SI8710590A8 - Continual process for pills forming - Google Patents

Description

KOMTIKUALNI POSTUPAK ZA TABL.BTIRA»AECOMTICUAL PROCEDURE FOR TABLET

1. Oblast tehnike1. Field of technology

Pronalazak .je iz oblasti farmaceutske industrije i odnosi se na kontinualni postupak za proizvodnju tableta. Prema internacionalno;] Klasifikaciji patenata pripada grupama A 61 J 5/10;The invention is from the pharmaceutical industry and relates to a continuous process for the manufacture of tablets. Internationally;] The classification of patents belongs to groups A 61 J 5/10;

A 61 K 9/22 i B 50 B 11/16.A 61 K 9/22 and B 50 B 11/16.

2· Tehnički problem2 · Technical problem

Pronalaskom se rošava tehnički problem postupka za kontinualno tabletiranje facmaceutskib smeša.The invention solves the technical problem of the process for the continuous tableting of facmaceutskib mixtures.

5· stanje tehnike5 · state of the art

Za sada se n farmaceut.skoj industriji za tabletiranje koriste stupnjeviti postupci koji koriste mašine sa oblikačem i matricom. Postupak u tom slučaju zahteva pripreraanje mase za tabletiranje prethodnim in Vezivnim mešanjem,pa je stoga sveukupno nzev višestepen .i. kcmplikovan.For the time being, the pharmaceutical tablet industry is using step-by-step processes using molding and die machines. The process in this case requires the preparation of the tabletting mass by prior in Binder mixing, and is therefore not multistage. kcmplikovan.

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4. Opis rešenja tehničkog problema sa primerima realizacije4. Description of the solution of a technical problem with examples of realization

Cilj pronalaska bio je razvijanje jednostavnog kontinualnog postupka za tabletiranje farmaceutskih smeša koje se mogu ekstrudirati. Prema pronalasku ovo je ostvareno tako što se smeša ekstrudira i dobivena traka, koja se može preoblikovati, presuje se izmedju dva valjka koji se medjusobno pokrecu u suprotnim pravcima, a koji imaju udubljenja locirana jedno naspram drugog č-iji oblik odredjuje oblik tableta. Ako se žele proizvesti tablete u obliku polulopti ili sa jednom ravnom stranom, jedan od omotača valjka se ostavlja da bude gladak.The object of the invention was to develop a simple continuous process for tabletting extruded pharmaceutical compositions. According to the invention, this is accomplished by extruding the mixture and obtaining a reshapable strip which is pressed between two rollers which move in opposite directions and which have recesses located opposite each other whose shape determines the shape of the tablets. If one wants to produce tablets in the shape of a hemisphere or with a flat face, one of the roll wrappers is left to be smooth.

Kako se mogu očekivati i slučajevi gde je potrebno predmešanje, pogodnije je umesto jednostavnog ekstrudera koristiti ekstruder sa mešanjem čime se eliminiše zahtevano predmešanje. Postupak prema pronalasku prikazan je na priloženoj šemi. Ekstruder sa mešanjem (1) može imati više nastavaka (2) za punjenje, u datom slučaju za odvojeno dodavanje čvrstih i tečnih sastojaka smeše, kao i cevasti nastavak za dovodjenje inertnog gasa (po pravilu azota) i/ili za degaziranje (odvodjenje gasa). Radi povečanja protola, ovaj ekstruder može imati više od jedne mlaznice (3).As can be expected in cases where mixing is required, it is more convenient to use a mixing extruder instead of a simple extruder, thus eliminating the required mixing. The process of the invention is shown in the attached Scheme. The mixing extruder (1) may have multiple filler extensions (2), optionally for the separate addition of solid and liquid constituents of the mixture, as well as a tubular extension for inert gas (as a rule of nitrogen) and / or for degassing (gas drainage) . To increase the protol, this extruder may have more than one nozzle (3).

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Da bi se obežbedio siguraa transport ekatrudirane trake i izbeglo njeno cepanje iaa mlaznice svrsishodno se ekstrudira koso na dole. Kajpogodniji ugao u datom slučaju zavisi od osobina proizvoda i načina kretanja (npr. od temperature ekstruzije i njene brzine).In order to ensure the safe transportation of the extruded strip and to avoid its splitting and the nozzle, it is purposefully extruded downward. The most appropriate angle in this case depends on the characteristics of the product and the mode of movement (eg the temperature of the extrusion and its velocity).

Oblikovanje se nadovezuje neposredno na proces ektruzije. Traka, koja se ektrudira i koja je jš uvek plastična, provodi se, u datom slučaju pomoču pogodnog Žleba za vodjenje, kroz jedan par faljaka (4), pri čemu omotačI oba ova valjka imaju udubljenja (5) koja leže jedna naspram drugih i koja na liniji dodira u vidu para obrazuju oblik željenih tableta, ϋ jednom pogodnoa obliku izvodjenja, naročito za lepljive mase, koje jače ili slabije prianjaju za zid kalupa (udubljenja 5), udubljenja su medjusobno povezana jednim otvorenim kanalom, tako da formirane tablete (6) ostaju medjueobno spojene preko kratke spojke (segmenta) (mesta za lomljenje tablete) (7). ka taj način, vec prema fleksibilnosti materijala, nastaju krute tvorevine ili tvorevine u obliku lan&ea perli koje sadrže vise tableta.The design complements the extrusion process directly. The extruding strip, which is still plastic, is preferably passed through a pair of blades (4), with the aid of a suitable guide groove (4), the wrappers and both rollers having recesses (5) lying opposite each other and which on the contact line, in the form of vapors, form the shape of the desired tablets, ϋ once suitable for the form of embodiment, especially for adhesive masses, which adhere more or less to the mold wall (recesses 5), the recesses are interconnected by a single open channel, so that the tablets formed (6) remain interconnected via a short (segment) (tablet breakage) (7). thus, already according to the flexibility of the material, solid or chain-shaped beads are formed which contain more tablets.

Tvorevine u obliku lanaca perli mogu se namotavati i potom racionalno pakovati uz primenu relativno prostih rnašina. Krute tvorevine mogu se lomiti na jednu željenu dužinu ili na pojedinačne tablete,Bead chains can be rolled up and then rationally packaged using relatively simple beads. Solid formulations can be broken into one desired length or into individual tablets,

Kada je adhezija obrazovanih tableta na zidovima kalupa (na udubljenjima u omotačima val jaka) dovoljno .mala, tako da pojedinačne tablete (koje nisu spojene preko spojki-segmenata) ne ostaju zalepljene, več ispadaju napolje iz udubljenja, tada se mogu izostaviti gore pomenuti segmenti za spajanje (spojke).When the adhesion of the formed tablets on the walls of the molds (on the recesses in the sheaths in the rolls is strong) is small, so that the individual tablets (which are not connected via couplings) do not remain glued but fall out of the recesses, then the above mentioned segments can be omitted. for couplings.

V tom slučaju se uzdužna udubljenja (za oblong-tablete ili za čepice) pogodno namestaju paralelno u odnosu na uzdužnu osu valjaka.In this case, the longitudinal recesses (for oblong tablets or for plugs) are conveniently positioned parallel to the longitudinal axis of the rollers.

Za hladjenje valjaka u principu je dovoljno prirodno vazdušno hladjenje. ϋ specijalnim slučajevima može biti pogodno da se ovi dopunski hlade ili čak i zagrevaju. Za takve slučajeve ovi valjci svrsishodno mogu biti takvi da se temperriraju što znači da poseduju jednu od Uobieajenih konstrukcija za provodjenje tečnog medijuma za hladjenje ili zagrevanje.In principle, natural air cooling is sufficient to cool the rollers. ϋ In special cases, it may be convenient to cool or even heat these supplementary ones. In such cases, these rollers purposefully may be such that they are tempered, which means that they have one of the common designs for conducting liquid medium for cooling or heating.

Ako ekstruder ima više--jedne al-azniee, tada, naravno, svakoj mlaznici pripada čitav niz udubljenja (5) za oblikovanje koja se nalaze na svako:» obimu val jaka u ravni normalno j na oso vinu.If the extruder has more than one al-aznie, then, of course, each nozzle is assigned a series of shaping recesses (5) which are located on each: »the circumference of the wave is strong in a plane normal to the axis.

Postupak prema ovom pronalasku je prvi kontinualni postupak za tabletiranje farmaceutskih smeša. h e aamo da je na ovaj način prostija, efektivnija a tirne i ekonomionija proizvodnja od uobič&jene proizvodnje tableta potem mašina za tabletiranje, več ovaj postupak ima i sledeče suštinseke prednosti:The process of the present invention is the first continuous process for tabletting pharmaceutical compositions. While we wish that in this way simpler, more efficient and economical production is more efficient than conventional tablet manufacturing then the tablet machine, this procedure also has the following essential advantages:

1. slobodno oblikovanje tableta (npr. sferno);1. free formulation of tablets (eg spherical);

2. prerada lepljivih i/jako viskoznih materijala, koji se ne može ili teško može preradjivati na uobičajeniia a&šinama za tabletiranje, moguca je primenom ovog postupka, jer težina odnosnih tableta omogueuje da se prevlada sila adhezije izmedju tablete i polovine kalupa.2. The processing of sticky and / or highly viscous materials, which cannot or cannot be processed by conventional tableting machines, is possible by the application of this method, since the weight of the respective tablets allows the adhesion force between the tablet and half of the mold to overcome.

Farmaceutske smeše koje ee mogu ekstrudovati su smeše najmanje jednog farmaceutski aktivnog materijala sa najaaanje jedno® pomočnoa isaterijom koja je uobičajena u proizvodnji faraiaceutskih tableta, a koje bilo mešanjem aa npr. vodom na toploti (najmanje 7C°C) ili stapanjem ili omekšavanjem jedne komponente postaju testaste a time i takve da se mogu ekstrudovati. Ίο su naročite smeše, koje sadrže farmakološki prihvatljive polimere (pri čemu temperatura ostakljivanja ove smeše nalazi se ispod temperature razlaganja svih komponenata smese),na primer, polivinilpirolidon (iVP), kopolimerizati Nrvinilpirolidona (ΟΙ) i vinilacetata, kopolimerizati vinilacetata i krotoneke kiseline, delimično saponifikovan polivinilacetat, polivinil alkohol, kopolimerizati etilen/vinilacetat, polihidroksietilmetakrilat, kopolimerizati metilmetakrilata i akrilne kiseline, estri celuloze, etri celuhoze, polietilenglikol, polietilen. K-vrednosti (prema li. Fikentscher-u, Gellose-Chemie 13 (1952), str. 5S-Č4 i 71-74) ovih polimera nalaze se u oblasti od 10 do ICO, pogodno od 12 do 70, naročito od 12 do 35» za iVl prvenstveno od 12 do 35 a najpogodnije od 12 do 17.Pharmaceutical compositions which may be extruded are mixtures of at least one pharmaceutically active material with the reinforcement of an isothermal isotherm which is common in the manufacture of pharmaceutical tablets, and which is by mixing aa e.g. with water in heat (at least 7C ° C), or by blending or softening one component, they become doughy and thus extrudable. Ίο are particular mixtures containing pharmacologically acceptable polymers (wherein the glass transition temperature of this mixture is below the decomposition temperature of all components of the mixture), for example, polyvinylpyrrolidone (iVP), copolymerizates of Nrvinylpyrrolidone (ΟΙ) and vinyl acetate, copolymerizates of vinyl acetate, and crotonic acid saponified polyvinyl acetate, polyvinyl alcohol, ethylene / vinyl acetate copolymerizates, polyhydroxyethylmethacrylate, methyl methacrylate and acrylic acid copolymers, cellulose esters, cellulose ethers, polyethylene glycol, polyethylene. The K-values (according to Fikentscher, Gellose-Chemie 13 (1952), pp. 5S-Č4 and 71-74) of these polymers are in the range from 10 to ICO, preferably from 12 to 70, especially from 12 to 35 "for iVl, preferably from 12 to 35 and most preferably from 12 to 17.

Polimerni vezivni materijal mora se u ukupnoj smeši svih koraponenata omekšavati ill topiti u oblasti od 50 do ISO, prvenstveno od 60 do 130°0, tako da se ova masa može ekstrudovati. Temperatura ,-4 relaza u etaklo ove smele mora u eavakom slučaju biti iepod 160, prvenstveno Ispod 130°C. lo potrebi se ona može sniziti pomoču uobičajenih farmakološki 'prihvatljivih pomočnih materija kao što su alkoholi dugog niza, etilenglikol, propilenglikol, trimetilenglikol, triaetilolpropan, ttrietilenglikol, butandioli, pentanoli, heksanoli, polietilenglikol!, silikoni, aromatični karbonski estri (estri aromatičnih karbonskih kiselina, npr, dialkilftalati, estri trimelitne kiseline, estri benzoeve kiseline, estri teref talne kiseline) ili estri alifatičnih dikarboaskih kiselina (npr. dialkiladipati, estri sebaoinske kiseline, estri azelainske kiselinea estri 1imunsk® i vinske kiseline) ili estri vilih masnih kiselina.The polymeric binder material must be softened or melted in the total mixture of all the coraponents in the range from 50 to ISO, preferably from 60 to 130 ° 0, so that this mass can be extruded. The temperature, -4 points to the glass of this bold must in any case be as low as 160, primarily below 130 ° C. if necessary, it may be reduced by conventional pharmacologically acceptable excipients such as long-chain alcohols, ethylene glycol, propylene glycol, trimethylene glycol, triethylene glycol, triethylene glycol, butanediols, pentanols, hexanols, polyethylene glycols, silicones, aromatic acids, aromatic acids, aromatic acids, aromatic acids, aromatic acids, aromatic acids, aromatics e.g., dialkyl phthalates, trimellitic esters, benzoic acid esters, terephthalic acid esters) or aliphatic dicarboxylic esters (e.g., dialkyladipates, sebaoic acid esters, azelaic acid esters 1imunsk® esters and tartaric acids) or esters of fatty acids.

Od prednosti su kiV-polimetizati koji se u smeši ea aktivnom materi jom i u datom slučaju sa uobičajenim g&Ierskim ponočnim materijama sa ili prvenstveno bez dodataka za omekšavanje tope ili omeksavaju u željen©j oblasti temperature.Topljenje ili omekšavanje ispod jedne odredjene temperature je u datom slučaju neophodno sa aspekta mogučeg termičkcg i/ili oksidativnog cštečenja ne samo aktivne materije več takodje i samog NVi-polimerizate. Ovaj bi mogao da požuti pri ekstrudovanju, zbog čega do sada nije bila uobičajena ekstruzija hiV-polimerizata. Cpaanost je medjutim neznatna pri eketrusionim temperaturama ispod 180%, pre svega ispod 150%, ako se polimerizat ne proizvodi u vodenom rastvoru uz primenu vodonikperoksida kao startera, več u organskom rantvai raču, ili čak i u vodi uz primenu organskog peroksida kao startera, na primer, prema postupku datom u neaačkoj patentno^ prijavi i 36 42 633.4 ili preaa postupku iz US 4 520 179 i 4 520 ISO.,Preferred are KiV-polymethysates, which are mixed with the active substance and optionally with conventional g & ier midnights with or primarily without additives to soften the melt or soften in the desired temperature range. Warming or softening below a certain temperature is optionally necessary from the point of view of possible thermal and / or oxidative degradation of not only the active substance but also of the NVi polymerizate itself. This one may turn yellow during extrusion, which is why the extrusion of hiV polymerizates has not been common so far. However, the content is insignificant at ectrusion temperatures below 180%, especially below 150%, if the polymerizate is not produced in aqueous solution using hydrogen peroxide as a starter, but in an organic ranch or bag, or even in water using organic peroxide as a starter, for example , according to the procedure set forth in the patent application and 36 42 633.4 or the procedure of US 4 520 179 and 4 520 ISO.,

Ako v rednost K iznosi vižo od 17, naročito preko 30 ili čak preko 40 (do maksimalno 70) i ako nije dodata jako oaaekšavajuča komponenta, tada kao i»¥i-^olimerizati dolaze u obzir samo oni ea temperaturo^ ostakljivanja Tg ispod 120, prvenstveno ispod 1CC°C, ili BVr-polimeriz&t (uključujuči hompolimer) ne eme se proizvoditi u vodi uz primenu vodonikperoksida kao startera. rri torne bi naiae mogle nastati polimerne terminalne grupe koje bi pri povišenoj temperaturi mogle dovesti da materijal požuti.If the magnitude of K is greater than 17, especially over 30 or even over 40 (up to a maximum of 70), and if no strongly accelerating component is added, then only those a i- ^ olimerizates consider only those with a glass transition temperature Tg below 120 , primarily below 1CC ° C, or BVr-polymerizate (including homopolymer) will not be produced in water using hydrogen peroxide as a starter. polymeric principles could form polymeric terminal groups that at high temperatures could cause the material to turn yellow.

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MVi-polimerizat može biti podešen jako ili slabo hidrofilnia (preko vrste i količine monomera več preaa Željenoj svrsi), tako da se iz. njega proizvedene tablete rastvore u ustiaa (bukal-tablete) ili h želucu ili tek u crevima (brzo ili μ u sporen o) ili tako nabubre da oslobadjaju aktivnu materija.The MVi polymerisate can be highly or weakly hydrophilic (via the type and amount of monomer already transferred to the desired purpose) so that from. the tablets produced are dissolved in the mouth (buccal tablets) or in the stomach or only in the intestines (fast or μ in spores) or swollen so as to release the active substance.

One su tada dovoljno sposobne za bubrenje kada pri skladištenju pri 9C?e~noj relativno j vlažnosti vazduha apsorbuju više od 10 tež. % vode. Kako je kod vezivnih materijala koji sadrže karboksilne grupe poželjno da oni aktivnu materiju oslobadjaju tek u alkalnoj sredini čreva, gornji podatak o meri apsorbovanja vode vali samo zn neutraiizovan oblik (oblik soli) ovih polimera (u kojem su protoni karboksilnih grupa potpuno ili delimično zamenjani jonima amonij uma, natrijuma ili kalijuma).They are then sufficiently capable of swelling when they absorb more than 10% by weight when stored at 9C relative humidity. % water. As it is desirable for binders containing carboxyl groups to release the active substance only in the alkaline center of the intestine, the above data on the extent of water absorption are only known by the untrained form (salt form) of these polymers (in which the protons of the carboxyl groups are completely or partially replaced by ions ammonium of mind, sodium or potassium).

Kao komonoaerl za SVr dolaze u obzir: nezasičene karbonske kiseline, npr. metakrilna, krotonska, maleinska, itakonska ;The following are considered as comonoyl for SVr: unsaturated carboxylic acids, e.g. methacrylic, crotonic, maleic, itaconic;

kiselina, kao i njihovi eatri aa alkoholika aa 1-12, prvenstveno ! sa 1-8 atoma ugljenika, dalje hidrokaietil- ili hidroksipropilakriMat i -metakrilat, akrilamid, me tak ril aa id, anhidridi i i poluestri aaleinske i itakonske kiseline (pri čemu se polueetar r prvenstveno obrazuje tek nakon polimerizacije), K-vinilkaprolaktaa i vinil pro pionat. Pogodni koaonoaieri su akrilna kiselina d naročito vinilacetat. Otuda su od prednosti hVr-poIimerizati koji sadrže upolimerizovan bilo samo NVr ili vinilacetat kao jedan jedini komonosaer. Vinilacetat i vinilpropionat mogu se nakon polimerizacije potpuno ili delimično sa^oniiikovati.acid as well as their eatri aa alcoholics aa 1-12, primarily! with 1-8 carbon atoms, further hydrocaethyl or hydroxypropylacrylate and methacrylate, acrylamide, metacryl aa id, anhydrides and semesters of aaleic and itaconic acids (whereby the polyether ether is formed only after polymerization), K-vinylcaprolacta and vinyl pro pionat. Suitable co-oonairs are acrylic acid d especially vinyl acetate. Therefore, the advantage of hVr-polymerizates that contain only polymerized NVr or vinyl acetate as a single co-carrier. Vinyl acetate and vinylpropionate may be completely or partially solubilized after polymerization.

Uobičajene galenske poaocne materije, čija ukupna količina moče iznostiti do ICO tež. % (u odnosu na saa poliaerizat), su npr. punila kao silikati ili inluzorijska zemlja, stearinska kiselina ilinjene soli sa npr. magnezijunom ili kalcijumom, metilceluloza, natrijum-karboRslmetllceluloza, talk, saharoza, laktoza, pšenični ili kukuruzni škrob, brašno od kroapira, polivinilalkohol, dalje sredstva za kvašenje, konzerviranje, širenje, adsorpoiju, bojenje, ukua (uporedi npr. H. Sucker, et al*, iharmazeutiaehe Technologie, Thieme-Verlag, Stuttgart, 1978).Common galenic poochics, whose total amount can be carried up to ICO weights. % (relative to saa polyetherisate), are e.g. fillers such as silicates or inclusion earth, stearic acid or salts with e.g. magnesium or calcium, methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose, wheat or corn starch, croupir flour, polyvinyl alcohol, further wetting, preserving, spreading, adsorpoy, dyeing, etching. al *, iharmazeutiaehe Technologie, Thieme-Verlag, Stuttgart, 1978).

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I.I.

Ako se to želi, tableta proizvedena prema pronalasku može biti snabdevenu uobicajenom prevlakom za poboljšanje izgleda i/ili ukusa (dražee) ili radi dopunskog uaporavanja oslobadjanja aktivne supstance. Sa tablete koje treba uzioati oralno 1 koje itaaju uaporeno oslobadjanje aktivne materije, može biti pogodno da se takva tebleta pravi prema jednoj od poznatih tehnika u obliku satvorene porozne čelije tako da pliva u Želucu 1 tiste u njemu produžava svoj bor&vak. Salje presto postupku prema ovom pronalasku mogu se proizvoditi vrlo male tablete koje se vrlo pogodno :aogu puniti u kapsule umesto kl&sišnih granulata*If desired, the tablet produced according to the invention may be provided with a conventional coating to enhance the appearance and / or taste (dragee) or to further evaporate the release of the active substance. From the tablets to be taken orally 1 that read sustained release of the active substance, it may be advantageous to make such tablets according to one of the known techniques in the form of a honeycomb porous cell so that it swims in the Stomach 1 those extending its fight. According to the method of the present invention, very small tablets can be produced which are very convenient: they can be filled into capsules instead of clay granules *

Šojam tableta u smislu ovog pronalaska nije vezan za jedna odredjen oblik ili samo za peroralno davanje, Oa obuhvata Čak šta više i Čepiče za rektalna priaenu koji se ne tope pri temperaturi tela.The tablet diet for the purposes of the present invention is not bound to one particular form or oral administration alone, Oa includes even more and rectal attachments which do not melt at body temperature.

pod iar&aeeutskim aktivnim substancama u eadLsla.ovog pronalaska podrazunevajn se sve materije sa iamaceutskim dejstvom i što je moguče man jim spore dnia dejztvista, ukoliko se no ra spada ju pod uslovima prerade». Količina aktivne ata tari je pod jedinici doze i koncentracija aogu varirati u Širokim graaicaaa ved prema delotvomosti i br&ini oslobadjanja. Jedini uslov je da je dovoljna sa postlzanje Soijengs dejstva, 'lako koncentracija aktivne uatsrije nože biti u oblasti od 0,1 do 95« pogodno od 2C do 6C» naročilo pogodno od 50 do 70 tež» &. Takodje se mogu upotrebiti i kombinacije aktivnih «upetanel. Aktivne supstance u smislu ovog pronalaska su takodje i vitamini.By iar & aauteic active substances in eadLsla.'s invention, all substances having a pharmaceutical effect and as little spore action as possible are considered, if they are treated under processing conditions ». The amount of active attar ture is below the unit dose and the concentration may vary in the wide range of cases, depending on the efficiency and the rate of release. The only condition is that with the Soijengs action sufficient, 'easy concentration of active uatri blade to be in the range of 0.1 to 95 "suitable from 2C to 6C" order suitable from 50 to 70 weight "&. Combinations of active "upetanel" may also be used. The active substances of the present invention are also vitamins.

Delovi i procenti koji su pomenuti u primerima odnose se na težinu.The parts and percentages mentioned in the examples refer to weight.

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- Ί Briaer 1 delova kopoliaerizata vrednosti M. «» 30 načinjenog od 60 tež.% B-vinilpirolidona 1 40 tež* % vinilacetata, 5 delova e t arilalkohola i 50 delova teofilina pomeša se i ekstrudira u ekstruderu ea dvojnim pužem. Temperatura orno taca ekstrudera sa lest Žarži iznoaila je 30, 60, 60, 60, 6o, 60 i 60°0i alaznica Je sagrejana na 100°0. Ovde dobivena traka direktno se pre suj e u oblong-tablete uz primenu uredjaja Ipisanog u zabtevisaa 2 15»- Ί Briaer 1 parts copolymerizate of value M. "" 30 made from 60 wt.% B-vinylpyrrolidone 1 40 wt.% Vinyl acetate, 5 parts e t aryl alcohol and 50 parts theophylline are mixed and extruded in an extruder ea by a double screw. The temperature of the ornamental tray of the extruder with the Jarzhi ladder was 30, 60, 60, 60, 6o, 60 and 60 ° 0 and the tray was heated to 100 ° 0. The tape obtained here is directly pre-dried into oblong tablets using a device described in Note 2 15 »

Iri toae naetaju krute trake tableta koje se lako raškidaju u pojedinaČne tablete, tako dobivene tablete bile su vrlo stabilne prema mebaničkia uticajima i nisu poKazale nekov veče bahanje pri transportu i pakovanju.Iri toae were invaded by rigid strips of tablets that could be easily dismantled into individual tablets, the tablets thus obtained were very stable to the mechanical influences and did not show any major swelling during transport and packaging.

Primer 2 delova kopolisierizata iz primera 1 i 50 delova teofilina pomešani su i ekstrudovani u ekstruderu sa dvojnim pužem. Za razliku od primera 1 temperatura punjenja je podešena na 30,Example 2 parts of the copolysierisates of Examples 1 and 50 parts of theophylline were mixed and extruded in a twin snail extruder. Unlike example 1, the charging temperature is set to 30,

60, 60, 60, 90 i 120°C, blaznica je takodje imala temperaturu od 12Q°C. bobivena traka je presov&na u oblong-tablete analogno primeru 1 uz primenu uredjaja opisanog u zahtevima 2 i 3. Takodje su i ove tablete analogno tabletama iz primera 1 stabilne protiv sjehaničkih utica ja.60, 60, 60, 90 and 120 ° C, the nozzle also had a temperature of 12Q ° C. the bobbin strip was pressed into oblong tablets analogously to example 1 using the apparatus described in claims 2 and 3. Also, these tablets are stable against mechanical influences by analogy to the tablets of example 1.

Primer 3Example 3

47,5 delova kopoliaerizata vrednosti k ® 30 iz 60 tež. %47.5 parts of copolymerizate of value k ® 30 from 60 wt. %

Χ-vinilpirolidona i 40 tež. % vinilacetata, 2,5 dela umreženog 171 kao sredstva za širenje (bubrenje) tableta) i 50 delova teofilina pomešaju ee i ekutruduju u ekstruderu sa dvojni® puie.a. Temperatura pet delova oaotuča isnosila ^e kod svakog 120°C, mlaznica je imala temperatura od 13c8c. Još uvek plastična z traka se presuje u obiong tablete kao sto je dato u primeru 1. Tablete su bile stabilne protiv mehaničkih uticaja.Of β-vinylpyrrolidone and 40 wt. % of vinyl acetate, 2.5 parts of crosslinked 171 as a tablet (swelling agent) and 50 parts of theophylline mixed ee and extruded in an extruder with dual® puie.a. The temperature of the five parts of the hull was at 120 ° C, the nozzle had a temperature of 13c8c. The still plastic z-band was compressed into obion tablets as in Example 1. The tablets were stable against mechanical influences.

* 8 * iriaeg 4 delova kopolimerisata ea K »52 Is 30 tež. % K-vinilpirolidona, i 70 tež. % vinilacetata i 50 delova teoiilina eu pomešani i ekstrudovani a ekstruderu sa dvojnim pužeau Temperatura pet delova omotača isnosila je 50, 60, 100, 100 i 120°0. Ml&snica js takodje zagrajena na 120°C. ješ uvek plastnična traka je preeovana u mehanički stabilne obloag-tablete na način kao što je dato u primeru 1,* 8 * iriaeg 4 parts copolymerize ea K »52 Is 30 wt. % K-vinylpyrrolidone, and 70 wt. % of vinyl acetate and 50 parts of teoylilin were mixed and extruded and with a double screw extruder. The temperature of the five parts of the sheath was 50, 60, 100, 100 and 120 ° 0. The broth was also heated to 120 ° C. you always have the plastic strip transformed into mechanically stable obloag tablets as in Example 1,

Smesa od 50 tež. % h-vinilpirolidon-homopolimera (IVI) sa vrednosou K datom sa svaki slučaj u priloženoj tabeli i 50 tež. % teofllina iatopljena ja i eketrudovana u ekstvuderu sa jednim vratiiora pri temperaturi noja je sa svaki primera data u navedenoj tabeli i potom je oblikovana u tablete kao ato je opisano u primeru 1.Mixture of 50 wt. % h-vinylpyrrolidone homopolymer (IVI) with a K value given in each case in the table below and 50 wt. % of theophylline was dissolved and extruded in a single-port extruder at the ostrich temperature of each example given in the above table and then molded into tablets as described in Example 1.

rr. /°p X / L·,rr. / ° p X / L ·,

primer example vrednost k value k 1. 1. 2, deo 2, part 3. 4. omotača 3. 4. wrapper 5* 5 * mlasnica mlasnica 5 5 vi.*·, you. * ·, ** A c JJ.? ** A c JJ.? 125 125 135 135 135 135 135 135 145 145 /ζ v / ζ v 17 17 ·#»··» t · # »··» t 125 125 135 145 135 145 Ά i r’ Ά and r ' 155 155 7 7 25 25 14? 14? 15? 15? 165. 175 165. 175 175 175 175 175 b b 30 30 150 150 160 160 160 170 160 170 180 180 180 180 $·» *A W<5». $ · »* A W <5 ». ί><5 ί> <5 150 150 160 160 160 170 160 170 180 180 180 180 irimer ; irimer; ) ) 4c dele; 4c parts; ίϋ KO ίϋ KO erisat erisat a iz a iz 6c tež» % 6c weight »% W-vin 5.1 W-vin 5.1 pirolidona i 40 of pyrrolidone and 40

% vinilacetata l - 50, 10 delova polihidrcksietilaetakrilata i 5C delova teoiilina preradjeni eu analogno primeru 1 u mehanički stabilne tablete. Temperatura delova omotača bia je 70, i&, 80,% vinyl acetate 1-50, 10 parts polyhydroxyethylacetyl acrylate and 5C parts teoyliline were processed in analogy to Example 1 into mechanically stable tablets. The temperature of the parts of the sheath bia is 70, and &, 80,

80, 80 °C. ilaanice; 9C°C.80, 80 ° C. ilaanice; 9C.

irimar 10 delova koaeroijalno uobičajenog do 80% sapocifikovanog poli vinilaeetata i 50 delova teofilina eu preradjeni analogno primeru 1. Temperatura pet delova omotača iznosila ja 100, 100, 110, 120, 13O°C. Manica 150°C.irimar 10 parts of coaeroally common up to 80% of sapocified poly vinyl acetate and 50 parts of theophylline were processed in analogy to Example 1. The temperature of the five parts of the jacket was 100, 100, 110, 120, 13O ° C. Flange 150 ° C.

irimer 11 delova polikidrokaietiliaetakrllata vrednosti K * 30 i 50 * .1 delova teofilina preradjeni su analogno primeru 1, Temperatura delova omotača iznosila je 120, 150» 150, 160, 16Q°C. Hlaznicaj 170°C.for example, 11 parts of polyhydroxyethylacetate of values K * 30 and 50 * .1 parts of theophylline were processed analogously to example 1, the temperature of the parts of the sheath was 120, 150 »150, 160, 16Q ° C. Fridge 170 ° C.

Primeri 12 do 14 dela kopolimerizata iz So tež. % M-vinilpirolidona i 40 teš, % vinilaeetata vrednosti K ^a 30, 4 dela stearilalkohola, delova teofilina i 20 delova primer 12) hkroba primer 13) laktoze primer 14) saharoze izmedša se u ekatruderu sa dvojnim pužea* sa 6 delova omotača i preradi u tablete na način dat u primeru 1« Temperatura delova omotača iznosila je 90, 100, 110, 120, 120, 130°C, temperatura mlaznice iznosila je 135 v. · irfaerl 15 do 17 delova kopoliaerizata iz primera 12 do 14 i 50 delova verapamila oblikovano je u tablete prema primerima 12 do 14.Examples 12 to 14 of the copolymerizate moiety of So wt. % Of M-vinylpyrrolidone and 40 parts by weight,% of vinyl acetate values of K ^a 30, 4 parts of stearyl alcohol, parts of theophylline and 20 parts example 12) starch example 13) lactose example 14) sucrose is mixed in a double snail extruder * with 6 parts wrapper and processed into tablets as described in Example 1 «The temperature of the sheath parts was 90, 100, 110, 120, 120, 130 ° C, the nozzle temperature was 135 v. · Irfaerl 15 to 17 parts of the copolymerizates of Examples 12 to 14 and 50 parts of verapamil were formed into tablets according to examples 12 to 14.

Analogno gornjim primerima izvedeni su sledeči primeri.The following examples are derived analogously to the examples above.

Valovi prerade'kao brzine oslobadjanja pri testu hali-ch&nge (uporediti k. Voigt, Lehrbuch der phara&zeutiscken Technologie,Waves of reworking rate of release at the hali-ch & nge test (compare k. Voigt, Lehrbuch der phara & zeutiscken Technologie,

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Najbolji način za privrednu primenu prijavljenog pronalaska koji je poznat prijaviocuThe best way to economically apply the claimed invention known to the applicant

Prema iskustvu prijavioca u ovu svrhu može da posluži sledeči primer realizacije postupka tabletiranja farmaceutske smeše.In the experience of the Applicant, the following example of carrying out the tabletting process of a pharmaceutical composition may serve as an example.

masenih delova kopolimerizata vrednosti K=50 napravljenog od 60 mas.?» .N-vinrlpirolidona i 40 mas.# vinilacetata, 5 masenih delova starilalkohola i 50 masenih delova teofilina se izmeša i ekstrudira u ekstruderu sa dvojnim pužem. Temperatura omotača ekstrudera sa sest šarži bila je 50,60,60,60,60,60 i 60°C dok je mlaznica zagrejana na 100^c0. Dobivena traka se dalje direktno presuje u oblong-tablete. Bor-ivene krute trake tableta se lako raskidaju dajuči pojedinačne tablete,stabilne na mehanička oštecenja i podesne za pakovanje.of the copolymerizate parts by weight of the value K = 50 made from 60 wt.?. of N-vinylpyrrolidone and 40 wt. # of vinyl acetate, 5 parts by weight of staryl alcohol and 50 parts by weight of theophylline are mixed and extruded in a double-screw extruder. The temperature of the six-batch extruder sheath was 50.60.60.60.60.60 and 60 ° C while the nozzle was heated to 100 ^c 0. The resulting strip was further compressed directly into oblong tablets. The combat solid tablet strips are easily dismantled giving individual tablets stable to mechanical damage and suitable for packaging.

Claims (3)

1 . Kontinualni postupak za tabletiranje farmaceutskih smeša koje se mogu ekstrudovati, naznačen time, što obuhvata mešanje farmaceutski aktivnog jedinjenja i polimera N-vinilpirolid-2-ona (NVP) koji sadrži 30 do 100% masenih NVP-a u ekstruderu radi obrazovanja istopine, pri čemu pomenuti polimer ima K vrednost od 10' do 100 a pomenuta smeša ima temperaturu prelaza u stakio manju od 18O°C, i ekstrudovanje istopine i presevanje još uvek deformabilnog ekstrudata izmedju površina dva valjka koji se pokreču u medjusobno suprotnim smerovima, pri čemu površine pomenutih valjaka imaju udubljenja postavljena jedna naspram drugih, tako da se obrazuju tablete koje imaju oblik sa naspramnim udubljenjima.1. A continuous process for tabletting extruded pharmaceutical compositions comprising mixing a pharmaceutically active compound and a polymer of N-vinylpyrrolid-2-one (NVP) containing 30 to 100% by weight of NVP in an extruder to form a solution, wherein said polymer having a K value of from 10 'to 100 and said mixture having a glass transition temperature of less than 18 ° C, and extrusion of the solution and sieving of a still deformable extrudate between the surfaces of two rollers moving in opposite directions, the surfaces of said rollers they have recesses facing each other so that tablets that have opposite recesses are formed. 2. Postupak prema zahtevu 1, naznačen time, što se istopina polimera N-vinilpirolid-2-ona (NVP), koja sadrži aktivno jedinjenje, ekstrudira i presuje, i što se polimer NVP spravlja ili u organskem rastvaraču ili koriščenjem organskog peroksida u vodi.2. The process of claim 1, wherein the polymer solution of N-vinylpyrrolid-2-one (NVP) containing the active compound is extruded and pressed, and the polymer of NVP is prepared either in an organic solvent or by using organic peroxide in water . 3. Postupak prema zahtevu 1, naznačen time, što je K vrednost polimera izmedju 12 i 25, što smeša ima tačku omekšavanja ili topljenja od 60° do 130°C, a temperaturu prelaza u stakio manju od 130°C.3. The method of claim 1, wherein the K value of the polymer is between 12 and 25, the mixture having a softening or melting point of 60 ° to 130 ° C and a glass transition temperature of less than 130 ° C.