DK148344B

DK148344B - PROCEDURE FOR THE PREPARATION OF A PHARMACEUTICAL PREPARATION WITH EXTENDED RELEASE OF ACTIVE SUBSTANCE

Info

Publication number: DK148344B
Application number: DK113676AA
Authority: DK
Inventors: Prabhakar Ranchhordas Sheth; Jacques Levon Tossounian
Original assignee: Hoffmann La Roche
Priority date: 1975-03-17
Filing date: 1976-03-16
Publication date: 1985-06-17
Also published as: NZ180321A; JPS51115910A; IE43083L; AR222624A1; DK148344C; AU505355B2; JPS638084B2; FR2304354A1; DE2611041A1; NL190313C; AT353415B; PH14927A; GB1546448A; CA1073358A; ES446075A1; NL7602776A; AU1204976A; PT64907B; CH630257A5; MC1101A1

Description

1A 8 3 ή A1A 8 3 ή A

Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af et farmaceutisk præparat med forlænget afgivelse af aktivt stof, ved hvilken det aktive stof blandes med hydrokolloider og terapeutisk inerte, farmaceutisk tolerable hjælpestoffer og eventuelt spiselige 5 fedtagtige materialer, hvorefter der af blandingen dannes en fast lægemiddelform til oral administration såsom en kapsel eller en tablet, eventuelt en to-lagstablet, hvor det ene lag ikke har forlænget afgivelse, hvilken fremgangsmåde er ejendommelig ved, at der anvendes a) 0,1-90 vægtprocent af ét eller flere lægemiddelaktive stoffer, 10 b) 3,6-60 vægtprocent af ét eller flere terapeutisk inerte, farmaceutisk tolerable hjælpestoffer, c) 0-60 vægtprocent af ét eller flere spiselige fedtagtige materialer med en vægtfylde på mindre end 1 g/cm3 og d) 5-99,9 vægtprocent af ét eller flere hydrokolloider, som hydrati- 15 seres af mavesaften, hvorhos hydrokolloidet eller hydrokolloiderne for størstedelens vedkommende tilsættes i tør ensartet form og blandes med den eller de i i det væsentlige tør tilstand forekommende komponent(er), og der foretages en eventuel bearbejdning i i det væsentlige tør tilstand, 20 idet mængden af hydrokolloider, hjælpestoffer og fedtagtigt materiale vælges således, at præparatet i kontakt med mavesaften får en massefylde på mindre end 1.The present invention relates to a process for the preparation of a sustained-release pharmaceutical composition wherein the active substance is admixed with hydrocolloids and therapeutically inert, pharmaceutically tolerable excipients and optionally edible fatty materials, after which a solid drug form is formed from the mixture. oral administration such as a capsule or tablet, optionally a two-layer tablet, one layer of which has not prolonged delivery, the method being characterized by using a) 0.1-90% by weight of one or more drug-active substances, 3.6-60% by weight of one or more therapeutically inert, pharmaceutically tolerable excipients; c) 0-60% by weight of one or more edible fatty materials having a density less than 1 g / cm3 and d) 5-99.9% by weight of one or more hydrocolloids which are hydrated by the gastric juice, wherein the hydrocolloid or hydrocolloids are for the most part is mixed in the dry uniform form and mixed with the component (s) present in the substantially dry state, and any processing is carried out in the substantially dry state, selecting the amount of hydrocolloids, adjuvants and fatty material so that the composition in contact with the gastric juice gets a density of less than 1.

Det fremstillede præparat svømmer oven på mavesaften og forbliver svømmende der, indtil praktisk taget alt det deri værende medikament 25 er frigivet. Andelen af et hydrokolloid eller en blanding af hydrokolloider bevirker, at der efter kontakt med mavesaften dannes et vanduigennemtrængeligt lag på overfladen af denne homogene blanding. Et præparat med forlænget afgivelse af aktivt stof kaldes herefter et " reta rdp ræpa rat".The prepared composition swims on top of the gastric juice and stays there until virtually all of the drug 25 contained therein is released. The proportion of a hydrocolloid or a mixture of hydrocolloids causes a water-impermeable layer to form on the surface of this homogeneous mixture upon contact with the gastric juice. A preparation with prolonged release of the active substance is then called a "reta rdp ræpa rat".

30 Fordelen ved administration af en enkeltdosis af et medikament, som frigør det aktive stof over en forlænget tidsperiode, i modsætning til administration af et antal enkeltdoser med bestemte intervaller, har længe været kendt i farmacien. Fordelen for patienten og klinikeren, som består i, at der i en forlænget tidsperiode er et konstant og 2 U 8344 ensartet blodspejl af medikamentet, er ligeledes velkendt. I de fleste retard præparater, som er kendt i farmacien, er det aktive stof enten overtrukket med forskellige tykkelser af bestemte typer relativt uopløseligt materiale eller indkapslet i et stift gitter af harpiksagtigt 5 materiale. Hovedformålet med sådanne præparater er den kontinuerlige absorption af aktivstoffet i blodbanen ved erstatning af det forbrugte materiale, medens lægemiddelformen passerer patientens gastrointesti -nåle kanal.The advantage of administering a single dose of a drug which releases the active substance over an extended period of time, as opposed to administering a number of single doses at specific intervals, has long been known in the pharmaceutical industry. The benefit to the patient and clinician, which consists in having a constant and consistent blood level of the drug for an extended period of time, is also well known. In most retard preparations known in the pharmaceutical, the active substance is either coated with various thicknesses of certain types of relatively insoluble material or encased in a rigid lattice of resinous material. The main purpose of such preparations is the continuous absorption of the active substance into the bloodstream by replacing the consumed material while the drug form passes the patient's gastrointestinal tract.

Den ovenfor i korthed skitserede sædvanlige måde til fremstilling af 10 præparater med forlænget afgivelse af aktivt stof kan have ulemper, da visse klasser af aktivstoffer på grund af deres fysiokemiske egenskaber og/eller egnede absorptionssteder ikke er egnet til absorption under passagen gennem gastrointestinalkanalen. Fx absorberes de fleste sure medikamenter hovedsageligt af maven, medens de fleste 15 basiske medikamenter først og fremmest absorberes af tarmene. De fleste medikamenter forandrer graden af deres opløselighed ved passagen fra de stærkt sure betingelser i maven til de neutrale til alkaliske betingelser i tarmene. Således er fx jernsalte bedre opløselige i maven end i tarmene. Endvidere findes der medikamenter, fx anta-20 cida, som skal virke i maven og derfor taber deres helbredende egenskaber, når de kommer ind i tarmene.The usual way outlined above for the preparation of 10 prolonged release active ingredient preparations may have drawbacks as certain classes of active substances due to their physicochemical properties and / or suitable absorption sites are not suitable for absorption during passage through the gastrointestinal tract. For example, most acidic drugs are mainly absorbed by the stomach, while most 15 basic drugs are primarily absorbed by the intestines. Most drugs change the degree of solubility of the passage from the highly acidic conditions in the stomach to the neutral to alkaline conditions in the intestines. Thus, for example, iron salts are better soluble in the stomach than in the intestines. Furthermore, there are medications, for example, antacids, which must work in the stomach and therefore lose their healing properties as they enter the intestines.

Under hensyntagen til de ovenfor anførte forklaringer er det klart, at et stort antal medikamenter ikke er egnede til sædvanlige retardpræ-parater, som ikke beholdes i maven, og som frigør medikamentet i 25 tarmene. Det er ligeledes klart, at et retardpræparat, som forbliver i maven, og som frigør medikamentet i maven i løbet af et forlænget tidsrum, er udmærket egnet til sådanne aktivstoffer. Et sådant retardpræparat fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse.Taking into account the explanations given above, it is clear that a large number of medications are not suitable for usual retardation preparations which are not retained in the stomach and which release the drug into the intestine. It is also clear that a retardant composition which remains in the stomach and which releases the drug into the stomach during an extended period of time is very suitable for such active substances. Such a retarding composition is prepared by the method of the present invention.

30 Retardprincippet, som karakteriserer det farmaceutiske præparat, der fremstilles ifølge den foreliggende opfindelse, er enestående, idet præparatet i et langt tidsrum forbliver frit svømmende på mavesaften, medens praktisk talt alt medikamentet frigøres. Selv om der kendes flere retardmekanismer, og selv om der er gjort udkast til et svøm-35 mende præparat, er den svømmende effekt, som udnyttes ved frem- 1A 8 3 A h 3 gangsmåden ifølge den foreliggende opfindelse, ikke tidligere blevet anvendt i forbindelse med retardpræparater.The retardation principle which characterizes the pharmaceutical composition prepared in accordance with the present invention is unique in that the composition remains freely swimming on the gastric juice for a long period of time while releasing virtually all of the drug. Although several retarding mechanisms are known, and although a swimming preparation has been drafted, the swimming effect utilized in the method of the present invention has not previously been used in conjunction with the present invention. with retard preparations.

I USA patentskrift nr. 3.418.999 er beskrevet en tablet, som er svømmende. Denne tablets svømmeevne er dog kun omtalt som hjælpe-5 middel ved synkningen, og det er ikke antydet, at dette svømmeprin-cip kan anvendes til retardpræparater. Desuden skal tabletterne ifølge ovennævnte USA patentskrift have en oprindelig vægtfylde på mindre end 1, hvorimod de tabletter, der fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse, ikke er begrænset på denne måde.U.S. Patent No. 3,418,999 discloses a tablet which is swimming. However, the swimming ability of this tablet is referred to only as an auxiliary agent in the sinking, and it is not suggested that this swimming principle can be used for retarding preparations. In addition, the tablets of the aforementioned United States Patent Specification must have an initial density of less than 1, whereas the tablets prepared by the process of the present invention are not limited in this way.

10 Tabletter, som kvælder op i kontakt med mavesaften, er ligeledes kendte. Fx beskrives der i USA patentskrift nr. 3.574.820 tabletter, som i kontakt med mavesaft kvælder op til en størrelse, der gør, at de ikke kan passere pylorus, og derfor forbliver i maven. Det er ganske klart, at disse tabletter ikke svømmer, idet deres størrelse 15 ikke ville have indflydelse på deres passage af pylorus, hvis de kunne svømme.10 tablets which swell in contact with the gastric juice are also known. For example, U.S. Patent No. 3,574,820 discloses tablets which, in contact with gastric juice, swell up to a size that prevents them from passing through the pylorus, and therefore remains in the stomach. It is quite clear that these tablets do not swim as their size 15 would not affect their passage of the pylorus if they could swim.

Inkorporeringen af et kvældbart hydrokolloid i en retardtablet er ligeledes kendt. I USA patentskrift nr. 3.147.187 er beskrevet inkorporeringen af en opkvældelig gummi eller et proteinholdigt materi-20 ale i en retardtablet, hvorhos denne foranstaltning skal hjælpe til ved opløsning af tabletten, hvorved en større overflade fordøjes. I det nævnte USA patentskrift er der dog ingen angivelse af, at denne tablet skulle være bestemt til at svømme. Dette fremgår endvidere klart af den kendsgerning, at alle komponenterne forenes i en smelte, 25 som derpå afkøles og granuleres. Hydrokolloidet formuleres derefter på lignende måde som sædvanlige tabletbindemidler, ganske i modsætning til den foreliggende opfindelse, hvor hydrokolloidet i tør, ensartet form sættes til præparatet, hvorved det opfylder den funktion at fremme tabletternes svømmeevne.The incorporation of a swellable hydrocolloid into a retard tablet is also known. U.S. Patent No. 3,147,187 discloses the incorporation of a swellable rubber or proteinaceous material into a retard tablet, which is to aid in the dissolution of the tablet, thereby digesting a larger surface. However, in the said United States patent, there is no indication that this tablet should be intended for swimming. This is further evident from the fact that all the components are combined into a melt, which is then cooled and granulated. The hydrocolloid is then formulated in a similar manner to conventional tablet binders, quite contrary to the present invention, wherein the hydrocolloid in dry, uniform form is added to the composition thereby fulfilling the function of promoting the swimming ability of the tablets.

30 Endelig beskrives i USA patentskrift nr. 3.065.143 anvendelsen af et hydrokolloid i retardtabletter, ifølge hvilket patentskrift der på tabletternes overflade dannes et vanduigennemtrængeligt lag, som lidt efter lidt eroderes og således i løbet af et forlænget tidsrum frigør 4Finally, U.S. Patent No. 3,065,143 discloses the use of a hydrocolloid in retard tablets, according to which a surface-impermeable layer is formed on the surface of the tablets, which is gradually eroded and thus releases over a prolonged period of time.

U83UU83U

det aktive stof. I det omtalte USA patentskrift kan der dog ikke findes nogen antydning af, at dette fænomen kunne anvendes til at fremstille en hydrodynamisk udlignet tablet, dvs. som svømmer på mavesaften i et længere tidsrum, sådan som det er tilfældet ifølge den 5 foreliggende opfindelse.the active substance. However, in the above-mentioned United States patent, there is no indication that this phenomenon could be used to produce a hydrodynamically equalized tablet, ie. which swim on the stomach juice for a longer period of time, as is the case of the present invention.

I dansk patentansøgning nr. 97S/75 beskrives præparater, der, ligesom de præparater, der fremstilles ved fremgangsmåden ifølge den foreliggende opfindelse, ikke synes at kunne forlade maven, fordi de svømmer på mavesaften og derved forhindres i at passere maveporten 10 (pylorus). Disse egenskaber, der er fælles for de to lægemiddelformer, opnås dog med helt forskellige tekniske midler. For de præparater, der er beskrevet i patentansøgning nr. 978/75, opnås svømmeev-nen ved, at der som bærer anvendes et legeme med svømmeevne, fx et hult legeme (kapsel) eller en skumstofpartikel, på hvis overflade 15 medikamentet anbringes. Som det skulle ventes, svømmer det således vundne præparat, såfremt bæreren i sig selv har tilstrækkelig opdrift. Det er helt anderledes med de præparater, der fremstilles ved fremgangsmåden iføige den foreliggende opfindelse. Her er præparatet ikke anbragt i mere eller mindre tynde lag på en inaktiv bærer, men 20 er fordelt regelmæssigt i hele lægemiddelbæreren (kapsel eller tablet).Danish Patent Application No. 97S / 75 discloses compositions which, like the compositions prepared by the method of the present invention, do not appear to be able to leave the stomach because they swim on the gastric juice and thereby are prevented from passing the gastric port 10 (pylorus). However, these properties common to the two drug forms are achieved by completely different technical means. For the compositions described in patent application No. 978/75, swimming ability is achieved by using as a carrier a swimming capability, e.g., a hollow body (capsule) or a foam particle on which the surface of the drug is applied. As would be expected, the thus-obtained composition swims if the carrier itself has sufficient buoyancy. It is quite different with the compositions prepared by the method of the present invention. Here, the composition is not placed in more or less thin layers on an inert carrier, but 20 is distributed regularly throughout the drug carrier (capsule or tablet).

At et sådant præparat svømmer, skyldes ikke simpelt hen den omstændighed, at dets massefylde er mindre end massefylden af mavesaften. Svømmeevnen skyldes, at de i præparatets ydre lag værende hydrokolloider ved kontakt med mavesaft hydratiseres, hvilket med-25 fører, at en øjeblikkelig yderligere indtrængen af væske i præparatet, altså en hurtig gennemfugtning af hele massen, bliver forhindret. En fuldstændig gennemfugtning ville få præparatet til at synke, hvorefter det snart ville forlade maven og gå over i tarmen. I den masse, fra hvis ydre lag aktivstoffet frigøres, foregår hydratiseringen af hydro-30 kotloiderne udefra og indefter og således også frigørelsen af aktivstof. Det er bemærkelsesværdigt og samtidig en bekræftelse af den ovenfor beskrevne virkningsmekanisme, at præparatet før indtagelsen ikke nødvendigvis skal have lavere massefylde end mavesaft (jfr. nedenfor). Massefylden kan nemlig nedsættes ved opkvældning. Der 35 er således en tydelig forskel mellem det præparat, der fremstilles ved fremgangsmåden ifølge opfindelsen, og det præparat, der er beskrevet i dansk patentansøgning nr. 978/75.The fact that such a preparation is swimming is not simply due to the fact that its density is less than the density of the gastric juice. The swimming ability is due to hydration of the hydrocolloids present in the composition by contact with gastric juice, which causes an immediate further penetration of fluid into the composition, ie a rapid wetting of the whole mass, is prevented. A complete moisturizing would cause the preparation to sink, after which it would soon leave the stomach and enter the intestine. In the mass from which the outer layer of the active substance is released, hydration of the hydrocotloids takes place from the outside and inward, and thus also the release of the active substance. It is noteworthy, and at the same time, a confirmation of the mechanism of action described above, that the preparation before ingestion should not necessarily have a lower density than gastric juice (see below). Namely, the density can be reduced by swelling. Thus, there is a clear difference between the composition produced by the process of the invention and the composition disclosed in Danish Patent Application No. 978/75.

148344 5148344 5

Hydrokolloiderne danner i kontakt med mavesaften ved legemstemperatur på overfladen af blandingen en gelatinøs masse, hvorved blandingen let udvider sig og således opnår en vægtfylde på mindre end 1 og derfor svømmer på mavesaften, som har en massefylde på mellem 5 1,004 og 1,010. Det aktive stof frigøres langsomt fra overfladen af denne gelatinøse masse, hvorhos massen på grund af sin svømmeevne forbliver svømmende på mavesaften. Efter at praktisk taget alt medikamentet endelig er frigjort, forsvinder den gelatinøse masse. Retard-præparatet administreres oralt i form af tabletter eller kapsler, fx 10 kapsler af hård eller blød gelatine.The hydrocolloids, in contact with the gastric juice at body temperature on the surface of the mixture, form a gelatinous mass, whereby the mixture easily expands and thus achieves a density of less than 1 and therefore swims on the gastric juice having a density of between 5,004 and 1,010. The active substance is slowly released from the surface of this gelatinous mass, whereby the mass, due to its swimming ability, remains swimming on the gastric juice. After practically all the drug is finally released, the gelatinous mass disappears. The retard preparation is orally administered in the form of tablets or capsules, e.g., 10 hard or soft gelatin capsules.

Efter den orale indtagelse af farmaceutiske præparater fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse opløses et tilstedeværende kapselindhylningsmateriale eller tabletfilmlag, hvorved indholdet kommer I kontakt med mavesaften. Efter kontakt med mavesaf-15 ten hydratiseres det yderste hydrofile kolloid og danner et ydre lag, som holder kapselformen eller tabletten sammen og derved forhindrer nedbrydning af massen. Dette hydratiserede lag opløses derefter langsomt og frigør aktivstof. En frigørelse af aktivstof foregår også ved udludning på eller ved massens overflade. Så snart en ny over-20 flade udsættes for mavesaften, foregår der hydratisering, hvorhos lagets ensartethed bibeholdes. Denne fremgangsmåde gentages bestandig, indtil praktisk taget alt aktivstoffet er udludet. Derefter opløses den resterende matrix, der som før svømmer på mavesaften og forsvinder.Following the oral ingestion of pharmaceutical compositions prepared by the method of the present invention, a capsule wrapping material or tablet film layer dissolved dissolves the contents into contact with the gastric juice. Upon contact with the gastric juice, the outermost hydrophilic colloid is hydrated to form an outer layer which holds the capsule form or tablet together, thereby preventing degradation of the pulp. This hydrated layer then dissolves slowly, releasing active substance. An active substance release also occurs by leaching on or at the surface of the pulp. As soon as a new surface is exposed to the gastric juice, hydration takes place, whereby the uniformity of the layer is maintained. This process is repeated repeatedly until practically all the active substance is leached. Then the remaining matrix dissolves, which, as before, swims on the stomach juice and disappears.

25 Den med retard præparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse opnåede frigørelsesforsinkelse og det opnåede blodspejl har fordele i forhold til kendte retardmekanismer. Disse fordele optræder især, når de indeholdte medikamenter hovedsagelig absorberes i maven eller duodenum eller udøver deres terapeutiske 30 aktivitet dér. Retardpræparaterne fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse medfører ganske uventet optimale blodspejl med visse medikamenter, fx chlordiazepoxid. Resultaterne med chlordiazepoxid er kendte, tidligere undersøgte retardpræpa rater overlegne, da de tidligere præparater fremkaldte utilstrækkelige 35 blodspejl. Desuden udgør retardpræpa ratet fremstillet ved fremgangs- 148344 6 måden ifølge den foreliggende opfindelse overraskende nok et udmærket middel til administration af antacida i løbet af et forlænget tidsrum.The release delay obtained by the method of the present invention and the blood level obtained have advantages over known retarding mechanisms. These benefits occur especially when the contained drugs are mainly absorbed in the stomach or duodenum or exert their therapeutic activity there. The retarding compositions prepared by the method of the present invention lead, quite unexpectedly, to optimal blood levels of certain medications, for example, chlordiazepoxide. The results of chlordiazepoxide are known, previously studied retardation rates are superior as the previous preparations induced insufficient blood levels. In addition, the retard preparation prepared by the method of the present invention surprisingly provides an excellent means of administering antacids over an extended period of time.

De til retardpræpa ratet fremstillet ved fremgangsmåden ifølge den 5 foreliggende opfindelse egnede hydrokolloider omfatter ét eller flere naturlige, helt eller delvis syntetiske anioniske eller fortrinsvis ikke-ioniske hydrofile gummiarter, modificerede celluloseagtige stoffer eller proteinagtige stoffer, fx acacia, traganthgummi, johannesbrødgummi, guargummi, karayagummi, agar, pectin, carrageen, opløselige og 10 uopløselige alginater, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, natriumcarboxymeth-ylcellulose, carboxypolymethylen (Carbopol®-Cabot Corporation), gelatine,, casein, zein, benton it og VeegumrM (R.T. Vanderbilt Co.).The hydrocolloids suitable for the retard formulation prepared by the process of the present invention include one or more natural, fully or partially synthetic anionic or preferably nonionic hydrophilic gums, modified cellulosic or proteinaceous substances, e.g., acacia, tragacanth gum, locust bean gum, , agar, pectin, carrageenan, soluble and insoluble alginates, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, carboxypolymethylene (Carbopol®-Cabot Corporation), gelatin, ).

Ifølge den foreliggende opfindelse foretrækkes methylcellulose, hydro-15 xypropylcellulos.e, hydroxypropylmethylcellulose, hydroxymethylcel- lulose, natriumcarboxymethylcellulose eller blandinger deraf som hydrokolloider. Anvendelse af hydroxypropylmethylcellulose i farmaceutiske præparater er kendt. Således beskrives i fx USA patentskrift nr. 3.555.151 anvendelsen af sådanne hydrokolloider i antacida-re-20 ta rdpræpa rater.According to the present invention, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose or mixtures thereof are preferred as hydrocolloids. Use of hydroxypropyl methyl cellulose in pharmaceutical compositions is known. Thus, for example, US Patent No. 3,555,151 discloses the use of such hydrocolloids in antacid preparations.

For at opnå et godt resultat med den foreliggende opfindelse må det anvendte hydrokolloid hydratiseres i surt medium, fx i mavesaft med en pH-værdi svarende til 0,1N saltsyreopløsning, dvs. ved en pH-værdi på ca. 1,2. Det er endvidere vigtigt, selv om den oprindelige 25 vægtfylde i præparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse kan være større end 1, at præparatet i kontakt med mavesaften har en vægtfylde på mindre end 1, således at svømmeevnen sikres. Der eksisterer en mængde metoder, ved hjælp af hvilke aktivstoffets frigørelseshastighed fra reta rdpræpa ratet fremstil-30 let ved fremgangsmåden ifølge den foreliggende opfindelse kan indstil les. En metode består i valget af et bestemt hydrokolloid eller en blanding af hydrokolloider, som øver indflydelse på frigørelseshastigheden· Således hydratiseres højviskose hydrokolloider, fx methylcellulose 60 HG, 4000 cps, langsommere end lavviskose hydrokolloider, 7 148344 fx methylcellulose 60 HG, 10 cps, og bibeholder derfor en blød masse i længere tid. Endvidere kan der til præparatet sættes spiselige, farmaceutisk inerte, fedtagtige stoffer med en vægtfylde på mindre end 1, hvorved præparatets hydrofile egenskaber formindskes, og 5 præparatets svømmeevne derfor forøges. Eksempler på sådanne stoffer er: en renset kvalitet af bivoks; langkædede fedtagtige alkoholer såsom cetylalkohol, myristylalkohol, stearylalkohol, glycerider såsom glycerylestere af fedtsyrer eller hydrerede aliphatiske syrer, fx glycerylmonostearat, glyceryldistearat og glycerylestere af hydreret 10 ricinusolie; olier såsom mineralolie.In order to obtain a good result with the present invention, the hydrocolloid used must be hydrated in acidic medium, for example in gastric juice with a pH equal to 0.1N hydrochloric acid solution, i.e. at a pH of approx. 1.2. It is further important, although the original density of the composition prepared by the method of the present invention may be greater than 1, that the composition in contact with the gastric juice has a density of less than 1, so that swimming ability is ensured. There are a variety of methods by which the rate of release of the active substance from the retardate prepared by the process of the present invention can be adjusted. One method consists in the selection of a particular hydrocolloid or a mixture of hydrocolloids that influence the release rate · Thus, high viscous hydrocolloids, e.g., methylcellulose 60 HG, 4000 cps, slower than low viscous hydrocolloids, 7 148344, e.g., methylcellulose 60 HG, are hydrated therefore retains a soft mass for an extended period of time. Furthermore, edible, pharmaceutically inert, fatty substances having a density of less than 1 may be added to the composition, thereby reducing the hydrophilic properties of the composition and therefore increasing the swimming ability of the composition. Examples of such substances are: a purified beeswax quality; long chain fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, glycerides such as glyceryl esters of fatty acids or hydrated aliphatic acids, for example glyceryl monostearate, glyceryl distearate and glyceryl esters of hydrated castor oil; oils such as mineral oil.

Retardpræparaterne fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse er yderligere tilsat spiselige, ikke-toxiske bestanddele, som er kendt ved fremstillingen af farmaceutiske præparater, fx excipienser, konserveringsmidler, stabiliseringsmidler og tablette-15 ringsglittemidler. Valget af og andelen af sådanne stoffer ligger inden for fagmandens viden. Det må dog påses, at sådanne sædvanlige farmaceutiske hjælpestoffer, som kan have en negativ indflydelse på retardpræparatets hydrodynamiske ligevægt, ikke anvendes ved den foreliggende opfindelse.The retarding compositions prepared by the process of the present invention are further added to edible, non-toxic ingredients known in the manufacture of pharmaceutical compositions, e.g., excipients, preservatives, stabilizers, and tableting lubricants. The choice and proportion of such substances is within the skill of the art. However, it should be noted that such conventional pharmaceutical excipients, which may adversely affect the hydrodynamic equilibrium of the retarding composition, are not used in the present invention.

20 Andelen af aktivstof eller aktivstofblandinger i retardpræparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse kan varieres inden for et bredt område, dvs. fra ca. 0,1 vægtprocent til ca. 90 vægtprocent. Andelen af aktivstoffer ligger sædvanligvis mellem ca. 5 vægtprocent og 50 vægtprocent. De faktorer, som be-25 stemmer andelen af aktivstofferne i retard præparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse, er fx den del, der kræves for at sikre fuldstændig terapeutisk dosering, aktivstoffernes vægtfylde, de hydrofile eller hydrofobe egenskaber hos aktivstofferne og deres stabilitet. Disse egenskaber er kendte eller kan let konsta-30 teres af fagmanden. De retningslinjer for formuleringen, der skal overholdes for at inkorporere et terapeutisk aktivt stof i et retard-præparat fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse, ligger ligeledes inden for fagmandens viden.The proportion of active ingredient or active ingredient mixtures in the retard preparation prepared by the method of the present invention can be varied within a wide range, i. from approx. 0.1% by weight to approx. 90% by weight. The proportion of active substances is usually between approx. 5% by weight and 50% by weight. For example, the factors that determine the proportion of the active substances in the retard preparation prepared by the method of the present invention are the portion required to ensure complete therapeutic dosage, the density of the active substances, the hydrophilic or hydrophobic properties of the active substances and their stability. These properties are known or readily ascertained by those skilled in the art. The guidelines of the formulation to be adhered to incorporate a therapeutically active substance into a retard preparation prepared by the method of the present invention are also within the skill of the art.

148344 8148344 8

Andelen af de tilstedeværende hydrokolloidbestanddele i retardpræpa-ratet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse kan ligeledes varieres inden for et bredt område, dvs. fra ca. 5 vægtprocent til ca. 99,9 vægtprocent. Den andel af hydrokolloidbe-5 standdel, som anvendes, varieres i forhold til andel og egenskaberne hos det aktive stof og de inerte farmaceutiske hjælpestoffer. Almindeligvis udgør andelen af hydrokolloid mellem ca. 20 vægtprocent og ca.The proportion of the hydrocolloid constituents present in the retard preparation prepared by the process of the present invention may also be varied within a wide range, i. from approx. 5% by weight to approx. 99.9% by weight. The proportion of hydrocolloid component used is varied in proportion to the proportion and properties of the active substance and the inert pharmaceutical excipients. Generally, the proportion of hydrocolloid is between ca. 20% by weight and approx.

75 vægtprocent.75% by weight.

Når der forekommer fedtagtigt stof eller en blanding deraf i retard-10 præparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse, udgør dette stof op til ca. 60 vægtprocent af det totale præparat. Såfremt præparatet indeholder et fedtagtigt stof, forekommer dette stof i almindelighed i en andel på ca. 5 - ca. 30 vægtprocent.When a greasy substance or a mixture thereof is present in the retard preparation prepared by the process of the present invention, this substance constitutes up to approx. 60% by weight of the total composition. If the composition contains a greasy substance, this substance generally occurs in a proportion of approx. 5 - approx. 30% by weight.

15 Den andel fedtagtigt stof, som anvendes, reguleres af andelen og de fysiske egenskaber hos både aktivstoffet og hydrokolioidet med det formål at opnå et hydrodynamisk udlignet præparat, dvs. et præparat, som i mavesaften får en massefylde på mindre end 1.The proportion of fatty substance used is regulated by the proportion and physical properties of both the active substance and the hydrocolloid in order to obtain a hydrodynamically equalized composition, ie. a preparation which in the gastric juice has a density of less than 1.

Andelen af spiselige, inerte farmaceutiske hjælpestoffer i retardpræ-20 paratet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse varierer ligeledes alt afhængigt af de andre bestanddeles andele og fysiske egenskaber. Stoffer, som på deres side har en vægtfylde på mindre end 1, vil forøge præparatets svømmeevne. Meget vigtigere er det, at det er muligt gennem valget af inerte farmaceutiske hjæl-25 pestoffer at modificere præparatets frigørelseshastighed. Således forhøjer opløselige excipienser såsom lactose og mannitol frigørelseshastigheden, hvorimod uopløselige excipienser såsom dicalciumphosphat og terra-alba nedsætter den. Sådanne sædvanlige farmaceutiske hjælpestoffer forekommer i andele på ca. 3,6 - ca. 60 vægtprocent af 30 præparatet. Anvendelsen og valget af sådanne stoffer ligger inden for fagmandens område.The proportion of edible inert pharmaceutical adjuvants in the retard preparation prepared by the process of the present invention also varies depending on the proportions and physical properties of the other ingredients. Substances which, on their part, have a density of less than 1, will increase the swimming ability of the preparation. More importantly, it is possible through the choice of inert pharmaceutical adjuvants to modify the rate of release of the composition. Thus, soluble excipients such as lactose and mannitol increase the release rate, whereas insoluble excipients such as dicalcium phosphate and terra-alba decrease it. Such usual pharmaceutical excipients occur in proportions of approx. 3.6 - approx. 60% by weight of the composition. The use and selection of such substances is within the skill of the art.

Retardpræparaterne fremstilles på i og for sig kendt måde. Såfremt præparatet fremstillet ved fremgangsmåden ifølge opfindelsen admini- 148344 9 streres i form af kapsler, kræves det kun, at alle ingredienser blandes godt og formales eller sønderdeles for at opnå en homogen blanding med relativt lille partikelstørrelse. For at opnå den rigtige indfyldningsvægt i kapslen må der dog ved visse lejligheder anvendes 5 sædvanlig teknik til fx agglomerering, vådgranulering eller ekstrusi-on. Den vundne blanding fyldes derefter i egnede farmaceutiske kapsler, hvorhos der foretrækkes kapsler af hård gelatine. Kapslerne skal være fuldstændig fyldte. Retningslinjerne til opnåelse af denne virkning er kendte for fagmanden.The retarding compositions are prepared in a manner known per se. If the preparation prepared by the method of the invention is administered in the form of capsules, it is only required that all ingredients be well mixed and ground or disintegrated to obtain a homogeneous mixture of relatively small particle size. However, in order to achieve the correct filling weight in the capsule, on certain occasions, 5 conventional techniques must be used for eg agglomeration, wet granulation or extrusion. The resulting mixture is then filled into suitable pharmaceutical capsules, with hard gelatin capsules being preferred. The capsules must be completely filled. The guidelines for achieving this effect are known to those skilled in the art.

10 Såfremt præparaterne fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse administreres i form af tabletter, fremstilles disse tabletter på i og for sig kendt måde. I mange tilfælde er det nødvendigt at benytte en vådgranuleringsteknik med påfølgende tabletpresning. Såfremt komponenternes fysiske egenskaber tillader 15 det, kan tabletterne også fremstilles ved direkte presning af en homogen blanding af bestanddelene. Sådanne tabletter indeholder sædvanlige tabletteringsglittemidler og andre farmaceutiske hjælpestoffer, og disse skal opfylde de ovenfor omtalte kriterier. Det skal bemærkes, at mange hydrokolloider, som anvendes til fremgangsmåden 20 ifølge den foreliggende opfindelse, også sædvanligvis anvendes som tabletbindemiddel ved tilberedningen af farmaceutiske præparater, og som sådant anvendes i form af en opløsning eller dispersion i et egnet opløsningsmiddel ved tabletformuleringen.10 If the compositions prepared by the process of the present invention are administered in the form of tablets, these tablets are prepared in a manner known per se. In many cases, it is necessary to use a wet granulation technique with subsequent tablet pressing. If the physical properties of the components allow, the tablets may also be prepared by direct pressing of a homogeneous mixture of the components. Such tablets contain conventional tableting lubricants and other pharmaceutical excipients, and these must meet the criteria set forth above. It should be noted that many hydrocolloids used for the process 20 of the present invention are also usually used as tablet binder in the preparation of pharmaceutical compositions and as such are used in the form of a solution or dispersion in a suitable solvent in the tablet formulation.

Ifølge den foreliggende opfindelse anvendes hydrokolloidbestanddelen i 25 præparatet dog i tør form, hvorved den er udelukket fra den våde granuleringsteknik, såfremt denne anvendes. En mindre procentdel af hydrokolloidbestanddelen kan dog anvendes som tabletbindemiddel i overensstemmelse med sædvanlig teknik. Såfremt et sådant hydrokol-loid anvendes på sædvanlig måde som tabletbindemiddel og i form af 30 en opløsning forenes med præparatet, letter et sådant hydrokolloid ikke de således fremstillede tabletters svømmeevne.However, according to the present invention, the hydrocolloid component of the composition is used in dry form, thereby being excluded from the wet granulation technique, if used. However, a smaller percentage of the hydrocolloid component can be used as a tablet binder in accordance with conventional techniques. If such a hydrocolloid is used in the usual manner as a tablet binder and in the form of a solution to be combined with the composition, such hydrocolloid does not facilitate the swimming ability of the tablets thus prepared.

Tabletter fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse kan fremstilles på sædvanlige tabletteringsmaskiner. Det er 148344 10 dog kritisk, at tabletterne ikke presses til en sådan hårdhedsgrad, at de i kontakt med mavesaften ikke opnår en vægtfylde på mindre end 1. ifølge den foreliggende opfindelse kan også tabletter, som oprindeligt har en massefylde på mere end 1, svømme på mavesaften.Tablets prepared by the method of the present invention may be prepared on conventional tableting machines. However, it is critical that the tablets are not pressed to such a degree of hardness that, in contact with the gastric juice, they do not reach a density of less than 1. According to the present invention, tablets which have a density of more than 1 may also swim. on the stomach.

5 Denne svømmeevne er resultatet af kombinationen af på den ene side en forøgelse af tablettens volumen, når den kommer i kontakt med mavesaften, fremkaldt af hydratiseringen og opkvældningen af hydro-kolloidpartiklerne på tabletoverfladen, og på den anden side den kendsgerning, at de i tabletkernen dannede indre tomme rum forbliver 10 tørre på grund af det af hydrokolloidpartiklerne dannede lag. Det er derfor kritisk, at tabletterne ikke presses til en sådan hårdhedsgrad, at porøsiteten rent stofligt reduceres, og at hydrokolloidpartiklerne på tabletoverfladen ikke sammenpresses så tæt, at en hurtig hydrati-sering forsinkes. Det skal iagttages, at den maksimale hårdhed, som 15 kræves for at opnå en tablet med en begyndelsesmassefylde på mere end 1, både afhænger af den nævnte begyndelsesmassefylde hos denne tablet samt af tablettens størrelse. Hårdheden for en tablet ligger mellem det maksimum, ved hvilket der kan fremstilles en svømmende tablet af den beskrevne art, og et minimum, som er betinget af 20 den farmaceutiske stabilitet under forsendelse og lignende. Dette hårdhedsområde kan let bestemmes ved farmaceutiske standard-hårdhedsmålinger, hvorhos samtidig svømmeevnen hos tabletprøver af forskellig hårdhed afprøves i mavesaft. Sådanne bestemmelser ligger inden for fagmandens område.This swimming ability results from the combination of, on the one hand, an increase in the volume of the tablet as it comes into contact with the gastric juice, caused by the hydration and swelling of the hydrocolloid particles on the tablet surface, and on the other hand the fact that in the tablet core formed inner voids remain 10 dry due to the layers formed by the hydrocolloid particles. It is therefore critical that the tablets are not pressed to such a degree of hardness that the porosity is purely reduced and that the hydrocolloid particles on the tablet surface are not compressed so tightly that a rapid hydration is delayed. It should be noted that the maximum hardness required to obtain a tablet having an initial density greater than 1 depends both on the said initial density on this tablet and on the size of the tablet. The hardness of a tablet lies between the maximum at which a swimming tablet of the type described can be prepared and a minimum which is conditioned by the pharmaceutical stability during shipment and the like. This hardness range can be easily determined by standard pharmaceutical hardness measurements, whereby the bathing ability of different hardness tablet samples is tested in gastric juice. Such provisions are within the scope of those skilled in the art.

25 Som aktivstof eller aktivstof kombination til retard præparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse kan der anvendes alle, som er egnet til oral administration, og som medicinsk er anbefalet til retardterapi. Det er klart, at den foreliggende opfindelse ikke kun er begrænset til bestemte aktivstoffer eller klasser af aktiv-30 . stoffer. Desuden er retardpræparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse ikke begrænset til medikamenter, som hovedsagelig absorberes i maven, da det har vist sig, at præparatet ligeledes er virksomt i forbindelse med medikamenter, som absorberes af tarmene, fx chlorpheniraminmaleat. Retardpræpa ratet 35 fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse kan 148344 η naturligvis ikke anvendes til medikamenter, som er følsomme over for syre. Til de forskellige klasser aktivstoffer, som fordelagtigt kan administreres i retardform, hører fx antibiotika, fx penicillin, cephalosporin og tetracyclin, catecholaminer, fx epinephrin og amphetami-5 nerne, og analgetika såsom aspirin, sedativer såsom barbiturater, antikonvulsiva, anti-brækningsmidler, muskelrelaxerende stoffer, hypotensiva og vitaminer. Det er beskrevet i litteraturen, at den af aspirin fremkaldte irritation i maven skyldes kontakten mellem dette meget sure stof og mavevæggene. Af denne grund er præparatet 10 fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse særlig egnet til administration af aspirin, da præparatet forbliver svømmende på mavesaften.As an active ingredient or active ingredient combination for the retard preparation prepared by the method of the present invention, anyone suitable for oral administration and medically recommended for retard therapy may be used. It is to be understood that the present invention is not limited to particular active substances or classes of active-30. substances. In addition, the retarding composition prepared by the method of the present invention is not limited to drugs which are mainly absorbed in the stomach, since it has been found that the preparation is also effective in connection with drugs absorbed by the intestine, e.g., chlorpheniramine maleate. Of course, the retard preparation 35 prepared by the method of the present invention cannot be used for drugs that are sensitive to acid. The various classes of active substances which may be advantageously administered in retard form include, for example, antibiotics, e.g., penicillin, cephalosporin and tetracycline, catecholamines, e.g., epinephrine and amphetamines, and analgesics such as aspirin, sedatives such as barbiturates, anticonvulsants, anti-vomiting agents, drugs, hypotensives and vitamins. It is described in the literature that the irritation caused by aspirin in the stomach is due to the contact between this very acidic substance and the stomach walls. For this reason, the composition 10 prepared by the method of the present invention is particularly suitable for the administration of aspirin, since the composition remains swimming on the gastric juice.

En klasse aktivstoffer, som er særlig velegnede til retardpræpa rater ifølge den foreliggende opfindelse, er benzodiazepiner, fx chlordiazep-15 oxid, diazepam, oxazepam og bromazepam. Det er bemærkelsesværdigt, at der efter et antal resultatløse forsøg med kendte retardmekanismer er opnået overlegne resultater med chlordiazepoxid under anvendelse af præparatet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse. Ved benzodiazepinerne anvendes præparaterne fremstillet 20 ved fremgangsmåden ifølge den foreliggende opfindelse fortrinsvis i form af en kapsel.One class of active substances particularly suitable for retarding preparations according to the present invention are benzodiazepines, for example, chlordiazepoxide, diazepam, oxazepam and bromazepam. It is noteworthy that, after a number of unsuccessful experiments with known retarding mechanisms, superior results were obtained with chlordiazepoxide using the preparation prepared by the method of the present invention. In the benzodiazepines, the compositions prepared by the method of the present invention are preferably used in the form of a capsule.

Retardpræpa ratet fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse er ligeledes særlig velegnet til administration af aktivstoffer, som kun absorberes i maven eller i den øvre del af 25 tarmene, fx jernsalte såsom jernfumarat, eller til aktivstoffer, som udøver deres terapeutiske virkning i maven, fx antacida såsom oxider, hydroxider og carbonater af magnesiumaluminiumhydroxid og magnesiumtrisilicat. Såfremt sådanne stoffer danner carbondioxid, opfanges boblerne af det hydratiserede ydre lag, og de forøger 30 således præparatets svømmeevne. Andele af carbondioxid-afgivende baser kan også anvendes i præparater, som ikke er antacida, for at forbedre svømmeevnen. Det ligger endvidere inden for rammerne af den foreliggende opfindelse at administrere det hydrodynamisk udlignede præparat fremstillet ved fremgangsmåden ifølge den foreliggende 35 opfindelse som det ene lag i en to-lagstablet. Det andet lag indeholder det aktive stof i et sædvanligt præparat, der er fri for de bestandde- U8344 12 le, som forsinker afgivelsen af det aktive stof. Denne enestående tablet bevirker efter indtagelsen deraf en omgående frigørelse af aktivstof og dannelse af et svømmende lag, som indeholder det aktiv-stof, som skal frigøres, og som holdes tilbage i maven i et tidsrum.The retardation formulation prepared by the method of the present invention is also particularly suitable for the administration of active substances which are absorbed only in the stomach or upper part of the intestine, e.g., iron salts such as iron fumarate, or for active substances which exert their therapeutic effect in the stomach, e.g. antacids such as oxides, hydroxides and carbonates of magnesium aluminum hydroxide and magnesium trisilicate. If such substances form carbon dioxide, the bubbles are captured by the hydrated outer layer, thus increasing the swimming ability of the composition. Proportions of carbon dioxide-releasing bases can also be used in non-antacid preparations to improve swimming performance. Further, it is within the scope of the present invention to administer the hydrodynamically equalized composition prepared by the process of the present invention as one layer in a two-layer tablet. The second layer contains the active substance in a conventional composition which is free of the constituents which delay the release of the active substance. This unique tablet, upon ingestion thereof, causes immediate release of active substance and formation of a swimming layer containing the active substance to be released and retained in the stomach for a period of time.

5 En sådan enestående to-lagstablet er særlig velegnet til administration af antacida.Such a unique two-layer tablet is particularly well suited for antacid administration.

Det har vist sig, at retardpræparater fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse forbliver svømmende på mavesaften, uanset, om der forekommer tensider eller næringsmidler. Det har 10 endvidere vist sig, at aktiviteten i et aktivstof ved anvendelse af retard præparatet ifølge den foreliggende opfindelse er uafhængig af det enkelte aktivstofs absorptionssted. Hos hunde, til hvilke der blev administreret bariumsulfatholdige kapsler i et præparat fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse, kunne det ved 15 røntgenstråleteknik vises, at præparatet forblev svømmende på mavesaften og ikke klæbede til niavevæggene.It has been found that retarding preparations prepared by the method of the present invention remain swimming on the gastric juice, regardless of whether surfactants or nutrients are present. It has further been found that the activity of an active substance using the retard composition of the present invention is independent of the absorption site of the individual active substance. In dogs to which barium sulphate-containing capsules were administered in a composition prepared by the method of the present invention, it could be shown by X-ray technique that the composition remained swimming on the gastric juice and did not adhere to the niave walls.

Opfindelsen belyses nærmere ved nedenstående eksempler: EKSEMPEL 1The invention is further illustrated by the following examples: EXAMPLE 1

En chlordiazepoxidholdig kapsel fremstilles på følgende måde: 20 Bestanddele mg/kapselA chlorodiazepoxide-containing capsule is prepared as follows: 20 Ingredients mg / capsule

Chlordiazepoxid 30,6Chlordiazepoxide 30.6

Hydroxypropylmethylcellulose, 4000 cps 100,4Hydroxypropyl methyl cellulose, 4000 cps 100.4

Vandfri lactose 30,0 25 Sterotex K* 58,0Anhydrous lactose 30.0 Sterotex K * 58.0

Talkum 50,0Talc 50.0

Magnesiumstearat 6,0Magnesium stearate 6.0

Totalvægt 275,0 30 * En hydreret bomuldsfrøolie fremstillet af Capital City Products,Total Weight 275.0 30 * A hydrated cotton seed oil manufactured by Capital City Products,

Columbus, Ohio, USA.Columbus, Ohio, USA.

13 14 8 3 4 Λ13 14 8 3 4 Λ

Chlordiazepoxidet, methylcellulosen og lactosen blandes homogent i et egnet blandeapparatur, hvorefter blandingen ved høj hastighed ledes gennem en desintegrator. Herefter sættes Sterotex K, talkum og magnesiumstearat til blandingen, og der blandes i yderligere 5 mi-5 nutter. Blandingen ledes derefter ved høj hastighed gennem en desintegrator. Blandings- og formalingstrinnet gentages, og blandingen fyldes i uigennemsigtige rosa kapsler af størrelse 2. De således vund-ne kapsler anvendes til bestemmelse af rigørelseshastigheden in vitro i kunstig mavesaft eller ”rotating-bottle"-teknikken.The chlorodiazepoxide, methylcellulose and lactose are homogeneously mixed in a suitable mixing apparatus, after which the mixture is passed at high speed through a disintegrator. Subsequently, Sterotex K, talc and magnesium stearate are added to the mixture and mixed for an additional 5 minutes. The mixture is then passed at high speed through a disintegrator. The mixing and grinding steps are repeated and the mixture is filled into opaque pink capsules of size 2. The capsules thus obtained are used to determine the rate of in vitro stirring in artificial gastric juice or the rotating-bottle technique.

10 Resultaterne af disse forsøg fremgår af nedenstående tabel I:The results of these experiments are shown in Table I below:

Tabel ITable I

Procent frigjort aktivstof Mavesaft Tid (timer) (pH-værdi 1,2) 15 ” ~~0 0 1 39 2 61 3,5 86 5 94 20 7 100Percent active substance Stomach juice Time (hours) (pH 1.2) 15 ”~ 0 0 1 39 2 61 3.5 86 5 94 20 7 100

Accelererede kemiske stabilitetsforsøg ved 55°C, ved lysforsøg og ved 37°C/85%'s relativ luftfugtighed, i begge tilfælde ravfarvede og poly-ethylenflasker med silicagelprop viser, at kapslerne har tilfredsstillende stabilitet.Accelerated chemical stability tests at 55 ° C, at light tests and at 37 ° C / 85% relative humidity, in both cases amber and polyethylene bottles with silica gel stopper, show that the capsules have satisfactory stability.

25 Prøver af de ovenfor anførte kapsler afprøves in vitro på mennesker i sammenligning med tre sædvanlige kapsler, som hver indeholder 10 mg chlordiazepoxid og administreres ved 0, 4 og 8 timer. Resultaterne fremgår af nedenstående tabel II.25 Samples of the above capsules are tested in humans in vitro as compared to three conventional capsules, each containing 10 mg of chlordiazepoxide and administered at 0, 4 and 8 hours. The results are shown in Table II below.

Tabel IITable II

1483 44 141483 44 14

Tid til opnåelse Blodspejlets Totalareaf af maksimalt højde (ϊ/rnl) under blod- blodspejl (timer) spejlskurven 5 _:___Time to achieve Blood level Total area of maximum height (ϊ / rnl) below blood level (hours) mirror curve 5 _: ___

Retardkapsei, 30 mg middelværdi 9,6 1,06 27,2 bredde (4-15) (0,064-1,87) (20,2-34,0) 10 antal forsøgspersoner 6 6 6Retard capsule, 30 mg mean 9.6 1.06 27.2 width (4-15) (0.064-1.87) (20.2-34.0) 10 subjects 6 6 6

Kapsler med 10 mg indtaget ved 0, 4 og 8 timer 15 middelværdi 9,4 1,04 24,5 bredde* (5,5-15) (0,64-1,73) (10,1-60,6) antal forsøgspersoner 17 17 17 * "bredde" angiver det område, der afgrænses af hhv. mindste og 20 største værdi10 mg capsules taken at 0, 4 and 8 hours mean 9.4 1.04 24.5 width * (5.5-15) (0.64-1.73) (10.1-60.6) number of subjects 17 17 17 * "width" indicates the area bounded by respectively. minimum and 20 largest value

Af de anførte data fremgår det, at retardkapslernes resultat stemmer meget godt overens med administration af kapsler med enkeltdoser.From the data presented, it appears that the results of the retard capsules are very consistent with the administration of single-dose capsules.

EKSEMPEL 2EXAMPLE 2

En antianæmisk retardkapsei fremstilles på følgende måde: 25 Bestanddele mg/kapse!An anti-anemic retard capsule is prepared as follows: 25 Ingredients mg / capsule!

Jernfumarat 150Iron fumarate 150

Hydroxypropylmethylcellulose, 4000 cps 100Hydroxypropyl methyl cellulose, 4000 cps 100

Lactose 100 30 Talkum 40Lactose 100 30 Talc 40

Magnesiumstearat 10Magnesium stearate 10

Totalvægt 400 U 8344 15Total weight 400 U 8344 15

Jernfumaratet, hydroxypropylmethylcellulosen og lactosen blandes homogent og ledes med moderat hastighed gennem en des integrator.The iron fumarate, hydroxypropyl methyl cellulose and lactose are homogeneously mixed and passed at a moderate rate through a des integrator.

Talkummet og magnesiumstearatet blandes med en alikvot af den oprindelige blanding, sigtes gennem en 60 mesh sigte og sættes der-5 efter til den resterende del af den oprindelige pulverblanding. Præparatet blandes derefter i yderligere 15 minutter og fyldes i kapsler af størrelse nr. 1.The talc and magnesium stearate are mixed with an aliquot of the original mixture, sieved through a 60 mesh screen, and then added to the remaining portion of the original powder mixture. The preparation is then mixed for a further 15 minutes and filled into size # 1 capsules.

Opløsningshastigheden for kapslen afprøves i mavesaft efter den modificerede NF-metode ved 40 omdrejninger pr. minut (NF = National 10 Formulary XIII; modifikationen er, at der kun anvendes kunstig mavesaft, pH=1,2, og at kun opløsningen, men ikke remanensen, analyseres). Resultaterne er anført i nedenstående tabel III.The dissolution rate of the capsule is tested in gastric juice according to the modified NF method at 40 rpm. per minute (NF = National 10 Formulary XIII; the modification is that only artificial gastric juice, pH = 1.2 is used and only the solution, but not the residue, is analyzed). The results are given in Table III below.

Tabel IIITable III

Procentdel frigjort aktivstof 15 MavesaftPercentage of active substance released 15 Stomach juice

Tid, timer (pH-værdi 1,2) 0 0 1 45 20 2 85,7 3 98,6Time, hours (pH 1.2) 0 0 1 45 20 2 85.7 3 98.6

Kapslen forbliver svømmende under forsøget. Frigørelsen af jern-fumarat fra kapsler, som afprøves i et medium med ændret pH-værdi, er meget ringe på grund af jernfumarats ringe opløselighed i medier 25 med relativt høj pH-værdi. Sådanne forsøgsresultater viser virkningen af jernfumarat i konventionelle retardpræparater, som ikke tilbageholdes i maven.The capsule stays swimming during the experiment. The release of iron fumarate from capsules tested in a medium of altered pH is very poor due to the poor solubility of iron fumarate in media of relatively high pH. Such experimental results show the effect of iron fumarate in conventional retardation preparations which are not retained in the stomach.

Antacida-retardkapsler fremstilles på følgende måde: 16 EKSEMPEL 3 148344Antacid retard capsules are prepared as follows: 16 EXAMPLE 3 148344

Bestanddele mg/kapsel 5 FMA-11* 254,7Ingredients mg / capsule 5 FMA-11 * 254.7

Magnesiumoxid, let 127,0Magnesium oxide, slightly 127.0

Vandholdig lactose 20,3Aqueous lactose 20.3

Hydroxypropylmethylcellulose, 4000 cps 63,0Hydroxypropyl methyl cellulose, 4000 cps 63.0

Karayagummi, Stein Hall 31,0 10 Talkum, tabletkvalitet 24,0Karaya rubber, Stein Hall 31.0 10 Talc, tablet quality 24.0

Magnesiumstearat 5,0Magnesium stearate 5.0

Totalvægt 525,0 * Aluminiumhydroxid-magnesiumcarbonat-copræcipitat, Reheis Co., 15 Berkley Heights, New Jersey, USA.Total weight 525.0 * Aluminum hydroxide magnesium carbonate coprecipitate, Reheis Co., 15 Berkley Heights, New Jersey, USA.

FMA-11, det lette magnesiumoxid, lactose og magnesiumstearat blandes i 10 minutter i et egnet blandeapparatur og ledes derefter gennem en desintegrator. Blandingen sønderdeles og briketteres derefter. Pressegodset findeles i en desintegrator, hvorpå de vundne korn blandes 20 grundigt med de øvrige bestanddele, hvorefter blandingen på sædvanlig måde under anvendelse af en kapselfyldemaskine fyldes i kapsler af størrelse nr. 0.The FMA-11, the light magnesium oxide, lactose and magnesium stearate are mixed for 10 minutes in a suitable mixer and then passed through a disintegrator. The mixture is then decomposed and briquetted. The compaction is comminuted in a disintegrator, whereupon the obtained grains are thoroughly mixed with the other ingredients, after which the mixture is loaded into conventional size 0 capsules in the usual manner.

Da der ikke findes en officiel specifik metode til afprøvning af re-tard-antacida-præparater, afprøves kapslerne på følgende måde: 25 En kapsel hældes i en kolbe indeholdende 300 ml 0,1N saltsyre, hvorefter kolben lukkes og roteres med 40 omdrejninger pr. minut. Efter en bestemt tid udtages en 50 ml's prøve, og den titreres med 0,1N natriumhydroxidopløsning til pH-værdi 3,5, hvilken værdi er det neutral isatronspunkt, der i "Federal Register" er angivet for neutrali-30 sationsevnen for syrer. De vundne resultater er anført i tabel IV.As there is no official specific method for testing retard antacid preparations, the capsules are tested as follows: 25 A capsule is poured into a flask containing 300 ml of 0.1N hydrochloric acid, after which the flask is closed and rotated at 40 rpm. minute. After a certain time, a 50 ml sample is taken and titrated with 0.1 N sodium hydroxide solution to pH 3.5, which is the neutral isotron point indicated in the Federal Register for the neutralization ability of acids. The results obtained are listed in Table IV.

Kapslerne forbliver svømmende under forsøget.The capsules remain swimming during the experiment.

Tabel IVTable IV

17 14834/.17 14834 /.

Tid Frigørelse af antacidet 5 1. time 42,1% 2. time 96,7% 3. time 104% EKSEMPEL 4Time Release of the Antacid 5 First Hour 42.1% 2nd Hour 96.7% 3rd Hour 104% EXAMPLE 4

Aspirin-retard kapsler fremstilles på følgende måde: 10 Bestanddele mg/kapselAspirin-retard capsules are prepared as follows: 10 Ingredients mg / capsule

Acetylsalicylsyre, mikroniseret 400Acetylsalicylic acid, micronized 400

Vandfrit dicalciumphosphat 20Anhydrous dicalcium phosphate 20

Hydroxypropylcellulose 40 15 Traganth 100Hydroxypropyl Cellulose 40 Traganth 100

Totalvægt 560Total weight 560

Alle bestanddele med undtagelse af traganthen genemblandes grundigt og ledes gennem en des integrator. Blandingen granuléres med vand-20 frit ethanol, tørres og formales. Traganthen blandes derefter med blandingen, og hele mængden fyldes i kapsler af størrelse nr. 0. Det har vist sig, at kapslerne forbliver svømmende på mavesaften.All ingredients except the tragacanth are thoroughly mixed and passed through a des integrator. The mixture is granulated with anhydrous ethanol, dried and ground. The tragacanth is then mixed with the mixture and the entire amount is filled into size 0 capsules. It has been found that the capsules remain swimming on the gastric juice.

Riboflavinholdige retardkapsler fremstilles på følgende måde: 18 EKSEMPEL 5 148344Riboflavin-containing retard capsules are prepared as follows: EXAMPLE 5 148344

Bestanddel mg/kapsel 5 Riboflavin type S* 15Ingredient mg / capsule 5 Riboflavin type S * 15

Hydroxypropylmethylcellulose 110Hydroxypropyl methylcellulose 110

Lactose 120Lactose 120

Talkum 30Talc 30

Magnesiumstearat 5 10 _Magnesium stearate 5 10 _

Totalvægt 280 * En type riboflavin, som er ejendommelig ved, at den er mindre opløselig og mere krystallinsk end riboflavinphosphat.Total weight 280 * A type of riboflavin which is peculiar in that it is less soluble and more crystalline than riboflavin phosphate.

Alle bestanddele blandes grundigt og fyldes i gelatinekapsler nr. 2.All ingredients are thoroughly mixed and filled into gelatin capsules # 2.

15 Frigørelseshastigheden i mavesaften konstateres efter den modificerede NF-metode ved 40 omdrejninger pr. minut. De vundne resultater fremgår af nedenstående tabel V.15 The rate of release in the gastric juice is determined by the modified NF method at 40 rpm. minute. The results obtained are shown in Table V below.

Tabel VTable V

Tid (timer) % frigjort 20 aktivstof 1/2 34 1 45,3 2 62,6 25 3 1/2 84,7 5 92,6Time (hours)% of released active ingredient 1/2 34 1 45.3 2 62.6 25 3 1/2 84.7 5 92.6

Riboflavinholdige retardkapsler fremstillet på følgende måde: 19 EKSEMPEL 6Riboflavin-containing retard capsules prepared as follows: 19 EXAMPLE 6

U83UU83U

Bestanddele mg/kapsel 5 Riboflavin, type S 15Ingredients mg / capsule 5 Riboflavin, type S 15

Guargummi 100Guar gum 100

Mannitolpulver 75Mannitol powder 75

Majsstivelse 60Corn starch 60

Traganth 30 10 _Traganth 30 10 _

Totalvægt 280Total weight 280

Alle bestanddele med undtagelse af traganthen sammenhældes og blandes i et egnet blandeapparatur. Den resulterende blanding granuleres med en blanding af lige dele vand og ethylalkohol. Det våde granulat 15 ledes gennem en des integrator. Granulatet tørres derefter og ledes igen gennem en desintegrator. Traganthen sættes tør til granulatet, hvorefter alt blandes grundigt og fyldes i gelatinekapsler af størrelse nr. 2. Frigørelseshastigheden for kapslerne bestemmes efter den modificerede NF-metode ved 40 omdrejninger pr. minut. Resultaterne 20 er anført i nedenstående tabel VI.All components except the tragacanth are combined and mixed in a suitable mixing apparatus. The resulting mixture is granulated with a mixture of equal parts water and ethyl alcohol. The wet granule 15 is passed through a des integrator. The granulate is then dried and passed through a disintegrator again. The tragacanth is dried to the granulate, after which everything is thoroughly mixed and filled into size 2 gelatin capsules. The release rate of the capsules is determined according to the modified NF method at 40 rpm. minute. The results 20 are given in Table VI below.

Tabel VITable VI

Tid (timer) % frigjort aktivstof 25 1/2 54,5 1 59,5 2 65,6 3 1/2 78,5 5 88,8 30 Kapslerne forbliver svømmende under forsøget.Time (hours)% of released active substance 25 1/2 54.5 1 59.5 2 65.6 3 1/2 78.5 5 88.8 30 The capsules remain swimming during the experiment.

20 EKSEMPEL 7 148344EXAMPLE 7 148344

Riboflavinholdige tabletter fremstilles ud fra nedenstående formulering:Riboflavin-containing tablets are prepared from the following formulation:

Bestanddele mg/tablet 5 _ _Ingredients mg / tablet 5 _

Riboflavin-5'-phosphatnatrium * 21,4Riboflavin-5'-phosphate sodium * 21.4

Methylcelluiose, 4000 cps 70,0Methyl cellulose, 4000 cps 70.0

Mannitol 25,0Mannitol 25.0

Natriumcarboxymethylcellulose, højviskos 110,0 10 Hydroxypropylmethylcellulose, 4000 cps 60,0Sodium Carboxymethyl Cellulose, High Viscosity 110.0 10 Hydroxypropyl Methyl Cellulose, 4000 cps 60.0

Polyvinylpyrrolidon 20,0Polyvinylpyrrolidone 20.0

Ethylcellulose 10 cps 80,6Ethyl cellulose 10 cps 80.6

Talkum 10,0Talc 10.0

Magnesiumstearat 3,0 15 __Magnesium stearate 3.0 15 __

Totalvægt 400,0 * Indeholder 2% vægtoverskud.Total weight 400.0 * Contains 2% excess weight.

Riboflavin og natriumcarboxymethylcellulose gennemblandes grundigt og granuleres med polyvinylpyrrolidon i en 10 vægtprocents opløsning 20 i alkohol. De øvrige bestanddele med undtagelse af talkum og magnesiumstearat gennemblandes grundigt og ledes gennem en desintegra-tor. Granulatet forenes med blandingen og gennemblandes grundigt.Riboflavin and sodium carboxymethyl cellulose are thoroughly mixed and granulated with polyvinylpyrrolidone in a 10% by weight solution 20 in alcohol. The other ingredients except talc and magnesium stearate are thoroughly mixed and passed through a disintegrator. The granulate is combined with the mixture and thoroughly mixed.

Talkum og magnesiumstearatet tilsættes derefter, og hele blandingen blandes homogent og presses til tabletter under anvendelse af bikon-25 vekse stempler. Tabletterne presses til en hårdhed på 4-6 Strong-Cobb-enheder (SCE), og det har vist sig, at hårdheden ikke må overstige 10 SCE. Det har vist sig, at tabletter med 4 SCE straks svømmer på kunstig mavesaft, hvorimod tabletter med 6 SCE temporært synker, før de når overfladen. Tabletter med 10 SCE er ikke 30 svømmende.Talc and magnesium stearate are then added and the whole mixture is homogeneously mixed and pressed into tablets using biconvex plungers. The tablets are pressed to a hardness of 4-6 Strong-Cobb Units (SCE) and it has been found that the hardness must not exceed 10 SCE. It has been found that tablets with 4 SCE immediately swim on artificial gastric juice, whereas tablets with 6 SCE temporarily sink before reaching the surface. Tablets with 10 SCE are not 30 swimming.

14 8 3 /s Λ 2114 8 3 / s Λ 21

Til kontrolformål fyldes gelatinekapsler med nedenstående præparat:For control purposes, gelatin capsules are filled with the following preparation:

Bestanddele mg/kapselIngredients mg / capsule

Riboflavin-5'-phosphatnatrium 21,4 5 Majsstivelse 73,6Riboflavin-5'-phosphate sodium 21.4 5 Corn starch 73.6

Vandholdig lactose 150,0Aqueous lactose 150.0

Talkum 30,0Talc 30.0

Magnesiumstearat 5,0 10 Totalvægt 280,0Magnesium stearate 5.0 Total weight 280.0

Der udføres in vitro-frigørelsesforsøg i mavesaft efter den modificerede NF-metode ved 40 omdrejninger pr. minut. Resultaterne fremgår af nedenstående tabel VII.In vitro release experiments are performed in gastric juice according to the modified NF method at 40 rpm. minute. The results are shown in Table VII below.

Tabel VIITable VII

15 % frigjort aktivstof15% released active substance

Tid (timer) Middelværdi Bredde 1/2 32 27-40 1 49 39-59 20 2 76 55-87 31/2 91 87-95 5 104 95-108Time (hours) Mean Width 1/2 32 27-40 1 49 39-59 20 2 76 55-87 31/2 91 87-95 5 104 95-108

Til sammenligning tjener, at 100% af det riboflavin, som indeholdes i kontrolkapslerne, frigøres i løbet af 1/2 time.In comparison, 100% of the riboflavin contained in the control capsules is released within 1/2 hour.

25 ("Bredde" angiver det område, der afgrænses af hhv. mindste og størsteværdi).25 ("Width" indicates the area bounded by minimum and maximum values, respectively).

Med fem frivillige personer. udføres et forsøg in vivo. Præparatet administreres 1-1/2 time efter morgenmaden. Som index for riboflavin-absorptionen analyseres urinprøver periodisk. Resultaterne er anført i 30 nedenstående tabel VIII.With five volunteers. an experiment is performed in vivo. The preparation is administered 1-1 / 2 hours after breakfast. As an index of riboflavin absorption, urine samples are analyzed periodically. The results are set out in Table VIII below.

148344 22148344 22

Tabel VI IITable VI II

Tidsinterval (timer) mg udskilt riboflavin (hos mennesker)Time interval (hours) mg of secreted riboflavin (in humans)

Kontrolkapsel Retardkapsel 5 0-2 2,03 0,98 2-4 2,11 1,79 4-6 0,84 1,14 6-8 0,47 1,14 8-12 0,84 3,23 10 12-24 0,38 1,86 6,87 10,14 % udskilt riboflavin på 25 timer 44% 67,5% 15 Resultaterne af dette forsøg viser klart, at de riboflavinholdige re-tardtabletter tilbageholdes i maven, da absorption af riboflavin kun foregår ved den ende af tyndtarmen, der vender mod maven. Når riboflavin administreres i sædvanlig kapselform, når kapslen, som jo ikke tilbageholdes i maven, meget hurtigt til stedet for resorptionen, 20 men fjerner sig også igen temmelig hurtigt. På tilsvarende måde kan der iagttages en relativt hurtig stigning og et relativt hurtigt fald i riboflavinspejlet i urinen (som er et mål for kroppens optagelse af riboflavin). Ved administration af riboflavin med et præparat, der er fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse, 25 udløses riboflavinet i maven fra tabletten, som ikke kan forlade maven. Riboflavin, der som sagt ikke resorberes i maven, når derefter temmelig jævnt sammen med de stoffer, der forlader maven, ned i tyndtarmen, hvor det optages af kroppen. Det langsomt stigende, men længere varende riboflavinindhold i urinen svarer til denne virk-30 ningsmekanisme. Resultaterne viser klart, at riboflavinet fra retard-tabletterne frigøres på det egnede absorption s sted over et forlænget tidsrum. De to udprægede "spidser" af riboflavin fra tabletten kan være fremkaldt af den enterohepatiske cirkulation, som, ifølge litteraturen, kan tilskrives en koncentrationsafhængig relation til leverens 35 behandling af riboflavin.Control capsule Retard capsule 5 0-2 2.03 0.98 2-4 2.11 1.79 4-6 0.84 1.14 6-8 0.47 1.14 8-12 0.84 3.23 10 12 -24 0.38 1.86 6.87 10.14% 25 hours excreted riboflavin 44% 67.5% 15 The results of this experiment clearly show that the riboflavin-containing retard tablets are retained in the stomach as absorption of riboflavin only occurs at the end of the small intestine facing the abdomen. When riboflavin is administered in the usual capsule form, the capsule, which is not retained in the stomach, reaches the site of resorption very quickly, but also recovers fairly quickly. Similarly, a relatively rapid increase and a relatively rapid decrease in the level of riboflavin in the urine (which is a measure of the body's absorption of riboflavin) can be observed. When administering riboflavin with a preparation prepared by the method of the present invention, the riboflavin is released into the stomach from the tablet which cannot leave the stomach. Riboflavin, which, as I said, is not resorbed in the stomach, then reaches fairly evenly with the substances that leave the stomach down into the small intestine where it is absorbed by the body. The slowly increasing but longer lasting riboflavin content in the urine corresponds to this mechanism of action. The results clearly show that the riboflavin from the retard tablets is released at the appropriate absorption site over an extended period of time. The two distinct "spikes" of riboflavin from the tablet may be induced by the enterohepatic circulation, which, according to the literature, can be attributed to a concentration-dependent relationship to the liver's treatment of riboflavin.

EKSEMPEL 8EXAMPLE 8

Aspirinholdige retardtabletter fremstilles ud fra følgende granulater; 23 14834*.Aspirin-containing retard tablets are prepared from the following granules; 23 14834 *.

Granulat A mg 5 Acetylsalicylsyre 500Granules A mg 5 Acetylsalicylic acid 500

Hydroxypropylmethylcellulose, 400 cps 125Hydroxypropyl methyl cellulose, 400 cps 125

Hydroxypropylmethylcellulose, 15 cps 3Hydroxypropyl methyl cellulose, 15 cps 3

Totalvægt 628Total weight 628

10 Granulat BGranules B

Fældet calciumcarbonat 65Precipitated calcium carbonate 65

Magnesiumcarbonat 20Magnesium carbonate 20

Mannitol 10 15 Carboxymethylcellulose 2Mannitol 10 Carboxymethyl cellulose 2

Totalvægt 97Total weight 97

De to granulater blandes homogent og presses med 5 mg talkum til tabletter med en hårdhed på 5-6 SCE. Hårdheden bør ikke overstige 20 11 SCE, hvis tabletterne skal forbliver svømmende.The two granules are homogeneously mixed and pressed with 5 mg of talc to tablets with a hardness of 5-6 SCE. The hardness should not exceed 20 11 SCE if the tablets are to remain swimming.

EKSEMPEL 9EXAMPLE 9

En antacida-retard-to-lagstablet kan fremstilles på følgende måde: 1 li 8 3 4 k 24An antacid retard two-layer tablet can be prepared as follows: 1 li 8 3 4 k 24

Lag A: omgående frigørelseLayer A: Immediate release

Bestanddele mg/tablet FMA-11* 160,0 5 Methylcellulose 5,8Ingredients mg / tablet FMA-11 * 160.0 5 Methylcellulose 5.8

Magnesiumoxid 80,0Magnesium oxide 80.0

Primojel®** 10,0Primojel® ** 10.0

Magnesiumstearat 2,5 10 Totalvægt 258,3 * Aluminiumhydroxid-magnesiumcarbonat-copræcipitat, Reheis Co.Magnesium stearate 2.5 Total weight 258.3 * Aluminum hydroxide magnesium carbonate coprecipitate, Reheis Co.

** Natriumcarboxymethylstivelse, E. Mendel & Co., Carmel, New York, USA.** Sodium Carboxymethyl Starch, E. Mendel & Co., Carmel, New York, USA.

FMA-11 og magnesiumoxidet blandes i et egnet blandeapparatur. Den 15 resulterende blanding granuleres under anvendelse af en 2,5%'s opløsning af methylcellulose i en blanding af lige dele vand og ethylal-kohol. Granulatet tørres natten over ved 60°C. Det tørre granulat formales, forenes med Primojel® og magnesiumstearat og blandes i 5 minutter. Den resulterende homogene blanding presses derefter på en 20 sædvanlig to-lagstabletpresse.The FMA-11 and the magnesium oxide are mixed in a suitable mixing apparatus. The resulting mixture is granulated using a 2.5% solution of methyl cellulose in a mixture of equal parts water and ethyl alcohol. The granulate is dried overnight at 60 ° C. The dry granulate is ground, combined with Primojel® and magnesium stearate and mixed for 5 minutes. The resulting homogeneous mixture is then pressed onto a conventional two-ply tablet press.

Lag B: forsinket frigørelseLayer B: delayed release

Bestanddele mg/tablet FMA-11* 170 25 Magnesiumoxid 85Ingredients mg / tablet FMA-11 * 170 25 Magnesium oxide 85

Methylcellulose, 4000 cps (tør) 90Methyl cellulose, 4000 cps (dry) 90

Methylcellulose, 4000 cps (våd) 6Methyl cellulose, 4000 cps (wet) 6

Ethylcellulose 90Ethyl cellulose 90

Stivelse til direkte kompression 35 30 Syloid® * 30Direct Compression Starch 35 30 Syloid® * 30

Magnesiumstearat 23Magnesium stearate 23

Totalvægt 529Total weight 529

Claims

148344 * Purified Silica - W.R. Grace & Co., Baltimore, Maryland, USA. The FMA-11 and the magnesium oxide are mixed in a suitable mixing apparatus. The resulting mixture is granulated with a solution of wet methyl cellulose in a mixture of equal parts water and ethyl alcohol, and then the granulate is dried overnight at 60 ° C. The obtained granulate is mixed with dry methyl cellulose, ethyl cellulose, the starch for direct compression and Syloid®, after which the whole mixture is thoroughly mixed for 10 minutes. The magnesium stearate is added and the mixture is stirred for a further 5 minutes. This mixture is pressed onto a conventional two-layer tablet machine together with layer A to a standard "concave capsule shape 0.79 cm x 1.91 cm". The acceptable hardness of the tablets is between 12 and 14 SCE and it has been found that the hardness must not exceed 16 SCE.

A sample of an antacida bilayer tablet thus prepared is placed in a beaker with gastric juice and then stirred with a low speed magnetic stirrer. It is found that the layer to be released immediately is separated and immediately in the form of fine particles sink to the bottom of the beaker. The retard layer stays swimming for 2 hours under slow release of active substance.

A process for preparing a sustained-release pharmaceutical composition wherein the active substance is admixed with hydrocolloids and therapeutically inert, pharmaceutically tolerable adjuvants and optionally edible fatty materials, after which a solid drug form is formed for oral use. administration such as a capsule or tablet, optionally a two-layer tablet, where one layer has not extended delivery, characterized in that 30 a) 0.1-90% by weight of one or more drug active substances is used;