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Formulacija i karakterizacija oralno-disperzibilnih farmaceutskih oblika sa visokim udelom lekovitih supstanci: doprinos mehanističkom razumevanju sistema

Formulation and characterization of orodispersible dosage forms containing high drug load: contribution to mechanistic system understanding

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2020
Disertacija.pdf (11.62Mb)
IzvestajKomisije22995.pdf (677.7Kb)
Authors
Drašković, Milica
Contributors
Parojčić, Jelena
Aleksić, Ivana
Radojević, Vesna
Doctoral thesis (Published version)
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Abstract
Oralno-disperzibilne tablete (ODT) i oralno-disperzibilni filmovi (ODF) predstavljajukompleksne formulacije koje su namenjene primeni u ustima, gde se u kontaktu sa salivom,gotovo trenutno raspadaju. Pored zahteva za brzo raspadanje, potrebno je da pokazuju iprihvatljivu mehaničku otpornosti kako bi se obezbedila adekvatna manipulacija tokomproizvodnje i primene leka. Cilj istraživanja je bilo ispitivanje i mehanističko objašnjenjeuticaja različitih faktora formulacije i procesnih parametara na raspadljivost i mehaničkekarakteristike, koji su prepoznati kao kritični atributi kvaliteta ODT/ODF.Dinamička analiza kompakcije i teorija perkolacije primenjene su sa ciljem procenefunkcionalnosti novih, direktno kompresibilnih, koprocesovanih ekscipijenasa dizajniranihposebno za razvoj formulacije ODT. Test na istezanje i oscilatorna reološka merenjasprovedena su u svrhu sveobuhvatne analize uticaja različitih ekscipijenasa (hidrofilnipolimeri, superdezintegratori) i variranja udela plastifika...tora na mehanička svojstva ODF,pripremljenih metodom izlivanja. Direktno oblaganje čestica sprovedeno je sa ciljemmaskiranja neprijatnog ukusa ispitivanih lekovitih supstanci, nakon čega je sprovedena in vivoi in vitro procena efikasnosti primenjenog pristupa. Fiziološki zasnovano farmakokinetičkomodelovanje primenjeno je sa ciljem simuliranja in vivo ponašanja ispitivanih preparata iprocene obima apsorpcije lekovite supstance iz odabranih ODT/ODF primenom nedavnorazvijenog prostornog modela apsorpcije i tranzita kroz usnu duplju (OCCATTM).Rezultati sveobuhvatne farmaceutsko-tehnološke karakterizacije i dinamičke analizekompakcije ispitivanih korpocesovanih ekscipijenasa ukazali su na kompleksne odnoseizmeđu osnovnih karakteristika materijala i njihove funkcionalnosti. Uprkos činjenici da sebrzo raspadanje najčešće dovodi u vezu sa lošijom mehaničkom otpornošću tableta, bilo jemoguće formulisati ODT sa visokim udelom lekovitih supstanci (37-67% kofeina, odnosno18-49% ibuprofena) bez narušavanja kritičnih karakteristika kvaliteta (vreme raspadanja < 3mi; zatezna čvrstina > 1 MPa). U slučaju ODF, ispitivani hidrofilni polimeri su obezbediliinkorporiranje 20-25% kofeina, odnosno ibuprofena uz održavanje brzog raspadanja iodgovarajućih mehaničkih svojstava. In vivo i in vitro procenom efikasnosti maskiranja ukusapotvrđena je uspešnost direktnog oblaganja čestica kao metode za maskiranje neprijatnogukusa lekovitih supstanci. Visok stepen korelacije između in vivo i in vitro podataka ukazujeda se modifikovani test dispergovanja lekovitih supstanci u maloj zapremini medijuma možekoristiti kao zamena za in vivo ispitivanja efikasnosti maskiranja ukusa. In silico rezultatisimulacije apsorpcije kofeina, odnosno ibuprofena iz pripremljenih oralno-disperzibilnihfarmaceutskih oblika ukazuju da se nakon primene ispitivanih formulacija može očekivatizanemarljiv obim intraoralne apsorpcije i biološka raspoloživost slična onoj koja se postiženakon primene konvencionalnih peroralnih farmaceutskih oblika sa trenutnim oslobađanjem.

Novel solid dosage forms, orodispersible tablets (ODTs) and orodispersible films (ODFs), aredeveloped as complex formulations providing fast dosage form disintegration in oral cavitycoupled with adequate mechanical resistance to withstand manipulation during manufactureand drug administration. The aim of the study was to investigate and mechanistically explainthe influence of different formulation factors and process parameters on dosage formdisintegration and mechanical properties identified as ODT/ODF critical quality attributes(CQAs).Dynamic compaction analysis and percolation theory were employed in order to explorematerial properties of novel, directly compressible coprocessed excipients designedspecifically for ODT formulation. Tensile tests and oscillatory rheology were employed forcomprehensive evaluation of various excipients selection, including film-forming polymers,superdisintegrants and plasticizer load on mechanical properties of ODFs prepared by solventcasting method. Di...rect drug coating was applied with the aim to mask unpleasant taste of theinvestigated active substances, accompanied with the in vivo and in vitro evaluation of tastemasking effectiveness. Physiologically based pharmacokinetic modeling has been performedwith the aim to simulate in vivo dosage form performance and predict drug absorption fromthe investigated ODT/ODF using recently developed Oral Cavity Compartmental Absorption& Transit (OCCATTM) model.Comprehensive pharmaceutical-technological evaluation and dynamic compaction analysis ofthe investigated coprocessed excipients revealed complex relation between fundamentalmaterial characteristics and their functionality. Despite the fact that fast disintegration is,generally, associated with poor mechanical resistance of the solid dosage form, it was possibleto obtain ODTs with high drug load (37-67% in the case of caffeine, and 18-49% in the caseof ibuprofen) without compromising the targeted CQAs (i.e. the obtained disintegration timewas less than 3 min, and tensile strength higher than 1 MPa). In the case of ODFs, theinvestigated film-forming agents have provided incorporation of 20-25% of caffeine, oribuprofen load while maintaining fast disintegration and suitable mechanical properties. Invivo and in vitro evaluation of drug taste masking effectiveness indicate usefulness of directdrug coating. Strong correlation between in vivo and in vitro data implicate that small-volumedissolution method may be used as a surrogate for human panel taste-masking assessment, inthe case of physical taste-masking approach application. Outcomes of physiologically basedpharmacokinetic modeling indicate that intraoral drug absorption from the investigatedODF/ODT would be negligible and that administration of orodispersible drug dosage formswould provide similar bioavailability as conventional immediate release dosage forms.

Keywords:
koprocesovani ekscipijensi / co-processed excipients / raspadljivost / mehanička svojstva / oralnodisperzibilnifarmaceutski oblici / dinamička analiza kompakcije / teorija perkolacije / OCCATTM / maskiranje ukusa / kofein / ibuprofen / disintegration / mechanical properties / orodispersibledrug dosage forms / dynamic compaction analysis / percolation theory / taste masking / OCCATTM / caffeine / ibuprofen
Source:
Универзитет у Београду, 2020
Publisher:
  • Универзитет у Београду, Фармацеутски факултет
Projects:
  • Advanced technologies for controlled release from solid drug delivery systems (RS-34007)
[ Google Scholar ]
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=7514
https://fedorabg.bg.ac.rs/fedora/get/o:22400/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=16614665
http://nardus.mpn.gov.rs/handle/123456789/17331
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3707
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