SI8710569A8

SI8710569A8 - Process of preparing controlled long-acting pharmaceutical formulation

Info

Publication number: SI8710569A8
Application number: SI8710569A
Authority: SI
Inventors: Hans Lowey
Original assignee: Hans Lowey
Priority date: 1986-04-04
Filing date: 1987-04-01
Publication date: 1996-12-31
Also published as: HRP930660A2

Description

Oblast tehnike ;Field of technology;

Pronalazak je iz oblasti farmaceutske industrije.The invention is in the field of pharmaceutical industry.

Tehnički problemTechnical problem

Pronalaskom se rešava tehnički problem postupka za dobivanje farmaceutske formulacije sa kontrolisanim dugotrajnim oslobadjanjem samim tim dugog dejstva ,u obliku dozne jedinice koja ima uniformne iThe invention solves the technical problem of the process for the preparation of a pharmaceutical formulation with controlled long-term release, thereby long acting, in the form of a dosage unit having uniform and

karakteristike biodostupnosti /koja sadrži aktivno terapeutsko sredstvo i bazni materijal nosača.bioavailability characteristics / containing active therapeutic agent and carrier base material.

Stanje tehnikeThe state of the art

Proizvodi čFugog dejstva prodaju se mnogo natržišfcu· farmaceutskih sredstava i sada predstavljaju značajan fafcior za davanje raznih aktivnih farmaceutskih sredstava. Prednosti takvih proizvoda dugog dejstva 111 usporednog oslobadjanje su sad« dobro shvačena 1 razvila se je velika Industrija oko ovih proizvoda. Proizvodi sa usporenln oslobadjanjem omoguduju da se razni lekovi daju tako da se jednobrazno 1 neprestano oslobadjaju tokom produženog vremenskog perioda tako da se u krvi postiže odredjenl nivo aktivnog sastojka u makoje vreme za koje se smatra da odgovara pacijentu. Takvo davanje ublažava potrebu za čestim davanjem aktivnog sastojka 1 ublažavaju se problemi koji su nedeljivi za obezbedj Ivanje pravovremenog 1 ponovljenog trošenja farmaceutskog proizvoda od strane pacljenta. Moguče je da se postlgnu stabilni nivoi aktivnih terapeutskih proizvoda u krvi i da se tako kontrolišu razna fiziološka stanja. Takodje se smanjuju 111 tak 1 e1im1n1št toksični 111 točni efekti koji su izazvanl čestim davanjem aktivnih sastojaka 1 putem maksimalnih 1 minimalnihFungicidal products are marketed to many pharmaceuticals and are now a significant contributor to the delivery of various active pharmaceuticals. The benefits of such long-acting 111 comparative release products are now well understood 1 a large industry has developed around these products. Slow-release products allow the various drugs to be administered by unilaterally releasing 1 continuously over a prolonged period of time so that a certain level of active ingredient is reached in the blood at whatever time is considered appropriate for the patient. Such administration alleviates the need for frequent administration of the active ingredient 1 to alleviate problems that are indivisible to ensure the timely 1 repeated consumption of the pharmaceutical product by the patient. It is possible to achieve stable levels of active therapeutic products in the blood and thus control various physiological conditions. It also reduces 111 so 1 e1im1n1št toxic 111 exact effects caused by the frequent administration of active ingredients 1 via the maximum 1 minimum

I nivoa u krvi izazvanlh vlšestrukla varenJem leka.And blood levels caused by multiple digestion of the drug.

Dobro je poznato koriščenje celuloznih derivata, naročito celuloznih etara· kao Što je h1droks1prop11-met11ce1u1oza, kao nosača u farmaceut$k1m~Torrnu1ac1jama dugog dejstva 111 sa usporenlm oslobadjanjem. Razni komercijalnl oblici celuloznih etara su komercijalno pristupačni 1 ovi uključuju metllcelulozu. hidroksipropiImet11celulozu, etllcelulozu. kerboksimetllceluloztf 1 h1droks1propi1ce1u1ozu, kao 1 njihove derivate, Izmedju drugih. Ovi celulozni etri su pristupačni sa Intervalom molekulskih težina 1 viskoziteta 1 pod raznim trgovačklm Imenlma.It is well known to use cellulose derivatives, especially cellulose ethers, such as hdrox1prop11-met11ce1u1ose, as a carrier in slow-release, long-acting pharmaceutically acceptable pharmaceuticals. Various commercial forms of cellulose ethers are commercially available 1 these include methylcellulose. hydroxypropylmethylcellulose, ethylcellulose. carboxymethylcellulose 1 h1drox1propylce1u1ose, as 1 derivatives thereof, Among others. These cellulose ethers are accessible with a Molecular Weight Interval of 1 Viscosity 1 under various trade names.

Hidroks1prop11met11ce1u1oza je naročito poželjan celulozni eter za preparate sa uzdržanlm oslobadjanjem 1z pronalaska 1 pristupačna je od Dotr Chemical Companp pod žigom METBOCIL. Me ko 11 ko hldrokslprop11-met11colulozolb proizvode Imaju razne metoks11 1 hidrokslproptksll sadržaje 1 različite «olekulsrke tetine. Tipično sadržaj metoksila varira od 16.S do 30 mas. procenata a sadržaj hldrokslproplla varira odtdo 32 »as. pri cenita. Viskozi teti hidrokslpropil celuloze nekoliko razllčltlh kvaliteta, kao Što au Izračunati aa bazi vlskozlteta 2% vodenog restvori na 20°C. variraju od S cps do 100,000 cps. Tipično se materijeli viŠeg vlskozlteta rastvaraju sporije i tsogu se koristiti u manjlm količinama od uporedivlh materijala koji Imaju manje vlskozitete.Hydrox1prop11met11ce1u1ose is a particularly preferred cellulosic ether for sustained release preparations 1 of invention 1 accessible from Dotr Chemical Companp under the METBOCIL seal. Each of the 11 co hldroxlprop11-met11colulozolb products have a variety of methoxy11 1 hydroxylproxyl contents of 1 different oleculus tendons. Typically, the methoxyl content varies from 16.S to 30 wt. percent and hldroxlpropl content varies from 32 »as. at appreciate. Viscous aesthetic hydroxyl propyl cellulose of several different qualities, such as Calculate a 2% aqueous solution at 20 ° C on a baseline basis. vary from S cps to 100,000 cps. Typically, materials of higher moisture damage dissolve more slowly and can be used in smaller quantities than comparable materials that have less moisture.

Ranija nauka datira na 1960-te godine. Chrlstiansen et al., U.S. Patent No. 3,065,143, oplsuju koriščenje hldroksipropll-met1Iceluloze u tabletama sa usporenlm oslobadjanjlma. Lowey et al., u U.S. Patentu No. 3,870,790 oplsuju postupke za mešanje aktivnog terapeutskog sastojka sa prethodno ovlaženoa h1droks1prop11met11celulozom koja se takodje može, opciono, mešati sa etilcelulozom. Osobine usporenog oslobadjanja doblvene smeše mogu se kontrolisati pomoču sadržaja vlage u nosečem materijalu što se opet reguliše u postupku ovlažlvanja gde se noseči materijal podvrgava uslovima povišane temperature 1 vlažnosti.Earlier science dates back to the 1960s. Chrlstiansen et al., U.S. Pat. Patent No. No. 3,065,143, utilize the use of hydroxypropyl-methyl-1-cellulose in slow-release tablets. Lowey et al., In U.S. Pat. No. No. 3,870,790 processes for mixing the active therapeutic ingredient with pre-moistened h1drox1prop11met11 cellulose that can also optionally be mixed with ethylcellulose. The slow release properties of the resulting mixture can be controlled by the moisture content of the carrier material, which is again regulated in the humidification process where the carrier material is subjected to conditions of elevated humidity 1.

Lowey, U.S. Patent No. 4,259,314, je episao proizvode sa usporenlm oslobadjanje* koj1 s« so sestojali od smeša hldrokslpropllmetllceluloze koja 1ma viskozitet od 50 do 4,000 cps 1 bldroksipropllceluloze. Ove smeše, kada se suše na sadržaj vlage manji od jednog procenta, podesno se koriste sa hlgroskopnlm aktivnim sredstvima.Lowey, U.S. Patent No. 4,259,314, disclosed sustained release products consisting of mixtures of hldroxylpropylmethylcellulose having a viscosity of 50 to 4,000 cps 1 bldroxypropylcellulose. These mixtures, when dried to a moisture content of less than one percent, are suitably used with hlgroscopic active agents.

Drugi Istraživačl, uključujučl Scbor-a et al., U.S. Pat. No. 4,389,393, opisali su preparate sa usporenlm oslobadjanje* gde se materijal za osnovu nosača bira od Izvesnlh poželjn1h oblika hldroksipropll-metllceluloze koji Imaju odredjene deflnisane viskozi tete, metoksll sadržaje, bldroksipropll sadržaje i odredjene prosečne brojeve molekulskih težina.Other Researchers, including Scbor et al., U.S. Pat. Pat. No. No. 4,389,393, disclosed sustained release preparations * wherein the carrier material is selected from certain preferred forms of hydroxypropyl methylcellulose having certain defined viscous viscosities, methoxy contents, bldroxypropyl content, and certain average molecular weight numbers.

Za pravljenje tableta prema postupcima Iz ranije nauke prvo se pravi materijal za osnovu nosača. Može se koristiti smeša celuloznih komponebata 1, ako se to smatra potrebnim, smeša za osnovu nosača može se tretlratl ovlažlvanjem 111 u drugim fazama postupka. Tada se na amterljal za osnovi nosača doda aktiven sastojak i potpuno se Izmeša sa osnovom tako da se obrazuje jednobrazna smeša. Smeša aktivnog sastojka 1 nosača se odvoji prema košu mašlne za tabletiranje. Takve mašlne su dobro poznate u tehnlcl 1 mogu Imati promenjljlve veličine probojaca 1 takodje se mogu podešavatl za kontroli sanje sabljanja tablete. Na primer, mogu se koristiti probojcl 1 matrice od 0.397 do 1.905 cm 1 mašlne za tabletiranje mogu se podešavatl da Im se pritisak sabljanja menja od 0.6 do 1.4 MPa. Ovi promenjljlvl parametri 1 njihova kontrola su dobro poznati u ranijoj tehnici 1 shvačeno je da su osobine za lagano oslobadjanje funkcija 1 veličine tablete 1 sabljanja kojerasu se podvrgavaju.To make tablets according to the methods In the prior art, the carrier material is first made. A mixture of cellulose constituents 1 may be used, if deemed necessary, the carrier-based mixture may be triturated with moistening 111 at other stages of the process. The active ingredient is then added to the amperchal of the carrier base and completely mixed with the base to form a uniform mixture. The mixture of the active ingredient 1 of the carrier is separated according to the basket of the tabletting machine. Such techniques are well known in the art 1 can have variable punch sizes 1 can also be adjusted to control the compression of the tablet. For example, piercing 1 dies from 0.397 to 1.905 cm 1 tableting machines can be adjusted to have the compression pressure change from 0.6 to 1.4 MPa. These variable parameters 1 their control are well known in the prior art 1 it is understood that the light release properties are a function of 1 size of the tablet 1 of the saber that they undergo.

Tako se prema postupcima Iz ranije nauke mogu proizvaditl tablete od 1/4 do 15.Thus, according to the methods of the former science, tablets of 1/4 to 15 can be produced.

Vrlo je značajno u davanju farmaceutskih tableta, lozengi 1 sličnih preparata sa kontroli sanim, dugotrajnim oslobadjanje®, da brzina oslobadjanja aktivnog sredstva Iz tablete bude konzistentna 1 jednobrazna u svim tabletama koje su napravljene u datoj partiji proizvodnje a 1 u svim tabletama koje su napravljene u različitim vremeni na u različitim partljma proizvodnje. Kritično je, i sa stanovišta bezbednosti davanja terapeutskog sredstva i sa stanovišta pouzdanostl, da su karakteristike blopristupačnosti napravljenih tableta suštlnskl jednobrazr.e 1 uporedive. U otsustvu takve pouzdanostl opasnosti za pacljenta su značajne zato što se aktivni sastojak može oslobadjatl bržim 111 sporljln brzinaua od pretpostavljenih.It is very important in the administration of pharmaceutical tablets, Lozenges 1 similar preparations with controlled, long-term release®, that the rate of release of the active agent From the tablet is consistent 1 uniform in all tablets made in a given batch and 1 in all tablets made in different times at different times of production. It is critical, both from the point of view of the safety of administering the therapeutic agent and from the point of view of reliability, that the characteristics of the unavailability of the tablets made are substantially unambiguous 1. In the absence of such reliability, the dangers to the patient are significant because the active ingredient can be released at a faster 111 slower rate than assumed.

Na primer, kada se nitroglicerin daje padjentlma od angine oralnim 111 podjezlčnlra tabletama, takva varijadja u oslobadjanju može ugrožavati život pacijenta. Problem neuporedlvih brzina oslobadjanja medju pretpostavljeno Identičnim tebletima jc naročito važna kod onih tableta koje su tipa jednom dnevno, gde se pacijent oslanja na jednobrazno 1 uporedivo oslobadjanje it tih tableta Iz dana u dan.For example, when nitroglycerin is given a drop of angina by oral 111 subcutaneous tablets, such variations in release may endanger the patient's life. The problem of incomparable release rates among supposedly identical tablets is especially important in those once-daily tablets, where the patient relies on a single, comparable release of those tablets day by day.

Problem na koji se nailazi u tehnici jeste pravljenje više tableta sa duglm dejstvom, pri čemu svaka tableta oslobadja jednobrazno 1 uporedivo aktivni sastojak. Za postizanjee pravilne biopristupačnostl aktivnog sastojka tokom vremena od tablete do tablete 1 od partije do partije, potrebno je ne samo da se unese Ista količina aktivnog sastojka u svaku tabletu, več i da se aktlbni sastojak potpuno Izmeša i veže za celulozni materijal osnove nosača na Isti način, tako da oslobadjanje nije brže u jednoj tableti nego u drugima.A problem encountered in the art is the manufacture of multiple long-acting tablets, with each tablet releasing a single, relatively active ingredient. In order to achieve proper bioavailability of the active ingredient over the time from tablet to tablet 1 from batch to batch, it is necessary not only to enter the same amount of active ingredient into each tablet, but also to mix and bind the active ingredient completely to the cellulose material of the carrier base on the same way, so release is not faster in one tablet than in others.

Opis rešenja tehničkog problema sa primerima izvodjenjaDescription of a solution to a technical problem with examples of execution

Primarni cilj ovog pronalaska jeste da obezbedi postupak za pravljenje farmaceutskih formulacija kontrolIsanog, dugotrajnog dejstva koje sadrže aktivno terapevtsko sredstvo 1 materljalThe primary object of the present invention is to provide a process for the manufacture of pharmaceutical formulations of controlled, long-acting, active substance-containing therapeutic agent.

'.jš osnove nosača, u obliku dozne jedlnlce, koji obezbedjuje da oblik dozne jedlnlce, bilo da je tableta, lozenga, supozitorlja,The base carrier is in the form of a dosage form, which ensures that the form is dosage form, be it a tablet, a password, a suppository,

111 neki drugi oblik, Ima jednobrazne 1 uporedlve karakteristike bloprlstupačnostl.111 some other form, has one-sided 1 comparable characteristics bloprlstupacostl.

Drugi cilj ovog pronalaska je da obezbedl postupak za pravljenje nogo doznlh jedinica farmaceutske foraulaclje sa kontrolisanim, dugim dejstvo·, pri čeou su ove dozne jedlnlce bezbednije 1 pouzdanlje za davanje padjentlma.Another object of the present invention is to provide a process for making legally shaped, long-acting pharmaceutical drug units, in which these dosage units are safer 1 more reliable for administering falls.

Dalji cilj ovog pronalaska jeste da se naprave oblici doznlh jedinica faraaceutsklh formulacija sa usporenia dejstvo«, koji iaaju prednost vede jednobraznosti 1 bloprlstupačnostl.A further object of the present invention is to provide a formulation of retarded pharmaceutical formulations with a retardant effect, which have the advantage of being homogeneous in its uniformity.

Qv1 1 drugi ciljevi pronalaska postižu se u postupku u koje® se aaterijal osnove nosača, koji obuhvata najmanje jedan celulozni etar, potpuno meša sa aktivnim terapeutski» sredstvom tako da se formira suštinski jednobrazne faraaceutska formulacija, mešanje se posle toga prekine, tako formirana smeša se ostavi da stoji tokom dovoljnog vremenskog perioda da se omogudi vezivanje terapeutskog sredstva za celulozni etar (faza koja se ovde zove temperlranje), 1 tako temperirana faraaceutska formulacija se oblikuje u podestan oblik dozne judlnice.Qv1 1 other objects of the invention are achieved in a process in which the carrier base material, comprising at least one cellulose ether, is completely mixed with the active therapeutic agent so as to form a substantially uniform pharmaceutical formulation, the mixing is then discontinued, allow it to stand for a sufficient period of time to allow the therapeutic agent to bind to the cellulose ether (a phase here called tempering), 1 the so-tempered pharmaceutical formulation is formed into a suitable dosage form.

Ciljevi pronalaska se postižu kada se odredjena količina materijala osnove nosača, koji se suštinski sastoji od jednog ili više celuloznih etara 1zabranih iz grupe koja sadrži hidroksipropilaetiIcelulozu, bidroksipropi1-celulozu i etil-celulozu ili njihove derivate, meša sa terapeutski aktivnim farmaceutsklm sredstvom u granularnom obliku 111 u obliku praha, smeša se mehanlčkl meša dok sredstvo i materijal osnove ne budu jednobrazni, faza mešanja se zaustavi i pusti se da jednobrazne smeša stoji tokom odredjenog vremenskog perioda, tipično od dva do dvadesetčetiri časa i1i duže, koji je dovoljen da primora granulu terapeutskog sredstva da postanu vezane fizičkim 1/111 flzičko-hemljskim prianjanjera za dellče materijala osnove nosača, 1, onda se tako temperirana smeša obdlkuje i sablja u oblik Čvrste dozne jedlnlce kao što je lozenga, podjezlčna tableta, oralna tableta 111 supozltorlja.The object of the invention is achieved when a certain amount of a carrier base material, essentially consisting of one or more cellulose ethers 1 selected from the group consisting of hydroxypropyl ethylcellulose, bidroxypropyl 1-cellulose and ethyl cellulose or derivatives thereof, is mixed with the therapeutically active pharmaceutical granular form 111 in powder form, the mixture is stirred until the agent and base material are uniform, the mixing phase is stopped and the single mixture is allowed to stand for a fixed period of time, typically from two to twenty-four hours and longer, which is allowed to force a granule of therapeutic agent to become bonded to the physical 1/111 flzicko-hem adhesions for a fraction of the carrier base material, 1, then the so-tempered mixture is coated and compacted into a solid dosage form such as lozenges, sublingual tablets, oral suppositories 111 tablets.

Oblici dozne jedinice napravljeni postupcima iz pronalaska odlikoju se karakteristi kana jednobraznog i uporedlvog vremena oslobadjanja» t.j.» aktivni sastojak se oslobadja uporedivim brzinaaa u svakoj od mnogo tableta koje su formirane Iz date partije mešovlteg nosečeg materijala 1 terapeutskog sredstva. Nasuprot preparatima iz ranije tehnike koji nisu temperirani prema pronalasku, karakteristike tablete za vreme oslobadjanja su jednobraznije« i varijaclje od partije do partije u karakteristikama vremena oslobadjanja su na sličan način suštinski smanjene.The dosage unit forms made by the methods of the invention are characterized by the characteristics of a single and comparable release time "i.e.," the active ingredient is released at a comparable rate in each of the many tablets formed from a given batch of mixed carrier material 1 of the therapeutic agent. In contrast to the prior art preparations which are not tempered according to the invention, the release characteristics of the tablet are more uniform ”and the variation from batch to batch in the release time characteristics is similarly substantially reduced.

Za postlzanje jednobraznog 1 uporedlvog vremena oslobadjanja aktivnog sastojka 111, rečeno drukčlje, za postlzanje jednobraznih 1 uporedlvlh karakteristika biopristupačnostl ze svaku doznu jediniču koja je napravljena Iz partije nosečeg materijala 1 aktivnog sastojka, potrebno je (1) da Ista količina aktivnog sastojka bude prisutna po jediniciosnovnog materijala u svakom obliku dozne jedinice 1 da je aktivni sastojak potpuno Umešan sa osnovom, i, (2) da se potpuno Iznesenem aktlvnom sastojku i materijalu osnove nosače dopusti da stoji, bez mešanja, tokom zadovoljavajučeg vremenskog perioda da se omoguči pojava temperiranja, t.j., tokom zadovoljavajučeg vremenskog perioda za omogučevenje de se aktivni sastojak veže za noseči materijal pomoču procesa flzlčkog prianjanja 111 hem1jsko-flzlčkog prianjanja.In order to achieve a single 1 comparable release time of active ingredient 111, to put it differently, to achieve single 1 comparable bioavailability characteristics for each dosage unit made from a batch of carrier material 1 of the active ingredient, it is necessary (1) that the same amount of active ingredient is present in the new ingredient of the material in each dosage unit form 1 that the active ingredient is fully in admixture with the base, and, (2) allowing the fully exposed active ingredient and carrier base material to stand, without stirring, for a sufficient period of time to allow tempering to occur, i. during a satisfactory period of time to allow the active ingredient to bind to the carrier material by means of a chemical bonding process 111.

bilo da osnova uključuje jedan celulozni etar 111 smešu celuloznih etara 111 jednog 111 više celuloznih etara koji Imaju različite karakteristike viskozitete, smeša te osnove 1 odredjenog aktivnog sastojka ne treba da se tabletira neposredno posle mešanja osnove 1 aktivnog sastojka. Prema tehnicl iz ranije nauke, ne postoji zadovoljavajuče reproduktivnost, od tablete do tablete,whether the base includes one cellulose ether 111 a mixture of cellulose ethers 111 one 111 multiple cellulose ethers having different viscosity characteristics, the mixture of that base 1 of the particular active ingredient should not be tableted immediately after mixing the base 1 of the active ingredient. According to the technical science of earlier science, there is no satisfactory reproducibility, from tablet to tablet,

111 od partije do partije, karakteristika vremenskog perioda oslobadjanja u oblicima doznih jedinica koji se tako proizvode.111 from batch to batch, a feature of the release time in the dosage unit forms thus produced.

Ovo dovodi do vrlo značajnih razlika u Časovlma vremena oslobadjanja u tabletama koje su napravljene iz različitih partija Iste formulacije nosač/aktlvnl sastojak, 1 dovodi do sušt1n$k1h razlika u časovlma vremena oslobadjanja aktivnog sastojka od tablete do tablete iz date partije osnove i aktivnog sastojka. Ovo je očevldno nezadovoljavajuče sa medlclnskog stanovlšta za davanje 1 može dovesti do značajnih problema u lečenju.This leads to very significant differences in release time in tablets made from different batches. The same formulation carrier / active ingredient, 1 results in a substantial $ k1h difference in release time of active ingredient from tablet to tablet from a given lot and active ingredient lot. This is clearly unsatisfactory from medlcln's point of view for administration of 1 can lead to significant treatment problems.

Misli se da prepust da se omoguči staeši nosač/aktivn1 sastojak da se temperira može dovesti do odvajanja aktivnog sastojka od materijala osnove kada se smešom rukuje za vreme faza oblikovanja 1 sabljanja, koje se vrše posle faze mešanja u ranijoj tehnici. U ovom pogledu zapaženo je da se proizvodnja tableta sa kontrol1san1m oslobadjanjem ne može pravilno uporedjlvatl sa prolzvodnjom regularnih oralnih farmaceutskih tableta. U poslednjem slučaju, važan faktor je da je oslobadjanje aktivnog sastojka što je brže moguče, dok se kod formulacija sa kontrol1san1m dejstvom traže karakteristike uporedivnog oslobadjanje.It is thought that allowing the standing carrier / active ingredient to be tempered may lead to the separation of the active ingredient from the base material when the mixture is handled during the molding stages 1, which are performed after the mixing step in the prior art. In this respect, it is noted that the production of controlled release tablets cannot be properly compared with the production of regular oral pharmaceutical tablets. In the latter case, an important factor is that the release of the active ingredient is as rapid as possible, whereas for the controlled-formulation formulations, comparative release characteristics are sought.

Tačna priroda veze Izmedju granula aktivnog sastojka 1 granula celuloznog etra ne može se precizno okarakterlsatl. Medjutim, u tehnici je shvačeno da su metll-celuloza 1 drugi celulozni etri korisni u adhetlvlma, da su termo p'Etične prirode, da Imaju termogel1rajuče osobine, 1 da se mogu medjusobno vezlvati u Samove tu j uče tablete. Prema torne, bez prlbvatanja »sakoje odredjene teorije, veruje se da je centralni aspekt za sadašnji pronalazak omogučavanje aktlvnom sastojku 1 materijalu osnove nosača da stoje, neporemečenl, tokom zadovoljavajučeg vremenskog perioda da se omoguči da se polimerni osnovni materijal 1 aktivan materijal vežu pod kontrolo»» makojeg flzlčkog 111 flzlčko-hemijskog procesa. Takodje se veruje da su reakcije vezlvanja koje $· vrše ravnotežne reakcije 1 da se zato prednosti ovog pronalaska postižu posle perioda temperlranja koji je zadovoljavajuči za omogučavanje da se dejtvo vezlvanja pribHZI ravnotežl.The exact nature of the bond Between the granules of the active ingredient 1 cellulose ether granules cannot be accurately characterized. However, it is understood in the art that methylcellulose 1 other cellulose ethers are useful in adhetyls, that they are thermo-p'etical in nature, that they have thermogelic properties, 1 that they can bind to each other's learned tablets. According to Thorne, without having to adhere to a "certain theory, it is believed that a central aspect of the present invention is to allow the active ingredient 1 of the carrier base material to stand undisturbed for a sufficient period of time to allow the polymeric base material 1 of the active material to be controlled" 111 of the flzl 111 chemical-chemical process. It is also believed that the bonding reactions performed by equilibrium reactions 1 are therefore to be achieved after the tempering period which is sufficient to allow the bonding effect to reach equilibrium.

Eflkasnost veze izmedju granularnog aktivnog sastojka 1 dellča materijala osnove nosača zavisi, kako se takodje veruje, od veličina samih dellča 1 njihove konfiguracije. Tako, kontrolisanje veličine dellča aktivnog 1 osnovnog materijala, 111 konfiguracije odgovarajučih dellča, tako da se kreira Interakcija brava-i-ključ može biti od suštlnske koristi za postupak temperlranja 1 može smanjltl količinu potrebnog vremena za postlzanje željene eavnote£e.The efficiency of the bond between the granular active ingredient 1 dellcheck of the carrier base material depends, as is also believed, on the size of the dellcheck itself 1 of their configuration. Thus, controlling the size of the dell of active 1 base material, 111 configuring the corresponding dell, so as to create a lock-and-key interaction can be essential to the tempering process 1 may reduce the amount of time required to achieve the desired equilibrium £ e.

Može b1t1 moguče, u Izvesnoj meri, da se kontrollšu karakteristike vremenskog oslobadjanja formulacija koje sadrže materijal osnove nosača 1 aktivno terapeutsko sredstvo, 1 to variranjen dužine vremena za koje se smeša temperira. To jeste, kada je potrebno veliko početno oslobadjanje da se terapeutski nivo dostigne Sto je pre moguče, može biti poželjno da se škrati dužina faze temperlranja. Nasuprot, kada je poželjna postojana 1 konstantna brzlna oslobadjanja tokom dužeg perioda vremena, može biti korlsno da se produžl faza temperlranja 1 de se pojala vez1vanje aktlvnog sastojka za materijal osnove nosače.B1t1 may possibly, to some extent, control the temporal release characteristics of formulations containing carrier base material 1 active therapeutic agent, 1 varying the length of time for which the mixture is tempered. That is, when a large initial release is required to reach the therapeutic level As soon as possible, it may be desirable to shorten the length of the tempering phase. Conversely, when a constant constant release rate is desired over a long period of time, it may be advantageous to extend the tempering phase to increase the binding of the active ingredient to the carrier base material.

Prilikom davanja leka sa suzdržanlm dejstvom* pnekad je poželjno Imati relativno brzo oslobadjanje leka do Izvesne koncentracije u krvi 1 da se onda održava 111 konstantna 111 neznatno opadajuča koncentracija nivoa u krvi. Ovi ;1ljev1 se postlžu sa pronalaskom, dok se u rani joj tehnld, kao Sto če b1t1 demonstrlrano u donji m komparativnim primerima, mogu javiti Široke varljaclje u bloprlstupačnostl aktlvnog sastojka kada se ne koristi postupak 1z pronalaska.When administering a drug with a restraining effect *, it is sometimes desirable to have a relatively rapid release of the drug to a certain concentration in the blood 1 to then maintain a 111 constant 111 slightly decreasing blood levels. These; 1l1 are related to the invention, whereas in its early techniques, such as b1t1 demonstrated in the comparative examples below, Wide variants of the active ingredient may occur when the method of the invention is not used.

Stručnjacl Če shvatltl da postupakm 1 z pronalaska tde korak Ispred tehnika o kojima se uči u Farmakopeji Sjedlnjenjlh Država za kontrolu jednobraznostl doza-obllk u komprlmovanlm tabletama. United States Pharmacopoela - NF, Drugi Dodatak, opisuje testove za varljadpu teži ne 1 jednobraznost sadržaja za tablete. Za sabijene tablete (prevučene 111 neprevučene), prepisani testovl zahtevaju testiranje varljaclje težlne 111 jednobraznostl sadržaja vHestrukih doznlh jedinica 1 statlstlčku analizu tih rezultata da se odredi da 11 su vlšestruke tablete u datoj partiji zadovoIjavajuče jednobrazne po svom sadržaju aktlvnog sastojka. Sledeči test citiran je 1z U.S.P. - NF, Second Suppleaent, Phys1cal Tests/ Unlformity of Oosage Unlts, strana 905.The Expert If you understand that step 1 of the invention is then a step ahead of the techniques taught in the Pharmacopoeia of the Sad State to control the uniformity of dose-obllk in compressed tablets. United States Pharmacopoela - NF, Second Appendix, describes cheat tests weighing not more than one tablet content uniformity. For compressed tablets (coated 111 uncoated), the transcribed test requires the testing of a cheat weight of 111 single content contents in Multiple sub-units 1 statistical analysis of these results to determine that 11 multiple tablets in a given lot are satisfactorily uniform in content of the active ingredient. The following test is quoted 1z U.S.P. - NF, Second Suppleaent, Phys1cal Tests / Unlformity of Oosage Unlts, page 905.

(A) Ako je prosel granlca speclflkovanlh u definiciji za snagu u pojedlnačnoj monografiji 100.0 procenata 111 manje -SABIJENE TABLETE (PREVUČENE ILI NEPREVUČENE), SUSPENZIJE U U KONTEJNERIMA ZA DOZNU JEDINICU, ČVRSTE SUPSTANCE (UKLJ14 CUJUČI SIERILNE ČVRSTE SUPSTANCE) U KONTEJNERIMA ZA DOZNU JEDINICU, 1 STERILNE ČVRSTE SUPSTANCE ZA PARENTERALNO KORIŠČENJE.(((A ((A ((A ((A ((A ( 1 STERILE SOLID SUBSTANCE FOR PARENTERAL USE.

Ako nije drukčije speciflkovano u pojedlnačnoj monografiji, zahtevi za jednobraznost doze Ispunjeveju se ako se količina aktlvnog sastojka u svakoj od 10 doznlh jedinica odredi na osnovu postupka za Varljaclju težlne Jednobraznostl sadržaja 1 leži unutar Intervala od δδ.Ο procenatado 115.0 procenata y - Iz zahteva za tablete a Relativna standardna devijadja je menja 111 jednaka 6.0 procenata.Unless otherwise specified in the individual monograph, dose uniformity requirements are fulfilled if the amount of active ingredient in each of the 10 dosage units is determined by the procedure for Weight Loss Content monosyllabus 1 lies within an interval of δδ.Ο percent 115.0 percent y - From the requirement for tablets a The relative standard deviation is 111 equals 6.0 percent.

Ako je 1 jedinica van Intervala 85.0 procenata do 115.0 procenata kako se kaže na etiketi 1 nljedna jedinica nije van Intervala o< 75.0 procenata do 125.0 procenata od zahteva na etiketi, 111 je Relativna standardna devijadja veča od 6.0 procenata, 111 ako oba uslova prevladavaju, testirati 20 dopunskih jedinica. Zahtevi se zadovoljavaju ako je ne više od 1 jedinice od 30 van Intervala od 85.0 procenata do 115.0 procenata od zahteva na etiketi 1 nljedna jedinica nije van zahteva od 75.0 procenata do 125.0 procenata 1z zahteva na etiketi a Relativna stabdardna devijadja 30 doznlh jedinica ne prenaša 7.8'procenta.If 1 unit outside the Interval is 85.0 percent to 115.0 percent as stated on the label 1 the next unit is not outside the Interval about <75.0 percent to 125.0 percent of the label requirement, 111 is a Relative Standard Deviation greater than 6.0 percent, 111 if both conditions prevail. test 20 supplementary units. Requirements are satisfied if no more than 1 unit of 30 is outside the interval of 85.0 percent to 115.0 percent of the label requirement 1 non-standard unit is no requirement of 75.0 percent to 125.0 percent of the 1z label requirement and the Relative stdard deviation of 30 extant units does not exceed 7.8 'percent.

Prethodnl testovl, bilo na bazi varijacije težine 111 jednobraznost1 sadržeja, nisu obavezno podesti za pravilno testiranje pouzdanosti oblika doznlh jedinica 1z partije formulacije sa nameravanim oslobadjanjem u odredjenom vremen s kon’ \>er1odu. To je zato što čak i sa zadovoljavajučom statlstlčkom performansom u odnosu na varljaclju težine 1 jednobraznost sadržaja, karakteristike oslobadjanja u vremenskom periodu aktivnog sastojka 1z takvih tableta mogu značajno varirati zato što akti vnoo sastojku nije bilo dopušteno da se veže za materijal nosača prema sadašnjem pronalasku.The previous tests, either on the basis of a variation in weight 111 of uniformity1, do not necessarily set out to properly test the reliability of the shape of the units 1z of the formulation batch with the intended release at a specified time with con '\> er1od. This is because, even with satisfactory performance in relation to the weight cheater 1 uniformity of content, the release characteristics over the time of the active ingredient 1 of such tablets can vary significantly because the active ingredient was not allowed to bind to the carrier material of the present invention.

Pronalazak nije ograničen na koriščenje makojeg pdredjenog celulozno g etra, 1 stručnjacl če shvatltl da se može koristiti jedan celulozni etar 111 smeša etara kao 1 razni kvaliteti vlskozlteta u nekoliko komercljalno prlstupačnlh celuloznih etara. široko govoreči, poželjno se koriste hidroksialkil-celuloza 1/111 hldrokslalkl1-alkilceluloza kao što su hldrokslpropil-metilceluloza, hldrokslpropl1-celuloza, hldroksletll-celuloza, karbokslmetllceluloza, karbokslmetll-celuloza 1 druga sllčba jedinjenja 111 derivati. Medju ovlma su poželjni hldrokslpropil-metilceluloza 1 hldrokslpropl1-ce1u1oza, pri čemu se prva može dobiti sa različltlm kvalitetloa vlskozlteta od 3 cps do 100,000 cps od Dow Chemical Company pod njenim trgovačklm Imenom Methocel a poslednja je prlstupačna od Hercules, Inc., pod trgovačklm Imenom Klucel. Podesne osnove nosača mogu se napraviti koriščenjem materijala Methocel E50 (50 cps), Methocel E4M (4,000 cps) 1 Methocel K15M (15,000 cps).The invention is not limited to the use of a further predetermined cellulose ether, one skilled in the art will appreciate that one cellulose ether 111 ether mixtures can be used as 1 different properties of cellulose in several commercially available cellulose ethers. Broadly speaking, hydroxyalkyl cellulose 1/111 hydroxyalkyl-1-alkylcellulose such as hydroxypropyl-methylcellulose, hydroxypropyl-cellulose, hydroxylethyl-cellulose, carboxymethylcellulose, carboxylmethylcellulose, carboxylic methylcellulose, carboxylic acid methylcellulose, carboxylic acid methylcellulose Hydroxylpropyl methylcellulose 1 hldroxlpropl1-ce1u1ose is preferred among the ovlms, the former being obtainable from various quality damages from 3 cps to 100,000 cps by the Dow Chemical Company under its trade name Methocel, and the latter is available as an affiliate, Inc. Klucel. Suitable carrier bases can be made using Methocel E50 (50 cps), Methocel E4M (4,000 cps) 1 Methocel K15M (15,000 cps).

Aktivni sastojci koji se kooblnuju sa materijalom osnove nosača mogu bit1 makojeg tipa koji dejstvuje sistemski 111 lokalno.The active ingredients that interact with the carrier base material may be of a type 1 acting locally.

.. ..« 14-:.. .. «14-:

Oni koji dejstvuju sistemski $e tipično daju oralno, a cilje je da se Isporučuju pouzdane 1 konstantne količine aktivnog sredstva u krvotok. Oni tlpovl aktivnih sastojaka koji dejstvuju lokalno mogu se koristiti u bukalnlm tabletama 111 u vaginalnim 111 rektalnim supozltorljama.Those who act systemically typically administer orally and aim to deliver a reliable 1 constant amount of active agent to the bloodstream. Those topically active topically acting ingredients can be used in buccal tablets 111 in vaginal 111 rectal suppositories.

Medju aktivnim terapeutskim sredstvima koja se mogu kombi novati sa materijalom osnove nosača prema postupku Izp pronalaska su sedativi» vitamini» ant1-1nflamatorna sredstva» vazodllatatorl, Stlmulantl» relaksantl, supresentl 1 mnogi drugi tlpovl terapeutsk1h sredstava.Among the active therapeutic agents that can be combined with the carrier base material according to the method of the invention are the sedative »vitamins» ant1-1 inflammatory agents »vasodllatatorl, Stylmulantl» relaxant, supersl 1 many other tlpovl therapeutic agents.

Medju aktivnim sastojclma koji se mogu koristiti u postupku 1z pronalaska su» na primer» 1zosorb1drd1n1trat 111 mononltrat (koritčen u lečenju angine pektorls), teofilln (kori5čen u tretiranju astme)· nitroglicerin» Ibuprofen 1 acetaminofen.Among the active ingredients that can be used in the method of the invention are "for example" 1zosorb1drd1n1trat 111 mononltrate (used in the treatment of angina), theophylline (used in the treatment of asthma) · nitroglycerin »Ibuprofen 1 acetaminophen.

U pravljenje farmaceutsklh preparata 1z pronalaska».željeni odnos aktivnog sestojka 1 materijala osnove nosače uvede se u sud za metanje. Drugls sastojd koji trebe de se uključe u finalni oblik dozne jedinice mogu se uvesti u sud ze metanje, na primer» punlla, sredstva za sušenje, maziva, sredstva za bojenje, škrob 1 drugi materijali koji su dobro poznati u tehnlcl.In the manufacture of the pharmaceutical composition 1z of the invention, the desired ratio of the active ingredient 1 of the carrier base material is introduced into the throwing vessel. Drugs to be incorporated into the final dosage unit form can be introduced into the container for example, for example fillers, drying agents, lubricants, coloring agents, starch 1 other materials well known in the art.

Posle toga osbovne smeta se tipično meta 1 mučka tokom 20 do 40 minuta 1 obično od 30 do 40 minuta da se postigne jednobraznost aktivnih sastojaka sa osnovnom smetom. Oprema za metanje može biti, na primer, Oey mlkser 111 Pony mlkser.Subsequently, the intrinsic target is typically targeted at 1 stutter for 20 to 40 minutes 1, usually 30 to 40 minutes, to achieve uniformity of the active ingredients with the basic nuisance. Throwing equipment may be, for example, Oey mlkser 111 Pony mlkser.

Faze temperalranje koja je kritična za sadatnjl pronalazak se obično vrti u istom 111 razllčltora sudu od onofa u kojem se vrti faza metanja. «Jednobrazno 1 zmetani materijal se pusti da stoji» suttlnskl naporemečen tokom perioda od 2 do 72 časa» poželjno 4 do 48 časa, dok se aktivni sastojak veže za plastičen materijal osnove noseča.The tempering phases that are critical to the present invention typically revolve in the same 111 different vessel than the one in which the throwing phase rotates. &Quot; Single-sided mixed material is allowed to stand " suttlnskl intermittent over a period of 2 to 72 hours, preferably 4 to 48 hours, while the active ingredient binds to the carrier base plastic material.

Potto se jednobrazna smeta temparlra tokom dovoljnog perioda da se Izazove vrtenje vezivanje» prenese se u fazu oblikovanja 1 sabljanja kao tto je poznato u tehnlcl. Opoema koja se koristi za takve faze mogu biti» ne primer» Stokaš 111 Colton rotaclone metine 111 drug« malin· za sabljanje tableta» Tipično sabljanje . . . .-11- :Therefore, the single-tempered interference of the temparlr over a sufficient period to cause the rotation of the binding »is carried to the phase of forming 1 of the saber as known in the technlcl. The opoema used for such phases may be "not an example" of a stockman 111 Colton rotaclone methine 111 drug "raspberry · for tablet compaction" Typical sabbatical. . . .-11-:

kor14čeno u fazi oblikovanja 1 sabljanja varira od 0.6 do 1.2 MPa 1 poželjno je u Intervalu 0.8 do 1.2 MPa. Oblici dozne jedinice napravljeni u ovoj flnalnoj fazi mogu uključlvatl oralne 111 bukalne tablete« lozenge, trošee, supozltorlje 1 druge oblike.used in the design phase 1 of the compaction ranges from 0.6 to 1.2 MPa 1, preferably at an interval of 0.8 to 1.2 MPa. Dosage unit forms made in this flnal phase may include oral 111 buccal tablets, lozenges, consumables, suppositories 1 other forms.

Pronalazak je dalje opisan u sledečim primerima 1 u crtežlma.The invention is further described in the following Examples 1 in the drawing.

PRIMERIEXAMPLES

Serija tableta sa suzdržanlm oslobadjanjem napravljene su postupkom 1z pronalaska 1 postupkom 1z ranlje nauke 1 testirane su Bjlhove performanse za suzdržano oslobadjanje.A series of restrained release tablets were made by Procedure 1z of Invention 1 by Procedure 1z of Early Science 1 and Bjlh's performance for restrained release was tested.

Primer I-IVExample I-IV

Postupak ze pravljenje tabletaThe process is to make tablets

Sastojcl osnove navedeni niže mešaju se oko 20 minuta u Day mlkseru za prah 111 Pony mlkseru. Aktivni sastojak se doda u osnovnu smešu 1 smeša se ponovo meša tokom oko 30 minuta sa dodavanjem maziva. Konačno se kompletna smeša pusti da se temperalra za vezivanje ne manje od 24 časa na sobnoj temperaturi. Tablete se sablju u tablete oblika kapsule. Veličina probojca bila je oThe base ingredients listed below are stirred for about 20 minutes in a Day ml 111 Pony mlkser powder. The active ingredient is added to the basic mixture. 1 The mixture is stirred again for about 30 minutes with the addition of lubricant. Finally, the complete mixture is allowed to bind at least 24 hours at room temperature. The tablets are sabered into capsule shaped tablets. The size of the breakthrough was Fr.

mm x 8.5 mm a tvrdoča je bila 9 kg/cm . U svakom slučaju« snaga tablete bile je 120 mg.mm x 8.5 mm and the hardness was 9 kg / cm. In each case, the strength of the tablet was 120 mg.

Oslobadjanje aktivnog sastojkaRelease of the active ingredient

Oslobadjanje aktivnog sastojka Iz tableta napravljenih u PrimerimaRelease of the active ingredient From the tablets made in the Examples

I-IV odredjeno je testovlma Izvršenim na krvotoku« u svakom slučaju« na šest dobrovoljaca. Prosečna vrednost aktivnog sastojka u krvi u naznačenim vr4mensk1m Intervallma prikazana je na Slikama 1-4.I-IV was assigned to a test performed on the bloodstream "in any case" by six volunteers. The average value of the active ingredient in the blood at the indicated vr4mensk1m Intervallma is shown in Figures 1-4.

Oslobadjanje aktivnog sastojka tokom vremena 1z tableta napravljenih kao Sto je opisano gore može se takodje odrediti pomoču vitro teste koji analizira procenat oslobodjenog laka sa jednoa tebletom u test vremenskih Intervale pomoču testa rastvaranja u padd1e“ aparatu (U.S.P. XX. strana 959). U ovom testu« jedna tablete se stavi u sud koji sedrži 500 al pufere pH 1.2 (simulira stomačnl fluld bez enzlma, U.S.P. XX, strana 1105) drži sa pod rotacijo» od 125 RPM (obrtaja u mlnutu) na 37°C za vreme testa. Na kraju prvog, četvrtog i Osmog časa odredi se apsorbanclja rastvora na oko 278 nm naspram pH 1.2.The release of the active ingredient over the time of 1z tablets made as described above can also be determined using in vitro assays that analyze the percentage of one tablet lacquer released at the time intervals using the padd1e dissolution test apparatus (U.S.P. XX p. 959). In this test, "one tablet is placed in a vessel containing 500 al pH 1.2 buffers (simulates a non-enzymatic stomach fluid, USP XX, page 1105) held at a rotation of 125 RPM (rpm) at 37 ° C during the test. . At the end of the first, fourth and eighth hours, the absorbance of the solution was determined at about 278 nm against pH 1.2.

Napravljene su sledeče tablete :The following tablets are made:

Primer I :Example I:

Aktiven sastojak X Active ingredient X 120 120 ga Mrs Hidroksipropil-metil celuloza Hydroxypropyl methyl cellulose HPMC E-50 (Dow) HPMC E-50 (Dow) 10 10 « « HPMC E-4M (Dow) HPMC E-4M (Dow) 50 50 n n Hidroksipropil-celuloza Hydroxypropyl cellulose HPC (Hercules) HPC (Hercules) 10 10 m m StearInska kiselina StearInic acid 1 1 « « Sylo1d Sylo1d 2 2 • •

Primer ΠExample Π

Aktiven sastojak X Active ingredient X 120 120 ga Mrs HPMC £-50 HPMC £ -50 30 30 « « HPMC E-4M HPMC E-4M 30 30 • • HPC HPC 10 10 m m Stearlnska kiselina Stearlic acid 1 1 a a Sy1o1d Sy1o1d 2 2 « «

Primer IIIExample III

Aktlvan sastojak X Active ingredient X 120 120 ga Mrs HPMC E-50 HPMC E-50 40 40 HPMC E-4M HPMC E-4M 20 20 n n HPC HPC 10 10 Stearlnska kiselina Stearlic acid 1 1 « « Sy1o1d Sy1o1d 2 2 N N

Primer IVExample IV

Aktiven sastojak X Active ingredient X 120 120 ga Mrs HPMC E-50 HPMC E-50 10 10 n n HPMC E-4M HPMC E-4M 50 50 M M HPC HPC 10 10 N N Stearlnska kiselina Stearlic acid 1 1 « « Sy1o1d Sy1o1d 2 2 « «

Komparativni primeri I-A - IV-AComparative Examples I-A - IV-A

Tableta su napravljene prema postupku 1z ranije nauke koriščenjem Iste smeše kao što je opisano u Prlmerima I-IV. Tablete Iz Primera IA-1VA napravljene su mešanjem osnovnih sastojaka navedenih gore tokom oko 20 minuta u Day mllseru za prah 111 Pony mlkseru, dodavanjem osnovnog mlksa 1 mešanjem Iste ponovo oko trideset minute uz dolivanje maziva. Tada se smela tabletlraThe tablets were made according to method 1z of prior art using the same mixture as described in Prlmer I-IV. The tablets of Example IA-1VA were made by mixing the basic ingredients listed above for about 20 minutes in a Day Pellet Powder 111 Pony mlkser, adding the basic mlks 1 by stirring the same again for about thirty minutes with refill. Then the tabletlra dared

-- . . .7 neposredno 1 bez dopuščanja da stoji 111 postane vezan prema pronalasku. Kao u Primerimo I-IV, tablete se sabljaju uaodmerene tablete oblika kapsule koriščenjem veličine proboljca 19 mm x 8.5 ram 1 tvrdoče 0.9 NPa. Oslobadjanje aktivnog sestojka odredjeno je kao Što je opisano u Prlmerlma I-IV:-. . .7 immediately 1 without allowing 111 to become attached to the invention. As in Example I-IV, the tablets are compacted into metered capsule shaped tablets using a 19 mm x 8.5 ram 1 piercer size 0.9 NPa hardness. The release of the active ingredient was determined as described in Prlmerlma I-IV:

Uporedjlvanje tableta 1z pronalaska se tabletama Iz ranije naukeComparison of tablets 1z of the invention is a tablet from a previous science

Sl. 1 prikazuje količinu aktivnog sastojka oslobodjenog 1z tablete Iz Primera I, referentni broj IG» 1 Iz tablete Iz PrimeraFIG. 1 shows the amount of active ingredient released from 1z tablet from Example I, reference number IG »1 From the Example tablet

I- A, referenčni broj 12. Vidljivo je da kompa tlvna tableta« tableta I-A, koja je napravljena Iz partije kojoj nije dopušteno da se veže, pokazuje oštar pad nivoa aktivnog sastojka posle oko tri časa. Štaviše, količina aktivnog sastojka koja je prlstupačna posle 12 Časova je suštinski niža nego u tableti koja je napravljena prema pronalasku kojoj je dopušteno da se vezuje tokom najmanje dvadesetčetlrl časa. štaviše, aktivan sestojak oslobodjen 1z tablete napravljene prema pronalasku Iraao je suštinski ujednačcne karakteristike oslobadjanja posle dostizanja najvlšeg nivoa aktivnog sastojka za oko dva časa.I-A, Reference No. 12. It is apparent that the Compact Tablet «I-A tablet, made from a non-bindable batch, shows a sharp decrease in the level of the active ingredient after about three hours. Moreover, the amount of active ingredient available after 12 hours is substantially lower than in a tablet made according to the invention which is allowed to bind for at least twenty-four hours. moreover, the active ingredient released by the 1z tablet made according to the invention of Iraao has essentially uniform release characteristics upon reaching the highest active ingredient level in about two hours.

Sl. 2 prikazuje krive za količinu aktivnog sastojka koji je oslobodjen Iz Tablete iz Primera II, 14, 1 1z tablete Iz PrimeraFIG. 2 shows the curves for the amount of active ingredient released from the Example Pills II, 14, 1 1z from the Example Pills

II- A. Oslobadjanje aktivnog sastojka opisano na Sl. 2 suštinski potvrdjuje superiornost vezane tablete. Postoji ekstremno oštar pad u aktivnom nivou posle oko 'tri časa iz tablete koja je napravljena prema tehnicl Iz ranije nauke (Primer II-A).II- A. The release of the active ingredient described in FIG. 2 substantially confirms the superiority of the bound tablet. There is an extremely sharp decline in the active level after about three hours from a tablet made according to the prior art (Example II-A).

Sl. 3 prikazuje krive za količinu aktivnog sastojka koji je oslobodjen Iz tablete iz Primera III, 18, 1 iz tablete Iz Primera III-A, 20. Rezultati opet potvrdjuju superiornost tableta napravljenih prema pronalasku. Pad u nivou aktivnog sastojka Iz komparativne tablete III-A bio je ekstremno oštar u trečem času.FIG. 3 shows the curves for the amount of active ingredient released from the tablet of Example III, 18, 1 from the tablet of Example III-A, 20. The results again confirm the superiority of the tablets made according to the invention. The drop in the level of the active ingredient Comparative tablet III-A was extremely sharp in the third hour.

Sl. 4 prikazuje krive za količinu aktivnog sastojka koji je oslobodjen iz tablete 1z Primera IV, 22 1 iz tablete Primera IV-A, 24. Potvrdjena je superiornost tablete iz pronalaska, pri čemu postoji oštar pad u nivou aktivnog sastojka Iz nevezane tablete (IV-A) tokom oko trečeg časa.FIG. 4 shows the curves for the amount of active ingredient released from the tablet 1z of Example IV, 22 1 from the tablet of Example IV-A, 24. The superiority of the tablet of the invention was confirmed, with a sharp decrease in the level of the active ingredient from the unbound tablet (IV-A ) during about the third hour.

Primer VExample V

Postupak za pravljenje tableteThe procedure for making a tablet

Osnovni sastojci navedeni niže melaju se oko 20 minuta u 0ay mlkseru ta prah 111 Pony mlkseru. Aktlvan sastojak se doda na osnovnu sae&u 1 smela se ponovo meša oko 30 minuta sa dodavanjem maziva. Flnlano se dopusti da se kompletna smela tomperlra za vezivanje ne manje od 24 časa na sobnoj temperaturi. Tablete se sabijaju u odmerene tablete oblika kapsule. Veličina probojca bila je 19.1 mm x 9.7 mm a tvrdoča 0.9 MPa. U svakom slučaju· snaga tablete bila je 85 mg.The basic ingredients listed below are melted for about 20 minutes in 0ay mlkser and 111 Pony mlkser powder. The active ingredient was added to the basic sae & in 1 bold again stirred for about 30 minutes with the addition of lubricant. Flnlano shall be allowed to bind the complete binder tomperlra for at least 24 hours at room temperature. The tablets are compressed into metered capsule shaped tablets. The breakthrough size was 19.1 mm x 9.7 mm and a hardness of 0.9 MPa. In each case, the strength of the tablet was 85 mg.

Oslobadjanje aktivnog sastojka eRelease of the active ingredient e

Oslobadjanje aktivnog sastojka 1z tableta napravljenih u Primeru V odredjeno je testovima nivoa u krvi, Izvršenim, u svakom slučaju, na fiestr dobrovoljaca. Prosečna vrednost nivoa aktivnog sastojka u krvi u naznačenim Interval Ima prikazana je na Sl. 5. Uzorcl venske krvi dobiveni su od svakog pacljenta tačno pre 1 posle 0.25, 0.5, 0.75, 1.00, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.O, 12.0, 24.0, 36.0 1 48.0 časa vremena pre doziranja. Kod svih lest (6) pacljenata takodje je roeren arterijski krvni pritisak tačno pre doziranja, 1 na 1.0, 2.0, 4.0, 6.0 1 9.0 časova posle doziranja.The release of the active ingredient of the 1z tablets made in Example V was determined by blood level tests, performed, in each case, on a fiestr of volunteers. The average value of the level of the active ingredient in the blood at the indicated Interval Ima is shown in Figs. 5. Venous blood samples were obtained from each patient just before 1 after 0.25, 0.5, 0.75, 1.00, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.O, 12.0, 24.0, 36.0 1 48.0 hours before dosing. In all patients (6) patients, arterial blood pressure was also born just before dosing, 1 at 1.0, 2.0, 4.0, 6.0 and 9.0 hours after dosing.

Oslobadjanje aktivnog sastojka tokom vremena takodje može da se odredi testom 1n vitro. Ovaj test odredjuje procenat oslobodjenog leka pomoču jedne tablete u fiksiranim vremenskim IntervalIma pomoču testa rastvaranja u paddle aparatu (U. S. P. XX, strana 959). dedna tableta se stavi u sud koji sadrži 500 ml pufera pH 1.2 (simulira stomačni fluld bez enzima, U.S.P. XX, strana 1105) 1 drži se pod rotacijom od 125 RPM na 37°C za vreme testa. Posle prvog, četvrtog 1 osmog časa, uzorcl se Izvleče 1 tretlraju sa hldrazlnsulfatom, sulfanllamidom 1 N-(1-naft1l)-et1Iend1am1nom hlorhidratoa 1 apsorbancija rastvora odredjuje se na oko 540 mm.The release of the active ingredient over time can also be determined by the 1n in vitro test. This test determines the percentage of drug released by a single tablet at fixed time intervals using a paddle dissolution test (U. S. P. XX, page 959). the grandfather tablet is placed in a container containing 500 ml of pH 1.2 buffer (simulates an enzyme-free stomach fluid, U.S.P. XX, page 1105) 1 held at 125 RPM at 37 ° C during the test. After the first, fourth, and eighth hours, the sample extracts were treated with chlorodenzyl sulfate, sulfanylamide 1 N- (1-naphthyl) -ethanylamine hydrochloride 1, and the absorbance of the solution was determined to be about 540 mm.

Sledeča smela napravljena je 1 tabletlrana kao gore.The following bold made 1 tablet as above.

V//-:In // -:

Aktivan sastojak Y Active ingredient Y 80 80 gm gm HPMC £-50 HPMC £ -50 20 20 « « HPMC E-4M HPMC E-4M 40 40 n n HPHC K-15 HPHC K-15 10 10 n n HPC HPC 10 10 H H Stearlnska kiselina Stearlic acid 1 1 H H Sylo1d Sylo1d 1 1 M M

Koinparati van Prtmer V-ACoinparatons van Prtmer V-A

Osnovni sastojci navedeni u Primeru S mešaju se oko 20 minuta u Oay mikseru za prah 111 u Pony mikseru. Aktivni sastojak se doda na osnovnu smešu 1 smeša se opet meša tokom oko 30 minuta sa dodavanjem maziva. Smeša se tada neposredno tablet a u Stokes 82 rotacionoj mašini 111 Manesty mašlnl postavijenoj na kompreslju od 0.9 HPa. Veličina probojca bila je 19.1 mm x 9.7 mm a tvrdoča 0.9 HPa. U svakom slučaju snaga tablete bila je 85 mg. Oslobadjanje aktivnog sastojka odredjeno je kao što je opisano u Primeru V.The basic ingredients listed in Example S were stirred for about 20 minutes in an Oay powder mixer 111 in a Pony mixer. The active ingredient is added to the basic mixture. 1 The mixture is stirred again for about 30 minutes with the addition of lubricant. The mixture was then directly tableted in a Stokes 82 rotary machine 111 Manesty machine set to a compress of 0.9 HPa. The breakthrough size was 19.1 mm x 9.7 mm and a hardness of 0.9 HPa. In each case, the strength of the tablet was 85 mg. The release of the active ingredient was determined as described in Example V.

Uporedjenja tableta 1z pronalaska sa tabletama iz ranije tehnikeComparisons of tablets 1z of the invention with tablets of the prior art

Sl. 5 prikazuje krive oslobadjanja aktivnog sastojka 1z dva seta tableta Iz Primera V, 26, bapravljenlh prema pronalasku 1 jednog seta tableta napravljenih prema postupku iz ranije nauke (Primer V-A) 28. Vidljivo je da je nevezana tableta (Primer V-A) dostigla najvišl nivo aktivnog sastojka gotovo neposredno 1 onda je oslobadjanje pretrpelo oštar pad posle trečeg časa. Nivo aktivnog sastojka 1z tablete komparativnog primera V-A bio je suštinski niži poslednjih časova testiranja nego u bilo kojoj od tableta napravljenih prema postupku Iz pronalaska.FIG. Figure 5 shows the release curves of the active ingredient 1 of two sets of tablets of Example V, 26, according to the invention 1 of one set of tablets made according to a method of prior art (Example VA) 28. It is seen that the unbound tablet (Example VA) has reached the highest level of the active ingredient almost immediately 1 then the liberation suffered a sharp decline after the third hour. The active ingredient level of the 1z tablet of Comparative Example V-A was substantially lower in the last hours of testing than in any of the tablets made according to the method of the invention.

Primer VIExample VI

Postupak za pravljenje tableteThe procedure for making a tablet

Osnovni sastojci navedeni niže mešaju se tokom oko 20 minuta u Oay mikseru za prah 111 u Pony mikseru. Aktivni sastojak se doda u osnovnu smešu 1 smeša se ponovo meša tokom oko 30 minuta sa dodavanjem maziva. Konačno te pusti da se kompletna smeša temperira radi vezlvanja tokom ne manje od 24 časa na sobnoj temperaturi. Smeša se tada tabletlra u Stokes 82 rotacionoj mašlnl 111 ManestyThe basic ingredients listed below are stirred for about 20 minutes in an Oay powder mixer 111 in a Pony mixer. The active ingredient is added to the basic mixture. 1 The mixture is stirred again for about 30 minutes with the addition of lubricant. Finally, allow the complete mixture to temper for freeing for at least 24 hours at room temperature. The mixture was then tableted in a Stokes 82 rotary machine 111 Manesty

-•---Ib- :- • --- Ib-:

mašini koja je podešena na kompreslju 0.9 MPa. Tablete se sabljaju u odmerene tablete, oblika kapsule. Veličina pro boj ca bila je 19.1 mm x 9.7 mm a tvrdoča je bila 0.9 MPa. U svakom slučaju, snaga tablete bila je 104 mg.machine set at 0.9 MPa compressor. The tablets are compressed into metered capsules. The size of the battles was 19.1 mm x 9.7 mm and the hardness was 0.9 MPa. In each case, the strength of the tablet was 104 mg.

Napravljena je sledeča formulacija :The following formulation was made:

Aktivni sastojak Z Active ingredient Z 100 100 gra gr HPMC E-50 HPMC E-50 20 20 u in HPMC E-414 HPMC E-414 40 40 M M HPMC K-15 HPMC K-15 10 10 M M HPC HPC 10 10 ft ft Stearinska kiselina Stearic acid 1 1 it it Sylo1d Sylo1d 1 1 9t 9т

Oslobadjanje aktivnog sastojkaRelease of the active ingredient

Oslobadjanje aktivnog sastojka 1z tableta napravljenih < Primeru VI odredjeno je testovlma u krvi Izvršenim, u svakom slučaju, na šest dobrovoljaca. Prosečna vrednost nivoa aktivnog sastojka u krvi u naznačenim vremenskim Intervalima prikazana je na Sl. 6. Ooblvenl su uzorcl venske krvi iz svakog pacijenta tačno pre 1 u 0.25, 0.5, 0.75, 1.00, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.0,The release of the active ingredient 1z tablets made <Example VI was determined by blood tests performed, in each case, on six volunteers. The average value of the level of the active ingredient in the blood at the indicated time intervals is shown in Figs. 6. Ooblvenl are venous blood samples from each patient exactly before 1 in 0.25, 0.5, 0.75, 1.00, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.0,

12.0» 24.0, 36.0 1 48 Časa posle doziranja. Kod svlh šest (6) pacljenata, takodje je moren arterijski krvni pritisak pre doziranja, 1 1.0, 2.0, 4.0, 6.0 1 9.0 časova posle doziranja.12.0 »24.0, 36.0 1 48 Hours after dosing. All six (6) patients also had arterial blood pressure before dosing, 1 1.0, 2.0, 4.0, 6.0 and 9.0 hours after dosing.

Oslobadjanje aktivnog sastojka tokom vremena može se takodje odrediti testom in vitro. Ovaj test odredjuje procenat oslobodjenog leka pomoču jedne tablete u fiksiranim vremensflrn intervalima pomoču testa rastvaranja u paddle aparatu (U. S. P. XX, strana 959). dedna tableta stavi se u sud koji sadrži 500 ml pufera pH 1.2 (simulirani stomačai fluld bez enzioe, U.S.P. XX, strana 1105) 1 drži se pod rotacljom od 125 RPM na 37°C za vreme testa. Posle prvog, četvrtog 1 osmog časa, Izvučenl su uzorcl 1 tretlraju se sa hldrazlnsulfatom, sulfanllami dom 1 N-(1-nafti1)-et1lendiaminhlorhldratom 1 apsorbanclja rastvora odredjuje se na oko 540 nm.The release of the active ingredient over time can also be determined by an in vitro test. This test determines the percentage of drug released by the aid of a single tablet at fixed timesflrn intervals by the dissolution test in a paddle apparatus (U. S. P. XX, p. 959). the grandfather tablet is placed in a container containing 500 ml of buffer pH 1.2 (simulated stomach without enzioe, U.S.P. XX, page 1105) 1 kept at 125 RPM at 37 ° C during the test. After the first, fourth, and eighth hours, Extracted 1 samples were treated with chlorodenzulfate, sulfanlamide 1 N- (1-naphthyl) -ethylenediamine chlorchlorate 1 absorbent solution, determined at about 540 nm.

Komparatlvan Primer Vl-AComparative Example Vl-A

Postupak za pravljenje tableteThe procedure for making a tablet

Osnovni sastojd navedeni u Primeru VI mešaju se oko 20 minuteThe basic ingredient listed in Example VI was stirred for about 20 minutes

... ~ 17 - .... ~ 17 -.

u Oay raikseru za prah 111 Pony mlkseru. Aktivni sastojak se doda u osnovnu smešu i smeša se ponovo meša tokom oko 30 minuta uz dodavanje maziva. Smeša se tada neposredno tabletlra u Stokes 82 rotacionoj mašinl 111 Manesty mašinl koja je podešena na kompreslju 0.9 MPa. Tablete se sabljaju u odmerene tablete oblika kapsule. Veličina pro bo j ca bila je 19.1 min x 9.7 mm a tvrdoča 0.9 MPa. U svakom slučaju, snaga tablete bila je 104 mg. Oslobadjanje aktivnog sastojka odredjeno je kao u Primeru VI.in Oay Powder Raxer 111 Pony mlkser. The active ingredient was added to the basic mixture and the mixture was stirred again for about 30 minutes with the addition of lubricant. The mixture was then directly tableted in a Stokes 82 rotary machine 111 Manesty machine which was adjusted to a 0.9 MPa compressor. The tablets are compressed into metered capsule shaped tablets. The projection size was 19.1 min x 9.7 mm and a hardness of 0.9 MPa. In each case, the strength of the tablet was 104 mg. The release of the active ingredient was determined as in Example VI.

Sl. 6 opisuje oslobadjanje aktivnog sastojka iz dva seta tableta IzbPrlmera VI napravljenih prema pronalasku, 1 komerdjalno prlstupačne tablete Iz ranije nauke, 32. Sl. 6 prikaz: e da obe tablete napravljene prema pronalasku dejstvuju na sličan način tokom perioda od 12 časova.FIG. 6 depicts the release of the active ingredient from two sets of tablets of IzbPrlmer VI made according to the invention, 1 commercially available tablets of Previous Science, 32. FIG. 6 shows that both tablets made according to the invention act in a similar manner over a period of 12 hours.

Primer VIIExample VII

Razllčitlg dana, kontrolna (za uporedjenje) partija proizvoda Z napravljena je sa Istom formulom kao u Primeru VI 1 flnlšlrane tablete testirane su opet na 1st1 način kao u Primeru VI za uporedjivanje rezultata. Sl. 7, referentni broj 34, demonstrira da oslobadjanje aktivnog sastojka Iz vezanih tableta jeste suštlnskl Isto kao 1 oslobadjanje aktivnog sastojka 1z tableta koje su napravljene ranije kao što je opisano u Primeru VI.On the other day, the control (for comparison) batch of product Z was made with the same formula as in Example VI 1 flnl tablets were tested again in the 1st1 manner as in Example VI for comparison of results. FIG. 7, Reference No. 34, demonstrates that release of the active ingredient from bound tablets is essentially the same as 1 release of the active ingredient 1z tablets that were made earlier as described in Example VI.

Najbolji način za upotrebu pronalaska u privredi koji je poznatThe best way to use invention in an economy that is known

PrijaviocuApplicant

Pronalazak sa može najbolje primeniti ako se farmaceutske formulacije sa kontroli sanira, dugotrajni« oslobadjanje« prave postupkom koji je detaljno opisan u radira Prlraeriroa 1 do 7 iz oplsanog dela prijave.The invention can best be applied if the controlled pharmaceutical pharmaceutical formulations are long-term "release" by the procedure described in detail in Prlraeriro 1 to 7 radius from the outlined part of the application.

Claims

A process for the preparation of a controlled release sustained release pharmaceutical formulation, wherein the carrier base material comprising at least one cellulose ether selected from the group consisting of hydroxyalkyl cellulose and hydroxyalkyl alkyl cellulose is mixed for a period of 20-40 minutes with a therapeutically active agent, and the resulting pharmaceutical pharmaceutical formulation is allowed to stand for 2-72 hours without stirring to bind a therapeutically active agent to said cellulose ether, after which 2 is compressed under pressure from 6 to 12 kg / cm in the form of a suitable dosage form.

And units.

2. The process according to claim 1, characterized in that the carrier comprises one or more cellulose ethers, hydroxypropyl methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose and ethyl cellulose or derivatives thereof.

The method of claim 1, wherein the base material is applied in particulate form.

The method of claim 1, wherein the therapeutically active agent is isosorbide mononitrate, isosorbide dinitrate, theophylline, nitroglycerin, ibuprofen or acetaminophen.

HANS LOWEY, USA

9/20/2005

Abstract of invention

A process for making multiple controlled-release, long-release controlled release pharmaceutical tablets is disclosed, each containing 1 cellulose ether base carrier material. The process involves the steps of adding an amount of cellulose ether base material. such as h1drok $ 1prop11-met11cellulose, and an active therapeutic agent so as to form a mixture, completely 1 uniform mixing of the mixture, interrupting the mixing, allowing the single mixture to stand for a period of time, typically two to twenty-four hours 111 longer, which 1 is allowed to cause the therapeutic agent to become attached to the base material by the carrier 1. The advantage of the process is that the time release is each tablet from the given; 'rt1 is of the formulation 1 of the time release feature of the tablets made in different batches, essentially more uniformly 1 side by side.