The impact of formulation and electrospraying method process parameters on the properties of polycaprolactone particles with simvastatin

Polimerni delci predstavljajo obetajoč dostavni sistem, ki omogoča tako vgrajevanje slabo topnih zdravilnih učinkovin kot tudi njihovo prirejeno sproščanje. Prav tako lahko s polimernimi delci dosežemo hiter začetek delovanja, ustrezno vzdrževanje terapevtske koncentracije učinkovine v plazmiin njeno zmanjšano pogostostodmerjanja,karnenazadnje vpliva tudi na večje sodelovanje bolnikov. Z metodo elektrostatskega razprševanja lahko izdelamo polimerne delce, ki poleg vsega zgoraj naštetega še prevedejo zdravilno učinkovino v amorfno stanje, kar pa poleg velikosti nastalih delcev vpliva tudi na njeno višjo metastabilno topnost, polimerno ogrodje pa omogoča zaščito pred njenim razpadom. Namen magistrske naloge je bil izvesti prvi korak v smeri povečanja topnosti slabo topne učinkovine, in sicer izdelati suhe, monodisperzne polikaprolaktonske (PCL) delce z vgrajenim simvastatinom (SIM) ob uporabi načrtovanja eksperimentov. Polimerne delce smo izdelali z metodo elektrostatskega razprševanja in dvema načrtoma eksperimentov, znotraj katerih smo preučevali vpliv procesnih in formulacijskih parametrov na lastnosti polimernih delcev. Morfologijo, velikost in porazdelitev velikosti delcev smo preučili s pomočjo slik zajetih z vrstičnim elektronskim mikroskopom ter uporabo programa ImageJ. V preliminarnem razvoju smo elektrostatsko razprševali raztopine z razmerjem PCL in SIM 2:1 v kloroformu oziroma trifluoroetanolu, pri katerem delci niso nastali ne glede na izbrano topilo oziroma procesne parametre. Ugotovili smo, da je na nastanek delcev signifikantno vplivalo razmerje koncentracije SIM in PCL. Zato smo v nadaljevanju z eksperimentalnima načrtoma skrbno preučevali vpliv vseh procesnih in formulacijskih parametrov na velikost in porazdelitev velikosti polimernih delcev. Ugotovili smo, da imata na velikost in porazdelitev velikostinajvečjivpliv pretok in koncentracija polimera v raztopini.Kot najbolj optimalni protokol smo določili elektrostatsko razprševanje polimerne raztopine z 9,5 % (m/V) PCL in 0,5 % (m/V) SIM s pretokom 300 μL/h pri relativni vlažnosti 40 % in temperaturi 25 °C, ki je vodil v nastanek delcev s povprečnim premerom 2,15 μm. Cilj magistrskega dela je bil dosežen z uspešno izdelavo PCL delcev s SIM, ki bi jih bilo v naslednjem koraku potrebno še fizikalno-kemijsko ovrednotiti.Polymeric particles represent a promising delivery system that enables the incorporation of poorly soluble drugsand modifiestheir release.Polymer particlescan also be used to achieve rapid onset of action, adequate maintenance of therapeutic plasma concentrations, and reduced dosing frequency, ultimately resulting in enhanced patient compliance. Electrospraying enables incorporation of a drug into polymeric particles in an amorphous state, which, along with the size of the particles, increases the drug\u27s metastable solubility. In addition, the polymer matrix protects the drug from disintegration. The aim of this master\u27s thesis was to develop dry, monodisperse polycaprolactone (PCL) particles loaded with simvastatin (SIM) using the design of experiments as the first step towards increasing its solubility. Polymer particles were developed by the electrospraying method and design of experiments, within which we studied the effects of process and formulation parameters on the properties of polymer particles. The morphology, size and size distribution of the particles were studied using images taken with a scanning electron microscope and the program ImageJ. In the initial experiments, we electrosprayed polymer solutions with a ratio of PCL and SIM of 2:1 in chloroform or trifluoroethanol, which did not result in the formation of particles regardlessof the solventor processparameters chosen.We found that the concentration ratio of SIM and PCL significantly affected the formation of particles. Further, we have investigated the effects of all process and formulation parameters on the size and size distribution of polymer particles using the designs of experiments. The flow rate and polymer concentration in the solution significantly impacted the size and size distribution of the particles. The most optimal protocol was electrospraying polymer solution containing 9.5 % (m/V) PCL and 0.5 % (m/V) SIM with a flow rate of 300 μL/h at a relative humidity of 40 % and a temperature of 25 °C. This resulted in particles with an average diameter of 2.15 μm. The objective of the master\u27s thesis was achieved by successful preparation of PCL particles with SIM, which have to be physico-chemically evaluated in the next step