NO138167B - PROCEDURE FOR THE PREPARATION OF AN ORAL QUICK-STABLE CORONARY AGENT - Google Patents

PROCEDURE FOR THE PREPARATION OF AN ORAL QUICK-STABLE CORONARY AGENT Download PDF

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NO138167B
NO138167B NO3021/72A NO302172A NO138167B NO 138167 B NO138167 B NO 138167B NO 3021/72 A NO3021/72 A NO 3021/72A NO 302172 A NO302172 A NO 302172A NO 138167 B NO138167 B NO 138167B
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dihydropyridine
dimethyl
dicarbomethoxy
nitrophenyl
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NO3021/72A
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NO138167C (en
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Friedrich Bossert
Wulf Vater
Kurt Bauer
Karl-Heinz Adams
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Bayer Ag
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Priority claimed from DE19722209526 external-priority patent/DE2209526C3/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S206/00—Special receptacle or package
    • Y10S206/828—Medicinal content

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

Fremgangsmåte til fremstilling av et oralt hurtigvirkende stabilt koronarmiddel.Process for the preparation of an orally fast-acting stable coronary agent.

Description

Oppfinnelsen vedrører en fremgangsmåte til fremstilling av et oralt hurtigvirkende stabilt koronarmiddel som inneholder 4-(2 '-nitrofenyl)-2 ,6-dimetyl-3,5-dikarbometoksy--1,4-dihydropyridin og en polyalkylenglykol. The invention relates to a method for producing an orally fast-acting stable coronary agent containing 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine and a polyalkylene glycol.

Anfallslignende opptredende forstyrrelser av koro-nargjennomblødningen, som klinisk manifisterer seg i form av såkalt pectangionøst anfall er en vital indikasjon, som ubetinget krever en omgående medikamentas behandling. Seizure-like disturbances of the coronary circulation, which clinically manifest in the form of a so-called pectangionous attack, are a vital indication, which unconditionally requires immediate drug treatment.

Da tidspunktet for opptreden av slike anfall ikke Then the time of occurrence of such attacks does not

kan forutsees må en pasient som lider av Angina pectoris ha med seg medikamenter, som muliggjør det å behandle seg selv under anfall. Disse medikamenter resp. deres tilberedningsformer, må can be foreseen, a patient suffering from Angina pectoris must carry medicines, which enable him to treat himself during an attack. These drugs or their forms of preparation, must

for å muliggjøre en hurtig og sikker selvbehandling oppfylle en rekke krav: to enable fast and safe self-treatment meet a number of requirements:

1. Disse medikamenters tilberedningsformer må være 1. The preparation forms of these medicines must be

av en sådan beskaffenhet at de kan inntas av pasienter på tross av begrenset handlingsevne under anfallet, sikkert og uten om-stendelige manipulasjoner. 2. Da stoffer som virker terapeutisk ved Angina pectoris, vanligvis er høyvirksomme medikamenter, som krever en nøyaktig dosering, må deres tilberedning være av en sådan beskaffenhet at det er sikret en adekvat dosering med sikkerhet. 3. Det pect-anginøse anfall foregår vanligvis med ulidelige smerter og store angstfølelser. Rent funksjonelt kan den i anfallet nedsatte gjennomblødning av hjertet ha til følge permanent beskadigelser av hjertemuskelen, som i ekstreme til-feller ville kunne føre til døden. Medikamenter som anvendes til terapi av Angina pectoris må følgelig være fullt virksomme i løpet av kort tid (i løpet av få minutter). of such a nature that they can be taken by patients despite limited ability to act during the attack, safely and without extensive manipulations. 2. As substances that have a therapeutic effect in Angina pectoris are usually highly effective drugs, which require a precise dosage, their preparation must be of such a nature that an adequate dosage is ensured with certainty. 3. The pect-anginous attack usually occurs with excruciating pain and great feelings of anxiety. Functionally, the reduced perfusion of the heart during the attack can result in permanent damage to the heart muscle, which in extreme cases could lead to death. Medicines used for the therapy of Angina pectoris must therefore be fully effective within a short time (within a few minutes).

De under punktene 1 til 3 nevnte krav kan ikke opp-fylles ved injeksjonsoppløsninger som bare kan tilføres parente-ralt resp. ved oralt inntagende oppløsninger som bare er doser-bare i form av dråper. Parenterale selvinjeksjoner er vanskelig for den uøvede og umulig i en tilstand av pect-anginøst anfall. Oralt appliserbare oppløsninger som må doseres med dråper, kan ikke doseres tilstrekkelig nøyaktig av pasienten, som er sterkt begrenset i sin reaksjonsevne. Det består fare for overdosering. The requirements mentioned under points 1 to 3 cannot be met with injection solutions that can only be administered parenterally or in the case of orally ingesting solutions which are dose-only in the form of drops. Parenteral self-injections are difficult for the untrained and impossible in a state of pect-anginous attack. Orally applicable solutions that must be dosed with drops cannot be dosed sufficiently precisely by the patient, who is severely limited in his ability to react. There is a risk of overdose.

Det er kjent at 1,4-dihydropyridin-derivater virker som koronardilatatorer og kan anvendes til behandling av overnevnte lidelse. Stoffer som hører til denne forbindelsesklasse er tungt oppløselige og fremfor, alt sterkt lysfølsomme. It is known that 1,4-dihydropyridine derivatives act as coronary dilators and can be used to treat the above-mentioned disorder. Substances belonging to this class of compounds are poorly soluble and, above all, highly light-sensitive.

Utsettes stoffene i oppløst form for dagslys, lar det seg allerede etter få minutter i UV-spektrofotometer påvise det irreversible spaltningsprodukt (2,6-dimetyl-3,5-diacetyl-4-(2'-nitrosofenyD-pyridin) . Alt etter intensiteten av det inn-virkende dagslys, spalter stoffet seg kvantitativt i et tidsrom fra 10 til 20 minutter. If the substances are exposed in dissolved form to daylight, the irreversible decomposition product (2,6-dimethyl-3,5-diacetyl-4-(2'-nitrosophenyD-pyridine) can be detected after only a few minutes in a UV spectrophotometer. Depending on the intensity of the influencing daylight, the substance breaks down quantitatively in a period of 10 to 20 minutes.

Por stabilisering av 1,^-dihydropyridinenes ytterst labile' redoxsystem har man tilsatt reduksjons- og oksydasjons-middel samt redoxsystemer (f.eks. Fe II / Fe III, askorbinsyre/ In order to stabilize the 1,^-dihydropyridines' extremely labile redox system, reducing and oxidizing agents as well as redox systems (e.g. Fe II / Fe III, ascorbic acid/

dehydroaskorbinsyre), men de kan ikke oppholde den raske spaltning. Oppbevaring av stoffet og dets oppløsning i tykkveggede, dehydroascorbic acid), but they cannot stop the rapid cleavage. Storage of the substance and its solution in thick-walled,

mørkebrune flasker forsinker spaltningen (når flasken er utsatt for dagslys), imidlertid lar det seg allerede etter 1 til 1^ time påvise spaltningsprodukt. dark brown bottles delay the decomposition (when the bottle is exposed to daylight), however, it is already possible to detect the decomposition product after 1 to 1^ hours.

Tabletter og drasjeer (britisk patent nr. 1.173-862), som inneholder disse virksomme stoffer virker på grunn av for langsom resorbering ikke hurtig nok, således at den hrfye potens av disse forbindelser ikke fullt ut kan utnyttes. Det består altså et absolutt behov for å stille 1,4-dihydropyridiner til disposisjon i en slik form at de for på den ene side er tilstrekkelig stabilisert og på den annen side at den sterke koronar-dilatoriske virkning av disse virksomme stoffer også kan utnyttes fullt ut i praksis. Tablets and dragees (British patent no. 1,173-862), which contain these active substances, do not work quickly enough due to too slow resorption, so that the high potency of these compounds cannot be fully utilized. There is therefore an absolute need to make 1,4-dihydropyridines available in such a form that, on the one hand, they are sufficiently stabilized and, on the other hand, that the strong coronary-dilatory effect of these active substances can also be fully utilized into practice.

Det er videre kjent at en hurtig resorpsjon og der-med en hurtigere inntredende virkning foregår ved perlingualt tilførte legemidler (f.eks. nitroglyserin (Sollman, T., "A Manual of Pharmacology", W.B. Saunders Co., Philadelphia,, Pa. s 1957, side 63D). It is also known that a rapid resorption and therefore a faster onset of effect takes place with drugs administered perlingually (e.g. nitroglycerin (Sollman, T., "A Manual of Pharmacology", W.B. Saunders Co., Philadelphia,, Pa. p 1957, page 63D).

Tilveiebringelse av tilberedningsformer som inneholder stabilisert 1,4-dihydropyridin og er beskaffen således at de også ved perlingual applikasjon resorberes, er følgelig et terapeutisk fremskritt. The provision of preparation forms which contain stabilized 1,4-dihydropyridine and are such that they are also resorbed by perlingual application is therefore a therapeutic advance.

Oppfinnelsen vedrører en fremgangsmåte til fremstilling av et stabilt, hurtigvirkende perlingualt resorbart koronarmiddel som inneholder 4-(2'-nitrofenyl)-2,6-dimetyl-3,5-dikarbometoksy-l,4-dihydropyridin og en polyalkylenglykol, idet fremgangsmåten er karakterisert ved at man under gult natriumlys i vilkårlig rekkefølge blander The invention relates to a method for producing a stable, fast-acting perlingually resorbable coronary agent containing 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine and a polyalkylene glycol, the method being characterized by mixing under yellow sodium light in random order

1 vektdel 4-(2'-nitrofenyl)-2,6-dimetyl-3,5-dikarbometoksy-1,M-dihydropyridin, 6 til 50, fortrinnsvis 15 til 35 vektdeler polyalkylenglykol med 2 til 3 karbonatomer i alkylenrestene og en gjennomsnittsmolekylvekt fra 200 til 600, 1 til 10 vektdeler lavere alkoholer med 1 til 3 hydroksylgrupper, spesielt glycerol, 1 til 10 vektdeler vann og eventuelt ytterligere vanlige formuleringshjelpemidler og 1 part by weight of 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,M-dihydropyridine, 6 to 50, preferably 15 to 35 parts by weight of polyalkylene glycol with 2 to 3 carbon atoms in the alkylene residues and an average molecular weight from 200 to 600, 1 to 10 parts by weight of lower alcohols with 1 to 3 hydroxyl groups, especially glycerol, 1 to 10 parts by weight of water and optionally further common formulation aids and

innfyller den således dannede oppløsning i gelatinbitekapsler, som inneholder et farvestoff, som absorberer lys av bølgelengde 280 til 420 nm, spesielt næringsmiddelfarvestoffet gulorange S (Color Index 15 985) og opakiseringsmiddel, spesielt titandioksyd. fills the thus formed solution into gelatin bite-sized capsules, which contain a dye, which absorbs light of wavelength 280 to 420 nm, in particular the food dye yellow orange S (Color Index 15 985) and opacifying agent, in particular titanium dioxide.

Det må anses som meget overraskende at oppløs-ningen av koronarvirksomt 1,4-dihydropyridin, som også opp-fylt i brune flasker eller ampuller allerede ved innvirkning av dagslys spaltes i løpet av kort tid sterkt til farmako-logiske, uvirksomme forbindelser er stabile i bitekapselen over flere måneder hvis hylster inneholder f.eks. titandioksyd og næringsmiddelfarvestoffet gulorange S (Color-Index 15 985). It must be considered very surprising that the solution of coronary-active 1,4-dihydropyridine, which is also filled in brown bottles or ampoules already on exposure to daylight, decomposes strongly within a short time into pharmacologically inactive compounds that are stable in the bite capsule over several months if the case contains e.g. titanium dioxide and the food dye yellow orange S (Color-Index 15 985).

Videre må det anses som meget overraskende at ved anvendelse av bitekapsler av et bestemt 1,4-dihydropyridin, nemlig ved 4-(2'-nitrofenyl)-2,6-dimetyl-3,5-dikarbometoksy-1,4-dihydropyridin, foregår-en meget hurtig virkningsinntreden. Dette spesielle 1,4-dihydropyridin viser nemlig overraskende en helt spesiell effekt. Det resorberes i motsetning til de andre 1,4-dihydropyridiner meget hurtig perlingualt, altså over tungen og over halsens slimhud. Furthermore, it must be considered very surprising that when using bite-sized capsules of a particular 1,4-dihydropyridine, namely with 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine, takes place - a very rapid onset of action. This particular 1,4-dihydropyridine surprisingly shows a very special effect. Unlike the other 1,4-dihydropyridines, it is absorbed very quickly perlingually, i.e. over the tongue and over the mucous membrane of the throat.

Dessuten er det overraskende at det lykkes å an-bringe dette relativt tungt oppløselige stoff i en meget hurtig resorberbar, altså flytende form i en gelatin-bitekapsel, som selv på grunn av materialet er temmelig oppløsningsfølsomt. Moreover, it is surprising that it is possible to place this relatively poorly soluble substance in a very quickly resorbable, i.e. liquid form in a gelatin bite capsule, which itself is quite sensitive to dissolution due to the material itself.

Anvendelse av 4-(2'-nitrofenyl)-2,6-dimetyl-3,5-dikarbometoksy-1,4-dihydropyridin. ved fremgangsmåten ifølge oppfinnelsen har følgende tekniske fordeler: Denne forbindelses tilstedeværelse i et preparat som straks inntas av en pasient som lider av et hjerteanfall får en tilstrekkelig kraftig virkning til å inntre i løpet av få minutter. Doseringen er entydig da den er gitt ved den virksomme stoffmengde innen en bitekapsel. Inngivelse er meget enkel, den foregår perlingualt uten at f.eks. det på forhånd må avtelles et bestemt antall av virksomme stoff-dråper. En slik prosess bortfaller i foreliggende tilfelle uten videre, fordi det virksomme stoff er for lysfølsomt. Denne lysfølsomhet kan tas helt spesielt hensyn til når gelatinkapselen inneholder opakiseringsmidler og et ikke toksisk farvestoff som absorberer lys av bølgelengde 250 til 460 nm. Use of 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine. the method according to the invention has the following technical advantages: The presence of this compound in a preparation which is immediately consumed by a patient suffering from a heart attack has a sufficiently powerful effect to occur within a few minutes. The dosage is unambiguous as it is given by the effective amount of substance within a bite capsule. Submission is very simple, it takes place perlingually without e.g. a specific number of drops of the active substance must be counted in advance. Such a process is omitted in the present case without further ado, because the active substance is too light-sensitive. This photosensitivity can be particularly taken into account when the gelatin capsule contains opacifiers and a non-toxic dye that absorbs light of wavelength 250 to 460 nm.

Det virksomme stoff som skal anvendes, ved fremgangsmåten ifølge oppfinnelsen er det kjente 4-(2<1->nitrofenyl)-2,6-dimetyl-3,5-dikarbometoksy-l,4-dihydropyridin (sammenlign britisk patent nr. 1.173-862) med formel The active substance to be used in the method according to the invention is the known 4-(2<1->nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine (compare British patent no. 1,173- 862) with formula

De ved fremgangsmåten ifølge oppfinnelsen anvendte polyalkylenglykoler er likeledes kjent. De har en gjennomsnittlig molekylvekt på 200 til MOOO. Fortrinnsvis anvender man polyetylen og/eller polypropylenglykol med en gjennomsnittsmolekylvekt fra 300 til 600 (f.eks. polyglykoler (Hoechst), "Lutrol 9" (BASF), "Polydioler" (Hiils), "Carbovoks" (Union Carbide)). The polyalkylene glycols used in the method according to the invention are also known. They have an average molecular weight of 200 to MOOO. Polyethylene and/or polypropylene glycol with an average molecular weight of 300 to 600 is preferably used (e.g. polyglycols (Hoechst), "Lutrol 9" (BASF), "Polydiols" (Hiils), "Carbovox" (Union Carbide)).

De ved fremgangsmåten ifølge oppfinnelsen anvendte lavere alkoholer med 2 til 8 karbonatomer og 1 til 3 hydroksylgrupper er likeledes kjent. Fortrinnsvis anvender man glyserol, propylenglykol eller butylenglykol. The lower alcohols with 2 to 8 carbon atoms and 1 to 3 hydroxyl groups used in the method according to the invention are likewise known. Preferably, glycerol, propylene glycol or butylene glycol is used.

Som ytterligere formuleringshjelpemiddel lar det seg anvende smakstoffer (aromaer) eller eterisk olje, fortrinnsvis Flavorings (aromas) or essential oil can be used as further formulation aids, preferably

.peppermynteolje, fenikkelolje, anilolje, karveolje, sitronolje eller eukalyptusolje, søtningsmiddel, f.eks. saccharin resp. saccharin-/natriumcyklamat, glycyrrhizinsyre-ammoniumsalt. De ved fremgangsmåten ifølge oppfinnelsen anvendte kapsler er bitekapsler som består av en gelatinhylse, som i bruksferdig tilstand inneholder 54 til 80$ gelatin, 10 til ~$ 6% glyserol og 7 til 15% vann og 0,5 til 5% opakiseringsmiddel som titandioksyd, jernoksyder som jernoksydgul, jernoksydrød, jernoksydbrun eller kalsiumkarbonat, men fortrinnsvis titandioksyd og farvestoffet gulorange S. Fremstillingen av gelatinmassen for kapselhylsen foregår ved at man i første rekke sammenblander 40 til 66% ren gelatin med 8 til J>6% glyserol (eller sorbit) og 22 til 34% vann og lar det svelle noen tid. Deretter smeltes massen ved ca. 60°C blærefri, opakiseringsmidlet og farvemidlet gulorange S (Color-Index 15985) og eventuelt dessuten konserver-ingsmiddel (f.eks. p-aminobenzosyreester, sorbinsyre, benzylalko-hol osv.) innarbeides homogent. .peppermint oil, fennel oil, anil oil, caraway oil, lemon oil or eucalyptus oil, sweetener, e.g. saccharin or saccharin/sodium cyclamate, glycyrrhizic acid ammonium salt. The capsules used in the method according to the invention are bite-size capsules which consist of a gelatin sleeve, which in the ready-to-use state contains 54 to 80$ gelatin, 10 to ~$ 6% glycerol and 7 to 15% water and 0.5 to 5% opacifying agent such as titanium dioxide, iron oxides such as iron oxide yellow, iron oxide red, iron oxide brown or calcium carbonate, but preferably titanium dioxide and the dye yellow orange S. The production of the gelatin mass for the capsule sleeve takes place by first mixing 40 to 66% pure gelatin with 8 to J>6% glycerol (or sorbitol) and 22 to 34% water and let it swell for some time. The mass is then melted at approx. 60°C blister-free, the opacifying agent and the coloring agent yellow-orange S (Color-Index 15985) and possibly also a preservative (e.g. p-aminobenzoic acid ester, sorbic acid, benzyl alcohol, etc.) are incorporated homogeneously.

Fremstillingen av preparatets kapselinnhold ved' fremgangsmåten ifølge oppfinnelsen foregår ved at man oppløser 4-(2'-nitrofenyl)-2,6-dimety1-3,5-dikarbometoksy-1,4-dihydropyridin i den lavere alkohol .og polyalkylenglykolen under svak oppvarming og omrøring i fravær av ovennevnte bølgelengde. Påfyllingen i gelatinkapsler foregikk etter kjente fremgangs-måter, f.eks. med Scherer-, Leiner-, Norton- eller Accogel-maskiner. Etter påfylling tørkes kapslene og er da bruksferdige. The preparation of the capsule contents of the preparation by the method according to the invention takes place by dissolving 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine in the lower alcohol and the polyalkylene glycol under gentle heating and stirring in the absence of the above wavelength. The filling in gelatin capsules took place according to known procedures, e.g. with Scherer, Leiner, Norton or Accogel machines. After filling, the capsules are dried and are then ready for use.

Applikasjonen av bitekapselen fremstilt ifølge oppfinnelsen foregår ved perlingual resorpsjon. The application of the bite capsule produced according to the invention takes place by perlingual resorption.

Den følgende figur viser den meget hurtige virkningsinntreden ved perlingual resorpsjon, spesielt sammenlignet med en peroral applikasjon av det samme virksomme stoff som anvendes ved fremgangsmåten ifølge oppfinnelsen, men blandet i tragant. The following figure shows the very rapid onset of action by perlingual resorption, especially compared to a peroral application of the same active substance used in the method according to the invention, but mixed in tragacanth.

Sammenligning av forskjellige applikasjonsformer. Forsøk på narkotiserte hjertesinuskateteriserte hunder. Comparison of different forms of application. Experiments on anesthetized cardiac sinus catheterized dogs.

1 mg/kg perlingualt (bitekapsel) 1 mg/kg perlingually (bite capsule)

Å A 1 mg/kg pr. os (tragant) Å A 1 mg/kg per os (traganta)

Middelverdi av hver gang 5 forsøk. Mean value of each time 5 trials.

På figuren er det vist virkningen av det virksomme stoff som anvendes ved fremgangsmåten ifølge oppfinnelsen i forskjellige applikasjons former på narkotiserte, hjertesinuskateteriserte hunder. Det ble målt økningen av oksygentrykket i koro-narvenøst blod etter 1 mg/kg virksomt stoff anvendt ved fremgangs- . måten ifølge oppfinnelsen perlingualt (innhold av gelatin-bitekapsel, glyserolpolyetylenglykol-vannblanding) sammenlignet med 1. mg/kg virksomt stoff anvendt ved fremgangsmåten ifølge oppfinnelsen applisert i maven (mikronisert stoff i tragant). Det dreier seg hver gang om middelverdier av 5 forsøk. The figure shows the effect of the active substance used in the method according to the invention in different forms of application on narcotized, cardiac sinus catheterized dogs. The increase in the oxygen pressure in coronary venous blood was measured after 1 mg/kg of active substance used in progress. the method according to the invention perlingually (contents of gelatin bite capsule, glycerol polyethylene glycol-water mixture) compared with 1. mg/kg of active substance used in the method according to the invention applied in the stomach (micronized substance in tragacanth). Each time it is about mean values of 5 trials.

Kurven viser tydelig den omgående virkningsinntredén etter perlingual applikasjon. Etter 5 minutter er maksimalverdien tilnærmet nådd, mens etter applikasjon i maven er oksygentrykket først øket etter 60 minutter til samme verdi. En applikasjon av det virksomme stoff i fast formulering, som tabletter, drasjeer eller lignende viser ennu ugunstigere verdier. The curve clearly shows the immediate onset of action after perlingual application. After 5 minutes the maximum value is almost reached, while after application in the stomach the oxygen pressure is only increased to the same value after 60 minutes. An application of the active substance in a solid formulation, such as tablets, dragees or the like, shows even more unfavorable values.

Det tidsmessige forløp av den fotokjemiske spaltning av det virksomme stoff i etanolisk oppløsning ved bestråling med lys av bølgelengde 360 nm er gjengitt i tabellen. The time course of the photochemical cleavage of the active substance in ethanolic solution by irradiation with light of wavelength 360 nm is reproduced in the table.

Eksempel for fremstiIling'av fyllingen av de øye-blikkelig oralt frigjørbare kapsler ( porsjon på 100 liter). Example for the preparation of the filling of the instant orally release capsules (portion of 100 litres).

94,21 kg polyetylenglykol med en gjennomsnittlig molekylvekt på 400 oppvarmes til en temperatur på 80°C. 2,94 kg 4-(2'-nitrofenyl)-2,6-dimety1-3,5-dikarbometoksy-l,4-dihydropyridin (virksomt stoff) tilsettes og oppløses under omrciring og blandingen avkjøles til 35°C. Deretter tilsettes 0,15 kg krystallinsk saccharin natriumsalt, 10,0 kg destillert vann, 94.21 kg of polyethylene glycol with an average molecular weight of 400 is heated to a temperature of 80°C. 2.94 kg of 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine (active ingredient) are added and dissolved under stirring and the mixture is cooled to 35°C. Then add 0.15 kg of crystalline saccharin sodium salt, 10.0 kg of distilled water,

6,0 kg glycerol og 0,2 kg peppermynteolje (ekstra sterk) under omrøring og avkjøles til 20°C. Blandingen filtreres under trykk gjennom cellulosefilteret. Fremgangsmåten utføres under gult natriumlys. Den fremstilte oppløsning som er klar til å fylles i kapsler har en pH-verdi på 5-7. 6.0 kg glycerol and 0.2 kg peppermint oil (extra strong) while stirring and cool to 20°C. The mixture is filtered under pressure through the cellulose filter. The procedure is performed under yellow sodium light. The prepared solution that is ready to be filled into capsules has a pH value of 5-7.

Sammensetning pr. kapsel: Composition per capsule:

Påfylling: Refill:

Mykgelatin (Scherer) tyggekapsler Soft gelatin (Scherer) chewable capsules

Kapselformat: 6 minimums oblong Capsule format: 6 minimum oblong

Kapselfarve: orange etter spesiell resept. Capsule colour: orange by special prescription.

Claims (1)

Fremgangsmåte til fremstilling av et stabilt, hurtig virkende perlingualt resorberbart koronarmiddel som inneholder 4-(2<1->nitrofenyl)-2,6-dimety1-3,5-dikarbometoksy-1,4-dihydropyridin og en polyalkylenglykol, karakterisert v e'd' at man under gult natriumlys i -ønskelig rekkefølge blanderProcess for the production of a stable, fast-acting perlingually resorbable coronary agent containing 4-(2<1->nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine and a polyalkylene glycol, characterized v e' d' that you mix under yellow sodium light in the -desired order 1 vektdel 4-(2'-nitrofeny1)-2,6-dimety1-3,5-dikarbometoksy-1,4-dihydropyridin, 6 til 50, fortrinnsvis 15 til 35 vektdeler polyalkylenglykol med 2 til 3 karbonatomer i alkylenresten og en gjennomsnittlig molekylvekt fra 200 til 600, 1 til 10 vektdeler lavere alkoholer med 1 til 3 hydroksylgrupper, spesielt glycerol, 1 til 10 vektdeler vann og eventuelt ytterligere vanlige formuleringshjelpemidler og innfyller den således dannede oppløsning i gelatinbitekapsler som inneholder et farvestoff som absorberer lys av en bølgelengde 280 til 420 nm, spesielt næringsmiddel-arvestoffet gulorange S (Color Index 15 985) og opakiseringsmiddel, spesielt titandioksyd .1 part by weight of 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropyridine, 6 to 50, preferably 15 to 35 parts by weight of polyalkylene glycol with 2 to 3 carbon atoms in the alkylene residue and an average molecular weight from 200 to 600, 1 to 10 parts by weight of lower alcohols with 1 to 3 hydroxyl groups, in particular glycerol, 1 to 10 parts by weight of water and optionally further common formulation aids and fills the thus formed solution into gelatin bite-sized capsules containing a dye that absorbs light of a wavelength of 280 to 420 nm, in particular the food genetic material yellow orange S (Color Index 15 985) and an opacifying agent, in particular titanium dioxide.
NO3021/72A 1971-08-24 1972-08-23 PROCEDURE FOR THE PREPARATION OF AN ORAL QUICK-STABLE CORONARY AGENT. NO138167C (en)

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DE2142316 1971-08-24
DE19722209526 DE2209526C3 (en) 1972-02-29 1972-02-29 Coronary therapeutic agent in the form of gelatine capsules

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FI53922C (en) 1979-09-07
FR2150848A1 (en) 1973-04-13
CY918A (en) 1977-12-23
NO138167C (en) 1978-07-26
DK130628B (en) 1975-03-17
RO88521B (en) 1987-05-01
IL40165A0 (en) 1972-10-29
SU432703A3 (en) 1974-06-15
ES406047A1 (en) 1981-08-16
KR780000433B1 (en) 1978-10-14
RO88521A (en) 1987-04-30
IE36891L (en) 1973-02-24
MY7800003A (en) 1978-12-31
SG34877G (en) 1987-04-03
BG27728A3 (en) 1979-12-12
GB1362627A (en) 1974-08-07
JPS5434048B2 (en) 1979-10-24
CA981582A (en) 1976-01-13
DK130628C (en) 1975-08-25
JPS53121921A (en) 1978-10-24
KE2756A (en) 1977-10-14
EG10633A (en) 1976-08-31
NL176836C (en) 1985-06-17
HK44877A (en) 1977-09-09
NL7211565A (en) 1973-02-27
IL40165A (en) 1975-03-13
DD99729A5 (en) 1973-08-20
JPS4828621A (en) 1973-04-16
LU65929A1 (en) 1973-01-15
NL176836B (en) 1985-01-16
FI53922B (en) 1978-05-31
FR2150848B1 (en) 1976-04-16
IE36891B1 (en) 1977-03-16
BE787951A (en) 1973-02-26
US3784684A (en) 1974-01-08

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