558

Farmaceutskatehnologijaikozmetologija

PharmaceuticalTechnologyandCosmetology

559

SADRŽAJ–CONTENTS

FTK-P1

INOVACIJEURAZVOJUORALNOGDISPERZIBILNOGFILMAISAVREMENIZAHTEVIZAKVALITET

INNOVATIONSINDEVELOPMENTOFORALDISPERSIBLEFILMSANDCURRENTQUALITYREQUIREMENTS

- Gordana Žigić, Ivana Džunić 570

FTK-P2

ISPITIVANJEUTICAJARAZLIČITIHFORMULACIJAINAČINAPROIZVODNJENABIOEKVIVALENTNOSTFILMTABLETADIKLOFENAKNATRIJUMA

TESTINGTHEINFLUENCEOFDIFFERENTFORMULATIONSANDPRODUCTIONMETHODSONDICLOFENACSODIUMFILMTABLETSBIOEQUIVALENCE

- Sanja Kecman, Svetlana Goločorbin Kon, Milan Jokanović, Ranko Škrbic, Momir Mikov 572

FTK-P3

DEVELOPMENTANDCHARACTERIZATIONOFNATURALHONEYLOZENGES

- Bojan Pavlović, Jelena Pešić, Katarina Jončić Savić, Hiroto Uchida 574

FTK-P4

FORMULATIONANDCHARACTERIZATIONOFNANOSIZEDCARRIERSASPOTENTIALPLATFORMSFORTOPICALDELIVERYOFANTIOXIDANTS

- Elena Drakalska, Bistra Angelovska, Marija Sterjova, Aleksandar Cvetkovski 575

FTK-P5

INVITROPROFILIBRZINERASTVARANJADVIJEFORMULACIJEDEKSKETOPROFENFILMTABLETA:KOMPARATIVNASTUDIJA

INVITRODISSOLUTIONPROFILESOFTWODEXKETOPROFENFILMCOATEDTABLETFORMULATIONS:ACOMPARATIVESTUDY

- Berina Pilipović, Maja Pašić-Kulenović, Larisa Alagić-Džambić, Vlado Mekinjić 576

560

FTK-P6

APPLICATIONOFMODERNSTATISTICALTOOLSFORDESIGNANDOPTIMIZATIONOFPHARMACEUTICALTECHNOLOGICALPROCESSOFWETGRANULATION

- Dejan Kuneski, Marija Glavas Dodov, Packa Antovska, Sonja Ugarkovic 578

FTK-P7

COMPARATIVEEVALUATIONOFWETGRANULATIONANDDIRECTCOMPRESSIONTECHNOLOGYDURINGDEVELOPMENTOFLOW‐DOSEIMMEDIATERELEASETABLET

- Katerina Tnokovska, Bosilka Stefanova, Natasa Karalija, Packa Antovska, Sonja Ugarković 579

FTK-P8

SCALE‐UPOFAHIGH‐SHEARGRANULATIONPROCESS

- Krume Toshev, Vlatko Kantardzioski, Elizabeta Ristevska Bogoevska, Natasha Anevska Stojanovska, Sonja Ugarković 580

FTK-P9

EVALUATIONOFPROCESSROBUSTNESSOFTABLETCOMPRESSIONBYEXPERIMENTALDESIGN

- Nadica Vanova, Dejan Kostovski, Ana Georgieva, Natasa Anevska Stojanovska, Sonja Ugarković 581

FTK-P10

ANINVESTIGATIONINTOTHEEFFECTOFPRE‐COMPRESSIONANDCOMPRESSIONFORCESONDRUGDISSOLUTIONFROMIMMEDIATERELEASETABLETS

- Oja Ali Memed, Sanja Simeonovska Gusic, Dejan Kostovski, Nikola Jovanovic, Ana Janevska, Packa Antovska, Sonja Ugarković 582

561

FTK-P11

UTICAJPROIZVODNIHPARAMETARAPROCESANAPROFILEBRZINERASTVARANJASULFAMETOKSAZOLAITRIMETOPRIMAIZTABLETA

INFLUENCEOFMANUFACTURINGPROCESSPARAMETERSONSULPHAMETHOXAZOLANDTRIMETHOPRIMTABLETDISSOLUTION

- Nermina Jahić, Midhat Vehabović, Maja Pašić-Kulenović, Larisa Alagić-Džambić, Ehlimana Osmanović Omerdić 583

FTK-P12

UTICAJRAZLIČITIHFAKTORAFORMULACIJEIPOSTUPKAIZRADENAFARMACEUTSKO‐TEHNOLOŠKEKARAKTERISTIKETABLETASABARIJUMSULFATOM

THEINFLUENCEOFDIFFERENTFORMULATIONFACTORSANDMETHODOFPREPARATIONONPHARMACEUTICALTECHNOLOGICALCHARACTERISTICSOFBARIUMSULPHATETABLETS

- Branka Grujić, Nebojša Cvetković, Jelena Kondić, Đorđe Medarević, Svetlana Ibrić 585

FTK-P13

LEKOVIZAHUMANUUPOTREBUKOJISADRŽEPŠENIČNISKROBIUSKLAĐIVANJESANOVOMREGULATIVOMKOJASEODNOSINAINFORMACIJEOGLUTENU‐ISKUSTVASRBIJE

HUMANMEDICINESCONTAININGWHEATSTARCHANDHARMONIZATIONWITHNEWREGULATIONONGLUTENINFORMATION‐EXPERIENCEOFSERBIA

- Sofija Vrcelj-Jovanović, Marija Čarapić, Ljiljana Vojvodić, Saša Jaćović 587

FTK-P14

PREPARATIPARACETAMOLAZAORALNUPRIMENUUPEDIJATRIJSKOJPOPULACIJI:PREGLEDEKSCIPIJENASA

PARACETAMOLPREPARATIONSFORORALUSEINPEDIATRICPOPULATION:AREVIEWOFEXCIPIENTS

- Božana Nikolić 589

562

FTK-P15

ALTERNATIVESTATISTICALMETHODSFORDISSOLUTIONSIMILARITYASSESSMENT

- Ivana Mitrevska, Ljupco Pejov, Ema Kikovska-Stojanovska, Suzan Memed-Sejfulah, Marija Jovanovska, Aneta Dimitrovska, Sonja Ugarković 591

FTK-P16

POBOLJŠANJEBRZINERASTVARANJAKLOPIDOGREL‐BISULFATAPRIMENOMČVRSTIHDISPERZIJA

DISSOLUTIONRATEIMPROVEMENTOFCLOPIDOGRELBISULPHATEBYSOLIDDISPERSIONMETHOD

- Ehlimana Osmanović Omerdić, Larisa Alagić-Džambić, Maja Pašić-Kulenović, Nermina Jahić, Dragana Vasiljević 592

FTK-P17

ISPITIVANJEMOGUĆNOSTIPRIMENEGLICERIL‐DIBEHENATAIPOLIETILENGLIKOLAZAKOPROCESOVANJELAKTOZEPOSTUPKOMGRANULACIJETOPLJENJEM

EXAMINATIONOFTHEPOTENTIALOFGLYCERYL‐DIBEHENATEANDPOLYETHYLENEGLYCOLAPPLICATIONFORCO‐PROCESSINGOFLACTOSEBYTHEMELTGRANULATIONTECHNIQUE

- Jelena Mudrić,Vladimir Dobričić, Svetlana Ibrić, Jelena Đuriš 594

FTK-P18

POREĐENJEFUNKCIONALNIHSVOJSTAVAPOLIETILENOKSIDNOGPOLIMERAUFORMULACIJIMUKOADHEZIVNIHFARMACEUTSKIHOBLIKA

COMPARISONOFTHEFUNCTIONALPROPERTIESOFPOLYETHYLENEOXIDEPOLYMERINFORMULATIONOFMUCOADHESIVEDOSAGEFORMS

- Ivana Kurćubić, Svetlana Ibrić, Jelena Đuriš 596

563

FTK-P19

PRIMENANOVOGKOPROCESOVANOGEKSCIPIJENSARETALAC®ZAIZRADUTABLETASAPRODUŽENIMOSLOBAĐANJEMLEKOVITESUPSTANCEPOSTUPKOMDIREKTNEKOMPRESIJE

INVESTIGATIONINTOSUITABILITYOFNOVELCO‐PROCESSEDEXCIPIENTRETALAC®FORPREPARATIONOFSUSTAINEDRELEASETABLETSBYDIRECTCOMPRESSION

- Biljana Gatarić, Nebojša Mandić-Kovačević, Ivana Vasiljević, Jelena Đuriš, Jelena Parojčić 598

FTK-P20

ISPITIVANJEMEHANIČKIHSVOJSTAVAPELETAPRIPREMLJENIHMETODOMEKSTRUZIJE/SFERONIZACIJEKORIŠĆENJEMRAZLIČITIHSMEŠAPOLIMERA

INVESTIGATIONINTOMECHANICALPROPERTIESOFPELLETSPREPAREDBYEXTRUSION/SPHERONIZATIONUSINGDIFFERENTPOLYMERBLENDS

- Ivana Vasiljević, Erna Turković, Michael Piller, Andreas Zimmer, Jelena Parojčić 600

FTK-P21

OPTIMIZACIJAPROCESNIHPARAMETARA3DŠTAMPANJAZAPROIZVODNJUPRINTLETASLATEHNOLOGIJOM

OPTIMIZATIONOFPRINTINGPROCESSPARAMETERSFORPRINTLETSFABRICATEDBYSLAPRINTING

- Mirjana Krkobabić, Marijana Madžarević, Svetlana Ibrić 602

FTK-P22

PREDLOGMETODAZAISPITIVANJEFUNKCIONALNIHSVOJSTAVAORALNIHFILMOVA

ACONTRIBUTIONONTHEMETHODSTODETERMINEFUNCTIONALCHARACTERISTICSOFBUCCALPATCHES

- Marko Krstić, Ana-Marija Meglić, Nikola Jakovljević, Jovana Talić, Sandra Cvijić 604

564

FTK-P23 INVITRO/INSILICOPRISTUPZAPROCENUDEPOZICIJEIAPSORPCIJEINHALACIONOPRIMENJENIHLEKOVAKODPACOVA:STUDIJASLUČAJA

INVITRO/INSILICOAPPROACHTOASSESSANINHALEDDRUGDEPOSITIONANDABSORPTIONINRATS:CASESTUDY

- Jelisaveta Ignjatović, Meihua Han, Dongmei Cun, Mingshi Yang, Jelena Đuriš, Jelena Parojčić, Sandra Cvijić 606

FTK-P24 AERODINAMIČKOODREĐIVANJEFRAKCIJESITNIHČESTICAPRAŠKOVAZAINHALACIJUFORMULISANIHUOBLIKULIPIDNIHMIKROČESTICA

AERODYNAMICASSESMENTOFFINEPARTICLESFRACTIONFORINHALATIONPOWDERSFORMULATEDASLIPIDMICROPARTICLES

- Jelisaveta Ignjatović, Sandra Cvijić, Vladimir Dobričić, Svetlana Ibrić, Jelena Đuriš 608

FTK-P25

STUDYONPHYSICALANDCHEMICALBEHAVIOROFβ–CYCLODEXTRINANDITSINCLUSIONCOMPLEXWITHCAPTOPRIL

- Adina Musuc, Irina Atkinson, Mirela Mitu, Oana Karampelas, Emma Cretu 610

FTK-P26

SAMOEMULGUJUĆISISTEMIZAISPORUKUSIMVASTATINA:UTICAJVRSTEKOSURFAKTANTANAVELIČINUKAPIIOSLOBAĐANJELEKOVITESUPSTANCESELF‐EMULSIFYINGDRUGDELIVERYSYSTEMS(SEDDS)OFSIMVASTATIN:THEINFLUENCEOFCOSURFACTANTTYPEONDROPLETSIZEANDDRUGRELEASE

- Zora Ćetković, Sandra Cvijić, Dragana Vasiljević 611

FTK-P27

ISPITIVANJEUTICAJAHIDROGELATIPAPOLIELEKTROLITNOGKOMPLEKSAHITOZAN/KSANTANNAINVITROKINETIKUOSLOBAĐANJAIBUPROFENAINVESTIGATIONOFTHEINFLUENCEOFPOLYELECTROLYTECOMPLEXCHITOSAN/XANTHANHYDROGELSONTHEINVITRORELEASEKINETICSOFIBUPROFEN- Ana Ćirić, Ljiljana Đekić 613

565

FTK-P28

UTICAJMOLEKULSKEMASEHITOZANANAFUNKCIONALNOSTHITOZAN‐HALOJZITNANOKOMPOZITNIHFILMOVAZALOKALNUISPORUKUANTIBIOTIKA

INFLUENCEOFCHITOSANMOLECULARWEIGHTONFUNCTIONALITYOFNANOCOMPOSITECHITOSAN‐HALLOYSITEFILMSFORLOCALDELIVERYOFANTIBIOTICS

- Bojan Čalija, Danina Krajišnik, Aleksandra Daković, Kata Trifković, Nikola Milašinović, Jela Milić 615

FTK-P29

CHARACTERIZATIONOFRISPERIDONELOADEDNANOSTRUCTUREDLIPIDCARRIERSFORDRUGDELIVERYTOTHEBRAIN

- Hristina Litovin, Blagorodna Koprivica, Monika Stojanovska, Gjorgji Petrusevski, Maja Simonoska Crcarevska, Marija Glavas Dodov 617

FTK-P30

INFLUENCEOFTHERELEASEPROPERTIESOFNANOLIPOSOMESONTHEANTIOXIDANTCAPACITYOFENCAPSULATEDROSEMARYEXTRACT

- Ljubica Mihailova, Dushko Shalabalija, Ivana Cvetkovikj Karanfilova, Maja Simonoska Crcarevska, Marija Glavas Dodov 618

FTK-P31

PHYTOPHARMACEUTICALSFORALZHEIMER’SDISEASETREATMENT:SALVIAOFF.LOADEDNANOSTRUCTUREDLIPIDCARRIERS

- Ljubica Mihailova, Monika Kostovska, Elena Markova, Lea Taneska, Dushko Shalabalija, Marija Glavas Dodov, Maja Simonoska Crcarevska 619

FTK-P32

AMINO‐MODIFIEDSILICANANOPARTICLESASCARRIERSFOR5‐FLUOROURACIL:INFLUENCEOFPREPARATIONPROCESSPARAMETERSONPHYSICO‐CHEMICALPROPERTIESANDDRUGRELEASE

- Beti Djurdjic, Katerina Goracinova, Nikola Geskovski, Boban Mugosa 620

566

FTK-P33

COMPARATIVEDRUGRELEASESTUDIESOFOXALIPLATINLOADEDORMOSILNANOPARTICLES

- Beti Djurdjic, Katerina Goracinova, Nikola Geskovski, Boban Mugosa 621

FTK-P34

PRELIMINARNOPRAĆENJEFIZIČKESTABILNOSTINANOSUSPENZIJAKURKUMINADOBIJENIHTOP‐DOWNMETODOM

PRELIMINARYMONITORINGOFCURCUMINNANOSUSPENSIONPHYSICALSTABILITYPRODUCEDBYTOP‐DOWNMETHOD

- Milica Todorović, Ines Nikolić, Jelena Đoković, Snežana Savić 622

FTK-P35

NANOSTRUKTURIRANELIPIDNENANOČESTICEKAOPOTENCIJALNINOSAČIDK‐I‐60‐3:PREFORMULACIONAIFORMULACIONAISTRAŽIVANJA

NANOSTRUCTUREDLIPIDNANOPARTICLESASPOTENTIALCARRIERSFORDK‐I‐60‐3:PREFORMULATIONANDFORMULATIONSTUDIES

- Jelena Mitrović, Jelena Đoković, Vladimir Dobričić, Bojan Čalija, Predrag Vulić, Miroslav Savić, Snežana Savić 624

FTK-P36

PEG‐ILOVANENANOEMULZIJE:UTICAJINKORPORACIJEKURKUMINAIIZBORAPROCESASTERILIZACIJENAFIZIČKO‐HEMIJSKEPERFORMANSE

PEG‐YLATEDNANOEMULSIONS:CURCUMINLOADINGANDSTERILIZATIONPROCESSIMPACTONPHYSICOCHEMICALPERFORMANCE

- Jelena Đoković, Sanela Savić, Jelena Mitrović, Dorota Watrobska-Swietlikowska, Snežana Savić 626

FTK-P37

ISPITIVANJEUTICAJALEVANANALIBERACIONEISENZORNEPROFILELEKOVAZAPRIMENUNAKOŽI

INVESTIGATIONOFLEVAN’SINFLUENCEONRELEASEANDSENSORYPROFILESOFTOPICALDRUGS

- Ivana Pantelić, Milica Lukić, Gordana Gojgić-Cvijović, Snežana Savić 628

567

FTK-P38 ISPITIVANJEUTICAJALEVANAKAOPOTENCIJALNOGMULTIFUNKCIONALNOGEKSCIPIJENSANAPROFILOSLOBAĐANJASALICILNEKISELINEIZEMULZIONOGSISTEMATIPAKREMA

LEVANASMULTIFUNCTIONALINGREDIENTANDITSINFLUENCEONLIBERATIONPROFILEOFSALICYLICACIDFROMEMULSIONSYSTEMOFCREAMTYPE

- Milica Lukić, Ines Nikolić, Ivana Pantelić, Snežana Savić 630

FTK-P39 NISKOENERGETSKENANOEMULZIJESAULJEMSEMENKIMALINEIANTIOKSIDANTNIMEKSTRAKTIMA–OPTIMIZACIJAFORMULACIJE,STUKTURNAIREOLOŠKAISPITIVANJA

LOWENERGYNANOEMULSIONSWITHREDRASPBERRYSEEDOILANDANTIOXIDANTEXTRACTS–FORMULATIONOPTIMIZATION,STRUCTURALANDRHEOLOGICALINVESTIGATIONS

- Ana Gledović, Veljko Krstonošić, Ines Nikolić, Danijela Ranđelović, Jelena Đoković, Sanela Savić, Snežana Savić 632

FTK-P40 RASTVORLJIVEMIKROIGLE–FIZIČKIINHENSERIDERMALNEISPORUKEANTIFUNGALNOGLIJEKA

DISSOLVABLEMICRONEEDLES–PHYSICALENHANCERSFORDERMALDELIVERYOFANANTIFUNGALDRUG

- Nataša Bubić Pajić, Sonja Vučen, Snežana Savić 634

FTK-P41 POLIMER‐MUCININTERAKCIJEUOKULARNIMLUBRIKANSIMANABAZIPOLISAHARIDA:REOLOŠKARAZMATRANJA

POLYMER–MUCININTERACTIONINPOLYSACCHARIDE‐BASEDOCULARLUBRICANTS:ARHEOLOGICALPOINTOFVIEW- Anđelka Račić, Danina Krajišnik, Bojan Čalija, Jela Milić 636

FTK-P42 PREFORMULACIONASTUDIJASISTEMAKOJIOBRAZUJUFILMNAPOVRŠINIKOŽEKAOPROSPEKTIVNIHNOSAČALEKOVA

PRE‐FORMULATIONSTUDYOFTOPICALFILM‐FORMINGSYSTEMSASPROSPECTIVEDRUGCARRIERS

- Mirjana Timotijević, Ivana Pantelić, Snežana Savić 638

568

FTK-P43

EMULZIJETIPAULJEUVODIKOJEPODLEŽUBRZOJINVERZIJIFAZANAKOŽISAINKORPORIRANIMANTIOKSIDANSIMABILJNOGPOREKLA:INVITROODREĐIVANJEFAKTORAZAŠTITEODSUNCA

FASTINVERTEDOIL‐IN‐WATEREMULSIONCONTAININGPLANTORIGINANTIOXIDANTS:INVITRODETERMINATIONOFSUNPROTECTIONFACTOR

- Radava Martić, Danina Krajišnik, Anđelija Malenović, Jela Milić 640

FTK-P44

INVITROISPITIVANJEANTIOKSIDATIVNEAKTIVNOSTIANTIOKSIDANASABILJNOGPOREKLAINKORPORIRANIHUEMULZIJETIPAULJEUVODIKOJEPODLEŽUBRZOJINVERZIJIFAZANAKOŽI

INVITROANTIOXIDANTACTIVITYTESTINGOFPLANTORIGINANTIOXIDANTSINCORPORATEDINTOFASTINVERTEDOIL‐IN‐WATEREMULSIONS

- Radava Martić, Danina Krajišnik, Jelena Kotur-Stevuljević, Vesna Spasojević-Kalimanovska, Jela Milić 642

FTK-P45

FORMULATION,PREPARATIONANDCHARACTERIZATIONOFAPHOTOPROTECTIVEEMULSIONBASEDONANEWBENZIMIDAZOLECOMPOUNDASSOCIATEDWITHVEGETALEXTRACTS

- Emma Adriana Cretu, Teodora Dalila Balaci, Cătălina Ancuta Fita, Eleonora Mircia, Cerasela Elena Gîrd 644

FTK-P46

HIDROGELSAEKSTRAKTOMALCHEMILLAVULGARISL.:INVIVO/INVITROPROCENABEZBEDNOSTIIUTICAJANAZARASTANJEMANJIHRANANAKOŽI

ALCHEMILLAVULGARISL.EXTRACTINHYDROGELVEHICLE:INVIVO/INVITROEVALUATIONOFSKINSAFETYPROFILEANDWOUNDHEALINGPOTENTIALINTHETREATMENTOFMINORCUTANEOUSWOUNDS

- Marija Tasić Kostov, Ivana Arsić, Dragana Pavlović, Sanja Stojanović, Stevo Najman, Dušan Ilić, Vanja Tadić 645

569

FTK-P47

ANTIOKSIDATIVNAAKTIVNOSTHIDROLIZATADOBIJENIHPROTEOLIZOMKOZJEGMLEKARAZLIČITIMPROTEAZAMA

ANTIOXIDATIVEACTIVITYOFHYDROLYSATESOBTAINEDBYPROTEOLYSISOFGOATMILKWITHVARIOUSPROTEASES

- Mila Vukašinović, Zorica Knežević Jugović, Snežana Savić 647

FTK-P48

ARGANOVOULJE–RIZNICADRAGOCENIHEFEKATA

ARGANOIL‐ATREASURETROVEOFVALUABLEEFFECTS

- Bojana Vučelić, Marija Bajčić, Mira Stojanović 649

FTK-P49

INTELLECTUALPROPERTYRIGHTSANDADVERTISINGOFCOSMETICPRODUCTS

- Biljana Nestorovska-Gjoshevska, Katerina Ancevska-Netkovska, Marija Glavas Dodov 651

FTK-P50

UTICAJULJANOGEKSTRAKTASMILJANAORGANOLEPTIČKEKARAKTERISTIKEKOZMETIČKIHKREMA

INFLUENCEOFIMMORTELLEOILEXTRACTSONORGANOLEPTICCHARACTERISTICSOFCOSMETICCREAMS

- Marina Kalić, Miroslav Sarač, Nataša Jovanović Lješković, Zorica Mrkonjić, Manda Dizdar, Branislava Teofilović, Tatjana Miljković 652

FTK-P51

FORMULACIJAIKARAKTERIZACIJAINVASOMASAKOENZIMOMQ10

FORMULATIONANDCHARACTERIZATIONOFCOENZYMEQ10‐LOADEDINVASOMES

- Nina Dragićević, Danijela Pecarski, Alfred Fahr 654

570

Arh.farm 2018;68: 570-571 FTK-P1

INOVACIJEURAZVOJUORALNOGDISPERZIBILNOGFILMAI

SAVREMENIZAHTEVIZAKVALITET

GordanaŽigić,IvanaDžunić

AgencijazalekoveimedicinskasredstvaSrbije(Srbija)

Formulacije koje pokazuju veoma kratko vreme raspadanja, kao što su oralni

disperzibilni filmovi(ODF), imajusvevećiznačajposlednjihgodina jersupogodnezapacijenta (naročito u stanjima otežanog gutanja), omogućavaju brzo oslobađanjeaktivnesupstancedirektnousistemskucirkulaciju,odnosnobrzodelovanjelekaiimajubrojneprednostiuodnosunaklasičneoralnečvrstefarmaceutskeoblike.Ciljradajedase prikažu savremena saznanja koja se odnose na razvoj formulacije i zahteve zakvalitet ODF. Pregledom najnovije literature i važeće regulative dat je sažeti prikazinovacijauoblastirazvojaformulacije,procesaproizvodnjeizahtevazakvalitetODF.

Najveći izazov u razvoju ODF formulacije predstavlja evaluacija ekscipijenasatako da se postigne izbalansiran odnos između vremena raspadljivosti, stabilnostiaktivne supstance, reoloških i organoleptičkihkarakteristikaproizvoda, uzkorišćenjeminimalnogbrojaekcipijenasa.Izboromodgovarajućegpolimerazaformiranjefilma,uadekvatnoj koncentraciji, postiže se homogena distribucija hidrosolubilnih ilinerastvorljivih(mikroinanočestice)aktivnihsupstanci,malihilivelikihmolekula,bezpromene fizičkih morfoloških osobina supstance (veličina čestica, naelektrisanje,kristalni oblik). Inovacije u razvoju procesa proizvodnje ODF uključuju proizvodnjuODF primenom 3D tehnologije štampanja u cilju dobijanja personalizovanih lekova iprimenu novog koncepta kontinuiranog procesa proizvodnje, naročito u postupkuekstruzijetopljenjem.

Dabisezadovoljilisavremenizahtevikvaliteta,ODFmoradaposedujeporoznustrukturu,ujednačenudebljinu,kratkovremeraspadanja,dobrustabilnost,adekvatnumehaničku otpornost u cilju sprečavanja oštećenja u toku rukovanja, ujednačen ihomogensadržaj,odgovarajućeoslobađanjeaktivnesupstance,prijatanukusiosećajuustima i dr. Zahtevani kvalitet ODF se potvrđuje primenom odgovarajućih testova.OčekujesedaćeODFimatisvevećiznačajubudućnostijersumnogaistraživanjakojasuutokuusmerenanaispitivanjepotencijalneprimeneODFuproizvodnjibiomolekula(vakcina) i formulacija samikro i nanočesticama aktivnih supstanciBCSklase II i IV,omogućavajućinatajnačinprelazaksaparenteralnognaoralnifarmaceutskioblikleka.

571

INNOVATIONSINDEVELOPMENTOFORALDISPERSIBLEFILMSAND

CURRENTQUALITYREQUIREMENTS

GordanaŽigić,IvanaDžunić

MedicinesandMedicalDevicesAgencyofSerbia(Serbia)

Fast disintegrating formulations, such as oral dispersible films (ODF), have

increasing importance in recent years because they are convenient for patients(especially those who have difficulty in swallowing), allow fast dissolution of activesubstancesdirectlytothesystemiccirculationprovidingrapidonsetofactionandhavenumerous advantages in comparisonwith conventional oral solid dosage forms. Theaimofthisstudyistopresenttherecentfindingsrelatedtoformulationdevelopmentand quality requirements for ODF. Review of the novel literature data and currentregulation,aswellasrecentinnovationsinthefieldofformulationandmanufacturingprocessdevelopmentandqualityrequirementsforODFispresented.

AmajorchallengeinODFformulationdevelopmentisevaluationofexcipientsinorder to achieve the right balance between disintegration time, stability of activesubstances,rheologicalandorganolepticproductcharacteristics,whileminimisingthenumber of excipients. The proper selection of film forming polymers, at appropriateconcentration, leadstohomogeneousdistributionofhydrosolubleor insoluble(microand nanoparticles) active substances of small and largemolecules without changingphysicalmorphologicalpropertiesofthesubstance(particlesize,charge,crystalform).Innovations inmanufacturing process development of ODF includemanufacturing ofODF applying 3D printing technology in order to get personalised medicines andapplication of a new concept of continuous manufacturing, especially in hot meltextrusionprocess.

Inordertofulfillcurrentqualityrequirements,ODFmusthaveporousstructure,uniformthickness, fastdisintegration,goodstability,adequatemechanicalstrengthtoresistbeingdamagedduringhandling,uniformandhomogeneouscontent,appropriatedissolution,pleasanttasteandmouthfeeletc.RequiredqualityofODFisdemonstratedbycarryingoutsuitabletests.ItisexpectedthatODFwillhavegrowingsignificanceinthefuturebecausemanyongoingstudiesarefocusedonpotentialapplicationofODFinmanufacturing of biomolecules (vaccines) and formulations with micro andnanoparticlesofBCSclassIIandIVactivesubstances,thusenablingtheswitchfromaparenteraldosageformtoanoralone.

572

Arh.farm 2018;68: 572-573 FTK-P2

ISPITIVANJEUTICAJARAZLIČITIHFORMULACIJAINAČINAPROIZVODNJENABIOEKVIVALENTNOSTFILMTABLETA

DIKLOFENAKNATRIJUMA

SanjaKecman1,SvetlanaGoločorbinKon2,MilanJokanović3,RankoŠkrbic4,MomirMikov5

1Hemofarmd.o.o,članStadagrupe,BanjaLuka,RepublikaSrpska(BosnaiHercegovina),2Katedrazafarmaciju,UniverzitetuNovomSadu‐Medicinskifakultet(Srbija),3Katedrazafarmaciju,UniverzitetuNišu‐Medicinskifakultet(Srbija),4Katedrazafarmakologijuitoksikologiju,UniverzitetuBanjojLuci‐Medicinskifakultet,RepublikaSrpska(BosnaiHercegovina),5Katedrazafarmakologiju,toksikologijuikliničkufarmaciju,UniverzitetuNovomSadu‐

Medicinskifakultet(Srbija)

Različiti tehnološki postupci proizvodnje i prisustvo različitih pomoćnih

supstanci u preparatu ne moraju da znače odsustvo njihove bioekvivalentnosti.Ispitivanjebioekvivalentnostiu invitro i invivouslovimasuvršenazadvatehnološkirazličita farmaceutskaproizvodakojasadrže istuaktivnusupstancu,aliserazlikujuuizboru sredstva za oblaganje tabletnih jezgara. Istraživanje je imalo za cilj da ispitauticajesredstvazaoblaganjenaprofileoslobađanja iresorpciju lekovitesupstance iztabletakojesadržediklofenak.FormulacijaIjesadržalaEudragitL30,aFormulacijaIIEudragitL100kaosredstvozaoblaganje.Dabiseoptimiziralastabilnosttableta,objeformulacijesusadržavalerazličitepomoćnesastojke.Invitro ispitivanjasuobuhvatilaispitivanje variranja mase, dijametra, čvrstine i raspadljivosti tableta, kao i brzinerastvaranjadiklofenakaiztableta.Udrugomdijeluistraživanja,nakonoralnogdavanjadiklofenak tableta zečevima, ispitivani su koncentracija lijeka u plazmi ifarmakokinetičkiparametri. Podaci iz sprovedenih istraživanja u invitro uslovima supokazalidapostoje razlike između ispitivanih formulacija I i II,doksu invivo testovipokazali njihovu ekvivalentnost. Prema rezultatima dobijenim u okviru in vivoispitivanja,nijebiloznačajnihrazlikaufarmakokinetičkimparametrima.

Istraživanjepokazujeda, iporedrazlikeuprofilimaoslobađanjadiklofenaka invitro, postoji bioekvivalentnost ispitivanih formulacija. Mogućnost uvođenja novogeksperimentalnog modela za poređenje farmakokinetike novog lijeka sa većregistrovanimlijekomnakunićimabi,ukolikosepotvrdibioekvivalentnost,omogućiloproizvođačimalekovadasesavećomsigurnošćuodlučezaispitivanjenaljudima.

573

TESTINGTHEINFLUENCEOFDIFFERENTFORMULATIONSANDPRODUCTIONMETHODSONDICLOFENACSODIUMFILMTABLETS

BIOEQUIVALENCE

SanjaKecman1,SvetlanaGoločorbinKon2,MilanJokanović3,RankoŠkrbic4,MomirMikov5

1Hemofarmd.o.o,aMemberofStadaGroup,BanjaLuka,RepublicofSrpska(BosniaandHerzegovina),2DepartmentofPharmacy,UniversityofNoviSad‐FacultyofMedicine(Serbia),3DepartmentofPharmacy,UniversityofNiš‐

FacultyofMedicine(Serbia),4DepartmentofPharmacology,UniversityofBanjaLuka‐FacultyofMedicine,RepublicofSrpska(BosniaandHerzegovina),5DepartmentofPharmacology,ToxicologyandClinicalPharmacology,

UniversityofNoviSad‐FacultyofMedicine(Serbia)

Different technologicalproductionproceduresand formulationcompositiondo

notnecessarilymeantheabsenceofdrugproductsbioequivalence.Invitroandinvivobioequivalencewas tested for twopharmaceuticalproducts containing the sameAPI,butdifferinginthecoatingagentsapplied.Theaimoftheresearchwasto investigatethe impact of different formulations and productionmethods on dissolution profilesandinvivoabsorptionofdiclofenacsodiumfromfilmcoatedtablets.

FormulationIcontainedEudragitL30,whileFormulationIIcontainedEudragitL100, as tablet coating agents. To optimise the tablet stability, both formulationscontained different excipients. The tabletswere tested in vitro with regards to theirweightvariation,hardness,diameter,massuniformity,disintegrationtime,dissolutionprofiles and drug content. In the second part of the research, after administeringdiclofenac tablets to rabbits orally, the drug concentration in plasma andpharmacokinetic parameterswere estimated. The data from performed in vitro testsshowedthenon‐equivalenceoftheinvestigatedformulationsIandII,whileinvivotestsshowed products equivalence. According to the in vivo test results, there were nosignificantdifferencesinthepharmacokineticparametersobserved.

The research shows that, although there was difference in diclofenac in vitrodissolution profiles, the bioequivalence of tested formulations has been observed invivo. The possibility of introducing a new experimental model for comparison ofpharmacokinetics of the new drugwith already registered drug on rabbits would, ifbioequivalenceisconfirmed,enablemanufacturerstodecidetoconductthetestingonhumans.

574

Arh.farm 2018;68: 574 FTK-P3

DEVELOPMENTANDCHARACTERIZATIONOFNATURALHONEY

LOZENGES

BojanPavlović1,JelenaPešić1,KatarinaJončićSavić1,HirotoUchida2

1Phytonetd.o.o.,Belgrade(Serbia),2TomitaPharmaceuticalCo.Ltd(Japan)

Honeyisanaturalproductthathasbeenwidelyusedforitstherapeuticeffects.

It is composed primarily of fructose and glucose but also contains fructo‐oligosaccharidesandmanyaminoacids,vitamins,mineralsandenzymes.Mostofthosecompoundsacttogethertoprovideasynergisticantioxidanteffect.Applicationofrawhoney in modern medicine has a limited use due to its specific physico‐chemicalproperties, which made them extremely unsuitable for the formulation of stable,modernpharmaceuticalforms.However,typicallyhoneypowderisadehydratedformofnaturalhoneyandcontainslessthan2%ofthenaturalliquidformofhoney,usuallypre‐treated at high or extremely low temperatures. The aim of this study was todevelop robust lozenge formulation that contains high concentration of natural rawhoney.UniqueCalciumSilicate(Florite®R,TomitaPharmaceuticalCo.,Ltd.)withitshighliquidadsorptionabilitywasusedforpreparingUniqueHoneyPowderloadedwithrawhoney,rangingfrom50to70%(w/w)bymixingonly.LozengeswereformulatedwithUnique Honey Powder due to its high compressibility. The factorial design ofexperiments was employed to systematically optimise thephysical characteristics oflozenges containing Unique Honey Powder and filler, keeping compression force asconstant. Lozenges were prepared by direct compression method. The compressedlozenges weree valuated for their hardness, thickness, weight variation, friability,appearanceandtaste.Theoptimumformulationwasselectedbydesirabilityfunction.The experimental results have shown that the ratio of Unique Honey Powder perlozengeupto60%(w/w)stillprovidedphysico‐chemicalproperties in theacceptablelimits.Furthermore,palatabilityandtasteofthelozengeswerefounddesirable.

Theadvantageofthedevelopedlozengesissignificantlyhighercontentsofrawhoneycomparedtoexistingproducts.TheuseofFlorite®Rprovidessimpleapplicationofliquidactivematerialsforformulatingdifferentstabledrypharmaceuticalforms.

575

Arh.farm 2018;68: 575 FTK-P4

FORMULATIONANDCHARACTERIZATIONOFNANOSIZEDCARRIERS

ASPOTENTIALPLATFORMSFORTOPICALDELIVERYOFANTIOXIDANTS

ElenaDrakalska,BistraAngelovska,MarijaSterjova,

AleksandarCvetkovski

University„GoceDelchev”,Shtip‐FacultyofMedicalSciences(Macedonia)

Skin is protected from the harmful effects of free radicals by the presence of

anendogenous antioxidant system. However, when exposed to ultraviolet (UV)radiation, there is an imbalance between pro‐oxidants and antioxidants, leading tooxidativestressandphotoagingoftheskin.Inordertopreventskinaging,useoftopicalantioxidants indifferentformulationsismethodofchoiceinpharmaceutical industry.However,manybioactivesubstancesareunstablewhenexposedto light, loseactivityduringstorageandpossesslowsolubilityandbioavailability.Theaimofthisstudyistopresent the advantages of incorporation of antioxidants into nanocarriers such asniosomes, liposomesandnanoemulsions as an intriguing strategy to overcome listedlimitations of antioxidants.We gathered the data needed for this study by searchingrelevantscientificandprofessionalliterature,madeacomparisonbetweenantioxidantloaded nanosystems and free solutions, listed the advantages and disadvantages,discussed the results of clinical studies on various antioxidants incorporated intonanoparticlesand listedthemarket’spatentedformulationsbynow.Obtainedresultsshowed significantly higher stability of antioxidants loaded nanocarriers comparedwithfreedrug,enhancedpenetrationintodermisandpotentiationofantioxidanteffect.From the collected and processed datawe concluded that nanocarriers are potentialplatforms for antioxidants providinghigher solubility, greater stability and enhancedbioavailability.

576

Arh.farm 2018;68: 576-577 FTK-P5

INVITROPROFILIBRZINERASTVARANJADVIJEFORMULACIJEDEKSKETOPROFENFILMTABLETA:KOMPARATIVNASTUDIJA

BerinaPilipović,MajaPašić‐Kulenović,LarisaAlagić‐Džambić,Vlado

Mekinjić

Bosnalijekd.d.,Sarajevo(BosnaiHercegovina)

Ispitivanjebrzine rastvaranja ljekovite supstance seobičnokoristi zaprocjenu

kvaliteta ljekovitih preparata. U ovoj studiji upoređeni su in vitro profili brzinerastvaranja deksketoprofen trometamola iz dvije formulacije film tableta, kao iodgovarajućeg referentnog preparata. Pripremljene su dvije formulacije film tabletakoje sadrže deksketoprofen trometamol metodom vlažne granulacije i sprovedenouporednoispitivanjebrzinerastvaranja.Formulacijesuserazlikovalepovrstiikoličinisredstvazadezintegraciju.Invitrotestbrzinerastvaranjadeksketoprofen25mgfilmtableta proveden je premaopštoj proceduri Ph. Eur. 2.9.3 (ili USP<711>)primenomaparature sa rotirajućom lopaticom. Kao medijum je korištena voda, 0,1 mol/l HCl,pH4,5,pH6,8ipH7,4volumen900mli75rpm.Uzorcisuuzetinakon5,10,15,20,30i45minuta.

U uporednim profilima brzine rastvaranja formulacija 01 (koja je sadržavalanatrijum‐skrobglikolat kao superdezintegrator) i referentnog lijeka, više od 85%aktivnesupstanceserastvaraurokuod15minuta,aprofilibrzinerastvaranjamogubitiprihvaćenikaosličnibezdaljematematičkeobrade.Uuporednimprofilimabrzinerastvaranjaformulacija02ireferentnoglijekanemasličnosti(vrijednostf250).Možesezaključitidapostojisličnostizmeđudeksketoprofen25mgfilmomobloženihtabletaformulacije 01 sa referentnim lijekom. Potvrđeno je da različiti pristupi formulacijimogu dovesti do velikih razlika u profilima brzine rastvaranja među formulacijama.Formulacija01 jeodabranazastudijubioekvivalencije,koja jedokazanauodnosunareferentnilijek.

577

INVITRODISSOLUTIONPROFILESOFTWODEXKETOPROFENFILM

COATEDTABLETFORMULATIONS:ACOMPARATIVESTUDY

BerinaPilipović,MajaPašić‐Kulenović,LarisaAlagić‐Džambić,VladoMekinjić

Bosnalijekd.d.,Sarajevo(BosniaandHercegovina)

Dissolution test is usually employed to evaluate the performance of drug

products.Inthisstudy,wecomparedtheinvitrodissolutionprofilesoftwofilmcoatedtablet formulations containing dexketoprofen trometamolwith the aim of evaluatingthe similarity with the reference product. Two formulations of film coated tabletscontaining dexketoprofen trometamol were evaluated and compared with referencedrug. The formulations differed by type and amount of disintegration agent. In vitrodissolutiontestingofdexketoprofen25mgfilmcoatedtabletswasperformedaccordingto the general procedure Ph. Eur. 2.9.3 (or USP <711>) using the rotating paddleapparatus.Evaluationhasbeencarriedout inwater,0.1mol/lHCl,pH4.5,pH6.8andpH7.4,media volume900ml,withpaddle rotation speedof 75 rpm.Media sampleshavebeentakenafter5,10,15,20,30and45minutes.

Comparative dissolution profiles for dexketoprofen 25 mg film coatedtabletsformulation01(whichcontainedsodiumstarchglycolateassuperdisintegrant)and reference drug revealed thatmore than 85% of the drug is dissolvedwithin 15minutes, and dissolution profiles may be accepted as similar without furthermathematical evaluation. Comparative dissolution profiles for dexketoprofen 25 mgfilmcoatedtabletsformulation02andreferencedrugindicatedabsenceofsimilarity(f250). It canbeconcluded that there is similaritybetweendexketoprofen25mg filmcoatedtabletsformulation01withreferencedrug.Ithasbeenconfirmedthatdifferentformulation strategies can lead to great differences in drug dissolution rates.Formulation01was selected for a bioequivalence study,whichwasdemonstrated inrelationtothereferencedrug.

578

Arh.farm 2018;68: 578 FTK-P6

APPLICATIONOFMODERNSTATISTICALTOOLSFORDESIGNANDOPTIMIZATIONOFPHARMACEUTICALTECHNOLOGICALPROCESS

OFWETGRANULATION

DejanKuneski1,MarijaGlavasDodov2,PackaAntovska1,SonjaUgarkovic1

1Research&Development,ALKALOIDADSkopje,2University„SsCyrilandMethodius”Skopje‐FacultyofPharmacy,Skopje(Macedonia)

High‐shear mixer granulation is complex process with many parameters for

adjustment, optimization and, especially, interpretation of their influence on thephysical characteristics of the obtained granulates. The aim of our study was tooptimize thehigh‐shearmixer granulation process duringwhich the influence of themostcriticalprocessparameterssuchas:thevolumeofwaterasgranulatingsolution,granulatingsolutionadditionrateandwetmassingtimeonthephysicalcharacteristicsof the obtained granulates (particle size distribution, porosity, compressibility index,flowabilityandfillingofthetabletingdies)willbedeterminedwiththeuseofmodernstatisticaltoolasCentralCompositeDesign.

Granulates without active substance were produced on laboratory high‐shearmixergranulatorwithexcipients: lactosemonohydrateas filler,starch,pregelatinizedand povidone as fillers and binders, crospovidone as disintegrant and magnesiumstearateaslubricant.Design‐Expert®V8wasusedasstatisticalsoftware.

Theparticlesizeof theproducedgranulateswaspositivelycorrelatedwith theprocessparameters.Porositywaspositivelycorrelatedwithquantityofthewaterandaddition rate, but negatively correlatedwith wetmassing time. Longer wetmassingtimedecreasetheairbetweentheparticles,whichleadstodecreasedporosityormoredensegranules.

The compressibility index was negatively correlated with the investigatedprocessparameters.Smallerparticlesleadtosmallerspecificsurfaceforcohesionandpackagingwhichleadstobiggerbulkdensity,lowertappeddensityandlowervalueofthe compressibility index. Flowability was positively correlated with the amount ofwater. Bigger particles give better flowability. Negative correlation was detectedbetweenprocessparametersandthefillingofthetabletingdies.Detectionofthenatureoftheinfluenceoftheprocessparametersandthecross‐validationofthemodelgivesusenoughconfidence foroptimizationof thehigh‐shearwetgranulationprocess inadirectionofgettingadesirablephysicalcharacteristicsoftheobtainedgranulates.

579

Arh.farm 2018;68: 579 FTK-P7

COMPARATIVEEVALUATIONOFWETGRANULATIONANDDIRECTCOMPRESSIONTECHNOLOGYDURINGDEVELOPMENTOFLOW‐

DOSEIMMEDIATERELEASETABLET

KaterinaTnokovska,BosilkaStefanova,NatasaKaralija,PackaAntovska,SonjaUgarkovic

Research&Development,ALKALOIDADSkopje(Macedonia)

Duringdevelopmentoflowdosedrugproducts,themainchallengesarerelated

to achieving and maintaining a homogeneous mix. Rationale selection of thetechnologicalprocessandexcipientsforthespecificstepsduringformulation/processdevelopment are critical factors to be considered to develop a homogeneous andsegregation‐free lowdose formulation. The aimof this studywas comparisonof twodifferent technologies: wet granulation and dry mixing/direct compression duringdevelopment of low‐dose tablets (0.195% API) in regards to homogeneity of finalblend, assay and drug dissolution. Two pilot batches have been produced usingdifferenttechnologicalprocesses:wetgranulationanddrymixing/directcompression.Homogeneity testing of final blend was carried out on samples collected from sixlocations.Furthermore,theproducedbatcheswereevaluatedonthefollowingcriticalqualityattributes(CQA)suchas:dissolutionandassayregardingthetabletsoriginatingfrombothtechnologicalprocesses.

Theobtainedresults regarding thehomogeneityof the finalblendhaveshownthatbothtechnologiesgiveresultsinpre‐determinedacceptancecriteria.However,asonemaynotice fromtheresults, theaveragevalueof theassay isclosertothetargetassayvalue inregardstothetechnologyofwetgranulation. Itcanbeconcludedfromthe results that bothCQA regarding two technological processes arewith‐in thepre‐determinedacceptancecriteria.However the results regarding thedissolutionprofilerelatedtowetgranulationtechnologyisrelatedwithmorecompletedissolutionoftheAPIfromthetabletincomparisontothedirectcompressiontechnology.Thepresentedresults in this study clearly indicate that wet granulation is more prone to be atechnologyofchoiceforsuchalowdoseformulationwhichwouldresultintabletswithuniformdistributionoftheAPIinthefinalblendandcompletereleaseoftheAPIfromthedesignedtablets.

580

Arh.farm 2018;68: 580 FTK-P8

SCALE‐UPOFAHIGH‐SHEARGRANULATIONPROCESS

KrumeToshev1,VlatkoKantardzioski2,ElizabetaRistevskaBogoevska1,

NatashaAnevskaStojanovska1,SonjaUgarkovic1

1Research&Development,AlkaloidAD,Skopje,2ProductionofSolidDosageForms,AlkaloidAD,Skopje(Macedonia)

Scale‐upofahigh‐shearwetgranulationprocesscanpresentmanychallenges.

Therearevariousapproachesforscale‐updescribedintheliteraturebutitseemsthatonegoldenruledoesn’texistandoftensomemodificationsshouldbemadeinordertoachievesimilarcharacteristicsofthegranulesondifferentproductionscales.Themostcommon rules for scale‐up of high‐shear wet granulation are applying a constantFroudenumber anda constant impeller tip speed.Theobjectiveof our studywas toperformascale‐upofthegranulationprocessofaBCSclassIVAPIonageometricallysimilarequipmentforhighsheargranulationandtocomparethecharacteristicsoftheproducedgranulesandtablets.Thescalingwasperformedfromgranulatorofvolume65Lto300L.TheimpellerspeedonthelargerscaleequipmentwasadjustedsothattheFroudenumberwaskeptconstantonbothscales.Thegranulationsolutiontopowdermass ratio andthe chopper speedwere also kept constant. Thewet granulation timewassetsothatsimilarincreaseinpowerconsumptionwasreached.

Theobtainedwetgranulesweresimilar inappearanceandhadsimilarparticlesizedistribution.Slightlyhigherparticledensitywasobservedforthegranulesonthelarger scale because by keeping the Froude‐number constant some over‐mixing canexistas the impeller tip speed ishigheron the largermixergranulator.Obtaineddrygranuleshadsimilarbulkdensity,tappeddensityandflowrate.Slightlyhigherparticledensity and smaller particle size was observed for the granules on the larger scalewhich canbe attributed to a higher attritionduring thedryingprocess. Physical andchemicalcharacteristicsoftabletswerewell‐withinacceptancecriteria.Thesimilarityofcharacteristicsofgranulesandtabletsonbothscalesconfirmthesuccessfulscale‐upoftheprocess.

581

Arh.farm 2018;68: 581 FTK-P9

EVALUATIONOFPROCESSROBUSTNESSOFTABLETCOMPRESSION

BYEXPERIMENTALDESIGN

NadicaVanova,DejanKostovski,AnaGeorgieva,NatasaAnevskaStojanovska,SonjaUgarkovic

InstituteforResearchandDevelopment,AlkaloidAD,Skopje(Macedonia)

Thekeystepinprocessunderstandinganddevelopingaproductwhichmeetsitspredeterminedacceptance criteriawhileperforming robustmanufacturingprocess istoidentifythepotentialcriticalprocessparameters(CPPs).Mechanisticunderstandingofmaterialpropertieswouldbeneededforhighlightingthecriticalprocessparameters.TheonlywaytoevaluatetheCPPsinfluenceoncriticalqualityattributes(CQAs)istoperform multiple experiments, where testing one factor at a time would be timeconsumingandnotrelevantforevaluationofeventualinteractionbetweenthecriticalfactors. The aim is to test the influence of the most prominent tablet compressionprocessparametersontheCQAsofafixedcombinationproductcontainingBCSclassIandIIIactivecompounds.

24fullfactorialdesignusingMODDEGo®withfourreplicatesinthecenterpointwasappliedwithvarying four factors: turretspeed(tablets/hour),maincompressionforce(kN),pre‐compressionforce(kN)andfeedrate(rpm),adjustedtoobtainlowandhigh levelsof the target range inorder toprovide flexibility in theprocesswhilestillproducingproductwhichmeetsrelevantqualitycriteria.

Evaluation of tablet compression process by factorial design showed that thetested factorswithin the testedrangehavenosignificant influenceontheCQAof thefinalproduct.Eachcombinationofthetestedparameterswithinthetestedrangewouldproduceproductwithacceptablequality.

Thechosenmethodisappropriate forrobustnesstestingoftabletcompressionprocess, considering the values for model validity and reproducibility where isdemonstrated that themodel is useful and reproducible with good control over theexperimentalerror.

582

Arh.farm 2018;68: 582 FTK-P10

ANINVESTIGATIONINTOTHEEFFECTOFPRE‐COMPRESSIONANDCOMPRESSIONFORCESONDRUGDISSOLUTIONFROMIMMEDIATE

RELEASETABLETS OjaAliMemed,SanjaSimeonovskaGusic,DejanKostovski,

NikolaJovanovic,AnaJanevska,PackaAntovska,SonjaUgarkovic

InstituteforResearchandDevelopment,ALKALOIDAD,Skopje(Macedonia)

Tableting process is one of the most important steps during development ofimmediate release tablets since relevant variables such as pre‐compression force,compressionforceandotherscanhavedirectimpactonthequalityofthefinalproduct.Theaimofourstudywastoevaluatetheeffectsofdifferentparametersofcompression(pre‐compression and compression force) on dissolution profile of the selectedformulationcontaininghighlypotentmodeldrug.

Final blend has been produced using wet granulation/direct compressiontechnology. During the process of tableting compression forceswere varied at threelevels: 0.4/12.9kN, 1.3/13.1kN and 1.6/10.0kN (i.e. pre‐compression/compressionforce, respectively). The samples preparedwere characterizedwith respect to tablethardness, thickness, diameter and disintegration time, aswell as drug dissolution indifferent dissolution media (0.1M HCl, pH 1.2, pH 4.5, pH 6.8). Dissolution profilesobtainedwerecomparedbasedonthesimilarityfactorvalues(f2).

Pharmaceutical ‐ technological characteristics of the samples prepared werewithin the pre‐determined acceptance criteria. Tablets prepared with different pre‐compression/compression forces were evaluated for in‐vitro dissolution test indifferentmediaandobtainedresultswerecomparedwiththedissolutionprofilesofthereferentproduct.

From the obtained results, the largest similarity of in vitro dissolutionprofilescompared with the referent product was noticed on tablets produced with pre‐compressionforce/compressionforce1.6kN/10.0kN.Increasingpre‐compressionforce(varied from 0.4kN to 1.6kN) caused a decrease in dissolution rate but increase insimilarityfactorf2.Thiswasprobablyduetobondingofthesoftergranulesintobiggergranules with smaller specific area during the tableting process. From the obtainedresultswecanconcludethatcompressionforcesaresignificantfactorsduringtabletingprocess which directly influence in vitro profile of the final product. Well‐designedformulation and setting of critical parameters during product development providesrepeatable/robustprocessthatensuresproductionoftabletswithdesiredquality.

583

Arh.farm 2018;68: 583-584 FTK-P11

UTICAJPROIZVODNIHPARAMETARAPROCESANAPROFILEBRZINERASTVARANJASULFAMETOKSAZOLAITRIMETOPRIMAIZTABLETA

NerminaJahić,MidhatVehabović,MajaPašić‐Kulenović,LarisaAlagić‐Džambić,EhlimanaOsmanovićOmerdić

Bosnalijekd.d.,SektorRazvojiregistracija,Sarajevo(BosnaiHercegovina)

Kombinacija trimetoprima i sulfametoksazola u masenom odnosu 1:5 (80 mg

trimetoprima i 400 mg sulfametoksazola) predstavlja antibiotik koji se koristi zalečenjerazličitihbakterijskihinfekcija.Ciljovestudijejedaseproceniefekatpromenasile kompresije i visine cilindra u procesu tabletiranja i uporede profili brzinerastvaranja aktivnih supstanci iz uzoraka ispitivane serije (sa različitim tvrdoćamatableta)uodnosunareferentnilek.

Svimaterijalikorišteniuformulacijisekonvencionalnoprimenjujuuformulacijičvrstihfarmaceutskihoblikalekova.OnisuopisaniutrenutnovažećemizdanjuPh.Eur.i ispunjavaju odgovarajuće zahteve kvaliteta. Ispitivana serija je pripremljena zatabletiranjemetodom vlažne granulacije u ultra brzommikseru. Dobijeni granulat jekomprimovan na rotacionoj tablet presi, na okruglim klipovima promera 12 mm ipodeljen u pet podserija na osnovu primenjene razlicite sile kompresije i dobijenetvrdoce tableta. Za analizu in vitro profila brzine rastvaranja aktivnih supstancikorištena je USP aparatura 2 (tipa lopatice), brzina obrtaja 75 rpm, temperatura37±0,5°C, 900 ml, tri medijuma za ispitivanje brzine rastvaranja (pH 1,2, 4,5; 6,8).Uzorcisuuzorkovaninakon10,15,30i45minutaianaliziraniHPLCmetodom.

Dobijeni rezultati pokazuju da promene u proizvodnim parametrima procesamogudovestidoznacajnorazlicitihpro ilabrzinerastvaranjaaktivnihsupstancizaistuformulaciju. Pro ili brzine rastvaranja trimetoprima i sulfametoksazola dobijenianalizompokazalisudasutabletekojesuproizvedenesanajvecomsilomkompresije(2500daN)na vrlo niskoj visini cilindra (2,25mm) slični referentnom lekuu sva trimedijuma za ispitivanje brzine rastvaranja različitih pH vrednosti. Vrednost faktorasličnosti (f2) između 50 i 100 ukazuje na to da su dva profila rastvaranja aktivnesupstanceslična.Povecanjesilekompresijeuprocesutabletiranjaznacajnojepovecalotvrdocutabletaiuticalonapro ilebrzinerastvaranjaaktivnihsupstanci.

584

INFLUENCEOFMANUFACTURINGPROCESSPARAMETERSON

SULPHAMETHOXAZOLANDTRIMETHOPRIMTABLETDISSOLUTION

NerminaJahić,MidhatVehabović,MajaPašić‐Kulenović,LarisaAlagić‐Džambić,EhlimanaOsmanovićOmerdić

Bosnalijekd.d.,DevelopmentandRegistrationDepartment,Sarajevo(BosniaandHerzegovina)

Combinationof trimethoprimandsulfamethoxazole in the1:5weightratio(80

mg trimethoprim and 400 mg sulfamethoxazole) is widely used antibiotic for thetreatmentofavarietyofbacterialinfections.Theaimofthisstudywastoevaluatetheeffect of changes in compression force and tablet cylinder height during tabletingprocess and compare dissolution profiles of the test batch (with different tablethardness)versusreferencebrandproducttablets.Allmaterialsusedinformulationareconventionallyappliedintheformulationofsoliddosageforms.TheyaredescribedinthecurrentPh.Eur.andcompliedtothequalityrequirements.Testbatchwaspreparedfortabletingusinghighshearmixergranulator.Thegranuleswerecompressedon12mm round shapepuncheson a rotary compressionmachine anddivided in five sub‐batchesbasedondifferentcompressionpressureappliedandobtainedtablethardness.In vitro dissolution testing was carried out using USP Apparatus 2 (paddle type),rotationspeed75rpm,at37±0.5°C,900mlinthreedissolutionmedia(pH1.2;4.5;6.8).Sampleswerewithdrawnat10,15,30and45minutesandanalyzedbyHPLCmethod.

Resultsindicatedthatchangesinthemanufacturingprocessparameterscanleadto significantly different dissolution profiles for the same formulation. Dissolutionprofiles of trimethoprim and sulfametoxazole obtained in the analysis demonstratedthattabletswhichareproducedwithhighestcompressionforce(2500daN)atverylowcylinder height (2.25mm) are similar to the brand product in all three testedmediawith different pH. Similarity factor value, f2 between 50 and 100 suggests that twodissolution profiles are similar. Increasing compression force in tableting processsignificantlyenhancedtablethardnessandaffecteddrugdissolutionrate.

585

Arh.farm 2018;68: 585-586 FTK-P12

UTICAJRAZLIČITIHFAKTORAFORMULACIJEIPOSTUPKAIZRADENAFARMACEUTSKO‐TEHNOLOŠKEKARAKTERISTIKETABLETASA

BARIJUMSULFATOM

BrankaGrujić1,NebojšaCvetković1,JelenaKondić1,ĐorđeMedarević2,SvetlanaIbrić2

1InstitutzaistraživanjeirazvojGalenikaa.d.,Beograd,2Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu–

Farmaceutskifakultet(Srbija)

U radu je ispitivan razvoj tableta sa barijum‐sulfatom koje se ne raspadaju u

digestivnom traktu, a koriste se kao kontrastno sredstvo za merenje tranzitnogvremena kroz kolon. Intaktnost tableta u digestivnom traktu postiže se primenompolimera ‐ polimetil‐metakrilata (PMMA) i Eudragit® RS PO, sinterovanih u pariorganskog rastvarača ‐ acetona ili izopropanola (IPA). Ispitano je više različitihformulacijaukojimajevarirano:vrstapolimera(Eudragit®RSPOiliPMMA),postupakizrade (vlažna granulacija ili direktna kompresija), granulacija punioca kalcijum‐hidrogenfosfat dihidrata (praškasti ili sitno granulisani) i vreme sinterovanja u pariacetonailiIPA.SinterovanjeupariacetonailiIPAjevršenoutoku7,14,21,28i35hna35ºC.Kao izlazniparametarpraćeni su zateznačvrstina, kaoznačajnakarakteristikatabletazadaljiprocessinterovanjairaspadljivostsinterovanihtableta.

Uzavršnomprocesuizrade‐sinterovanjutabletakorišćenesusamoformulacijekod kojih je zatezna čvrstina tableta bila ≥20 MPa. Iz tog razloga tablete izrađenedirektnomkompresijom, kao i tablete izrađene vlažnom granulacijom sa PMMA nisusinterovane.ZateznečvrstinetabletapreiposlesinterovanjaukazujudaseprimenomIPAupostupkuvlažnegranulacijedobijajugranulekojeseboljekompaktiraju(dobijajuse tablete veće zatezne čvrstine), dok je aceton u procesu sinterovanja na 35°Cefikasniji,štojeiočekivanosobziromnavišinaponparenatojtemperaturiuodnosunaIPA.

Ispitivanjasupokazaladajenajadekvatnijaformulacijakojausvomsastavuimakalcijum‐hidrogenfosfat dihidrat, prašak, polimere Eudragit® RS PO i PMMA umasenom odnosu 1:1, izrađena postupkom vlažne granulacije gde se kao rastvarač,osimetanolaivodekoristiIPA,aprocessinterovanjavršiupariacetonana35°Cutoku35h.Kodnavedeneformulacijeispunjenjepropisanikriterijumoneraspadanjutabletauvremenskomintervaluod7dana.

586

THEINFLUENCEOFDIFFERENTFORMULATIONFACTORSAND

METHODOFPREPARATIONONPHARMACEUTICALTECHNOLOGICALCHARACTERISTICSOFBARIUMSULPHATE

TABLETS

BrankaGrujić1,NebojšaCvetković1,JelenaKondić1,ĐorđeMedarević2,SvetlanaIbrić2

1ResearchandDevelopment,Galenikaa.d.,Belgrade,2Departmentof

PharmaceuticalTechnologyandCosmetology,UniversityofBelgrade–FacultyofPharmacy(Serbia)

This study investigates development of non‐disintegrating tabletswith barium

sulphatewhichareusedasacontrastagentformeasuringoftransittimethroughthecolon. Tablet intactness is achieved using polymers ‐ Poly(methyl methacrylate)(PMMA)andEudragit®RSPO, sintered in the vapouroforganic solvent ‐ acetoneorisopropylalcohol(IPA).Differentformulationsweretestedwithvariationsofpolymertype (Eudragit® RS PO or PMMA),method of preparation (wet granulation or directcompression), grade of diluent calcium hydrogenphosphate dihydrate (powdered orfinely granulated grade) and duration of sintering in the vapour of acetone or IPA.SinteringinthevapourofacetoneorIPAwasperformedduring7,14,21,28and35hat35ºC.Tensilestrengthasan important tabletcharacteristic for furthersinteringaswell as disintegrationof sintered tabletswere tested as outputs. Tablet formulationswithtensilestrength≥20MPawereonlyusedforsintering.Duetothisreason,tabletspreparedbydirectcompressionandtabletspreparedbywetgranulationwithPMMAwere not sintered. Tensile strength of tablets before and after sintering showed thatusing of IPA in wet granulation process gives granules with better compactionproperties(tabletswithhighertensilestrengthwereobtained),whileacetoneismoreefficient for sintering at 35°C, as expected due to higher vapour pressure at thistemperature, compared to IPA. Performed testing showed the best properties offormulation containing calcium hydrogenphosphate dihydrate, powder, Eudragit® RSPOandPMMAinmassratio1:1,whichwaspreparedbywetgranulationusingmixtureofethanol,waterand IPAandsintered in thevapourofacetoneduring35hat35ºC.Thisformulationfulfilledcriteriaofnon‐disintegrationduring7days.

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Arh.farm 2018;68: 587-588 FTK-P13

LEKOVIZAHUMANUUPOTREBUKOJISADRŽEPŠENIČNISKROBIUSKLAĐIVANJESANOVOMREGULATIVOMKOJASEODNOSINA

INFORMACIJEOGLUTENU‐ISKUSTVASRBIJE

SofijaVrcelj‐Jovanović,MarijaČarapić,LjiljanaVojvodić,SašaJaćović

AgencijazalekoveimedicinskasredstavaSrbije(Srbija)

Gluten je protein ili smeša prolamin proteina koji se uglavnom mogu naći u

pšenici, ali i u ječmu, raži imanje u ovsu. Poremećaji povezani sa intolerancijom nagluten su: celijačna bolest, alergija na pšenicu i necelijačna preosetljivost na gluten.CeliaklijajesistemskaimunabolestičestjeporemećajuEvropisaprevalencomod1‐2%. Srbija takođe ima visoku učestalost celijakije 1:100 (oko 70 000 ljudi).Skrob se često koristi kao sredstvo za dopunjavanje/vezivanje/raspadanje u čvrstimfarmaceutskimoblicimalekova, iliunovimoblicima/sistemimazaisporukulekovanaciljanom mestu. Prema monografiji Ph.Eur., za pšenični skrob zahtev za ukupneproteine,uključujući i gluten, jenajviše0,3%.NovaEMAsmernicadefinišepreciznijepodatkezaglutenkojesemorajunavestinapakovanjuiuUputstvuzalek.Zbogčestihpitanja upućenih Agenciji za lekove koja se odnose na prisustvo glutena u lekovima,izvršena je evaluacija prisustva skroba u svim lekovima za humanu upotrebu, safokusom na pšenični skrob. Pregled baze podataka ALIMS‐a i statistička analizarezultataizvršenisuzaključnosa30.09.2017.

Čvrsti farmaceutski oblici sadrže različite vrste skroba: kukuruzni, krompirov,pšenični, pirinčani, skrob preželatinizovan, natrijum‐skrobglikolat, alumijnum‐skroboktenilsukcinat, hidroksietil skrob. Utvrđeno je da u poslednjih pet godina nijeuočenoznačajnopovećanjebrojalekovakojisadržepšeničniskrobidasamonjihoko1%sadrži ovaj skrob, što je manje od odobrenih u UK premaEMA/CHMP/704219/2013. Potrebno je definisati poreklo skroba prilikom dobijanjadozvole za lek, kako bi se utvrdilo prisustvo/odsustvo glutena, izbeći unakrsnekontaminacijesaproizvodimakojisadržegluteniuskladiti informacijeo lekusaEMAsmernicom u vezi sa upozorenjem koje se odnosi na pšenični skrob (gluten). PoredSmPC‐aiPIL‐akojisudostupninainternetstraniciALIMS,omogućitidaspisaklekovakojisadržepšeničniskrobbudedostupanjavnosti.

588

HUMANMEDICINESCONTAININGWHEATSTARCHANDHARMONIZATIONWITHNEWREGULATIONONGLUTEN

INFORMATION‐EXPERIENCEOFSERBIA

SofijaVrcelj‐Jovanović,MarijaČarapić,LjiljanaVojvodić,SašaJaćović

MedicinesandMedicalDevicesAgencyofSerbia(Serbia)

Glutenisaproteinoramixtureofprolamineproteinfoundmainlyinwheat,but

also inbarley, rye and less inoat.Humandisorders related togluten intolerance areceliac disease, allergy to wheat and non‐celiac gluten sensitivity. CD is frequentdisorderinEuropewithaprevalenceof1‐2%.SerbiaalsohasahighincidenceofCD:1:100 (approximately 70000 people). Starch is commonly used as a filler, binder,disintegrantinsoliddosageformsorwithinnoveldrugdeliverysystems.ThePh.Eur.Wheatstarchmonographsetsrequirementsfortotalprotein(includingglutenprotein),withmaximumlimitof0.3%.ThenewEMAguidancedefineswithmoreprecisionthestatementsinthePILandpackaging.NumerousquestionswereaddressedtoALIMSinrelation to thepossiblepresenceofgluten inmedicines.Thepresenceof starch inallhumanmedicineswasevaluated,withfocusonthewheatstarch.SearchwasperformedbyreviewingALIMSdatabaseandbyanalyzingtheresultsinordertodetectmedicineswhichcontaindifferenttypesofstarch(closedon30.September2017).

Soliddosageformscontainstarchoriginatingfrommaize,potato,wheat,rice,aswell as pregelatinized starch, sodium starch glycolate aluminum starchoctenylsuccinate,calcium‐carbonatestarchmixture,hydroxyethylstarch.Itwasfoundthattheincreaseinthenumberofmedicinescontainingwheatstarchwaslowinpastfive years. A small number, approximately 1% of human medicines, contain wheatstarch, which is lower in comparison to UK results according toEMA/CHMP/704219/2013.Vegetableoriginofstarchshouldbedefined inmarketingauthorization applicationin order to justify the presence/absence of gluten. Also thecross‐contamination with products containing gluten should be avoided.Harmonization of product information with the updated EMA guidance is necessaryconcerningwheatstarchsafetywarnings.Aspeciallistofhumanmedicinescontainingwheatstarchshouldbemadepubliclyavailable.

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Arh.farm 2018;68: 589-590 FTK-P14

PREPARATIPARACETAMOLAZAORALNUPRIMENUUPEDIJATRIJSKOJPOPULACIJI:PREGLEDEKSCIPIJENASA

BožanaNikolić

UniverzitetuNovomSadu‐Medicinskifakultet,DomzdravljaNoviSad(Srbija)

Neželjenereakcijenalekovemogubitiuvezinesamosaaktivnimsupstancama

nego i sa ekscipijensima. U ovomkontekstu, pedijatrijski pacijenti se razmatraju kaoposebno vulnerabilna populacija. U okviru ovog pregleda fokus je na preparatimaparcetamolasobziromnarasprostranjenuupotrebuistihupedijatrijskojpopulaciji.Ciljistraživanja jebiodase identifikujuekscipijensiprisutniupreparatimaparacetamolaza oralnu primenu kod dece, i da se razmotri njihov bezbednosni profil. Sažecikarakteristika leka za selektovane lekove (n=12) supreuzeti sa veb‐sajtaAgencije zalekove i medicinska sredstva Srbije; i iskazi od značaja su ekstrahovani iz odeljka 2(Kvalitativniikvantitativnisastav)isubodeljka6.1(Listapomoćnihsupstanci).

Deset ekscipijenasa (parabeni, natrijum‐benzoat, boje, etanol, propilenglikol,saharoza, sorbitol, saharin, aspartam, maltitol) sa potencijalnim uticajem nabezbednosniprofiljeidentifikovano.Konzervansi,bojeikorastvaračisubiliprisutniu5,3 i3preparata,sledstveno.Uproseku,podvazaslađivačajebiloprisutnoutečnimpreparatima; a saharoza, sorbitol i saharin su bili najzastupljeniji. U vezi sabezbednosnim profilom identifikovanih ekscipijenasa, boje i parabeni moguprouzorkovati alergijske reakcije, i u slučaju parabena one su često odloženog tipa.Korastvarači(etanol,propilenglikol)sufarmakološkiaktivnesupstanceiakoseunesuuneuobičajenovelikimvolumenima(npr,od0,2do1,8mLetanolanedeljno(1ml≈0,8g) kod preterminske novorođenčadi, ili > 0,4 ml/kg etanola kod dece; ili, 60 mlpropilenglikolabilokaopojedinačnadozailipodeljenouvišedozatokomperiodaod24časaili8dana)moguprecipitiratisimptomeintoksikacije,posebnokodmaledecezbogograničenogmetaboličkog i renalnog klirensa. Zaslađivači maskiraju neprijatan ukusleka i presudni su za adherencu kod pedijatrijskih pacijenata; međutim, saharoza ipolioli(sorbitolimaltitol)nisudobarizborekscipijensakoddecesaintolerancijomnafruktozu;asaharinbitrebaloizbećikoddecesaalergijomnasulfonamide.

U selekciji najprikladnijeg paracetamol preparata od značaja je razmotritibezbednosni profil ekscipijenasa, posebno kodmale dece i one sa istorijom reakcijahipersenzitivnostiiliretkihgenetskiprenosivihporemećajametaboličkogporekla.

590

PARACETAMOLPREPARATIONSFORORALUSEINPEDIATRIC

POPULATION:AREVIEWOFEXCIPIENTS

BožanaNikolić

UniversityofNoviSad‐FacultyofMedicine,HealthCenterNoviSad(Serbia)

Adverse drug effects can be related not only to active substances but also to

excipients. In thiscontext,pediatricpatientsareconsideredasparticularyvulnerablepopulation.Inthisreview,afocusisonparacetamolpreparationswithrespecttotheirwidespreaduseinpediatricpopulation.Theaimofthestudywastoidentifyexcipientspresent in paracetamol preparations for oral use in children, and to consider theirsafetyprofile.SummaryofProductCharacteristicsfortheselectedpreparations(n=12)wereretrievedfromtheMedicinesandMedicalDevicesAgencyofSerbiawebsite;andstatements of interest were extracted from section 2 (Qualitative and quantitativecomposition)andsubsection6.1(Listofexcipents).

Tenexcipients(parabens,sodiumbenzoate,coloringagents,ethanol,propyleneglycol,sucrose,sorbitol,saccharin,aspartame,maltitol)withpotentialimpactonsafetyprofilewereidentified.Preservatives,coloringsandcosolventswerepresentedin5,3and 3 preparations, respectively. On average, two sweetenerswere present in liquidpreparations; and sucrose, sorbitol and saccharin were the most common. Inassociationwiththesafetyprofileof theidentifiedexcipients,parabensandcoloringscancauseallergicreactions,andincaseofparabenstheyarecommonlyofdelayedtype.Cosolvents (ethanol,propyleneglycol)arepharmacologicallyactivesubstancesand iftheyareingestedinunusuallylargevolumes(eg,from0.2to1.8ml/weekofethanol(1ml ≈ 0.8 g) in preterm neonates, or > 0.4ml/kg of ethanol in children; or, 60ml ofpropyleneglycoleitherasasingledoseordivideddosesovera24hourperiodora8dayone)mayprecipitatesymptomsofintoxication,especiallyinyoungchildrenduetolimited renal and metabolic clearance. Sweeteners mask the unpleasant taste ofmedicines and they are crucial for adherence in pediatric patients; however, sucroseand polyols (sorbitol, maltitol) are not a good choice of excipient in children withfructose intolerance; and saccharin should be avoided in children with sulfonamideallergy.

Intheselectionofthemostappropriateparacetamolpreparationisimportanttoconsidersafetyprofileofexcipients,especiallyinyoungchildrenandthosewithhistoryof hypersensitivity reactions or rare genetically‐transmitted disorders of metabolicorigin.

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Arh.farm 2018;68: 591 FTK-P15

ALTERNATIVESTATISTICALMETHODSFORDISSOLUTION

SIMILARITYASSESSMENT

IvanaMitrevska1,LjupcoPejov2,EmaKikovska‐Stojanovska1,SuzanMemed‐Sejfulah1,MarijaJovanovska1,AnetaDimitrovska3,

SonjaUgarkovic1

1AlkaloidADSkopje,2InstituteofChemistry,‘Ss.CyrilandMethodius”University‐FacultyofNaturalSciencesandMathematics,Skopje,3InstituteofAppliedChemistryandPharmaceuticalAnalysis,‘Ss.CyrilandMethodius”

University‐FacultyofPharmacy,Skopje(Macedonia)

Invitrodissolutiontestingplaysacriticalroleinthelifecycleofagenericdrugproduct.In developing a dissolution test for a generic product intended to be marketed, thedissolution method should be „sufficiently rugged and reproducible for dailyoperations, capable of being transferred between laboratories and adequatelydiscriminating to distinguish any changes that could affect the product’s in vivoperformance”. Thus, dissolution studies may be related to the bioavailability of thedrugsinthebody.

Similarity of dissolution is assessed by comparison of the dissolution profiles(usually%drugdissolvedvstime)basedonthesimilarityfactorvalue(f2)asdescribedintherelevantEMAandFDAguidelines.

In cases when the f2 statistics is not applicable, the guideline addresses thepossibility for using alternative statistical tools, using model‐dependent or model‐independentmethods. In relation to this, herein we present a case study of genericimmediate release drug product ‐ conventional tablets (further referred to as testproduct) thathavebeenevaluated for comparativedissolutionperformanceversus areferencedrugproductinacasewhenthef2statisticswasnotapplicable.

From a regulatory point of view, the FDA guideline on Dissolution testingprovides more detailed approach on the particulars in employing the alternativestatistical methodologies for dissolution profiles comparison. This concept has beenfurther elaborated in few studies, yet not many publications demonstrate real casestudies on using alternative statistical methodologies for comparative dissolutionanalysis, hence it would be highly beneficial to further elaborate this concept andpresentadetailedregulatoryapprovedapproach.

The test product evaluated contains BCS 1 drug (high solubility, highpermeability) and comparative dissolution analysis with the reference product wasperformed. f2 statisticswasnot applicable since the requirement ‘Notmore thanonemeanvalueof>85%dissolvedforanyoftheformulations’wasnotfulfilled.Therefore,alternative statisticalmethodologieswere employed:model‐independent andmodel‐dependent.

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Arh.farm 2018;68: 592-593 FTK-P16

POBOLJŠANJEBRZINERASTVARANJAKLOPIDOGREL‐BISULFATA

PRIMENOMČVRSTIHDISPERZIJA

EhlimanaOsmanovićOmerdić1,LarisaAlagić‐Džambić1,MajaPašić‐Kulenović1,NerminaJahić1,DraganaVasiljević2

1Bosnalijekd.d.,Sektorzarazvojiregistraciju,Sarajevo(BosnaiHercegovina),2Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu–

Farmaceutskifakultet(Srbija)

Klopidogrel‐bisulfat(CB)jeantiagregacionilek,kojipripadaklasiIIBSK.Čvrste

disperzije (SD) su disperzije ljekovite supstance u inertnom hidrofilnom nosaču. Ciljrada je bio ispitivanje uticaja vrste i koncentracije hidrofilnog polimera na brzinurastvaranja klopidogrel bisulfata iz čvrstih disperzija. SD su izrađene metodomrastvaranja,korišćenjemčetirirazličitahidrofilnapolimera:makrogol6000(Polyglycol6000 S), povidon (Kollidon® 30), kopovidon (Kollidon® VA 64) i poloksamer 407(KolliphorTMP407) ičetirimasenaodnosaCB‐polimer(1:1,1:3,1:5,1:9).UzorciSD iprašak CB su punjeni u kapsule, tako da sadrže 75mg CB (terapijska doza). In vitroispitivanjebrzinerastvaranjajeizvršenonaUSPaparaturi1,ufosfatnompuferupH6,8,kao medijumu. Koncentracija CB je određivana nakon 15, 30, 45 i 60 minuta, HPLCmetodom sa UV detektorom. Profili brzine oslobađanja CB iz SD su poređeni saprofilombrzineoslobađanjačistesupstance.

SD izrađene sa hidrofilnim polimerima su pokazale poboljšanje brzinerastvaranja CB, u poređenju sa čistom aktivnom supstancom, gdje je koncentracijarastvorenogCBbila32%,nakon60minuta.Sapovećanjemudjelapolimeraučvrstimdisperzijama dolazi do povećanja brzine rastvaranja CB. Ovo povećanje brzinerastvaranja aktivne supstance može se objasniti smanjenjem veličine čestica ipovećanjemefektivnepovršineaktivnesupstance.Nakon60minuta,zaudiopolimera1:1,najvišeseCBoslobodiloizSDsakopovidonom(54%),zaudiopolimera1:3izSDsakopovidonom i makrogolom (po 63%), za udio polimera 1:5 iz SD sa makrogolom(93%)izaudiopolimera1:9izSDsapoloksamerom407(96%).

Čvrste disperzije sa ispitivanim polimerima su omogućile poboljšanje brzinerastvaranja CB, u poređenju sa čistom aktivnom supstancom.Najveći procenat CB seoslobodio iz SD sa poloksamerom 407 (1:9) ‐ 96% za 60 minuta. Ovi rezultati supokazalidapravilanizborvrsteikoncentracijepolimeraigravažnuuloguupovećanjubrzinerastvaranjaCB.

593

DISSOLUTIONRATEIMPROVEMENTOFCLOPIDOGRELBISULPHATE

BYSOLIDDISPERSIONMETHOD

EhlimanaOsmanovićOmerdić1,LarisaAlagić‐Džambić1,MajaPašić‐Kulenović1,NerminaJahić1,DraganaVasiljević2

1Bosnalijekd.d.,DevelopmentandRegistrationDepartment,Sarajevo(Bosnia

andHerzegovina),2DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Clopidogrelbisulfate(CB)isapotentantiplateletdrug,whichbelongstoBCSII

class drugs. Solid dispersion (SD) is a dispersion of active ingredient in hydrophilicinertcarriermatrix.Theaimofthisstudywastoassess influenceofSDformationontheCBdissolutionrate.Fourdifferenthydrophilicpolymers:macrogol6000(Polyglycol6000S),povidone (Kollidon®30), copovidone (Kollidon®VA64)andpoloxamer407(KolliphorTM P 407), and four CB‐polymer ratios (1:1, 1:3, 1:5, 1:9) were used toformulateSDusingsolventevaporationmethod.AllSDandpureCBsampleswerefilledin capsules in order to contain 75 mg of CB (therapeutic dose). In vitro dissolutiontestingwasperformed inUSPapparatus1, inphosphatebufferpH6.8, as amedium.Concentration of CB was determined by HPLC‐UV method after 15, 30, 45 and 60minutes.DissolutionprofileswerecomparedtodissolutionprofileofCBpuredrug.

SD prepared with hydrophyllic polymers showed improved dissolutioncomparedtopuredrugwhere32%ofCBwasreleasedafter60min. Itwasobservedthattheincreaseinamountofpolymersincreaseddissolutionrate.Thisimprovementcould be due particle size reduction and an increase in the effective surface area.Results suggest that the best efficiency after 60min for 1:1weight ratio showed SDwithcopovidone (54%), for1:3 ratioSDwithmacrogol6000andcopovidone (63%),for1:5 ratioSDwithmacrogol6000 (93%)and for1:9 ratioSDwithpoloxamer407(96%).

Preparation of binary SD with investigated polymers improved the drugdissolution rate compared to pure CB. SD with poloxamer 407 (1:9) was the mosteffective,providing96%ofdrugreleasedafter60min.Thisstudyhasshownthattheproper selection of type and concentration of polymer plays important role inincreasingthedissolutionrateofCB.

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Arh.farm 2018;68: 594-595 FTK-P17

ISPITIVANJEMOGUĆNOSTIPRIMENEGLICERIL‐DIBEHENATAI

POLIETILENGLIKOLAZAKOPROCESOVANJELAKTOZEPOSTUPKOMGRANULACIJETOPLJENJEM

JelenaMudrić1,VladimirDobričić2,SvetlanaIbrić1,JelenaĐuriš1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐

Farmaceutskifakultet,2Katedrazafarmaceutskuhemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Koprocesovani ekscipijensi (KPE) predstavljaju kombinaciju dva ili više

ekscipijenasakojisuobrađeniodgovarajućimpostupkomiimajuunapređenasvojstvauodnosunafizičkusmešuistogsastava.PosebnojeznačajanrazvojKPEkojisekoristepridirektnojkompresiji.Uovojstudijiispitanajemogućnostkoprocesovanjalaktozesagliceril‐dibehenatom (GDB) ili polietilenglikolom (PEG) postupkom granulacijetopljenjem.

KPE su imali sledeći sastav – laktoza, monohidrat (70%); kalcijum‐hidrogenfosfat(15%);natrijum‐skrobglikolat(5%)ivezivnosredstvo(10%),pričemujeKPEAsadržaoPEG4000,dokjeKPEBsadržaoGDB(Compritol®888ATO).Koprocesovanjejevršenogranulacijomtopljenjem,aKPEsupoređenisafizičkimsmešamaistogsastava.Potencijalne hemijske interakcije između ekscipijenasa ispitivane su infracrvenomspektroskopijom(FTIR).Komprimatisu izrađivaninasimulatorukompresije(GamlenInstruments, Velika Britanija) pri pritiscima u opsegu 80‐130 MPa. Karakteristikematerijalaprocenjenesu ispitivanjemprotočnosti, gustine,otpornostikomprimatanalomljenje, raspadljivosti i izračunavanjem Carr‐ovog indeksa,Hausner‐ovog odnosa izateznečvrstoćekomprimata.

FTIRspektroskopijomjeutvrđenodaprikoprocesovanjunijedošlodohemijskihpromenaekscipijenasa.Obakoprocesovanaekscipijensaimajuunapređenuprotočnostu odnosu na fizičke smeše.KPEA imaunapređenu tabletabilnost u odnosu na fizičkusmešu(zateznačvrstoćapripritiskuod130MPaiznosilaje2MPazaKPEAupoređenjusa1,5MPazakomprimovanufizičkusmešu).KomprimatisaKPEBposedovalisuneštonižu zateznučvrstoćuuodnosuna fizičku smešu.Duževremebilo jepotrebnoda seraspadnu komprimati sa KPEA (52 s), u odnosu na komprimate sa KPEB (31 s).KomprimatifizičkihsmešasuseraspalizaistovremekaoiodgovarajućiKPE.

Koprocesovani ekscipijens, koji je kao vezivno sredstvo sadržao PEG posedujeboljuprotočnostimehaničkekarakteristikeupoređenjusaonimkojijesadržaoGDB.Uslučaju oba KPE nije potrebno koristiti lubrikans pri izradi tableta, što predstavljadodatnuprednostkoprocesovanihekscipijenasa.

595

EXAMINATIONOFTHEPOTENTIALOFGLYCERYL‐DIBEHENATEANDPOLYETHYLENEGLYCOLAPPLICATIONFORCO‐PROCESSINGOF

LACTOSEBYTHEMELTGRANULATIONTECHNIQUE

JelenaMudrić1,VladimirDobričić2,SvetlanaIbrić1,JelenaĐuriš1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofPharmaceuticalChemistry,

UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Co‐processed excipients (CPEs) are combinations of two or more

excipients,obtained by the appropriate procedure, that possess superior propertiescomparedtothephysicalmixturesofthesamecombinationofexcipients.DevelopmentofCPEsfordirectcompressionisespeciallyimportant.Thisstudyhasinvestigatedthepossibilityofco‐processingof lactosewithglyceryldibehenate(GDB)orpolyethyleneglycol4000(PEG)bythemeltgranulationtechnique.

CPEs were composed of lactose monohydrate (70%), calcium‐hydrogenphosphate(15%),sodiumstarchglycolate(5%)and10%ofthemeltablebinder(PEG4000 or Compritol® 888 ATO for co‐processed excipient A or B, respectively). CPEsweremadebythemeltgranulationtechniqueandcomparedtothephysicalmixturesofthe same composition. Infrared spectroscopy (FTIR) has been applied to analyze thepotentialforchemicalinteractionsbetweenexcipients.Thecomprimatesweremadebypowder compaction under the pressure in the range of 80‐130 MPa. Properties ofmaterials were estimated by determination of flowability, density, hardness,desintegrationandbycalculatingCarr’s index,Hausner'sratioandtensilestrengthofcomprimates.

FTIR spectroscopy revealed no chemical changes upon co‐procesinssing ofexcipients.BothCPEshadimprovedflowabilityincomparisontothephysicalmixtures.CPEA has enhanced tabletability (tensile strength under the compaction pressure of130 was 2 MPa for CPEA in comparison to 1.5 MPa forcomprimates ofthe physicalmixture).CompactswithCPEBpossessed slightly lower tensile strengthcompared tothe physicalmixture. Disintegration time for tabletswith CPEA (52 s)was longer incomparisontoCPEBcomprimates(31s).ComprimatesofphysicalmixtureshadalmostthesamedisintegrationtimeasCPEs.

Excipient co‐processed with PEG has superior mechanical properties andflowabilityincomparisontoCPEwithGDB.InthecaseofbothCPEsthereisnoneedforadditionallubrication,whichisadventageofco‐processedexcipients.

596

Arh.farm 2018;68: 596-597 FTK-P18

POREĐENJEFUNKCIONALNIHSVOJSTAVAPOLIETILENOKSIDNOGPOLIMERAUFORMULACIJIMUKOADHEZIVNIHFARMACEUTSKIH

OBLIKA

IvanaKurćubić,SvetlanaIbrić,JelenaĐuriš

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Hidrofilni polimeri nalaze veliku primenu u razvoju farmaceutskih preparata.

Polietilenoksidni polimeri, kaonejonskipolimeri sapHnezavisnimbubrenjem, imajusvojstvodamodifikujubrzinuoslobađanja lekovite supstance, a sve više se ispituju injihova bioadhezivna svojstva kao posledica interakcije između polimernih lanaca imakromolekula sa površine sluzokoža. Cilj ovog rada je bilo ispitivanje osnovnihfunkcionalnih svojstva odabranog polietilenoksidnog polimera u formulacijimukadhezivnihfarmaceutskihoblika.

Hidrofilne matriks tablete izrađene su postupkom direktne kompresije naekscenter tablet mašini (EK0 single press punch, Korsch, Nemačka) sapolietilenoksidnimpolimerom(PEO)molekulskemase600000saudelomod20i60%,dok su postupkom istiskivanja pripremljeni ekstrudati u obliku diska koji su potompodvrgnuti sušenju mikrotalasima. Ekstrudati su sadržali isti polimer sa udelomod30%.Sprovedenojeispitivanjestepenabubrenjaierozijetabletaiekstrudatakaoi invitroispitivanjemukoadhezivnostiuzkorišćenjemodifikovanevagesatasovimai10%disperzijemucina.

Analizomstepenabubrenjauočeno jedaekstrudatiapsorbujunajvećukoličinuvode (~ 330% nakon 2 sata), dok su tablete sa većim udelom polimera vezale većukoličinu vode (~ 180 %) i znatno sporije erodirale u odnosu na tablete sa manjimudelom polimera. Ekstrudati su takođe pokazali i najveći stepen mukoadhezivnosti(~ 660 N/m2), zatim slede tablete sa 60% (~ 500 N/m2) i na kraju tablete sa 20%polimera(~300N/m2).

IspitivanjemmukoadhezivnogsvojstvaPEOpolimerautvrđenojedaiudeoovoghidrofilnog polimera i vrsta farmaceutskog oblika utiču na silu vezivanja (polimer –mucin). Ekstrudate i tablete sa većim udelom polimera odlikuje visok stepenmukoadhezije, dobra sposobnost apsorbovanja vode i sporija erozija. Ova saznanjapredstavljaju dobru osnovu za dalji razvoj mukoadhezivnih sistema za isporukulekovitihsupstanci.

597

COMPARISONOFTHEFUNCTIONALPROPERTIESOFPOLYETHYLENEOXIDEPOLYMERINFORMULATIONOF

MUCOADHESIVEDOSAGEFORMS

IvanaKurćubić,SvetlanaIbrić,JelenaĐuriš

DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Hydrophilic polymers are broadly used in the development of pharmaceutical

preparations. Polyethylene oxide polymers (PEO), as pH‐independent nonionicpolymers, have the ability tomodify the release rate of the drug. Their bioadhesiveproperties,resultingfromtheinteractionbetweenpolymerchainsandmacromoleculesofthemucousmembranes,areofgreatinterest.Theaimofthisstudywastoexaminethe basic functional properties of the selected polyethylene oxide polymer in theformulationofmucodhesivepharmaceuticaldosageforms.

ThehydrophilicmatrixtabletsweredirectlycompressedwithaPEOpolymerof600,000molecularweight,intheamountof20and60%,whileextrudatesintheformofdisk were prepared and subsequently exposed to microwaves. The concentration ofpolymerinfilmswas30%.Degreeofswellinganderosionoftabletsandextrudateswastested,aswellasinvitromucoadhesivestrength,whichwasmeasuredonthemodifiedweight scalebyusing10%porcinegastricmucindispersion.Analysisof the swellingratedemonstratedthattheextrudatesabsorbedthehighestamountofwater(~330%oftheinitialtabletweightafter2hours),whiletabletswithahigherproportionofthepolymerboundedhigheramountsofwater(~180%)anderodedsignificantlyslowercompared to tablets with a smaller proportion of polymer. Extrudates also had thehighest degree of mucoadhesion (~ 660 N/m2), followed by tablets with 60%(~500N/m2)andfinallytabletswith20%ofpolymer(~290N/m2).

Obtained results revealed that thehydrophilic polymer amount, aswell as thedosage form, have influenceon the degree of mucoadhesion. Extrudates and tabletswith the higher amount of polymer have high degree of mucoadhesion, good waterabsorptioncapacityanderodeslowly.These findingsareagoodbasis for the furtherdevelopmentofmucoadhesivedeliverysystems.

598

Arh.farm 2018;68: 598-599 FTK-P19

PRIMENANOVOGKOPROCESOVANOGEKSCIPIJENSARETALAC®ZAIZRADUTABLETAZAPRODUŽENIMOSLOBAĐANJEMLEKOVITE

SUPSTANCEPOSTUPKOMDIREKTNEKOMPRESIJE

BiljanaGatarić1,NebojšaMandić‐Kovačević2,IvanaVasiljević2,JelenaĐuriš2,JelenaParojčić2

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBanjojLuci

–Medicinskifakultet(BosnaiHercegovina),2Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

Koprocesovani ekscipijensi su razvijeni da bi se prevazišla ograničena

protočnost ikompresibilnostikojemogudase javeprilikomformulacije tableta.Novikoprocesovani ekscipijens, RetaLac®,dobijen je koprocesovanjem hipromeloze ilaktoze,adizajniranjetakodaomogućavaizradutabletasaproduženimoslobađanjemlekovite supstance postupkom direktne kompresije. Cilj ovog rada bio je procenamogućnosti primene RetaLac®‐a u formulaciju tableta sa produženim oslobađanjem,kao i ispitivanje uticaja masenog odnosa RetaLac®/lekovita supstanca na brzinuoslobađanja različitih model lekovitih supstanci. Ispitivane formulacije su sadržaleRetaLac®‐a i odabranu model supstancu (karbamazepin, acetilsalicilna kiselina,paracetamolikofein)uodnosu1:1,odnosno3:1.Smešezatabletiranjesupripremljenepomoćumešalice za praškove (FarmalaborTech powdermixer, Farmalabor, Italija) ikomprimovane pomoću ekscentar tablet mašine (EK0 single press punch, Korsch,Nemačka). Izrađene tablete suokarakterisaneupogledumehaničkihosobina ibrzineoslobađanjalekovitesupstance.

Primenom RetaLac® koprocesovanog ekscipijensa omogućena je direktnakompresija svih pripremljenih smeša, bez obzira na udeo lekovite supstance iprotočnost smeše praškova. Ispitivani uzorci pokazali su zadovoljavajuću zateznučvrstoću(0,5‐2MPa),izuzevtabletaizrađenihsavećimudelomkofeinaiparacetamola.Mehanizam oslobađanja lekovite supstance za sve uzorke je bio anomalni transportusledbubrenjairelaksacijepolimerauispitivanommedijumu.

Direktna kompresija smeše RetaLac®/lekovita supstanca je bila moguća bezobzira na udeo lekovite supstance i protočnost smeše. Produženo oslobađanje jepostignuto u svim ispitivanim uzorcima, a mehanizam oslobađanja je bio anomalnitransport.Studija jepokazalada jeRetaLac®pogodanekscipijensza izradutabletasaproduženim oslobađanjem sa relativno visokim udelom lekovitih supstanci različitihkarakteristika,postupkomdirektnekompresije.

599

INVESTIGATIONINTOSUITABILITYOFNOVELCO‐PROCESSED

EXCIPIENTRETALAC®FORPREPARATIONOFSUSTAINEDRELEASETABLETSBYDIRECTCOMPRESSION

BiljanaGatarić1,NebojšaMandić‐Kovačević2,IvanaVasiljević2,JelenaĐuriš2,JelenaParojčić2

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBanjaLuka–FacultyofMedicine(BosniaandHercegovina),2DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade–Faculty

ofPharmacy(Serbia)

Co-processed excipients have been developed to overcome flowability and

compressibility issues related to different tablet formulations. RetaLac® ishypromellose/lactose based, novel coprocessed excipient designed as directcompressionaidforobtainingsustaineddrugrelease.Theaimofthepresentworkwasto estimate RetaLac® suitability for tablet formulation and evaluate the effect ofRetaLac®/drug ratio on the release rate of different model drugs. The investigatedsamples were composed of RetaLac® and selected model drug (carbamazepine,acetylsalicylic acid, paracetamol and caffeine) in the 1:1 and 3:1weight ratio. Tabletingredients were mixed using powder mixer (Farmalabor tech powder mixer,Farmalabor, Italy,) and compressed using a single punch‐tabletmachine (EK0 singlepunch press, Korsch, Germany). Prepared samples have been characterized withrespecttotheirmechanicalpropertiesanddrugrelease.

RetaLac®enableddirectcompressionofall themixturesprepared, irrespectiveofthedrugloadandmixtureflowability.Theinvestigatedsamplesexhibiteddesirabletensile strength (0.5‐2 MPa), except the samples prepared with higher drug load ofcaffeineandparacetamol.Drugreleasemechanismforallthesampleswasanomalous,non‐Fickiandiffusion.Thiswaslikelyduetoswellingandrelaxationofthepolymerinthedissolutionmedia.

Compression of RetaLac®/drug mixtures into compacts with satisfyingcharacteristics was possible regardless of the drug load and mixture flowability.Sustained drug release was obtained for all the investigated samples. Drug releasemechanismwasanomalous,non‐Fickiandiffusion.ThestudyhasshownthatRetaLac®canbeusedascontrolledreleaseagentforpreparationofmodifiedreleasetabletswithrelativelyhighdrugcontentusingdirectcompressionasthemethodofchoice.

600

Arh.farm 2018;68: 600-601 FTK-P20

ISPITIVANJEMEHANIČKIHSVOJSTAVAPELETAPRIPREMLJENIH

METODOMEKSTRUZIJE/SFERONIZACIJEKORIŠĆENJEMRAZLIČITIHSMEŠAPOLIMERA

IvanaVasiljević1,ErnaTurković1,MichaelPiller2,

AndreasZimmer3,JelenaParojčić1 1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu–

Farmaceutskifakultet(Srbija),2Istraživačkicentarzafarmaceutskoinženjerstvo,Grac(Austrija),3Institutfarmaceutskihnauka,Katedrazafarmaceutskutehnologijuibiofarmaciju,UniverzitetuGracu(Austrija)

Mehaničkasvojstvavišečestičnihsistemasuznačajnazaprocenupogodnostiza

pakovanje i transport, kao i ponašanje prilikom kompresije. Sastav formulacije,posebno priroda i udeo polimera, značajno utiče na čvrstinu i elastičnost peleta. Ciljovog rada bio je ispitivanje uticaja polimera na mehanička svojstva peletapripremljenihesktruzijom/sferonizacijom,korišćenjemrazličitihsmešapolimera.

Pelete sa 5, 7,5 ili 10% poli(etilen)oksida (PEO WSR303) ili karbomera(Carbopol974P),50%kofeina imikrokristalnomcelulozompripremljenesuvlažnomekstruzijom/sferonizacijom, korišćenjem sita promera 0,8 mm (uzorci P1‐3 i C1‐3,redom). Pripremljeni uzorci ispitani su u pogledu sadržaja vlage, raspodele veličinačestica,odnosadimenzijaipravegustine.Čvrstinapeletaispitanajepomoćureometrasaploča‐pločasistemombezrotacije,izračunatesuzateznačvrstinaiJungovmodul.

Svi uzorci supripremljeni uspešno, osimuzorkaP3 sa 10%PEO, usled niskogprinosa.Sadržajvlagepeletabiojemanjiod3%,medijanaveličine834,21μm(P2)do915,17μm(C3), apravagustina1,4573g/cm3 (C3)do1,4800g/cm3 (C1).Većiudeopolimeradoveo jedo smanjenjapravegustine. Svi uzorcipokazali su zadovoljavajućiodnos dimenzija.Ispitivanjem čvrstine peleta utvrđeno je da uzorci sa PEO pokazujuplastična svojstva, a pelete sa karbomeromkrti lom. Pelete sa karbomerom imale suznačajno veće vrednosti zatezne čvrstine (27,75 MPa za C1, do 33,25 MPa za C3) upoređenjusaPEOuzorcima(7,18MPazaP1,7,80MPa,zaP2),kaoivrednostiJangovogmodula. Ovo ukazuje na veću krutost i manju elastičnost peleta sa karbomerom.Povećanje udela polimera u okviru ispitivanog raspona neznatno je uticalo namehaničkasvojstvapeleta:zateznačvrstinajebilaveća,avrednosti Jungovogmodulasmanjene.

Dobijeni rezultati ukazuju da polimer u formulaciji utiče na procesabilnostvlažnemase,kaoinamehaničkasvojstvapeletadobijenihekstruzijom/sferonizacijom.Povećanjeudelapolimerapovećalojevrednostizateznečvrstine,alisuprinosisfernostpripremljenihpeletabiliniži.

601

INVESTIGATIONINTOMECHANICALPROPERTIESOFPELLETS

PREPAREDBYEXTRUSION/SPHERONIZATIONUSINGDIFFERENTPOLYMERBLENDS

IvanaVasiljević1,ErnaTurković1,MichaelPiller2,

AndreasZimmer3,JelenaParojčić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia),2ResearchCenterPharmaceuticalEngineeringGmbH,Graz(Austria),3InstituteofPharmaceuticalSciences,DepartmentofPharmaceuticalTechnologyandBiopharmacy,Universityof

Graz(Austria) Multiparticulatesmechanical properties are important for assessing suitability

for packaging and transport, as well as their compression behavior. Formulationcomposition,especiallypolymernatureandconcentration,affectspellethardnessandelasticity. The aim of this studywas to investigate polymer effect on themechanicalproperties of pellets prepared by extrusion/spheronization using different polymerblends.

Pelletscontaining5,7.5or10%poly(ethylene)oxide(PEOWSR303)orcarbomer(Carbopol 974P), 50% caffeine andmicrocrystalline cellulose were prepared by wetextrusion/spheronization using the sieve aperture 0.8 mm (samples P1‐3 and C1‐3,respectively). The samples prepared were characterized with respect to moisturecontent, particle size distribution, aspect ratio and true density. Pellet hardnesswasdetermined by rheometer with a plate‐plate system in non‐rotational mode, tensilestrengthandYoung’smoduluswerecalculatedsubsequently.

All sampleswere successfully prepared, apart from P3 (containing 10%PEO),whose yield was low. Pellet moisture content was less than 3%; median pellet size834.21μm(P2)to915.17μm(C3),whiletheirtruedensitywas1.4573g/cm3(C3)to1.4800 g/cm3 (C1). All the investigated samples showed satisfying aspect ratio forpharmaceuticalapplication.HardnesstestingresultsrevealedductilepropertiesofPEOpellets, while carbomer pellets exhibited brittle fracture. Carbomer pellets hadsignificantlyhighertensilestrength(27.75MPaforC1,to33.25MPaforC3)comparedwithPEOsamples(7.18MPaforP1,7.80MPaforP2),aswellasYoung’smodulus.Thisindicatesthatcarbomerpelletswerestifferandlesselastic.Increaseinpolymercontentwithin the investigated experimental range slightly affected pellet hardness: tensilestrengthincreased,whileYoung’smoduluswaslower.

The results obtained indicate that polymers employed can influencewetmassprocessability and mechanical properties of pellets obtained by extrusionspheronisation. Increase in polymer content resulted in slightly increased tensilestrength,butledtoreducedyieldandaspectratioofthepelletsobtained.

602

Arh.farm 2018;68: 602-603 FTK-P21

OPTIMIZACIJAPROCESNIHPARAMETARA3DŠTAMPANJAZA

PROIZVODNJUPRINTLETASLATEHNOLOGIJOM

MirjanaKrkobabić,MarijanaMadžarević,SvetlanaIbrić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,(Srbija)

Stereolitografija(SLA)sezasnivanadejstvu laserakojidovodidoočvršćavanja

prethodno pripremljenog fotopolimerizujućeg rastvora u kome se nalazi lekovitasupstanca,polimerifotoinicijator.Najznačajnijiparametrikodovevrsteštampanjasusnaga izvora svetlosti, vreme izlaganja laseru i količine primenjenih polimera ifotoinicijatora.Ciljradabiojedaseispitauticajsadržajavodeuformulacijinapotrebnovreme izlaganja pripremljenih rezina dejstvu lasera kako bi se postiglo uspešnoštampanjeprintleta.Dobijenimprintletamasuispitanemehaničkekarakteristike.

Pripremljeni su rezini koje sadrže polietilenglikol diakrilat (PEGDA),polietilenglikol400(PEG400),ibuprofen,voduiriboflavin.Usvakojformulacijisadržajibuprofena bio je 5%, a sadržaj vode je variran od 5 do 30%. Model printleta jenapravljen u programu 3D Builder i preveden je u .stl dokument, a parametri suoptimizovani u Creation Workshop X programu. Printlete su štampane na SLAštampačuDuplicator7,Wanhao.Debljinasvakogslojautokuštampanjabilaje100µm.Sa 5% vode uspešno su štampane printlete uz vreme izloženosti laserskim zracima100000ms.Štampanja samanjimvremenom izloženosti rezinabila suneuspešna jeruslednedovoljne izloženosti laserunije došlodo očvršćavanja formulacija. Povećanjesadržajavodena10,1%zahtevalojedavremeizloženostibudenajmanje400000ms,asa30%vodeuformulacijištampanjeprintletabilojemogućeprivremenuekspozicijeod 800000 ms. Mehaničke karakteristike ispitivanih printleta bile su ujednačene.Najvećučvrstinupokazalesuprintletesa10,1%vode(60,30±20,20N).

Sadržaj vode utiče na vreme izloženosti laserskim zracima tako da je sapovećanjemsadržajavodeu formulacijipotrebnoduževremeizlaganja.Preporukezavremeizloženostilaserskimzracimanepostoje,pajezbogtogapotrebnooptimizovatiovaj parametar za svaku formulaciju pojedinačno da bi se omogućilo uspešnoštampanjeprintleta.

603

OPTIMIZATIONOFPRINTINGPROCESSPARAMETERSFOR

PRINTLETSFABRICATEDBYSLAPRINTING

MirjanaKrkobabić,MarijanaMadžarević,SvetlanaIbrić

DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Stereolithography (SLA) is based on the solidification of a liquid resin by

photopolymerization.Resinshouldcontaindrug,polymerandphotoinitiator.Themostimportant parameters for this technology are the power of the light source, theexposure time, and the amount of polymers andphotoinitiator. The aimof the studywastoevaluatetheinfluenceofthewatercontentintheformulationontheexposuretimeinordertosuccessfullyfabricateprintlets.Theobtainedprintletsweretestedformechanicalproperties.

Resins are prepared of polyethyleneglycol diacrylate (PEGDA),polyethyleneglycol 400 (PEG 400), ibuprofen, water, and riboflavin. In eachformulation, ibuprofen contentwas 5% and thewater contentwas varied from5 to30%.Thetemplatesusedtoprinttheprintletsweredesignedwith3DBuildersoftwareandexportedasastereolithographyfile(.stl)intosoftwareCreationWorkshopXwhereparametersare set.Printletswere fabricatedwithSLAprinterDuplicator7,Wanhao.The layer thickness was 100 µm. With 5% of water, printlets were successfullyfabricatedwithexposuretimeof100000ms.Therewasnosolidificationoftheresinswitha lowerexposure time.The increase inwater contentup to10.1%required theexposure time to be at least 400000ms, andwith 30% of water in the formulationprintingwaspossibleatexposuretimeof800000ms.Themechanicalcharacteristicsoftheprintletswereuniform.Thehighest strengthwas shownbyprintletswith10.1%water(60.30±20.20N).

The water content affects the exposure time to the laser beams. With theincrease in thewater content in the formulation, a longer exposure time is required.The guideline for exposure time does not exist, so it is necessary to optimize thisparameterforeachformulationindividuallytosuccessfullyfabricateprintlets.

604

Arh.farm 2018;68: 604-605 FTK-P22

PREDLOGMETODAZAISPITIVANJEFUNKCIONALNIHSVOJSTAVA

ORALNIHFILMOVA

MarkoKrstić1,Ana‐MarijaMeglić2,NikolaJakovljević2,JovanaTalić2,SandraCvijić2

1ZUAJulijaPharm,2Katedrazafarmaceutskutehnologijuikozmetologiju,

UniverzitetuBeogradu–Farmaceutskifakultet(Srbija)

Mukoadhezivni oralni filmovi predstavljaju novi pristup u formulaciji

farmaceutskih preparata koji pokazuje određene prednosti u odnosu nakonvencionalne preparate za oralnu primenu. Međutim, farmakopeje i regulatornivodiči ne navode uslove i kriterijume za ispitivanje ovih farmaceutskih oblika. Ciljistraživanjajebiodaseproceniuticajsastavaformulacijeinačinaizradenamehaničkeiadhezivneosobineoralnihfilmovabaziranihnahidroksipropilmetilcelulozi(HPMC).

Ispitivani filmovi su se sastojali iz polimera (HPMC), plastifikatora (makrogol400)ipiroksikamakaoaktivnesupstance.Kaorastvaračizaizradudisperzijakorišćenisuapsolutnietanoliprečišćenavoda.Ispitivanjasuobuhvatilaodređivanjemehaničkihkarakteristika, variranja mase i debljine filmova, raspadljivosti, vremena kvašenja,brzine apsorpcije medijuma, mukoadhezivnosti na bukalnoj svinjskoj sluzokoži,sadržajapiroksikamaipHvrednostdisperzijazaizradufilmova.Rezultatisuukazalinauniformnost debljine i mase izrađenih filmova. Sadržaj piroksikama bio je 97,55‐103,83% a pH vrednost disperzije 4,09‐4,70 što je posledica blago kisele prirodepiroksikama. Deblji filmovi su pokazali veću mehaničku čvrstinu u odnosu na tanjefilmove istog sastava, dok su se oni sa dodatkom plastifikatora odlikovali većomfleksibilnošćuiprocentomistezanja.Takođe,pokazanojedatanji filmovibržeupijajuveštačku salivu od debljih filmova istog sastava. Povećanje debljine filma i udelapolimera produžilo je vreme raspadanja filmova. In vitro ispitivanje sa bukalnomsvinjskomsluzokožomuuravnoteženomsistemuzaprocenuadhezivnostipokazalo jeda sa porastom udela polimera raste mukoadhezivnost, dok dodatak plastifikatoranegativnoutičenajačinuadhezije.

Prilikomrazvojaoralnihfilmovavažnojeizvršitiopsežnaistraživanjakakobiseidentifikovalaoptimalnaformulacijakojazadovoljavaunapredodređenekarakteristikekvaliteta. Ovakav farmaceutski oblik bi usled jednostavnog načina primene znatnopoboljšao komplijansu pacijenata. Predlozi načina i uslova ispitivanja izneti u ovojstudijipredstavljajudoprinosutomsmeru.

605

ACONTRIBUTIONONTHEMETHODSTODETERMINEFUNCTIONAL

CHARACTERISTICSOFBUCCALPATCHES

MarkoKrstić1,Ana‐MarijaMeglić2,NikolaJakovljević2,JovanaTalić2,SandraCvijić2

1ZUAJulijaPharm,2DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Mucoadhesive buccal patches represent a new approach in drug formulation

with certain advantages in comparison to conventional oral dosage forms.However,pharmacopoeiasandregulatoryguidancesdonotproposeexperimentalconditionsnorrequirements for theassessmentof thesedosage forms.Theaimof the studywas toevaluate the influence of formulation composition and method of preparation onmechanical and adhesive properties of hydroxypropylmethylcellulose (HPMC)‐basedbuccalpatches.

The investigated patches consisted of polymer (HPMC), plasticizer (macrogol400),andpiroxicamasthemodeldrug.Absoluteethanolandpurifiedwaterwereusedas solvents. The investigation of patches included determination of: mechanicalcharacteristics,variation inmassandthickness,disintegrationtime,wettingtimeandsalivauptake,mucoadhesivityonporcinebuccalmucosa,drugcontentandpHvalueofthedispersionsforpatchespreparation.

Theobtainedresultsindicateduniformityofthicknessandmassofthepatches.Piroxicamcontentwas97.55‐103.83%,andpHvalueofthedispersionswas4.09‐4.70due to slightly acidic nature of piroxicam. Thicker patches had higher mechanicalstrenghtcomparedtothinnerpatchesofthesamecomposition,whilepatcheswiththeadditionofmacrogolshowedgreaterflexibilityandpercentofelongation.Salivauptakewas faster for thinner patches in comparison to thicker patches of the samecomposition. Disintegration time was influenced by thickness of the patches andamountofHPMC.InvitrotestingonporcinebuccalmucosarevealedthatincreaseintheamountofHPMCleadtostrongermucoadhesion,whiletheadditionofplasticizerhadnegativeeffectontheadhesionstrengthofthepatches.

Developmentofbuccalpatchesrequiresextensiveresearch inorder to identifytheoptimalformulationthatmeetspredefinedqualitycharacteristics.Suchoraldosageform would significantly increase patients adherence. Recommendations on themethodsandconditionstoassessthecharacteristicsofbuccalpatches,providedinthisstudy,representsacontributioninthisdirection.

606

Arh.farm 2018;68: 606-607 FTK-P23

INVITRO/INSILICOPRISTUPZAPROCENUDEPOZICIJEIAPSORPCIJE

INHALACIONOPRIMENJENIHLEKOVAKODPACOVA:STUDIJASLUČAJA

JelisavetaIgnjatović1,MeihuaHan2,DongmeiCun2,MingshiYang2,3,

JelenaĐuriš1,JelenaParojčić1,SandraCvijić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu–Farmaceutskifakultet(Srbija),2WuyaCollegeofInnovation,ShenyangPharmaceuticalUniversity(Kina),3Odsekzafarmaciju,UniverzitetuKopenhagenu‐Fakultetzdravstvenihimedicinskihnauka(Danska)

Fiziološki zasnovani in silico modeli za predviđanje depozicije i apsorpcije

inhalaciono primenjenih lekova se odnedavno koriste za biofarmaceutskukarakterizaciju ovih lekova. Međutim, nepotpuno poznavanje određenih fiziološkihprocesa i ponašanja leka u plućima neke su od prepreka koje ograničavaju primenupomenutihmodela.Ciljstudijebio jedaseanalizirastrategijarazvoja insilicomodelaza predviđanje depozicije i apsorpcije inhalaciono primenjenih lekova, koristećibudesonidkaomodelsupstancu.

MPPD model (v. 3.04, ARA Inc, USA) korišćen je za predviđanje depozicijebudesonidauplućimapacova,aGastroPlusTMprogram(v.9.0.0007,SimulationPlusInc,USA)zapredviđanjeapsorpcijebudesonida.Podaciodepozicijilekaporegionimaplućai koncentraciji u plazmi dobijeni su u in vivo studiji na Sprague‐Dawley pacovima(težine 180‐220 g). Farmakokinetički parametri generisani su pomoću GastroPlusTMPKPlusmodula.Rezultatiinvivoispitivanjasupokazalidajefrakcijadeponovanogleka(u obliku mikročestica) u alveolama (61%) znatno veća u odnosu na in silicopredviđenuvrednost (4,37%),dok jeodstupanje između invivo određene (36,80%) ipredviđene (56,15%) vrednosti nešto manje u slučaju inhaliranih nanočestica leka.PKPlus analiza je pokazala da se farmakokinetika budesonida najbolje može opisatitroprostornimmodelom,madanekeranijeobjavljenestudijepredlažuprimenujedno‐ilidvoprostornihmodela.Insilicorezultatisupokazalidaseprimenomtroprostornogfarmakokinetičkogmodelaukombinacijisainvivopodacimaodepozicijilekauplućimauspešnijepredviđakoncentracijabudesonidauplazmiuodnosunapodatkedobijenekorišćenjemjedno‐ilidvoprostornogfarmakokinetičkogmodelaiinsilicopredviđenihvrednostizaregionalniprofildepozicije.

Depozicija leka jedan je od ključnih faktora koji utiču na apsorpciju leka uplućima.Međutim,pokazanojedaMPPDmodelnesimuliraadekvatnodepozicijulekauplućimapacova.Takođe,kakofarmakokinetičkiparametriuvelikojmeriutičunaprofilkoncentracije leka u plazmi, neophodno je adekvatno dizajnirati in vivo studije napacovimaiobraditidobijenerezultate.

607

INVITRO/INSILICOAPPROACHTOASSESSANINHALEDDRUGDEPOSITIONANDABSORPTIONINRATS:CASESTUDY

JelisavetaIgnjatović1,MeihuaHan2,DongmeiCun2,MingshiYang2,3,

JelenaĐuriš1,JelenaParojčić1,SandraCvijić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade–FacultyofPharmacy(Serbia),2WuyaCollegeofInnovation,ShenyangPharmaceuticalUniversity(China),3DepartmentofPharmacy,

UniversityofCopenhagen‐FacultyofHealthandMedicalSciences(Denmark)

Physiologically based in silico models for the prediction of inhaled drugs

deposition and absorption recently emerged as advantageous biopharmaceuticalassessment tool. However, lack of knowledge on certain physiological processes anddrugperformanceinthelungsaresomeoftheobstaclesthathinderwideruseofthesemodels. The aim of this studywas to analyze the strategy for generating an in silicomodel for thepredictionof inhaleddrugdepositionandabsorptionusingbudesonideasamodeldrug.

MPPDmodel(v.3.04,ARAInc,USA)wasusedtopredictbudesonidedepositioninrats,andGastroplusTMsoftware(v.9.0.0007,SimulationPlusInc,USA)wasusedtoestimate the drug absorption profile. In vivo data on lung regional deposition andplasma concentration profiles were collected using Sprague‐Dawley rats (180‐220 gbody weight). Drug pharmacokinetic parameters were obtained using GastroPlusTMPKPlusmodule.Invivoresultsshowedthatthedepositeddrugfractioninalveoli(61%)wasmuchhigherthanthepredictedvalue(4.37%)fortheinhaledmicroparticles,whilethedifferencebetweenobserved(36.80%)andpredicted(56.15%)valuesforinhalednanocrystals was less pronounced. PKPlus analysis indicated that budesonidepharmacokinetics is best described by three compartmental model although somepreviously published studies suggested one or two compartmental model. Modelingresultsindicatedthatthreecompartmentalpharmacokineticmodelcoupledwithinvivodeposition data gave better prediction of drug plasma concentration profile incomparison to one or two compartmental pharmacokinetic model and in silicodepositiondata.

Drugdeposition isoneof thekey factorsaffectingpulmonarydrugabsorption.However,availableMPPDmodeldoesnotseemtoaccuratelypredictdrugdepositioninrats. In addition, since pharmacokinetic parameters inevitably affect drug plasmaconcentrationprofile,itisofparamountimportancetoproperlydesigninvivostudiesinratsandanalyzetheobtainedresults.

608

Arh.farm 2018;68: 608-609 FTK-P24

AERODINAMIČKOODREĐIVANJEFRAKCIJESITNIHČESTICA

PRAŠKOVAZAINHALACIJUFORMULISANIHUOBLIKULIPIDNIHMIKROČESTICA

JelisavetaIgnjatović1,SandraCvijić1,VladimirDobričić2,

SvetlanaIbrić1,JelenaĐuriš1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu–Farmaceutskifakultet,2Katedrazafarmaceutskuhemiju,Univerzitetu

Beogradu–Farmaceutskifakultet(Srbija)

Lipidne mikročestice izrađene od biokompatibilnih i biodegradabilnih

ekscipijenasa imaju veliki potencijal za primenu u obliku praškova za inhalaciju. Ciljrada bio je da se ispita veza između geometrijske i aerodinamičke veličine lipidnihmikročestica,idaseutvrdiuticajbrzineprotokavazduhanafrakcijusitnihčestica.

U studiji su korišćene dve formulacije lipidnihmikročestica, F1 i F2, izrađenemetodom emulgovanja topljenjem, pri čemu je za izradu formulacije F1 kao lipidnakomponentakorišćenglicerildibehenat,astearilalkoholzaF2.Geometrijskaraspodelaveličine čestica određena je metodom laserske difrakcije (Mastersizer, Malvern UK).Aerodinamičko određivanje frakcije sitnih čestica vršeno je u staklenom impindžeru(Aparatura A, Ph. Eur. 9.0), primenom dve brzine protoka vazduha, 60±5 i 100±5L/min. Sadržaj aktivne supstance, salbutamol‐sulfata određen je metodom tečnehromatografijeukombinacijisamasenomspekrometrijom(TSQQuantumAccessMAX,USA). Rezultati su pokazali nešto manji geometrijski prečnik čestica formulacije F2(d50=11,00μm)uodnosunaF1(d50=13,45μm)ivećufrakcijusitnihčestica,manjihod5μm(21,36%zaF2 i17,11%zaF1).Međutim,rezultatiaerodinamičkogodređivanjasitnih čestica pokazali su znatno manju frakciju sitnih čestica (2,76‐5,77% za obeformulacije). Ovakve razlike su najverovatnije uslovljene oblikom čestica koje nisusferne, kao i nešto većom gustinom čestica (> 1 g/cm3). Takođe, pokazano je da nepostojiznačajnarazlikauudelusitnihčesticapripromenibrzineprotokavazduha,kaonipriprimenikapsulanapunjenihpraškomuodnosunadirektnopunjenje inhalatorapraškom.Ovaj podatak ukazuje da zanemarljiva količina praška zaostaje na omotačukapsule,tejerizikodneujednačenogdoziranjasmanjen.

Dobijenirezultatipokazujudajezaisporukuefektivnedozesalbutamol‐sulfataupluća neophodno razviti formulacije sa manjim geometrijskim i aerodinamičkimprečnikomčesticai,posledično,većomfrakcijomsitnihčestica.

609

AERODYNAMICASSESMENTOFFINEPARTICLESFRACTIONFORINHALATIONPOWDERSFORMULATEDASLIPIDMICROPARTICLES

JelisavetaIgnjatović1,SandraCvijić1,VladimirDobričić2,

SvetlanaIbrić1,JelenaĐuriš1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade–FacultyofPharmacy,2DepartmentofPharmaceuticalChemistry,

UniversityofBelgrade–FacultyofPharmacy(Serbia)

Lipidmicroparticles composed of biocompatible and biodegradable excipients

havebeenrecognizedaspotentiallyusefuldeliversystemsforinhaleddrugs.Theaimofthis study was to determine the relationship between geometric and aerodynamicparticlesizeoflipidmicroparticles,andtodeterminetheeffectofdifferentairflowsonfineparticlefraction.

Twolipidmicroparticleformulations,F1andF2,weretestedinthisstudy.Bothformulationswerepreparedbymelt emulsificationmethod; F1wasmadeof glyceryldibehenate and F2 of stearyl alcohol. Geometric particle size distribution wasdeterminedby laserdiffraction(Mastersizer,MalvernUK).Glass impinger (apparatusA,Ph.Eur.9.0)wasused foraerodynamicassessmentof fineparticles fraction,usingtwoairflows,60±5and100±5L/min.Salbutamol‐sulphatecontentwasdeterminedbyliquid chromatography tandem mass spectrometry. The results indicated smallergeometric particle diameter for F2 (d50= 11.00 μm) compared to F1 microparticles(d50=13.45μm),andhigherfractionofparticlessmallerthan5μm(21.36%forF2and17.11% forF1).However, the resultsofaerodynamicassesmentshowedsignificantlysmaller fine particles fraction (2.76‐5.77% for both formulations). These differenciesprobably result from the lack of particle sphericity or higher particle density (>1g/cm3).Inaddition,therewasnosignificantdifferenceoffineparticlesfractionunderdifferent air flows, nor between testingwith capsules filledwith powder and testingwithpowderdirectlyfilledintheinhaler.Thesedataindicatethatnegligibleamountofpowder adheres to the capsule shell, and therefore the risk of inconsistent dosing isdecreased.

Theresultssuggest that improvementof the formulations inorder todecreasegeometric and aerodynamic diameter, and increase fine particles fraction, arenecessarytodelivertheeffectivesalbutamol‐sulphatedosetothelung.

610

Arh.farm 2018;68: 610 FTK-P25

STUDYONPHYSICALANDCHEMICALBEHAVIOROF

β–CYCLODEXTRINANDITSINCLUSIONCOMPLEXWITHCAPTOPRIL

AdinaMusuc1,IrinaAtkinson1,MirelaMitu2,

OanaKarampelas2,EmmaCretu2

1RomanianAcademy,„IlieMurgulescu”InstituteofPhysicalChemistry,Bucharest,2UniversityofMedicineandPharmacy„CarolDavila”Bucharest,

FacultyofPharmacy(Romania)

Captopril (CAP), (2S)‐1‐[(2S)‐2‐methyl‐3‐sulfanylpropanoyl] pyrrolidine – 2 ‐

carboxylicacid isasuitablecandidate tobe formulated insublingual tablets, thebestemergencypharmaceutical formtobeusedbythepatienthimself.CAP is included inclassIIIofBiopharmaceuticsClassificationSystem;thatmeansithasalowmembranepermeabilitywhichdecreasesitsabsorptionandinordertoprovidethisdruginamoreaccessible and patient compliant form, its bitter taste must be masked. Also, CAPundergoes oxidative dimerization to the major degradation product captoprildisulphide in aqueous solutions.By its formulation as an inclusion complexwithβ –cyclodextrinwearetryingtoadjusttheseinconvenients,andtoobtainastableandeasytousesolidsublingualpharmaceuticalformwithanincreasedbioavailability.Theaimofthecurrentstudyistoevaluatetheabilityofβ‐cyclodextrintoincludecaptopril.

Thepastamethodofcomplexationinsolidstatewasusedtoobtaintheinclusioncomplexes. For comparison was prepared a simple physical mixture. Physical andchemicalcharacterizationofrawmaterials,physicalmixtureandtheinclusioncomplexweremadeusingFouriertransform–infraredspectroscopy,X‐raydiffraction,scanningelectronmicroscopyandsimultaneousthermalanalysis.Theresultsobtainedusingallthese analytical techniques, proved that captopril forms stable complexes with β‐cyclodextrinin1:2molarratio,andthecomplexationwasalmostcomplete.TheresultsofthepresentstudiesprovethatCAP‐β‐CDinclusioncomplexcanbeembeddedasanactive ingredient of sublingual tablets that can be successfully used in therapeuticpractice.

611

Arh.farm 2018;68: 611-612 FTK-P26

SAMOEMULGUJUĆISISTEMIZAISPORUKUSIMVASTATINA:UTICAJVRSTEKOSURFAKTANTANAVELIČINUKAPIIOSLOBAĐANJE

LEKOVITESUPSTANCE

ZoraĆetković1,SandraCvijić2,DraganaVasiljević2

1KliničkicentarSrbije,2Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Samoemulgujući sistemi su napredni sistemi za isporuku slabo rastvorljivih

lekovitih supstanci, kao što je simvastatin. U njihov sastav mogu da uđu različitepomoćnesupstance,aizborzavisiodželjenihkarakteristikaovihsistema.Ciljstudijejebio da se ispita uticaj različitihkosurfaktanatana veličinu emulgovanih kapi i brzinuoslobađanjasimvastatina,kaomodelsupstance.

Samoemulgujuci sistemi su izrađeni koriscenjem oleil makrogol‐6 glicerida(Labrafil®) (10,0%) kao uljane faze, kaprilokaproil makrogol‐8 glicerida (Labrasol®)(67,5%) kao surfaktanta i četiri različita kosurfaktanta (22,5%): polisorbata 80,makrogol‐15 hidroksistearata (Kolliphor® HS15), saharoze palmitata (D‐1616) ilisaharoze stearata (D‐1816). Sadržaj simvastatina bio je 5% u svim formulacijama.Karakterizacijaizrađenihsistemaobuhvatilajeprocenusposobnostisamoemulgovanja,kao i određivanja veličine emulgovanih kapi, indeksa polidisperziteta i brzineoslobađanjasimvastatina.Vremesamoemulgovanjasvihuzorakabilojeveomakratko(manje od 1 min). Tečni samoemulgujući sistemi, izrađeni sa polisorbatom 80 iliKolliphor®‐om HS15 kao kosurfaktantom, imali su malu prosečnu veličinu kapi(14,36±0,07 i 17,53±0,17 nm) i nizak indeks polidisperziteta (0,181±0,006 i0,085±0,011). Polučvrsti samoemulgujući sistemi, izrađeni sa šećernim estrima(saharozapalmitatomilisaharozastearatom),kaokosurfaktantimaprirodnogporekla,imali su vecu prosecnu velicinu kapi (251,4±0,64 i 277,0±1,65 nm) i veći indekspolidisperziteta (0,237±0,041 i 0,392±0,005). Iako je uočena razlika u veličini kapiizmeđu uzoraka koji sadrže sintetičke ili prirodne kosurfaktante, nije bilo razlike ubrzini oslobađanja simvastatina između ovih samoemulgujućih sistema. Lekovitasupstancasepotpunooslobodila izsvih formulacijanakonprvih5minuta ispitivanja.Osim toga, polučvrsti samoemulgujući sistemi su pokazali bolja svojstva u pogledulakoćepunjenjautvrdekapsule.

Ova ispitivanja su pokazala da se korišćenjem šećernih estara, kaokosurfaktanata,mogudobitipolučvrsti samoemulgujući sistemi, kaopotencijalninovinosači lekovitih supstanci. Opisani sistemi obezbeđuju odgovarajuću brzinuoslobađanjainkorporiraneteškorastvorljivelekovitesupstance,adodatnaprednostuodnosunatečnesistemeimjelakšepunjenjeutvrdekapsule.

612

SELF‐EMULSIFYINGDRUGDELIVERYSYSTEMS(SEDDS)OFSIMVASTATIN:THEINFLUENCEOFCOSURFACTANTTYPEON

DROPLETSIZEANDDRUGRELEASE

ZoraĆetković1,SandraCvijić2,DraganaVasiljević2

1ClinicalCenterofSerbia,2DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Self‐emulsifyingdrugdeliverysystems(SEDDS)arepromisingdeliverysystems

forpoorlywater‐solubledrugslikesimvastatin.Anumberofexcipientsmaybeusedtoformulate these systems, and the choice of composition depends on the desiredcharacteristics of the resulting SEDDS. The aim of this study was to investigate theinfluence of different cosurfactants on droplet size of SEDDS and release rate ofsimvastatinasamodeldrug.

SEDDSwereformulatedusingoleoylmacrogol‐6glycerides(Labrafil®)(10.0%)as oil phase, caprylocaproylmacrogol‐8 glycerides (Labrasol®) (67.5%) as surfactantandfourdifferentcosurfactants(22.5%):polisorbate80,macrogol‐15‐hydroxystearate(Kolliphor® HS15), sucrose palmitate (D‐1616) or sucrose stearate (D‐1816).Simvastatin content was 5% (w/w) in all formulations. Prepared formulations wereevaluatedforself‐emulsifyingability,dropletsize,polydispersityindex(PDI),anddrugreleaserate.Allformulationsshowedveryshortemulsificationtimeoflessthan1min.TheliquidSEDDS,containingpolisorbate80orKolliphor®HS15ascosurfactants,hadsmall mean droplet size (14.36±0.07 and 17.53±0.17 nm), and low PDI values(0.181±0.006and0.085±0.011).Semi‐solidSEDDS, incorporatingnaturalsugar‐basedexcipients (sucrose palmitate or sucrose stearate) as cosurfactants, had largermeandroplet size (251.4±0.64 and 277.0±1.65 nm), and PDI values (0.237±0.041 and0.392±0.005). Although there was a notable difference in droplet size betweenformulationscontainingsyntheticandnaturalcosurfactants,therewasnodifferenceinsimvastatinreleaseratebetweentheseSEDDS.Acompletedrugreleaseoccurredfromall formulations within the first 5 minutes. In addition, semi‐solid SEDDS werefavorableintermsofeasecapsulefilling.

Thisstudyrevealedthatinclusionofnaturalexcipients,sucroseesters,inSEDDSresults in the formation of semi‐solid systems. These novel SEDDS provide anappropriatereleaserateofincorporatedpoorlywater‐solubledrug.Additionally,theirconsistencyismoreappropriateforfillingintohardcapsules.

613

Arh.farm 2018;68: 613-614 FTK-P27

ISPITIVANJEUTICAJAHIDROGELATIPAPOLIELEKTROLITNOGKOMPLEKSAHITOZAN/KSANTANNAINVITROKINETIKU

OSLOBAĐANJAIBUPROFENA

AnaĆirić,LjiljanaĐekić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Ibuprofen je jedan od najčešće korišćenih nesteroidnih antiinflamatornih

analgetika. Zbog kratkog poluvremena eliminacije (t1/2~2h) neophodna je čestaprimena farmaceutskih preparata sa trenutnim oslobađanjem. Radi smanjenjaučestalosti doziranja razmatraju se formulacije sa produženim oslobađanjem.Biokompatibilni ibiodegradabilnikompleksihitozanasaanjonskimpolimerimamogupotencijalnouticatinakinetikuoslobađanjaperoralnoprimenjenihlekova.Ciljradabioje ispitivanjeuticajahidrogelova tipapolielektrolitnogkompleksahitozan/ksantannainvitrokinetikuoslobađanjaslaborastvorljivogibuprofena.

Pripremljeni su hidrogelovi mešanjem vodenih disperzija hitozana 0,65% (pH5,6;0,1MHCli0,2MNaOH)iksantana0,65%,nasobnojtemperaturi.Nakonuklanjanjaviškavode,ispiranjaisušenjadobijenisuviostatak(hidrogel)jeusitnjen,prosejan(sito600μm)iupotrebljenzapripremufizičkihsmešasaibuprofenomumasenomodnosu1:1 i 1:2. Smeše su napunjene u kapsule veličine 0 i ispitivan je in vitro profiloslobađanjauaparaturisalopaticom(50rpm)(ErwekaDT70,Nemačka),uzkorišćenje900mlakceptorskogmedijuma(fosfatnipuferpH7,2)na37±1°C.Dobijenihidrogeluhidratisanom obliku bio je opalescentan, a suvi ostatak bledožute boje. ZahtevAmeričke farmakopeje (USP) za in vitro ispitivanje brzine rastvaranja ibuprofena izkonvencionalnihčvrstihfarmaceutskihoblika(tableta)jedasenajmanje80%lekovitesupstance oslobodi nakon 60 min. Kod ispitivane formulacije sa odnosomhidrogel:ibuprofen1:1nakon60minoslobođeno je16,20%lekovitesupstance,akodformulacije sa odnosom hidrogel:ibuprofen 1:2 utvrđeno je da se nakon 60 minrastvorilo9,78%ibuprofena.Dobijeniprofilioslobađanjaibuprofenabilisuuskladusakinetikomnultogreda(r2>0,95),abrzinarastvaranjaiznosilaje0,416mg/min(maseniodnos1:1)i0,396mg/min(maseniodnos1:2).

Na osnovu dobijenih rezultata može se zaključiti da se korišćenjem hidrogelatipapolielektrolitnogkompleksahitozan/ksantanmožepostićiproduženooslobađanjeibuprofena,pričemujeispitivanimaseniodnoshidrogelaiibuprofenaznačajnouticaonabrzinurastvaranjaaktivnesupstance.

614

INVESTIGATIONOFTHEINFLUENCEOFPOLYELECTROLYTE

COMPLEXCHITOSAN/XANTHANHYDROGELSONTHEINVITRORELEASEKINETICSOFIBUPROFEN

AnaĆirić,LjiljanaĐekić

DepartmentofPharmaceuticalTechnologyandCosmetology,Universityof

Belgrade‐FacultyofPharmacy(Serbia)

Ibuprofen is one of the most frequently used non‐steroidal anti‐inflammatory

analgesics. Due to its short half‐life (t1/2~2h), frequent administration of immediaterelease dosage forms is necessary. To reduce the frequency of dosing, prolongedrelease formulations are considered. Biocompatible and biodegradable chitosancomplexeswithanionicpolymerscanpotentiallyinfluencethereleasekineticsoforallyadministered drugs. The aim of this paper was to investigate the influence ofpolyelectrolyte complex chitosan/xanthan hydrogels on in vitro release kinetics ofpoorlysolubleibuprofen.

Hydrogelswerepreparedbymixingaqueousdispersionsofchitosan0.65%(pH5.6, 0.1M HCl and 0.2M NaOH) and xanthan 0.65% at room temperature. Afterremoving excesswater, rinsing anddrying, resultingdried residue is crushed, sieved(sieve600μm)andusedtopreparephysicalmixtureswithibuprofeninmassratio1:1and1:2.Themixtureswerefilledintocapsulessize0andinvitroreleaseprofileinthepaddleapparatus(50rpm)(ErwekaDT70,Germany)wasperformedusing900mlofacceptormedium(phosphatebufferpH7.2)at37±1°C.

Theresultinghydrogelinhydratedformwasopalescent,anddriedresiduepaleyellow.TheUSPharmacopoeiarequirementforinvitrodissolutiontestingofibuprofenfrom tablets is that at least 80% of ibuprofen is released after 60 min. In theinvestigatedformulationwithmassratiohydrogel:ibuprofen1:1,after60min16.20%of ibuprofenwasreleased,andintheformulationwithmassratiohydrogel:ibuprofen1:2,after60min9.78%ofibuprofenwasreleased.Resultingibuprofenreleaseprofileswereinaccordancewithzeroorderkinetics(r2>0.95)anddissolutionratewas0.416mg/min(massratio1:1)and0.396mg/min(massratio1:2).

Itcanbeconcludedthatprolongedreleaseofibuprofencanbeachievedbyusingpolyelectrolytecomplexchitosan/xanthanhydrogels,whereininvestigatedmassratiohydrogel:ibuprofensignificantlyinfluencethedissolutionrate.

615

Arh.farm 2018;68: 615-616 FTK-P28

UTICAJMOLEKULSKEMASEHITOZANANAFUNKCIONALNOST

HITOZAN‐HALOJZITNANOKOMPOZITNIHFILMOVAZALOKALNUISPORUKUANTIBIOTIKA

BojanČalija1,DaninaKrajišnik1,AleksandraDaković2,

KataTrifković3,NikolaMilašinović4,JelaMilić1 1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Institutzatehnologijunuklearnihidrugihmineralnih

sirovina,3Katedrazahemijskoinženjerstvo,UniverzitetuBeogradu–Tehnološko‐metalurškifakultet,4Katedraforenzike,Kriminalističko‐policijska

akademija(Srbija)

Dodatkom glina, poput halojzita, moguće je unaprediti funkcionalnosthitozanskih filmova, poboljšanjem termičke stabilnosti, mehaničkih i optičkihkarakteristika.Karakteristikehitozan‐halojzit kompozita zaviseod svojstava i odnosakonstituenata inačina/postupka izrade.Molekulskamasahitozanaprepoznata jekaoključna funkcionalna karakteristika ovog polimera kada se koristi za izradu nosačalekovitih supstanci. Cilj studije je ispitivanje uticaja molekulske mase hitozana nafunkcionalnost hitozan‐halojzit nanokompozitnih filmova kao potencijalnih nosača zalokalnuisporukuantibiotika.

Filmovi su izrađeni postupkom izlivanja 0,5% (m/m) disperzije halojzita urastvoru1,5%(m/m)hitozanai0,5%(m/m)tetraciklin‐hidrohloridauakrilnekalupe.Zaizradudisperzijakorišćenisuvisokodeacetilovaninisko‐(253,7kDa),srednje(417,7kDa) i visokomolekularni (547,3 kDa) hitozan. Nakon sušenja, filmovi su podvrgnutiodređivanju mase i debljine, mehaničkoj, strukturnoj i termičkoj karakterizaciji iispitivanjubrzineoslobađanjatetraciklin‐hidrohloridaufosfatnompuferupHvrednosti5,8. Nanokompozitni filmovi su opalescentni i žuti, usled prisustva halojzita itetraciklin‐hidrohlorida. Masa i debljina filmova su opadale od 76,77±3,29 do63,18±1,84 mg, odnosno od 89,12±6,83 do 77,7±2,3 µm, redom, sa porastommolekulskemasehitozana.Porastmolekulskemasehitozanadovodiojeidosmanjenjaizduženjaprikidanju (od60,94±5,05do23,42±1,31%), aporastanaponaprikidanju(od 24,66±2,56 do 230,04±33,44 MPa) i modula elastičnosti (od 40,45±2,16 do491,64±62,94 MPa). FT‐IR i termičkom analizom potvrđene su hitozan‐halojzitinterakcije i poboljšana termička stabilnost nanokompozitnih filmova u odnosu nahitozanske, ali nije uočen uticaj molekulske mase hitozana na strukturu i termičkeosobine filmova. Tetraciklin‐hidrohlorid se usporeno oslobađao iz nanokompozitnihfilmova, a posebno iz filmova izrađenih od niskomolekularnog hitozana (t50%≈5,5 h;t90%>8h).Dobijenirezultatiukazujudamolekulskamasahitozanaimaznačajanuticajna masu, debljinu i mehaničke karakteristike hitozan‐halojzit nanokompozitnihfilmova, kao i na brzinu oslobađanja tetraciklin‐hidrohlorida, ali ne i na njihovustrukturuitermičkasvojstva.

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INFLUENCEOFCHITOSANMOLECULARWEIGHTON

FUNCTIONALITYOFNANOCOMPOSITECHITOSAN‐HALLOYSITEFILMSFORLOCALDELIVERYOFANTIBIOTICS

BojanČalija1,DaninaKrajišnik1,AleksandraDaković2,

KataTrifković3,NikolaMilašinović4,JelaMilić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2InstitutefortheTechnologyofNuclearand

OtherMineralRawMaterials,3DepartmentofChemicalEngineering,UniversityofBelgrade‐FacultyofTechnologyandMetallurgy,4DepartmentofForensics,

AcademyofCriminalisticandPoliceStudies(Serbia) Additionofclays,suchashalloysite,mayimprovefunctionalityofchitosanfilms

by improving their thermal stability, mechanical and optical characteristics.Characteristicsofchitosan‐halloysitecompositesdependoncharacteristicsandratioofindividual constituents, and preparation procedure.Molecularweight is identified asone of the key functionality‐related characteristics of this polymer, as excipients fordrug delivery devices. This study was aimed to investigate influence of chitosanmolecular weight on functionality of chitosan‐halloysite nanocomposite films aspotentialcarriersforsustaineddeliveryofantibiotics.

The filmswere prepared by casting 0.5% (w/w) halloysite dispersion in 1.5%(w/w)chitosanand0.5%(w/w)tetracyclinehydrochloridesolutionintoacrylicmolds.Highlydeacetylatedchitosanshavingaveragemolecularweightof253.7,417.7i547.3kDa,labelledaslow‐,medium‐andhighmolecularweightchitosan,respectively,wereusedforpreparationofthedispersions.Upondryingfilmsweresubjectedtomassandthicknessdetermination,mechanical,structuralandthermalcharacterizationanddrugrelease studies in phosphate buffer solution pH 5.8. Nanocomposite films wereopalescent and yellow‐colored due to presence of halloysite and tetracyclinehydrochloride.Filmsmassandthicknessdecreasedfrom76.77±3.29mgto63.18±1.84and from 89.12±6.83 to 77.7±2.3 µm, respectively, following the increase in thechitosanmolecularweight.Increaseinchitosanmolecularweightalsoledtodecreasein elongation at break (from 60.94±5.05 to 23.42±1.31%), and increase in tensilestrength (from 24.66±2.56 to 230.04±33.44 MPa) and elastic modulus (from40.45±2.16 to 491.64±62.94 MPa). FT‐IR and thermal analysis confirmed chitosan‐halloysite interactions and improved thermal stability of nanocomposite films incomparisontochitosanfilms,butdidnotrevealinfluenceofchitosanmolecularweighton structure and thermal properties of the films. Tetracycline hydrochloride releasefromfilmswassustained,particularlyfromthefilmsconsistedoflowmolecularweightchitosan(t50%≈5.5h;t90%>8h).

Obtainedresultsrevealedsignificant influenceofchitosanmolecularweightonmass, thickness,mechanical and drug release properties of nanocomposite chitosan‐halloysitefilms,butnotontheirstructureandthermalproperties.

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CHARACTERIZATIONOFRISPERIDONELOADEDNANOSTRUCTURED

LIPIDFORDRUGDELIVERYTOTHEBRAIN

HristinaLitovin1,BlagorodnaKoprivica1,MonikaStojanovska2,GjorgjiPetrusevski2,MajaSimonoskaCrcarevska1,MarijaGlavasDodov1

1InstituteofPharmaceuticalTechnology,Ss.Cyril&MethodiusUniversity‐

FacultyofPharmacy,Skopje,2InstituteforResearchandDevelopment,AlkaloidAD,Skopje(Macedonia)

DrugdeliverytotheCNSposesaformidablechallenge.TheBBBandtheblood‐

cerebrospinalfluidbarriercanhampereffectivetransportofdrugsintothebrain.Themain objective of the study was to formulate and characterize risperidone (RISP)loaded nanostructured lipid carriers (NLC's) as a parenteral delivery carrier withprolonged circulatory time which favors interaction and penetration into brainendothelialcells.

Different formulations of NLC's loaded with RISP were prepared by phaseinversion temperature (PIT)method. Particle size and particle size distribution, zetapotential encapsulation efficiency (EE), drug loading (DL), drug release, and thermalbehavior of the prepared samples were determined. Optimized NLC’s were surface‐modifiedwithTween80,PEG400andSolutolHS15 (3.5 –4.5%) toassesswhetherthey show reduction of total protein adsorption thus leading to site‐specificaccumulation(targeting)intothebrain.

Byusing19.96%lipidmatrixconstituents(56%cetylpalmitateand44%Miglyol812asoil),5%RISP,1.5%phospholipid,17%SolutolHS15ashydrophilicemulsifier,nanoparticleswith an average diameter of 133 nm (PdI~0.4)with unimodal narrowsizedistributionwereprepared,zetapotential‐13.8mV,EE(89.24%),DL(31.3mg/g)and gradual drug release after 96 h up to 81.87%. DSC scans and calculatedrecrystallization index showed that the lipid phase in formulatedNLC`s remained incrystalline state with RISP solubilized in lipid matrix. Optimized NLC’s formulationshowedBSAadsorptionof0.75mg/glipid.

PresentstudyrevealspotentialofRISPloadedNLC'sasdrugdeliverysystemforparenteral administration with prolonged blood circulation time, thus favoring site‐specificbraindelivery.

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INFLUENCEOFTHERELEASEPROPERTIESOFNANOLIPOSOMESONTHEANTIOXIDANTCAPACITYOFENCAPSULATEDROSEMARY

EXTRACT

LjubicaMihailova1,DushkoShalabalija1,IvanaCvetkovikjKaranfilova2,MajaSimonoskaCrcarevska1,MarijaGlavasDodov1

1InstituteofPharmaceuticalTechnology,Ss.Cyril&MethodiusUniversity‐

FacultyofPharmacy,Skopje2InstituteofPharmacognosy,Ss.Cyril&MethodiusUniversity‐FacultyofPharmacy,Skopje(Macedonia)

Freeradicalsinducelipidperoxidationincellmembranesandinitiateneuronal

dysfunction and death. Therefore, oxidative stress is a cardinal hallmark ofneurodegenerative disorders such as Alzheimer’s disease (AD). In addition to thenumerouseffects,Rosemaryextract(RE)exhibitsanantioxidantactivity,consideredasa possible source for AD prevention. Within this framework RE loaded NLs werepreparedandthecorrelationbetweeninvitrodrugreleasepropertiesandantioxidantpotentialwasexamined.

RE loadedNLs (lechitin:cholesterol:PEG=8.7:1:1.7and9:1:0.17 forS1andS2,respectively)werepreparedbymodifiedlipidfilmhydrationtechnique.REloadingwasdeterminedandinvitroreleasefromNLswascarriedoutinphosphatebufferpH7.4bypreviouslyvalidatedHPLCmethod.AntioxidantcapacityofREloadedNLsandREwasdetermined using Oxygen Radical Antioxidant Capacity (ORAC) assay based on theoxidation of a fluorescent probe by peroxyl radicals from 2,2’‐Azobis (2‐amidinopropane)dihydrochloride.Fluorescencewasmeasuredevery30min(VICTOR,PerkinElmer,USA)during the examinationperiodof120min.All experimentswereconducted in triplicate and statistical analysis was done using ANOVA. RE loading,expressed through rosmarinic acid (RA), in NLs was 4.10 ‐ 4.28 mg/100 mg lipid.Obtained drug release profiles pointed that prepared NLs were characterized withcontrolledreleaseproperties(0.55and0.99mgRAreleasedwithin120minforS1andS2, respectively). RE loaded NLs showed statistically significant higher antioxidantactivity(95.03±0.69%and96.40±0.73%oftheinitialfluorescence)comparedtonativeRE (90.04±2.51%), probably due to the presence of lecithin in the formulations andtheir controlled release properties. In this study an efficient in vitro antioxidantcapacityofREloadedNLswasconfirmed,whichmayserveasapromisingstrategyforADprevention.

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PHYTOPHARMACEUTICALSFORALZHEIMER’SDISEASE

TREATMENT:SALVIAOFF.LOADEDNANOSTRUCTUREDLIPIDCARRIERS

LjubicaMihailova,MonikaKostovska,ElenaMarkova,LeaTaneska,DushkoShalabalija,MarijaGlavasDodov,MajaSimonoskaCrcarevska

InstituteofPharmaceuticalTechnology,CenterofPharmaceutical

Nanotechnology,Ss.Cyril&MethodiusUniversity‐FacultyofPharmacy,Skopje(Macedonia)

Combining the current knowledge of phytotherapy and pharmaceutics,

nanostructured lipidparticles (NLC) loadedwith freezedriedSalviaoff.Lmethanolicextract(FSE)forefficientAlzheimer’sdiseasetreatmentcouldbeengineered.TheaimofthestudywastodeterminetheinfluenceofquantityofhydrophilicsurfactantuponNLC‐FSE physico‐chemical and biopharmaceutical properties and their possiblecorrelationwithantioxidantactivity.

Foursamples(S5‐S8)ofNLC‐FSEwerepreparedbysolventevaporationmethod.Lipidphaseconsistedofphospolipon90H(kindlydonatedbyPhospholipid,Germany)assolid lipidandoleicacidas liquidlipidinratioof2.3:1.Total lipidsalongwithFSEweredissolved inethanolasorganicsolvent(1:0.11:20,respectively).Aqueousphasewascomposedofmixedwatersolutionof0.5%Poloxamer407and1.1%(S5),2%(S6),2.8%(S7)and3.4%(S8)ofTween80.Ratiooflipidtoaqueousphasewas1:2.Physico‐chemical and biopharmaceutical properties were determined, as well as antioxidantactivity.

Surface morphology, particle size and size distribution, zeta potential andprotein‐bindingpropertieswerediscussedelsewhere.IncreasedquantityofTween80resultedwithdecreasedencapsulationefficiency(79.74%,62.17%,48.94%and47.9%forS5,S6,S7andS8,accordingly)probablyduetothesmallerparticlesize,aswellashighersolubilisationofFSEthuspromotingitspartitioningintotheouterwaterphase.InvitrodissolutionstudiesindicatedprolongedFSEreleasefor24h‐44.98%;24.17%,20.52% and 18.77% for S5, S6, S7 and S8, respectively. Comparing the values ofcorrelationcoefficientofdifferentkineticsmodels, thebestfitwasestablishedforthePeppas andSahlinmodel,wherevaluesofk1 andk2 indicateddominanceofFickiandiffusionand insignificant effect of case II transport.Results ofmodifiedORACassayindicatedthathighestantioxidantactivitywasassociatedwithfastestFSErelease.

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AMINO‐MODIFIEDSILICANANOPARTICLESASCARRIERSFOR5‐FLUOROURACIL:INFLUENCEOFPREPARATIONPROCESS

PARAMETERSONPHYSICO‐CHEMICALPROPERTIESANDDRUGRELEASE

BetiDjurdjic1,KaterinaGoracinova2,3,NikolaGeskovski2,BobanMugosa4

1DepartmentofPharmacy,UniversityofMontenegro‐FacultyofMedicine

(Montenegro),2UniversitySsCyrilandMethodius‐FacultyofPharmacy,Skopje(Macedonia),3QatarUniversity‐CollegeofPharmacy,Doha(Qatar),4Institute

ofPublicHealth,Podgorica(Montenegro)

Theaimofthisstudywastosynthesizeamino‐functionalizedsilicananoparticles

assystemsforcontrolledreleaseof5‐fluorouracil(5‐FU)aswellasto investigatetheeffectsoftheprocessparametersupontheparticlesize,drugencapsulationefficacyanddrugrelease.

Silicananoparticlesweresynthesizedbysol‐gelmethodatroom(samplesS1andS2)andelevatedtemperature(45°C)(S3andS4).Themolarratio(mmol)ofthesilicasol componentswas tetraethyl‐orthosilicate: 3‐aminopropyltriethoxysilane : ethanol :water:aceticacid=4.433:0.0427:428:611:8.735.5‐Fluorouracilwasaddedtothesilica sol at the start of hydrolysis process (S1 and S3) and during the synthesis ofpolymericmatrix(S2andS4).Preparedsampleswerecharacterizedintermsofmeanparticle size anddrug loading efficiency. In vitrodrug release studies atdifferentpHvalues(pH1.2and7.4)wereperformed.

Themeanparticlesizeofnanoparticleswas418,652,144and207nmforS1,S2,S3 and S4, respectively. Encapsulation efficacy and drug content of samples were24.57%and1.08 (S1), 29.70%and1.50 (S2), 56.68%and3.89 (S3) and44.10%and2.04 µg 5‐FU/mg nanoparticles (S4). The experimental results suggest that thetemperatureincreaseduringthesynthesiswillresultinproductionofsmallerparticleswithhigherdrugloadingefficiency.Also,higher5‐FUloadingwasobservedwhentheactive substance was added at the start of hydrolysis process. Dissolution studiesrevealedsimilarpHdependentdrugreleasebehavior(fasterreleaserateatpH7.4)inall prepared formulations, starting with an initial burst release phase which wasfollowed by controlled release of the encapsulated drug. The investigated sol‐gelprocess parameters can affect the critical formulation attributes and should beconsideredassignificantfactorsinfurtheroptimizationstudies.

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COMPARATIVEDRUGRELEASESTUDIESOFOXALIPLATINLOADED

ORMOSILNANOPARTICLES

BetiDjurdjic1,KaterinaGoracinova2,3,NikolaGeskovski2,BobanMugosa4

1DepartmentofPharmacy,UniversityofMontenegro‐FacultyofMedicine(Montenegro),2UniversitySsCyrilandMethodius‐FacultyofPharmacy,Skopje(Macedonia),3QatarUniversity‐CollegeofPharmacy,Doha(Qatar),4Institute

ofPublicHealth,Podgorica(Montenegro)

Themainpurposeof this researchwas toprepareoxaliplatin‐loadedORMOSIL

nanoparticleswith twodifferentmethods,and investigate their influenceonthedrugreleasebehavior.

ORMOSIL nanoparticles were prepared at elevated temperature by one‐stepacid‐catalyzed hydrolysis using two different approaches: the addition of tetraethyl‐orthosilicate and 3‐aminopropyltriethoxysilane together at the beginning of thehydrolysis process (co‐condensation method) (formulation F1) or with post‐modification (adding 3‐aminopropyltriethoxysilane in hydrolised silica sol)(formulation F2). Nanoparticles size and drug loading were determined and drugreleasestudiesunderdifferentpHconditions (0.1MHClpH1.2andphosphatebufferpH 7.4) were performed. Kinetic parameters were obtained by mathematicalprocessingofthedrugreleasedatawithDDSolverusingdifferentmodels(zero‐order,first‐order,Higuchi,Korsmeyer‐Peppas).

The particle size distribution of the prepared nanoparticles appeared asunimodal with average particle sizes 151 nm (F1) and 163 nm (F2). The content ofoxaliplatinwas1.53µg/mg(35.78EE%) forF1and3.42µg/mgnanoparticles(53.17EE%) forF2.Thedifferentmethodsoforganicmodificationresulted inproductionofnanoparticles with different matrix structure, hydrophilicity and porosity. Theformulation prepared with co‐condensation method presented lower encapsulationefficiency and faster release rate of oxaliplatin, relative to the formulation producedusing post‐modification method. The drug release data showed the best fit toKorsmeyer‐Peppasequation: r2were0.9932and0.9892 (F1)and0.9865and0.9870(F2)atpH1.2andpH7.4, respectively.Obtainednvalues forsamplesF1(0.291and0.230) and samples F2 (0.249 and 0.076) at pH 1.2 and 7.4, respectively pointed todiffusiongoverneddrugreleasefromporousmaterial.Ourstudydemonstratedthatthepreparationmethodcouldaffect the internal structureof theORMOSILnanoparticlesresulting in significant differences in the encapsulation efficiency and release rate ofoxaliplatin.

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PRELIMINARNOPRAĆENJEFIZIČKESTABILNOSTINANOSUSPENZIJA

KURKUMINADOBIJENIHTOP‐DOWNMETODOM

MilicaTodorović,InesNikolić,JelenaĐoković,SnežanaSavić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Uprkos brojnim prednostima nanosuspenzija, nanometarska veličina čestica

dovodi do povećanja slobodne površinske energije, koje je izvor inheretne fizičkenestabilnosti sistema. Kako bi se ovo preveniralo, koriste se različiti stabilizatori(polimeri, surfaktanti ili njihove kombinacije). Međutim, upotreba surfaktanata sepovezuje sa brojnim problemima (narušavanje kristalne rešetke, kompatibilnost sapredviđenim putem primene…). Stoga je cilj ovog rada preliminarno ispitivanjestabilizacionog potencijala odabranih ekscipijenasa u formulaciji nanosuspenzija sakurkuminom (CUR) kao model aktivnom supstancom (niska rastvorljivost ipermeabilnost).

Primarna disperzija je dobijena dispergovanjem kurkumina i stabilizatora(polisorbat 80 i Poloksamer 188 (1:1 m/m) ili PVP K25 ili PVP K30) uvisokoprečišćenoj vodi uz pomoć rotor‐stator homogenizatora (Ultra‐Turrax T25).Gruba disperzija je potom preneta u mikrotube sa kuglicama cirkonijum‐oksida(medijum za usitnjavanje). Dalje smanjenje veličine čestica je postignuto uz pomoććelijskogdisraptora (DisruptorGenie). Veličina i polidisperzni indeks (PDI) čestica suodređenimetodomfotonkorelacionespektroskopije(ZetasizerNanoZS90),pričemusumerenjavršena24h,7i30dananakonizradenanosuspenzije.

Nakon celokupnog perioda praćenja, nanosuspenzije sa odnosom CUR istabilizatora2,5:1(m/m)nisupokazalestatističkiznačajnopovećanjeveličinečesticaipromenu PDI (Repeated measures ANOVA, IBM SPSS statistics 23). Dobijeni opsegveličina čestica se kreće od 129,5 do 191,3 nm, a PDI između 0,155 i 0,263. Ukombinaciji polisorbata 80 i Poloksamera 188 su dobijene čestice najmanje veličine(129,5 – 148,6 nm), dok su kod nanosuspenzija stabilizovanih povidonima dobijeneznatnovećečestice(162–171,9nm,PVPK30,odnosno177,6–191,3nmPVPK25)uzniževrednostiPDI(0,15‐0,25)priidentičnimuslovimamlevenja(brojidužinatrajanjaciklusa).

Pored odnosa CUR/stabilizator i uticajamehaničkog stresa, pokazano je da naveličinu i distribuciju veličine čestica utiče i tip stabilizatora. Dalja ispitivanja ćepokazati da li je došlo do izmena u kristalnoj strukturi tokommlevenja i eventualniuticajpolimeranatakvepojave.

623

PRELIMINARYMONITORINGOFCURCUMINNANOSUSPENSIONPHYSICALSTABILITYPRODUCEDBYTOP‐DOWNMETHOD

MilicaTodorović,InesNikolić,JelenaĐoković,SnežanaSavić

DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Despite the advantages of nanosuspensions, particle nanonisation leads to

significant increase of free superficial energy, which is intrinsic source of systeminstability. To prevent this, different stabilizers are used. However, the use ofsurfactants is related to various issues (crystal structure deterioration, route ofadministrationcompatibility…).Theaimofthispaperispreliminarystabilityscreeningofcurcumin(CUR, lowsolubilityandpermeability)nanosuspensions formulatedwithdifferentexcipients.

The primary dispersion was obtained by dispersing curcumin and stabilizers(polysorbate 80 and Poloxamer 188 (1:1 m/m) or PVP K25 or PVP K30) in highlypurified water by using rotor‐stator homogenizer (Ultra‐Turrax T25). The coarsedispersion was transferred into microtubes with zirconia‐oxide beads (millingmedium). The further diminution of particles was accomplished by cell disruptor(DisruptorGenie).SizeandPDIweredeterminedbyphotoncorrelationspectroscopy(ZetasizerNanoZS90)24h,sevenandthirtydaysafternanosuspensionpreparation.

Throughout the whole monitoring period, nanosuspensions with CUR tostabilizerratio2.5:1(m/m)didnotshowthestatisticallysignificantincreaseinparticlesizeandchangesinPDI(RepeatedmeasuresANOVA,IBMSPSSstatistics23).Obtainedparticle size rangewas from129.5 to 191.3 nm,with PDI between 0.155 and 0.263.Nanosuspensionwith amixtureof Polysorbate80 andPoloxamer188 as a stabilizershowed the smallest particle size (129.5 – 148.6 nm) in comparison with othernanosuspensions.PVPK30andPVPK25showedsignificantlylargerparticlesize(162–171.9nmand177.6–191.3nm,respectively),butwithsmallerPDIvalues(0.15‐0.25)underidenticalgrindingconditions(number/durationofthecycles).

Besides CUR/stabilizer ratio andmechanical stress, these resultsmay indicatethat particle size anddistributionmaybe affected by stabilizer type. Further studieswillshowwhethertherehavebeenchangesinthecrystallinestructureduringgrindingandthepossibleimpactofthestabilizeronsuchoccurrences.

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NANOSTRUKTURIRANELIPIDNENANOČESTICEKAOPOTENCIJALNI

NOSAČIDK‐I‐60‐3:PREFORMULACIONAIFORMULACIONAISTRAŽIVANJA

JelenaMitrović1,JelenaĐoković1,VladimirDobričić2,BojanČalija1,

PredragVulić3,MiroslavSavić4,SnežanaSavić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Katedrazafarmaceutskuhemiju,Univerzitetu

Beogradu–Farmaceutskifakultet,3Katedrazamineralogiju,UniverzitetuBeogradu–Rudarsko‐geološkifakultet,4Katedrazafarmakologiju,Univerzitet

uBeogradu–Farmaceutskifakultet(Srbija)

Pirazolohinoloni, ligandi za GABAa receptore, proučavaju se za terapijuneuropsihijatrijskih oboljenja. Za isporuku u mozak slabo rastvorljivih lekovitihsupstanci intenzivno se razvijaju lipidne nanočestice. Cilj istraživanja je ispitivanjerastvorljivosti DK‐I‐60‐3 u tečnim i čvrstim lipidima i izrada nanostrukturiranihlipidnihnosača(NLC)homogenizacijompodvisokimpritiskom.

Rastvorljivost DK‐I‐60‐3 u uljima određivana je shake‐flask metodom ianaliziranaLC‐MS/MSmetodom.SmešeSoftisan154itrigliceridasrednjedužinelanca(MCT)(1:4,2:3,1:1,3:2,3:7,4:1)iSoftisan154,MCTiDK‐I‐60‐3sarazličitimodnosimačvrstog i tečnog lipida (3:2, 3:7) i udelom DK‐I‐60‐3 (1%, 5%) analizirane sudiferencijalnomskenirajućomkalorimetrijom(DSC)idifrakcijomX‐zraka.FormulacijeNLCsa10%lipidnefaze(čvrst:tečanlipid1:1,3:2,3:7)stabilizovanepolisorbatom80(2%) izrađene su homogenizacijom pod visokim pritiskom (60°C, 10 ciklusa).Uzorkovanjasuvršenanakonsvakogciklusahomogenizacije.Nakonizradeodređivanisu veličina čestica (Z‐ave) i indeks polidisperznosti (PDI). U cilju ispitivanja uticajaprocesnih parametara na Z‐ave i PDI varirani su pritisak homogenizacije (500 i 800bar)ihlađenjenakonhomogenizacije(sobnatemperaturailedenokupatilo).

DK‐I‐60‐3 je slabo rastvorljiv u uljima (MCT 0,046 mg/ml, sojino ulje 0,048mg/ml, ricinusovo ulje 1,244 mg/ml). Ipak, DSC rezultati ukazuju na delimičnusolubilizacijuDK‐I‐60‐3usmešamalipida,doksutemperaturetopljenjasvihispitivanihsmeša ostale iznad 40°C. Izrađene NLC su bile tečne, mlečno bele, sa plavičastimodsjajem. Formulacije izrađene pod višimpritiskom i hlađene na sobnoj temperaturiimalesunižeZ‐ave.Veličinačesticasepovećavalasapovećanjemudelauljaulipidnommatriksu.Nakon5ciklusahomogenizacijesveformulacijesuimaleZ‐ave180‐210nmiPDI0,100‐0,161,adaljomhomogenizacijomnisuseznačajnomenjalioviparametri.

NLC semoguproučavati kaonosačiDK‐I‐60‐3 i homogenizacijompodvisokimpritiskom (60°C, 800 bar, 5 ciklusa) mogu se dobiti NLC zadovoljavajućihfizičkohemijskihkarakteristika.

625

NANOSTRUCTUREDLIPIDNANOPARTICLESASPOTENTIAL

CARRIERSFORDK‐I‐60‐3:PREFORMULATIONANDFORMULATIONSTUDIES

JelenaMitrović1,JelenaĐoković1,VladimirDobričić2,BojanČalija1,

PredragVulić3,MiroslavSavić4,SnežanaSavić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofPharmaceuticalChemistry,

UniversityofBeograde–FacultyofPharmacy,3ChairofMineralogy,UniversityofBeograde–FacultyofMiningandGeology,4DepartmentofPharmacology,

UniversityofBeograde–FacultyofPharmacy(Serbia) Pyrazoloquinolinones, GABAa receptor ligands, are investigated for

neuropsychiatricdisorderstreatment.Forbraindeliveryofpoorlysolubleactives,lipidnanoparticles are intensively developed. The aimwas DK‐I‐60‐3 solubility testing inliquid and solid lipids and nanostructured lipid carriers (NLC) preparation by highpressurehomogenization.

DK‐I‐60‐3solubilityinoilswasinvestigatedbyshake‐flaskmethodandanalyzedbyLC‐MS/MSmethod.MixturesofSoftisan154andmediumchaintriglycerides(MCT)(1:4, 2:3, 1:1, 3:2, 3:7, 4:1) and Softisan 154, MCT and DK‐I‐60‐3 with differentsolid:liquid lipid ratio (3:2, 3:7) and DK‐I‐60‐3 content (1%, 5%) were analyzed bydifferentialscanningcalorimetry(DSC)andX‐raydiffraction.NLCwith10%lipidphase(solid:liquidlipidratio1:1,3:2i3:7),stabilizedbypolysorbate80(2%)werepreparedby high pressure homogenization (60°C, 10 cycles). Samples were taken after everyhomogenizationcycle.Afterwardsparticlesize(Z‐ave)andpolydispersity index(PDI)were determined. In order to investigate process parameters influence on Z‐ave andPDI, homogenization pressure (500 and 800 bar) and cooling after homogenization(roomtemperatureandicebath)werevaried.

DK‐I‐60‐3ispoorlysolubleinoils(MCT0.046mg/ml,Soybeanoil0.048mg/ml,Castoroil1.244mg/ml).However,DSCresults indicatepartial solubilizationofDK‐I‐60‐3inlipidmixtures,whilemeltingtemperatureofallinvestigatedmixturesremainedabove 40°C. After preparation, NLC were liquid, milky‐white, with bluish reflection.Formulations prepared under higher pressure and cooled at room temperature hadlowerZ‐ave. Particle sizewas increasedby increasing the oil content in lipidmatrix.After5homogenizationcycles,allformulationshadZ‐ave180‐210nmandPDI0.100‐0.161,furtherhomogenizationdidn’tsignificantlychangetheseparameters.

NLC could be investigated as carriers for DK‐I‐60‐3 and by high pressurehomogenization (60°C, 800 bar, 5 cycles) NLC with satisfying physicochemicalcharacteristicscouldbeobtained.

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Arh.farm 2018;68: 626-627 FTK-P36

PEG‐ILOVANENANOEMULZIJE:UTICAJINKORPORACIJE

KURKUMINAIIZBORAPROCESASTERILIZACIJENAFIZIČKO‐HEMIJSKEPERFORMANSE

JelenaĐoković1,SanelaSavić2,JelenaMitrović1,

DorotaWatrobska‐Swietlikowska3,SnežanaSavić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2DCPHemigal,Leskovac(Srbija),3Katedrazafarmaceutskutehnologiju,MedicinskiUniverzitetuGdanjsku(Poljska)

U cilju povećanja rastvorljivosti i biološke raspoloživosti kurkumina (K),

razvijene sunanoemulzije sakurkuminom (KNE).PEG‐ilovani fosfolipidi (PEG‐FL) sudodatiradiproduženjavremenacirkulacijenanoemulzionih(NE)kapi.Ciljovestudijeje procena uticaja dodavanja kurkumina u formulaciju i procesa sterilizacije ‐autoklaviranja ili aseptične filtracije na fizičkohemijske karakteristike (veličinu kapi izetapotencijal)NE,PEG‐ilovanihine‐PEG‐ilovanih.

NE su pripremljenemetodom homogenizacije pod visokim pritiskom na 50°C.Masna faza (sojino ulje, benzil alkohol, trigliceridi srednje dužine lanca, lecitin soje ibutilhidroksitoluen) je dodatau vodenu fazu (glicerol, polisorbat 80, natrijumoleat ivisokoprečišćenavoda)ihomogenizovananahomogenizatorupodvisokimpritiskom10 ciklusa na 800 bara (EmulsiFlex‐C3, Avestin Inc., Canada). PEG‐FL: PEG2000‐DSPE/PEG5000‐DPPE, su dodati u masnu ili u vodenu fazu u koncentraciji od0,1%/0,3%.KodKNE,K jeprvorastvorenubenzil alkoholu,apotomdodatumasnufazu.NakonizradesveNEsubilefiltriranekrozmembranskifilterdimenzijapora0,22µm, a placebo nanoemulzije (bez kurkumina) su bile autoklavirane (121°C; 15min).Izmerenajeveličinakapi(Z‐Ave,d10,d50,d100), indekspolidisperznosti(PDI) izetapotencijal.

Veličina kapi (Z‐Ave) svih nanoemulzija je bila od 101 do 108 nm, što jepotvrđenolaserskomdifrakcijom‐vrednostd50zasveformulacijesenalazilauopseguod105do113nm.Nijeuočenoprisustvovećihkapi.PDI jebiomanjiod0,15,azetapotencijalnižiod‐40mV,štodokazujedasusverazvijeneNEpogodnezaparenteralnuprimenu.

Merenjaveličinekapiizetapotencijalasupokazaladanepostojiznačajnarazlikaizmeđu PEG‐ilovanih i ne PEG‐ilovanih NE bilo da sadrže kurkumin ili ne, da li suautoklavirane, filtrirane ilinesterilisane, štoznačidaPEG‐ilovanenanoemulzijemogudabudusterilisaneili/iimsemožedodatikurkuminbeznarušavanjafizičko‐hemijskestabilnostisistema.

627

PEG‐YLATEDNANOEMULSIONS:CURCUMINLOADINGANDSTERILIZATIONPROCESSIMPACTONPHYSICOCHEMICAL

PERFORMANCE

JelenaĐoković1,SanelaSavić2,JelenaMitrović1,DorotaWatrobska‐Swietlikowska3,SnežanaSavić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,Universityof

Belgrade‐FacultyofPharmacy,2DCPHemigal,Leskovac(Serbia),3DepartmentofPharmaceuticalTechnology,MedicalUniversityofGdansk(Poland)

In order to increase solubility and bioavaibility of curcumin (C), C‐loaded

nanoemulsions (CNEs) were developed. PEG‐ylated phospholipids (PEG‐PLs) wereaddedtoprolongthecirculation timeofnanoemulsion(NE)droplets.Theaimof thisstudywas toassess the impactofC‐loadingandsterilizationprocess ‐autoclavingoraseptic filtration on the NEs physicochemical characteristics (droplet size and zetapotential),bothPEG‐ylatedandnon‐PEG‐ylated.

NEswerepreparedbyhighpressurehomogenizationmethodat50°C.Oilphase(soybean oil, benzyl alcohol, medium chain triglycerides, soybean lecithin andbutylhydroxytoluene) was added to water phase (glycerol, polysorbate 80, sodiumoleate and highly purifiedwater) and homogenizedwith high‐pressure homogenizer(EmulsiFlex‐C3, Avestin Inc., Canada) for 10 cycles at 800 bar. PEG‐PLs – PEG2000‐DSPE/PEG5000‐DPPE, were added to the oil or water phase at 0,1%/0,3%concentration.ForCNEs,Cwasfirstdissolvedinbenzylalcohol,andthenaddedintooilphase.Afterpreparation, allNEswere filtered through0,22µmmembrane filter andplacebo nanoemulsions – without curcumin were autoclaved (121°C; 15 min). NEdropletsize(Z‐Ave,d10,d50,d100),polydispersityindex(PDI)andzetapotentialweremeasured.

Mean droplet size (Z‐Ave) of all NEs (C‐loaded and placebo, non‐sterilized,autoclavedandfiltered)wasintherangeof101–108nm,confirmedbylaserdiffractionmeasurements ‐ d50 values for all formulations was between 105 and 113 nm. Nolargerdropletsweredetected.PDIwasbelow0.15andZPbelow‐40mV,suggestingthatalldevelopedNEsweresuitableforparenteraluse.

Droplets size/PDI and zeta potential measurements showed no significantdifference between PEG‐ylated and non‐PEG‐ylated NEs, both with and withoutcurcumin,autoclaved,filteredornon‐sterilized,whichmeansthatPEG‐ylatedNEscanbesterilizedand/orcurcuminloadedwithoutcompromisingphysicochemicalstabilityofthesystem.

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Arh.farm 2018;68: 628-629 FTK-P37

ISPITIVANJEUTICAJALEVANANALIBERACIONEISENZORNE

PROFILELEKOVAZAPRIMENUNAKOŽI

IvanaPantelić1,MilicaLukić1,GordanaGojgić‐Cvijović2,SnežanaSavić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Centarzahemiju,IHTM,UniverzitetuBeogradu(Srbija)

Od savremenih farmaceutskih ekscipijenasa sve češće se očekuje da daju i

izvestandoprinospoboljšanjuadherence.Egzopolisaharidipoput levanapredstavljajuobećavajućugrupumaterijalaprirodnogporekla,sabrojnimanticipiranimulogamaodkojih se najčešće ističe stvaranje kontinuiranog filma na mestu nanošenja, koji biomogućiomanječestuprimenuleka,pasledstvenoiboljuadherencu.Ipak,uticajovogsloženogfruktananasenzornekarakteristikelekovajošuveknijerazmatran.

Primenom imerzionih ćelija ispitan je uticaj dodatka levana velikemolekulskemase na profile oslobađanja ketoprofena i diklofenak‐dietilamina, kao model lekovarazličitih karakteristika (rastvorljivost, amfifilnost, termodinamička aktivnost).Dodatak levana u emulzione sisteme variran je na 4 nivoa (0/0,2/1/3% m/m), uzistovremenuvarijacijuvrsteprimarnogstabilizatorasistema(nejonski/anjonski).Uztosprovedenajeipreliminarnasenzornaanalizauzorakasa0,2%levanaupoređenjusauzorcimabezlevanaiuzorcimaukojimajelevanzamenjenksantangumom.

Preliminarni skrining fizičko‐hemijskih osobina levana potvrdio je neutralnupriroduovogbiopolimera,koganeodlikujesposobnostbubrenjaprilikomobrazovanjaveomatankogfilmanapovršinikože. Izračunavanjesaturacionihkoncentracijamodellekova u ispitivanim uzorcima pokazalo je da je inicijalna koncentracija leka u filmumnogo veća od njegove rastvorljivosti u podlozi. Na taj način potvrđeni su osnovnipreduslovizaprimenuHigučijevejednačinekaoprihvaćenogpokazateljakontrolisaneisporuke lekovitih supstanci iz polučvrstih preparata za primenu na koži. Uporednaanalizavrednostifluksaikumulativnekoličineoslobođenoglekaukazalajenarazličiteoptimalne koncentracije levana shodno prirodi osnovnog stabilizatora sistema: 1%levana u slučaju anjonskog, a 0,2% u slučaju nejonskog mešanog emulgatora. Osimblagoguticajanabojuuzoraka,dodataklevananijeznačajnouticaonanjihovinicijalnisenzorniprofil.Odposebnogznačajajeizostanakuticajalevananalepljivostuzorka,štojepoznatnedostatakprimeneksantangume.

Dobijenirezultatiukazujunapotencijalprimenelevanakaomultifunkcionalnogekscipijensasadirektnimuticajemnapoboljšanjeadherencekodlekovazaprimenunakoži.

629

INVESTIGATIONOFLEVAN’SINFLUENCEONRELEASEANDSENSORY

PROFILESOFTOPICALDRUGS

IvanaPantelić1,MilicaLukić1,GordanaGojgić‐Cvijović2,SnežanaSavić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofChemistry,IHTM,Universityof

Belgrade(Serbia)

Apart from their basic function(s), novel pharmaceutical excipients should

preferably also improve adherence. Exopolysaccharides such as levan represent apromising group of natural‐origin materials, with numerous anticipated functions.Amongthose,theirfilm‐formingcapacityisusuallystressed,sinceitcouldenablelessfrequentdrugapplicationand,hence,betteradherence.However,theinfluenceofthiscomplexfructanonsensorycharacteristicsoftopicaldrugshasnotbeenaddressedyet.

Immersion cells were used to assess the influence of high‐molecular levan onketoprofenanddiclofenac‐diethylaminereleaseprofiles,beingmodeldrugsofdiverseproperties(solubility,amphiphilicity,thermodynamicactivity).Theadditionoflevantoemulsion systems was varied in 4 levels (0/0.2/1/3%m/m), with alteration of theprimarysystemstabilizertype(non‐ionic/anionic).Additionally,apreliminarysensorystudy of samples with and without 0.2% levan was performed, and compared tocorrespondingxanthangumsamples.

Preliminary screening of levan’s physicochemical properties confirmed theneutralnatureofthisbiopolymer,withnoswellingphasewhilegeneratingaverythinfilm.Saturationconcentrationsofthemodeldrugsintheinvestigatedsamplesshowedthattheinitialdrugconcentrationinthefilmismuchhigherthandrugsolubilityinthebase.Thus,fundamentalprerequisitesfortheapplicationoftheHiguchiequationweremet,allowingforthequantificationofthecontrolleddrugrelease.Comparativeanalysisof flux and cumulative amounts of drug released indicated different optimal levanconcentrations relative to the nature of the primary system stabilizer: 1% levan foranionic,and0.2%fornon‐ionicmixedemulsifier.Apartfromaslight influenceonthesamples’colour,theadditionoflevandidnotsignificantlychangetheirinitialsensoryprofile. The absence of levan’s contribution to sample stickiness was of specialimportance,sincethisisaknowndrawbackofxanthangum.Theobtainedresultsrevealthe potential use of levan as a multifunctional excipient with direct influence onimprovingadherencetotopicaldrugs.

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Arh.farm 2018;68: 630-631 FTK-P38

ISPITIVANJEUTICAJALEVANAKAOPOTENCIJALNOG

MULTIFUNKCIONALNOGEKSCIPIJENSANAPROFILOSLOBAĐANJASALICILNEKISELINEIZEMULZIONOGSISTEMATIPAKREMA

MilicaLukić,InesNikolić,IvanaPantelić,SnežanaSavić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

U skladu sa aktuelnim ispitivanjima mogućnosti primene sirovina prirodnog

porekla kao multifunkcionalnih sastojaka u razvoju farmaceutskih i kozmetičkihnosača, posebnu pažnju brojnih istraživača privlači levan. Ovaj biopolisaharidinteresantan je i kao aktivna supstanca i kao funkcionalni ekscipijens/kozmetičkisastojak.Saciljemdaseupotpunenašaprethodnaistraživanja,uovojstudiji ispitivalismo uticaj prisustva levana na profile oslobađanja salicilne kiseline (SK) iz kremovakojisustabilizovanitečno‐kristalnimlamelarnimfazama.

Izrađenasu4uzorkakrema:placebo,kremsa1%levana,kremsa2%SKikremsa 2% SK i 1% levana. Pored inicijalne fizičko‐hemijske karakterizacije primenompolarizacione mikroskopije i merenja pH, provodljivosti i kontinualnog reološkogponašanja, sprovedeno je i in vitro ispitivanje liberacionih profila SK, primenomdvatipadifuzionihćelija:Franz‐ovaiVanKel‐ovaimerzionaćelija.

Dodatak levana i SK nije uticao na specifičnu strukturu krema. Sam levan nijeznačajnouticaonapromenupHvrednostiiprovodljivostiniplacebanikremasaSK,alijepovećaonjihoveviskoziteteihistereznepovršine.LiberacioniprofilikremovasaSKnezavisno od prisustva levana prate Higuchi‐evu kinetiku oslobađanja, ali se SK uprisustvu levana otpušta postepeno, beležeći manje vrednosti permeacionogkoeficijenta(189g/cm2/hi201g/cm2/h). Iako ječinjenicadaugušćivanjesistemazaposledicu ima sporije oslobađanje aktivne supstance, za tačno razumevanje uticajaprisutnog levananabrzinuoslobađanjaneophodnasudodatna istraživanjavezanazanjegovdoprinosspecifičnojstrukturi.

Kroz sprovedeni set eksperimenata pokazano je da levan ne samo da utiče nastabilizaciju iaplikativnasvojstvarazvijenihkremova,većmožemodifikovatikinetikuoslobađanja model supstance. To ga zajedno sa njegovim prirodnim poreklom ibiodegradabilnošćučiniatraktivnimmultifunkcionalnimekscipijensom.

631

LEVANASMULTIFUNCTIONALINGREDIENTANDITSINFLUENCEONLIBERATIONPROFILEOFSALICYLICACIDFROMEMULSIONSYSTEM

OFCREAMTYPE

MilicaLukić,InesNikolić,IvanaPantelić,SnežanaSavić

DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Inaccordancewiththeactualinvestigationsrelatedtotheuseofsubstanceswithnatural origin as multifunctional ingredients in development of pharmaceutical orcosmetic vehicles, levan is gaining special attention. This biopolysaccharide isinteresting as an active substance as well as the functional excipient/cosmeticingredient. In this study we have investigated the influence of levan on liberationprofiles of salicylic acid (SA) which was incorporated in creams stabilized with thespecificliquid‐crystallinelamellarphases.

Four cream sampleswere prepared: placebo sample, creamwith 1%of levan,creamwith2%ofSAandcreamwith2%ofSAand1%of levan.Besidethephysical‐chemical characterization performed using polarization microscopy, pH andconductivitymeasurementsandcontinualrheology, invitroscreeningofmodeldrugsliberationprofileswasperformedwiththeuseoftwotypesofdiffusioncells:FranzandVanKelimmersioncell.

Additionof levanandSAdidnotalter thespecificstructureofplacebosample.AlthoughlevandidnotsignificantlyinfluencethepHandconductivityvaluesofplaceboandcreamwithSA, itdid inducean increase inviscosityandhysteresisareasofbothcreams.LiberationprofilesofcreamswithSA,regardlesstothelevanpresence,followthe Higuchi liberation kinetics. But, with the levan in cream the release of SA wasretarded,andobtainedpermeationcoefficientswerelowercomparedtocreamwithoutlevan(189g/cm2/hand201g/cm2/h).Althoughthickeninginducesretardedliberationofanactivesubstance,additionalinvestigationregardingtheinfluenceoflevanonthespecificsystem'sstructureisnecessary.

Throughthepreformedsetofexperimentsitwasshownthatlevancanbeusedas stabilizer and rheology modifier of developed creams, but it also can modify theliberationkineticof themodel substance.Thismakes levan, togetherwith itsnaturaloriginandbiodegradability,anattractivemultifunctionalexcipient.

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Arh.farm 2018;68: 632-633 FTK-P39

NISKOENERGETSKENANOEMULZIJESAULJEMSEMENKIMALINEIANTIOKSIDANTNIMEKSTRAKTIMA–OPTIMIZACIJAFORMULACIJE,

STUKTURNAIREOLOŠKAISPITIVANJA

AnaGledović1,VeljkoKrstonošić2,InesNikolić1,DanijelaRanđelović3,JelenaĐoković1,SanelaSavić4,SnežanaSavić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐

Farmaceutskifakultet,2Katedrazafarmaciju,UniverzitetuNovomSadu‐Medicinskifakultet,3Centarzamikroelektronsketehnologije‐ICTM,

UniverzitetuBeogradu,4DCPHemigal,Leskovac(Srbija)

Plodmaline je bogat izvor kozmetički aktivnih sastojaka: ulje semenkimaline

(RO)poznatojepovisokojzastupljenostipolinezasićenihmasnihkiselina,tokoferolaitokotrienola,aekstraktplodamalinesadržiantioksidanse(tanine,vitaminC)išećere.Niskoenergetske nanoemulzije (NE) formulisane su u cilju očuvanja stabilnosti iaktivnosti prirodnih sastojaka upotrebom metode inverzije faza (EPI) na sobnojtemperaturi. Takođe, izvršena je i karakterizacija tranzicione gel faze kao kritičnemeđufazeuprocesunastankaNE.

NEsuizrađenetitracijomrazličitihsmešapolisorbata80−surfaktant, tokoferilacetata−kostabilizatoriorganskogRO(hladnoceđenouljeiliCO2ekstrakt)vodenomfazomsadodatimkosurfaktantima(glicerolilivodeno‐glikolniekstraktplodamaline/francuskog hrasta). Karakterizacija prelaznih gel faza izvršena je vizuelno,polarizacionim (PLM) i optičkim mikroskopom (OM), merenjem provodljivosti ioscilatornim reološkim merenjima. Odgovarajuće NE okarakterisane su vizuelno,merenjem veličine kapi i polidisperznog indeksa (PDI) upotrebom foton korelacionesprektroskopije (PCS) i laserske difrakcije (LD), PLM i OM,mikroskopijom atomskihsila (AFM), merenjem pH vrednosti i provodljivosti kao i kontinualnim reološkimmerenjima.

PLM i OM mikroskopija potvrdile su prisustvo izotropne gel međufaze, aviskoelastičniparametri(G’,G’’,kompleksniviskozitet)istovremenoukazujunakubnutečno‐kristalnustrukturugela;odgovarajućeNEnastaleizovihgelfazaponašajusekaoNjutnovske tečnosti. IakosuNE imalepoželjnuveličinukapi (130do150nm iPDI≤0.1)PLMiOMsudetektovalevelikeaglomerate(do20µm)uNEsaROCO2doksuNEsa hladno ceđenimRO imaleponeki aglomerat (do2µm).AFM je pokazala razlikuutopografijiiveličinamauljanihkapiNEizrađenihsarazličitimROiotkrilajedasukapinepravilnogoblika.

Različitemikroskopsketehnikesupokazaledajeizborsirovina(tipauljamaline)od ključnog značaja za dobijanje stabilnih NE odgovarajućih karakteristika. Reološkaispitivanjaposlužilasuurasvetljavanjustruktureveomaviskoznekubnegelfaze.

633

LOWENERGYNANOEMULSIONSWITHREDRASPBERRYSEEDOILANDANTIOXIDANTEXTRACTS–FORMULATIONOPTIMIZATION,

STRUCTURALANDRHEOLOGICALINVESTIGATIONS

AnaGledović1,VeljkoKrstonošić2,InesNikolić1,DanijelaRanđelović3,JelenaĐoković1,SanelaSavić4,SnežanaSavić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofPharmacy,UniversityofNoviSad‐FacultyofMedicine,3InstituteofMicroelectronicTechnologies‐ICTM,

UniversityofBelgrade,4DCPHemigal,Leskovac(Serbia) Redraspberryfruitisarichsourceofvaluablecosmeticactives:seedoil(RO)is

known for high content of polyunsaturated fatty acids, tocopherols and tocotrienols,while fruit extract contains antioxidants (tannins, vitamin C) and sugars. In order tokeep the stability and activity of natural ingredients we developed low energynanoemulsions (LE NEs) by using Emulsion Phase Inversion (EPI) method at roomtemperature. We also characterized transient gel phase as crucial phase in NEformationprocess.

NEswerepreparedbytitratingdifferentmixturesofPolysorbate80−surfactant,Tocopheryl acetate – co‐stabilizer andorganicRO (coldpressedorCO2 extract)withthewaterphase(withcosurfactants:glycerol,orhydro‐glycolicraspberryfruit/Frenchoakfruitextracts).Transientgelphaseswerecharacterizedvisually,bypolarizedlight(PLM) and optical microscopy (OM), conductivity and oscillatory rheologicalmeasurements. The corresponding NEs were characterized visually;droplet size andpolydispersity index (PDI)weremeasured by photon correlation spectroscopy (PCS)and laser diffraction (LD), PLM and OM, atomic force microscopy (AFM), pH,conductivity,andcontinualrheologicalmeasurements.

Microscopy (PLM, OM) confirmed the presence of isotropic gel phase whileviscoelasticparameters(G’,G’’,complexviscosity)alsoindicatecubicliquidcrystallinegel structure; the corresponding NEs have flow characteristics of Newtonian fluids.AlthoughNEshaddropletsizesfrom130to150nmandPDIvalues≤0.1,PLMandOMdetected large agglomerates (up to 20 µm) inNEs preparedwithROCO2,whileNEswithROcoldpressedhadafewagglomerates(upto2µm).AFMshowedthedifferenceintopographyandsizesofoildropletsinNEspreparedwithdifferentROandrevealedtheirnon‐sphericalshape.

Different microscopic techniques revealed that raspberry oil type had crucialimpact on NE properties and stability. Rheological investigations were useful toelucidatethestructureofveryviscouscubicgelphase.

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Arh.farm 2018;68: 634-635 FTK-P40

RASTVORLJIVEMIKROIGLE–FIZIČKIINHENSERIDERMALNE

ISPORUKEANTIFUNGALNOGLIJEKA

NatašaBubićPajić1,SonjaVučen2,SnežanaSavić3

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBanjojLuci‐Medicinskifakultet(BosnaiHercegovina),2Farmaceutskifakultet‐UniverzitetuKorku(Irska),3Katedrazafarmaceutskutehnologijui

kozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Efikasnost terapije gljivičnih infekcija kože zavisi odpotencijala formulacijeda

isporučiefektivnukoličinu lijekaudubljeslojevekože,naročitouvijabilniepidermis.Rastvorljivemikroigle, kao fizički inhenseripenetracije, omogućuju isporuku lijeka iliformulacije aktivne supstance direktno u/kroz kožu. Cilj ovog rada je formulacijarastvorljivih mikroigala zasnovanih na niskomolekularnom polivinilpirolidonu(Kollidon17PF),kaonosačazadermalnuisporukuantifungalnoglijeka‐sertakonazol‐nitrata.

Izrada je vršenametodompunjenja silikonskih kalupa (na kojima je niz od25mikroigala visine 500 µm na 1 cm2) tečnom formulacijom nakon čega su kalupistavljaniuvakuum.Kalupikojisukorištenizadobijanjerastvorljivihmikroigalabilisuizrađeni od polidimetilsiloksana u Nacionalnom Institutu Tyndall (Irska). U ciljuutvrđivanja optimalnih uslova za fabrikaciju punih nizova rastvorljivih mikroigalavariranajekoncentracijapolimera(5,10,20i30%m/V)ilijeka(5,25ili66,7mg/ml).Pomoću svjetlosnog mikroskopa su analizirane morfološke karakteristike (fizičkiintegritet, oblik i izgled) dobijenih rastvorljivih mikroigala i izvršena je njihovaevaluacija. Odabrana formulacija je podvrgnuta testiranju mehaničke otpornosti ibrzinerastvaranja.

Nizovi mikroigala zadovoljavajućeg kvaliteta su dobijeni kada se kao polaznimaterijal koristi lijek u koncentraciji 25 mg/ml, rastvoren u 30% (m/V) rastvorupovidona u metanolu. Zbog prisustva metanola u formulaciji, kritičan parametar uizradi je očekavano bio način sušenja mikroigala. Dobijene mikroigle su bile pune,pravilnog piramidalnog oblika, oštrih vrhova i pravilnih baza. Mehanička otpornostnizovamikroigala (4,5±0,1 N) je bila zadovoljavajuća za očekivanu inserciju u kožu.Takođe je pokazano da se dobijenemikroigle rastvaraju u potpunosti u ispitivanommedijumunakon5min.

Dobijeni rezultati ukazuju da formulisane rastvorljive mikroigle mogu da sefabrikuju i koriste kao pogodan nosač za brzu isporuku sertakonazol‐nitrata u kožu.Međutim,odgovarajućimexvivoiinvivoispitivanjimanakožijepotrebnopotvrditidajelijekisporučenuciljanomjestoukoži.

635

DISSOLVABLEMICRONEEDLES–PHYSICALENHANCERSFOR

DERMALDELIVERYOFANANTIFUNGALDRUG

NatašaBubićPajić1,SonjaVučen2,SnežanaSavić3

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBanjaLuka‐FacultyofMedicine(BosniaandHerzegovina),2Schoolof

Pharmacy‐UniversityCollegeCork(Ireland),3DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy

(Serbia)

Theefficacyofthedermalantifungaltreatmentispredominantlydependenton

the formulation's potential to deliver the effective drug concentration into deeperlayers of the skin, particularly into viable epidermis. Dissolvable microneedles, asphysicalpenetrationenhancers,aidthedeliveryofvariousdrugsdirectlyinto/throughtheskin.Theaimof thisworkwas formulationofdissolvablemicroneedlesbasedonlow molecular grade polyvinylpyrrolidone (Kollidon® 17PF, BASF, Germany) as acarrierfordermaldeliveryofanantifungaldrug–sertaconazolenitrate.

Microneedles were fabricated by filling microneedle molds with liquidformulationusingvacuum.Thedimensionsofmicroneedlesonthearraywere500µmin height at a density of 25 needles per 1 cm2. Molds were manufactured frompolydimethylsiloxane by the Tyndall National Institute (Ireland). In order to findoptimal conditions formicroneedle fabrication,polymer concentration (5,10,20 and30% w/v) and drug content (5, 25 and 66.7 mg/ml) were varied. Morphologicalcharacteristicsandmicroneedlesevaluationwereanalyzedbyusing lightmicroscopy.Theselectedformulationwassubjectedtothemechanicalstrengthtestanddissolutiontest.

Processing parameters combining povidone and the drug in concentrations of30% w/V and 25 mg/ml, respectively, produced microneedles which had completefidelitytothemastermolds.Duetothepresenceofmethanol,thecriticalparameterformicroneedle fabrication was the drying process. The obtained microneedles hadregular shape, pyramidal structure and sharp tips and were able to withstandcompressionandfractureof4.5±0.1N,suggestingasuccessfulinsertionintotheskin.Acompletedissolutionofthemicroneedleswasachievedin5min.

Our findings indicate that the dissolvable microneedles can be successfullyfabricated and used as carriers for rapid dermal delivery of sertaconazole nitrate.However, the appropriate ex vivo and in vivo skin studies are strongly required toconfirmthedrugistransportedtothetargetedskinlayers.

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Arh.farm 2018;68: 636-637 FTK-P41

POLIMER‐MUCININTERAKCIJEUOKULARNIMLUBRIKANSIMANA

BAZIPOLISAHARIDA:REOLOŠKARAZMATRANJA AnđelkaRačić1,DaninaKrajišnik2,BojanČalija2,JelaMilić2

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBanjojLuci

‐Medicinskifakultet(BosnaiHercegovina),2Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet

(Srbija)

Nedostatak konvencionalnih okularnih lubrikansa je kratkoročna kontrola

simptoma kod sindroma suvog oka. Kako bi se produžilo vreme zadržavanja iposledično delovanje primenjenog preparata, razvijeni su viskozni oftalmološkivehikulumi koji sadrže mukadhezivne polimere. Cilj ove studije je bila procenamukoadhezivnih svojstava i određivanje tipa polimer‐mucin interakcije izrađenihokularnih lubrikanasa koji sadrže hidroksipropilguar gumu (HP GG), hitozan (H) ihidroksietilcelulozu(HEC)primenomreološkeanalize.

Vodenivehikulumikojisadržehitozan(1,0%;F1),kombinacijupolimera(HPGG0,5%/H1,0%;F2)i(HPGG0,5%/HEC1,0%;F3)pomešanisuujednakimzapreminamasadisperzijomsvinjskogmucina(20%m/m).Nadobijenimsmešama(označenimkaoF1M,F2M,F3M),ukojimasukoncentracijepolimerabilejednakeonimaukojimabisekoristili u izrađenim okularnim lubrikansima, sprovedeno je ispitivanjemukoadhezivnosti primenom rotacionih reoloških merenja. Mukoadhezivnost jeizražena izračunavanjem „normalizovanog reološkog sinergizma” (Δη/η). U ciljuodređivanja tipa polimer‐mucin interakcije, sprovedena su dinamička viskoelastičnamerenja.

Svi ispitivani lubrikansipokazalisupozitivnuvrednost(Δη/η)uopsegubrzinesmicanja (50–100 s‐1), ukazujući na interakcije sa mucinom. Izračunati reološkiparamater imao jesledećiredosledvrednosti (pri100s‐1):2,24(F2M)1,85(F1M)0,63 (F3M). Vrednosti izmerenih viskoelastičnih parametara ukazale su primarno napojavufizičkogpreplitanjaizmeđupolimeraimucina(G’≤G”).Redosledvrednostitan(pri1,13Hz)bioje:1,22(F3M)1,14(F2M)0,69(F1M),ukazujućinadominantnoelastičnoponašanjedisperzijeF1M,aviševiskoznozaF2MiF3M,štoverovatnoimazaposledicuefikasnijuinterakcijuizmeđupolimeraimucina.

DisperzijaF2M, kojaodgovara izrađenomokularnom lubrikansukoji sadržiHPGG0,25%/H0,5%,pokazalajeoptimalnamukoadhezivnasvojstvanaosnovuvrednostiizračunatog normalizovanog reološkog sinergizma i celokupnog viskoelastičnogponašanja. Interakcija između polimera i mucina, utvrđena reološkomkarakterizacijom,omogućavadužikontaktlubrikansasapovršinomoka.

637

POLYMER–MUCININTERACTIONINPOLYSACCHARIDE‐BASED

OCULARLUBRICANTS:ARHEOLOGICALPOINTOFVIEW

AnđelkaRačić1,DaninaKrajišnik2,BojanČalija2,JelaMilić2

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBanjaLuka‐FacultyofMedicine(BosniaandHerzegovina),2DepartmentofPharmaceuticalTechnologyandCosmetologyUniversityofBelgrade‐Faculty

ofPharmacy(Serbia)

The limitation of conventional ocular lubricants is short duration of dry eye

symptomcontrol.Toprolongtheresidencetimeandconsequentlytheeffectofappliedpreparation, viscous ophthalmic vehicles with mucoadhesive polymers have beendeveloped.Theaimofthisstudywastoevaluatemucoadhesivepropertiesandtypeofmucin‐polymerinteractionofcompoundedocularlubricantscontaininghydroxypropylguar gum (HP GG), chitosan (CS) and hydroxyethylcellulose (HEC) by means ofrheologicalevaluation.

Aqueous vehicles containing CS (1.0%; F1), combination of polymers (HP GG0.5%/CS1.0%;F2)and(HPGG0.5%/HEC1.0%;F3)weremixedinequivalentvolumeswithporcinemucin (20%m/m)dispersion.Theobtainedmixtures(denotedasF1M,F2M,F3M),containingpolymersinconcentrationsequaltothoseinwhichtheywouldbe used in compounded ocular lubricants, were tested for mucoadhesion usingrotational rheological measurements. The mucoadhesiveness was expressed bycalculating „normalized rheological synergism” (Δη/η). To investigate the type ofpolymer‐mucininteractiondynamicviscoelasticmeasurementswereperformed.

All the tested lubricants showed positive values of (Δη/η) within shear raterange (50–100 s‐1), indicating the occurrence of an interactionwithmucin. The rankorderofcalculatedparameters(at100s‐1)was2.24(F2M)1.85(F1M)0.63(F3M).The values of viscoelastic parameters pointed on mainly physical entanglementsbetweenpolymerandmucin(G’≤G”).Therankorderof tan (at1.13Hz)was1.22(F3M)1.14(F2M)0.69(F1M),revealingdominationofelasticbehaviorforF1M,andmore viscous for F2M and F3M,which probably enables amore efficacious polymer‐mucininteraction.

The dispersion F2M corresponding to compounded ocular lubricant containingHPGG0.25%/CS0.5%, showedoptimalmucoadhesivepropertiesbasedon theΔη/ηvalues and overall viscoelastic behavior. The interaction of polymers and mucin,estimated by rheological characterization, provides longer contact time of lubricantswithocularsurface.

638

Arh.farm 2018;68: 638-639 FTK-P42

PREFORMULACIONASTUDIJASISTEMAKOJIOBRAZUJUFILMNA

POVRŠINIKOŽEKAOPROSPEKTIVNIHNOSAČALEKOVA

MirjanaTimotijević,IvanaPantelić,SnežanaSavić

Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Transportni sistemi na bazi polimera, dizajnirani kao noviji nosači lekova koji

formiraju tanak film na površini kože i obezbeđuju produženu isporuku aktivnesupstance, mogu da budu veoma pogodni za lokalnu primenu na koži i dermalnuisporukuihidrofilnihilipofilnihlekova.Ovapreformulacionastudijauključuje,različitetipovepolimerailinjihovekombinacije,poputEudragit®RS,Eudragit®NE30D,Klucel®GF u različitim koncentracijama, kombinovane sa različitim plastifikatorima,uključujućitrietilcitrat(TEC),tributilcitrat(TBC),propilenglikoliglicerol,opcionosainhenserom penetracije ili nejonskim surfaktantom (polisorbat 80) i sa različitimsistemimarastvarača.

Dobijene formulacije su procenjene u odnosu na organoleptički izgled, vremesušenjafilmanasobnojtemperaturiinatemperaturikože,lepljivostobrazovanogfilmanakonsušenja,morfologijuobrazovanogfilmanamikroskopskojpločici,debljinufilmaistabilnostformulacija.Fleksibilnostimehaničkaotpornostfilmasuispitivanetehnikomuvijanjanagumenojtraci.

Pre‐formulaciona studija je ukazala na 3 različite obećavajuće formulacije sapolimerom Eudragit® RS pri 8,5%, 10% i 17,5%. Ovaj polimer može biti idealnokombinovansaplastifikatorimaTECilipropilenglikolom(20%m/msuvogpolimera).Otkriveno je da nejonski surfaktant polisorbat 80 pri 1 % značajno poboljšavafleksibilnost i mehaničku otpornost filma, čak i pri nižoj koncentraciji Eudragit® RS(8,5%).PovećanjekoncentracijeEudragit®RSod10%na17,5%nijeznačajnijeuticalona vreme sušenja filma na 32 °C, dok je prisustvo Polisorbata 80 od 1% produžilovreme sušenja na 32 °C. Debljina formiranog filma u ispitivanim film‐formirajućimsistemima uglavnom zavisi od izabranog polimera i njegove koncentracije. Studija jepokazala da su razvijeni sistemi koji obrazuju film podesni kao prospektivni nosačilekova,podstičućinjihovdaljiformulacionirazvoj.

639

PRE‐FORMULATIONSTUDYOFTOPICALFILM‐FORMINGSYSTEMS

ASPROSPECTIVEDRUGCARRIERS

MirjanaTimotijević,IvanaPantelić,SnežanaSavić

DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Polymer‐baseddeliverysystems,designedasnoveldrugcarrierswhich forma

thin film on the surface of the skin and provide a sustained delivery of an activesubstance,mightbeveryconvenientfortopicalapplicationanddermaldeliveryofbothhydrophilicandlipophilicdrugs.Thispre‐formulationstudyinvolvesdifferenttypesofpolymersorcombinationsthereofsuchasEudragit®RS,Eudragit®NE30D,Klucel®GFinvarious concentrations, combined with a diversity of plasticizers including triethylcitrate (TEC), tributyl citrate (TBC), propylene glycol and glycerol, optionally with apenetration enhancer or a nonionic surfactant (polysorbate 80), andwith a differentsolventsystems.

The obtained formulations were evaluated with respect to visual appearance,dryingtimeofthefilmatroomandskintemperature,stickinessoftheformedfilmafterdrying, the surface of the formed film on a microscopic slide, film thickness, andstabilityoftheformulations.Theflexibilityandmechanicalpropertiesofthefilmswereevaluatedbyafoldingtechniqueonarubberband.

A pre‐formulation study indicated on 3 different promising formulations withpolymerEudragit®RSat8.5%,10%,and17.5%.Thispolymercanbeideallycombinedwith the plasticizers TEC or propylene glycol (20%w/wof the dry polymer). Itwasfound that the nonionic surfactant polysorbate 80 at 1% significantly enhancesflexibility and mechanical resistance of the film, even at lower (8,5%) Eudragit®RSconcentration.IncreasingtheconcentrationofEudragit®RSfrom10%to17,5%hadnosignificant influence on film drying time at 32 °C, while the presence of 1% ofpolysorbate80prolongedthedryingtimeat32°C.Thethicknessoftheformedfilminevaluated film‐forming systems depends principally on the chosen polymer and itsconcentration.Astudyhasshownthatthedevelopedfilm‐formingsystemsarefeasibleasprospectivedrugcarriers,encouragingtheirfurtherformulationdevelopment.

640

Arh.farm 2018;68: 640-641 FTK-P43

EMULZIJETIPAULJEUVODIKOJEPODLEŽUBRZOJINVERZIJIFAZA

NAKOŽISAINKORPORIRANIMANTIOKSIDANSIMABILJNOGPOREKLA:INVITROODREĐIVANJEFAKTORAZAŠTITEODSUNCA

RadavaMartić1,DaninaKrajišnik1,AnđelijaMalenović2,JelaMilić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet,2Katedrazaanalitikulekova,UniverzitetuBeogradu‐

Farmaceutskifakultet(Srbija)

SWOP (engl. Switch‐Oil‐Phase) emulzije koje karakteriše brza inverzija faza u

emulzijetipavodauulju,kaoiformiranjevodootpornogslojatokomnjihoveprimenena koži, prepoznate su kao pogodni nosači za kozmetičke sirovine u proizvodima zazaštituodsunčevogzračenja.Flavonoidikvercetin(Q)idihidrokvercetin(DHQ),kaoiβ‐karoten (βC) se koriste kao antioksidansi u kozmetickim proizvodima. Dodatno,lavonoidi se mogu koristiti za smanjenje ostecenja koze uzrokovanih suncevimzračenjem zbog njihove apsorpcije u UV oblasti. Cilj ove studije je bio da u in vitrouslovima utvrdi faktor zaštite od sunca (eng. Sun Protection Factor – SPF) SWOPemulzijasa0,5%Q(SQ),0,5%DHQ(SDHQ)ikombinacijom0,5%DHQi0,2%βC(SDHQβC)primenomUVspektrofotometrije.

SWOP emulzija (S) i SWOP emulzija sa dodatim antioksidansima (SQ, SDHQ iSDHQβC)pripremljenesupostupkomemulgovanjatoplo/toplo.Apsorbancijekozmetickihsastojaka (u oblasti 200 do 370 nm)merene su u etanolnim ekstraktima ispitivanihemulzija. Vrednosti SPF su izracunatepomocuMansur‐ove jednacine. Zapoređenje jekoriscenkomercijalnikozmetičkiproizvodkojisadržiβC(SPF6).

EmulzijaSDHQjepokazalaboljuUVapsorbancijuupoređenjusaSQ(SPF4,65,tj.3,35)štoukazujedajeDHQboljiUVapsorberodQ.SPFemulzijeSDHQβCjenajviši(5,19)verovatnozbogzajedničkogdoprinosaDHQ iβC.EmulzijaS je imalazanemarljivSPF(1,67),dokjeSPFkomercijalnogproizvodaiznosio6,81.

DobijenirezultatipokazalisudajefaktorzaštiteodsuncazaSWOPemulzijusainkorporiranimDHQ i βC veci upoređenju sa emulzijomkoja sadrzi samoDHQ. IakonijetipičanUV‐apsorber,βCverovatnozbogsvojeantioksidantneaktivnosti,štitiDHQod oksidacije i doprinosi njegovoj apsorpciji u UV oblasti. Upotrebom UVspektrofotometrijskog postupka određene su i dobijene uporedive vrednosti SPF zaSDHQβCemulzijuikomercijalniproizvodkojisadržiβC.

641

FASTINVERTEDOIL‐IN‐WATEREMULSIONCONTAININGPLANTORIGINANTIOXIDANTS:INVITRODETERMINATIONOFSUN

PROTECTIONFACTOR

RadavaMartić1,DaninaKrajišnik1,AnđelijaMalenović2,JelaMilić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofDrugAnalysis,Universityof

Belgrade‐FacultyofPharmacy(Serbia)

The Switch‐Oil‐Phase (SWOP) emulsions characterized by fast inversion into

water‐in‐oil emulsionsduring application on the skin and consequent formation of awater‐resistance layer are recognized as suitable cosmetic vehicles in sun protectionproducts.Flavonoidsquercetin(Q)anddihydroquercetin(DHQ),aswellasβ‐carotene(βC) are used as antioxidants in cosmetics. Additionally, flavonoidsmay be used fordiminishing skin damage caused by solar radiation due to their absorption in UVspectrum.Theaimofstudywasinvitrodeterminationofsunprotectionfactor(SPF)forSWOP emulsions containing 0.5%Q (SQ), 0.5%DHQ (SDHQ) and combination of 0.5%DHQand0.2%βC(SDHQβC)byUVspectrometry.

The SWOP emulsion base (S) and the SWOP emulsion with incorporatedantioxidants (SQ, SDHQ and SDHQβC) were prepared using hot/hot emulsificationprocedure. Absorbance of the cosmetic ingredients (from 200 to 370 nm) weredetermined in ethanolic extracts of the tested emulsions. SPF valueswere calculatedusingMansurequation.AcommercialcosmeticproductcontainingβC(SPF6)wasusedforcomparison.

The SDHQ showed better UV absorption compared with SQ (SPF 4.65, i.e., 3.35,respectively) indicating thatDHQabsorbedbetter inUVspectrumthanQ.TheSPFofSDHQβCwasthehighest(5.19)probablyduetocontributionofbothDHQandβC.Whilethe SPFof emulsion base Swas negligible (1.67), determined SPF of the commercialproductwas6.81.

ObtainedresultsshowedthattheSPFofSWOPemulsionwithincorporatedbothDHQandβCwashighercomparedwiththeemulsioncontainingonlyDHQ.AlthoughβCisnot a typicalUVabsorber,due to its antioxidantactivity, itprobablyprotectsDHQfromoxidation and supports its absorbance inUV spectrum.UsingUV spectrometricmethod, comparable SPF values of SDHQβC emulsion and the commercial productcontainingβCwereobtained.

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Arh.farm 2018;68: 642-643 FTK-P44

INVITROISPITIVANJEANTIOKSIDATIVNEAKTIVNOSTI

ANTIOKSIDANASABILJNOGPOREKLAINKORPORIRANIHUEMULZIJETIPAULJEUVODIKOJEPODLEŽUBRZOJINVERZIJIFAZA

NAKOŽI

RadavaMartić1,DaninaKrajišnik1,JelenaKotur‐Stevuljević2,VesnaSpasojević‐Kalimanovska2,JelaMilić1

1Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐

Farmaceutskifakultet,2Katedrazamedicinskubiohemiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Flavonoidi kvercetin (QUE) i dihidrokercetetin (DHQ), kao i β‐karoten (βC) se

koriste kao antioksidansi u kozmetičkim proizvodima. Iako njihova antioksidativnaaktivnost sama po sebi može biti merena korišćenjem različitih analitičkih tehnika,procenanjihovebiohemijskeaktivnostiugotovomproizvodupredstavlja izazovzbogsloženog sastava kozmetičkih formulacija. Cilj ove studije je bio da se utvrdiantioksidativnaaktivnostovihkozmetičkihsastojakaugrađenihuemulziju tipauljeuvodikojapodležebrzojinverzijifazanakoži(SWOPemulzija):0,5%QUE(SQUE),0,5%DHQ (SDHQ) i kombinacija 0,5% DHQ i 0,2 % βC (SDHQβC) pri in vitro izazvanomoksidativnom stresu u biološkom uzorku i upoređivanje njihovog antioksidativnogpotencijala.

RastvoriemulzijaSQUE,SDHQiSDHQβC(1%)iQUEiDHQ(0,005%)upropilenglikolu(PG) pomešani su sa serumom sakupljenim od zdravih dobrovoljaca, uekstracelularnommodel sistemuza invitroprocenuantioksidativnihosobina.Efekatirazličitih antioksidanasa bez i sa serumom, uz dodatak 0,5 mmol/l terc‐butilhidroperoksida (TBH‐egzogeni prooksidans) praćeni su u odnosu na njihov uticaj naparametreoksidativnogstresa iantioksidativneparametre.Analizesu izvedenena20°Ci37°C.VrednostiposmatranihparametaraanaliziranesukoriscenjemKruskal‐Wallisi post‐hoc Mann‐Whitney testa. Antioksidativne vrednosti na 20 °C bile su redom:QUE/PG i SQUE/PG ‐0,33 (‐5,11–6,17) > SDHQβC/PG ‐5,50 (‐14,67–3,67) > DHQ/PG iSDHQ/PG ‐9,33 (‐9,89–(‐7,50), sa značajnomrazlikom izmeđuposlednjedve grupe.Na37 °C, redosled antioksidativne vrednosti bio je: QUE/PG i SQUE/PG ‐7,34 (‐14,50–(‐3,00)) > SDHQβC/PG ‐33,50 (‐45,67–(‐21,33)) > DHQ/PG i SDHQ/PG ‐37,33 (‐39,00–(‐34,67)),dokrazlikaizmeđuposlednjedvegrupenijebilaznačajna.

Emulzija tipa ulje u vodi koja podleže brzoj inverziji faza na koži i sadržikombinaciju DHQ i βC pokazala je blagi porast antioksidativnog efekta u odnosu naemulziju sa DHQ i značajno smanjenje egzogenih prooksidativnih efekata izazvanihdodatkomTBH.

643

INVITROANTIOXIDANTACTIVITYTESTINGOFPLANTORIGINANTIOXIDANTSINCORPORATEDINTOFASTINVERTEDOIL‐IN‐

WATEREMULSIONS RadavaMartić1,DaninaKrajišnik1,JelenaKotur‐Stevuljević2,

VesnaSpasojević‐Kalimanovska2,JelaMilić1

1DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐FacultyofPharmacy,2DepartmentofMedicalBiochemistry,

UniversityofBelgrade‐FacultyofPharmacy(Serbia)

Flavonoidsquercetin(QUE)anddihydroquercetin(DHQ),aswellasβ‐carotene

(βC)areusedasantioxidantsincosmeticproducts.Althoughtheirantioxidantactivityper se can be measured using different analytical techniques, estimation of theirbiochemical activity in a finished product is a challenging task due to the complexcomposition of cosmetic formulations. The aim of this study was to determineantioxidantactivityofthesecosmeticingredientsincorporatedintofastinvertedoil‐in‐wateremulsion(SWOPemulsion):0.5%QUE(SQUE),0.5%DHQ(SDHQ)andcombinationof 0.5% DHQ and 0.2% βC (SDHQβC) at in vitro induced oxidative stress in biologicalsampleandtocomparetheirantioxidantpotential.

Solutions in propylene glycol (PG)of SQUE, SDHQ and SDHQβC (1%) andbothQUEandDHQ(0.005%)werepreparedandmixedwithserumpoolcollectedfromhealthyvolunteers, in an extracellular model system for in vitro antioxidative propertiesestimation.Theeffectsofdifferentantioxidantsalone,orinserumwith0.5mmol/ltert‐butyl hydroperoxide (TBH‐exogenous prooxidant) added, were monitored regardingtheir influence on oxidative stress parameters and parameters of antioxidativeprotection.Theanalyseswereperformedat20Cand37C,respectively.Valuesofthemonitored parameters were analyzed using Kruskal‐Wallis test and Mann‐Whitneypost‐hoctest.Antioxidativescorevaluesat20CwereinrangeQUE/PGandSQUE/PG‐0.33(‐5.11–6.17)SDHQβC/PG‐5.50(‐14.67–3.67)DHQ/PGandSDHQ/PG‐9.33(‐9.89–(‐7.50),withsignificantdifferencebetweenlasttwogroups.At37C,therankorderwasQUE/PG and SQUE/PG ‐7.34 (‐14.50–(‐3.00))SDHQβC/PG ‐33.50 (‐45.67–(‐21.33))DHQ/PG and SDHQ/PG ‐37.33(‐39.00–(‐34.67)), and the difference between last twogroupswasinsignificant.

Fast inverted oil‐in‐water emulsion containing combination of DHQ and βCshowed slight antioxidative effects amplification compared to the same cosmeticvehiclewithDHQ,andsignificantdecreaseinexogenousprooxidativeeffects,causedbyTBH.

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FORMULATION,PREPARATIONANDCHARACTERIZATIONOFA

PHOTOPROTECTIVEEMULSIONBASEDONANEWBENZIMIDAZOLECOMPOUNDASSOCIATEDWITHVEGETALEXTRACTS

EmmaAdrianaCretu1,TeodoraDalilaBalaci1,CătălinaAncutaFita1,

EleonoraMircia2,CeraselaElenaGîrd1

1UniversityofMedicineandPharmacy„CarolDavila”Bucharest,FacultyofPharmacy,2UniversityofMedicineandPharmacy,TarguMures,Facultyof

Pharmacy(Romania)

The exposure to UV radiation is responsible for damaging the skin’s natural

defense, leading to various adverse effects, from sunburns to skin cancer; makingnecessary toapplyon theskinphotoprotectiveproductswhichare safeandefficient.Thestudiesconsistinthefollowing:selectionoftheactiveingredientsandtheuseofaproper technological process for preparation of a dermo‐cosmetic emulsion having agoodphysicalandchemicalstability,suitableorganolepticandrheologicalpropertiesinordertoensuretheinnocuityandpleasantadministratingfeatures.

We have used one new organic filtering photo protective substance:1‐(4‐dimethylamino)benzyl‐2‐(4‐dimethylaminophenyl)‐H‐1,3benzimidazole.Inordertoreducethe toxicityandtheamountofUV filtersused incosmetic formulations,UVfilters were incorporated into nanostructured lipid carriers (NLCs). Besides organiccompound we have also used: two inorganic screen photoprotective substances:titaniumdioxide(coatedwithaluminaandsilicon)andzincoxide;vegetalextractsrichin flavonoids with antioxidant action and protective capillary and coumarins withscreen effect, collagen used for theskin elasticity, hydration and revitalizing effect,vitamins, natural products having a slight photoprotective, hydrating and emollientactions.ThepreparationofNLCswasthemeltemulsificationmethodcoupledwithhighshear homogenization.NLCs characterizationwas based on particle size analysis (bydynamiclightscattering),PdIandZetapotentialanalysis,afterthis,theywereincludedin a dermato‐cosmetic emulsionwhichwas studied under the following aspects: theorganoleptic properties, pH, spreadibility, viscosity, the degree of hydration, in vitrodeterminationofSPF.

Starting from the lyophilized benzimidazole‐lipid nanostructures, efficientcosmetic formulationswithbroadphotoprotectivepropertieswereobtainedbyusingthe new benzimidazole compound as organic UV filter, metal oxides and vegetableextracts,oilsandotheringredients.Theobtainedemulsionhasprovedqualitiesforskinapplicationpossessingsuitablephysicochemicalcharacteristics.

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HIDROGELSAEKSTRAKTOMALCHEMILLAVULGARISL.:INVIVO/INVITROPROCENABEZBEDNOSTIIUTICAJANAZARASTANJEMANJIH

RANANAKOŽI

MarijaTasićKostov1,IvanaArsić1,DraganaPavlović1,SanjaStojanović2,StevoNajman2,DušanIlić3,VanjaTadić4

1Katedrazafarmaciju,UniverzitetuNišu‐Medicinskifakultet,2UniverzitetuNišu‐Medicinskifakultet,3ZUADonafarmNiš,4Institut„DrJosifPančić”

Beograd(Srbija) Rane na koži, prvenstveno hronične, predstavljaju zdravstveni problem

globalnih razmera; lečenje zahteva lokalni tretman. Novija relevantna naučnaistraživanja ukazuju na veliki potencijal upotrebe biljnih ekstrakata u ove svrhe.Uzimajućiuobzirznačajizboranosača/podloge,ciljradajebioformulacijaiispitivanjehidrogelazalokalnitretmanmanjihranasaekstraktomAlchemillavulgarisL.Ispitivanigel označen je sa GAE i izrađen inkorporiranjem 2% etanolnog ekstraktaAlchemillavulgarisL.ukarbomernigelkojijeslužiokaoplacebokontrola‐P.Bezbednostprimenenakožijeodređivanainvitro(testcitotoksičnostinafibroblastima)iinvivomerenjembiofizičkih parametara kože: transepidermalni gubitak vode (TEGV), električnakapacitivnost (EC) i eritema indeks (EI). Određivanje efikasnosti kao uticaja nazarastanjemanjihranavršenojeinvivo(merenjemTEGViECnakonoštećenjabarijereSC surfaktantom) i in vitro (merenjem brzine zatvaranja veštački napravljene rane uslojuL929fibroblasta imigracijećelija).UzorakP jebionegativna,amedijumzarastćelijapozitivnakontrola.OdređenjesadržajfenolauGAEuzorkuHPLCmetodom.

Oba uzorka pokazuju povoljan profil bezbednosti na koži in vitro i in vivo, ukoličinama uobičajenim pri aplikaciji dermofarmaceutskih preparata. Uzorak GAEpokazujeprocentualnovećipotencijaldaubrzazarastanje (45%zatvaranjauodnosuna dimenzije inicijalne rane) u odnosu na P (28%), ali niži u odnosu na pozitivnukontrolu ‐ medijum kao idealnu sredinu za rast ćelija (80%). U in vivo studijisedmodnevna primena uzorka GAE je, u odnosu na uzorak P i netretiranu oštećenukožu, značajno smanjila TEGV, a povećala EC; normalizuju se vrednosti parametaraporemećene delovanjem surfaktanta. HPLC analizom identifikovano je 8 fenolnihjedinjenjakaopotencijalnih aktivnihsupstanci. Invivo/invitro ispitivanjimautvrđenisu pozitivni efekti GAE na proces zarastanjamanjih rana su u korelaciji sa fenolnimsastavom.RezultatiukazujunamogućnostprimenehidrogelasaekstraktomAlchemillavulgarisL.utretmanumanjihiprevencijinastankahroničnihrananakoži.

Rad je podržan od strane Ministarstva prosvete, nauke i tehnološkog razvoja

RepublikeSrbije(projekatIII45017).

646

ALCHEMILLAVULGARISL.EXTRACTINHYDROGELVEHICLE:INVIVO/INVITROEVALUATIONOFSKINSAFETYPROFILEANDWOUNDHEALINGPOTENTIALINTHETREATMENTOFMINOR

CUTANEOUSWOUNDS

MarijaTasićKostov1,IvanaArsić1,DraganaPavlović1,SanjaStojanović2,StevoNajman2,DušanIlić3,VanjaTadić4

1DepartmentofPharmacy,UniversityofNiš‐FacultyofMedicine,2UniversityofNiš‐FacultyofMedicine,3PharmacyDonafarmNiš,4Institute„DrJosifPančić”

Belgrade(Serbia) Treatmentandmanagementofwounds,particularlychronicwounds,becamea

multibillion‐dollar global health problem. The use of plant extracts is an importanttrendinthisarea,asprovenbynumerousscientificstudies.Regardingtheimportanceofapropervehicle,weaimedatdevelopinghydrogelwithAlchemillavulgarisL.extract,intendedfortopicaltreatmentofminorwounds.

Carbomergel(markedasplacebo‐P)wasusedasavehiclefor2%ofethanolicAlchemilla vulgaris L. extract (active sample GAE). Skin safety profile was evaluatedusingboth invitro (cytotoxicityassayonL929 fibroblasts)and invivomethods.Skinparametersmeasuredwere transepidermalwater loss (TEWL), electrical capacitance(EC) and erythema index (EI). To analyze the wound healing potential, we usedcomplementarymethods‐invitrowoundhealingassaywithL929fibroblasts(placebosamplewasnegative,whilecellculturemediumservedaspositivecontrol)andinvivoassessment of skin barrier repair potential (TEWL and EC measurements) after thebarrier impairment induced by surfactant. Chemical profile of the GAE sample wasachievedapplyingHPLCmethod.BothPandGAEshowedsatisfyinginvivo/invitroskinsafety profile, when used in quantities usual for real application regime ofdermopharmaceuticals.GAEinducedahigherextentofwoundclosure(45%ofclosurecomparedtoinitialwound)invitrocomparedtoP(28%),butthispotentialwaslowerwhencomparedtopositivecontrol(80%).Regarding invivostudy,significantbarrierrepairandskinhydratingpotentialofactivesamplewasrecordedaftersevendaysofapplicationcomparedtoPoruntreatedimpairedskin.ApplicationofGAEreversedthevaluesofTEWLandECdisturbedbysurfactant. In total,8phenoliccompoundswereidentifiedbyHPLC.Our studyoffers invivo/invitro evidenceson the folkloricuseofAlchemilla vulgaris in a treatment of minor wounds; phenolic compounds could beconsideredresponsible forrecordedwoundhealingactivity. Investigatedgelcouldbeusedinthetreatmentofminorwoundsandpreventionofchronicwoundformation.

ThisworkwassupportedbytheMinistryofEducation,ScienceandTechnological

Development,RepublicofSerbia(projektIII45017).

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ANTIOKSIDATIVNAAKTIVNOSTHIDROLIZATADOBIJENIHPROTEOLIZOMKOZJEGMLEKARAZLIČITIMPROTEAZAMA

MilaVukašinović1,ZoricaKneževićJugović2,SnežanaSavić3

1Službazafarmaceutskudelatnostisnabdevanje‐KliničkicentarSrbije,

2Katedrazabiohemijskoinženjerstvoibiotehnologiju,UniverzitetuBeogradu‐Tehnološkometalurškifakultet,3Katedrazafarmaceutskutehnologijuikozmetologiju,UniverzitetuBeogradu‐Farmaceutskifakultet(Srbija)

Peptidi dobijeni iz proteina hrane pokazuju širok spektar bioloških aktivnosti

(antioksidativno, antiinflamatorno, antimikrobno, antikancerogeno). Cilj ovog rada jeprocena sposobnosti smešapeptidadobijenih enzimskomhidrolizomproteinakozjegmlekadahvatajuslobodneradikale.

Proteini kozjeg mleka razloženi su jednostepenom metodom pomoću trikomercijalneproteaze različitogporekla: alkalaze,papaina ipankreatina.Hidroliza jesprovedenanatemperaturiipHoptimalnimzasvakienzim.ReakcijajepraćenapH‐statmetodom. Obim proteinske hidrolize procenjen je određivanjem stepena hidrolize(DH). Antioksidativna aktivnost hidrolizata ispitana je ABTS [2.2’‐azino‐bis (3‐etilbenztiazolin‐6‐sulfonska kiselina)], 2.2‐difenil‐1‐pikrilhidrazil (DPPH) ideoksiriboza(aktivnosthvatanjahidroksilradikala)metodama.

Najveći stepen hidrolize dobijen je primenom papaina, a najmanji sapankreatinom.Tokomispitivanjaantioksidativneaktivnosti,svihidrolizatipokazalisuznačajan potencijal hvatanja slobodnih radikala u trima metodama, koji je direktnoproporcionalan koncentraciji peptida. Registrovan je i veći potencijal inhibicijeslobodnogABTS•+ radikala, u poređenju sa inhibicijomhidroksil odnosno slobodnogDPPH•radikala.

Dobijeni rezultati pokazuju da razlaganje proteina kozjegmleka proteolitičkimenzimimagenerišehidrosolubilnepeptideznačajnesposobnostihvatanjaraznovrsnihslobodnih radikala, pa se mogu koristiti kao prirodni bioaktivni sastojci kojipoboljšavaju antioksidativna svojstva različitih prehrambenih, farmaceutskih ikozmetičkihproizvoda.

648

ANTIOXIDATIVEACTIVITYOFHYDROLYSATESOBTAINEDBYPROTEOLYSISOFGOATMILKWITHVARIOUSPROTEASES

MilaVukašinović1,ZoricaKneževićJugović2,SnežanaSavić3

1DepartmentofPharmaceuticalServiceandSupply‐ClinicalCenterofSerbia,2DepartmentodBiochemicalEngeneeringandBiotechnology,Universityof

Belgrade‐FacultyofTechnologyandMetallurgy,3DepartmentofPharmaceuticalTechnologyandCosmetology,UniversityofBelgrade‐Faculty

ofPharmacy(Serbia)

Peptides derived from dietary proteins have been reported to display a wide

spectrum of biological activities (antioxidant, antiinflamatory, antimicrobial,anticancer). The objective of thisworkwas to evaluate radical scavenging activity ofpeptidemixturesobtainedbytheenzymatichydrolysisofgoatmilkproteins.

Goatmilk proteinswere digested via one stepmethodwith three commercialfood grade proteases of different origin: alcalase, papain and pancreatin. Hydrolysiswas carried out at temperature and pH optimal for each enzyme. The reaction wasmonitored by the pH‐stat procedure. Extent of protein hydrolysis was evaluated bymeasuringthedegreeofhydrolysis(DH).Theantioxidantactivityof thehydrolysateswas tested by ABTS [2.2’‐azino‐bis (3‐ethylbenzthiazoline‐6‐sulphonic acid)], 2.2‐diphenyl‐1‐picrylhydrazyl (DPPH) and deoxyribose (hydroxyl radical scavengingactivity)methods.

The highest DH value was obtained by using papain and the lowest bypancreatin.Determining the antioxidant activity, all hydrolysates showedmeaningfulconcentration dependent radical scavenging potency in all three assays; higherinhibition of free radical ABTS•+ was detected in all peptide mixtures compared toinhibitionofhydroxylradicalandfreeradicalDPPH•.

The results demonstrate that digestion of goat milk proteins with proteolyticenzymesgenerates soluble peptideswithnotable ability to scavenge various radicalsand that could be used as natural bioactive ingredients in enhancing antioxidantpropertiesofdifferentfood,pharmaceuticalandcosmeticproducts.

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ARGANOVOULJE–RIZNICADRAGOCENIHEFEKATA

BojanaVučelić,MarijaBajčić,MiraStojanović

Apoteka„Beograd”(Srbija)

Arganovo ulјe je bilјno ulјe proizvedeno iz semena arganovog drveta (Argania

Spinosa,Sapotaceae).OvodrvojeendemskabiljnavrstauMarokuiimavelikuekološkuisocioekonomskuvrednostuovompodručju.Poznatojeikao„marokanskoulje”.

Arganovo ulјe, koje se koristi u kozmetičkoj industriji, dobija se hladnimceđenjem‐gnječenjemneprženihsemenaarganovogploda iodlikujesezlatnožutombojom. Bogato je vitaminom E, polifenolima, karotenoidima i masnim kiselinama,posebno omega‐6 i omega‐9. Sadrži oko 40‐50% oleinske kiseline i oko 30‐40%linoleinskekiseline.

Koristiseukozmetičkimproizvodimazaneguiomekšavanjekože,aposebnojeefikasnou smanjenjuvidljivostibora ihiperpigmentacija.Takođe sekoristi zanegu izaštituosetljivedečijekože.Imaipozitivneefekteuprevencijinastankastrija.Izraženje efekat arganovog ulja na poboljšanje kvaliteta kose i noktiju, a za njihovu negunajčešćesekoristiusvomčistomobliku.

Osimkozmetičkihefekatanegeizaštitekože,koseinoktiju,arganovouljemožebiti efikasno i u tretmanu određenih kožnih oboljenja. Koristi se u tretmanumladalačkihakni ibubuljica,kao iutretmanuekcemaipsorijaze.Delotvorno je ikodšuge,opekotina iranakadasekoristiučistomobliku ili inkorporiranuodgovarajućupodlogu.

U skorije vreme arganovo ulje je postalo predmet brojnih medicinskihistraživanja pa dobija novu oblast upotrebe i postaje veoma efikasano u tretmanumnogihbolesti,kaoštosusrčanebolesti,gojaznost,povišenekoncentracijeholesterolai triglicerida u krvi, reumatizam, varenje, hormonski disbalans i drugo. Ovi efekti seispoljavajunakonperoralneupotrebečistogarganovogulja.

650

ARGANOIL‐ATREASURETROVEOFVALUABLEEFFECTS

BojanaVučelić,MarijaBajčić,MiraStojanović

Pharmacy„Belgrade”(Serbia)

Argan oil is a vegetable oil produced from argan wood (Argania Spinosa,

Sapotaceae).ThistreeisanendemicplantspeciesinMoroccoandhasgreatecologicalandsocioeconomicvalueinthisarea.Itisalsoknownas„Moroccanoil”.

Arganoilused in the cosmetics industry isobtainedby coldsealing ‐ crushinguntried seeds of argan fruit and distinguished by a golden yellow color. It is rich invitaminE,polyphenols,carotenoidsandfattyacids,especiallyomega‐6andomega‐9.Itcontainsabout40‐50%oleicacidandabout30‐40%oflinoleicacid.

Itisusedincosmeticproductsfortheskincareandsoftening,andisespeciallyeffectiveinreducingthevisibilityofwrinklesandhyperpigmentation.Itisalsousedforthe care and protection of sensitive baby skin. There are also positive effects in theprevention of stretchmarks. The effect of argan oil on the improvement of hair andnailsqualityisexpressed,andfortheircareismostoftenusedinitspureform.

Apartfromthecosmeticeffectsofskincareandprotection,hairandnails,arganoilcanbeeffectiveinthetreatmentofcertainskindiseases.Itisusedinthetreatmentofteenageacneandpimples,aswellasinthetreatmentofeczemaandpsoriasis.It isalsoeffectiveinsprays,burnsandwoundswhenusedinpureformorincorporatedintoasuitablebase.

Morerecently,arganoilhasbecomethesubjectofnumerousmedical researchandhasbeengivenanewfieldofuseandhasbecomeveryeffectiveinthetreatmentofmanydiseases, suchasheartdisease,obesity,highbloodcholesterol and triglyceridelevels, rheumatism, digestion, hormonal imbalance and other. These effects appearafteroraladministrationofpurearganoil.

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INTELLECTUALPROPERTYRIGHTSANDADVERTISINGOF

COSMETICPRODUCTS

BiljanaNestorovska‐Gjoshevska,KaterinaAncevska‐Netkovska,MarijaGlavasDodov

Ss.Cyril&MethodiusUniversityofSkopje‐FacultyofPharmacy(Macedonia)

Whenlaunchinganadvertisingcampaign,businessesmayneedtocomplywitha

rangeoflawsandregulationsgoverning.Theselawsdifferfromcountrytocountryanddepending on the content of the advertisement. Today, it is impossible to be asuccessful advertiser without understanding the legal framework surrounding thebusiness of advertising. A lack of caution can lead to the loss of a company’s ownintellectual property (IP) rights or liability for infringing the IP rights of others. Toavoidcostlymistakes,businessesshouldconductrigorouschecksbothfromthegenerallegal perspective and from an IP perspective before launching a new advertisingcampaign. Misleading advertising means any advertising which, including itspresentation,deceives or is likely to deceive the persons towhom it is addressed orwhom it reaches andwhichby reasonof itsdeceptivenature, is likely to affect theireconomic behavior or which, for those reasons, injures or is likely to injure acompetitor.

Facing with problemswithmisleading and comparative advertisingand takingintoconsiderationintellectualpropertyrightswewouldtopointoutthepossiblewaysforprotectionoftheconsumersandtraders.Themethodusedisaresearchfollowedbya descriptive study. Secondary data were collected from available scientificpublications, databases andbooksprovided.A survey about consumers’ reactions onadvertising cosmetic productswas prepared and analyzed. Through the researchwehave obtaineda clearer picture on the perception, awareness and behavior of theconsumers on misleading advertising. As misleading and unfair comparativeadvertisingareverypresentnowadaysandcanharmbothconsumersandtraders,veryimportant is tohaveclearanddefinedwaysofdealingwith themaccordingtoactualregulative taking in consideration how regulative is harmonized from country tocountry.

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UTICAJULJANOGEKSTRAKTASMILJANAORGANOLEPTIČKE

KARAKTERISTIKEKOZMETIČKIHKREMA

MarinaKalić1,MiroslavSarač1,NatašaJovanovićLješković1,ZoricaMrkonjić1,MandaDizdar1,BranislavaTeofilović1,

TatjanaMiljković2

1UniverzitetPrivrednaAkademijauNovomSadu‐FarmaceutskifakultetNoviSad,Srbija,2UniverzitetuNovomSadu‐Medicinskifakultet(Srbija)

Zahvaljujući velikoj potražnji u Evropi i svetu, poslednjih godina je uzgajanje

smilja doživelo pravu ekspanziju. Sastojci izolovani iz cvetova smilja (α‐pinen, nerilacetat) ispoljavaju različite kozmetičke efekte, zbog čega je ekstrakt smilja sve češćisastojak kozmetičkih proizvoda. Cilj rada je bio izrada uljanog ekstrakta smiljametodommaceracije,različitedužinetrajanja,zatimizradakremasa10%(m/m)i20%(m/m) uljanog ekstrakta i praćenje organoleptičkih karakteristika (boje i mirisa,razmazivosti,aplikativnogirezidualnogefektanakonprimene),kaoifizičkestabilnosti(odvajanjefaza)izrađenihkrema,tokomšestnedelja.

Uljani ekstrakti su izrađeni koristeći 15 g suvih cvetova smilja (Helichrysumitalicum(Roth)G.Donfil.)i370gmaslinovogulja.Dužinamaceracijejeiznosila14,28i42 dana. Izrađeni uljani ekstrakti su ručno inkorporirani u komercijalnu ambifilnupodlogu (Belobaza®),ukoncentracijamaod10%(m/m) i20%(m/m).Nakon izrade,kremesuostavljeneuplastičnojambalažinasobnojtemperaturi,nasuvomitamnommestuipraćenesupromenetokomšestnedelja.

Svekremesa10%uljanogekstraktasmilja,kojisudobijenimaceracijomrazličitedužine trajanja, bile su svetložute boje, slabog karakterističnog mirisa na maslinovoulje, dobre razmazivosti i prijatnog aplikativnog i rezidualnog efekta na koži, tokomšestnedeljapraćenja.Kremesa20%uljanogekstraktasmiljasubiletamnijeboje.Kodnjihsuseprviznacinestabilnostijavilinakontrećenedeljepraćenja,uviduodvajanjafaza,štoihčinineprihvatljivimzaupotrebu.

Na organoleptičke osobine i kratkoročnu fizičku stabilnost ispitivanih kremautiče koncentracija uljanog ekstrakta smilja. Sve kreme izrađene sa 10% uljanogekstrakta smilja, koji su dobijeni maceracijom različite dužine trajanja, su bileprihvatljivog izgleda, razmazivosti, aplikativnog i rezidualnog efekta na koži, bezznakovaodvajanjafazauperioduodšestnedelja.

653

INFLUENCEOFIMMORTELLEOILEXTRACTSONORGANOLEPTIC

CHARACTERISTICSOFCOSMETICCREAMS

MarinaKalić1,MiroslavSarač1,NatašaJovanovićLješković1,ZoricaMrkonjić1,MandaDizdar1,BranislavaTeofilović1,

TatjanaMiljković2

1UniversityBusinessAcademyinNoviSad‐FacultyofPharmacyNoviSad,2UniversityofNoviSad‐FacultyofMedicine(Serbia)

Cultivation and processing of immortelle has drastically expanded in the pastfewyears.Itsingredients(α‐pinene,nerylacetate)showcosmeticeffects,whatmakesimmortelleextractcommoningredientincosmeticproductsnowadays.Theaimofthisworkwas to prepare immortelle oil extracts by using differentmaceration times, tomakecreamscontaining10%(w/w)and20%(w/w)oftheseextracts,andtoevaluateorganoleptic characteristics (odour, color, spreadability, applicative and residualeffects)andstability(phaseseparation)ofsuchpreparationsoversixweeks.

Oil extracts were made using 15 g of dry immortelle (Helichrysum italicum(Roth)G.Donfil.)flowersand370gofoliveoil.Macerationlengthwas14,28and42days. Finished oil extracts were incorporated in commercial ambiphilic cream(Belobaza®)byhand,reachingconcetrationsof10%(w/w)and20%(w/w).Afterthat,creamswereplacedinplasticcontainersandleftonroomtemperature,inadark,dryplaceandtheircharacteristicswereobservedoversixweeksofstorage.

All creams containing 10% of oil extract remained light yellow, having weaktypicaloliveoilscentthroughoutthesixweeks,regardlessmacerationlength,withverygood spreadability and pleasant applicative and residual effects. Creams containing20%ofoilextractweredarkeratthebeginning.Firstinstabilitysignsoccurredatthirdweek of storage, as phase separation, which made them unacceptable as cosmeticproducts.

Organoleptic characteristics and short‐term stability of creams are affected bytheamountofaddedimmortelleoilextract.Textureandappearance,aswellasgeneralliking of creams containing 20% of oil extract, were significantly lower than withpreparationscontaining10%ofoilextract.

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FORMULACIJAIKARAKTERIZACIJAINVASOMASAKOENZIMOMQ10

NinaDragićević1,DanijelaPecarski2,AlfredFahr3

1Apoteka"Beograd",2Visokazdravstvenaškolastrukovnihstudija,Beograd(Srbija),3Katedrazafarmaceutskutehnologiju,Friedrich‐SchillerUniverzitet,

Jena(Nemačka)

Koenzim Q10 (Q10) se uspešno koristi zahvaljujući svojoj osobini „hvatača

radikala“ulečenjuneurodermatitisa,psorijazeisprečavanjufotostarenja.Međutim,Q10pokazuje i nedostatke, kao što su osetljivost na oksidaciju, posebno u aerobnimuslovimaipoduticajemsvetlosti.Q10jeliposolubilanistogajenjegovoinkorporiranjeukozmetičke proizvode komplikovano, jer je u većini kozmetičih preparata spoljašnjafazahidrofilna.

Cilj ovog rada je bio da se Q10 inkorporira u nanonosač kako bi se povećalanjegovastabilnost iolakšalo inkorporiranjeu formulacije.Stogasmorazvili invasomesaQ10.Invasomizarazlikuodkonvencionalnihliposomasadržeumembranamaporedfosfolipida, i terpene usled čega poseduju elastične membrane, te su bolji ubrzivačipenetracijesupstanciu/krozkožuodkonvencionalnihliposoma.

Izrađene su invasomske disperzije sa Q10 i različitim sadržajem terpena tj.cineola 1, 1,5 i 2%, u cilju povećanja fleksibilnosti membrana invasoma. Ispitana jeveličina čestica invasomske disperzije, distribucija veličine čestica (indekspolidisperziteta (PDI)), zeta potencijal, Q10‐sadržaj, pH vrednost i oksidacioni indeks.Ispitivana je stabilnost invasomskih disperzija zaštićenih od svetlosti, čuvanih natemperaturi4°Cutrajanjuod6meseci.

Invasomisunakon izradebilimaleveličine (od104,8±0,4do155,8±0,6nm),negativno naelektrisani (od ‐19,1±1,3 do ‐20,6±1,1mV), disperzije su bile homogene(PDI od 0,075±0,005 do 0,095±0,007), blago kisele pH vrednosti, sa prihvatlјivimoksidacionim indeksom i sadržajem Q10 u okviru deklarisanog sadržaja. Krio‐elektronskommikroskopijomjepokazanodasuvezikulebilepretežnosfernogoblikaiunilamelarne. Sa porastom sadržaja cineola od 1 do 2% rastao je broj deformisanihvezikulau invasomskimdisperzijama,ukazujućinavisokudeformabilnost/elastičnostinvasoma sa višim sadržajem cineola. Studija stabilnosti je pokazala da se fizičkiparametriinvasomskihdisperzijanisuznačajnomenjalitokomšestomesečnogčuvanja,ukazujući na visoku fizičku stabilnost invasoma.Većinahemijskihparametara se nijemenjalatokomčuvanjainvasoma,izuzevsadržajaQ10kojiseznačajnosmanjio.

Q10‐invasomska disperzija sa 1% cineola pokazala se kao fizički i hemijskinajstabilnijaformulacija.

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FORMULATIONANDCHARACTERIZATIONOFCOENZYMEQ10‐

LOADEDINVASOMES

NinaDragićević1,DanijelaPecarski2,AlfredFahr3

1Pharmacy"Belgrade",2CollegeofProfessionalHealthStudies,Belgrade(Serbia),3DepartmentofPharmaceuticalTechnology,Friedrich‐Schiller‐

University,Jena(Germany)

CoenzymeQ10(Q10)hasbeensuccessfullyappliedduetoitsradicalscavenger

properties in treating neurodermatitis, psoriasis and in preventing photoageing. Q10showsalsodisadvantages,suchassusceptibilitytooxidation,especiallyunderaerobicconditions and light exposure. Q10 is liposoluble and its incorporation into cosmeticformulations is complicated, as in most cosmetic formulations the outer phase ishydrophilic.TheaimofthisstudywastoincorporateQ10intoananocarriersysteminorder to enhance its stability, aswell as tomake its incorporation into formulationseasier. Thus, we developed invasomes loaded with Q10. Invasomes, in contrast toconventional liposomes, contain in their membranes besides phospholipids alsoterpenes, due to which they possess elastic membranes, and are more potentpercutaneouspenetrationenhancerscomparedtoconventionalliposomes.

Q10‐loadedinvasomedispersionswithdifferentterpenei.e.cineolecontent1,1.5 and 2% were prepared and characterized for particle size, size distribution(polydispersityindex(PDI)),zetapotential,Q10‐content,pHvalueandoxidationindex,andsubjectedtoastability investigationduring 6monthsstorageat4°C,underlightprotection.

Invasomeswere, after preparation, of small particle size (from 104.8±0.4 to155.8±0.6nm),negativelycharged(from‐19.1±1.3to‐20.6±1.1mV),dispersionswerehomogeneous (PDI from 0.075±0.005 to 0.095±0.007), of mild acid pH value,acceptable oxidation index and contained Q10 in the declared concentration range.Cryo‐electronmicroscopy revealed that vesicles weremostly of spherical shape andunilamellar.Withtheincreaseofcineolecontentfrom1to2%,thenumberofdeformedvesicles increased, indicating high deformability/elasticity of invasomes containinghigher cineole amount. The stability investigation revealed that physical parametersdid not change significantly during storage indicating high physical stability ofinvasomes. Most chemical parameters did not change during storage of invasomes,excepttheQ10‐contentwhichdecreasedsignificantly.

Q10‐loaded invasome dispersion with 1% cineole has shown to be thephysicallyandchemicallymoststableformulation.