Ioan Tomuta

UNIVERSITATEA DE MEDICIN I FARMACIE IULIU HAIEGANU CLUJ-NAPOCA

FACULTATEA DE FARMACIE

OPTIMIZAREA FORMULRII UNORPREPARATE MEDICAMENTOASE CU CEDARE LA NIVELUL COLONULUI

- REZUMAT TEZ DE DOCTORAT -

Conductor tiinific:

Prof. dr. Sorin E. LeucuaDoctorand:Ioan Tomu

2006

OPTIMIZAREA FORMULRII UNOR PREPARATE MEDICAMENTOASE CU CEDARE LA NIVELUL COLONULUI - REZUMAT TEZ DE DOCTORAT -

CUPRINSINTRODUCERE ........................................................................................................... 1 I. PARTEA GENERAL. STADIUL ACTUAL AL CUNOATERII ............ 41. Forme farmaceutice cu eliberare colonic ........................................................................ 51.1. Generaliti ..................................................................................................................................... 5 1.2. Tipuri de forme farmaceutice cu eliberare colonic ...................................................................... 7

2. Utilizarea planurilor experimentale n domeniul tehnologiei farmaceutice, inclusiv a formulrii medicamentelor cu cedare colonic ............................................................... 162.1. Generaliti ................................................................................................................................... 16 2.2. Strategii de cercetare .................................................................................................................... 18 2.3. Variabilele unui proces de optimizare ......................................................................................... 24 2.4. Planuri factoriale complete cu dou niveluri 2k ........................................................................... 25 2.5. Planuri factoriale fracionate (reduse) cu dou niveluri 2k-p ........................................................ 30 2.6. Planuri factoriale cu trei niveluri 3k ............................................................................................. 33 2.7. Alte planuri factoriale .................................................................................................................. 35 2.8. Alegerea planului experimental ................................................................................................... 40

3. Alegerea indometacinului ca substan medicamentoas model pentru cercetrile experimentale de formulare a unor forme farmaceutice cu cedare colonic ................................................................................................................... 42 II. PARTEA EXPERIMENTAL. CONTRIBUII PERSONALE ................. 541. Optimizarea metodei de obinere a peletelor cu indometacin prin metoda stratificrii, n toba de drajefiere ........................................................................................................... 461.1. Introducere .................................................................................................................................. 46 1.2. Materiale i metode ...................................................................................................................... 49 1.3. Rezultate i discuii ...................................................................................................................... 56 1.3.1. Analiza planului experimental redus (25-2) ............................................................................ 57 1.3.2. Analiza planului experimental complet (plan experimental redus + plan factorial complementar) ...................................................................................................................... 64 1.4. Concluzii ...................................................................................................................................... 82

2. Prepararea unor pelete cu eliberarea substanei medicamentoase la nivelul colonului utiliznd hidroxipropil metilceluloz (HPMC) ca agent de umflare i rupere a filmului polimeric ............................................................................................................................. 842.1. Introducere ................................................................................................................................... 84 2.2. Materiale i metode ...................................................................................................................... 87 2.3. Rezultate i discuii ...................................................................................................................... 92 2.3.1. Cedarea substanei medicamentoase n mediu acid la pH 1,2 .............................................. 92 2.3.2. Cedarea substanei medicamentoase n mediu neutru la pH 6,8 ........................................... 93 2.3.2.1. Fitarea planului experimental ........................................................................................ 94 2.3.2.2. Analiza cantitii de HPMC (X1) .................................................................................... 98 2.3.2.3. Analiza cantitii de Eudragit RS 30D (X2) .................................................................. 100 2.3.2.4. Analiza cantitii de trietilcitrat (X3) ............................................................................ 102 2.4. Concluzii .................................................................................................................................... 103

3. Prepararea unor pelete care elibereaz substana medicamentoas la nivelul colonului utiliznd superdezagregani ca ageni de umflare i rupere a filmului polimeric

................................................................................................................................ 1053.1. Introducere ................................................................................................................................. 105 3.2. Materiale i metode .................................................................................................................... 107 3.3. Rezultate i discuii .................................................................................................................... 111 3.3.1. Cedarea substanei medicamentoase n mediul acid (pH 1,2) ............................................. 111

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3.3.2. Cedarea substanei medicamentoase n mediul neutru (pH 6,8) ......................................... 112 3.3.2.1. Fitarea planului experimental ...................................................................................... 114 3.3.2.2. Analiza influenei factorului X1 (tipul de superdezagregant) ....................................... 116 3.3.2.3. Analiza influenei factorului X2 (cantitatea de superdezagregant) .............................. 117 3.3.2.4. Analiza influenei factorului X3 (cantitatea de Eudragit RS 30D) ............................... 119 3.3.2.5. Analiza influenei factorului X4 (cantitatea de plastifiant) .......................................... 120 3.4. Concluzii .................................................................................................................................... 121

4. Influena tratamentului termic asupra cedrii substanei medicamentoase din pelete acoperite cu Eudragit RS 30D ........................................................................................ 123

5. Preparararea unor minicomprimate cu eliberare colonic a indometacinului ...................................................................................................................................... 1315.1. Optimizarea metodei de preparare a unor minicomprimate cu eliberare colonic a indometacinului ..................................................................................................................1315.1.1. Introducere .......................................................................................................................... 131 5.1.2. Materiale i metode ............................................................................................................. 134 5.1.3. Rezultate i discuii ............................................................................................................. 138 5.1.3.1. Cedarea substanei medicamentoase n mediu acid la pH 1,2 ..................................... 138 5.1.3.2. Cedarea substanei medicamentoase n mediu neutru la pH 6,8.................................. 139 5.1.3.2.1. Fitarea planului experimental ............................................................................... 140 5.1.3.2.2. Analiza cantitii de Eudragit RS 30D (X1) ........................................................... 142 5.1.3.2.3. Analiza cantitii de HPMC (X2) ........................................................................... 143 5.1.3.2.4. Determinarea formulrii optime ........................................................................... 144 5.1.4. Concluzii ............................................................................................................................. 145

5.2. Validarea metodei de preparare a minicomprimatelor cu cedare colonic a indometacinului, pe serie de laborator .............................................................................. 1475.2.1. Protocol de Validare ........................................................................................................... 147 5.2.2. Raport de Validare ............................................................................................................. 165

6. Evaluarea in vivo a unor minicomprimate cu eliberare colonic care conin indometacin .......................................................................................................... 1806.1. Introducere ................................................................................................................................. 180 6.2. Materiale i metode .................................................................................................................... 181 6.3. Rezultate i discuii .................................................................................................................... 183 6.3.1. Concentraii plasmatice ....................................................................................................... 183 6.3.2. Parametrii farmcocinetici .................................................................................................... 184 6.3.2.1. Timpul de realizare a concentraiilor maxime (Tmax) ................................................. 184 6.3.2.2. Timpul de laten (Tlag) ................................................................................................. 185 6.3.2.3. Concentraia maxim (Cmax) ...................................................................................... 185 6.3.2.4. Aria de sub curb (ASC) ............................................................................................... 186 6.4. Concluzii .................................................................................................................................... 186

CONCLUZII FINALE .............................................................................................. 188 ANEXE ....................................................................................................................... 193Anexa 1. Protocol de validare: dozarea substanei medicamentoase (indometacin) din pelete obinute prin stratificare ....................................................................................................................... 193 Anexa 2. Raport de validare: dozarea substanei medicamentoase (indometacin) din pelete obinute prin stratificare ....................................................................................................................... 202 Anexa 3. Protocol de validare: dozarea substanei medicamentoase (indometacin) din sistemele farmaceutice preparate, n timpul studiilor de dizolvare ........................................................ 205 Anexa 4. Raport de validare: dozarea substanei medicamentoase (indometacin) din sistemele farmaceutice preparate, n timpul studiilor de dizolvare ........................................................ 209

BIBLIOGRAFIE ....................................................................................................... 213 .

CUVINTE

formularea medicamentelor, cedare colonic, planuri experimentale, optimizare, Eudragit, acoperire n pat fluidizat, pelete, minicomprimate, indometacin. 2

CHEIE:


INTRODUCERE Studiile actuale n domeniul medicamentului au ca direcii importante, printre altele, descoperirea i introducerea n terapie de noi molecule bioactive i modularea vitezei/locului de eliberare a substanelor medicamentoase, folosite uzual n terapie. A doua direcie de cercetare presupune utilizarea diferitelor tehnologii farmaceutice n vederea modulrii vitezei de cedare a substanei medicamentoase (controlled drug release) sau cedarea substanei medicamentoase la locul aciunii (drug targeting). Scopul principal al modulrii vitezei de cedare sau locului de cedare este creterea eficienei i reducerea efectelor adverse ale substanelor medicamentoase existente n arsenalul terapeutic la ora actual. Interesul uria pe care l reprezint acest domeniu de cercetare este reflectat de numrul imens de articole de specialitate publicate n revistele de specialitate din ultimii ani (Advanced Drug Delivery Reviews, Journal of Controlled Release, Journal of Drug Targeting, International Journal of Pharmaceutics, etc.). Cercetrile de formulare a unor produse farmaceutice cu cedare controlat includ i pe cele care vizeaz transportul i eliberarea substanei medicamentoase specific la nivelul colonului. Transportul i eliberarea substanei medicamentoase specific la nivelul colonului prezint interes din punct de vedere terapeutic din urmtoarele motive: 1. creterea eficienei tratamentului oral al unor afeciuni inflamatorii nespecifice de la nivelul colonului (colita ulcero-hemoragic i boala Crohn), foarte dificil de tratat; 2. creterea eficienei tratamentului oral al unor afeciuni a cror simptomatologia atinge maximul n timpul nopii spre diminea (orele 4-6 dimineaa), cum sunt: astmul bronic, angina pectoral, artrita reumatoid; 3. se poate realiza administrarea oral a proteinelor cu eliberarea i absorbia lor la nivelul colonului, mai ales n cazul utilizrii unor promotori de absorbie. Acest lucru este posibil datorit faptului c activitatea proteolitic a enzimelor de la nivelul colonului este mult inferioar celei de la nivelul stomacului sau intestinului subire i datorit faptului c tranzitul prin colon este mult mai lung comparativ cu cel partea superioar a tractului gastro-intestinal. I. PARTEA GENERAL.

STADIUL ACTUAL AL CUNOATERII1. Forme farmaceutice cu eliberare colonic

Transportul i cedarea substanelor medicamentoase n mod specific la nivelul colonului (cedarea colonic) dup administrarea lor oral se poate realiza utiliznd caracteristicile fiziologice ale tubului digestiv. Principalele caracteristici fiziologice care pot fi exploatate pentru realizarea transportului i cedrii specifice la nivelul colonului sunt: diferena dintre pH-ul coninutului intestinului subire i pH-ul coninutului colonului; timpul de tranzit intestinal n intestinul subire relativ constant de aproximativ 3 ore; activitatea florei microbiene specifice de la nivelul colonului; 3


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timpul de reziden ndelungat la nivelul colonului; presiunea ridicat din coninutul intestinal de la nivelul colonului determinat de micrile peristaltice ale musculaturii colonului i creterea vscozitii coninutului intestinal n urma absorbiei apei de la acest nivel.

2. Utilizarea planurilor experimentale n domeniul tehnologiei farmaceutice, inclusiv a formulrii medicamentelor cu cedare colonic

Planurile experimentale reprezint strategii moderne de cercetare, prelucrare statistic i interpretare a rezultatelor, strategii care permit reducerea numrului de determinri experimentale fr a pierde din acurateea rezultatelor obinute. Planurile experimentale reprezint strategia optim de studiu a unui fenomen (formularea unui medicament) care permite aflarea celor mai multe informaii despre fenomen n urma unui numr minim de determinri experimentale. Ele permit studiul simultan a numeroi factorii de formulare cu meninerea numrului de determinri experimentale la o valoare rezonabil. Alte avantaje ale planurilor experimentale sunt c pot s prevad eventualele interaciuni dintre factori de formulare sau tehnologici i permit determinarea optimului (a celei mai bune combinaii dintre factori astfel nct s se obin rspunsul dorit).

II PARTEA EXPERIMENTAL.

CONTRIBUII PERSONALE1. Optimizarea metodei de obinere a peletelor cu indometacin prin metoda stratificrii, n toba de drajefiere

n prima parte a studiilor experimentale s-a realizat optimizarea metodei de preparare a peletelor prin stratificare cu pulberi n toba de drajefiere clasic. n aceast etap s-a dorit punerea la punct a condiiilor experimentale care permit obinerea (n condiii de reproductibilitate i cu randamente superioare) de pelete medicamentoase de foarte bun calitate. Pentru a realiza acest deziderat s-a folosit un plan factorial redus cu cinci factori i trei nivele cu ajutorul cruia s-a studiat influena a trei factori de formulare i a doi factori tehnologici asupra proprietilor farmacotehnice ale peletelor obinute prin stratificare cu pulberi n toba de drajefiere clasic. Studiul s-a realizat n dou etape, n prima etap s-a utilizat un plan factorial redus de rezoluie III cu ajutorul cruia s-a realizat un screening pentru identificarea factorilor care influeneaz procesul de obinerea a peletelor. Din cauza rezoluiei reduse (rezoluie III) efectele nu sunt efecte pure i se confund cu interaciunile. Pentru un studiu mai detaliat al factorilor de formulare asupra rspunsurilor sunt necesare determinri suplimentare. Din acest motiv studiul a fost continuat cu un plan factorial complementar realizat prin tehnica foldover. Dup realizarea i analiza planului complementar s-a putut realiza un studiu detaliat al influenei factorilor de formulare i al interaciunilor dintre factori asupra procesului de obinere a peletelor prin stratificare cu pulberi, n vederea determinrii condiiilor optime. Condiiile optime de lucru pentru obinerea peletelor cu bune proprieti farmacotehnice (procent redus de pelete lipite, pelete cu friabilitate sczut i cu bune proprieti de curgere) i care permit obinerea unui randament de ncrcare crescut sunt: vitez de rotaie a tobei relativ ridicat (35-40 rpm); concentraie ridicat a soluiei

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de liant (8% sau mai mare); frecven medie de adugare a pulberii de acoperire; adugare de talc n compoziia pulberii de ncrcare (minim 1%). Aceste condiii experimentale optime au fost utilizate la prepararea peletelor folosite n determinrile ulterioare (la ncrcarea peletelor neutre cu indometacin; la ncrcarea peletelor cu indometacin cu hidroxipropil metilceluloz HPMC; la ncrcarea peletelor cu indometacin cu superdezagregant).2. Prepararea unor pelete cu eliberare a substanei medicamentoase la nivelul colonului utiliznd hidroxipropil metilceluloz (HPMC) ca agent de umflare i rupere a filmului polimeric

Studiile experimentale sau continuat cu formularea unui sistem farmaceutice de tip pelete acoperite, cu cedare colonic. Sistemul farmaceutic s-a preparat plecnd de la pelete cu indometacin acoperite cu dou filme polimerice: un film interior insolubil indiferent de pH, dar permeabil (Eudragit RS) i un film exterior insolubil i impermeabil la pH acid dar uor solubil la pH mai mare de 5,5 (Eudragit L). Sub filmul interior insolubil dar permeabil s-a plasat agentul de umflare care are rolul de a se umfla i de a determina ruperea filmului insolubil dar permeabil (Eudragit RS) i eliberarea substanei medicamentoase. Pentru studierea i realizarea acestui sistem farmaceutic de tip pelete (care conine ca i agent de umflare i rupere a filmului HPMC) s-a folosit un plan experimental Box-Benken cu ajutorul crui s-a studiat efectul a trei factori de formulare (procentul de HPMC, procentul de Eudragit RS i concentraia plastifiantului) asupra performanelor sistemului in vitro. Factorii cheie n realizarea sistemului farmaceutic sunt: determinarea cantitii optime de HPMC pentru obinerea unei fore suficiente pentru ruperea filmului de Eudragit; stabilirea raportului optim dintre grosimea filmului de Eudragit RS i procentul de plastifiant din interiorul filmului (raport necesar pentru obinerea unui film flexibil care s reziste aproximativ 3-4 ore la presiunea exercitat de umflarea stratului de HPMC, dup care s se rup i s permit cedarea substanei medicamentoase). Principala deficien a acestui sistem este faptul c, dup timpul de laten de 3-4 ore, eliberarea substanei medicamentoase nu are loc rapid ci n mod susinut, pe o perioad de 12-16 ore. n urma analizei i interpretrii datelor experimentale avute la dispoziie n acel moment s-a ajuns la concluzia c creterea vitezei de eliberare a substanei medicamentoase dup perioada de laten se poate realiza prin: scderea elasticiti filmului de Eudragit RS prin utilizarea unei cantiti minime de plastifiant; scderea grosimii i respectiv a permeabilitii filmului de Eudragit RS; creterea forei exercitate de statul de umflare prin creterea grosimii filmului de HPMC. Din cauz c utilizarea unui film mai subire sau mai puin rezistent poate crete riscul eliberrii premature a substanei medicamentase (sau a procentului crescut de substan medicamentoas eliberat n perioada de laten) s-a considerat c creterea vitezei de cedare a substanei medicamentoase dup perioada de laten se poate obine prin utilizarea unui polimer cu capacitate de umflare mai mare, care este capabil s exercite o for mai mare pentru ruperea filmului, chiar n condiiile n care este utilizat n concentraie relativ mic iar care dac este folosit n concentraie relativ mare nu formeaz un strat de gel care s mpiedice eliberarea substanei medicamentoase (fenomene care s-au observat n cazul HPMC-ului).3. Prepararea unor pelete care elibereaz substana medicamentoas la nivelul colonului utiliznd superdezagregani ca ageni de umflare i rupere a filmului polimeric

Ca urmare, cercetrile au continuat cu prepararea celui de al doilea sistem farmaceutic cu eliberare colonic de tip pelete la care s-au folosit superdezagregani ca i ageni de umflare i rupere a filmului.

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Pentru a realiza acest obiectiv s-a utilizat un plan factorial redus cu ajutorul cruia sa studiat influena urmtorilor factori: tipului de agent de umflare, cantitatea de agent de umflare, cantitatea de film polimeric i procentul de plastifiant din film, asupra cedrii in vitro a substanei medicamentoase din pelete cu cedare colonic controlat de timp i pH. Factorii cheie n obinerea profilului de cedare dorit sunt: utilizarea amidonglicolatului de sodiu ca i agent de umflare, stabilirea cantitii de amidonglicolat de sodiu necesar pentru obinerea unei fore suficiente pentru ruperea filmului de Eudragit RS i a raportului optim dintre grosimea filmului de Eudragit RS i procentul de plastifiant din interiorul acestuia care permite obinerea unui film flexibil, care s reziste aproximativ 3 ore la presiunea exercitat de umflarea amidonglicolatului de sodiu, dup care s se rup i s permit cedarea substanei medicamentoas. Fa de sistemul la care s-a utilizat HPMC ca agent de umflare, sistemul preparat utiliznd ca agent de umflare superdezagregant cedeaz substana medicamentoas mai rapid, n decurs de 8-10 ore dup perioada de laten, ceea ce prezint un progres semnificativ. Dar spre deosebire de sistemul cu HPMC, a crescut i procentul de substan medicamentoas cedat n perioada de laten. La acest sistem creterea procentului de substan medicamentoas cedat n perioada de laten se poate explica prin faptul c n contact cu apa, mbibarea i umflarea superdezagregantului are loc mai rapid comparativ cu HPMC-ul, iar superdezagregantul prin mbibare nu formeaz un gel care s mpiedice eliberarea substanei medicamentoase. Conform rezultatelor obinute in vitro acest sistem farmaceutic ar putea fi capabil s cedeze cea mai mare parte din substana medicamentoas la nivelul colonului.4. Influena tratamentului termic asupra cedrii substanei medicamentoase din pelete acoperite cu Eudragit RS 30D

Condiiile de aplicare a unui tratament termic asupra peletelor are o influen foarte mare asupra cedrii substanei medicamentoase din sisteme farmaceutice de tip rezervor acoperite cu filme polimerice. Viteza de cedare a substanei medicamentoase se modific n funcie de temperatura i timpul de aplicare a tratamentului termic. La temperatur de 600C stabilizarea filmului are loc mult mai rapid, dup prima or de tratament. Viteza de stabilizare a prioritilor de cedare a filmului polimeric depinde i de grosimea i compoziia filmului aplicat. Pentru obinerea unor pelete cu profil de cedarea reproductibil se recomand un tratament termic de minim o or la 600C sau 12 ore la 400C. 5. Preparararea unor minicomprimate cu eliberare colonic a indometacinului Cercetrile cu continuat cu ncercarea dezvoltrii unui sistem farmaceutic cu eliberare colonic de tip minicomprimate, cu diametrul de 5mm, care pot fi condiionate n capsule gelatinoase tari de mrime 0. Principalul avantaj al utilizrii minicomprimatelor este simplitatea i uurina cu care pot fi obinute nucleele medicamentoase (minicomprimate biconvexe cu diametrul de 5mm) comparativ cu peletele. Avnd la baz experiena acumulat n obinerea peletelor cu eliberare colonic, n partea a doua a tezei, s-a ncercat mbuntirea acestui sistem prin prepararea unor minicomprimate cu eliberare colonic controlat de pH i timp. Pentru optimizarea rapid a metodei de preparare s-a folosit un plan experimental Central Compozit cu doi factori i trei niveluri 23. n urma analizei i interpretrii planului experimental s-a constatat c varianta optim se afl n domeniul experimental. Ca urmare s-a determinat varianta optim teoretic care s-a efectuat i practic. Rezultatele

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obinute practic au fost foarte apropiate de cele prevzute teoretic, ceea ce a validat experimentul i a demonstrat avantajele utilizrii planurilor experimentale la rezolvarea problemelor complexe din timpul formulrii medicamentelor. Deoarece un proces tehnologic de preparare a medicamentelor nu are nici o valoare dac rezultatele obinute pe serii diferite nu sunt reproductibile, nainte de a realiza un studiu in vivo s-a luat decizia validrii procedeul tehnologic de preparare a sistemului farmaceutic cu eliberare colonic. Pentru validare s-a ales varianta optim de preparare a minicomprimatelor determinat cu ajutorul planului experimental. Validarea s-a realizat pe trei serii iar rezultatele obinute la determinarea parametrilor de calitate stabilii n protocolul de validare s-au ncadrat n limitele stabilite. Mai mult, nu au existat diferene semnificative ntre rezultatele obinute pe cele trei serii pe care s-a efectuat validarea. Acest lucru nseamn c procesul tehnologic de preparare a minicomprimatelor cu eliberare colonic la nivel de serie de laborator, este reproductibil i permite obinerea n mod constant de comprimate care s ntruneasc condiiile de calitate prestabilite. 6. Evaluarea in vivo a unor minicomprimate cu eliberare colonic care conin indometacin Pentru c procesul de preparare este reproductibil, iar rezultatele obinute la cedarea in vitro sunt n limitele parametrilor prestabilii (n urma consultrii literaturii de specialitate), s-a luat hotrrea testrii in vivo a sistemului farmaceutic de tip minicomprimate, pe voluntari sntoi, pentru a verifica performana acestui sistem n condiiile utilizrii clinice. Conform datelor obinute absorbia indometacinului din minicomprimatele cu cedare colonic apare dup un timp de laten de aproximativ 4 ore (ceea ce nseamn c eliberarea substanei medicamentose a nceput n ultima parte a ileonului sau n colon), iar concentraia plasmatic maxim se realizeaz dup 7 ore (ceea ce nseamn c cedarea substanei medicamentoase din minicomprimatele realizate are loc preponderent la nivelul intestinului gros). Acest lucru demonstreaz performana sistemului farmaceutic dezvoltat i faptul c acest tip de minicomprimate sunt capabile s cedeze substanele medicamentoase intit la nivelul colonului i s previn eliberarea lor n prima parte a tubului digestiv. CONCLUZII FINALE A fost dezvoltat i validat o tehnologie de preparare a unui sistem farmaceutic cu cedare colonic, folosind echipamente i excipieni utilizai curent n industria farmaceutic. Rezultatele obinute in vivo au demonstrat performana sistemului farmaceutic dezvoltat i faptul c acest tip de minicomprimate sunt capabile s cedeze substana medicamentoas intit la nivelul colonului i s previn eliberarea ei n prima parte a tubului digestiv. Acest sistem farmaceutic poate fi folosit pentru transportul i eliberarea intit a substanei medicamentoase la nivelul colonului, n cazul unor tratamente locale cu substane medicamentoase care n mod normal se absorb rapid n prima parte a tubului digestiv (antiinflamatoare steroidiene i nesteroidiene) sau pentru a preveni degradarea i a permite absorbia sistemic dup administrarea oral a unor substane medicamentoase care sunt degradate n prima parte a tubului digestiv (proteine i polipeptide).

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Curriculum Vitae IOAN TOMU -

TOMU IOANCurriculum Vitae

DATE PERSONALE Data i locul naterii: 23.09.1975, Sibiu Domiciliu stabil: loc. Rui, nr. 32, Jud. Sibiu, 557243 - Romnia flotant: loc. Cluj-Napoca, str. Gorunului nr. 26, ap. 23, Jud. Cluj, 400187 Romnia, Tel: 0745-253323 Adres serviciu: Universitatea de Medicin i Farmacie Iuliu Haieganu, Facultatea de Farmacie, Catedra de Tehnologie Farmaceutic i Biofarmacie, loc. Cluj-Napoca, str. V. Babe, nr 42, 400023 Romnia, Tel/Fax 0264595770 E-mail: [email protected] PREGTIRE PROFESIONAL 2004-2006 Masterat n specialitatea Managementul Calitii, Facultatea de Inginerie Hermann Oberth, Universitatea Lucian Blaga, Sibiu; din ianuarie 2005 rezident n specialitatea Laborator Farmaceutic; din noiembrie 2001 doctorand fr frecven, domeniul fundamental tiine medicale, domeniul farmacie, Universitatea de Medicin i Farmacie Iuliu Haieganu, Cluj-Napoca (ndrumtor Prof. Dr. S.E. Leucua); noiembrie 2004 obinerea titlului de farmacist specialist, specialitatea Industrie Farmaceutic i Cosmetic; 2001-2004 rezident n specialitatea Industrie Farmaceutic i Cosmetic; 2001-2003 Masterat n specialitatea Tehnologie Farmaceutic Industrial, Universitatea de Medicin i Farmacie Iuliu Haieganu; 1995-2000 Facultatea de Farmacie, Universitatea de Medicin i Farmacie Iuliu Haieganu; 1990-1994 Liceul D.P. BARCIANU (Grup colar Agricol) Sibiu, secia vetrinar. ACTIVITATE PROFESIONAL ianuarie 2005 - prezent consultant extern n probleme de formularea medicamentelor i configurarea linilor tehnologice din industria farmaceutic pentru companii farmaceutice romneti; octombrie 2004 - prezent asistent universitar, Catedra de Tehnologie Farmaceutic i Biofarmacie, Facultatea de Farmacie, Universitatea de Medicin i Farmacie Iuliu Haieganu; octombrie 2001 - prezent responsabil studii in vitro, Laboratorul de Bioechivalen, Facultatea de Farmacie, Universitatea de Medicin i Farmacie Iuliu Haieganu; octombrie 2001 - septembrie 2004 preparator la Catedra de Tehnologie farmaceutic i Biofarmacie, Facultatea de Farmacie, Universitatea de Medicin i Farmacie Iuliu Haieganu; ianuarie 2001 - octombrie 2001 farmacist stagiar la Farmacia Clinicilor, Spitalul Clinic Judeean Cluj; octombrie 2000 - ianuarie 2001 farmacist stagiar la S.C. Farmacon S.R.L., farmacie privat n Cluj-Napoca. 1


PARTICIPAREA LA CURSURI/ SIMPOZIOANE INTERNAIONALE 1. Conferina EUFEPS When poor solubility becomes an issue: from early stage to proof of principles, 26 27 Aprilie 2006, Verona, Italia; 2. International GALENOS Intensive Course and Workshop on Advanced approaches to dosage forms design, Universitatea Charles, 16 27 Ianuarie 2006, Hradec Kralove, Cehia; 3. Modified Release Forum, Colorcon, 20 21 Septembrie 2005, Heidelberg, Germania 4. HandsonDissolution Workshop, Faculty of Pharmacy, 6 7 Octombrie, 2005, Bucureti, Romnia; 5. HPLC-GMP in theory and practice for pharmaceutical companies, Groen QA Expert bv, 17 18 Februarie 2005, Bucureti, Romnia; 6. International Regulatory Workshop on Bioequivalence and Dissolution, 4 5 Decembrie 2003, Bucureti, Romnia; 7. Design of Experiments, Academia Umetrics, 23 25 Septembrie 2003, Amsterdam, Olanda; 8. Colorcon Autumn Coating School, Colorcon, 18 20 Septembrie 2002, Budapesta, Ungaria; 9. Pharmaceutical Coating Technology, European Continuing Education College, 13 15 Mai 2002, Londra, Marea Britanie. PARTICIPAREA LA CURSURI/SIMPOZIOANE NAIONALE 1. IMA EST Complete solution for solid dosage forms processing and packaging, 15 16 Martie 2006, Braov; 2. Cursurile internaionale de var pentru farmaciti MAMAIA 2005, 30 mai 4 iulie 2005, Constana; 3. Simpozionul Naional Farmacia astzi, ntre promovare i cercetare, 20 29 Mai, 2005, Timioara; 4. Simpozionul Farmaceutica Marisiensis 7 9 Octombrie, 2004, Trgu Mure; 5. Al doilea simpozion internaional Noi resurse n industria farmaceutic, 27 30 mai, 2004, Constana; 6. Simpozionul Farmacistul furnizor de servicii de sntate 24 mai 2003, ClujNapoca; 7. Primul simpozion internaional Noi resurse n industria farmaceutic, 5 8 iunie, 2003, Constana; 8. Tehnici i metode cromatografice i spectrale n calitatea medicamentului, UMF Iuliu Haieganu, 2 16 martie 2002, Cluj-Napoca; 9. Al XII Congres Naional de Farmacie, 17 19 octombrie 2002, Bucureti; 10. Al VII-lea Simpozion de Biofarmacie i Farmacocinetic, 18 19 octombrie 2002, Bucureti. PUBLICAII 31 articole (14 prim autor) co-autor la trei cri: TECHNOLOGIE PHARMACEUTIQUE (francez), Sorin Leucua, Marcela Achim, Elena Dinte, Ioan Tomu, Laurian Vlase, Editura Medical Universitar Iuliu Haieganu Cluj-Napoca, 2006; TEHNOLOGIE FARMACEUTIC INDUSTRIAL. PROCEDEE DE LABORATOR, (romn), Sorin E. Leucua, Marcela Achim, Ioan Tomu, Editura Medical Universitar Iuliu Haieganu Cluj-Napoca, 2005; 2


TRAVAUX PRATIQUES. TECHNOLOGIE PHARMACEUTIQUE, (francez), Sorin E. Leucua, Marcela Achim, Ioan Tomu, Editura Medical Universitar Iuliu Haieganu Cluj-Napoca, 2005.

MEMBRU N ASOCIAII PROFESIONALE Colegiul Farmacitilor din Romnia, din 2000 Societatea de tiine Farmaceutice din Romnia, din 2001 Societatea Romn de Chimie, din 2004 Societatea de tiine Farmaceutice din Canada, din 2005 DOMENII DE INTERES Formularea/preformularea medicamentelor i optimizarea cineticii de cedare a substanei medicamentoase Utilizarea planurilor experimentale la formularea medicamentelor Studii de preformulare i compatibilitate/interaciuni ntre excipieni sau ntre excipieni i substan medicamentoas care afecteaz stabilitatea formelor farmaceutice solide cu administrare oral Acoperirea peletelor i a comprimatelor Dezvoltarea de forme farmaceutice cu cedare modificat: - cedarea substanei medicamentoase n colon - comprimate cu cedarea prelungit matri hidrofil - comprimate/capsule cu cedarea prelungit de tip rezervor Obinerea de pelete medicamentoase Granulare (n special granulare n pat de aer fluidizat) Biodisponibilitatea i bioechivalena medicamentelor Studii de dizolvare in vitro Evaluarea cedrii substanei medicamentoase in vitro n diferite medii, screening pentru gsirea condiiilor de dizolvare adecvate Dezvoltarea i validarea de metode HPLC (detecie UV), spectrofotometrice UV-Vis pentru analiza substanei medicamentoase din forme farmaceutice n timpul formulrii i/sau produciei Analiza profilurilor de dizolvare utiliznd metode model dependente, evaluarea mecanismului de cedare a substanei medicamentoase din forme farmaceutice Corelare in vitro - in vivo Prepararea industrial a medicamentelor Formularea i prepararea comprimatelor prin comprimare direct Scale up (serie laborator serie pilot, serie pilot serie industrial) Validarea proceselor tehnologice Process analytical technology (PAT) LIMBI STRINE Englez Francez

Cluj Napoca 12.06.2006

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Lista cu lucrri publicate, cuprinse n teza de doctorat IOAN TOMU -

LISTA CU LUCRRI PUBLICATE, CUPRINSE N TEZA DE DOCTORAT:1. I. TOMUTA, S.E. LEUCUTA, Use of experimental design for identifying the most important formulation and technological variables in pelletization by powder layering, J. Drug Del. Sci. Tech., 14 (3), 215-221, 2004 2. 3. I. TOMU, S. E. LEUCUA, Preparation and in vitro characterization of colon release pellets with pH and time control mechanism Farmacia LVI 1, 51-60, 2006 I. TOMU, S.E. LEUCUA, Prepararea unor pelete destinate eliberrii substanei medicamentoase la nivelul colonului, Clujul-Medical, LXXVIII, 3, 629637, 2005 I. TOMU, S.E. LEUCUA, Colonic delivery minitablets preparation and optimization using experimental design, Farmacia III, 6, 80-88, 2005 I. TOMU, S.E. LEUCUA, Influena tratamentului termic asupra cedrii substanei medicamentoase din pelete acoperite cu Eudragit RS 30D, Revista de Medicin i Farmacie (Orcosi es Gyogyszereszeti Syemel), vol. 50, Supliment II, 121125, 2004

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UNIVERSITY OF MEDICINE AND PHARMACY IULIU HAIEGANU CLUJ-NAPOCA FACULTY OF PHARMACY

FORMULATION OPTIMIZATION OF SOME SOLID DOSAGE FORMS WITH COLONICDRUG RELEASE

- PHD THESIS ABSTRACT -

Scientific supervisor:

Prof. dr. Sorin E. LeucuaPhD Student:Ioan Tomu

2006

FORMULATION OPTIMIZATION OF SOME SOLID DOSAGE FORMS WITH COLONIC DRUG RELEASE - PHD THESIS ABSTRACT -

CONTENTSINTRODUCTION ......................................................................................................... 1 I. GENERAL PART. THE CURRENT STAGE OF KNOWLEDGE .. 41. Pharmaceutical dosage forms with colonic drug release ................................................. 51.1. General aspect ................................................................................................................................ 5 1.2. Types of pharmaceutical dosage forms with colon drug release ................................................... 7

2. The use of experimental design in pharmaceutical technology filed and inclusive for formulation solid dosage forms with colonic drug release ..................... 162.1. General aspect............................................................................................................................... 16 2.2. Research strategies ............................................................................................... 18 2.3. Variables during optimization ........................................................................................ 24 2.4. Experimental designs complete with two levels 2k ...................................................................... 25 2.5. Experimental designs fractioned with two levels 2k-p .......................................................... 30 2.6. Experimental designs with three levels 3k ................................................................................... 33 2.7. Others experimental designs ........................................................................................................ 35 2.8. Selection of experimental design ................................................................................................. 40

3. Selection the indomethacin as model drug for experimental research in development of colonic drug release dosage forms ......................................... 42 II. EXPERIMENTAL PART. PERSONAL CONTRIBUTION ................ 541. Powder layering pellets method preparation optimization ....................................... 461.1. Introduction ................................................................................................................................. 46 1.2. Materials and methods.................................................................................................................. 49 1.3. Results and discussions ................................................................................................................ 56 1.3.1. Fractional experimental design analysis (25-2) ...................................................................... 57 1.3.2. Complete experimental design analysis (fractional experimental design + complemented fractional experimental design) ............................................................................................ 64 1.4. Conclusions .................................................................................................................................. 82

2. Colonic drug release pellets with (hydroxypropyl methylcellulose ) HPMC as agent for swelling and polymeric film breaking preparation .................................... 842.1. Introduction .................................................................................................................................. 84 2.2. Materials and methods ................................................................................................................. 87 2.3. Results and discussions ............................................................................................................ 92 2.3.1. Drug release in acid medium at pH 1.2 ............................................. 92 2.3.2. Drug release in neutral medium at pH 6,8 ........................................ 93 2.3.2.1. Experimental design fitting ........................................................................................ 94 2.3.2.2. Influence the amount of HPMC (X1) analysis ................................................................ 98 2.3.2.3. Influence the amount of Eudragit RS 30D (X2) analysis .......................................... 100 2.3.2.4. Influence the amount of triethyl citrate (X3) analysis .............................................. 102 2.4. Conclusions ................................................................................................................................ 103

3. Colonic drug release pellets with super-disintegrants as agent for swelling and polymeric film breaking preparation .................................................. 1053.1. Introduction ................................................................................................................................ 105 3.2. Materials and methods ............................................................................................................... 107 3.3. Results and discussions .............................................................................................................. 111 3.3.1. Drug release in acid medium at pH 1.2 ........................................... 111 3.3.2. Drug release in neutral medium at pH 6,8 .......................................... 112 3.3.2.1. Experimental design fitting ....................................................................................... 114 3.3.2.2. Influence of factor X1 (type of super disintegrants) analysis ................................ 116 3.3.2.3. Influence of factor X2 (amount of super disintegrants) analysis .............................. 117

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3.3.2.4. Influence of factor X3 (amount of Eudragit RS 30D) analysis ................................ 119 3.3.2.5. Influence of factor X4 (amount of plasticizer) analysis............................................ 120 3.4. Conclusions ................................................................................................................................ 121

4. Study the influence of curring condition on drug release from pellets coated with Eudrgit RS 30D .................................................................................................... 123

5. Minitablets with colonic drug release preparation ....................................... 1315.1. Method of preparation of minitablets with colonic release of indomethacin optimization ............1315.1.1. Introduction ......................................................................................................................... 131 5.1.2. Materials and methods ........................................................................................................ 134 5.1.3. Results and discussions ....................................................................................................... 138 5.1.3.1. Drug release in acid medium at pH 1.2 .................................... 138 5.1.3.2. Drug release in neutral medium at pH 6,8 ................................ 139 5.1.3.2.1. Experimental design fitting ................................................................................ 140 5.1.3.2.2. Influence the amount of Eudragit RS 30D (X1) analysis ........................................ 142 5.1.3.2.3. Influence the amount of HPMC (X2) analysis ....................................................... 143 5.1.3.2.4. Optimum formula determination ............................................................................ 144 5.1.4. Conclusions ......................................................................................................................... 145

5.2. Method of preparation of minitablets with colonic release of intometacin validation (laboratory scale) ....................................... 1475.2.1. Protocol of Validation.......................................................................................................... 147 5.2.2. Report of Validation ............................................................................................................ 165

6. In vivo evaluation of some minitablets with colonic release of indomethacin ........................................................................................................ 1806.1. Introduction ................................................................................................................................ 180 6.2. Materials and methods ............................................................................................................... 181 6.3. Results and discussions .............................................................................................................. 183 6.3.1. Plasma level concentration of indomethacin ................................................................... 183 6.3.2. Pharmacokinetics parameters .............................................................................................. 184 6.3.2.1.Time for maximul plasma level(Tmax) .................................................. 184 6.3.2.2. Lag time (Tlag) ............................................................................................... 185 6.3.2.3. Maximum plasma level (Cmax) ................................................................................ 185 6.3.2.4. Aria under curve (ASC) ............................................................................................ 186 6.4. Conclusions ............................................................................................................................... 186

FINAL CONCLUSIONS .......................................................................................... 188 ANNEXES .................................................................................................................. 193Annex 1. Validation protocol: drug assay (indomethacin) from pellets obtained by powder layering 193 Annex 2. Validation report: drug assay (indomethacin) from pellets obtained by powder layering ... 202 Annex 3. Validation protocol: drug assay (indomethacin) from prepared dosage forms, during dissolution studies .......................................................... 205 Annex 4. Validation report: drug assay (indomethacin) from prepared dosage forms, during dissolution studies......................................................... 209

REFERENCES ...................................................................................................... 213 .KEYWORDS: drug formulation, colon drug release, colon drug delivery, lag time

release, experimental design, optimization, Eudragit, fluid bed coating, pellets, minitablets, indomethacin,

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INTRODUCTION The current studies in drug research have as important direction, amongst others, to discover and introduce in therapy new pharmaceutical active ingredients and to modulate the kinetic/the site release of common pharmaceutical active ingredients used actually in therapy The second research direction employment pharmaceutical technologies for modulate kinetic release of drug (controlled drug release) or to modulate the release of the drug to the specific site of action (drug targeting). The major goal on modulate kinetic of drug release and modulate targeting of drug is to increase the pharmacological response and to reduce the side effects of the drug that are common used actually in therapy. The big interest on this field of research area is proved by huge numbers of articles published in the lasts years in research journals (Advanced Drug Delivery Reviews, Journal of Controlled Release, Journal of Drug Targeting, International Journal of Pharmaceutics, etc.). The formulation studies for development new pharmaceutical dosages forms with control drug release include also the studies for modulate the targeting and release the drug to the colon. Targeting and site specific release of the drug to the colon is interested from therapeutic point of view for the following reason: 1. to improve the efficacy of pharmacotherapy treatment of specific disorders of the large intestine, (such as irritable bowel syndrome, colitis, Crohns disease); 2. to improve the efficacy of oral treatment of some disorders with maximum symptomatology during the night at 4 6 oclock in the morning (bronchia asthma, pectoral angina, rheumatoid arthritis); 3. for oral taken of proteins/polypeptides with release and absorption to the colon, specially when promoters enhances is used. Protein absorption to colon is possible because the proteolytic activity of enzymes on this site is very low in comparison with activity from stomach and small intestine and the intestinal transit time is longer in comparison with superior part of gastro intestinal tract.

I. GENERAL PART

THE CURRENT STAGE OF KNOWLEDGE1. Pharmaceutical dosage forms with colonic drug release

Targeting and release the drug to the colon after oral administration can be approach using physiological characteristics of gastro intestinal tract. The main physiological characteristics that can be used for colon drug release and colon drug targeting are: the difference between pH content of small intestine and pH content of colon relative constant transit time through small intestine (approximate 3 hours); the specific enzymatic activity of the colon microflora (enzymecontrolled drug release); 3


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long residential time of drug to the colon; high pressure of intestinal content determinate for peristaltic movement of colon musculature and increasing the viscosity of content after water absorption.

2. The use of experimentalism designs in pharmaceutical technology filed and inclusive for formulation solid dosage forms with colonic drug release

The experimental designs are modern strategies for research, statistic analysis, and results interpretations that allow tot reduce the number of experiments to minimum without lose on the accuracy of the obtained results. The experimental designs represent the optimum strategy for a phenomenon study (drug formulation), which allow obtaining the maximum knowledge about phenomenon after a minimum number of experiments. They are allowing to simultaneous study of a large number of formulation factors after a relative low number of experiments. Others advantages of experimental designs are: identification the interaction between formulation factors or technological factors and optimum formula determination (the best combination between factors that allow to obtain the desirables responses). II. EXPERIMENTAL PART

PERSONAL CONTRIBUTION1. Powder layering pellets method preparation optimization

In the first part of experimental studies, the preparation method of pellets by powder layering in classical coating pan was optimized. In this step, the goal of experimental studies was to find experimental conditions that allow to obtain (in reproducible condition and with high efficiency) high quality pellets. To make this a fractional experimental design with five factors and three levels it was used. This experimental design allowed to studies the influence of three formulation factors and two technological factors on pharmacotechnical properties pellets obtained by powder layering in classical coating pan. The study was achieved in two steps, in the first step a fractional experimental design (resolution III) it was used for screening in order to identify the factors that have a very important influence on powder layering process. Because this experimental design has a low resolution (resolution III), the factor effect are not pure, the are confounding with interactions. For a more detailed study of formulation factor on response supplementary experiments are needed. For this reason the studies was continued with an experimental design complementary attain by fold-over technique. After achieved and analysis of complementary experimental design it was possible to realize a detailed study of formulation factors and interactions between factors on powder layering process, in order to find optimal condition to work. Optimal condition to work that allow to obtain pellets with good pharmacotechnical properties (low percent of sticked-pellets, pellets with low friability and good flow properties) and to obtain high powder layering efficiency are: relatively high pan speed of coating (35-40); high concentration of binder solution (8% or greater), medium powder application frequency and talcum (minimum 1%) in powder layering composition.

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This optimum experimental condition was used to prepare pellets in the next steps of experimental studies (to load neutral pellets with indomethacin, to load pellets with indomethacin with hydroxypropyl methylcellulose, to load pellets with indomethacin with super-disintegrants)2. Colonic drug release pellets with (hydroxypropyl methylcellulose ) HPMC as agent for swelling and polymeric film breaking preparation

The experimental studies were continued with formulation of a pharmaceutical system (coated pellets type), with colon release. The pharmaceutical system was prepared starting from indomethacin pellets coated with tow polymeric layers: an inlet film polymeric layer insoluble but permeable pH independent (Eudragit RS 30D) and a outlet film polymeric layer insoluble and impermeable at acidic pH but easy soluble at pH higher that 5.5 (Eudragit L 55 30D). Under inlet film polymeric layer it was put a swelling agent that has the role to swell and to break the insoluble but permeable film (Eudragit RS 30D) and release the drug. For study and realize this pharmaceutical system pellets type (that contain HPMC as swelling and breaking polymeric film) a BoxBenken experimental design it was used. With this experimental design the effect of three formulation factors (ratio of HPMC, ratio of Eudragit RS and ratio of plasticizer) on in vitro performances it was studied. The key factors for pharmaceutical system development are: finding the optimum amount of HPMC in order to obtain a sufficient pressure to break Eudragit RS polymeric film; finding the optimum ratio between Eudragit RS polymeric film thickness and ratio of plasticizer in polymeric film that leads to obtain a flexible polymeric film capable to prevent drug release in the first 3 4 h and after that can be easy break under pressure exerted by swelling the HPMC layer. The major deficiency of this pharmaceutical system is lack of immediate release of drug after lag time of 3 4 hours (the release of drug after lag time sustained release for a period of 12 16 hours). In the wake of analysis and interpretation of experimental data in that stage the conclusion was that the increase of the speed of drug release after lag time can be performed by: reduction the elasticity of Eudragit RS film (using a minimum amount of plasticizer); reduction the thickness of polymeric film of Eudragit RS and increasing the pressure exerted by swelling the HPMC layer by increasing HPMC layer thickness. Because utilization a thinness and weak polymeric film increase the risk of premature drug release (or increase the ratio released in lag time period) the best results can be obtain by using a polymer that have a very high swelling capacity when is used in low ratio or has not high capacity to make a gel (that can delay drug release) when is used in relative high ratio.3. Colonic drug release pellets with super-disintegrants as agent for swelling and polymeric film breaking preparation

With in the mind this consideration the experiments was continued with preparation and analysis the second pharmaceutical system with colon release, pellets type, with super-disintegrants as agent for swelling and polymeric film breaking. To realize is objective a fractional experimental design it was used in order to study the fowling factors: type of swelling agent, amount of swelling agent, amount of polymeric film and ratio of plasticizer in polymeric film on in vitro drug release from pellets with pH and time colon release.

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The most important formulation factors for colonic delivery are: use the sodium starch glycolate as swelling agent, the amount of sodium starch glycolate that expand a sufficient force to break Eudagit RS layer and the optimum ratio among thickness of Eudragit RS and amount of plasticisant that allow to obtain a flexible polimeric film who resists 2,5-3,5 h in 6,8 pH medium and then break to force exercised by sodium starch glycolate swelling. The best formulation contains: 10% sodium starch glycolate, 10,5% Eudragit RS and 12% plasticisant In comparison with system with HPMC as agent for swelling and polymeric film breaking, this system is able to release the drug more quickly after lag time, for a period of 8-10 hours, that is a significant progress. Unfortunately, at this system the ratio of drug release in lag time period was growing. According with in vitro results this system is able to release the most important amount of drug to the colon.4. Study the influence of curing condition on drug release from pellets coated with

Eudrgit RS 30D The curing conditions of pellets have a very important influence on drug release from pharmaceutical system, coated with polymeric films, reservoir type. The release ratio is different function time of curing and curing temperature. At 600C film stabilized occur quickly, after 1 hours of curing. Speed of drug release properties stabilized is different function on thickness and composition of polymeric film. In order to obtain pellets with reproducible release profile a curing for minimum 1 hours at 600C or minimum 12 hours at 400C it is necessary. 5. Minitablets with colonic drug release preparation The researches was continued with development a pharmaceutical system with colon release, minitablets type (with diameter 5mm and that can put in capsules size 0). The main advantages of using minitablets in comparison with pellets are the unpretentiousness and easiness method to obtain drug cores (biconvex minitablets with 5 mm diameter in comparison with pellets). With accumulated experience in obtain pellets with colon release, in the second part of thesis, it was tried to improve this system by preparation minitablets with pH and time control to the colon. For quickly optimize preparation method a Central Composite experimental design with two factors ant three level 23 it was used. After analysis and interpretation of experimental design, it was found that optimum formula is in experimental area. Pursuant to the optimum formula was calculated theoretical and realized experimental. The practical results was very close to theoretical value predicted with experimental design and in consequence validated the experiment and proved the advantage of using experimental design to solve complex problems during drug formulation. Because technological process preparation of drug has a little value if the result obtain in different batches are not reproducible, before a in vivo study it was decide to validate technological process to obtain minitablets with colon release. For validation optimum formula calculate with experimental design was choused. Validation of technological process was performed on three different batches and the obtain results of quality parameters established in validation protocol was in limits. More, there are not significant differences between the three batches. This means that technological process of minitablets with colon release is robust and allow to obtain consistently minitablets that have pre-requested proprieties and quality condition

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6. In vivo evaluation of some minitablets with colonic release of indomethacin Because pharmaceutical process is robust, and results obtain to in vitro release are in limits (established in concordance with pharmaceutical literature), it was decided to test pharmaceutical system with colonic release, minitablets type, in vivo on healthed voluntaries in order to check the performances of pharmaceutical system in conditions of clinical usage. In concordance with data obtain, the absorption of indomethacin from minitablets with colon release occur after a lag time of 4 hours (that means the release of drug begin in the last part of ileum or in colon), and the maximum plasma level is after 7 hours (that means the great part of drug is release in the large intestine). These results data prove the performances of developed pharmaceutical system and prove that this type of pharmaceutical system is able to release drugs targeting to the colon ant to prevent drugs release in the first part of gastro intestinal tract.

FINAL CONCLUSIONS It was developed and validated a preparation technology of a pharmaceutical system with colon release, using equipments and excipients commune used in pharmaceutical industry. In vivo results was proved the performance of development pharmaceutical system and that this type of pharmaceutical system is able to release drugs targeting to the colon and to prevent drugs release in the first part of gastro intestinal tract. This pharmaceutical system can be use for drugs targeting and delivery specific to the colon, for local treatment of colon specific diseases with drugs that normally are absorbed in the first part of gastro intestinal tract (steroid and nonsteroid inflammatory) or to prevent degradation and to permit systemic absorption of drug that are degraded in the first part of gastro intestinal tract (proteins and peptides).

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TOMU IOAN

Curriculum Vitae

PERSONAL DATES Date and place of birth: Personal address: Work address:

Email:

September 23, 1975, Sibiu, Romania loc. Cluj-Napoca, street. Gorunului no. 26, ap. 23, 400187 Romania, Tel +40-745-253323 University of Medicine and Pharmacy Iuliu Hatieganu, Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Cluj-Napoca, 41 V. Babe, 400023 Romania, Tel/Fax +40-264-595770 [email protected]

EDUCATION 2004-2006 MD in speciality Quality Management at Faculty of Engineering Hermann Oberth, Lucian Blaga University, Sibiu; from 2005 resident pharmacist in speciality Pharmaceutical Laboratory; from November 2001 PhD student (fundamental domain Health Sciences, domain Pharmacy), University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, (supervisor Prof. Dr. S.E. Leucua); November 2004 - Specialist Pharmacist Degree, speciality Industrial Pharmaceutical and Cosmetic Technology; 2001-2004 resident pharmacist in speciality Industrial Pharmaceutical and Cosmetic Technology; 2001-2003 MD in speciality Industrial Pharmaceutical Technology at Faculty of Pharmacy, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca; 1995-2000 Faculty of Pharmacy University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca; 1990-1994 graduate high-school D.P. BARCIANU(Agrarian High-School), Sibiu, veterinary section. PROFESSIONAL EXPERIENCE from January 2005 extern consultant in field of drug formulation and industrial pharmaceutical technological line configuration for Romanian Drug Companies; from October 2001 teaching assistant, Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy - University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca; from October 2001 responsible for in vitro studies, Bioechivalence Laboratory, Faculty of Pharmacy - University of Medicine and Pharmacy Iuliu Hatieganu ClujNapoca; January 2001 October 2001 probationer pharmacist, Pharmacy of Clinics from Clinical Municipal Hospital, Cluj-Napoca; October 2000 January 2001 probationer pharmacist at S.C. Farmacon S.R.L., private public pharmacy in Cluj-Napoca. 1


PARTICIPATION AT INTERNATIONAL COURSES/CONFERENCE 1. EUFEPS Conference When poor solubility becomes an issue: from early stage to proof of principles, 26th 27th April 2006, Verona, Italy; 2. International GALENOS Intensive Course and Workshop on Advanced approaches to dosage forms design, 16th 27th January 2006, Charles University, Hradec Kralove, Czech Republic; 3. Modified Release Forum, Colorcon, 20th21th September 2005, Heidelberg, Germany; 4. HandsonDissolution Workshop, Faculty of Pharmacy, 6th7th October, 2005, Bucharest, Romania; 5. HPLC-GMP in theory and practice for pharmaceutical companies, Groen QA Expert bv, 17th 8th February 2005, Bucharest, Romania; 6. International Regulatory Workshop on Bioequivalence and Dissolution, 4th5th December 2003, Bucharest, Romania; 7. Design of Experiments, Umetrics Academy, 23th25th September 2003, Amsterdam, Netherlands; 8. Colorcon Autumn Coating School, Colorcon, 18th20th September 2002, Budapest, Hungary; 9. Pharmaceutical Coating Technology, European Continuing Education College, 13th 15th May 2002, London, UK. PARTICIPATION AT NATIONAL COURSES/CONFERENCE 1. IMA EST Complete solution for solid dosage forms processing and packaging, 16th 16th March 2006, Braov; 2. International Summer Courses for Pharmacists MAMAIA 2005, 30th May 4th June, 2005, Constana; 3. The National Symposium The Pharmacy Today Between Promotion and Research 26th - 28th Mai, 2005, Timioara; 4. Scientific Symposium Farmaceutica Marisiensis 7th - 9th Octombrie, 2004, Trgu Mure 5. The Second International Symposium New resources in pharmaceutical industry, 27th - 30th May, 2004, Constana; 6. Symposium The Pharmacist supplier of health services, 24th May 2003, ClujNapoca 7. The First International Symposium New resources in pharmaceutical industry 5th 8th June, 2003, Constana; 8. Techniques and methods chromatographic and spectral in drug quality, UMF Iuliu Haieganu, 2th 16th March 2002, Cluj-Napoca; 9. The 12th National Congers of Pharmacy, 17th 19th October 2002, Bucharest 10. The 7th Biopharmacy and Pharmacokinetic Symposium, 18th 19th October 2002, Bucharest. PUBLICATIONS 31 papers published (14 first-author) co-author at three books: TECHNOLOGIE PHARMACEUTIQUE (French), Sorin Leucua, Marcela Achim, Elena Dinte, Ioan Tomu, Laurian Vlase, University of Medicine and Pharmacy Iuliu Haieganu Publisher, Cluj-Napoca, 2006; INDUSTRIAL PHARMACEUTICAL TECHNOLOGY - TUTORIAL, (Romanian), Sorin E. Leucua, Marcela Achim, Ioan Tomu, University of Medicine and Pharmacy Iuliu Haieganu Publisher, Cluj-Napoca, 2005; 2


TRAVAUX PRATIQUES. TECHNOLOGIE PHARMACEUTIQUE, (French), Sorin E. Leucua, Marcela Achim, Ioan Tomu, University of Medicine and Pharmacy Iuliu Haieganu Publisher, Cluj-Napoca, 2005. MEMBER IN PROFESSIONAL ASSOCIATION Romanian Pharmaceutical Professional Association, since 2000 Romanian Society for Pharmaceutical Sciences, since 2001 Romanian Society for Chemical Sciences, since 2004 Canadian Society for Pharmaceutical Sciences, since 2005 FIELD OF INTEREST Drug preformulation/formulation and kinetic release optimization Experimental Design in drug formulation Preformulation and compatibility studies excipient and/or drug interaction with affect the stability of the drug in solid dosage forms Pharmaceutical coating (especially fluid bed coating) Modified release dosage forms development: - release drug to the colon - prolong release tablets hydrophilic matrix - prolong release tablets/capsules beds coating Pelletization technology Pharmaceutical granulation (especially fluid bed granulation) Drug Bioavailability and Bioequivalence In vitro dissolution studies In vitro drug release evaluation in different dissolution media, screening for relevant dissolution media HPLC, UV-Vis spectrometry method development and validation for drugs analysis from pharmaceuticals dosage forms during development and/or production Analysis of dissolution profiles using model-dependent methods, assessment of mechanism of release/dissolution of drug from pharmaceuticals in vitro - in vivo correlation Industrial pharmaceutical production Tablet formulation and production by direct compression Scale up (laboratory pivotal batch, pivotal batch industrial batch) Pharmaceutical process validation Process analytical technology (PAT) FOREIGN LANGUAGES English French

Cluj - Napoca 12.06.2006

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List of work paper from PhD thesis IOAN TOMU -

List of work paper from PhD thesis:1. I. TOMUTA, S.E. LEUCUTA, Use of experimental design for identifying the most important formulation and technological variables in pelletization by powder layering, J. Drug Del. Sci. Tech., 14 (3), 215-221, 2004 2. I. TOMU, S. E. LEUCUA, Preparation and in vitro characterization of colon release pellets with pH and time control mechanism Farmacia LVI 1, 51-60, 2006 3. I. TOMU, S.E. LEUCUA Pellets preparation for colonic delivery, ClujulMedical, LXXVIII, 3, 629-637, 2005 4. I. TOMU, S.E. LEUCUA, Colonic delivery minitablets preparation and optimization using experimental design, Farmacia III, 6, 80-88, 2005 5. I. TOMU, S.E. LEUCUA, Study the influence of curring condition on drug release from pellets coated with Eudrgit RS 30D, Revista de Medicin i Farmacie (Orcosi es Gyogyszereszeti Syemel), vol. 50, Supliment II, 121-125, 2004

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Ioan Tomuta

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Transcript of Ioan Tomuta