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Formulation and characterization of solid self-dispersing carriers of carbamazepine prepared with porous adsorbents

dc.contributor.advisorIbrić, Svetlana
dc.contributor.otherPrimorac, Marija
dc.contributor.otherRažić, Slavica
dc.contributor.otherVasiljević, Dragana
dc.contributor.otherLazarević, Nenad
dc.creatorKrstić, Marko Z.
dc.date.accessioned2020-07-03T09:47:42Z
dc.date.available2020-07-03T09:47:42Z
dc.date.issued2015-12-28
dc.identifier.urihttp://nardus.mpn.gov.rs/handle/123456789/4239
dc.identifier.urihttp://eteze.bg.ac.rs/application/showtheses?thesesId=2311
dc.identifier.urihttps://fedorabg.bg.ac.rs/fedora/get/o:10217/bdef:Content/download
dc.identifier.urihttp://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=47495695
dc.description.abstractPoslednjih godina sve veći broj novosintetisanih lekovitih supstanci su nisko rastvorljive u vodi. Jedan od načina za povećanje brzine rastvaranja/rastvorljivosti lekovitih supstanci jeste formulacija čvrstih samo-dispergujućih sistema. Sveobuhvatni cilj ove doktorske disertacije jeste formulacija, izrada i karakterizacija čvrstih samo-dispergujućih sistema sa karbamazepinom, uz korišćenje prirodnih i sintetskih adsorpcionih nosača, radi povećanja brzine rastvaranja i permeabilnosti karbamazepina. U prvoj fazi istraživanja izvršen je odabir tečnih samo-dispergujućih sistema, različitog stepena disperziteta, za različite kombinacije ulja/surfaktanta/kosurfaktanta (korastvarača). U prvom delu su, nakon metode titracije vodom, za sisteme trigliceridi srednje dužine lanaca/Polisorbat 80/Makrogol 400/voda i trigliceridi srednje dužine lanaca/Cremophor® EL/Makrogol 400/voda, konstruisani pseudo-ternerni fazni dijagrami. Odabran je tečni samo-mikroemulgujući nosač (SMEDDS) trigliceridi srednje dužine lanaca/Cremophor® EL/Makrogol 400 (10:66,75:22,25). U nastavku ove faze je na isti način odabran tečni samo-emulgujući nosač (SEDDS) trigliceridi srednje dužine lanaca/Polisorbat 80/Transcutol® HP (20:60:20). Primenom eksperimentalnog dizajna, dizajna smeše, odabran je tečni samo-nanoemulgujući nosač (SNEDDS) za kombinaciju trigliceridi srednje dužine lanaca/Polisorbat 80/Labrasol®/Transcutol® HP (21,21:21,12:21,12:36,64). U ovoj fazi je pokazano veliko slaganje između predviđenih i eksperimentalno dobijenih vrednosti za veličinu kapi i PdI. U drugoj fazi istraživanja izvršena je formulacija, izrada i karakterizacija čvrstih samo- dispergujućih nosača. U prvom delu, izrađene su binarne čvrste disperzije karbamazepina i adsorpcionih nosača (Neusilin® UFL2, Neusilin® FL2, Sylysia® 320, dijatomiti), uz variranje odnosa karbamazepin/nosač 1:1, 1:2 i 1:6 i dve metode izrade, uparavanja etanola na sobnoj temperaturi i na 70 °C. Uočeno je da se formulacijom čvrstih disperzija sa Neusilin®-om UFL2, Neusilin®-om FL2 i Sylysia®-om 320, pri odnosima karbamazepin/nosač 1:2 i 1:6 postiže značajno povećanje brzine rastvaranja karbamazepina, dok je iz čvrstih disperzija sa karbamazepinom, pri odnosu 1:1 i u svim formulacijama sa dijatomitima brzina oslobađanja slična prašku karbamazepina. U svim formulacijama je došlo do prelaska karbamazepina u amorfni oblik ili u polimorfni oblik II. U nastavku ove faze pristupilo se formulaciji, izradi i karakterizaciji čvrstih samo-mikroemulgujućih sistema sa karbamazepinom (SSMEDDS), pri čemu je udeo karbamazepina bio stalan (20%), dok je odnos SMEDDS/nosač (Neusilin® UFL2, Neusilin® FL2, Sylysia® 320 i dijatomiti) variran i iznosio je 1:1 ili 3:1. Formulacije su izrađene korišćenjem dve metode (metoda direktne аdsorpcije i metoda uparavanja). Uočeno je da metoda uparavanja, uz korišćenje etanola, nije pogodna zbog prelaska karbamazepina u polimorfni oblik II. Iz SSMEDDS postiže se značajno povećanje brzine rastvaranja (preko 90% za 30 minuta). Rezultati ispitivanja brzine rastvaranja karbamzapina iz izrađenih SSMEDDS pokazuju da se redosled brzine oslobađanja karbamazepina smanjuje redom korišćenjem sledećih nosača Neusilin® UFL2 > Sylysia® 320 > Neusilin® FL2 > dijаtomiti. Značajna razlika u brzini oslobađanja karbamazepina iz formulacija izrađenih sa različitim odnosima adsorpcioni nosač/SMEDDS nije uočena. Čvrsti samo-nanoemulgujući sistemi sa karbamazepinom (SSNEDDS) izrađen su metodom direktne adsorpcije, uz variranje odnosa SNEDDS/nosač (Neusilin® UFL2, Neusilin® FL2, Sylysia® 320 i dijatomiti) 1:1 ili 2:1, pri čemu je udeo karbamazepina bio stalan (20%). Formulacija SSNEDDS iz koje je postignuto najbrže oslobađanje karbamazepina sadrži jednak udeo SNEDDS-a i adsorpcionog nosača (Sylysia® 320), iz ove formulacije je za 30 minuta oslobođeno oko 90% karbamazepina...sr
dc.description.abstractIn latest years, an increasing number of newly synthetized drugs have low solubility in water. Formulation of solid self-dispersing drug delivery systems is one of many approaches to increase the dissolution rate/solubility of these drugs. The overall aim of this doctoral dissertation is formulation, making and characterization of solid self-dispersing drug delivery systems with carbamazepine, using natural and synthetic solid carriers, in order to increase the dissolution rate and permeability of carbamazepine. In phase I of this research, proper selection of solid self-dispersing drug delivery systems, with different dispersity degree, for different oil/surfactant/cosurfactant (cosolvent) ratio was done. In the first part, after titration with water, pseudo-ternary phase diagrams were constructed for systems medium chain triglycerides/Polysorbate 80/Macrogol 400/water, and medium chain triglycerides/Cremophor® EL/Macrogol 400/water. Liquid self-emulsifying system (SEDDS) composed of medium chain triglycerides/Cremophor® EL/Macrogol 400, in a 10:66,75:22,25 ratio was selected. Furthermore, liquid self-nanoemulsifying system (SNEDDS) composed of medium chain triglycerides/Polysorbate 80/Transcutol® HP, in 20:60:20 ratio was also selected. Using mixture experimental design, liquid self-nanoemulsifying system (SNEDDS) composed of medium chain triglycerides/Polysorbate 80/Labrasol®/ Transcutol® HP, in 21,21:21,12:21,12:36,64 was selected. In this phase, a high matching between the predicted and the experimentally obtained values for droplet size and PdI was demonstrated. In phase II of the research, formulation, preparation and characterization of solid dispersing drug delivery systems were conducted. In its first stage, binary solid dispersions of carbamazepine and solid carriers (Neusilin® UFL2, Neusilin® FL2, Sylysia® 320, diatomites) were prepared, varying the carbamazepine/carrier ratio (1:1, 1:2 and 1:6) and two formulation methods - evaporation of ethanol at room temperature, and at 70 °C. It was observed that solid dispersions made of Neusilin® UFL2, Neusilin® FL2 and Sylysia® 320, with carbamazepine/carrier ratios 1:2 and 1:6 leads to a significant increase in the dissolution rate of carbamazepine, whereas in formulations with a 1:1 carbamazepine/carrier ratio, and also in all formulations with diatomites, the dissolution rate of carbamazepine was similar to carbamazepine powder. In all formulations, carbamazepine was converted to the amorphous form or to polymorph form II. In the next stage of this phase, formulation, preparation and characterization of solid self-microemulsifying drug delivery systems with carbamazepine (SSMEDS) were done. The carbamazepine ratio was constant (20%), while the SMEDDS/carrier (Neusilin® UFL2, Neusilin® FL2, Sylysia® 320, diatomites) ratio was varied (1:1 and 3:1). Formulations were made using two methods (direct adsorption and evaporation with ethanol (99,5% v/v)). It was noted that the ethanol formulation method is not adequate, because of the conversion of carbamazepine into polymorph form II. A significant increase in the dissolution rate of carbamazepine from SSMEDS occurred (more than 90% in 30 minutes). The results of the dissolution test show that the dissolution rate of carbamazepine from SSMEDS formulations decreases with use of Neusilin® UFL2, Sylysia® 320, Neusilin® FL2 and diatomites, respectively. A significant difference in dissolution rate of carbamazepine from formulations with different carbamazepine/carrier ratio was not observed. Solid self-nanoemulsifying drug delivery system with carbamazepine (SSNEDS) was made by direct adsorption method, whereby carbamazepine ratio was constant (20%), and the SNEDDS/carrier (Neusilin® UFL2, Neusilin® FL2, Sylysia® 320, diatomites) ratio was varied (1:1 and 2:1)...en
dc.formatapplication/pdf
dc.languagesr
dc.publisherУниверзитет у Београду, Фармацеутски факултетsr
dc.relationinfo:eu-repo/grantAgreement/MESTD/Technological Development (TD or TR)/34007/RS//
dc.rightsopenAccessen
dc.sourceУниверзитет у Београдуsr
dc.subjectčvrsti samo-dispergujući sistemisr
dc.subjectsolid self-dispersing drug delivery systemsen
dc.subjectadsorpcioni nosačisr
dc.subjectPAMPA testsr
dc.subjectSimcyp®sr
dc.subjectfazno ponašanjesr
dc.subjectveličina kapisr
dc.subjectindeks polidisperzitetasr
dc.subjecteksperimentalni dizajnsr
dc.subjectpolimorfni oblik karbamazepinasr
dc.subjectadsorbent carriersen
dc.subjectPAMPA testen
dc.subjectSimcyp®en
dc.subjectphase behavioren
dc.subjectdroplet sizeen
dc.subjectpolydispersity indexen
dc.subjectexperimental designen
dc.subjectpolymorph form of carbamazepineen
dc.titleFormulacija i karakterizacija čvrstih samo-dispergujućih nosača karbamazepina izrađenih sa poroznim adsorbensimasr
dc.titleFormulation and characterization of solid self-dispersing carriers of carbamazepine prepared with porous adsorbentsen
dc.typedoctoralThesis
dc.rights.licenseBY-NC-ND
dcterms.abstractИбрић, Светлана; Приморац, Марија; Ражић, Славица; Васиљевић, Драгана; Лазаревић, Ненад; Крстић, Марко З.; Формулација и карактеризација чврстих само-диспергујућих носача карбамазепина израђених са порозним адсорбенсима; Формулација и карактеризација чврстих само-диспергујућих носача карбамазепина израђених са порозним адсорбенсима;
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24258/Marko_Krstic_referat_FF.pdf
dc.identifier.fulltexthttp://nardus.mpn.gov.rs/bitstream/id/24257/Disertacija75.pdf


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