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Nanašanje zdravilnih učinkovin na biokompatibilne podlage s tehnologijo 2D tiskanja predstavlja inovativen in učinkovit način prilagajanja odmerka zdravilnih učinkovin vsakemu posamezniku. S takim načinom zdravljenja bi lahko uspeli rešiti izzive, ki se pojavljajo zlasti pri zdravljenju kroničnih bolezni, pri zdravljenju otrok in starostnikov ter pri visokopotentnih učinkovinah in/ali učinkovinah z ozkim terapevtskim oknom. Pomembna prednost tehnologije 2D tiskanja se kaže tudi v možnosti priprave farmacevtske oblike neposredno pred izdajo bolniku z dispergiranjem suhih delcev v osnovnem mediju črnila in njihovim tiskanjem na biokompatibilne podlage. Zato je bil cilj našega raziskovalnega dela pripraviti suhe delce s simvastatinom z metodo sušenja z razprševanjem, ki bi bili primerni za dispergiranje v mediju črnil in bi ostali fizikalno-kemijsko dovolj stabilni tekom celotnega obdobja uporabe. Izdelali smo tri različne emulzije z laktozo, kalcijevim silikatom in kombinacijo laktoze in nanoceluloze kot antiadhezivi. Delce smo pripravili z metodo sušenja z razprševanjem omenjenih emulzij, pri čemer je prišlo do pretvorbe simvastatina v amorfno obliko, kar smo potrdili z diferenčno dinamično kalorimetrijo in z infrardečo spektroskopijo s Fourierjevo transformacijo. Pripravili smo delce brez in z dodatkom askorbinske kisline, da bi preverili vpliv antioksidanta na kemijsko stabilnost simvastatina v delcih. Delce smo dispergirali v treh medijih, ki so vsebovali različne deleže propilen glikola in vode. Opravili smo enomesečno stabilnostno študijo pri čemer smo suhe in dispergirane delce shranili pri 25 °C in 40 % RV ter pri 40 °C in 75 % RV. Vzorce smo analizirali s tekočinsko kromatografijo ultra visoke ločljivosti ter določili vsebnost simvastatina v delcih. Ugotovili smo, da dodatek askorbinske kisline pomembno vpliva na kemijsko stabilnost delcev, ki smo jih pripravili z uporabo laktoze ter s kombinacijo laktoze in nanoceluloze. Omenjeni delci po enem mesecu shranjevanja izkazujejo zadovoljivo kemijsko stabilnost. Svežim in dispergiranim delcem smo z lasersko difrakcijo izmerili velikost ter z vrstičnim elektronskim mikroskopom ovrednotili njihove morfološke lastnosti. Zanimal nas je vpliv lokacije vzorčenja, uporabljenega antiadheziva, medija ter temperature shranjevanja na velikost dispergiranih delcev, saj je le-ta ključna, da ne prihaja do neželenega mašenja šob glave tiskalnika. Potrdimo lahko, da ustrezno velikost in fizikalno-kemijsko stabilnost izkazujejo predvsem delci s kombinacijo laktoze in nanoceluloze, ki vsebujejo antioksidant in so dispergirani v najbolj viskoznem mediju. Applying active pharmaceutical ingredients to biocompatible substrates using 2D printing technology is an innovative and effective way to customise the dosage of active pharmaceutical ingredients to each individual. This treatment modality could address the challenges that arise in particular in the treatment of chronic diseases, in the treatment of children and the elderly, and in the treatment of high-potency active substances and/or active substances with a narrow therapeutic window. Another important advantage of 2D printing technology is the possibility to prepare the dosage form immediately prior to dispensing to the patient by dispersing the dry particles in the base ink medium and printing them on biocompatible substrates. Therefore, the aim of our research work was to prepare simvastatin dry particles by spray-drying which are suitable for dispersion in the ink media and remain sufficiently physicochemically stable over the entire shelf life. Three different emulsions were produced with lactose, calcium silicate and a combination of lactose and nanocellulose as anti-adhesives. The particles were prepared by spray-drying of the emulsions and the conversion of simvastatin to an amorphous form which was verified by differential scanning calorimetry and Fourier transform infrared spectroscopy. Particles were prepared without and with the addition of ascorbic acid in order to verify the effect of the antioxidant on the chemical stability of simvastatin in the particles. The particles were dispersed in three media containing different proportions of propylene glycol and water. A stability study was carried out for one month, where both dry and dispersed particles were stored at 25 °C and 40 % RH and at 40 °C and 75 % RH. The samples were analysed by ultra-high performance liquid chromatography and the particle content of simvastatin was determined. We found that the addition of ascorbic acid had a significant effect on the chemical stability of the particles prepared using lactose and a combination of lactose and nanocellulose. These particles show satisfactory chemical stability after 1 month of storage. The fresh and dispersed particles were measured for size by laser diffraction and their morphological properties were evaluated by scanning electron microscopy. We were interested in the influence of the sampling location, the used anti-adhesive, the medium and the storage temperature on the size of the dispersed particles, since it is crucial to avoid unwanted lubrication of the printer head nozzles. It can be confirmed that the particles with the combination of lactose and nanocellulose, which contain an antioxidant and are dispersed in the most viscous medium, show the appropriate size and physico-chemical stability.

Dry emulsions are lipid drug delivery systems, where in the process of drying the outer water phase of an oil-in-water emulsion is being replaced with different matrix formers. Currently, dry emulsions are neglected in drug delivery, as they often provide low drug loading and exhibit poor flow properties, consequently, there is a need to improve dry emulsion formulation and/or find alternative methods of production. The main objective of this doctoral thesis was to resolve challenges of utilizing dry emulsions for the delivery of highly lipophilic drugs. In the first part, fluid bed layering was established as a new, alternative method for dry emulsion production. It was demonstrated that the modified Wurster chamber with swirl air flow generator was needed to successfully perform layering experiments. Based on results of microscopy techniques, we were able to confirm that oil phase was homogeneously dispersed in distinct oil droplets within the solid matrix of the pellet coating. Mixture design methodology was successfully employed to optimize stability and reconstitution ability of the dry emulsion layered pellets. Dry emulsion coated pellets provided good flow properties and increased dissolution performance of the model drug simvastatin with low water solubility. In the second part, process and dry emulsion formulation optimization was attempted in combination with spray drying method, as commonly used method for dry emulsion preparation. Nozzle geometry was identified, as a novel process parameter and its extensive effect on all critical quality attributes of dry emulsion powder was confirmed. Utilizing response surface methodology, five optimized products were produced with adequate process yield, particle size distribution, reconstitution ability and improved dissolution profile. However, dry emulsion powders provided poor flow properties. To further optimize flowability and reconstitution ability of spray dried dry emulsions, nanocrystalline cellulose and macroporous silica were introduced in the formulation as insoluble matrix formers. It was shown that macroporous silica had a positive effect on dry emulsion reconstitution ability and flow properties, due to its porous nature and large particles size, yet it partially trapped the oil-simvastatin solution within its pores. Nanocrystalline cellulose eased oil release, but due to its shape, impaired product flow properties. The last part of experimental work focuses on the comparison of fluid bed layering and spray drying as technologies for the production of dry emulsions. Fluid bed layering excelled in all studied responses, namely process yield, encapsulation efficiency, dry emulsion particle size, reconstituted emulsion droplet size distribution, and relative drug chemical stability, except for the maximum drug loading, where spray drying allowed for broader formulation changes and thus higher drug loads. In the conducted bioavailability study in rats, dry emulsion layered pellets provided a remarkable increase in relative bioavailability of 115 %, compared with the reference physical mixture with simvastatin. This work provides an in depth study of dry emulsion systems and their methods of production. The obtained results facilitate dry emulsion production method selection and enable wider use of dry emulsion systems for delivery of lipophilic drugs as they give insight into process and formulation understanding. Posušene emulzije so na lipidih osnovani sistemi, kjer v procesu sušenja zunanjo vodno fazo emulzije tipa olje v vodi nadomestijo različni tvorci ogrodja. Trenutno so posušene emulzije spregledan dostavni sistem, saj običajno ne zagotavljajo dovolj visokega odmerka zdravilne učinkovine, obenem pa izkazujejo slabe pretočne lastnosti. Posledično obstaja realna potreba po izboljšanju tovrstnih formulacij in/ali iskanju alternativnih tehnoloških procesov za izdelavo posušenih emulzij. Glavni cilj doktorske disertacije je bil premostiti izzive, povezane z uporabo posušenih emulzij za namen dostave učinkovin z izrazito lipofilnostjo. V prvem delu raziskav smo kot prvi pokazali, da je metoda oblaganja s tehnologijo z vrtinčenjem primerna za izdelavo sistemov posušenih emulzij. Pokazali smo, da je oblaganje pelet z emulzijo možno le ob uporabi Wursterjeve komore z dodatnim generatorjem krožno simetričnega vrtinčenja zraka. Na podlagi rezultatov mikroskopskih tehnik smo potrdili, da so oljne kapljice homogeno razporejene znotraj trdnega ogrodja obloge pelet. Metoda načrta zmesi je bila uspešno uporabljena za optimizacijo stabilnosti in rekonstitucijske sposobnosti s posušenimi emulzijami obloženih pelet. Tako obložene pelete so izkazovale dobre pretočne lastnosti in izboljšan profil sproščanja simvastatina, modelne učinkovine s slabo topnostjo. V drugem delu smo izvedli optimizacijo procesa in formulacije posušene emulzije v kombinaciji s tehnologijo sušenja z razprševanjem, ki je najpogosteje uporabljena metoda za izdelavo posušenih emulzij. Geometrija šobe je bila prepoznana kot pomemben procesni parameter, pri čemer je bil potrjen njen vpliv na vse proučevane kritične atribute kakovosti. Z uporabo metode odzivnih površin je bilo izdelanih pet produktov, ki so izkazovali ustrezen izkoristek procesa, porazdelitev velikosti delcev, sposobnost rekonstitucije in izboljšan profil sproščanja, a hkrati slabe pretočne lastnosti. Za namen izboljšanja pretočnih lastnosti in sposobnosti rekonstitucije posušenih emulzij smo v formulacijo uvedli makroporozni SiO2 in nanokristalno celulozo. Pokazali smo, da je imel makroporozni SiO2 ugoden vpliv na sposobnost rekonstitucije in pretočne lastnosti, zaradi svoje poroznosti in velikosti delcev, vendar je hkrati v porah deloma zadržal raztopino simvastatina v olju. Nanokristalna celuloza je izboljšala sproščanje oljne faze, vendar je zaradi oblike delcev negativno vplivala na pretočne lastnosti. V zadnjem delu raziskav smo primerjali tehnologijo oblaganja v zvrtinčenih plasteh ter sušenja z razprševanjem, kot tehnologiji izdelave posušenih emulzij. Tehnologija oblaganja v zvrtinčenih plasteh je izkazovala prednost pri vseh proučevanih odzivih, t.j. izkoristku procesa, učinkovitosti vgradnje učinkovine, velikosti posušenih delcev, porazdelitvi velikosti kapljic rekonstituirane emulzije in relativni kemijski stabilnosti, z izjemo vsebnosti zdravilne učinkovine, kjer je tehnologija sušenja z razprševanjem dovoljevala formulacijske spremembe znotraj širšega koncentracijskega intervala in s tem višjo vsebnost učinkovine. V študiji biološke uporabnosti na podganah so s posušenimi emulzijami obložene pelete izkazale izrazito 115 % povečanje biološke uporabnosti v primerjavi z referenčno fizikalno zmesjo z učinkovino. Doktorsko delo predstavlja poglobljeno študijo sistemov posušenih emulzij in tehnologij izdelave. Dobljeni rezultati olajšajo izbiro metode za izdelavo in omogočajo širšo uporabo posušenih emulzij za dostavo lipofilnih zdravilnih učinkovin, saj prispevajo k boljšemu razumevanju formulacij posušenih emulzij ter metod za njihovo izdelavo.

Respiratory devices such as metered dose inhalers (MDI), nebulizers and dry powder inhalers (DPI) have been used to administer active pharmaceutical ingredients to treat lung diseases. Inhalable drug particles for DPI formulation are conventionally produced by a top down approach through crystallization followed by milling. This approach tends to generate partially amorphous materials that require post-processing to improve the formulations’ stability. Other methods involve homogenization or precipitation and often require the use of stabilizers, mostly surfactants. The purpose of our work was therefore to develop a novel method for preparation of fine drug particles using a microfluidic reactor and to find an appropriate particle isolation method, in this case ultrasonic spray freeze drying, hence avoiding the need of additional homogenization step or use of a stabilizer. Different active pharmaceutical ingredients and excipients were tested for compatibility with budesonide and beclomethasone dipropionate found to be the most appropriate for further characterization. In the final developed method, a commercial T-junction microfluidic reactor was employed to produce the particle suspension (using an ethanol–water, methanol-water and an acetone–water systems), which was directly fed into an ultrasonic atomization probe, followed by direct feeding to liquid nitrogen. Freeze drying was the final step in the process. The result were fine crystalline budesonide and beclomethasone dipropionate powders that were characterized by the following analytical techniques: optical microscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), dynamic light scattering (DLS), dynamic vapor sorption (DVS), thermal gravimetric analysis (TGA), X-ray powder diffraction (XRD) and aerosol performance with Next Generation Impactor (NGI). When blended with lactose and dispersed using an Aerolizer at 100 L/min air flow rate, budesonide generated fine particle fraction in the range 47.6±2.8% to 54.9±1.8%, thus exhibiting a good aerosol performance. Drug product formulations were compared to commercially available products and showed comparable aerosol performance. Subsequent sample analysis confirmed the suitability of the developed method to produce inhalable drug particles without additional homogenization or stabilizers. The developed method provides a general viable solution for particle isolation from microfluidic reactor. Pri zdravljenju pljučnih bolezni učinkovine običajno doziramo z uporabo inhalacijskih naprav kot so inhalatorji pod tlakom (MDI), inhalatorji s suhim prahom (DPI) in nebulatorji. Običajno se delci za DPI formulacije pripravljajo s “top-down” pristopom, kjer s kristalizacijo in nato mletjem dosežemo ustrezno velikost delcev. S tem pristopom običajno dobimo amorfen material, ki za izboljšanje fizikalne stabilnosti potrebuje dodatne tehnološke korake. Druge sorodne tehnike vsebujejo homogenizacijo ali obarjanje in običajno zahtevajo uporabo stabilizatorjev oziroma površinsko aktivnih snovi. Namen našega dela je bil razviti novo metodo za pripravo delcev za inhaliranje z uporabo mikrofluidnega reaktorja, hkrati pa poiskati primerno metodo za izolacijo teh delcev. Sušenje z razprševanjem in zamrzovanjem se je izkazalo za najbolj primerno, saj smo se na ta način lahko izognili uporabi dodatne homogenizacije in uporabe stabilizatorjev. Med testiranimi učinkovinami in ekscipienti, sta se kot najprimernejša izkazala Budezonid in Beklometazon dipropionat. Metoda izdelave delcev je vsebovala komercialno dostopen mikrofluidni reaktor s T-stikom (uporabili smo etanolno-vodni, metanolno-vodni ter aceton-vodni sistem), ki je bil neposredno sklopljen z ultrazvočno šobo za razprševanje, usmerjeno v čašo s tekočim dušikom. Sušenje z razprševanjem in zamrzovanjem je predstavljalo zadnji procesni korak. Pridobljene mikronizirane delce smo analizirali z mnogimi analitskimi tehnikami kot: optična mikroskopija, vrstična elektronska mikroskopija (SEM), diferenčna dinamična kalorimetrija (DSC), dinamično sipanje svetlobe (DLS), dinamična sorpcija pare (DVS), termogravimetrija (TGA), rentgenska praškovna difrakcija (XRD) in določanje aerodinamskih lastnosti z NGI. Pripravili smo DPI formulacijo tako pripravljenega budezonida in komercialne laktoze, ter jo z uporabo Aerolizerja pri pretoku zraka 100 L/min analizirali z NGI. Delež delcev z aerodinamičnim premerom manjšim od 5 μm je bi med 47.6±2.8% in 54.9±1.8%, kar je pomenilo dobre aerodinamske lastnosti za inhalacije. Izdelane formulacije so bile primerjane s komercialno dostopnimi izdelki in izkazale podobne aerodinamske lastnosti kot referenčni izdelki. Analize so potrdile primernost nove metode za izdelavo delcev, ki se lahko uporabijo v inhalacijah brez dodatne homogenizacije ali stabilizatorjev. Razvita metoda izolacije je prav tako splošno uporabno rešitev za izolacijo delcev v mikrofluidiki.

Nizka peroralna biološka uporabnost kot posledica nizke topnosti učinkovin v vodi predstavlja vedno večji izziv. Eden izmed pristopov, kako izboljšati raztapljanje in s tem biološko uporabnost slabo vodotopnih učinkovin, je tudi izdelava različnih formulacij na osnovi lipidov. Slednje so lahko v obliki emulzij ali talin, za pretvorbo v trdno stanje pa lahko uporabimo pristope, kot so (mikro)kapsuliranje, direktna adsorpcija na mezoporozne nosilce, granuliranje in druge. Namen magistrske naloge je bil izdelati trdno formulacijo slabo vodotopnih antioksidantov resveratrola in koencima Q10, ki se bo hitro dispergirala v vodnem mediju in izboljšala topnost vgrajenih antioksidantov. Tako resveratrol kot tudi koencim Q10 po biofarmacevtskem klasifikacijskem sistemu uvrščamo v II. razred, saj imata oba slabo vodotopnost in dobro permeabilnost. Za izboljšanje dispergiranja obeh antioksidantov v vodni fazi smo uporabili metodo emulgiranja, in sicer smo resveratrol vgradili v emulzije tipa olje-v-vodi, ki so kot oljno fazo vsebovale srednje- (Captex 355) ali dolgoverižni (olivno olje) triglicerid. Pri koencimu Q10 smo zaradi nizke temperature tališča kot oljno fazo uporabili talino koencima Q10. Kot najboljši emulgator se je v obeh sistemih izkazal Tween 80. Vse emulzije smo pretvorili v hitro disperzibilne prahove, pri čemer smo kot trdni nosilec uporabili mezoporozni Syloid 244 FP. Emulzije z resveratrolom smo solidificirali s pomočjo sušenja z razprševanjem. Pri formulacijah s koencimom Q10 pa smo uporabili tudi ročno granuliranje s talino ter granuliranje s talino v hitro vrtečem mešalniku. Low oral bioavailability as a consequence of the low solubility of active compounds in water poses an increasing challenge. One of the approaches how to improve the dissolution and thus the bioavailability of poorly water-soluble active compounds is also the production of various lipid-based formulations. The latter can be in the form of emulsions or melts. Different approaches can be used for conversion to a solid state, such as (micro)encapsulation, direct adsorption on mesoporous carriers, granulation, and others. The purpose of the master's thesis was to produce a solid formulation of poorly water-soluble antioxidants of resveratrol and coenzyme Q10 which will disperse rapidly in an aqueous medium and improve the solubility of embedded antioxidants. According to the biopharmaceutical classification system, both resveratrol and coenzyme Q10 are classified in II. class because both have poor water solubility and good permeability. To improve the dispersibility of both antioxidants in the aqueous phase, we used the emulsification method, namely resveratrol was incorporated into oil-in-water emulsions which contained medium- (Captex 355) or long-chain (olive oil) triglyceride as the oil phase. Because of the low melting point of coenzyme Q10, the melt of coenzyme Q10 was used as the oil phase in its case. Tween 80 proved to be the best emulsifier in both systems. All emulsions were converted to fast dispersible powders using mesoporous Syloid 244 FP as a solid support. Resveratrol emulsions were solidified by spray drying. In coenzyme Q10 formulations, we used also manual melt granulation and melt granulation in a high-shear mixer.

The encapsulation of proteins into core-shell structures is a widely utilised strategy for controlling protein stability, delivery and release. Despite the recognised utility of these microstructures, however, core-shell fabrication routes are often too costly or poorly scalable to allow for industrial translation. Furthermore, many scalable routes rely upon emulsion-techniques implicating denaturing or environmentally harmful organic solvents. Herein, we investigate core-shell protein encapsulation through single-feed, aqueous spray drying: a cheap, industrially ubiquitous particle-formation technology in the absence of organic solvents. We show that an excipient’s preference for the surface of the spray dried particle is well-predicted by its hydrodynamic diameter (Dh) under relevant feed buffer conditions (pH and ionic strength) and that the predictive power of Dh is improved when measured at the spray dryer outlet temperature compared to room temperature (R2 = 0.64 vs. 0.59). Lastly, we leverage these findings to propose an adaptable design framework for fabricating core-shell protein encapsulates by single-feed aqueous spray drying.

V zadnjih letih prihaja na trg vedno več zdravilnih učinkovin s slabo vodotopnostjo in posledično slabo biološko uporabnostjo pri peroralni aplikaciji. Eden izmed načinov povečevanja topnosti in hitrosti raztapljanja zdravilnih učinkovin je izdelava trdnih disperzij s sušenjem z razprševanjem z uporabo različnih topil in nosilcev. Namen magistrske naloge je bil literaturni pregled raziskav, v katerih so raziskovalci z namenom povečevanja topnosti in hitrosti raztapljanja slabo vodotopnih zdravilnih učinkovin izdelali trdne disperzije z metodo sušenja z razprševanjem z uporabo različnih nosilcev in topil. S sistematičnim literaturnim pregledom smo iz dveh velikih podatkovnih baz pridobili 60 raziskav, ki so ustrezale namenu našega dela. Ugotovili smo, da so raziskovalci v svoje raziskave vključili veliko različnih zdravilnih učinkovin, ki sodijo v različne terapevtske skupine. Največ zdravilnih učinkovin je sodilo v skupino zdravil za bolezni srca in ožilja, ki se tudi v vsakdanjem življenju pogosto uporabljajo. Da so dosegli ustrezno raztapljanje zdravilne učinkovine in nosilca, so uporabili različna topila, največkrat organska. Trdne disperzije so izdelali z uporabo različnih nosilcev, med katerimi so najpogosteje uporabili hidrofilne polimerne nosilce, med njimi največkrat PVP in HPMC, med tem ko so bili mezoporozni nosilci uporabljeni najmanjkrat, kar nas je glede na njihove dobre lastnosti nekoliko presenetilo. V raziskavah so izdelane trdne disperzije tudi vrednotili. Velikost delcev je sicer vrednotilo zelo malo raziskav, so pa v večini teh izdelali manjše delce kot so bili delci uporabljene zdravilne učinkovine. V večini raziskav so dosegli tudi popolno amorfizacijo zdravilne učinkovine v trdni disperziji, ki je v večini raziskav tudi ostala stabilna skozi določeno časovno obdobje pri uporabljenih pogojih testiranja. Izkoristki procesa so bili slabi, so pa raziskovalci dosegli visoke deleže vgrajene zdravilne učinkovine v trdno disperzijo. Skoraj v vseh raziskavah so z izdelavo trdnih disperzij slabo vodotopnih zdravilnih učinkovin dosegli izboljšanje hitrosti raztapljanja v primerjavi s čisto obliko zdravilne učinkovine ali fizikalno zmesjo. Zelo malo raziskav se je ukvarjalo z vgradnjo trdne disperzije v končno farmacevtsko obliko. Raziskav z izdelavo trdnih disperzij, izdelanih s sušenjem z razprševanjem je sicer veliko, vendar med njimi zelo malo z mezoporoznimi nosilci, zato bi bilo v prihodnosti smiselno načrtovati več raziskav z njihovo uporabo. Čeprav so trdne disperzije zelo proučevano področje, je število formulacij na trgu še vedno majhno, zato bi bilo v prihodnje smiselno raziskovati tudi v tej smeri. In recent years, more and more active ingredients have come onto the market that are poorly soluble in water and consequently have low oral bioavailability. One way to increase the solubility and dissolution rate of active ingredients is to prepare solid dispersions by spray drying using different solvents and carriers. The aim of this Master Thesis was to review the literature on studies in which researchers have prepared solid dispersions by spray drying using different carriers and solvents to increase the solubility and dissolution rate of poorly water soluble active pharmaceutical ingredients. Our systematic literature search identified 60 studies from two major databases that were relevant for the purposes of our work. We found that researchers included many different active ingredients in their studies, belonging to different therapeutic groups. Most of the agents belonged to the group of cardiovascular drugs, which are also widely used in daily life. Different solvents, mostly organic, were used to achieve proper dissolution of the drug and carrier. Solid dispersions were prepared using a variety of carriers, with hydrophilic polymeric carriers being the most commonly used, especially PVP and HPMC. Mesoporous carriers were the least used, which was somewhat surprising given their good properties. The surveys also evaluated the solid dispersions prepared. Although very few studies evaluated particle size, most of them produced particles smaller than those of the active ingredient used. Most of the studies also achieved complete amorphization of the active ingredient in the solid dispersion, which remained stable for a period of time under the test conditions used. The process yields were low, but the researchers achieved high percentages of the active ingredient incorporated into the solid dispersion. In almost all the studies, preparation of solid dispersions of poorly water soluble active pharmaceutical ingredients resulted in improvement in dissolution rate as compared to pure form of active pharmaceutical ingredient or physical mixture. Very few articles dealt with the incorporation of solid dispersions into the final dosage form. While there has been a lot of research on the preparation of spray-dried solid dispersions, very little of it has been done with mesoporous carriers, and it would be worthwhile to do more research with them in the future. Although solid dispersions are well researched, the number of formulations on the market is still small, so it would be useful to research them further in the future.

The objective of this study was to explore the possible use of a new combination of two excipients, i.e., nanocrystalline cellulose (NCC) and macroporous silica (MS), as matrix materials for the compounding of dry emulsion systems and the effects these two excipients have on the characteristics of dry emulsion powders produced by the spray drying process. A previously developed liquid O/W nanoemulsion, comprised of simvastatin, 1-oleoyl-rac-glycerol, Miglyol 812 and Tween 20, was employed. In order to comprehend the effects that these two matrix formers have on the spray drying process and on dry emulsion powder characteristics, alone and in combination, a DoE (Design of Experiment) approach was used. The physicochemical properties of dry emulsion samples were characterised by atomic force microscopy, scanning electron microscopy, mercury intrusion porosimetry, energy-dispersive X-ray spectroscopy and laser diffraction analysis. Additionally, total release and dissolution experiments were performed to assess drug release from multiple formulations. It was found that the macroporous silica matrix drastically improved flow properties of dry emulsion powders, however, it partially trapped the oil—drug mixture inside the pores and hindered complete release. NCC showed its potential to reduce oil entrapment in MS, but because of its rod-shaped particles deposited on the MS surface, powder flowability was deteriorated.

Težnja po posamezniku prilagojenemu načinu zdravljenja se iz leta v leto povečuje, saj se potek bolezni in fiziološke lastnosti posameznih bolnikov razlikujejo. Zato si v prihodnosti želimo čimbolj upoštevati specifičnost vsakega posameznika in odmerke zdravil prilagoditi s pomočjo posamezniku prilagojenih farmacevtskih izdelkov. Eden izmed pristopov izdelave takih izdelkov je tudi uporaba tehnologije 2D tiskanja pri ex tempore pripravi, ki predstavlja realno možnost prilagajanja odmerka nizkoodmernih učinkovin. V nalogi smo iz emulzije s kloroformom izdelali delce, ki so vsebovali zdravilno učinkovino simvastatin in polimer polikaprolakton in pri tem zasledovali doseganje najmanjših možnih velikosti delcev. Delce smo izdelali s postopkom sušenja z razprševanjem pri nastavitvah procesnih parametrov, določenih z eksperimentalnim načrtom, in jih kasneje dispergirali v različnih zmeseh propilen glikola in vode. Na podlagi rezultatov eksperimentalnega načrta in vzporedno še z uporabo nevronskih mrež smo poskušali najti optimalno kombinacijo procesnih parametrov. Po prvotni uporabi laktoze, z namenom zmanjšanja adhezije med delci, smo poskušali pod enakimi pogoji izdelati še delce s kalcijevim silikatom ter delce s kombinacijo nanoceluloze in laktoze. S pomočjo vrstične elektronske mikroskopije smo ugotovili, da se tako izdelani delci glede na morfološke lastnosti med seboj bistveno razlikujejo, saj so delci ob prisotnosti laktoze in le-te v kombinaciji z nanocelulozo sprijeti v grozde, medtem ko so po dodatku kalcijevega silikata v emulzijo za razprševanje samostojni. Kljub podobnim velikostnim razredom izdelanih delcev, smo tekom dispergiranja zaznali pomembne razlike. Grozdi delcev z laktozo so se zmanjšali kot posledica raztapljanja laktoze, medtem ko so grozdi izdelani s kombinacijo nanoceluloze in laktoze razpadli do osnovnih delcev grozda kot posledica ločitve antiadheziva od polimernega delca s simvastatinom. Produkt s kalcijevim silikatom ni izkazoval nobenih posebnosti, saj so delci po dispergiranju ostali podobnih velikosti kot v suhi obliki. Istočasno smo vrednotili še vpliv različnih načinov dispergiranja, hranjenja dispergiranega vzorca (en mesec, sobni pogoji, nizka vlažnost) in različnih viskoznosti medija za dispergiranje na velikost dispergiranih delcev. Ustrezna kombinacija procesnih parametrov izdelave je bila ugotovljena z modelom, ki je bil osnovan z eksperimentalnim načrtom. Primeren produkt za uporabo v kartušah za tiskanje je tisti, ki vsebuje zmes nanoceluloze in laktoze in ga dispergiramo v mediju z 90 vol. % propilen glikola. Therapy timeline of numerous diseases and physiological characteristics differ among individuals. The future goal is to consider specifics of each patient and to modify the medicine doses with the use of individual adjusted pharmaceutical products. One of such approaches is also the introduction of two-dimensional printing technology by ex tempore preparation, which can provide real-time dose adjustment of the low-dose APIs. In our work we produced particles consisting of a drug simvastatin and polymer polycaprolactone and monitored reaching the particles of smallest possible size. Particles were prepared by spray drying an emulsion with chloroform as an organic phase and lactose as an antiadhesive material. A spray-drying process parameters giving the smallest particles were determined by using design of experiment. Later, the particles were dispersed in a liquid mixture of propylene glycol and water. The existence of any other process parameters combination, that could result even in smaller particles, was researched using artificial neural network. Our aim was also minimizing adhesion between particles, so other substances like calcium silicate and combination of nanocellulose and lactose were tested in order to examine their influence on size of produced particles. Using scanning electron microscope we found important differences in particle morphology. Smaller particles produced in the presence of lactose and combination of it with nanocellulose were joined into the bigger clusters, while adding calcium silicate in spraying emulsion contributed to individual particles appearing. Despite of similar particle size ranges of each group, we found an important differences also after their dispergation in the medium. Particle clusters of lactose decreased in size due to dissolution of lactose, when the particle clusters produced with combination of nanocellulose and lactose fell apart to individual particles what probably appeared due to the separation of antiadhesive substance from the polymer particle with simvastatin. After dispergation of calcium silicate particles they showed no significant differences in particle size. Parallelly, we evaluated also the influence of different dispergation ways, different liquid mixture viscosity and sample storage for 1 month at room conditions with low humidity to dispersed particle size differences. The appropriate combination of process parameters to reach smallest particle size was established by design of experiment. Potential suitable particles for usage in printing cartridges includes combination of nanocellulose and lactose and are dispersed in liquid mixture containing 90 vol. % of propylene glycol.

Med novo odkritimi zdravilnimi učinkovinami (ZU) prevladujejo slabo vodotopne učinkovine. Slaba vodotopnost negativno vpliva na absorpcijo teh učinkovin, kar ima za posledico nizko biološko uporabnost (BU). Da dosežemo terapevtske koncentracije tovrstnih ZU v sistemskem krvnem obtoku, je potrebna bodisi aplikacija večjega odmerka ZU, kar lahko vodi do neželenih učinkov, ali izboljšanje njene vodotopnosti s pomočjo različnih pristopov. Eden izmed tehnoloških pristopov je vgradnja ZU v na lipidnih osnovane dostavne sisteme, med katerimi so najbolj proučevani samo-(mikro)emulgirajoči sistemi (SMES). V njih je ZU raztopljena, po zaužitju pa v prebavnem traktu v prisotnosti vodne faze pride do spontane tvorbe (mikro)emulzije tipa olje v vodi. Ker so SMES v tekoči obliki, je v zadnjih desetih letih veliko pozornosti usmerjene v postopek njhove pretvorbe v trdno obliko, v kateri bi bile prednosti tekočih SMES združene s prednostmi bolj zaželenih trdnih farmacevtskih oblik. V magistrski nalogi smo se osredotočili na pretvorbo tekočega SMES v trdno obliko z metodama direktne adsorpcije in sušenja z razprševanjem z uporabo trdnih poroznih nosilcev ter ovrednotenje dobljenih produktov. Kot modelno učinkovino smo uporabili karvedilol, ki spada v II. razred po biofarmacevtskem klasifikacijskem sistemu (slabo topna v vodi in dobro permeabilna ZU). V procesu izdelave trdnih samo-(mikro)emulgirajočih prahov smo tekoči SMES z ZU adsorbirali na oziroma v porozne nosilce (Aeroperl® 300 Pharma, Florite® R, Neusilin® US2, Syloid® 244 FP in Syloid® XDP 3050), pri čemer smo spreminjali razmerje med tekočim SMES z ZU in nosilcem (1:1 in 2:1). V literaturi je opisano nepopolno sproščanje ZU iz nosilcev, zato smo za dosego popolnega sproščanja površino slednjim delno deaktivirali z delno zapolnitvijo por. Za to smo uporabili polimere Pharmacoat® 606, PVP K30 in PVP K90. Tako metoda direktne adsorpcije kot sušenje z razprševanjem sta se izkazali kot primerni za pripravo trdnih SMES (ang. »solid« SMES oziroma S-SMES), pri čemer je delna deaktivacija površine nosilcev nekoliko znižala kapaciteto slednjih za adsorpcijo SMES, a povečala obseg sproščene ZU tako v mediju s pH=1,2 kot tudi v pH=6,8. Samo-(mikro)emulgirajočim prahovom smo določili tudi pretočne lastnosti, ki bi jih bilo pred postopkom tabletiranja ali kapsuliranja potrebno izboljšati z dodatkom drsil. Proučevali smo tudi močenje nosilcev pred in po deaktivaciji površine ter trdnih produktov z vodo, SMES ter vodno disperzijo SMES z metodo merjenja stičnega kota sedeče kapljice. Zanimalo nas je, ali obstaja korelacija med močenjem nosilcev z izbranimi tekočinami in določenimi lastnostmi S-SMES (deaktivacija površine, hitrost sproščanja ZU, izkoristek procesa sušenja z razprševanjem). V skladu s pričakovanji je bil stični kot vode nižji na produktih z večjim deležem SMES, kar potrjuje večjo adsorpcijo slednjega na površino nosilcev. Delna deaktivacija površine je vplivala na povečanje kota močenja, kar nakazuje na nalaganje polimera na površino nosilcev. Z metodo diferenčne dinamične kalorimetrije smo potrdili, da ZU v S-SMES ne kristalizira. Zaradi hitre sprostitve ZU iz S-SMES, ki smo jo opazili pri in vitro testu sproščanja, lahko predvidevamo tudi povečano BU. Z veliko količino hkrati sproščene ZU bi lahko nasitili jetrne encime in s tem zmanjšali obseg predsistemskega metabolizma, ki je v primeru karvedilola en od poglavitnih razlogov za slabo BU. Many newly discovered pharmacologically active ingredients are poorly water-soluble. Consequently, the absorption and bioavailability of such drugs are compromised and higher dosages are required to achieve desired therapeutic concentrations. To reduce adverse effects related to higher administered dosages, it is possible to improve the drug solubility by incorporating the active pharmaceutical ingredients (APIs) into lipid formulations. Among the most studied are self-(micro)emulsifying drug delivery systems (S(M)EDDS), where API is already present in the dissolved state. S(M)EDDS spontaneously form oil-in-water (micro)emulsion in an aqueous medium of our gastrointestinal tract after oral intake. During the last ten years, research was widely focused on the S(M)EDDS solidification to optimize advantages of preferred solid pharmaceutical dosage forms while keeping their desired properties. The aim of our work was the transformation of liquid S(M)EDDS into solid state by direct adsorption method and spray drying with the use of solid porous carriers, followed by evaluation of products. Carvedilol was used as a model of poorly soluble drug it belongs to the Class II according to Biopharmaceutical Classification System because of its poor solubility and good permeability. In the process of making solid S(M)EDDS (S-S(M)EDDS), carvedilol loaded S(M)EDDS were adsorbed onto porous carriers (Aeroperl® 300 Pharma, Florite® R, Neusilin® US2, Syloid® 244 FP and Syloid® XDP 3050) in different ratios (1:1 and 2:1). Since incomplete desorption of API from carriers was reported in literature, the surface of used carriers was partially deactivated with partial pre-filling of pores with polymers (Pharmacoat® 606, PVP K30 and PVP K90) to achieve a higher API desorption from S-S(M)EDDS after redispersion. S-S(M)EDDS were successfully produced with both solidification methods. Pre-filling of the pores lowered the capacity for adsorption of S(M)EDDS onto carrier but allowed a higher desorption of API in the medium with pH=1,2 and pH=6,8. The flowability of the products would have to be improved by addition of lubricants prior to compressing into tablets or filling into capsules. The wettability was determined by sessile drop method with water, S(M)EDDS and S(M)EDDS dissolution before and after the deactivation of carrier’s surface. Additionally, the wettability was measured on S-S(M)EDDS. The correlation between wettability of the carriers and S-S(M)EDDS characteristics was assessed by comparing deactivation of the surface, the rate of API desorption and yield of spray drying method. The wetting angle of water on S-S(M)EDDS was lower when the ratio between S(M)EDDS and carriers was higher, which suggests that more S(M)EDDS was adsorbed onto the surface. Partial deactivation of carrier’s surface resulted in a higher wetting angle, which shows that polymer was also adsorbed on the surface. API did not crystalize in S-S(M)EDDS according to our analysis with differential scanning calorimetry. A desorption rate of API from S-S(M)EDDS observed by performing in vitro dissolution tests was fast, indicating the possibility of achieving a higher bioavailability using such systems. Because of a high dose of API released over a short period of time after oral intake, the drug metabolizing enzymes in the liver could be saturated, resulting in a lower first pass metabolism of carvedilol and subsequently, a higher bioavailability of the drug after oral intake.

Liposomi so sferični lipidni vezikli, ki zaradi sposobnosti vgradnje tako hidro- kot tudi lipofilnih učinkovin in tarčne dostave v farmaciji pridobivajo na svoji veljavi kot obetavni nanodostavni sistemi. Eden večjih izzivov je priprava liposomov v industrijskem merilu, kjer sušenje z razprševanjem predstavlja izreden potencial. Izhajajoč iz slednjega, je bil cilj magistrske naloge ovrednotiti vpliv različnih topil in parametrov sušenja z razprševanjem na izdelavo liposomov s predhodno določeno sestavo, s čimer bi pridobili pomembne podatke o možnosti prenosa metode izdelave na proizvodno raven. Na podlagi literature in eksperimentov smo poiskali primerno topilo za raztapljanje fosfolipidov (distearoilfosfatidilholin (DSPC), natrijeva sol distearoilfosfatidilglicerol (DSPG-Na)) in holesterola. Liposome smo izdelali tako, da smo raztopino pomožnih snovi sušili z razprševanjem pri različnih parametrih (hitrost razprševanja, hitrost in temperatura vstopnega zraka). Vmesni produkt smo nato rehidrirali z vodnim medijem ter nastale liposome ekstrudirali skozi polikarbonatno membrano. Na vmesnem produktu smo izvedli termično analizo, liposomom pa smo izmerili hidrodinamski premer, polidisperzni indeks in zeta potencial. Pri eksperimentalnem delu in analizi podatkov smo upoštevali princip načrtovanja eksperimentov, ki nam omogoča, da na majhnem številu eksperimentov dobimo maksimalno količino informacij za ovrednotenje procesa in končnega produkta. Glede na topnost pomožnih snovi in ICH smernic smo za pripravo disperzije izbrali dve topili: mešanico diklorometana in metanola v volumskem razmerju 1:1 in metanol. Proces raztapljanja DSPG-Na v topilih pa smo pospešili s segrevanjem disperzije na 40 °C. Z analizo nastalih liposomov smo ugotovili, da sta nanje imela vpliv le dva parametra sušenja z razprševanjem. Pri nižji hitrosti pretoka zraka dobimo večji izkoristek procesa, če zvišamo temperaturo vstopnega zraka po redispergiranju suhega produkta, pa dobimo manjše liposome. Premer začetnih liposomov se je s približno 800 nm po ekstruziji zmanjšal na 150 nm, medtem ko je bil zeta potencial v obeh primerih praktično enak. Z metodo termične analize vzorcev smo dokazali tudi odsotnost zaostanka topil v suhem produktu. Ključna ugotovitev magistrskega dela je, da se z ekstruzijo liposomov vplivi parametrov sušenja z razprševanjem na velikost in porazdelitev velikosti liposomov izničijo. Liposomes are spherical lipid vesicles constantly gaining ground in drug development as potential drug nanodelivery systems due to their ability to incorporate hydrophilic as well as lipophilic active ingredients. One of the major challenges is liposome production on an industrial scale where spray drying offers great potential. Stemming from the latter, the aim of this master's thesis was to evaluate the effects of different solvents and spray drying parameters on the production of liposomes with predetermined composition in order to obtain information on the possibility of transferring method to the production level. Based on literature and experiments we found suitable solvents for dissolving phospholipids (distearoyl phosphatidylcholine.(DSPC), distearoyl phosphatidylglycerole sodium salt (DSPG-Na)) and cholesterol. Liposomes were prepared by spray drying the lipid dispersion at varying parameters (air flow rate, feed rate and inlet temperature). The spray dried product was rehydrated in aqueous medium and the resulting liposomes were extruded through polycarbonate membrane. Thermal analysis was performed on spray dry powder and hydrodynamic diameter, polydispersity index and zeta potential of liposomes were measured. In experimental work and data analysis, we followed the principle of experimental design which allows us to obtain maximum amount of information for process and end product evaluation on a small number of experiments. Based on excipients solubility and ICH guidelines two solvents were selected for spray drying experiments: a mixture of dichloromethane and methanol in 1:1 volume ratio and methanol. The process of dissolving DSPG-Na was accelerated by heating the dispersion to 40 °C. By analysing the resulting liposomes, we found that their properties were influenced by two spray drying parameters. Higher process yield was obtained at lower air flow rate and smaller liposomes were obtained if the inlet gas temperature was raised. The diameter of the resulting liposomes was about 800 nm and decreased to 150 nm after extrusion, while zeta potential remained the same in both cases. The absence of solvent residue in dry product was proved by thermal analysis of samples. The key finding of the master's thesis was that by extrusion of liposomes the effects of spray-drying parameters on the size and polydispersity index of liposomes are practically eliminated.

Peroralna pot dostave zdravilnih učinkovin je pri bolnikih še vedno najbolj zaželena. Izziv peroralne aplikacije zdravil, ki vsebujejo slabo vodotopne zdravilne učinkovine, je slaba biološka uporabnost le-teh. Biološko uporabnost slabo vodotopnih lipofilnih učinkovin lahko izboljšamo z uporabo na lipidih osnovanih sistemov, med katere spadajo tudi posušene emulzije. V nalogi smo se lotili izdelave posušene emulzije z modelno zdravilno učinkovino simvastatin. Za pripravo posušene emulzije s simvastatinom smo uporabili proces sušenja z razprševanjem. Z uporabo metode načrtovanja eksperimentov (DOE) in programa Minitab smo v prvi fazi preučili vpliv formulacijskih in procesnih parametrov na lastnosti dobljenih produktov. Vhodni parametri, ki smo jih spreminjali so bili: deleži komponent za pripravo emulzije (delež olja, delež površinsko aktivne snovi, koncentracija nevodnih komponent disperzije), geometrija šobe za razprševanje in tlak razprševanja. V drugi fazi smo na podlagi postavitve modelov in analize poiskali vrednosti parametrov - faktorjev, ki so imeli za rezultat optimalne vrednosti predhodno izbranih kritičnih atributov kakovosti. Parametri, ki smo jih optimizirali so bili: srednja velikost delcev, širina porazdelitve velikosti (span) delcev, maksimalna polnjenost vrtečega bobna, povprečna lomljenost konture površine praška v bobnu, in izkoristek procesa. Za določitev atributov velikosti delcev (srednja vrednost in span) smo uporabili metodo laserske difrakcije, za določitev atributov pretočnih lastnosti (povprečna lomljenost konture površine in maksimalna polnjenost) pa smo uporabili metodo vrtečega bobna. Izkoristek smo izračunali na podlagi bilance mas. Po izdelavi optimiziranih produktov, smo preučevane lastnosti tudi preverili in primerjali z vrednostmi, ki jih je predvidel matematični model. Ugotovili smo, da so naše eksperimentalne vrednosti optimiziranih parametrov precej blizu vrednostim, ki jih je napovedal matematični model. S tem lahko potrdimo ustreznost uporabljenih matematičnih modelov za namene napovedovanja parametrov porazdelitve velikosti delcev, povprečne lomljenosti konture površine, maksimalne polnjenosti in izkoristka procesa sušenja z razprševanjem. Prav tako smo ugotovili, da produkti izkazujejo precej slabe pretočne lastnosti. Za izboljšanje pretočnih lastnosti izdelanih produktov bi tako potrebovali dodatne tehnološke postopke (granulacija, dodatek drsil itd.). S testom raztapljanja smo uspeli potrditi, da se simvastatin iz sušene emulzije sprosti bistveno hitreje in v večjem obsegu v primerjavi s čistim simvastatinom in sproščanjem simvastatina iz generične tablete. Oral route of drug administration is still the preferred route among patients. One drawback of the oral application of medication, that contains poorly soluble active ingredients, is the inferior bioavailability of active pharmaceutical ingredients. Bioavailability can be increased by formulating lipophilic active ingredients as lipid-based systems. One option is the preparation of dried emulsions. In the thesis dried emulsions with simvastatin were prepared. Process of spray drying was used to obtain the product. In the first part the design of experiments methodology (DOE) together with Minitab software was used to determine the effect of various formulation and process parameters on the properties of spray dried products. Varied input parameters were: percentages of starting emulsion components (oil component percentage, percentage of surfactants, dispersion concentration), spraying nozzle position and spraying pressure. In the second part of experiments the input parameters that yielded the best results for the previously determined product critical attributes were established, i.e. based on analyzed data and mathematical models. These product attributes were: particles median size, span of particles size distribution, average normalized boarder length, maximum filling of the rotating cylinder and the process yield. To determine the values of particles median size and size distribution span we used the laser diffraction method. Rotating cylinder method was used to determine the flow properties of prepared products. Process yields were calculated from the mass balance before and after the process. After the optimized spray drying products were produced, we analyzed the desired properties and compared them with the values that were predicted by the mathematical model. We found out that the experimental values are similar to the predicted ones. Considering the results we can say that established models are capable of predicting the output values of particles median size, size distribution span, average normalized boarder length, maximum filling ratio and process yield based on the input process and formulation parameters. Also, based on the flow properties data analysis, we concluded that finished products have poor flow properties and would require additional technological processes (e.g. granulation, adding lubricants etc.) to render them usable for pharmaceutical industry applications. With the utilization of dissolution tests we managed to demonstrate that the release of simvastatin is substantially faster and complete in comparison with the pure simvastatin and the release of simvastatin from the generic tablet.

Več kot 40 % zdravilnih učinkovin, odkritih v zadnjih dveh desetletjih, je slabo topnih v vodi in fizioloških tekočinah. Zagotavljanje zadostne koncentracije teh učinkovin na mestu delovanja predstavlja velik izziv številnim razvijalcem formulacij. Eno od možnih rešitev tega izziva predstavlja oblikovanje posušenih emulzij, ki so postale zanimive po odkritju, da dodatek nekaterih lipofilnih pomožnih snovi v farmacevtske oblike spodbuja absorpcijo zdravil iz prebavil po limfni poti. Posušene emulzije je moč pripraviti s procesom sušenja z razprševanjem, ki v enem koraku, z odstranitvijo zunanje faze, spremeni emulzijo v suh prašek v obliki trdne disperzije oljne faze. S spremembo agregatnega stanja klasičnih emulzij v trdnega, se izognemo težavam klasičnih emulzij - združevanju oljnih kapljic in potencialni kemijski razgradnji, ki povzroča nestabilnost formulacije. Za ustrezno razporeditev oljne faze po sušenju se pogosto uporabijo trdni nosilci. V naši nalogi smo uporabili makroporozne delce silicijevega dioksida, ki spadajo med visokoporozne nosilce ter nanokristalno celulozo, ki spada med polimerne nosilce. Trdno fazo sistema sta sicer tvorila še manitol in hidroksipropilmetilceluloza. Eksperimentalni del naloge je obsegal preliminarno študijo, v kateri smo ugotavljali meje količin pomožnih snovi v formulacijah, ki jih še lahko izdelamo s sušenjem z razprševanjem. Te smo nato vstavili v programsko opremo Minitab in izdelali eksperimentalni načrt, ki je obsegal 17 različnih poskusov. Formulacije smo razpršili, posušenim emulzijam pa pomerili več različnih lastnosti - odzivov, ki smo jih uporabili pri modeliranju. Z metodo laserske difrakcije smo izmerili več velikosti: velikost kapljic izhodiščne emulzije, delce suspenzije nosilnih delcev v emulziji, posušenih emulzij ter velikost oljnih kapljic po redispergiranju posušenih emulzij v vodi. Prav tako smo opazovali pretočne lastnosti suhega produkta. Ugotovili smo, da silicijev dioksid izboljša pretočnost posušenih emulzij ter viša izkoristek procesa sušenja z razprševanjem, a se zaradi visoke poroznosti tega trdnega nosilca oljne kapljice z zdravilno učinkovino ne morejo v celoti sprostiti v stiku z vodo ali medijem za sproščanje. Sproščanje izboljša dodatek nanokristalne celuloze v formulacijo, saj ta predvidoma obda površino sten por silicijevega dioksida. Deleža teh dveh pomožnih snovi v formulaciji moramo uravnotežiti, saj višji delež nanokristalne celuloze niža izkoristke procesa sušenja ter poslabša pretočne lastnosti suhega produkta. More than 40 % of active pharmaceutical ingredients (APIs) discovered in last two decades are poorly soluble in water or body fluids. When developing a drug formulation, it is a great challenge to ensure concentration of API which is high enough, to furnish pharmacological activity. One of possible solutions to overcome this challenge are dry emulsions, which gained interest after scientists have discovered that adding certain lipophilic excipients to drug formulation enhances drug absorption in the gastrointestinal tract. Spray drying is a viable procedure for preparation of dry emulsions. It is the process which changes the emulsion into dry powder in one step, i.e. with drying the outer aqueous phase of emulsion. Changing the aggregate state of emulsion from liquid to solid state is a great way to avoid drawbacks of classic emulsions such as creaming, flocculation, droplet coalescence and potential drug instability. Solid carriers are often used, to ensure the proper oil droplet size distribution after the drying procedure. In our formulations we used macroporous silica as a highly porous carrier and nanocrystalline cellulose as a polymer carrier. Dried emulsion solid phase contained mannitol and hydroxypropyl methylcellulose as well. Experimental work began with screening (preliminary study), where the ranges of excipients in the formulation, that are still possible to spray dry, were identified. We entered those ranges in statistical software Minitab and used Design of Experiments (DoE) to generate 17 different experiments that were performed in random order. After spray drying formulations from experimental plan, we measured their properties – responses. We used lasser difraction to measure the emulsion droplet size distribution, particle size of solid carriers, that were not soluble in water/emusion, particle size of dry emulsion systems and size distribution of oil droplets in samples, after they were redispersed in water. Besides droplet and particle size, flow properties of dry emulsion powders were one of the observed attributes in our study. We analysed the responses data and figured out, that inclusion of porous silica improves product flow properties and process yield, but does not release all drug containing oil droplets into aqueous medium due to carrier particle high porosity. Addition of nanocrystalline cellulose in formulation improves the dissolution of the simvastatin but reduces process yields and flow properties, presumably due to pore surface coverage. Therefore we have to make a compromise between silica and nanocrystalline cellulose concentrations to get the formulation with desired properties.

Simvastatin spada v II. razred BCS klasifikacije zdravilnih učinkovin, kar pomeni, da ima slabo vodotopnost in dobro permeabilnost. Slaba vodotopnost simvastatina vodi do pomislekov pri kronični uporabi zaradi nižje biološke uporabnosti. Uporaba na lipidih osnovanih sistemov se je uveljavila kot eden izmed pristopov povečanja topnosti in posledično biološke uporabnosti slabo vodotopnih lipofilnih zdravilnih učinkovin. Dodatno lahko na lipidih osnovani sistemi, ob ustreznih pogojih, nudijo tudi zmanjšanje učinka metabolizma prvega prehoda z izkoriščanjem alternativne poti absorpcije preko limfnega obtoka. Tekoče emulzije nudijo številne prednosti na lipidih osnovanih sistemov, vendar imajo tudi nekatere slabosti, kot sta fizikalna nestabilnost in zmanjšana kemijska stabilnost zdravilne učinkovine. S pretvorbo tekočih emulzij v posušene emulzije smo poskušali oblikovati formulacijo za peroralno dostavo učinkovine, ki bi odpravila slabosti tekočih emulzij ter z redispergiranjem ohranila prednosti na lipidih osnovanih sistemov. S postopkom sušenja z razprševanjem smo oblikovali delce, ki so nam v vodnem mediju omogočili samodejno redispergiranje posušene emulzije. Izdelane posušene emulzije smo vrednotili z vidika porazdelitve velikosti delcev, izkoristka procesa, pretočnih lastnosti, vsebnosti vlage, stabilnosti vgrajene učinkovine, učinkovitosti redispergiranja, učinkovitosti vgradnje učinkovine in profila sproščanja. Rezultati preliminarnih testiranj v začetnih stopnjah eksperimentalnega dela so služili kot izhodišče za določitev mej neodvisnih spremenljivk in postavitev eksperimentalnega načrta. Neodvisne spremenljivke so zajemale: koncentracijo nevodnih komponent, masni delež olja in emulgatorja, geometrijo šobe in tlak na šobi. Na podlagi rezultatov izvedenih poskusov eksperimentalnega načrta smo postavili modele kvantitativnega vpliva faktorjev na odzive, z relativno visokimi koeficienti determinacije ter optimizirali tako sestavo emulzije kot procesne parametre z vidika ključnih atributov kakovosti produkta. Optimizirali smo ustreznost redispergiranja, kemijsko stabilnost simvastatina in učinkovitost vgradnje simvastatina. Ustreznost optimizacije se je izkazala v izboljšanju enomesečne stabilnosti simvastatina v posušenih emulzijah in v izboljšani rekonstituciji emulzije. S pripravo optimizirane formulacije in merjenjem odziva, modela učinkovitosti vgradnje učinkovine nismo potrdili, zato ne moremo trditi kateri parametri in v kakšni meri vplivajo na vgradnjo simvastatina v posušene emulzije. Izboljšanje profila sproščanja v primerjavi s trenutno dostopnimi produkti na tržišču nakazuje na potencial povečanja biološke uporabnosti simvastatina po peroralni aplikaciji. Simvastatin is classified as a Biopharmaceutics Classification System Class – II active pharmaceutical ingredient, which means that it has low water solubility and high permeability. The poor water solubility of simvastatin leads to concerns with chronic use, due to it's lower bioavailability. The use of lipid-based drug delivery systems has emerged as one of the approaches to increase the solubility and consequently bioavailability of poorly water soluble lipophilic active pharmaceutical ingredients. In addition, lipid-based systems may, under appropriate conditions, also reduce the effect of first-pass metabolism by exploiting an alternative route of absorption through the lymphatic circulation. Liquid emulsions offer many advantages of lipid-based systems, but they also have some disadvantages, such as physical instability and reduced chemical stability of active pharmaceutical ingredient. By converting emulsions into dry emulsions, we tried to design a solid dosage form for oral application, which would eliminate the disadvantages of liquid emulsions and maintain the advantages of lipid-based systems by redispersion. Through the spray drying technology we formed particles that allowed us to automatically redisperse the dry emulsion in an aqueous medium. Dry emulsions produced were evaluated in terms of particle size distribution, process yield, flow properties, moisture content, stability of simvastatin in dry emulsion, emulsion reconstitution ability, efficiency of incorporation of the active ingredient and dissolution profile. The results of preliminary formulation development in the initial stages of experimental work served as a starting point for determining the boundaries of the independent variables and setting the experimental design. The independent variables included: concentration of non-aqueous components, oil and emulsifier mass fraction, nozzle geometry and nozzle pressure. Based on the results of the experimental design experiments, we set up models with relatively high determination coefficients and optimize both the emulsion composition and the process parameters in terms of key product quality attributes. We optimized the adequacy of redispersion, chemical stability of simvastatin, and the effectiveness of simvastatin incorporation. Optimization adequacy has been demonstrated in improving the one-month stability of simvastatin in dry emulsions and in the improved reconstitution of the emulsion. By preparing an optimized formulation and measuring the response, we have not confirmed the drug loading model, so we cannot state which parameters and to what extent affect the drug loading of simvastatin into dry emulsions. Enhanced dissolution profile, compared to currently available products on the market, indicates the potential for increased bioavailability after oral administration.

Namen magistrske naloge je bil razvoj vodotopnega propolisa z liofilizacijo in sušenjem z razprševanjem v arabski gumi in mešanico arabskega gumija in maltodekstrina. Analizirali smo učinkovitosti kapsulacije, antioksidativni potencial, disperzibilnost v vodi, morfološke značilnosti in velikosti nastalih kapsul. Tako liofilizacija kot sušenje z razprševanjem sta uspešno kapsulirala etanolni ekstrakt propolisa. Vzorci, ki so bili kapsulirani z liofilizacijo, so imeli višjo vsebnost fenolnih spojin in kapsulacijsko učinkovitost ter antioksidativni potencial. Še posebej visoko vsebnost fenolov in antioksidativni potencial so imeli vzorci, ki predhodno niso bili centrifugirani. Sušenje z razprševanjem je ustvarilo kroglaste kapsule bolj uniformnih oblik in manjših velikosti kot liofilizacija, kjer so bile kapsule neenakomernih oblik z velikim razponom v velikosti. The objective of the master's thesis was the development of water-soluble propolis with lyophilisation and spray drying methods in gum arabic and gum arabic and maltodextrin mixture. We have analysed the encapsulation efficiency, antoxidative potential, water solubility, morphological characteristics and size of the capsules. Both lyophilisation and spray drying were successful at encapsulating the propolis ethanol extract. The samples that were encapsulated with lyophilisation had higher total phenol contents, encapsulation efficiencies, and antioxidant potential and prolonged the oxidation of fish oil for longer than the samples that were obtained with spray drying. The samples that were not centrifuged before encapsulation had the highest phenol contents and antioxidant potential but the lowest solubility. Spray drying created capsules with uniform circular shapes that were smaller in diameter than the ones created with lyophilisation that were uneven in shape and generally larger.

Salicilna kislina je kozmetično aktivna spojina, ki se pod določenimi omejitvami, navedenimi v Uredbi (ES) št. 1223/2009 o kozmetičnih izdelkih že dolgo časa uporablja kot aktivna sestavina predvsem v izdelkih za nego mastne kože, nagnjene k nastanku aken ter v šamponih proti prhljaju. V boju proti komedonom ima pred drugimi keratolitiki to prednost, da je lipofilna, ima pa tudi slabe strani - ker je molekula salicilne kisline majhna, zlahka penetrira v globlje plasti kože, kar v tem primeru ni zaželeno, saj se tako le majhen čas po aplikaciji zadrži na roženi plasti. Poleg tega lahko na bolj občutljivi koži povzroča draženje. To sta bila tudi glavna vzroka, ki sta nas pripeljala do ideje, da to kozmetično aktivno spojino vgradimo v mikrokapsule. V okviru diplomske naloge smo pripravljali disperzije ogrodnih materialov arabskega gumija in maltodekstrina v različnih razmerjih. V prvem primeru smo salicilno kislino raztopili v etanolu, v drugem pa v olju. Emulzijo smo pred sušenjem z razprševanjem stabilizirali s Tween-om 20. Iz formulacij, ki so vsebovale etanol, smo dobili delce, velike 27 µm, v katere se salicilna kislina ni vgradila, kar smo ugotovili s pomočjo profila raztapljanja. Ko smo raztopini arabskega gumija z dodano površinsko aktivno snovjo dodali salicilno kislino, predhodno raztopljeno v sončničnem olju, ter nastalo emulzijo posušili s postopkom sušenja z razprševanjem nam je uspelo narediti mikrokapsule z visoko vsebnostjo učinkovine. Profil sproščanja učinkovine v vodi je pokazal, da je sproščanje preveč podaljšano. Sprememba medija iz nevtralnega v kisel pH (4 in 5) ni pokazala razlik. V alkalnem mediju (pH 8) se je sprostilo nekaj več učinkovine, vendar v predolgem časovnem okvirju, da bi bila vgradnja naših mikrokapsul v kozmetični izdelek smiselna. V prihodnosti bi bilo smiselno optimizirati pogoje sušenja, predvsem pa formulacijo – na primer z dodatkom hidroksipropil metil celuloze ali katerega drugega vodotopnega polimera. Salicylic acid is a cosmetically active ingredient, which has long been used as an active ingredient, especially in products for oily skin prone to acne and in anti-dandruff shampoos. It is used under certain restrictions, listed in the Regulation (EC) No. 1223/2009 on cosmetic products. In the fight against comedones, it has the advantage over other keratolytics because of its lipophilic nature. Nonetheless, it has some disadvantages as well - the molecule of the salicylic acid is small, so it can easily penetrate into deeper layers of the skin, which is not desirable in this case, as the active ingredient is retained on the corneal layer only for a short period of time. In addition, it can cause irritation on sensitive skin. These were also the main reasons that led us to the idea of incorporating this cosmetically active compound into microcapsules. Within the frame of the diploma thesis, dispersions of arabic gum and maltodextrin were prepared in various proportions. In the first case, the salicylic acid was dissolved in ethanol, and in the second case, it was dissolved in oil. The emulsion was stabilized before spray-drying with Tween 20. The formulations containing ethanol yielded 27-µm large particles in which the salicylic acid was not incorporated - this was determined by the dissolution profile. When the salicylic acid, previously dissolved in sunflower oil, was added to a solution of arabic gum with a surfactant, and the resulting emulsion was dried by a spray-drying, we were able to make microcapsules with a high content of the active substance. The release profile of the active substance in water showed that the release was too prolonged. Changing the medium from neutral to acidic (pH 4 and 5) showed no difference. A little more substance was released in the alkaline medium (pH 8), but it was still not enough to make sense of incorporating our microcapsules into a cosmetic product. In the future, it would be wise to optimize the drying conditions and the formulation, for example, by adding hydroxypropyl methyl cellulose or any other water-soluble polymer.

Minitablets in orodispersible form constitute a flexible drug delivery tool for paediatric and geriatric population as they eliminate the risk of chocking and do not require drinking water in the application. Due to their direct contact with taste buds, taste sensation is an important factor. Preparing microparticles with taste masking polymers utilizing spray drying is an efficient technique for reducing the bitterness of drugs. Ethylcellulose is a hydrophobic polymer widely used as a taste masking material. Rupatadine fumarate, one of the newest antihistamines, features an intensive bitter taste, hence in designing orodispersible formulations, achieving an acceptable taste is a crucial issue. The main objective of this work was to formulate orodispersible minitablets containing taste masked ethylcellulose-based microparticles with rupatadine fumarate and evaluation of their quality, especially in terms of taste masking efficacy. The accessed data indicated that all obtained minitablets were characterized by beneficial pharmaceutical properties. Three independent methods: in vivo with healthy volunteers, in vitro drug dissolution, and &ldquo, electronic tongue&rdquo, confirmed that all designed formulations provided satisfactory taste masking rate and that formulation F15 (prepared with Pearlitol&reg, Flash and Surelease&reg, microparticles with rupatadine fumarate) was characterized by the lowest bitterness score.

Namen magistrskega dela je prikazati razvoj tehnološkega procesa proizvodnje prehrambenih kalcijevih fosfatov s poudarkom na sušenju z razprševanjem. V TKI Hrastnik smo edini proizvajalci prehrambenih kalcijevih fosfatov v Sloveniji, prav tako je na razpolago zelo malo literature o proizvodnih postopkih pridobivanja le-teh, zato se pri razvoju tehnološkega postopka opiramo predvsem na zahteve kupcev, ki določajo, kakšen naj bo produkt. Seveda je potrebno upoštevati tudi zahteve, ki jih narekujejo predpisi. Prva faza razvoja tehnološkega procesa prehrambenih kalcijevih fosfatov je potekala v prostorih Kemijskega inštituta v Ljubljani, kjer smo na pilotni napravi testirali in definirali procesne parametre kot so pH vrednost napajalne raztopine (slurry-ja), temperatura reakcije, vstopna in izstopna temperatura napajalne raztopine za sušenje na razpršilnem sušilniku. Druga faza razvoja prehrambenih kalcijevih fosfatov pa je prenos iz pilotne naprave v proizvodni proces, kjer smo definirali še preostale procesne parametre, kot so pretok napajalne raztopine na razpršilni disk, hitrost razprševanja oziroma hitrost vrtenja razpršilnega diska. Ugotovili smo, da samo s sušenjem in sejanjem ne dosežemo ustrezne porazdelitve velikosti delcev, prav tako pa samo s povečanjem hitrosti razprševanja problema neustrezne porazdelitve velikosti delcev ne rešimo. Potrebna je še dodatna operacija in to je mletje. The purpose of this master’s thesis is to show the developement of the technological process for obtaining food calcium phosphates with an emphesis on spray drying. TKI Hrastnik is the only producer of food calcium phosphates in Slovenia. Literature containing a description of the stages for producing food grade calcium phosphates are scarce, and therefore we always follow the clients demands (about the end product), when addressing and developing the technological stages. At the same time regulations are followed as demanded. The first stage in the developement of technological process for obtaining calcium phosphates was conducted at the Chemical institut in Ljubljana (Kemijski inštitut v Ljubljani), where parameters of the process, such as the pH of the feed, the temperature of the reaction, the ingoing and outgoing temperature of the feed for the spray drying were tested and defined. The experiments were conducted on a pilot plant. The second stage in the developement of technological process for obtaining calcium phosphates was the transfer of the process from the pilot plant to the production scale where we later defined the remaining parameters of the process, such as the flow of the feed onto the spray disc, and the speed of spraying/ the speed at which the spray disc rotates. It was found that with drying and sieving the suitable particle size distribution can not be achieved and that by increasing the speed of spraying this particular problem can not be solved. To properly solve this problem another process must be added into the chain – milling.