RS52647B - CONTROLLED RELEASE TABLETS OF DICLOFENAC SODIUM - Google Patents
CONTROLLED RELEASE TABLETS OF DICLOFENAC SODIUMInfo
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- RS52647B RS52647B YU20060371A YUP20060371A RS52647B RS 52647 B RS52647 B RS 52647B YU 20060371 A YU20060371 A YU 20060371A YU P20060371 A YUP20060371 A YU P20060371A RS 52647 B RS52647 B RS 52647B
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Abstract
Farmaceutska formulacija dvostruko obloženih gastrorezistentnih tableta sa kontrolisanim oslobađanjem diklofenak natrijuma, kao aktivne supstance, naznačene time, što je gastrorezistentna obloga, koja sadrži kopolimere metakrilne kiseline, nanesena na film oblogu, što omogućava ciljano oslobađanje, posle trećeg sata u određenom delu gastrointestinalnog trakta, počev od proksimalnog dela tankog creva, inicijalne doze diklofenak natrijuma iz film obloge, gde film obloga sadrži hidroksipropilmetilcelulozu niskog viskoziteta od 3 do 10 cP i štiti jezgro koje sadrži dozu održavanja diklofenak natrijuma, a kao vezivno sredstvo, derivate celuloze visokog viskoziteta od 3000 do 100000 cP, i zajedno sa ostalim pomoćnim supstancama, a to su sredstva za dopunjavanje i lubrikansi, obezbeđuje kontrolisano oslobađanje diklofenak natrijuma u toku 12 do 24 sata.Prijava sadrži još 10 patentnih zahteva.Diclofenac sodium controlled release dual-coated gastro-resistant tablet formulation as an active ingredient, characterized in that it is a gastroresistant coating containing methacrylic acid copolymers applied to the film coating allowing targeted release after a third hour in a particular portion of the gastrointestinal tract from the proximal portion of the small intestine, the initial dose of diclofenac sodium from the film coating, wherein the film coating contains low viscosity hydroxypropyl methylcellulose from 3 to 10 cP and protects a core containing a maintenance dose of diclofenac sodium, and as a binder, high viscosity cellulose derivatives of 3000 to000000 , and together with other excipients, such as fillers and lubricants, ensures the controlled release of diclofenac sodium for 12 to 24 hours. The application contains 10 more patent claims.
Description
1. Oblast tehnike1. Technical field
Pronalazak pripada oblasti farmaceutske tehnologije, tačnije oblasti izrade farmaceutskog preparata u obliku tableta za humanu medicinu. Prema međunarodnoj klasifikaciji patenata pronalazak pripada klasi A 61 K. The invention belongs to the field of pharmaceutical technology, more specifically to the field of manufacturing a pharmaceutical preparation in the form of tablets for human medicine. According to the international classification of patents, the invention belongs to class A 61 K.
2. Tehnički problem2. Technical problem
Ovim pronalaskom se štiti novi farmaceutski oblik, jednostruko obložene i dvostruko obložene - gastrorezistentne tablete, sa diklofenak natrijumom kao aktivnom supstancom. Specifičnost formulacije je u hidrosolubilnoj film oblozi iz koje se oslobađa inicijalna doza (33% odnosno 50% od deklarisane doze) aktivnog principa, dok jezgro čini bubreći matriks sistem na bazi derivata celuloze različitog viskoziteta koji, zajedno sa ostalim pomoćnim supstancama, obezbeđuje kontrolisano oslobađanje diklofenak natrijuma u toku 12 do 24 sata, uz održavanje određenog nivoa aktivne supstance u plazmi. Kod formulacije koja sadrži i dodatnu, gastrorezistentnu oblogu pored kontrolisanog postignuto je i ciljano oslobađanje aktivne supstance u određenom delu gastrointestinalnog trakta (počev od proksimalnog dela tankog creva). This invention protects a new pharmaceutical form, single-coated and double-coated - gastro-resistant tablets, with diclofenac sodium as an active substance. The specificity of the formulation is in the hydrosoluble film coating from which the initial dose (33% or 50% of the declared dose) of the active principle is released, while the core is a swelling matrix system based on cellulose derivatives of different viscosity which, together with other auxiliary substances, ensures the controlled release of diclofenac sodium within 12 to 24 hours, while maintaining a certain level of the active substance in the plasma. With the formulation containing an additional, gastro-resistant coating, in addition to the controlled one, a targeted release of the active substance was achieved in a certain part of the gastrointestinal tract (starting from the proximal part of the small intestine).
3.Stanje tehnike3. State of the art
Preparati sa diklofenakom ili njegovim solima, najčešće primenjivanim nesteroidnim antireumatikom, ispoljavaju antiinflamatorno, analgetsko i antipiretičko delovanje. Veća primena diklofenak natrijuma u odnosu na diklofenak, koji se prema BSC klasifikaciji svrstava u drugu grupu (teško rastvorljive, ali veoma permeabilne aktivne supstance) zasniva se na njegovoj boljoj rastvor ljivosti. Preparations with diclofenac or its salts, the most commonly used nonsteroidal antirheumatic drug, exhibit anti-inflammatory, analgesic and antipyretic effects. Greater application of diclofenac sodium compared to diclofenac, which according to the BSC classification is classified in the second group (hardly soluble, but highly permeable active substances) is based on its better solubility.
Farmaceutski dozirani oblici koji precizno mogu kontrolisati vreme ili mesto, kao i brzinu oslobađanja leka, vreme ili mesto delovanja aktivne supstance u organizmu imaju u poslednje vreme sve veći medicinski, ali i ekonomski značaj. Jedna od prednosti sistema sa kontrolisanim oslobađanjem, pored povećanja efikasnosti leka, je i smanjenje neželjenih efekata ili toksičnosti. Zbog niza ovih prednosti broj preparata sa kontrolisanim oslobađanjem je u stalnom porastu, kako u oblasti humanih lekova tako i u stomatologiji i veterini. Pharmaceutical dosage forms that can precisely control the time or place, as well as the rate of release of the drug, the time or place of action of the active substance in the body, have recently been of increasing medical and economic importance. One of the advantages of the controlled release system, in addition to increasing the effectiveness of the drug, is the reduction of side effects or toxicity. Due to a series of these advantages, the number of preparations with controlled release is constantly increasing, both in the field of human medicines and in dentistry and veterinary medicine.
S obzirom na mehanizam oslobađanja aktivnog principa ovi sistemi se mogu podeliti u nekoliko osnovnih grupa: 1.Dozirani oblici sa modifikovanim (kontrolisanim) oslobađanjem,kod kojih se najčešće odmah oslobodi inicijalna doza leka, a doza održanja u željenom vremenskom periodu; 2.Dozirani oblici sa produženim delovanjemkoji obezbeđuju bar dvostruko smanjenje intervala doziranja u poređenju sa standardnim doziranim oblikom; 3.Dozirani oblici sa odloženim oslobađanjem,iz kojih se aktivna supstanca ne oslobađa odmah posle primene, već kada stigne do željenog mesta delovanja u organizmu, na pr. With regard to the mechanism of release of the active principle, these systems can be divided into several basic groups: 1. Dosed forms with modified (controlled) release, in which the initial dose of the drug is usually released immediately, and the maintenance dose in the desired period of time; 2. Dosed forms with extended action that provide at least a two-fold reduction in the dosing interval compared to the standard dosage form; 3. Dosed forms with delayed release, from which the active substance is not released immediately after application, but when it reaches the desired site of action in the body, e.g.
gastrorezistentne tablete koje se rastvaraju u donjim delovima intestinalnog trakta. gastroresistant tablets that dissolve in the lower parts of the intestinal tract.
Za kreiranje jednog takvog sistema potrebno je primeniti savremena dostignuća iz oblasti farmacije, koja se pre svega odnose na korišćenje novih pomoćnih supstanci i postupaka izrade. Novi polimerni materijali, kao što su polianhidrati, hitozan poliestri, polifosfati, hidrogeli, bioadhezivni materijali, nalaze danas sve veću primenu upravo u formulisanju preparata sa kontrolisanim oslobađanjem. To create such a system, it is necessary to apply modern achievements in the field of pharmacy, which primarily relate to the use of new auxiliary substances and manufacturing procedures. New polymer materials, such as polyanhydrates, chitosan polyesters, polyphosphates, hydrogels, bioadhesive materials, are increasingly used in the formulation of preparations with controlled release.
Oralna primena sistema sa kontrolisanim oslobađanjem je najzastupljeniji oblik aplikacije većine terapijskih agenasa. Prvi sistemi sa kontrolisanim oslobađanjem zasnivali su se na oblaganju Oral administration of controlled release systems is the most common form of administration of most therapeutic agents. The first controlled release systems were based on coating
tableta voskovima, koji su produžavali oslobađanje aktivne supstance. Zatim je usledio razvoj peleta, sa inkorporiranom aktivnom supstancom u više slojeva obloge, a željeni profil oslobađanja postizao se različitom debljinom film obloge. Primena gastrorezistentnih polimera, nerastvorljivih pri nižim, a rastvorljivih pri višim pH vrednostima, obezbedila je nesmetani transport aktivne supstance kroz gornje delove GIT-a i ciljano oslobađanje i apsorpciju ili lokalno delovanje u tankom ili čak debelom crevu. tablets with waxes, which prolonged the release of the active substance. Then followed the development of pellets, with the active substance incorporated in multiple layers of the coating, and the desired release profile was achieved by varying the thickness of the film coating. The use of gastroresistant polymers, insoluble at lower and soluble at higher pH values, ensured smooth transport of the active substance through the upper parts of the GIT and targeted release and absorption or local action in the small or even large intestine.
Hipromeloza, poznatija kao hidroksipropilmetilceluloza (HPMC), je polimer koji se široko primenjuje u proizvodnji sistema sa kontrolisanim oslobađanjem. U kontaktu sa vodom ili biološkim tečnostima, polimer počinje da hidratiše, bubri i formura gel barijeru koja usporava difuziju aktivne supstance iz matriksa. Povećanje debljine matriksa posle bubrenja HPMC matriks tableta je veće ukoliko se koriste celuloze veće molekulske mase, što se objašnjava velikom hidrodinamičkom zapreminom nastalom usled hidratacije lanaca veće molekulske mase. U toku hidratacije polimer vezujuje vodu, slabe medjumolekulske sile izmedju polimernih lanaca i u jednom trenutku se dostiže koncentracija "razmrežavanja", što predstavlja kritičnu koncentraciju polimera ispod koje se lanci polimera razmrežavaju i odvajaju od geliranog matriksa. Polimer zatim podleže eroziji, rastvaranju i difuziji u balk medijum što dovodi do dalje erozije matriksa. Rastvorljive supstance oslobađaju se iz sistema difuzijom kroz gel matriksa, a teško rastvorljive erozijom matriksa. Hypromellose, commonly known as hydroxypropylmethylcellulose (HPMC), is a polymer widely used in the production of controlled release systems. In contact with water or biological fluids, the polymer begins to hydrate, swell and form a gel barrier that slows down the diffusion of the active substance from the matrix. The increase in matrix thickness after swelling of HPMC matrix tablets is greater if celluloses of higher molecular weight are used, which is explained by the large hydrodynamic volume resulting from the hydration of chains of higher molecular weight. During hydration, the polymer binds water, weakens the intermolecular forces between the polymer chains, and at one point the "de-crosslinking" concentration is reached, which represents a critical polymer concentration below which the polymer chains are de-cross-linked and separated from the gelled matrix. The polymer then undergoes erosion, dissolution and diffusion into the bulk medium leading to further erosion of the matrix. Soluble substances are released from the system by diffusion through the matrix gel, and poorly soluble substances by matrix erosion.
Iako je oralna primena sistema sa kontrolisanim oslobađanjem najkonformnija postoje i brojna ograničenja koja utiču na to da se formulaciji peroralnih lekova sa određenim aktivnim supstancama mora pristupiti sa posebnom pažnjom. Hemijski sastav digestivnih sokova GIT-a je veoma promenljiv. pH varira od 0.9 do 1.5 u želucu, 7.8 u terminalnom ileumu do 8.5 u kolonu. U obzir treba uzeti i prisustvo žučnih soli i digestivnih enzima, koji mogu reagovati sa aktivnim principom. Neke aktivne supstance mogu delovati iritiraj uće na sluzokožu želuca, a neke se mogu razgraditi u kiselom želudačnom soku. Stoga se u toku razvoja formulacije aktivnih supstanci posebna pažnja mora posvetiti zaštiti od takvih neželjenih efekata u GIT-u. Oblaganjem tableta može se postići specifično oslobađanje aktivne supstance u određenom delu GIT-a. Priroda filmogene supstance određuje mesto GI trakta u kome će doći do oslobađanja. Osobine rastvorljivosti i permeabilnosti filmogene materije određene su funkcionalnim grupama koje se nalaze duž polimernog lanca. Aktivne supstance koje iritiraju sluzokožu želuca, kao što je slučaj sa na pr. diklofenak natrijumom, mogu se dati u obliku tableta obloženih anjonskim smolama, tj. enterosolubilnim smolama. Although the oral administration of controlled-release systems is the most compliant, there are also numerous limitations that affect the formulation of oral drugs with certain active substances that must be approached with special care. The chemical composition of the digestive juices of the GIT is highly variable. The pH varies from 0.9 to 1.5 in the stomach, 7.8 in the terminal ileum to 8.5 in the colon. The presence of bile salts and digestive enzymes, which can react with the active principle, should also be taken into account. Some active substances can irritate the gastric mucosa, and some can be broken down in acidic gastric juice. Therefore, during the development of the formulation of active substances, special attention must be paid to protection against such side effects in the GIT. By coating the tablets, a specific release of the active substance can be achieved in a certain part of the GIT. The nature of the film-forming substance determines the location of the GI tract where release will occur. The properties of solubility and permeability of the film-forming substance are determined by the functional groups located along the polymer chain. Active substances that irritate the mucous membrane of the stomach, as is the case with e.g. diclofenac sodium, can be given in the form of tablets coated with anionic resins, i.e. enterosoluble resins.
Oralni preparati sa kontrolisanim oslobađanjem su namenjeni za primenu u dvanestočasovnim ili dvadesetčetvoročasovnim intervalima. Dozni intervali za oralne sisteme sa kontrolisanim oslobađanjem dužim od 24 sata su ograničeni fiziološkim karakteirstikama, jer tranzit kroz GIT prosečno traje do 24 sata, ali može da varira od nekoliko sati do nekoliko dana. Stoga svaka primena oralnih preparata u interavlima dužim od 24 sata je diskutabilna. Controlled-release oral preparations are intended for use at twelve-hour or twenty-four-hour intervals. Dose intervals for oral systems with controlled release longer than 24 hours are limited by physiological characteristics, because the transit through the GIT lasts on average up to 24 hours, but can vary from several hours to several days. Therefore, any application of oral preparations at intervals longer than 24 hours is debatable.
U PCT prijavi sa objavom broj WO 03/074033 Al, kompanije Pliva dd, opisan je čvrsti dozirani oblik tablete, sa aktivnom supstancom (diklofenak Na, ranitidin HC1 ili torasemid), čije se produženo oslobađanje postiže prisustvom, u vodi nerastvorljivog, ali permeabilnog polimera, na bazi kopolimera metakrilne kiseline, etilceluloze ili njihove mešavine. Tablete se pripremaju granulisanjem dela aktivne supstance (ili njene mešavine sa laktozom i mikrokristalnom celulozom) sa disperzijom polimera. Ekstragranularno se dodaje preostala količina aktivne supstance, gliceriltristearat, hidrogenizovano buljno ulje, talk i magnezijum stearat i masa koprimuje u tablete. Tablete se mogu obložiti film oblogom koja sadrži polimer, plastifikator i boju. In the PCT application with publication number WO 03/074033 Al, of the company Pliva dd, a solid dosage form of a tablet is described, with an active substance (diclofenac Na, ranitidine HC1 or torasemide), the prolonged release of which is achieved by the presence of a water-insoluble but permeable polymer, based on a copolymer of methacrylic acid, ethyl cellulose or their mixture. Tablets are prepared by granulating part of the active substance (or its mixture with lactose and microcrystalline cellulose) with a polymer dispersion. The remaining amount of the active substance, glyceryl tristearate, hydrogenated vegetable oil, talc and magnesium stearate is added extragranularly and the mass is compressed into tablets. Tablets can be coated with a coating film containing polymer, plasticizer and color.
U patentu US 5,702,724 kompanije Ciba-Geigy opisane su tablete ili dražeje sa diklofenakom, ili nekom od njegovih soli, inkorporiranim u y-cikloderkstine u inkluzioni kompleks koji obezbeđuje izradu gotovog proizvoda postupkom direktne kompresije. Pomenuti kompleks meša se sa pomoćnim supstancama koje se uobičajeno dodaju prilikom izrade tableta (dezintegrator-mikrokristalna celuloza, natrijum-skrobglikolat, kukuruzni škrob), sredstvo za vezivanje (PVP, kukuruzni škrob), sredstvo za klizanje (koloidni silicijum dioksid) i lubrikans (magnezijum stearat). US patent 5,702,724 of the company Ciba-Geigy describes tablets or dragees with diclofenac, or one of its salts, incorporated into γ-cyclodextrins in an inclusion complex that ensures the production of the finished product by the direct compression process. The mentioned complex is mixed with auxiliary substances that are usually added during the production of tablets (disintegrator-microcrystalline cellulose, sodium starch glycolate, corn starch), binding agent (PVP, corn starch), sliding agent (colloidal silicon dioxide) and lubricant (magnesium stearate).
U svom patentu US 4,948,581 Sawayanagi i grupa autora predlažu postupak oblaganja granula sastavljenih od diklofenak natrijuma, kukuruznog škroba, saharoze i hidroksipropil celuloze, gastrorezistentnom oblogom koja obezbeđuje produženo oslobađanje aktivne supstance. Oblogu mogu činiti kopolimer metilakrilne kiseline-metil metakrilata S ili L (rastvorljivi u pH oblasti između 6 i 7) koji sprečavaju njenu razgradnju u gornjim delovima GIT-a), estri masnih kiselina i talk. Ovako dobijen preparat može se puniti i u tvrde želatinske kapsule ili komprimovati u In their patent US 4,948,581 Sawayanagi and a group of authors propose a process of coating granules composed of diclofenac sodium, corn starch, sucrose and hydroxypropyl cellulose, with a gastro-resistant coating that ensures prolonged release of the active substance. The coating can consist of a copolymer of methylacrylic acid-methyl methacrylate S or L (soluble in the pH range between 6 and 7), which prevent its decomposition in the upper parts of the GIT), fatty acid esters and talc. The preparation obtained in this way can be filled into hard gelatin capsules or compressed into
tablete. tablets.
Patentom US 4,968,505 opisana je izrada preparata sa produženim oslobađanjem diklofenak-natrijuma u prisustvu neke organske kiseline (limunska, askorbinska, fumarna, vinska, sukcinska, maleinska i adipinska kiselina, kao i njihove mešavine). Aktivna supstanca i organska kiselina se mogu izmešati sa ostalim pomoćnim supstancama (kukuruznim škrobom, saharozom) i pokvasiti rastvorom hidroksipropilceluloze u cilju dobijanja granula, koje se se mogu komprimovati u tablete. Za oblaganje se koriste u vodi nerastvorljivi polimeri (etilceluloza, kopolimeri aminoalkil-metakrilati, polivinilacetat, polivinilhlorid i si.) ili polimeri rastvorljivi pri pH vrednostima od 5.5 do 7 (celulozaacetatftalat, hidroksipropilmetilcelulozaacetat-sukcinat, karboksimetilceluloza, kopolimeri metakrilne kiseline i si.). Neobložene i obložene granule se zatim mešaju u određenom odnosu i pune u kapsule. Kontrolisanim oslobađanjem aktivne supstance iz doziranog oblika njena koncentracija u krvi održava se konstantnom u dužem vremenskom periodu što je od posebnog značaja za pacijente koji preparat primenjuju učestalo jer je na ovaj način smanjen rizik od neželjenih efekata. US patent 4,968,505 describes the preparation of a preparation with extended release of diclofenac sodium in the presence of some organic acid (citric, ascorbic, fumaric, tartaric, succinic, maleic and adipic acid, as well as their mixtures). The active substance and organic acid can be mixed with other auxiliary substances (corn starch, sucrose) and moistened with a solution of hydroxypropylcellulose in order to obtain granules, which can be compressed into tablets. Water-insoluble polymers (ethylcellulose, aminoalkyl-methacrylate copolymers, polyvinyl acetate, polyvinyl chloride, etc.) or polymers soluble at pH values from 5.5 to 7 (cellulose acetate phthalate, hydroxypropylmethylcellulose acetate-succinate, carboxymethylcellulose, methacrylic acid copolymers, etc.) are used for coating. Uncoated and coated granules are then mixed in a specific ratio and filled into capsules. Through the controlled release of the active substance from the dosage form, its concentration in the blood is kept constant for a long period of time, which is of particular importance for patients who apply the preparation frequently, because in this way the risk of side effects is reduced.
Opšte je poznato da prilikom komprimovanja obloženih granula, opisanih npr. u prethodnom patentu, može doći do oštećenja obloge koja kontroliše oslobađanje aktivne supstance, pa pomenuto patentno rešenje obuhvata samo kapsule kao dozirani oblik. Da bi se prevazišao pomenuti problem grupa istraživača US patentu 5,186,943 predlaže dodatak nebubrećeg polimera u neobložene granule, koji će prilikom njihovog mešanja i komprimovanja sa obloženim granulama sprečiti destrukciju filma. Kao nebubreći pomeri koriste se etilceluloza, kopolimer aminoalkilmetilakrilata, polivinilalkohol, celulozaacetatftalat, kopolimeri metakrilne kiseline i dr. Ovi polimeri su veoma kompresibilni, ali imaju loša dezintegraciona svojstva. Efikasni su u koncentracijama većim od 10% od ukupne mase neobloženih granula. Posle dodatka uobičajenih pomoćnih supstanci (veziva, dezintegratora, lubrikansa, boje, korigensa, stabilizatora) masa se komprimuje u dvoslojne ili klasične tablete, koje se zatim mogu oblagati film ili šećernom oblogom. It is generally known that when compressing coated granules, described e.g. in the previous patent, there may be damage to the coating that controls the release of the active substance, so the mentioned patent solution includes only capsules as a dosage form. In order to overcome the mentioned problem, a group of researchers in US patent 5,186,943 proposes the addition of a non-swelling polymer to the uncoated granules, which will prevent the destruction of the film when they are mixed and compressed with the coated granules. Ethylcellulose, aminoalkylmethylacrylate copolymer, polyvinyl alcohol, cellulose acetate phthalate, methacrylic acid copolymers, etc. are used as non-swelling agents. These polymers are highly compressible, but have poor disintegration properties. They are effective in concentrations greater than 10% of the total mass of uncoated granules. After the addition of the usual auxiliary substances (binders, disintegrators, lubricants, dyes, corrigents, stabilizers), the mass is compressed into two-layer or classic tablets, which can then be coated with a film or sugar coating.
PCT prijava sa objavom broj P197/97 opisuje farmaceutske preparate na bazi diklofenaka ili njegove soli, kao i postupke za njihovo pripremanje, kod kojih se smanjenje nus pojava i neprijatnog ukusa lekovite supstance postiže dodatkom karbonata i bikarbonata alkalnih metala ili njihovih mešavina. Ovaj efekat se dodatno potencira inkorporiranjem korigensa (arome nane, anisa, amonijum glicirizinata ili njihovim mešavinama), a istovremeno se obezbeđuje brže oslobađanje aktivne supstance iz doziranog oblika. Kao farmaceutski oblici zaštićeni su: granule, PCT application with publication number P197/97 describes pharmaceutical preparations based on diclofenac or its salts, as well as procedures for their preparation, in which the reduction of side effects and the unpleasant taste of the medicinal substance is achieved by the addition of carbonates and bicarbonates of alkali metals or their mixtures. This effect is further enhanced by incorporating corrigents (mint aroma, anise, ammonium glycyrrhizinate or their mixtures), and at the same time, a faster release of the active substance from the dosage form is ensured. The following pharmaceutical forms are protected: granules,
tablete, dvoslojne tablete, kapi, rastvor i pasta. tablets, bilayer tablets, drops, solution and paste.
4. Suštinapronalaska4. Essence of the invention
Ovim pronalaskom se štiti novi farmaceutski oblik, jednostruko obložene i dvostruko obložene gastrorezistentne tablete sa diklofenak natrijumom kao aktivnom supstancom. Specifičnost formulacije je u film oblozi iz koje se oslobađa inicijalna doza aktivnog principa, dok jezgro čini matriks sistem na bazi derivata celuloze viokog viskoziteta koji, zajedno sa ostalim pomoćnim supstancama, obezbeđuje kontrolisano oslobađanje diklofenak natrijuma u toku 12 do 24 sata, uz održavanje određenog nivoa aktivne supstance u plazmi. This invention protects a new pharmaceutical form, single-coated and double-coated gastro-resistant tablets with diclofenac sodium as an active substance. The specificity of the formulation is in the film coating from which the initial dose of the active principle is released, while the core forms a matrix system based on high-viscosity cellulose derivatives which, together with other auxiliary substances, ensures the controlled release of diclofenac sodium during 12 to 24 hours, while maintaining a certain level of the active substance in the plasma.
U slučaju jednostruko obloženih negastrorezistentnih tableta brzo se oslobodi inicijalna doza leka od 25 mg, odnosno 50 mg aktivne supstance, a ostatak, 50 mg se oslobađa postepeno u toku 12 do 24 sata. Ovakav profil oslobađanja postignut je primenom postupka oblaganja tableta film suspenzijom koja sadrži hidrofilnu filmogenu supstancu i aktivni princip. Za tabletno jezgro odabrani su derivati celuloze visokog viskoziteta koji obezbeđuju produženo oslobađanje leka. Gastrorezistentna formulacija sa kontrolisanim oslobađanjem (slika 1.) ima dodatnu oblogu koja sadrži kopolimere metakrilne kiseline. Ova obloga obezbeđuje specifično oslobađanje inicijalne doze diklofenak natrijuma u određenom delu gastrointestinalnog trakta (proksimalni deo tankog creva). Na ovaj način se smanjuje nadražajno delovanje leka na sluznicu želuca. Posle rastvaranja gastrorezistentne obloge i oslobađanja inicijalne doze od 25 mg, odnosno 50 mg aktivne supstance, oslobađa se postepeno u toku 12 do 24 časa ostalih 50 mg aktivne supstance. Najniža doza aktivne supstance je 75 mg (50 mg u jezgru + 25 mg u oblozi), a najviša je 100 mg (50 mg u jezgru + 50 mg u oblozi). Jezgro sa aktivnom supstancom sadrži kompatibilne pomoćne supstance, a njihove količine mogu varirati u zavisnosti od željene doze aktivne supstance, a obično se kreću između 40 i 70%. In the case of single-coated non-gastroresistant tablets, the initial drug dose of 25 mg, i.e. 50 mg of the active substance, is released quickly, and the rest, 50 mg, is released gradually over 12 to 24 hours. This release profile was achieved by applying the procedure of coating tablets with a film suspension containing a hydrophilic filmogenic substance and an active principle. High-viscosity cellulose derivatives were selected for the tablet core, which ensure prolonged release of the drug. The controlled-release gastro-resistant formulation (Figure 1) has an additional coating containing methacrylic acid copolymers. This coating provides a specific release of the initial dose of diclofenac sodium in a certain part of the gastrointestinal tract (proximal part of the small intestine). In this way, the irritating effect of the drug on the stomach lining is reduced. After dissolving the gastro-resistant coating and releasing the initial dose of 25 mg, that is, 50 mg of the active substance, the remaining 50 mg of the active substance is released gradually over the course of 12 to 24 hours. The lowest dose of the active substance is 75 mg (50 mg in the core + 25 mg in the coating), and the highest is 100 mg (50 mg in the core + 50 mg in the coating). The core with the active substance contains compatible excipients, and their amounts may vary depending on the desired dose of the active substance, and usually range between 40 and 70%.
Fizičko-hemijska svojstva aktivne supstance imaju značajan uticaj na brzinu oslobađanja aktivne supstance iz određenog doziranog oblika. Postoji direktna zavisnost između površine čestice u kontaktu sa medijumom za rastvaranje i brzine rastvaranja. Kako se površina povećava sa smanjenjem veličine čestica, brže rastvaranje se može očekivati kada su čestice sitnije. To je takođe bitan parameter prilikom izrade film disperzije, s obzirom na osetljivost opreme (veličina otvora dizne za raspršivanje) koja se koristi u procesu oblaganja. Prema našem rešenju veličina čestica diklofenak natijuma koji ulazi u sastav film obloge sa inicijalnom dozom aktivne supstance je do 60 um sa zastupljenošću najmanj 95%. The physico-chemical properties of the active substance have a significant influence on the release rate of the active substance from a certain dosage form. There is a direct relationship between the surface area of the particle in contact with the dissolution medium and the dissolution rate. As the surface area increases with decreasing particle size, faster dissolution can be expected when the particles are smaller. It is also an important parameter when making a dispersion film, considering the sensitivity of the equipment (spray nozzle opening size) used in the coating process. According to our solution, the particle size of diclofenac sodium, which is part of the film coating with the initial dose of the active substance, is up to 60 μm with a representation of at least 95%.
Većina supstanci u obliku praška nema dovoljno dobru protočnost ni kompresibilnost neophodnu za dobijanje kvalitetnog doziranog oblika bez prethodne obrade, odnosno granulacije. Dodatkom neke tečnosti za granulaciju ili rastvora vezivne materije smeši praška i prevođenjem u granulat, eliminišu se pomenute teškoće. Stoga je za izradu tableta primenjen postupak vlažne granulacije, a kao rastvarač u procesu granulacije korišćen je etanol. Postupkom vlažne granulacije prethodno izmešane praškaste supstance se granulišu dodatkom rastvora sredstava za vezivanje. Sušenje granulata se sprovodi u fluidnoj sušnici. Formulacija izrađena postupkom direktne kompresije pokazuje malu otpornost na habanje. Uočava se daje sredstvo za vezivanje efikasnije ukoliko se primeni u obliku rastvora (vlažna granulacija). Razlog zašto je ista količina vezivnog sredstva mnogo efikasnija u obliku rastvora nego u suvom stanju je da praškasto sredstvo za vezivanje nije tako homogeno distribuirano kao u slučaju kada se dodaje u obliku rastvora, i da se zato ne može svaka čestica smeše praška koji se granuliše obložiti i povezati. Jedno ili više vezivnih sredstava može biti korišćeno u formulaciji u koncentracijama od 2 - 30%. Most substances in the form of powder do not have a sufficiently good flowability or compressibility necessary to obtain a high-quality dosage form without prior processing, i.e. granulation. By adding some granulation liquid or binder solution to the powder mixture and turning it into a granulate, the mentioned difficulties are eliminated. Therefore, the wet granulation procedure was used for the production of tablets, and ethanol was used as a solvent in the granulation process. Using the wet granulation process, previously mixed powdery substances are granulated by adding a solution of binding agents. Granulate drying is carried out in a fluid dryer. The formulation made by the direct compression process shows little wear resistance. It is observed that the binding agent is more effective if it is applied in the form of a solution (wet granulation). The reason why the same amount of binder is much more effective in the form of a solution than in the dry state is that the powder binder is not as homogeneously distributed as in the case when it is added in the form of a solution, and therefore not every particle of the powder mixture being granulated can be coated and bonded. One or more binders may be used in the formulation in concentrations of 2 - 30%.
Kontrolisano oslobađanje aktivne supstance postignuto je korišćenjem bubrećih polimera. Prodirući u tabletu voda izaziva hitrataciju polimera i stvaranje gustog gel sloja. Mehanizam oslobađanja rastvorljivih aktivne supstanci je difuzija kroz gel sloj. Postoje izvesne razlike u stepenu hidratacije različitih derivata celuloze, što treba uzeti u obzir prilikom formulisanja tableta. K tip hidroksipropilmetilceluloze (HPMC) preporučuje se zbog veoma brze hidratacije, a veličina čestica je takva da obezbeđuje odgovarajuće proricanje mase u toku procesa tabletiranja. Primenom derivata celuloze većih molekulskih masa usporava se oslobađanje aktivne, jer dolazi do formiranja viskoznog gela koji se sporije rastvara i kroz koji se difuzija sporije ostvaruje. U cilju postizanja modifikovanog oslobađanja u našem tehnološkom rešenju kombinovali smo HPMC različitog viskoziteta od 3.000 do 100.000 cP. Controlled release of the active substance was achieved by using swelling polymers. Penetrating into the tablet, water causes hydration of the polymer and the formation of a thick gel layer. The mechanism of release of soluble active substances is diffusion through the gel layer. There are certain differences in the degree of hydration of different cellulose derivatives, which should be taken into account when formulating tablets. K type Hydroxypropylmethylcellulose (HPMC) is recommended because of its very fast hydration, and the particle size is such that it ensures proper mass prediction during the tableting process. The use of cellulose derivatives with higher molecular weights slows down the release of the active ingredient, because a viscous gel is formed that dissolves more slowly and through which diffusion is realized more slowly. In order to achieve a modified release in our technological solution, we combined HPMC with different viscosities from 3,000 to 100,000 cP.
Sredstva za dopunjavanje treba da poboljšaju protočne i vezivne osobine smeše praškova. Laktoza monohidrat i anhidrovana, škrobovi, modifikovanih škrobovi, celuloze, celulozni praškovi, šećeri Fillers should improve the flow and binding properties of the powder mixture. Lactose monohydrate and anhydrous, starches, modified starches, cellulose, cellulose powders, sugars
(saharoza, dekstroza) i šećerni alkoholi (manitol ili sorbitol) kalcijum hidrogenfosfata, kalcijum fosfata, kalcijum sulfata se danas najviše upotrebljava u te svrhe u koncentraciji od 5 do 20%. Osnovni smisao primene lubrikansa u tabletama je obezbeđenje protočnosti granula ili praška u matricu tablet mašine, smanjenje trenja između granulata i zidova matrice za vreme kompresije i prilikom izbacivanja tablete iz matrice. (sucrose, dextrose) and sugar alcohols (mannitol or sorbitol) calcium hydrogen phosphate, calcium phosphate, calcium sulfate are mostly used for these purposes today in a concentration of 5 to 20%. The basic purpose of using lubricants in tablets is to ensure the flow of granules or powder into the matrix of the tablet machine, to reduce the friction between the granules and the walls of the matrix during compression and when ejecting the tablet from the matrix.
Međutim, lubrikansi mogu doprineti povećanju hidrofobnosti tablete i na taj način sprečiti prodiranje medijuma. Najveći broj efikasnih lubrikanasa je u vodi nerastvorljiv, a čak i neki u vodi rastvorljivi lubrikansi su voskaste prirode i rastvaraju se polako, a lubrikantna sposobnost im je znatno slabija u poređenju sa nerastvorljivim lubrikansima. U cilju obezbeđenje protočnosti granula primenjen je magnezijum stearat, ali se mogu primeniti i kalcijum stearat, stearinska kiselina, parafin, talk, biljne i životinjske masti, ulja i voskovi, PEG molekulske mase 1000-5000 i silikoni u koncentraciji od 0.1 do 2.0%. However, lubricants can contribute to increase the hydrophobicity of the tablet and thus prevent the penetration of the medium. Most effective lubricants are insoluble in water, and even some water-soluble lubricants are waxy in nature and dissolve slowly, and their lubricating ability is significantly weaker compared to insoluble lubricants. In order to ensure the flowability of the granules, magnesium stearate was used, but calcium stearate, stearic acid, paraffin, talc, vegetable and animal fats, oils and waxes, PEG molecular weight 1000-5000 and silicones in a concentration of 0.1 to 2.0% can also be used.
Oblaganje tableta film oblogom sprovodi se iz više razloga: da se zaštiti jezgro, maskira neprijatan ukus aktivne supstance, da se obezbedi lakše gutanje i postigne ciljano oslobađanje leka u proksimalnom delu tankog creva. Mi smo nanošenjem film obloge sa inicijalnom dozom aktivne supstance obezbedili brzo oslobađanje diklofenak natrijuma. U sastavu tog sloja - obloge ulazi HPMC niskog viskoziteta u koncentraciji u suspenziji od 2 do 10%, pa je oslobađanje aktivne supstance brzo. Polivinilpirolidon je, takođe, primenjen kao lako rastvorna filmogena supstanca u oblozi u koncentracijama od 2 do 10% filmogene disperzije. Zbog svoje plastičnosti poboljčava i mehaničke karakteristike filma, ali se zbog visokog sadržaja diklofenak natrijuma u filmu dodaje i plastifikator. Najčešće se polietilen glikol primenjuje kao plastifikator, ali su ispitivanja vršena i sa glicerolom, propilenglikolom, citratnim i ftalatnim estrima u koncentracijama od 0.1 do 1.0% filmogene disperzije. Kao antipeneće sredstvo dodaje se silikonski antipenušavac u koncentraciji od 0.05 do 0.1% filmogene disperzije. Kao rastvarač za izradu film obloge sa inicijalnom dozom aktivne supstance korišćena je prečišćena voda, čija primena je ne samo ekonomski, već je i ekološki najpogodnija. Coating tablets with a film coating is carried out for several reasons: to protect the core, to mask the unpleasant taste of the active substance, to ensure easier swallowing and to achieve a targeted release of the drug in the proximal part of the small intestine. By applying a film coating with an initial dose of the active substance, we ensured a rapid release of diclofenac sodium. The composition of that layer - coating includes HPMC of low viscosity in a suspension concentration of 2 to 10%, so the release of the active substance is fast. Polyvinylpyrrolidone was also used as an easily soluble filmogenic substance in the coating in concentrations of 2 to 10% of the filmogenic dispersion. Due to its plasticity, it also improves the mechanical characteristics of the film, but due to the high content of diclofenac sodium in the film, a plasticizer is also added. Most often, polyethylene glycol is used as a plasticizer, but tests were also performed with glycerol, propylene glycol, citrate and phthalate esters in concentrations of 0.1 to 1.0% of the film-forming dispersion. Silicone antifoam is added as an antifoaming agent in a concentration of 0.05 to 0.1% of the film-forming dispersion. Purified water was used as a solvent for the production of the film coating with the initial dose of the active substance, the application of which is not only economical, but also ecologically the most suitable.
Gastrorezistentne obloge sa kopolimerima metakrilne kiseline primenjuju se za postizanje oslobađanja aktivne supstance iz oralnih doziranih oblika počev od duodenuma. Rastvorljivost različitih kopolimerima metakrilne kiseline zavisi od pH vrednosti sredine: Gastro-resistant coatings with copolymers of methacrylic acid are applied to achieve the release of the active substance from oral dosage forms starting from the duodenum. The solubility of various copolymers of methacrylic acid depends on the pH value of the environment:
- za oslobađanje aktivne supstance na pH vrednosti iznad 5.5 (u duodenumu): - for the release of the active substance at a pH value above 5.5 (in the duodenum):
koristi se EUDRAGIT L 100-55 ili EUDRAGIT L 100-55 is used or
vodenom disperzijom EUDRAGIT L 30 D-55 water dispersion EUDRAGIT L 30 D-55
- za oslobađanje aktivne supstance na pH vrednosti iznad 6.0 (u jejunumu ) - to release the active substance at a pH value above 6.0 (in the jejunum)
koristi se EUDRAGIT L 100 EUDRAGIT L 100 is used.
ili mešavinom EUDRAGIT L 100 i EUDRAGIT S 100 ( za pH opseg od 6.0 do 6.5) or a mixture of EUDRAGIT L 100 and EUDRAGIT S 100 (for pH range from 6.0 to 6.5)
- za oslobađanje aktivne supstance na pH opsegu od 6.5 do 7.5 (terminalni ileum) - for the release of the active substance in the pH range from 6.5 to 7.5 (terminal ileum)
koristi se EUDRAGIT S 100. EUDRAGIT S 100 is used.
U našem slučaju ciljano oslobađanje aktivne supstance postignuto je primenom Eudragit-a L ili u obliku organskog rastvora 12.5%, ili u obliku vodene disperzije Eudragita L-100-55 (u količini 0.5-5% u filmogenoj disperziji). U slučaju organskog filma kao rastvarač korišćena je smeša izopropanola i acetona. Pored navedenih akrilatnih polimera za pripremanje film obloga mogu se koristiti i celulozaacetatftalat, hidroksipropilmetilcelulozaftalat ili polivinilacetatftalat u gore navedenim koncentracijama. In our case, the targeted release of the active substance was achieved using Eudragit L either in the form of an organic solution 12.5%, or in the form of an aqueous dispersion of Eudragit L-100-55 (in the amount of 0.5-5% in a filmogenic dispersion). In the case of the organic film, a mixture of isopropanol and acetone was used as a solvent. In addition to the above-mentioned acrylate polymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate or polyvinylacetate phthalate can also be used for the preparation of film coverings in the concentrations mentioned above.
Za postizanje odgovarajućeg izgleda proizvoda upotrebljeni su odgovarajući pigmenti i boje, a u određenim okolnostima oni mogu poboljšati i fizička svojstva nanetog filma. U cilju poboljšanja njihove efikasnosti primenjuju se kao mikronizirani prahovi. U našem pronalasku korišćeni su titan dioksid u koncentraciji od 0.1 do 1.0% i crveni gvožđe III oksid u koncentracijama od 0.05 do 0.1%. Appropriate pigments and dyes are used to achieve the appropriate appearance of the product, and in certain circumstances they can also improve the physical properties of the applied film. In order to improve their efficiency, they are applied as micronized powders. In our invention, titanium dioxide in a concentration of 0.1 to 1.0% and red iron III oxide in a concentration of 0.05 to 0.1% were used.
Upotrebom navedenih pomoćnih supstanci dobijaju se tablete odgovarajućih farmaceutsko-tehnoloških karakteristika, u skladu sa zahtevima savremenih farmakopeja. By using the mentioned auxiliary substances, tablets with appropriate pharmaceutical-technological characteristics are obtained, in accordance with the requirements of modern pharmacopoeias.
U ciljuin vitropraćenja otpuštanja aktivne supstance u slučaju jednostruko obloženih tableta sa kontrolisanim oslobađanjem primenjuje se aparatura II - sa lopaticama (Ph Eur, USP). Kao medijum se koristi fosfatni pufer (900 ml, pH 6.8), pri brzini 75 o/min lopatice. Očekivaniin vitroprofil oslobađanja je kod tableta koje imaju 25 mg diklofenak natrijuma inicijalne doze u 1. satu je 20-40% ukupne količine aktivne supstance, a u 12. satu najmanje 65%. Kod tableta koje imaju 50 mg diklofenak natrijuma inicijalne doze u 1. satu se oslobodi 40-60% ukupne količine aktivne supstance, a u 12. satu najmanje 70% ukupne doze aktivne supstance. In order to in vitro monitor the release of the active substance in the case of single-coated tablets with controlled release, apparatus II - with paddles (Ph Eur, USP) is used. Phosphate buffer (900 ml, pH 6.8) is used as a medium, at a blade speed of 75 rpm. The expected in vitro release profile for tablets containing 25 mg diclofenac sodium initial dose in the 1st hour is 20-40% of the total amount of active substance, and in the 12th hour at least 65%. In the case of tablets containing 50 mg diclofenac sodium in the initial dose, 40-60% of the total amount of the active substance is released in the 1st hour, and at least 70% of the total dose of the active substance is released in the 12th hour.
Pri ispitivanju disolucije gastrorezistentnih tableta (dvostruko obložene) sa kontrolisanim oslobađanjem, takođe se primenjuje aparatura II sa lopaticama pri 75 obrtaja/min. Kao medijum u toku prva 2 sata se koristi 0.1 mol/l hlorovodonična kiselina (900 ml, pH 1.2), a zatim se u toku daljeg testa koristi fosfatni pufer (900 ml, pH 6.8). Kod tableta sa 25 mg diklofenak natrijuma u inicijalnoj dozi očekivaniin vitroprofil oslobađanja je: u 2. satu ne više od 10%, u 3. satu 20-40%, u 12. satu najmanje 70% ukupne doze aktivne supstance. When testing the dissolution of gastro-resistant tablets (double-coated) with controlled release, apparatus II with paddles at 75 revolutions/min is also applied. 0.1 mol/l hydrochloric acid (900 ml, pH 1.2) is used as a medium during the first 2 hours, and then phosphate buffer (900 ml, pH 6.8) is used during the further test. For tablets with 25 mg diclofenac sodium in the initial dose, the expected in vitro release profile is: in the 2nd hour no more than 10%, in the 3rd hour 20-40%, in the 12th hour at least 70% of the total dose of the active substance.
Kod gastrorezistentnih tableta (dvostruko obložene) sa kontrolisanim oslobađanjem i 50 mg diklofenak natrijuma u inicijalnoj dozi očekivaniin vitroprofil oslobađanja je: u 2. satu ne više od 10%, u 3. satu 40-60%, u 12. satu najmanje 75%. With gastro-resistant tablets (double-coated) with controlled release and 50 mg diclofenac sodium in the initial dose, the expected in vitro release profile is: in the 2nd hour no more than 10%, in the 3rd hour 40-60%, in the 12th hour at least 75%.
Postupci prema pronalasku su dalje prikazani kroz primere, bez namere da se na njih ograniči. The methods of the invention are further illustrated by way of examples, without the intention of being limited thereto.
PRIMER 1 EXAMPLE 1
Izrada obloženih tabletaProduction of coated tablets
I Pripremanje tabletnog jezgra sa diklofenak natrijumomI Preparation of tablet core with diclofenac sodium
U koncentrovanom etanolu (120.00 g) se disperguje hipromeloza K 100 M (24.00 g). Ovom disperzijom se pokvasi diklofenak natrijum (400.00 g), a zatim se u porcijama dodaje preostala količina hipromeloze K 100 M (296.00 g) i meša dok se ne dobije homogeno aglomerisana masa. Homogeno aglomerisana masa se pokvasi sa još koncentrovanog etanola (80.00 g), izmeša i suši u fluidizovanom sloju na temperaturi od 50°C dok se ne dobije osušen granulat sa najviše 2% gubitka sušenjem. Osušen granulat se prosita na oscilatornom granulatoru. Prositanom suvom granulatu dodaju se magnezijum stearat (4.00 g) i talk (12.00 g), izmešaju se, a zatim se homogena mešavina komprimuje na ekscentar mašini za tabletiranje u tablete sledećih karakteristika: Hypromellose K 100 M (24.00 g) is dispersed in concentrated ethanol (120.00 g). Diclofenac sodium (400.00 g) is wetted with this dispersion, and then the remaining amount of hypromellose K 100 M (296.00 g) is added in portions and mixed until a homogeneous agglomerated mass is obtained. The homogenously agglomerated mass is moistened with more concentrated ethanol (80.00 g), mixed and dried in a fluidized bed at a temperature of 50°C until a dried granulate with a maximum of 2% drying loss is obtained. The dried granulate is sieved on an oscillatory granulator. Magnesium stearate (4.00 g) and talc (12.00 g) are added to the sieved dry granulate, mixed, and then the homogeneous mixture is compressed on an eccentric tabletting machine into tablets with the following characteristics:
II Postupak oblaganja tabletnih jezgara film oblogom sa inicijalnom dozom aktivneII The procedure of coating tablet cores with a film coating with an initial dose of active ingredient
supstancesubstances
Makrogol 4000 (28.00 g) se rastvori u prečišćenoj vodi (700.00 g), uz zagrevanje na 40 oC. Hipromeloza E-5 (19.20 g) se rastvori uz mešanje u prečišćenoj vodi (250.00 g). Diklofenak natrijum (200.00 g) se disperguje u vodenom rastvoru makrogola, a zatim se disperzija homogenizuje u toku 10 min na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Disperziji se, zatim, doda silikonski antipenušavac (0.80 g) i na kraju vodeni rastvor hipromeloze uz mešanje. Tablete se oblažu pripremljenom suspenzijom u bubnju za filmovanje raspršivanjem film suspenzije pri pritisku vazduha 3-7 bara i uz sušenje vazduhom na 40 do 50 oC. Macrogol 4000 (28.00 g) is dissolved in purified water (700.00 g), while heating to 40 oC. Hypromellose E-5 (19.20 g) was dissolved with stirring in purified water (250.00 g). Diclofenac sodium (200.00 g) is dispersed in an aqueous solution of macrogol, and then the dispersion is homogenized for 10 min on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. Silicone antifoam (0.80 g) is then added to the dispersion and finally the aqueous solution of hypromellose with stirring. The tablets are coated with the prepared suspension in a drum for filming by spraying the film suspension at an air pressure of 3-7 bar and with air drying at 40 to 50 oC.
Tablete obložene film obloga sa inicijalnom dozom leka imaju sledeće karakteristike: Film-coated tablets with an initial dose of the drug have the following characteristics:
III Postupak oblaganja gastrorezistentnom oblogomIII The procedure of coating with a gastro-resistant coating
Makrogol 6000 (2.40 g) se rastvori uz zagrevanje na 40 0C u prečišćenoj vodi (10.00 g). Pripremi se suspenzija sledećih supstanci: boje crveni gvožđe (III) oksid CI 77491 (0.80 g), titan dioksida (10.40 g), talka (13.20 g), vodenog rastvora makrogola, izopropanola (30.00 g) i acetona (30.00 Macrogol 6000 (2.40 g) was dissolved in purified water (10.00 g) with heating at 40 0C. Prepare a suspension of the following substances: dye red iron (III) oxide CI 77491 (0.80 g), titanium dioxide (10.40 g), talc (13.20 g), aqueous solution of macrogol, isopropanol (30.00 g) and acetone (30.00
g). Disperzija pigmenata se homogenizuje na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Disperziji pigmenata doda se uz mešanje rastvor metil-akrilat kopolimera u g). The dispersion of pigments is homogenized on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. A methyl-acrylate copolymer solution is added to the pigment dispersion with stirring
mešavini izopropanola i acetona (218.50 g). Tablete sa nanesenom inicijalnom dozom aktivne supstance se oblažu pripremljenom gastrorezistentnom suspenzijom u bubnju za filmovanje raspršivanjem film suspenzije pri pritisku vazduha 3-7 bara i uz sušenje vazduhom na 35 do 40°C. mixture of isopropanol and acetone (218.50 g). Tablets with an applied initial dose of the active substance are coated with a prepared gastro-resistant suspension in a filming drum by spraying the film suspension at an air pressure of 3-7 bar and with air drying at 35 to 40°C.
Tablete obložene gastrorezistentnom oblogom imaju sledeće karakteristike: Gastro-resistant tablets have the following characteristics:
Rezultati prikazani na si. 2 dobijeni su izvođenjemin vitrotesta za praćenje oslobađanja diklofenak natrijuma iz gastrorezistentnih tableta sa kontrolisanim oslobađanjem: Medijum: 0.1 mol/l HC1 u toku 2 sata, zatim fosfatni pufer pH 6.8 u toku narednih 12 sati Zapremina: 900 ml Results shown on si. 2 were obtained from the performance of the in vitro test for monitoring the release of diclofenac sodium from gastro-resistant tablets with controlled release: Medium: 0.1 mol/l HC1 during 2 hours, then phosphate buffer pH 6.8 during the next 12 hours Volume: 900 ml
Aparatura II - sa lopaticama, brzina 75 obrtaja/min Apparatus II - with paddles, speed 75 revolutions/min
Rezultati predstavljaju srednju vrednost merenja 6 tableta. The results represent the mean value of the measurement of 6 tablets.
Očekivaniin vitroprofil oslobađanja je: u 2. satu ne više od 10%, u 3. satu 20-40%, u 4. satu: 30-50%, u 5. satu 40-60%, u 6. satu 50-70%, u 7. satu 55-75%, u 8. satu 60-80%, u 9. satu 62-82%, u 10. satu 65-85%, u 11. satu 68-88%, u 12. satu najmanje 70%. The expected in vitro release profile is: in the 2nd hour no more than 10%, in the 3rd hour 20-40%, in the 4th hour: 30-50%, in the 5th hour 40-60%, in the 6th hour 50-70%, in the 7th hour 55-75%, in the 8th hour 60-80%, in the 9th hour 62-82%, in in the 10th hour 65-85%, in the 11th hour 68-88%, in the 12th hour at least 70%.
PRIMER 2 EXAMPLE 2
Film obloga sa inicijalnom dozom aktivne supstance Film coating with an initial dose of active substance
Izrada obloženih tabletaProduction of coated tablets
I Pripremanje tabletnog jezgra sa diklofenak natrijumomI Preparation of tablet core with diclofenac sodium
U koncentrovanom etanolu (120.00 g) se disperguje hipromeloza K 100 M (24.00 g). Ovom disperzijom se pokvasi diklofenak natrijum (400.00 g), a zatim se u porcijama dodaje preostala količina hipromeloze K 100 M (248.00 g) i hipromeloze K 4 M (40.00 g) i mesa dok se ne dobije homogeno aglomerisana masa. Homogeno aglomerisana masa se pokvasi sa još koncentrovanog etanola (80.00 g), izmeša i suši u fluidizovanom sloju na temperaturi od 50°C dok se ne dobije osušen granulat sa najviše 2% gubitka sušenjem. Osušen granulat se prosita na oscilatornom granulatoru. Prositanom suvom granulatu doda se magnezijum stearat (8.00 g), izmeša se, a zatim se homogena mešavina komprimuje na ekscentar mašini za tabletiranje u tablete sledećih karakteristika: Hypromellose K 100 M (24.00 g) is dispersed in concentrated ethanol (120.00 g). Diclofenac sodium (400.00 g) is wetted with this dispersion, and then the remaining amount of hypromellose K 100 M (248.00 g) and hypromellose K 4 M (40.00 g) and meat are added in portions until a homogeneous agglomerated mass is obtained. The homogenously agglomerated mass is moistened with more concentrated ethanol (80.00 g), mixed and dried in a fluidized bed at a temperature of 50°C until a dried granulate with a maximum of 2% drying loss is obtained. The dried granulate is sieved on an oscillatory granulator. Magnesium stearate (8.00 g) is added to the sifted dry granulate, mixed, and then the homogeneous mixture is compressed on an eccentric tabletting machine into tablets with the following characteristics:
IIPostupak oblaganja tabletnih jezgara film oblogom sa inicijalnom dozom aktivne supstance IIProcedure of coating the tablet cores with a film coating with an initial dose of the active substance
Makrogol 4000 (12.00 g) se rastvori u prečišćenoj vodi (700.00 g), uz zagrevanje na 40°C. Hipromeloza E-5 (23.20 g) se rastvori uz mešanje u prečišćenoj vodi (250.00 g). Diklofenak natrijum (200.00 g) se disperguje u vodenom rastvoru makrogola, a zatim se disperzija homogenizuje u toku 10 min na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Povidon K-25 (44.00 g) se rastvori u prečišćenoj vodi (300.00 g) uz mešanje, a zatim se rastvor doda disperziji diklofenak natrijuma. Disperziji se, zatim, doda silikonski antipenušavac (0.80 g) i na kraju vodeni rastvor hipromeloze uz mešanje. Tablete se oblažu pripremljenom suspenzijom u bubnju za filmovanje raspršivanjem film suspenzije pri pritisku vazduha 3-7 bara i uz sušenje vazduhom na 40 do 50 DC. Macrogol 4000 (12.00 g) is dissolved in purified water (700.00 g), while heating to 40°C. Hypromellose E-5 (23.20 g) was dissolved with stirring in purified water (250.00 g). Diclofenac sodium (200.00 g) is dispersed in an aqueous solution of macrogol, and then the dispersion is homogenized for 10 min on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. Povidone K-25 (44.00 g) was dissolved in purified water (300.00 g) with stirring, and then the solution was added to the diclofenac sodium dispersion. Silicone antifoam (0.80 g) and finally an aqueous solution of hypromellose are added to the dispersion with stirring. The tablets are coated with the prepared suspension in a film drum by spraying the film suspension at an air pressure of 3-7 bar and with air drying at 40 to 50 DC.
Tablete obložene film obloga sa inicijalnom dozom aktivne supstance imaju sledeće karakteristike: Film-coated tablets with an initial dose of the active substance have the following characteristics:
III Postupak oblaganja gastrorezistentnom oblogomIII The procedure of coating with a gastro-resistant coating
Pripremi se suspenzija sledećih supstanci: boje crveni gvožđe (III) oksid CI 77491 (1.22 g), titan dioksida (13.80 g), talka (18.72 g) i prečišćene vode (100.00 g). Disperziji pigmenata se doda trietilcitrat (5.58 g) i silikonski antipenušavac (0.40 g) i zatim se homogenizuje na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Disperguje se Eudragit L 100-55 (metil-akrilat etil-akrilat kopolimer 1:1) (55.80 g) u prečišćenoj vodi (115.00 g) uz intezivno mešanje propelerskom mešalicom, a zatim uz dalje mešanje u kapima dodaje rastvor 1 N NaOH (18.91 g) u toku 5 min. Nastavi se sa mešanjem još 30 min da se dobije mlečno bela disperzija. Ovoj disperziji se uz dalje mešanje doda disperzija pigmenata i ostatak prečišćene vode (125.00 Prepare a suspension of the following substances: red iron (III) oxide color CI 77491 (1.22 g), titanium dioxide (13.80 g), talc (18.72 g) and purified water (100.00 g). Triethylcitrate (5.58 g) and silicone antifoam (0.40 g) were added to the pigment dispersion and then homogenized on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. Eudragit L 100-55 (methyl-acrylate ethyl-acrylate copolymer 1:1) (55.80 g) is dispersed in purified water (115.00 g) with intensive mixing with a propeller mixer, and then with further mixing, a solution of 1 N NaOH (18.91 g) is added dropwise for 5 min. Continue mixing for another 30 min to obtain a milky white dispersion. To this dispersion, with further mixing, add the dispersion of pigments and the rest of purified water (125.00
g). Ovako pripremljenom suspenzijom oblažu se tablete sa nanešenom inicijalnom dozom aktivne supstance u bubnju za filmovanje raspršivanjem gastrorezistentne film suspenzije pri g). Tablets with the initial dose of the active substance applied in the drum for filming are coated with the suspension prepared in this way by spraying the gastro-resistant film suspension at
pritisku vazduha 3-7 bara i uz sušenje vazduhom na 45 do 50°C. air pressure of 3-7 bar and with air drying at 45 to 50°C.
Tablete obložene gastrorezistentnom oblogom imaju sledeće karakteristike: Gastro-resistant tablets have the following characteristics:
PRIMER 3 EXAMPLE 3
Izrada obloženih tabletaProduction of coated tablets
I Pripremanje tabletnog jezgra sa diklofenak natrijumomI Preparation of tablet core with diclofenac sodium
U koncentrovanom etanolu (120.00 g) se disperguje hipromeloza K 4 M (24.00 g). Ovom disperzijom se pokvasi diklofenak natrijum (400.00 g) i kalcijum-hidrogenfosfat (80.00 g), a zatim se u porcijama dodaje hipromeloza K 100 M (280.00 g) i mesa dok se ne dobije homogeno aglomerisana masa. Homogeno aglomerisana masa se pokvasi sa još koncentrovanog etanola (80.00 g), izmeša i suši u fluidizovanom sloju na temperaturi od 50°C dok se ne dobije osušen granulat sa najviše 2% gubitka sušenjem. Osušen granulat se prosita na oscilatornom granulatoru. Prositanom suvom granulatu dodaju se magnezijum stearat (4.00 g) i talk (12.00 g), izmešaju se, a zatim se homogena mešavina komprimuje na ekscentar mašini za tabletiranje u Hypromellose K 4 M (24.00 g) is dispersed in concentrated ethanol (120.00 g). Diclofenac sodium (400.00 g) and calcium hydrogen phosphate (80.00 g) are wetted with this dispersion, and then hypromellose K 100 M (280.00 g) and meat are added in portions until a homogeneous agglomerated mass is obtained. The homogenously agglomerated mass is moistened with more concentrated ethanol (80.00 g), mixed and dried in a fluidized bed at a temperature of 50°C until a dried granulate with a maximum of 2% drying loss is obtained. The dried granulate is sieved on an oscillatory granulator. Magnesium stearate (4.00 g) and talc (12.00 g) are added to the sifted dry granulate, mixed, and then the homogeneous mixture is compressed on an eccentric tabletting machine in
tablete sledećih karakteristika: tablets with the following characteristics:
II Postupak oblaganja tabletnih jezgara film oblogom sa inicijalnom dozom aktivneII The procedure of coating tablet cores with a film coating with an initial dose of active ingredient
supstancesubstances
Makrogol 4000 (12.00 g) se rastvori u prečišćenoj vodi (700.00 g), uz zagrevanje na 40 oC. Hipromeloza E-5 (23.20 g) se rastvori uz mešanje u prečišćenoj vodi (250.00 g). Diklofenak natrijum (200.00 g) se disperguje u vodenom rastvoru makrogola, a zatim se disperzija homogenizuje u toku 10 min na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Povidon K-25 (44.00 g) se rastvori u prečišćenoj vodi (300.00 g) uz mešanje, a zatim se rastvor doda disperziji diklofenak natrijuma. Disperziji se, zatim, doda silikonski antipenušavac (0.80 g) i na kraju vodeni rastvor hipromeloze uz mešanje. Tablete se oblažu pripremljenom suspenzijom u bubnju za filmovanje raspršivanjem film suspenzije pri pritisku vazduha 3-7 bara i uz sušenje vazduhom na 40 do 50°C. Macrogol 4000 (12.00 g) is dissolved in purified water (700.00 g), while heating to 40 oC. Hypromellose E-5 (23.20 g) was dissolved with stirring in purified water (250.00 g). Diclofenac sodium (200.00 g) is dispersed in an aqueous solution of macrogol, and then the dispersion is homogenized for 10 min on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. Povidone K-25 (44.00 g) was dissolved in purified water (300.00 g) with stirring, and then the solution was added to the diclofenac sodium dispersion. Silicone antifoam (0.80 g) is then added to the dispersion and finally the aqueous solution of hypromellose with stirring. The tablets are coated with the prepared suspension in a filming drum by spraying the film suspension at an air pressure of 3-7 bar and with air drying at 40 to 50°C.
Tablete obložene film obloga sa inicijalnom dozom aktivne supstance imaju sledeće karakteristike: Film-coated tablets with an initial dose of the active substance have the following characteristics:
III Postupak oblaganja gastrorezistentnom oblogomIII The procedure of coating with a gastro-resistant coating
Pripremi se suspenzija sledećih supstanci: boje crveni gvožđe (III) oksid CI 77491 (0.80 g), titan dioksida (10.40 g), talka (13.20 g), izopropanola (30.00 g) i acetona (30.00 g). Disperzija pigmenata se homogenizuje na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Disperziji pigmenata doda se uz mešanje rastvor metil-akrilat kopolimera u mešavini izopropanola i acetona (218.50 g) i na kraju dietil ftalat (18.40 g). Ovako pripremljenom suspenzijom oblažu se tablete sa nanešenom inicijalnom dozom leka u bubnju za filmovanje raspršivanjem gastrorezistentne film suspenzije pri pritisku vazduha 3-7 bara i uz sušenje vazduhom na 35 do 40 C. Prepare a suspension of the following substances: red iron (III) oxide color CI 77491 (0.80 g), titanium dioxide (10.40 g), talc (13.20 g), isopropanol (30.00 g) and acetone (30.00 g). The dispersion of pigments is homogenized on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. A solution of methyl acrylate copolymer in a mixture of isopropanol and acetone (218.50 g) and finally diethyl phthalate (18.40 g) are added to the dispersion of pigments with stirring. Tablets with an initial dose of the drug are coated with the suspension prepared in this way in a filming drum by spraying the gastro-resistant film suspension at an air pressure of 3-7 bar and with air drying at 35 to 40 C.
Tablete obložene gastrorezistentnom oblogom imaju sledeće karakteristike: Gastro-resistant tablets have the following characteristics:
PRIMER 4 EXAMPLE 4
Izrada obloženih tabletaProduction of coated tablets
Postupci izrade tabletnog jezgra i oblaganja film oblogom sa inicijalnom dozom aktivne supstance su isti kao u Primeru 3. Karakteristike tabletnog jezgra i obloženih tableta sa inicijalnom dozom leka su iste kao u Primeru 3. The procedures for making the tablet core and covering it with a film coating with the initial dose of the active substance are the same as in Example 3. The characteristics of the tablet core and the coated tablets with the initial dose of the drug are the same as in Example 3.
Rezultati prikazani na si. 3 dobijeni suin vitrotestom za praćenje oslobađanja diklofenak natrijuma iz gastrorezistentnih tableta sa kontrolisanim oslobađanjem: Results shown on si. 3 obtained by the in vitro test for monitoring the release of diclofenac sodium from controlled-release gastro-resistant tablets:
Medijum: fosfatni pufer, pH 6.8 u toku 12 sati Medium: phosphate buffer, pH 6.8 for 12 hours
Zapremina: 900 ml Volume: 900 ml
Aparatura II - sa lopaticama, brzina 75 obrtaja/min Apparatus II - with paddles, speed 75 revolutions/min
Rezultati predstavljaju srednju vrednost merenja 6 tableta. The results represent the mean value of the measurement of 6 tablets.
Očekivaniin vitroprofil oslobađanja je: u 1. satu 20-40%, u 2. satu 25-45%, u 3. satu 30-50%, u 4. satu 35-55%, u 5. satu 40-60%, u 6. satu: 45-65%, u 7. satu 48-68%, u 8. satu 52-72%, u 9. satu 55-75%, u 10. satu 60-80%, uli. satu 62-82%, u 12. satu najmanje 65%. The expected in vitro release profile is: in the 1st hour 20-40%, in the 2nd hour 25-45%, in the 3rd hour 30-50%, in the 4th hour 35-55%, in the 5th hour 40-60%, in the 6th hour: 45-65%, in the 7th hour 48-68%, in the 8th hour 52-72%, in in the 9th hour 55-75%, in the 10th hour 60-80%, ul. hour 62-82%, in the 12th hour at least 65%.
PRIMER 5 EXAMPLE 5
Izrada obloženih tabletaProduction of coated tablets
I Pripremanje tabletnog jezgra sa diklofenak natrijumomI Preparation of tablet core with diclofenac sodium
U koncentrovanom etanolu (120.00 g) se disperguje hipromeloza K 100 M (24.00 g). Ovom disperzijom se pokvasi diklofenak natrijum (400.00 g), a zatim se u porcijama dodaje preostala količina hipromeloze K 100 M (296.00 g) i meša dok se ne dobije homogeno aglomerisana masa. Homogeno aglomerisana masa se pokvasi sa još koncentrovanog etanola (80.00 g), izmeša i suši u fluidizovanom sloju na temperaturi od 50 C dok se ne dobije osušen granulat sa najviše 2% gubitka sušenjem. Osušen granulat se prosita na oscilatornom granulatoru. Prositanom suvom granulatu dodaju se magnezijum stearat (4.00 g) i talk (12.00 g), izmešaju se, a zatim se homogena mešavina komprimuje na ekscentar mašini za tabletiranje u tablete sledećih karakteristika: Hypromellose K 100 M (24.00 g) is dispersed in concentrated ethanol (120.00 g). Diclofenac sodium (400.00 g) is wetted with this dispersion, and then the remaining amount of hypromellose K 100 M (296.00 g) is added in portions and mixed until a homogeneous agglomerated mass is obtained. The homogenously agglomerated mass is wetted with still concentrated ethanol (80.00 g), mixed and dried in a fluidized bed at a temperature of 50 C until a dried granulate with a maximum of 2% drying loss is obtained. The dried granulate is sieved on an oscillatory granulator. Magnesium stearate (4.00 g) and talc (12.00 g) are added to the sieved dry granulate, mixed, and then the homogeneous mixture is compressed on an eccentric tabletting machine into tablets with the following characteristics:
II Postupak oblaganja tabletnih jezgara film oblogom sa inicijalnom dozom aktivneII The procedure of coating tablet cores with a film coating with an initial dose of active ingredient
supstancesubstances
Makrogol 4000 (24.00 g) se rastvori u prečišćenoj vodi (1400.00 g), uz zagrevanje na 40°C. Hipromeloza E-5 (26.40 g) se rastvori uz mešanje u prečišćenoj vodi (500.00 g). Diklofenak natrijum (400.00 g) se disperguje u vodenom rastvoru makrogola, a zatim se disperzija homogenizuje u toku 10 min na visokosmicajnoj mešalici (Ultraturaks) pri brzini od 10 000 rpm. Povidon K-25 (88.00 g) se rastvori u prečišćenoj vodi (600.00 g) uz mešanje, a zatim se rastvor doda disperziji diklofenak natrijuma. Disperziji se, zatim, doda silikonski antipenušavac (1.60 g) i na kraju vodeni rastvor hipromeloze uz mešanje. Tablete se oblažu pripremljenom suspenzijom u bubnju za filmovanje raspršivanjem film suspenzije pri pritisku vazduha 3-7 bara i uz sušenje vazduhom na 40 do 50°C. Macrogol 4000 (24.00 g) is dissolved in purified water (1400.00 g), while heating to 40°C. Hypromellose E-5 (26.40 g) was dissolved with stirring in purified water (500.00 g). Diclofenac sodium (400.00 g) is dispersed in an aqueous solution of macrogol, and then the dispersion is homogenized for 10 min on a high-shear mixer (Ultraturax) at a speed of 10,000 rpm. Povidone K-25 (88.00 g) was dissolved in purified water (600.00 g) with stirring, and then the solution was added to the diclofenac sodium dispersion. Silicone antifoam (1.60 g) and finally an aqueous solution of hypromellose are added to the dispersion with stirring. The tablets are coated with the prepared suspension in a filming drum by spraying the film suspension at an air pressure of 3-7 bar and with air drying at 40 to 50°C.
Tablete obložene film oblogom sa inicijalnom dozom aktivne supstance imaju sledeće karakteristike: Film-coated tablets with an initial dose of the active substance have the following characteristics:
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU20060371A RS52647B (en) | 2006-06-08 | 2006-06-08 | CONTROLLED RELEASE TABLETS OF DICLOFENAC SODIUM |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU20060371A RS52647B (en) | 2006-06-08 | 2006-06-08 | CONTROLLED RELEASE TABLETS OF DICLOFENAC SODIUM |
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| RS52647B true RS52647B (en) | 2013-06-28 |
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| Application Number | Title | Priority Date | Filing Date |
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