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Primarni cilj istraživanja ove doktorske disertacije je bila procena mogućnosti da se razvojemi primenom mikroemulzija (kao opcije hemijskog inhensera penetracije) poboljša dermalnaisporuka slabo rastvorljivih lekovitih supstanci – adapalena (ADA) i sertakonazol-nitrata (SN), kojepripadaju različitim farmakoterapijskim grupama, imaju različite fizičkohemijske osobine iprimenjuju se u različitim terapijskim koncentracijama. Mikroemulzije su stabilizovane nejonskimsurfaktantima novije generacije – alkil poligukozidima (APG) ili polioksietilen(glicerol) estrimamasnih kiselina. U cilju komparativne procene doprinosa različitih vrsta nosača dermalnojraspoloživosti model leka, posebna pažnja je posvećena analizi sposobnosti različitih vrstamikroigala (fizički inhenseri penetracije) da pojačaju isporuku SN u kožu (čvrste silikonske vs.rastvorljive mikroigle).Rezultati su ukazali da se još uvek nedovoljno korišćeni APG surfaktanti i gliceret-7-kaprilat/kaprat mogu uspešno primeniti u formulaciji mikroemulzija. Razvijene (invertne)bikontinuirane mikroemulzije su se pokazale kao pogodni nosači za solubilizovanje ADA i SN, upogledu njihovih fizičkohemijskih osobina, bezbednosti i stabilnosti, i, najvažnije, u pogledunjihovog potencijala za poboljšanje dermalne isporuke ovih lekova in vitro. Dodatno, rastvorljivemikroigle su uspešno formulisane kao nosači za dermalnu isporuku teško rastvorljivog SN iobezbedile komparabilno deponovanje leka u koži kao mikroemulzije, međutim uz prisustvo invitro transdermalne isporuke dela primenjene doze leka. Sinergističko delovanje mikroigala imikroemulzija bilo je superiorno u odnosu primenu samog fizičkog i samog hemijskogpremošćivača barijere stratum corneum-a, bez značajnog povećanja permeacije leka., The aim of this doctoral dissertation was to evaluate the possibility of using microemulsions(as chemical penetration inerters) for improvment of dermal delivery of a poorly soluble modeldugs having different physicochemical characteristics, belonging to different pharmacotherapeuticgroups, i.e. applied in different therapeutic concentrations (adapalene (ADA) and sertaconazolenitrate (SN)). Microemulsions were stabilized with newer nonionic surfactants - alkylpolygucosides (APG) or polyoxyethylene (glycerol) fatty acid esters. In order to compare thecontribution of different types of carriers to the enhancement of dermal availability of the modeldrug, a special attention has been paid to the assessment of microneedles ability to significantlyimprove delivery of SN into the skin (dissolvable vs. solid silicone microneedles).The obtained results showed that newer and so far insufficiently used APG surfactants andglycereth-7-caprylate/caprate can be successfully applied in the formulation of microemulsions. Thedeveloped (invert) bicontinuous microemulsion formulations have proved to be suitable carriers forsolubilizing the investigated model drugs, in terms of their physicochemical properties, safetyprofile and stability, and, most importantly, their great potential of improving dermal delivery ofADA and SN in vitro. In addition, dissolvable microneedles were successfully fabricated as carriersfor dermal delivery o highly lipophilic SN and provided comparable drug deposition in the skin asmicroemulsions, but coupled with transdermal delivery of a portion of the administered drug dose.The synergistic action of microneedles and microemulsions was superior over the application eitherof physical or chemical enhancer alone, without reaching a significant increase in drug permeationas compared to the use of dissolvable microneedles.

Primarni cilj istraživanja ove doktorske disertacije je bila procena mogućnosti da se razvojem i primenom mikroemulzija (kao opcije hemijskog inhensera penetracije) poboljša dermalna isporuka slabo rastvorljivih lekovitih supstanci – adapalena (ADA) i sertakonazol-nitrata (SN), koje pripadaju različitim farmakoterapijskim grupama, imaju različite fizičkohemijske osobine i primenjuju se u različitim terapijskim koncentracijama. Mikroemulzije su stabilizovane nejonskim surfaktantima novije generacije – alkil poligukozidima (APG) ili polioksietilen(glicerol) estrima masnih kiselina. U cilju komparativne procene doprinosa različitih vrsta nosača dermalnoj raspoloživosti model leka, posebna pažnja je posvećena analizi sposobnosti različitih vrsta mikroigala (fizički inhenseri penetracije) da pojačaju isporuku SN u kožu (čvrste silikonske vs. rastvorljive mikroigle). Rezultati su ukazali da se još uvek nedovoljno korišćeni APG surfaktanti i gliceret-7- kaprilat/kaprat mogu uspešno primeniti u formulaciji mikroemulzija. Razvijene (invertne) bikontinuirane mikroemulzije su se pokazale kao pogodni nosači za solubilizovanje ADA i SN, u pogledu njihovih fizičkohemijskih osobina, bezbednosti i stabilnosti, i, najvažnije, u pogledu njihovog potencijala za poboljšanje dermalne isporuke ovih lekova in vitro. Dodatno, rastvorljive mikroigle su uspešno formulisane kao nosači za dermalnu isporuku teško rastvorljivog SN i obezbedile komparabilno deponovanje leka u koži kao mikroemulzije, međutim uz prisustvo in vitro transdermalne isporuke dela primenjene doze leka. Sinergističko delovanje mikroigala i mikroemulzija bilo je superiorno u odnosu primenu samog fizičkog i samog hemijskog premošćivača barijere stratum corneum-a, bez značajnog povećanja permeacije leka., The aim of this doctoral dissertation was to evaluate the possibility of using microemulsions (as chemical penetration inerters) for improvment of dermal delivery of a poorly soluble model dugs having different physicochemical characteristics, belonging to different pharmacotherapeutic groups, i.e. applied in different therapeutic concentrations (adapalene (ADA) and sertaconazole nitrate (SN)). Microemulsions were stabilized with newer nonionic surfactants - alkyl polygucosides (APG) or polyoxyethylene (glycerol) fatty acid esters. In order to compare the contribution of different types of carriers to the enhancement of dermal availability of the model drug, a special attention has been paid to the assessment of microneedles ability to significantly improve delivery of SN into the skin (dissolvable vs. solid silicone microneedles). The obtained results showed that newer and so far insufficiently used APG surfactants and glycereth-7-caprylate/caprate can be successfully applied in the formulation of microemulsions. The developed (invert) bicontinuous microemulsion formulations have proved to be suitable carriers for solubilizing the investigated model drugs, in terms of their physicochemical properties, safety profile and stability, and, most importantly, their great potential of improving dermal delivery of ADA and SN in vitro. In addition, dissolvable microneedles were successfully fabricated as carriers for dermal delivery o highly lipophilic SN and provided comparable drug deposition in the skin as microemulsions, but coupled with transdermal delivery of a portion of the administered drug dose. The synergistic action of microneedles and microemulsions was superior over the application either of physical or chemical enhancer alone, without reaching a significant increase in drug permeation as compared to the use of dissolvable microneedles.

The efficiency of(trans)dermal drug delivery has been severely reduced by the inability of most drugs to penetrate the skin at therapeutically useful rates. Recently, the use of micron-scale needles has been shown to increase skin permeability and significantly improve (trans)dermal drug delivery, particularly for macromolecules. Using the tools of the microelectronics industry and different materials, microneedles of various sizes and shapes have been fabricated. Due to their micron size (less than 300 μm in diameter and 50-900 μm in length), these needles do not reach the nerve endings in the dermis, providing a painless application, which is considered as their main advantage over hypodermic needles. Pathways created using microneedles are orders of magnitude bigger than molecular dimensions and, therefore, should readily permit transport of macromolecules, as well as possibly supramolecular complexes and microparticles Recently, in vivo studies have demonstrated a successful delivery of oligonucleotides, insulin, and many other drugs using a microneedles, as well as induction of the immune response from protein and DNA vaccines. Numerous studies conducted in this research field have led to launching the first microneedle-based (trans)dermal drug delivery systems on the market., Efikasnost terapijskih sistema za (trans)dermalnu isporuku lijekova je u znatnoj mjeri umanjena zbog otežanog prolaska lijekova u/kroz kožu. Nedavno je pokazano da je upotrebom igala mikronskih veličina moguće povećati permeabilnost kože i znatno poboljšati (trans)dermalnu isporuku, naročito u slučaju makromolekula. Primjenom dostignuća mikroelektronske industrije, od različitih materijala su proizvedene mikroigle različitih veličina i oblika. S obzirom na svoje mikronske veličine (prečnika obično oko 1 μm i dužine 50-900 μm), ovakve igle ne dopiru do nervnih završetaka u dermisu, čime obezbjeđuju bezbolnu primjenu, što se smatra njihovom osnovnom prednošću u odnosu na potkožne igle. Nastale pore u koži su nekoliko puta veće od dimenzija molekula, te je omogućen transport makromolekula, kao i supramolekularnih kompleksa i nano/mikročestica. Dosadašnje in vivo studije su pokazale uspješnu (trans)dermalnu isporuku oligonukleotida, insulina i drugih lijekova primjenom mikroigala, kao i indukciju imunskog odgovora proteinskim i DNK vakcinama. Brojni radovi sprovedeni u ovoj oblasti istraživanja doveli su i do pojave na tržištu prvih sistema za (trans)dermalnu isporuku lijekova zasnovanih na tehnologiji mikroigala.

Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth-7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs.

Poster presented at the 3rd European Science Foundation Summer School Nanomedicine 2011, 19-24 June 2011

The objectives of this study were to prepare films from submicron chitosan/Eudragit((R)) L100-55 polyelectrolyte complexes (CH/EL PEC) and to assess the influence of CH molecular weight and CH/EL mass ratio on their structure and drug-release properties. The films were obtained by a simple, environmentally friendly, casting/solvent evaporation method and the verapamil hydrochloride (VH) was used as model drug. Submicron size, narrow size distribution, and acceptable stability of CH/EL PECs were confirmed by DLS and laser Doppler microelectrophoresis. SEM analysis revealed nonporous inner structure and flat surface of the films. Interactions between comprising polymers and formation of CH/EL PEC were established by DSC and FT-IR spectroscopy. In vitro swelling and drug release studies revealed the pH sensitivity of the films, with burst drug release in acidic conditions (pH 1.2) and sustained release in phosphate buffers pH 5.8, 6.8, and 7.4. The slowest VH release was achieved from the films prepared from equal amounts of EL and CH of higher molecular weight, confirming the significance of the CH/EL ratio and CH molecular weight on their ability to sustain drug release. The obtained results suggested that presented, simple, and eco-friendly preparation procedure can be used to obtain pH-sensitive CH/EL PEC films with a promising potential as drug carriers.

U širokoj oblasti nanotehnologija, nanomedicina predstavlja disciplinu koja se veoma brzo razvija i pruža obećavajuće mogućnosti za značajno poboljšanje medicinske dijagnostike i terapije. Posebno značajan istraživački interes u nanomedicini usmjeren je ka ispitivanju širokog spektra biomedicinskih nanomaterijala, razvijenih za izradu nosača dijagnostičkih sredstava i lijekova. Među brojnim biomaterijalima neorganskog i organskog porijekla, polimeri su pronašli široku upotrebu u formulaciji nanosistema za kontrolisanu i ciljanu isporuku lijekova. Poli-D,L-mliječna kiselina (PDLLA) je sintetski polimer koji je odobren za kliničku primjenu, budući da se njegovi biokompatibilni degradacioni proizvodi metabolišu i uklanjaju iz organizma ciklusom limunske kiseline. Koloidni nosači ljekovitih supstanci izrađeni od ovog polimera intenzivno se istražuju zbog svoje male veličine koja omogućava permeaciju lijeka kroz biološke barijere i njegovu produženu isporuku u ciljna tkiva. Pored sposobnosti da kontrolišu oslobađanje lijeka, polimerne nanočestice takođe poboljšavaju isporuku lijekova slabo rastvornih u vodi, smanjuju pojavu neželjenih efekata, pružaju mogućnost stabilizacije i zaštite inkorporirane ljekovite supstance od hemijske i enzimske degradacije, omogućavaju njenu bolju penetraciju i efikasniju akumulaciju na ciljnim mjestima. Imajući u vidu sve navedene aspekte, kao model supstanca u ovom radu izabran je ketoprofen, slabo rastvoran lijek u vodi koji ima kratko poluvrijeme eliminacije i ispoljava veliki broj neželjenih efekata nakon (per)oralne primjene. Osim primjene nanonosača ljekovitih supstanci, još jedan pristup za poboljšanje transdermalne isporuke lijeka je fizičko premošćavanje stratum corneum-a (SC) primjenom mikroigala. Neinvazivnom i bezbolnom primjenom mikroigala formiraju se mikrokanali u koži, koji obezbjeđuju intradermalni i transdermalni transport ljekovite supstance. Na temelju prethodnih razmatranja, osnovni cilj istraživanja ove doktorske diser, In the broad field of nanotechnology, nanomedicine is a fast growing discipline which offers promising possibilities to significantly improve medical diagnosis and therapy. The major research interest in nanomedicine has particularly focused on wide spectrum of novel biomedical nanomaterials developed for formulation of carriers for diagnostics and drug delivery. Among numerous biomaterials based on inorganic or organic matter, polymers are considered to be widely used in formulation of nanosystems for controlled and targeted drug delivery. Poly(D, L-lactic acid) (PDLLA) is a synthetic polymer approved for clinical use since its degradation products are biocompatible, metabolisable and removable from the body by the citric acid cycle. Colloidal drug carriers based on this polymer are extensively investigated because of their small particle size that allows permeation through biological barriers and drug delivery to the body over prolonged periods of time. In addition to their ability to control drug release, polymeric nanoparticles are also capable to improve the delivery of water-insoluble drugs, reduce the drug-associated side effects, protect the compounds from inactivation, increase the intracellular penetration and enhance a higher drug-target accumulation. Considering all these aspects, ketoprofen was selected as a model drug as it has low water solubility, short half-life and exhibits numerous side-effects after oral application. In addition to nanocarriers, another transdermal delivery approach that has been applied is the use of microneedles, as a physical method for overcoming the stratum corneum (SC) barrier. Microneedles provide a minimally invasive, painless way of creating microchannels in the skin which can allow intradermal and transdermal drug transport. Based on these considerations, the principal objective of this work was to develop and characterize a novel polymeric nanoparticulate systems that are capable of controlled and prolonged ketoprofen

ObjectivesThe aim of our study was to evaluate the effect of designing ketoprofen-loaded nanosized spheres and combining them with solid silicon microneedles for enhanced and sustained percutaneous drug delivery.MethodsKetoprofen-loaded nanoparticles (KET-NP) were designed by modified solvent displacement method, using poly (D, L-lactic acid) (PDLLA). All prepared nanoparticles were characterised with regard to their particle size distribution, morphology, surface properties, thermal behaviour, drug content, drug release and stability. In-vitro skin permeation studies were conducted on Franz-type diffusion cells using porcine skin treated with ImmuPatch silicon microneedles (Tyndall Nation Institute, Cork, Ireland).Key findingsThe study showed that uniform nanospheres were prepared with high encapsulation efficiency and retained stable for 2 months. After an initial burst release, the PDLLA nanoparticles were capable of sustaining and controlling ketoprofen release that followed Korsmeyer–Peppas kinetics. An enhanced flux of ketoprofen was observed in the skin treated with silicon microneedles over a prolonged period of time.ConclusionsFollowing application of silicon microneedle arrays, KET-NP were able to enhance ketoprofen flux and supply the porcine skin with drug over a prolonged (24 h) period of time. Our findings indicate that the delivery strategy described here could be used for the further development of effective and painless administration systems for sustained percutaneous delivery of ketoprofen.