digitalis glykosidet. Digitalis glycosides generally have a narrow therapeutic index, i.e. the dose thereof that produces toxic or other unwanted side effects is not much greater than the therapeutically effective dose. Many side effects, e.g. nausea and arrhythmia that occur in treatment with cardiac glycosides associated with a peak in the plasma concentration that often occurs a few hours after administration of a dose. For this reason, it is highly desirable to produce compositions which provide a delayed release of the cardiac glycosides. However, biopharmaceutical studies have shown that previously known delayed-release preparations have the disadvantage of giving a weakened bioactivity of the digitalis glycoside.
Oppfinnelsen vedrører altså en fremgangsmåte for fremstilling av et farmasøytisk preparat, omfattende et hjerteglykosid i kombinasjon med en polymer idet fremgangsmåten er karakterisert ved at det farmasøytiske preparat gis form av flere smålegemer, hvert legeme omfattende en del av den terapeutiske effektive dose av hjerteglykosidet, ved tilveiebringelse av et stort antall kjerner i en sik.tfraksjon mellom 0,1 og 3,0 mm, dannet av farmasøytiske inndifferent materiale, med et lag som består av en blanding omfattende hjerteglykosider og en anionisk karboksylpolymer som er vanskelig oppløselig eller uoppløselig under en gitt pH-verdi i området på pH 4-7,5, men oppløselig ved pH over den angitte verdi, idet det nevnte lags vekt utgjør mellom 0,01 og 0,5-ganger vekten av kjernen. Det ytre lag kan påføres ved tilsetning av en oppløsning av komponentene herav. The invention thus relates to a method for producing a pharmaceutical preparation, comprising a cardiac glycoside in combination with a polymer, the method being characterized by the pharmaceutical preparation being given the form of several small bodies, each body comprising part of the therapeutically effective dose of the cardiac glycoside, by providing of a large number of cores in a sieve fraction between 0.1 and 3.0 mm, formed from pharmaceutical indifferent material, with a layer consisting of a mixture comprising cardiac glycosides and an anionic carboxyl polymer that is difficult to dissolve or insoluble under a given pH -value in the range of pH 4-7.5, but soluble at a pH above the specified value, the weight of said layer being between 0.01 and 0.5 times the weight of the core. The outer layer can be applied by adding a solution of the components thereof.
Normalt inneholder hver dosisenhet ca. 10 til Normally, each dosage unit contains approx. 10 more
10 legemer. Fortrinnsvis er antall legemer 200-1000. 10 bodies. Preferably, the number of bodies is 200-1000.
Således skal hvert legeme av preparatet: inneholdende en frak-sjon av en terapeutisk effektiv dose av hjerteglykosidet. Fraksjonen er normalt 1.10~<6> til 1,10~ ganger slik dose, og fortrinnsvis 1,10 -3 til 5,10 -3ganger slik dose. Blant egnede doseenheter nevnes spesielt tabletter og kapsler. Farma-søytiske godtagbare tilsetninger kan innbefattes i dose- Thus, each body of the preparation should: contain a fraction of a therapeutically effective dose of the cardiac glycoside. The fraction is normally 1.10~<6> to 1.10~ times such dose, and preferably 1.10 -3 to 5.10 -3 times such dose. Among suitable dosage units, tablets and capsules are mentioned in particular. Pharmaceutically acceptable additives may be included in the dosage
enhetene sammen med preparatet fremstilt ifølge oppfinnelsen. Preparatene hvori de faste legemer er i blanding med flytende medium, ligger også innenfor oppfinnelsens ramme. the units together with the preparation produced according to the invention. The preparations in which the solid bodies are mixed with a liquid medium are also within the scope of the invention.
Kjernen av legemene i preparatet fremstilt ifølge oppfinnelsen kan dannes av farmasøytisk indifferente materialer i granulær eller pulverform av den type som normalt benyttes i fa-rmasøytiske preparater som sukker, mikrokrystallinsk cellulose, stivelse og voks. "Farmasøytisk indifferent" betyr at materi-alene er indifferente med hensyn til både den organisme som behandles og det anvendte aktive stoff. Størrelsen av kjernene kan være sjiktefraksjoner mellom 0,1 og 3,0 mm, fortrinnsvis mellom 0,5 og 1,5 mm. The core of the bodies in the preparation produced according to the invention can be formed from pharmaceutically indifferent materials in granular or powder form of the type normally used in pharmaceutical preparations such as sugar, microcrystalline cellulose, starch and wax. "Pharmaceutically indifferent" means that the materials are indifferent with regard to both the organism being treated and the active substance used. The size of the cores can be layer fractions between 0.1 and 3.0 mm, preferably between 0.5 and 1.5 mm.
Blant aktive stoffer som kan anvendes i preparatene fremstilt ifølge oppfinnelsen er terapeutisk effektive mengder inneholdende ringsystemer av digitoxigenin. eller scillaridin A Among active substances that can be used in the preparations produced according to the invention are therapeutically effective amounts containing ring systems of digitoxigenin. or scillaridin A
eller derivater herav. Av slike aktive stoffer kan det spesielt nevnes digoxin, digitoxin, lanatoside C, acetyl-digoxin, metyldigoxin, procillaridin, metylprocillaridin, pentaacetylgttoxin, 16-epigitoxin og actodigin. or derivatives thereof. Of such active substances, digoxin, digitoxin, lanatoside C, acetyl-digoxin, methyldigoxin, procillaridine, methylprocillaridine, pentaacetylgttoxin, 16-epigitoxin and actodigin can be mentioned in particular.
Polymerstoffet kan velges fra gruppene av The polymeric substance can be selected from the groups of
anioniske karboksylpolymere som er nyttige for farmasøy- anionic carboxyl polymers useful for pharmaceutical
tiske formål og er vanskelig oppløselige ved en lav pH, men er oppløselige ved høyere pH, idet pH-grensen for oppløselig-het er intervallet på pH J til 7,5, idet gruppen omfatter celluloseacetat-ftalat (CAP) (5,0-5,5) hydroksypropylmetyl-cellulose-ftalat, f. eks. en kvalitet solgt under navnet HP 55 (5,0-5,5), polyvinylacetat-ftalat (PVAP) (4,5-5,0) og akrylsyrepolymere f. eks.delvis metylforestret metacyklisk syrepolymere som "Eudragit L" (6,0) og "Eudragit S" (7,0), tical purposes and are hardly soluble at a low pH, but are soluble at a higher pH, the pH limit for solubility being the interval of pH J to 7.5, the group comprising cellulose acetate phthalate (CAP) (5.0- 5.5) hydroxypropylmethyl cellulose phthalate, e.g. a quality sold under the name HP 55 (5.0-5.5), polyvinyl acetate phthalate (PVAP) (4.5-5.0) and acrylic acid polymers e.g. partially methyl esterified metacyclic acid polymers such as "Eudragit L" (6, 0) and "Eudragit S" (7.0),
og metakrylat - metakrylsyrekopolymere som MPM-05 (5,0). and methacrylate - methacrylic acid copolymers such as MPM-05 (5.0).
Tallene i parentes er tilnærmet pH-grenser, Disse polymere The numbers in brackets are approximate pH limits, these polymers
kan benyttes alene eller i kombinasjon med hverandre. De polymere kan blandes med mykningsmidler som dietyl eller di-butyl-ftalater, sitronsyreestere, f. eks. acetyltributyl-sitrater (Citrofelx A-4), stearinsyre og fettalkoholer som cetanol. Fortrinnsvis velges en polymer som er uoppløselig eller vanskelig oppløselig i mavesaft, med oppløselig i tarm-saft. En foretrukket polymer er hydroksypropylmetylcellulose-ftalat. Ytterligere foretrukne polymere er "Eudragit A" i kombinasjon med hydroksypropylmetylcell.uloseftalat eller MPM-05. can be used alone or in combination with each other. The polymers can be mixed with plasticizers such as diethyl or dibutyl phthalates, citric acid esters, e.g. acetyltributyl citrates (Citrofelx A-4), stearic acid and fatty alcohols such as cetanol. Preferably, a polymer is chosen which is insoluble or difficult to dissolve in gastric juice, with soluble in intestinal juice. A preferred polymer is hydroxypropylmethylcellulose phthalate. Further preferred polymers are "Eudragit A" in combination with hydroxypropyl methyl cellulose phthalate or MPM-05.
De relative mengder av kjernemateriale og materiale som utgjør laget påført derpå kan variere avhengig av bl.a. av egenskapene av de anvendte komponenter. Fortrinnsvis er vekten av kjernen i forhold til vekten av belegget 1 til mellom 0,01 og 0,5, fortrinnsvis mellom 0,01 og 0,30. The relative amounts of core material and material making up the layer applied thereon may vary depending on, among other things, of the properties of the components used. Preferably, the weight of the core in relation to the weight of the coating is 1 to between 0.01 and 0.5, preferably between 0.01 and 0.30.
Legemene som fremstilles har fortrinnsvis stør-relsen på 0,1 til 3 mm. Deres form, delvis avhengig av formen av kjernene er fortrinnsvis sfærisk eller tilnærmet sfærisk. The bodies that are produced preferably have a size of 0.1 to 3 mm. Their shape, partly depending on the shape of the cores, is preferably spherical or nearly spherical.
Ifølge oppfinnelsen er det overraskende funnet mulig å oppnå beskyttelse av det aktive stoff ved å inn- According to the invention, the surprising discovery is that it is possible to achieve protection of the active substance by introducing
befatte det aktive stoff i tilblanding med den syreresistente polymer. Blant fordelene av preparatene fremstilt ifølge opp- contain the active substance in admixture with the acid-resistant polymer. Among the advantages of the preparations prepared according to
finnelsen skal videre nevnes at de har en forbedret biologisk utnyttelsesgrad sammenlignet med vanlige tabletter som har et enterisk belegg. Frigjøringen av den aktive komponent in vitro, ved en pH over den valgte pH-grense, f. eks. pH av i fordøyelsesvæske, er hurtig med preparatene ifølge oppfinnelsen. i Dette er fordelaktig og bevirker delvis den forbedrede biologiske j aktivitet, imidlertid in vivo vil det opptre en forsinket frigjøring da de mange legemer i preparatet tømmes fra j maven i tynntarmen over en lengre tidsperiode. Preparatet fremstilt ifølge oppfinnelsen gir derfor mindre variasjon i plasmakonsentrasjonen hos pasienter under kontinuerlig behandling enn det som kan oppnås ved vanlige tabletter. En ytterligere j fordel er den forbedrede produksjonsøkonomi som er oppnåelig da en porsjon av preparatet kan fremstilles i løpet av kort tid, f. eks. 15-20 minutter, og møte de spesielle krav ved preparater av hjerteglykosider. the invention should also be mentioned that they have an improved degree of biological utilization compared to ordinary tablets that have an enteric coating. The release of the active component in vitro, at a pH above the selected pH limit, e.g. The pH of the digestive fluid is rapid with the preparations according to the invention. i This is advantageous and partially causes the improved biological j activity, however in vivo a delayed release will occur as the many bodies in the preparation are emptied from the j stomach into the small intestine over a longer period of time. The preparation produced according to the invention therefore gives less variation in the plasma concentration in patients under continuous treatment than can be achieved with ordinary tablets. A further j advantage is the improved production economy which is achievable as a portion of the preparation can be produced within a short time, e.g. 15-20 minutes, and meet the special requirements for preparations of cardiac glycosides.
Alle komponenter av preparatet anvendt ved fremgangsmåten ifølge oppfinnelsen er som nedenfor angitt. Op<p>løsningsmidlene som anvendes ifølge fremgangsmåten ifølge oppfinnelsen er oppløsningsmidler som har en tilstrekkelig dyktighet til å fordampe under applikasjonsbetingelsene og etter- All components of the preparation used in the method according to the invention are as indicated below. The solvents used according to the method according to the invention are solvents which have a sufficient ability to evaporate under the application conditions and after-
late et lag av faste stoff på overflaten av kjernen eller legemet som ble fremstilt. Fortrinnsvis bennyttes organiske oppløsnings-midler som alkoholer, hydrokarboner og estere, såvel som i derivater som klorerte hydrokarboner. Fremgangsmåten for påføring leave a layer of solid matter on the surface of the core or body that was produced. Organic solvents such as alcohols, hydrocarbons and esters, as well as derivatives such as chlorinated hydrocarbons, are preferably used. The method of application
av lagene kan utføres i et apparat normalt benyttet i den farmasøytiske industri for å belegge faste farmasøytiske preparater som en drageringspanne eller et hvirvelsjiktapparat. Fremgangsmåten utføres normalt ved omgivelsesbetingelser, imidler- of the layers can be carried out in an apparatus normally used in the pharmaceutical industry to coat solid pharmaceutical preparations such as a coating pan or a fluidized bed apparatus. The procedure is normally carried out at ambient conditions, although
tid kan temperatur-og trykk-betingelsene varieres innen vide grenser. I en hvirvelsjikt-dusje-fremgangsmåte er tempera-turen av innløpsluften hensiktsmessig 15 til 60°C. time, the temperature and pressure conditions can be varied within wide limits. In a fluidized bed shower method, the temperature of the inlet air is suitably 15 to 60°C.
Hjertesykdommer kan behandles ved anvendelse av Heart diseases can be treated using
det farmasøytiske preparat angitt ovenfor. Den terapeutiske effektive dose av hjerteglykosidene i preparatene er ikke større enn de som normalt foreskrives, dvs. 0,05 til 1,5 mg/dag av de angitte forbindelser, anhengig av variasjoner mellom i the pharmaceutical preparation indicated above. The therapeutically effective dose of the cardiac glycosides in the preparations is not greater than those normally prescribed, i.e. 0.05 to 1.5 mg/day of the specified compounds, subject to variations between
forskjellige pasienter. Imidlertid er det mange ganger mulig a anvende doser som er lavere enn de som normalt foreskrives. different patients. However, it is often possible to use doses that are lower than those normally prescribed.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler, hvor eksempel 6 antas å representere den beste metode hittil kjent. The invention will be explained in more detail with the help of some examples, where example 6 is believed to represent the best method known to date.
Eksempler 1- 9 Examples 1-9
På 500 g kjernemateriale, 0 0,6-0,7 mm, be-stående av 30 % stivelse og 70 % sukker ble det påført et lag ved å dusje en oppløsning med en sammensetning vist i tabell 1 i et hvirvelsjikt. On 500 g of core material, 0 0.6-0.7 mm, consisting of 30% starch and 70% sugar, a layer was applied by showering a solution with a composition shown in Table 1 in a fluidized bed.
De belagte granuler ble analysert ifølge den såkalte beger-metoden (Levy et al. New England J. of Med. vol. 262, side 1053-1058) (1960). Frigjøringen av det aktive stoff ble undersøkt i kunstig mavesaft pH 1,0 og fosfatpuffer pH 6,5 ved 37 - 0,1°C. The coated granules were analyzed according to the so-called beaker method (Levy et al. New England J. of Med. vol. 262, pages 1053-1058) (1960). The release of the active substance was investigated in artificial gastric juice pH 1.0 and phosphate buffer pH 6.5 at 37 - 0.1°C.
Resultatene fremgår av tabell 2. The results appear in table 2.
Mengder av belagte granuler fremstilt ifølge eks. 6 og 7 tilsvarer en dose på Oi 38 mg digoxin ble fylt i hårde gelatinkapsler av størrelse nr. 4. Amounts of coated granules produced according to e.g. 6 and 7 correspond to a dose of Oi 38 mg digoxin was filled in hard gelatin capsules of size No. 4.
Eksempel 10 Example 10
460 g av kjernemateriale, 0 0,2-0,55 mm, be-stående av vannfri laktose, ble påført et lag ved dusjing i et hvirvelsjikt med en oppløsning med følgende sammensetning: 460 g of core material, 0 0.2-0.55 mm, consisting of anhydrous lactose, was applied in a layer by showering in a fluidized bed with a solution of the following composition:
Frigjøring av digoxinj in vitro i prosent ifølge fremgangsmåten referert til i eksempel 1-7: Release of digoxinj in vitro in percent according to the method referred to in examples 1-7:
i in
i in
Eksempel 11 Example 11
Eksempel 8 ble gjentatt under anvendelse av 460 g av polyvinylacetat (Vinac ASB 576) 0 <0,5 mm, som kjernemateriale. Example 8 was repeated using 460 g of polyvinyl acetate (Vinac ASB 576) 0 <0.5 mm, as core material.
Frigjøring av digoxin: Release of digoxin:
Claims (2)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE7813245A SE426548B (en) | 1978-12-05 | 1978-12-22 | SOLID PHARMACEUTICAL PREPARATION INCLUDING A THERAPEUTICALLY EFFECTIVE HEART GYCLOSIDE AND POLYMER |
Publications (3)
Publication Number | Publication Date |
---|---|
NO794251L NO794251L (en) | 1980-06-24 |
NO152634B true NO152634B (en) | 1985-07-22 |
NO152634C NO152634C (en) | 1985-10-30 |
Family
ID=20336688
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO794251A NO152634C (en) | 1978-12-22 | 1979-12-21 | PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION comprising a cardiac glycoside in combination with a polymer |
Country Status (6)
Country | Link |
---|---|
DE (1) | DE2966037D1 (en) |
ES (1) | ES8101888A1 (en) |
GR (1) | GR74016B (en) |
IE (1) | IE48717B1 (en) |
NO (1) | NO152634C (en) |
PT (1) | PT70618A (en) |
-
1979
- 1979-12-13 DE DE7979850111T patent/DE2966037D1/en not_active Expired
- 1979-12-18 IE IE245579A patent/IE48717B1/en unknown
- 1979-12-20 PT PT7061879A patent/PT70618A/en unknown
- 1979-12-21 NO NO794251A patent/NO152634C/en unknown
- 1979-12-21 GR GR60840A patent/GR74016B/el unknown
- 1979-12-21 ES ES487182A patent/ES8101888A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
NO152634C (en) | 1985-10-30 |
IE48717B1 (en) | 1985-05-01 |
ES487182A0 (en) | 1980-12-16 |
PT70618A (en) | 1980-01-01 |
DE2966037D1 (en) | 1983-09-08 |
NO794251L (en) | 1980-06-24 |
ES8101888A1 (en) | 1980-12-16 |
GR74016B (en) | 1984-06-06 |
IE792455L (en) | 1980-06-22 |
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