iovanov rares.pdf

8/21/2019 iovanov rares.pdf

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UNIVERSITATEA DE MEDICINI FARMACIEIULIU HAIEGANU CLUJ-NAPOCA

FACULTATEA DE FARMACIE

RAREIULIU IOVANOV

FORMULAREA UNOR SISTEME FARMACEUTICESOLIDE CU CEDARE PRELUNGITA

FELODIPINEI

Rezumatul tezeipentru obinerea titlului deDoctor n Stiine Medicale, domeniul Farmacie

Conductor tiinific:Prof. Dr. SORIN E. LEUCUA

2010


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CUPRINS

INTRODUCERE ............................................................................................................................................................ 5I. STADIUL ACTUAL AL CUNOATERII ................................................................................................................ 91. GENERALITI CU PRIVIRE LA PREPARATELE FARMACEUTICE CU CEDARE PRELUNGIT ... 101.1. Avantajele formelor farmaceutice cu cedare prelungit ........................................................................................... 121.2. Dezavantajele formelor farmaceutice cu cedare prelungit...................................................................................... 131.3. Limitele preparatelor farmaceutice cu cedare prelungit ......................................................................................... 132. MODALITATI DE PRELUNGIRE A DURATEI DE ACIUNE ....................................................................... 142.1. Administrarea unei doze mai mari ........................................................................................................................... 142.2. Micorarea valorii constantei de viteza a eliminrii ................................................................................................. 142.3. Micorarea valorii constantei de viteza absorbiei................................................................................................. 152.4. Forme farmaceutice orale cu eliberare prelungit .................................................................................................... 15

2.4.1. Preparate de tip matri .................................................................................................................................... 152.4.1.1. Matrihidrofil....................................................................................................................................... 16

2.4.1.1.1. Formulri pe bazde hidroxipropilmetilceluloz ............................................................................ 172.4.1.1.2. Formulri pe bazde polietilenoxid................................................................................................ 19

2.4.1.2. Matriinert(nedigerabil) .................................................................................................................... 202.4.1.2.1. Formulri pe bazde Kollidon SR .................................................................................................. 212.4.1.2.2. Formulri pe bazde derivai acrilici i etilceluloz ....................................................................... 21

2.4.1.3. Matrilipofil......................................................................................................................................... 232.4.1.3.1. Formulri pe bazde Compritol i Precirol..................................................................................... 23

2.4.2. Preparate cu nvelis polimeric (membran) sau de tip rezervor ....................................................................... 242.4.2.1. Preparate de tip rezervor cu eliberare continu........................................................................................ 252.4.2.2. Preparate de tip rezervor cu eliberare discontinu ................................................................................... 252.4.2.3. Tipuri de polimeri utilizai la prepararea formelor farmaceutice de tip rezervor ..................................... 252.4.2.4. Formulri pe bazde etilceluloz ............................................................................................................ 262.4.2.5. Formulri pe bazde Eudragit................................................................................................................. 272.4.2.6. Formulri pe bazde Kollicoat SR 30 D................................................................................................. 29

2.4.3. Pompe osmotice............................................................................................................................................... 302.4.3.1. Pompe osmotice elementare .................................................................................................................... 312.4.3.2. Pompe osmotice cu porozitate controlat ................................................................................................ 322.4.3.3. Pompe osmotice push-pull ................................................................................................................... 33

2.4.4. Preparate bucale bioadezive............................................................................................................................. 342.4.5. Sisteme microparticulate.................................................................................................................................. 352.4.6. Compleci greu solubili rini schimbtoare de ioni..................................................................................... 35

3. TEHNOLOGII INDUSTRIALE FOLOSITE LA PREPARAREA MEDICAMENTELOR CU CEDAREPRELUNGIT.............................................................................................................................................................. 373.1. Metode de obinere a preparatelor farmaceutice de tip matri ................................................................................ 37

3.1.1.Comprimarea .................................................................................................................................................... 373.1.2. Granularea ....................................................................................................................................................... 37

3.1.2.1. Granularea uscat .................................................................................................................................... 383.1.2.2. Granularea umed.................................................................................................................................... 38

3.2. Acoperirea cu filme polimerice................................................................................................................................ 393.2.1. Generaliti ...................................................................................................................................................... 393.2.2. Polimeri formatori de film ............................................................................................................................... 40

3.2.3. Plastifiani........................................................................................................................................................ 403.2.4. Colorani .......................................................................................................................................................... 403.2.5. Solveni............................................................................................................................................................ 403.2.6. Procedee industriale de acoperire cu filme polimerice..................................................................................... 413.2.7. Pelete ............................................................................................................................................................... 41

4. CINETICA CEDRII. MODELE MATEMATICE DE CEDARE...................................................................... 414.1. Cinetica de ordinul zero ........................................................................................................................................... 424.2. Cinetica de ordinul nti........................................................................................................................................... 424.3. Difuzia Fickian. Modelul Higuchi .......................................................................................................................... 434.4. Modele exponeniale................................................................................................................................................ 44

4.4.1. Modelul Korsmeyer i Peppas ......................................................................................................................... 444.4.2. Modelul Peppas i Sahlin, modelul Kopcha .................................................................................................... 464.4.3. Modelul Hopfenberg........................................................................................................................................ 464.4.4. Modelul Baker Lonsdale............................................................................................................................... 47


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4.4.5. Modelul Hixson-Crowell ................................................................................................................................. 474.4.6. Modelul Weibull.............................................................................................................................................. 47

5. ALEGEREA FELODIPINEI CA SUBSTAN MEDICAMENTOAS MODEL PENTRU PREPARATEFARMACEUTICE SOLIDE CU CEDARE PRELUNGIT.................................................................................... 48

5.1. Denumire chimic .................................................................................................................................................... 485.2. Formula bruti masa molecular ........................................................................................................................... 485.3. Formula structural .................................................................................................................................................. 495.4. Proprieti fizico-chimice......................................................................................................................................... 495.5. Proprieti biofarmaceutice i farmacocinetice ........................................................................................................ 495.6. Proprieti farmacodinamice.................................................................................................................................... 495.7. Motivarea alegerii felodipinei ca substanmedicamentoasmodel........................................................................ 506. CONCLUZII LA STADIUL ACTUAL AL CUNOATERII ............................................................................... 50II. CONTRIBUII PERSONALE ............................................................................................................................... 511. FORMULAREA I OPTIMIZAREA UNOR PREPARATE CU CEDARE PRELUNGIT DE TIPMATRIPE BAZDE POLIVINILACETAT CU FELODIPIN...................................................................... 521.1. Introducere............................................................................................................................................................... 521.2. Materiale i metode.................................................................................................................................................. 53

1.2.1. Materiale.......................................................................................................................................................... 531.2.2. Metode de preparare ........................................................................................................................................ 54

1.2.2.1. Echipamente............................................................................................................................................ 541.2.2.2. Software .................................................................................................................................................. 541.2.2.3. Prepararea comprimatelor de tip matricu felodipina............................................................................ 55

1.2.3. Metode de control ............................................................................................................................................ 561.2.3.1. Determinarea cineticii de tasare a pulberilor ........................................................................................... 561.2.3.2. Determinarea caracteristicilor fizice a comprimatelor preparate ............................................................. 581.2.3.3. Testarea dizolvrii in vitro....................................................................................................................... 58

1.3. Rezultate i discuii .................................................................................................................................................. 591.3.1. Cinetica de tasare............................................................................................................................................. 591.3.2. Rezistena la rostogolire................................................................................................................................... 601.3.3. Rezistena mecanic......................................................................................................................................... 601.3.4. Analiza planului experimental ......................................................................................................................... 611.3.5. Fitarea datelor .................................................................................................................................................. 621.3.6. Analiza influenei factorilor de formulare asupra proprietilor amestecului de pulberi pentru comprimare

directi a comprimatelor preparate.......................................................................................................................... 771.3.6.1. Analiza Indicelui Carr ............................................................................................................................. 771.3.6.2. Analiza raportului Hausner...................................................................................................................... 781.3.6.3. Analiza rezistenei mecanice a comprimatelor ........................................................................................ 791.3.6.4. Analiza CV rezistenmecanic ........................................................................................................... 801.3.6.5. Analiza friabilitatii................................................................................................................................... 811.3.6.6. Analiza CV uniformitatea masei........................................................................................................... 821.3.6.7. Analiza cedrii substanei medicamentoase............................................................................................. 831.3.6.8. Influena factorilor de formulare asupra cineticii de cedare..................................................................... 871.3.6.9. Analiza cineticii de cedare....................................................................................................................... 881.3.6.10. Determinarea formulrii optimizate....................................................................................................... 90

1.4. Concluzii.................................................................................................................................................................. 912. PREPARATE CU CEDARE PRELUNGIT DE TIP MATRI PE BAZ DE HIDROXIPROPILMETILCELULOZI POLIETILEN OXID CONINND FELODIPIN ........................................................ 932.1. Introducere............................................................................................................................................................... 93

2.2. Materiale i metode.................................................................................................................................................. 942.2.1. Materiale.......................................................................................................................................................... 942.2.2. Metode de preparare ........................................................................................................................................ 94

2.2.2.1. Aparatur ................................................................................................................................................. 942.2.2.2. Software .................................................................................................................................................. 952.2.2.3. Planul experimental................................................................................................................................. 952.2.2.4. Prepararea comprimatelor cu felodipin .................................................................................................. 972.2.2.5. Determinarea profilurilor de cedare in vitro a felodipinei din comprimatelor preparate ......................... 98

2.3. Rezultate i discuii .................................................................................................................................................. 992.3.1. Cedarea in vitro a felodipinei........................................................................................................................... 992.3.2. Fitarea rezultatelor planului experimental ..................................................................................................... 1012.3.3. Analiza influenei factorilor de formulare asupra caracteristicilor de cedare a felodipinei............................ 112

2.3.3.1. Influena factorilor de formulare asupra cedrii felodipinei .................................................................. 1122.3.3.2. Influena factorilor de formulare asupra cineticii de cedare a felodipinei.............................................. 121


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2.4. Concluzii................................................................................................................................................................ 1233. OPTIMIZAREA UNOR COMPRIMATE DE TIP MATRI PE BAZ DE ETILCELULOZCONINND FELODIPIN .................................................................................................................................... 1253.1. Introducere............................................................................................................................................................. 125

3.2. Materiale i metode................................................................................................................................................ 1263.2.1. Materiale........................................................................................................................................................ 1263.2.2. Metode........................................................................................................................................................... 126

3.2.2.1. Aparatur ............................................................................................................................................... 1263.2.2.2. Software ................................................................................................................................................ 1273.2.2.3. Planul experimental............................................................................................................................... 1273.2.2.4. Prepararea comprimatelor cu felodipin ................................................................................................ 1303.3.2.5. Determinarea profilurilor de cedare in vitro a felodipinei din comprimatelor studiate.......................... 131

3.3. Rezultate i discuii ................................................................................................................................................ 1323.3.1. Cedarea in vitro a felodipinei.132

3.3.2. Fitarea rezultatelor planului experimental ..................................................................................................... 1343.3.3. Cedarea felodipinei din comprimatele studiate .............................................................................................. 144

3.3.3.1. Influena factorilor de formulare asupra cedrii felodipinei .................................................................. 1443.3.4. Cinetica de cedare.......................................................................................................................................... 149

3.3.4.1. Influena factorilor de formulare asupra cineticii de cedare................................................................... 1513.3.5. Determinarea formulei optimizate ................................................................................................................. 153

3.4. Concluzii................................................................................................................................................................ 1544. PREPARAREA UNUI GRANULAT CU FELODIPINACOPERIT CU DIFERII POLIMERI PENTRUASIGURAREA CEDRII PRELUNGITE .............................................................................................................. 1564.1. Introducere............................................................................................................................................................. 1564.2. Materiale i metode................................................................................................................................................ 157

4.2.1. Materiale........................................................................................................................................................ 1574.2.2. Metode de preparare ...................................................................................................................................... 157

4.2.2.1. Echipamente.......................................................................................................................................... 1574.2.2.2. Prepararea granulatelor medicamentoase neacoperite ........................................................................... 1584.2.2.3. Acoperirea granulatelor cu diferii polimeri de acoperire...................................................................... 160

4.2.3. Metode de control .......................................................................................................................................... 1624.2.3.1. Determinarea profilurilor de cedare in vitro a felodipinei din granulatele acoperite studiate ................ 162

4.3. Rezultate i discuii ................................................................................................................................................ 163

4.3.1. Cedarea in vitroa felodipinei......................................................................................................................... 1634.3.1.1. Influena filmelor polimerice de Eudragit RS 30D................................................................................ 1634.3.1.2. Influena filmelor polimerice de Eudragit NE 40D................................................................................ 1644.3.1.3. Influena filmelor polimerice de Surelease E719040............................................................................. 1654.3.1.4. Influena metodei de acoperire a granulatelor medicamentoase ............................................................ 1664.3.1.5. Influena procentului de etilcelulozncrcat asupra cedrii felodipinei din granulatele studiate ......... 1674.3.1.6. Influena procentului de formator de pori n cazul unei ncrcri de 45% etilceluloz .......................... 168

4.3.1.6.1. Cinetica de cedare a felodipinei din granulatele acoperite cu 45% Surelease coninnd proporiidiferite de formator de pori ........................................................................................................................... 168

4.4. Concluzii................................................................................................................................................................ 1695.CONCLUZII GENERALE ..................................................................................................................................... 171REFERINE BIBLIOGRAFICE.............................................................................................................................. 174

CUVINTE CHEIE: Felodipin; planuri de experiene; comprimate de tip matri;granulat acoperit cu filmpolimeric; cedare prelungit.


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INTRODUCERE

n ultimii ani, s-a manifestat un interes crescut n dezvoltarea i utilizarea unorcomprimate cu cedare prelungit, care selibereze lent substana activ, dupingerare. nacest fel are loc o absorbie prelungit a substanei medicamentoase, prelungireaconcentraiei sale plasmatice terapeutice i implicit prelungirea duratei de aciune.Formularea n acest mod a medicamentelor determincreterea complianei pacienilor lamodul de administrare i reducerea frecvenei reaciilor adverse.

Obiectivul prezentei teze de doctorat este studiul formulrii felodipinei npreparate farmaceutice solide cu cedare prelungit(preparate monolitice comprimate ipreparate multiparticulate granulate) n scopul realizarii unor profiluri de cedare pe operioadde 10 12 ore, utiliznd diferii polimeri i diverse tehnici de preparare.

Felodipina a fost aleas ca substan model datorit faptului c prezintparticulariti necesare pentru a fi formulatn forme farmaceutice cu cedare prelungit:timp de njumtire biologicscurt, indice terapeutic relativ mare.

Lucrarea cuprinde o parte generali o parte de contribuii personale.n partea generalau fost trecute n revist: modalitile prin care se poate realiza

prelungirea cedrii din forme farmaceutice solide de uz oral; tehnologiile industrialefolosite la prepararea acestui tip de forme farmaceutice; detalii n legturcu cinetica decedare a substanelor medicamentoase din formele farmaceutice cu cedare prelungitcti motivele pentru care felodipina a fost aleasca substanmodel n studiile realizate.

Partea de cercetri personale cuprinde patru capitole.n primul capitol sunt expuse rezultatele cercetrii experimentale referitoare la

influena factorilor de formulare asupra prelungirii cedrii felodipinei din comprimate detip matripe bazde polivinilacetat.

Cel de-al doilea capitol s-a axat pe studierea influenei factorilor de formulareasupra cedrii substanei medicamentoase model din comprimate de tip matripe bazde amestecuri binare ale unor polimeri hidrofili.

Capitolul 3 redcercetrile cu privire la influena factorilor de formulare asupracedrii felodipinei din comprimate de tip matripe bazde etilceluloz.

Cel de-al patrulea capitol al cercetrilor personale, a abordat studierea influeneifactorilor de formulare asupra cedrii substanei medicamentoase model din formefarmaceutice multiparticulate, n cazul de fagranulate, acoperite cu un film polimericprin care se controleazviteza de cedare.

Lucrarea se ncheie cu concluziile generale ale tezei i cu referinele bibliografice.Sunt anexate i copiile celor douarticole publicate in extenson reviste de specialitate,avnd teme abordate n cercetarea personaldin cadrul tezei.

CONTRIBUII PERSONALE

1. FORMULAREA I OPTIMIZAREA UNOR PREPARATE CU CEDAREPRELUNGITDE TIP MATRIPE BAZDE POLIVINILACETAT CU

FELODIPIN

n cercetarea efectuat s-a urmrit realizarea de comprimate de tip matri cucedare prelungitpe o perioada de 12 ore utiliznd un excipient coprocesat, Kollidon SR


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(BASF, Germania), (compus din 80 de pri polivinilacetat componenthidrofobi 20pri polivinilpirolidon component hidrofil). Excipientul preparat industrial estedestinat formulrii de forme farmaceutice solide pentru uz oral, cu cedare prelungit.

Pentru o abordare rational a formulrii, avnd n vedere numeroii factori deformulare i tehnologici care pot influena proprietile dorite ale comprimatelor, s-afolosit un plan experimental de cercetare cu doi factori i trei nivele de rezoluie. Scopulplanului experimental dezvoltat a fost de a vedea influena proporiei de polimer formatorde matri din formulare (20%, 40% i 60%), ct i cea a tipului de excipient diluant(lactoz, manitol i celuloza microcristalin) asupra cedrii substanei model alese.

Toate amestecurile de pulberi preparate n vederea obinerii comprimatelor cufelodipina au prezentat o curgere bunsau foarte bunn urma analizei indicelui Carr i araportului Hausner.

Comprimatele au fost preparate prin metoda comprimrii directe i au fostcaracterizate din punct de vedere al proprietilor farmaco-tehnice (rezistenmecanic,

friabilitate i profil de cedare in vitro).Friabilitatea i rezistena mecanic a comprimatelor studiate s-au ncadrat n

limitele impuse de ctre Ph. Eur. 6. n urma analizrii datelor obinute din studiile decedare in vitro s-a observat cviteza de cedare a substanei active din matriele preparatescade cu creterea concentraiei de Kollidon SR din formulare, de la 20% la 60%.

Mecanismul de cedare a felodipinei din comprimatele studiate a prezentat o fitarebun cu modelul Peppas, mecanism de cedare guvernat de fenomenele de difuzie asubstanei active prin canaliculele matriei i de eroziunea acesteia.

Pe baza rezultatelor obinute s-a realizat o formulare optimizatcare s-a doveditsimilardin punct de vedere al profilului de cedare in vitro cu o formulare de referin,existenta pe piaa de medicamente. Aceasta a fost preparatfolosind 31% Kollidon SR i

lactozcu rol de excipient diluant.

2. PREPARATE CU CEDARE PRELUNGITDE TIP MATRIPE BAZDEHIDROXIPROPIL METILCELULOZI POLIETILEN OXID CONINND

FELODIPIN

n al doilea capitol s-au realizat prin comprimare directmatrie hidrofile pe bazaunor amestecuri binare de hidroxipropilmetilceluloz (HPMC) i polietilenoxid (PEO).Pentru a studia influena factorilor de formulare asupra cedrii felodipinei s-au dezvoltatdouplanuri experimentale, diferena calitativntre acestea fiind tipul de polietilenoxid(Polyox WSR 1105 i Polyox WSR Coagulant, Dow Chemical Company, S.U.A)Variabilele de formulare studiate n ambele planuri experimentale au fost: procentul deamestec de polimeri hidrofili din formulare care a fost cuprins ntre 30% i 50%, tipul deHPMC utilizat Methocel E4MCR i Methocel K100M (Colorcon, UK) i raportul decombinare dintre polimerii formatori de matri (HPMC:PEO = 1:0, 1:1 sau 1:2).

Comprimatele de tip matris-au preparat prin metoda comprimrii directe i aufost caracterizate din punct de vedere al proprietilor farmaco-tehnice (rezistenmecanic, friabilitate i profil de cedare in vitro). Acestea au prezentat o friabilitate irezistenmecanicsatisfctoare, valorile acestora ncadrndu-se n limitele indicate de


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ctre Ph. Eur. 6. Viteza de cedare a felodipinei din formulrile realizate scade cucreterea proporiei de amestec de polimeri hidrofili n formulare de la 30% la 50%.

Profiluri de cedare adecvate, care s fie conforme cu criteriile de acceptabilitateprevzute n USP 30 (procentul de felodipincedat: la 2 ore sfie cuprins ntre 10% i30%; la 6 ore s fie cuprins ntre 42% i 68%; la 10 ore s fie de minim 75%), se potobine la utilizarea unui procent de 30% formator de matri (Methocel K100M).

3. OPTIMIZAREA UNOR COMPRIMATE DE TIP MATRIPE BAZDEETILCELULOZCONINND FELODIPIN

n cel de-al treilea capitol al cercetrii personale s-au realizat i studiat 21formulri de comprimate de tip matri pe baz de etilceluloz. Comprimatele s-auobinut prin metoda comprimrii directe avnd la baz un plan experimental cu trei

variabile i trei nivele de rezoluie. Variabilele planului experimental au fost: procentulde formator de matridin comprimat cuprins ntre 6% i 14%, tipul excipientului diluantdin formulare lactoz, izomalt i manitol i procentul de PVP n amestec cu formatorulde matricuprins ntre 0% i 20%.

Comprimatele s-au preparat prin metoda comprimrii directe i s-au caracterizatdin punct de vedere al proprietilor farmaco-tehnice (rezistenmecanic, friabilitate iprofil de cedare in vitro). Valorile obinute n urma testrii friabilitii i a rezisteneimecanice s-au ncadrat n limitele impuse de ctre Ph. Eur. 6. n urma analizrii datelorde cedare in vitro s-a constatat o prelungire a duratei cedrii substanei active n cazulcreterii procentului de etilceluloz din formulare, de la 6% la 14%. Utilizareamanitolului cu rol de excipient diluant, determin o cedare rapid a felodipinei,comparativ cu izomaltul sau lactoza.

Toate comprimatele studiate au prezentat o cinetic de cedare care s-a fitat celmai bine cu modelul Peppas, model care ne arat c cedarea este influenat defenomenele de difuzie a felodipinei din comprimat i de eroziunea matriei preparate.

Utilizarea unei proporii de aproximativ 13% etilceluloz n formulare i alactozei cu rol diluant determinobinerea unui profil de cedare a felodipinei similar cuprofilul de cedare a felodipinei dintr-o formulare comercialde referin.

4. PREPARAREA UNUI GRANULAT CU FELODIPINACOPERIT CUDIFERII POLIMERI PENTRU ASIGURAREA CEDRII PRELUNGITE

n cel de-al patrulea capitol s-au studiat 18 formulri de preparate farmaceuticemultiparticulate, i anume granulate cu felodipin, acoperite cu diferite filme polimericeinsolubile, dar permeabile, n vederea prelungirii cedrii substanei active pe o perioadde 12 ore. Variabilele de formulare care s-au studiat la prepararea acestor granulateacoperite au fost: mrimea granulatului neacoperit (100 150 m i 315 500 m);polimerul formator de film din categoria polimetacrilailor (Eudragit RS 30D, EudragitNE 40D Degussa/Evonix, Germania) sau etilceluloza (Surelease E719040, Colorcon,SUA); proporia de formator de pori din filmul polimeric (HPMC cu vscozitate mic -Methocel E5LV, Colorcon, SUA) 5%, 10% i 15% i modul de acoperite ntr-unaparatul n pat fluidizat Strea 1 (Aeromatic, Elveia) dotat cu dispozitiv pentru top spraysau bottom spray (dispozitiv Wrster).


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n cazul acoperirii granulatelor cu granulometrie mic(100 150 m), indiferentde polimerul de acoperire folosit i de ncrcarea realizat, cedarea felodipinei nu esteprelungitsuficient.

La prepararea de granulate acoperite cu etilceluloz prin metoda top-spray s-aobservat ccedarea felodipinei se prelungete mai mult dect n cazul metodei bottom-spray.

ncrcarea granulatelor cu granulometrie mare (315 500 m) cu procentecrescnde de etilceluloz cu rol de formator de film (15, 30 i 45%) determin oprelungire a cedrii felodipinei pe o perioada de 12 ore sau mai mare. n cazul unorncrcri de 45% etilcelulozcu formator de pori n proporie de 5, 10 sau 15% se obinprofiluri de cedare adecvate pentru substana medicamentoas ncorporat. Cedarea dinaceste granulate a urmat modelul Higuchi, mecanism care descrie cedarea prinmecanisme difuzionale i de mbibare.

CONCLUZII GENERALE

n urma cercetrilor experimentale efectuate n cadrul acestei teze de doctorat amobinut preparate farmaceutice solide (monolitice i multiparticulate) cu cedare prelungita felodipinei pe o perioad de 10 12 ore. La prepararea acestora am utilizat o marediversitate: de polimeri (insolubili polivinilacetat, hidrofili hidroxipropilmetilceluloz, polietilenoxid i termoplastici etilceluloz); polimetacrilatii etilceluloz n dispersii apoase pentru acoperirea cu film polimeric a granulatului; idiferite tehnici de preparare (comprimare direct, granulare/acoperire n pat de aerfluidizat prin metoda top-spray sau bottom spray).

Influena factorilor de formulare studiai asupra caracteristicilor formelor

farmaceutice preparate au fost determinate utiliznd planuri de experien i analizastatistica datelor experimentale.

n primul capitol am obinut prin comprimare direct comprimate cu cedareprelungitde tip matri, pe bazde polivinilacetat, din care felodipina este cedatpe operioadde 12 ore. S-a constatat co influensemnificativasupra prelungirii cedriifelodipinei din comprimate o are creterea cantitii de formator de matri. Pe baza uneiformulri experimentale s-a realizat o formulare optimizatcare s-a dovedit similardinpunct de vedere al profilului de cedare cu profilul de cedare al unie formulri de referint.

n al doilea capitol s-au realizat comprimate de tip matri prin comprimareadirecta unui amestec de hidroxipropilmetilcelulozi polietilenoxid. n urma analizriidatelor experimentale s-a obsevat c prin creterea proporiei de polimeri formatori de

matridin comprimat se poate prelungi cedarea felodipinei din comprimatele studiate.Un profil de cedare adecvat, pe o perioad de 10 ore a substanei active, se obine lautilizarea unui procent de 30% formator de matrin comprimat (HPMC K100M).

n al treilea capitol pe bazde etilcelulozs-au preparat prin comprimare directcomprimate cu cedare prelungit continnd felodipin. S-a constatat c prelungireacedrii substanei active din comprimate se poate realiza prin creterea proporiei deformator de matri(etilceluloz). n urma optimizrii formulrii s-a reuit obinerea unuiprofil de cedare, pe o perioadde 12 ore, similar cu profilul de cedare a felodipinei dintr-un produs industrial de referin.


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n al patrulea capitol s-au preparat granulate cu felodipinacoperite prin diferitemetode i utiliznd diferite tipuri de formator de film. S-a observat c prin cretereamrimii granulatului care ulterior a fost acoperit cu un film pe bazde etilcelulozntr-oanumit proporie i n condiiile experimentale precizate, se obine prelungirea cedriifelodipinei pe o perioadde 12 ore.


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CURRICULUM VITAE

DATE PERSONALE:

Nume: IOVANOVPrenume: RareIuliuData i locul naterii: 04.07.1981, AradCetenie: RomnStare civil: NecstoritDomiciliu stabil:str. Banu Mrcine, Bl. 10, Ap. 19, Arad, judeul Arad,

RomniaTelefon:+40(0)723651018Adresa e-mail:[email protected], [email protected]

PREGTIRE PROFESIONAL:

- 2009 2010 masterand n specialitatea Tehnologie FarmaceuticIndustrial, Universitatea de Medicini Farmacie IULIU HAIEGANU,Cluj-Napoca, Romnia

- 2005 pn n prezent - doctorand cu frecven la catedra de Tehnologie

Farmaceutici Biofarmacie, Facultatea de Farmacie din cadrul Universitiide Medicini Farmacie IULIU HAIEGANU, Cluj-Napoca, Romnia

- 2000 2005 - liceniat al Facultii de Farmacie din cadrul Universitii deMedicini Farmacie IULIU HAIEGANU, Cluj-Napoca, Romnia

- 2 martie 31mai 2005 stagiu Erasmus efectuat la Departamentul deFarmacie Galenic (echivalent al Tehnologiei Farmaceutice) al Facultii deFarmacie din cadrul Universit Aix-Marseille II, Marsilia, Frana

- 1996 2000 absolvent al Colegiului Naional Elena Ghiba Birta seciachimie-biologie, Arad, Romnia

EXPERIENPROFESIONAL:

- Martie 2009 pn n prezent asistent universitar n cadrul catedrei deTehnologie Farmaceutic i Biofarmacie, Facultatea de Farmacie din cadrulUniversitii de Medicini Farmacie IULIU HATIEGANU, Cluj-Napoca,Romnia

- Martie 2008 Februarie 2009 preparator universitar n cadrul catedrei deTehnologie Farmaceutic i Biofarmacie, Facultatea de Farmacie din cadrulUniversitii de Medicini Farmacie IULIU HATIEGANU, Cluj-Napoca,Romnia


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CURSURI POST-UNIVERSITARE DE PREGTIRE CONTINU:

1.European IP Galenos Course Skin Barrier Function: Pharmaceutic and CosmeticApplications, 15-29 septembrie 2006, Lion, Frana2. Workshop & Seminar: Production & Laboratory Solutions for PharmaceuticalIndustry, 19-20 octombrie 2006, Facultatea de Farmacie, Cluj-Napoca, Romnia3.Colorcon Coating School, 12-14 martie 2007, Budapesta, Ungaria4.Pharma Seminarium by LGC Promochem, 30 noiembrie 2007, Cluj-Napoca, Romnia5.Colorcon Modified Release Forum, 5-6 februarie 2008, Bucureti, Romnia6. 13th Summer Course on Pharmaceutical Analysis - Advanced AnalyticalMethodologies in Drug Discovery, 21-23 septembrie 2008, Rimini, Italia7. 14th Summer School on Pharmaceutical Analysis - ADVANCED ANALYTICALMETHODOLOGIES IN DRUG DEVELOPMENT, 7-9 septembrie 2009, Milano, Italia8.13 thInternational Meeting on Recent Developments in Pharmaceutical Analysis, 9-12

septembrie 2009, Milano, Italia9. 15th Summer School on Pharmaceutical Analysis - ADVANCED ANALYTICALMETHODOLOGIES IN DRUG PRE-FORMULATION AND QUALITY CONTROL,13-18 iunie 2010, Rimini, Italia

LUCRRI SUSINUTE LA CONFERINE/SIMPOZIOANETIINIFICE:

1. Congresul National de Farmacie, septembrie 2006, Cluj-Napoca, Romnia, Rare I.IOVANOV, Elena DINTE, Sorin E. LEUCUA, The study of metronidazole bucal

bioadhesive tablets based on hydrophilic polymers(prezentare poster)2. Pharmaceutical Sciences World Congress, 22-25 aprilie 2007, Amsterdam, Olanda,Rare I. IOVANOV, Ioan TOMU, Sorin E. LEUCUA, Multivariate method informulation of extended release felodipine matrix tablets based on polyethylene oxydeand hydroxypropylmethylcellulose(prezentare poster)3. 7th Central European Symposium on Pharmaceutical Technology and BiodeliverySystems, 18-20 septembrie 2008, Ljubljana, Slovenia, Rare I. IOVANOV, IoanTOMU, Sorin E. LEUCUA,Influence of some formulation factors on the release offelodipine from prolonged release matrix tablets(prezentare poster)

ARTICOLE PUBLICATE IN EXTENSO:1.R.I. IOVANOV, I. TOMU, S.E. LEUCUA, The optimization of prolonged releaseof matrix tablets with felodipine, Farmacia, 2008, LIV (3), 290-299

2. Rare I. IOVANOV, Ioan TOMU, Sorin E. LEUCUA, Influence of someformulation factors on the release of felodipine from extended release hydrophilic matrixtablets, Farmacia, 2009, LVII (5), 582-589


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PARTICIPARE N GRANTURI DE CERCETARE:

a)

director grant:a) Grant PN II TD 276, Strategii de formulare a unor sisteme farmaceutice cucedare prelungita a felodipinei, 2007-2009.

b)membru n colectiv:1) Grant CNCSIS PN II IDEI 457: Screeningul variabilelor de formulare i

tehnologice pentru modificarea farmacocineticii i aciunii biologice a unor

substane medicamentoase n scopul realizrii unor forme farmaceuticemoderne, 2007-2010, director proiect: Prof. dr. Sorin E. Leucua;

2) Grant CNCSIS AT 94:Dezvoltarea i optimizarea formulrii i preparriiunui sistem farmaceutic de uz oral pentru transportul i cedarea substanei

medicamentoase cu specificitate la nivelul colonului; 2007 2008; directorproiect: Sef luc. dr. Ioan Tomu;3) Grant CNCSIS PN II PARTENERIATE 41_072: Dezvoltarea prin

cercetare interdisciplinar a unei noi terapii medicamentoase destinatasigurrii neuroprotectie n ischemia cerebral, 2007-2010, director proiect:Conf. dr. Achim Marcela;

4) Grant CNCSIS PNII IDEI 1350:Dezvoltarea unei noi tehnologii, rapide i

non-destructive, bazat pe spectroscopie NIR i chemometrie pentrumonitorizarea procesului tehnologic de preparare a comprimatelor, 2009 2011, director proiect: Sef luc. dr. Ioan Tomu;

5) Grant CNCSIS PNII IDEI 1157: Sisteme mucoadezive medicamentoare

formatoare de cheag artificial in situ, dup aplicare n alveolapostextractional la pacienti cu ostoenecroz,2009 2011, director proiect:Sef luc. dr. Elena Dinte

MEMBRU N ASOCIAII PROFESIONALE:1) Colegiul Farmacitilor din Romnia2) Societatea de tiine Farmaceutice din Romnia

LIMBI STRINE:- francez: certificat de competen lingvistic eliberat de Catedra de Limbi

Moderne a Universitii de Medicini Farmacie IULIU HAIEGANU Cluj-Napoca, Romnia

- englez: mediu- maghiar: mediu


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UNIVERSITY OF MEDICINE AND PHARMACYIULIU HAIEGANU CLUJ-NAPOCA

FACULTY OF PHARMACY

RAREIULIU IOVANOV

THE FORMULATION OF SOME SOLIDPROLONGED RELEASE PHARMACEUTICAL

SYSTEMS WITH FELODIPINE

Summary of the PhD ThesisIn order to acquire the scientific title of Doctor of Medical Science

Field of Pharmacy

Scientific Coordinator:Prof. Dr. SORIN E. LEUCUA

2010


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TABLE OF CONTENTS

INTRODUCTION .................................................................................................................................................5

I. GENERAL PART ..............................................................................................................................................91. GENERALITIES REGARDING THE PROLONGED RELEASE PHARMACEUTICAL DOSAGEFORMS.................................................................................................................................................................101.1. Advantages of the prolonged release pharmaceutical dosage forms ...............................................................121.2. Disadvantages of the prolonged release pharmaceutical dosage forms ..........................................................131.3. Limits of the prolonged release pharmaceutical dosage forms .......................................................................132. MEANS TO ACHIEVE A PROLONGED ACTIVITY ...............................................................................142.1. Administration of a bigger dose......................................................................................................................142.2. Decrease of the elimination speed constant value...........................................................................................142.3. Decrease of the absorption speed constant value ............................................................................................152.4. Prolonged release pharmaceutical forms ........................................................................................................15

2.4.1. Matrix preparations.................................................................................................................................152.4.1.1. Hydrophilic matrices.......................................................................................................................16

2.4.1.1.1. Hydroxypropylmethylcellulose based formulations ...............................................................17

2.4.1.1.2. Polyethylene oxide based formulations...................................................................................192.4.1.2. Inert matrices ..................................................................................................................................202.4.1.2.1. Kollidon SR based formulations .............................................................................................212.4.1.2.2. Acrylic derivatives and ethylcellulose based formulations .....................................................21

2.4.1.3. Lipophilic matrices .........................................................................................................................232.4.1.3.1. Compritol and Precirol based formulations ............................................................................23

2.4.2. Coated preparations or reservoir type preparations.................................................................................242.4.2.1. Continuous liberation reservoir type preparations ..........................................................................252.4.2.2. Discontinuous liberation reservoir type preparations......................................................................252.4.2.3. Polymer types used in the preparation of reservoir type pharmaceutical preparations ...................252.4.2.4. Ethylcellulose based formulations ..................................................................................................262.4.2.5. Eudragit based formulations ...........................................................................................................272.4.2.6. Kollicoat SR 30 D based formulations............................................................................................29

2.4.3. Osmotic pumps .......................................................................................................................................30

2.4.3.1. Elementary osmotic pumps.............................................................................................................312.4.3.2. Controlled porosity osmotic pumps ................................................................................................322.4.3.3. Push-pull osmotic pumps ............................................................................................................33

2.4.4. Oral bioadhesive preparations.................................................................................................................342.4.5. Micro particulate systems .......................................................................................................................352.4.6. Ion exchange resins.................................................................................................................................35

3. INDUSTRIAL TECHNOLOGIES USED FOR THE PREPARATION OF THE PROLOGEDRELEASE PHARMACEUTICAL SOLID DOSAGE FORMS.......................................................................373.1. Methods used for the preparation of matrix type tablets .................................................................................37

3.1.1.Compression ............................................................................................................................................373.1.2. Granulation .............................................................................................................................................37

3.1.2.1. Dry granulation...............................................................................................................................383.1.2.2. Wet granulation...............................................................................................................................38

3.2. Coating............................................................................................................................................................39

3.2.1. Generalities.............................................................................................................................................393.2.2. Film forming polymers ...........................................................................................................................403.2.3. Plasticizers ..............................................................................................................................................403.2.4. Colorants.................................................................................................................................................403.2.5. Solvents ..................................................................................................................................................403.2.6. Industrial processes for film coating.......................................................................................................413.2.7. Pellets......................................................................................................................................................41

4. RELEASE KINETICS. MATHEMATICAL RELEASE MODELS...........................................................414.1. First order release kinetics ..............................................................................................................................424.2. Second order release kinetics..........................................................................................................................424.3. Ficks diffusion. Higuchi model .....................................................................................................................434.4. Exponential models.........................................................................................................................................44

4.4.1. Korsmeyer and Peppas model.................................................................................................................444.4.2. Peppas and Sahlin model, Kopcha model ...............................................................................................46


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4.4.3. Hopfenberg model ..................................................................................................................................464.4.4. Baker Lonsdale model .........................................................................................................................474.4.5. Hixson-Crowell model............................................................................................................................474.4.6. Weibull model ........................................................................................................................................47

5. THE CHOICE OF FELODIPINE AS MODEL DRUG FOR PROLOGED RELEASEPHARMACEUTICAL PREPARATIONS ........................................................................................................485.1. Chemical name ...............................................................................................................................................485.2. Chemical formula and molecular mass...........................................................................................................485.3. Structure..........................................................................................................................................................495.4. Physical-chemical properties ..........................................................................................................................495.5. Biopharmaceutical properties and pharmacokinetics......................................................................................495.6. Pharmacodynamic properties..........................................................................................................................495.7. Choice of felodipine as model drug ................................................................................................................506. CONCLUSIONS ..............................................................................................................................................50II. ORIGINAL RESEARCH...............................................................................................................................511. THE FORMULATION AND OPTIMIZATION OF SOME PROLONGED RELEASE MATRIX TYPEPHARMACEUTICAL PREPARATIONS BASED ON POLYVINYL ACETATE WITH FELODIPINE 521.1. Introduction.....................................................................................................................................................521.2. Materials and Methods....................................................................................................................................53

1.2.1. Materials .................................................................................................................................................531.2.2. Preparation methods ...............................................................................................................................54

1.2.2.1. Equipment.......................................................................................................................................541.2.2.2. Software..........................................................................................................................................541.2.2.3. Preparation of matrix type tablets with felodipine ..........................................................................55

1.2.3. Control methods......................................................................................................................................561.2.3.1. Tap density determination...............................................................................................................561.2.3.2. Physical characterisation of the prepared tablets ............................................................................581.2.3.3.In vitro dissolution testing ..............................................................................................................58

1.3. Results and Discussions..................................................................................................................................591.3.1. Tap density..............................................................................................................................................591.3.2. Friability .................................................................................................................................................601.3.3. Mechanical strenght ................................................................................................................................601.3.4. Experimental design analysis..................................................................................................................611.3.5. Data fit ....................................................................................................................................................621.3.6. Analysis of the influence of the formulation factors on the properties of the powders for directcompression and on the prepared tablets ..........................................................................................................77

1.3.6.1. Carr Index analysis .........................................................................................................................771.3.6.2. Hausner ratio analysis .....................................................................................................................781.3.6.3. Mechanical strenght analysis ..........................................................................................................791.3.6.4. CV mechanical strenght analysis .................................................................................................801.3.6.5. Friability analysis............................................................................................................................811.3.6.6. CV mass uniformity analysis .......................................................................................................821.3.6.7.In vitro release analysis...................................................................................................................831.3.6.8. Influence of the formulation factors over the release kinetics.........................................................871.3.6.9. Release kinetics analysis.................................................................................................................881.3.6.10. Determination of the optimum formula ........................................................................................90

1.4. Conclusions.....................................................................................................................................................912. HYDROXYPROPYL METHYLCELLULOSE AND POLYETHYLENE OXYDE BASED MATRIXTABLETS WITH FELODIPINE .......................................................................................................................932.1. Introduction.....................................................................................................................................................932.2. Materials and Methods....................................................................................................................................94

2.2.1. Materials .................................................................................................................................................942.2.2. Preparation methods ...............................................................................................................................94

2.2.2.1. Equipment.......................................................................................................................................942.2.2.2. Software..........................................................................................................................................952.2.2.3. Experimental design .......................................................................................................................952.2.2.4. Preparation of felodipine tablets .....................................................................................................972.2.2.5.In vitro felodipine dissolution profile assesed for the prepared tablets...........................................98

2.3. Results and Discussions..................................................................................................................................99


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2.3.1.In vitrorelease analysis...........................................................................................................................992.3.2. Experimental data fit.............................................................................................................................1012.3.3. Analysis of the formulation factors influence on the release characteristics of felodipine ...................112

2.3.3.1. Influence of the formulation factors on the release of felodipine..................................................1122.3.3.2. Influence of the formulation factors on the release kinetics of felodipine ....................................121

2.4. Conclusions...................................................................................................................................................1233. OPTIMIZATION OF SOME ETHYLCELLULOSE BASED MATRIX TYPE TABLETS WITHFELODIPINE ....................................................................................................................................................1253.1. Introduction...................................................................................................................................................1253.2. Materials and Methods..................................................................................................................................126

3.2.1. Materials ...............................................................................................................................................1263.2.2. Preparation methods .............................................................................................................................126

3.2.2.1. Equipment.....................................................................................................................................1263.2.2.2. Software........................................................................................................................................1273.2.2.3. Experimental desing .....................................................................................................................1273.2.2.4. Preparation of felodipine tablets ...................................................................................................1303.3.2.5.In vitrofelodipine dissolution profile assesd for the studied tablets .............................................131

3.3. Results and Discussions................................................................................................................................1323.3.1. In vitro release analysis.........................................................................................................................1323.3.2. Experimental data fit.............................................................................................................................1343.3.3. Release of felodipine from the studied tablets ......................................................................................144

3.3.3.1. Influence of the formulation factors on the release of felodipine..................................................1443.3.4. Release kinetics.....................................................................................................................................149

3.3.4.1. Influence of the formulation factors on the release kinetics of felodipine ....................................1513.3.5. Determination of the optimum formula ................................................................................................153

3.4. Conclusions...................................................................................................................................................1544. PREPARATION OF FELODIPINE GRANULES COATED WITH DIFFERENT POLYMERS INORDER TO ACHIEVE A PROLONGED RELEASE...................................................................................1564.1. Introduction...................................................................................................................................................1564.2. Materials and Methods..................................................................................................................................157

4.2.1. Materials ...............................................................................................................................................1574.2.2. Preparation methods .............................................................................................................................157

4.2.2.1. Equipment.....................................................................................................................................1574.2.2.2. Uncoated drug loaded granules preparation..................................................................................1584.2.2.3. Coating of the granules with different coating polymers ..............................................................160

4.2.3. Control methods....................................................................................................................................1624.2.3.1.In vitrofelodipine dissolution profile assesed for the studied coated granules.............................162

4.3. Results and Discussions................................................................................................................................1634.3.1.In vitro release of felodipine .................................................................................................................163

4.3.1.1. Influence of Eudragit RS 30D polymeric coating .........................................................................1634.3.1.2. Influence of Eudragit NE 40D polymeric coating.........................................................................1644.3.1.3. Influence of Surelease E719040 polymeric coating......................................................................1654.3.1.4. Influence of the drug loaded granules coating method .................................................................1664.3.1.5. Influence of ethylcellulose loadings over the release of felodipine from the studied granules ....1674.3.1.6. Influence of the percent of pore formation agent in case of 45% ethylcellulose loading..............168

4.3.1.6.1. Felodipine release kinetics from the 45% ethylcellulose coated granules with different percentof pore formation agent.........................................................................................................................168

4.4. Conclusions...................................................................................................................................................1695.GENERAL CONCLUSIONS ........................................................................................................................171REFERENCES ..................................................................................................................................................174

KEYWORDS:Felodipine; experimental design, matrix type tablets; coated granuleswith polymeric coating; prolonged release.


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INTRODUCTION

In recent years, researchers attention has been focused on the development anduse of some prolonged release tablets, from which the active substance is slowly releasedafter ingestion. Thus, several goals are achieved: prolonged absorption, prolongedtherapeutic plasmatic concentrations and prolonged therapeutic activity. The formulationof the drug in this manner increases the compliance of the patient with respect to theadministration protocol and can be related to a reduction of the adverse effects.

The objective of this PhD thesis is the study of the formulation of prolongedrelease solid pharmaceutical preparations containing felodipine (monolithic preparations tablets and multi-particulate preparations granules). The aim was to obtain a 10 12hours dissolution profile for the active substance and was achieved by using differentpolymers and different preparation techniques.

The short biological half time, the relatively high therapeutic index are several ofthe felodipines particularities allowing for the use of this substance as model drug for theformulation of prolonged release pharmaceutical preparations.

The thesis comprises a general part and an experimental part.In the general part several issues were reviewed: the means by which we can

prolong the drugs release from solid pharmaceutical forms; the industrial technologiesused to prepare such pharmaceutical forms; details about the release kinetics of the activesubstances from these pharmaceutical preparation and the reasons why felodipine hasbeen chosen as model drug for the current studies.

The original research part comprises four chapters.The first chapter dwells upon the influence of various formulation factors on the

release of felodipine from polyvinyl acetate matrix type tablets.The second chapter focuses on the study of the influence of the formulation

factors on the release of the model drug substance from binary mixtures of hydrophilicpolymer based matrix type tablets

The third chapter of the original research is centered on the influence of theformulation factors on the release of felodipine from ethylcellulose based matrix typetablets.

The fourth chapter is centered on the study of the formulation factors and theirinfluence of the release of the model drug from multiparticulate pharmaceuticalpreparations, that is granules, coated with polymeric films controlling the release rate ofthe active substance.

The final chapters of the thesis are the general conclusions and references. Theresults of the original research have been published in extenso. As appendix, copies of thetwo published papers are attached.


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ORIGINAL RESEARCH

1. THE FORMULATION AND OPTIMIZATION OF SOME PROLONGEDRELEASE MATRIX TYPE PHARMACEUTICAL PREPARATIONS BASED ON

POLYVINYL ACETATE WITH FELODIPINE

In the present research we have followed the preparation of prolonged releasematrix type tablets based on a co-processed excipient, Kollidon SR (BASF, Germany),(composed of 80 parts polyvinyl acetate hydrophobic component and 20 parts ofpolyvinylpirolidone hydrophilic component), over 12 hours. This industrially preparedexcipient is especially designed for prolonged release oral pharmaceutical dosage forms.

For a rational approach of the formulation, considering the numerous formulationand technological factors which can influence the desired properties, an experimentaldesign with two factors and three resolution levels has been developed. The aim of the

developed experimental design was to asses the influence of the matrix polymer ratio inthe formulation (20%, 40% and 60%), and also to asses the influence of the filler type(lactose, mannitol and microcrystalline cellulose) on the release of the model drug.

After the analysis of the Carr index and Hausner ratio all the prepared powdermixtures in order to obtain felodipine tablets presented good or excellent flow properties.

The tablets were prepared by direct compression and they were characterisedconsidering their pharmacotechnical properties (mechanical strength, friability an in vitrodissolution profile). The friability and the mechanical strength of the prepared tabletswhere according to the limits proposed by Eur. Ph. 6. After the analysis of theexperimental data from the in vitro release studies we have observed that the releasespeed of the active substance from the matrix tablets is diminished with the increase of

the Kollidon SR concentration, from 20% to 60%.The release mechanism of the studied preparations presented a good fit with the

Peppas model, in which the release mechanism is governed by the diffusion phenomenaand the erosion of the matrix.

Based on the obtained results an optimized formulation has been developed whichproved to be similar with the dissolution profile of a reference industrial product. Thiswas prepared using 31% Kollidon SR and lactose as filler.

2. HYDROXYPROPYL METHYLCELLULOSE AND POLYETHYLENE OXYDEBASED MATRIX TABLETS WITH FELODIPINE

In the second chapter we have prepared by direct compression hydrophilic matrixtablets, based on a binary mixture of hydroxylpropylmethylcellulose (HPMC) andpolyethylene oxide (PEO). To study the influence of the formulation factors on therelease of felodipine, two experimental design where developed. The qualitativedifference between these was the type of polyethylene oxide (Polyox WSR 1105 andPolyox WSR Coagulant, Dow Chemical Company, USA). The studied formulationvariables in both experimental designs where: the percent of hydrophilic polymer mixturein the tablet, between 30% and 50%; the type of HPMC used in the formulation(Methocel E4MCR and Methocel K100M, Colorcon, UK) and the ratio between the twopolymers in the matrix tablet (HPMC:PEO = 1:0, 1:1 sau 1:2).


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The tablets where prepared by direct compression and they were characterisedconsidering their pharmacotechnical properties (mechanical strength, friability an in vitrodissolution profile). The friability and the mechanical strength of the prepared tabletswhere according to the limits proposed by Eur. Ph. 6. The release rate of felodipine, fromthe prepared formulations, is diminished with the increase of polymer blend in the tablet,from 30% to 50%.

An appropriate dissolution profile, that complies to the acceptability criteria of theUSP 30 (felodipine released at 2 hours is between 10% and 30%, at 6 hours is between42% and 68% and at 10 hours not less than 75% of the felodipine should be released) canbe achieved using 30% matrix former (Methocel K100M).

3. OPTIMIZATION OF SOME ETHYLCELLULOSE BASED MATRIX TYPETABLETS WITH FELODIPINE

In the third chapter of the personal research we have prepared and studied 21ethylcellulose based prolonged release matrix tablets formulations. The tablets whereprepared by direct compression following and experimental design with three variablesand three resolution levels. The experimental design variables where: the percent of thematrix former polymer between 6% and 14%; the filler type lactose, isomalt andmannitol and the percent of PVP mixed with de matrix forming agent, between 0% and20%.

The tablets where prepared by direct compression and they were characterisedconsidering their pharmacotechnical properties (mechanical strength, friability an in vitrodissolution profile). The friability and the mechanical strength of the prepared tabletswhere according to the limits proposed by Eur. Ph. 6. Analysing the in vitro release data

we can conclude that increase of the ethylcellulose percent in the tablet determines theprolongation of felodipine release. Using mannitol as filler we can achieve a fasterrelease of the model drug in comparison with isomalt and lactose.

All the studied formulations presented a release kinetics that fit well with thePeppas kinetic model, in which the release mechanism is influenced by the diffusionphenomena of felodipine from the tablet and by the erosion prepared matrix tablet.

An optimized formulation has been developed using 13% ethylecellulose andlactose as filler. This formulation proved to be similar with the dissolution profile of areference industrial product.

4. PREPARATION OF FELODIPINE GRANULES COATED WITH DIFFERENT

POLYMERS IN ORDER TO ACHIEVE A PROLONGED RELEASE

In the fourth chapter we have studied 18 formulations of multiparticulatepharmaceutical preparations, in this case granules, coated with different insoluble butpermeable polymeric films, in order to obtain the prolongation of felodipine over 12hours. The studied formulation variables where: the size of uncoated granule (100 150m and 315 500 m); the type of the coating polymer form polymethacrilates class(Eudragit RS 30D, Eudragit NE 40D Degussa/Evonix, Germany) and ethylcellulose(Surelease E719040, Colorcon, SUA); the percent of pore forming agent (low viscosityHPMC Methocel E5LV, Colorcon, SUA) 5%, 10% and 15% and the coating method


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in a fluid bed coater Strea 1(Aeromatic, Elveia), equipped with top spray or bottom spray(Wrster) device.

In the case of small size granules (100 150 m) coating, indifferent of theloading and the type of coating polymer, the prolongation of the release of felodipine itsnot sufficient.

Preparing the coated granules with ethylcellulose we can observe that the topspray coating technique prolongs more the release of felodipine compared to bottomspray technique.

Loading the bigger granules (315 500 m) with different proportions ofethylcellulose as coating polymer (15, 30 i 45%) determines the prolongation of thefelodipine release on 12 hours or more. In the case of 45% ethylcellulose loading withdifferent percentages of pore forming agent (5%, 10% or 15%) we can obtainappropriates dissolution profiles for the model drug. The release kinetics of felodipinefrom these granules followed the Higuchi model, which describes the release by diffusion

and swelling mechanisms.

GENERAL CONCLUSIONS

In the original research of this thesis we have prepared solid pharmaceuticaldosage forms (monolithic and multiparticulate products) with prolonged release offelodipine over 12 hours. To prepare these preparations, we have used a wide range of:polymers (insoluble polyvinyl acetate, hydrophilic hydroxylpropylmethylcelluloseand polyethylene oxide and thermoplastic ethylcellulose); polymethacrilates andethylcellulose based aqueous dispersions for polymeric coating of granules; preparationtechniques (direct compression, granulation/coating in fluid bed apparatus equipped with

top-spray or bottom-spray device).The influence of the studied formulation factors on the prepared pharmaceutical

preparations properties was assessed using experimental designs and statistical dataanalysis.

In the first chapter we have prepared prolonged release polyvinyl acetate basedmatrix type tablets by direct compression from which felodipine is released over a periodof 12 hours. The findings showed that a significant prolongation of the felodipine releasecan be achieved with the increase of matrix forming material in the tablet. Based on anexperimental formulation an optimum formulation has been developed that proved to besimilar with the dissolution profile of felodipine from a reference drug product.

In the second chapter, hydroxylpropylmethylcellulose and polyethylene oxide

matrix tablets where prepared by direct compression. After the data analysis has beenperformed we have found that by increasing the polymer mixture ratio in the matrix tabletwe can achieve a prolonged release of felodipine. Appropriate dissolution behaviour over10 hours for the model drug can be achieved using 30% polymer ratio in the tablet(HPMC K100M).

In the third chapter, based on ethylcellulose, we have prepared by directcompression prolonged release tablets containing felodipine. The prolongation of therelease of the model drug can be achieved with the increase of ethylcellulose ratio (matrixforming agent) in the tablet. By optimizing the formulation we have achieved a felodipine


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dissolution profile that proved to be similar with the dissolution profile of a referenceindustrial product.

In the fourth chapter we have prepared coated felodipine loaded granules usingdifferent coating techniques and different coating polymers. A prolonged release profilefor felodipine can be achieved with the increase of the uncoated granule size, granule thathas been coated with a certain amount of ethylcellulose at certain experimentalconditions.


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CURRICULUM VITAE

PERSONAL DATA:

Name: IOVANOVFirst name: Rares IuliuDate and place of birth: 04.07.1981, Arad

Nationality: RomanianMarital status: CelibateAddress: Banu Mrcine Street, No. 10, Ap. 19, Arad, Arad County,RomaniaPhone: +40(0)723651018Email: [email protected], [email protected]

EDUCATION:- 2009 2010 master student in Industrial Pharmaceutical Technology -

University of Medicine and Pharmacy Iuliu Haieganu Cluj-Napoca, Romania- 2005 present PhD student at the department of Pharmaceutical

Technology and Biopharmaceutics, Faculty of Pharmacy, University ofMedicine and Pharmacy Iuliu Haieganu Cluj-Napoca, Romania

-

2000 2005 - Pharmacist Degree - Faculty of Pharmacy, University ofMedicine and Pharmacy Iuliu Haieganu Cluj-Napoca,Romania

- March 2nd may 31st 2005 Erasmus stage at the Department ofPharmaceutical Technology of the Faculty of Pharmacy, Universit Aix-Marseille II, Marseille, France

- 1996 2000- Baccalaureate Diploma, Elena Ghiba Birta High School,major in biology and chemistry

CARREER:- March 2009 present Teaching assistant, Pharmaceutical Technology

and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and

Pharmacy Iuliu Haieganu Cluj-Napoca, Romania- March 2008 February 2009 Junior teaching assistant, Pharmaceutical

Technology and Biopharmaceutics, Faculty of Pharmacy, University ofMedicine and Pharmacy Iuliu Haieganu Cluj-Napoca, Romania

COURSES AND RESEARCH POSITIONS

1.European IP Galenos Course Skin Barrier Function: Pharmaceutic and CosmeticApplications, 15.09.2006 29.09.2006, Lyon, France2. Workshop & Seminar: Production & Laboratory Solutions for PharmaceuticalIndustry, 19.10.2006 20.10.2006, Faculty of Pharmacy, Cluj-Napoca, Romania


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3.Colorcon Coating School, 12.03.2007- 14.03.2007, Budapest, Hungary4.Pharma Seminarium by LGC Promochem, 30.11.2007, Cluj-Napoca, Romania5.Colorcon Modified Release Forum, 05.02.2008 06.02.2008, Bucharest, Romania6. 13th Summer Course on Pharmaceutical Analysis - Advanced AnalyticalMethodologies in Drug Discovery, 21.09.2008 23.09.2008, Rimini, Italy7. 14th Summer School on Pharmaceutical Analysis - ADVANCED ANALYTICALMETHODOLOGIES IN DRUG DEVELOPMENT, 07.09.2009 09.09.2009, Milan,Italy8. 13th International Meeting on Recent Developments in Pharmaceutical Analysis,09.09.2009 12.09.2009, Milan, Italy9. 15th Summer School on Pharmaceutical Analysis - ADVANCED ANALYTICALMETHODOLOGIES IN DRUG PRE-FORMULATION AND QUALITY CONTROL,13.06.2010 18.06.2010, Rimini, Italy

PAPER PRESENTED AND/OR PUBLISHED IN ABSTRACTS

1.The National Congress of Pharmacy, September 2006, Cluj-Napoca, Romania, RareI.IOVANOV, Elena DINTE, Sorin E. LEUCUA, The study of metronidazole bucalbioadhesive tablets based on hydrophilic polymers(poster presentation)2. Pharmaceutical Sciences World Congress, 22.04.2007 24.04.2007, Amsterdam,Holland, RareI. IOVANOV, Ioan TOMU, Sorin E. LEUCUA,Multivariate methodin formulation of extended release felodipine matrix tablets based on polyethylene oxydeand hydroxypropylmethylcellulose(poster presentation)3. 7th Central European Symposium on Pharmaceutical Technology and BiodeliverySystems, 18.09.2008 20.09.2008, Ljubljana, Slovenia, Rare I. IOVANOV, Ioan

TOMU, Sorin E. LEUCUA,Influence of some formulation factors on the release offelodipine from prolonged release matrix tablets(poster presentation)

ARTICLESIN EXTENSO

1.R.I. IOVANOV, I. TOMU, S.E. LEUCUA, The optimization of prolonged releaseof matrix tablets with felodipine, Farmacia, 2008, LIV (3), 290-299

2. Rare I. IOVANOV, Ioan TOMU, Sorin E. LEUCUA, Influence of someformulation factors on the release of felodipine from extended release hydrophilic matrixtablets, Farmacia, 2009, LVII (5), 582-589

RESEARCH PROJECTS Director of project:- PN II Grant TD 276, Formulation strategies of some prolonged release

pharmaceutical systems with felodipine, 2007-2009

Member of the research team:- CNCSIS PN II Grant 457: Screening of technological variables for the

modification of drug pharmacokinetics and biological action for synthesis of

modern pharmaceutical forms;


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- CNCSIS Grant AT 94:Development and optimization of formulation andpreparation of a pharmaceutical systems for oral use with specific targeting and

release of the active ingredient in the colon;

-

Grant CNCSIS PN II Grant 41_072:Development of a new therapy forneuroprotection in cerebral ischemia by interdisciplinary research;

- Grant CNCSIS PNII IDEI 1350:Development of a new, fast, non destructivetechnology for the monitorization of tablet preparation, based on NIRspectroscopy and chemometrics;

- CNCSIS PNII Grant 1157: Post extraction application of in situ artificial clothforming mucoadhesive therapeutic systems, at patients with osteonecrosis.

MEMBER OF PROFESSIONAL SOCIETIES

- College of Pharmacist from Romania

-

Romanian Society of Pharmaceutical Sciences

FOREIGN LANGUAGES- French good- English medium- Hungarian - medium

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