Solubility enhancement of clarithromycin by incorporation into polymeric microparticles using electrospraying technique

Velik delež novoodkritih učinkovin v vodi izkazuje slabo topnost in nizko hitrost raztapljanja, kar se kaže v majhni biološki uporabnosti zdravila. Izboljšanje topnosti in hitrosti raztapljanja učinkovine je zato zelo pomemben raziskovalni vidik farmacevtske industrije. Obetaven pristop za izboljšanje topnosti učinkovine je elektrostatsko razprševanje, pri čemer nastanejo trdne disperzije v obliki polimernih mikro- in nanodelcev z vgrajeno učinkovino. V raziskovalnem delu smo najprej z uporabo različnih matematičnih modelov proučili interakcije med klaritromicinom in polimeri, kar je bistvenega pomena za uspešno pripravo trdnih disperzij. Te smo pripravili z odparevanjem topila in elektrostatskim razprševanjem. Za elektrostatsko razprševanje smo na podlagi proučenih interakcij, literaturnih podatkov in preliminarnih poskusov elektrostatskega raprševanja izbrali polimer PVP K30. Da bi dosegli čim bolj stabilen proces elektrostatskega razprševanja smo preizkusili različna topila in njihove kombinacije. S stabilnostnega in toksikološkega vidika se je najbolje izkazala kombinacija n-butanola in tetrahidrofurana. Z omenjeno kombinacijo topil smo pripravili 8% raztopino klaritromicina in PVP K30 1:1 (m/m), ki smo jo razprševali z večkanalno šobo, pri čemer so nastali delci velikosti 1840 nm. Delce in klasično trdno disperzijo, pripravljeno z odparevanjem topila, smo analizirali z DSC, TGA, FTIR, XRPD in in-vitro testom raztapljanja v deionizirani vodi in fosfatnem pufru (pH = 6,8). Ugotovili smo, da se klaritromicin v delcih nahaja v amorfni obliki, v klasični trdni disperziji pa v kristalni obliki solvata z n-butanolom. Obe formulaciji v vodi in pufru izkazujeta višjo hitrost raztapljanja in topnost od same učinkovine. Delce in trdno disperzijo smo starali 1 mesec pri 25°C in RH=0% ter z zgornjimi analiznimi tehnikami ocenili njuno stabilnost. Lastnosti delcev se med staranjem niso spreminjale, pri trdni disperziji pa je prišlo do manjših sprememb trdnega stanja snovi. Elektrostatsko razprševanje je enostavna in učinkovita metoda za pripravo trdnih disperzij v obliki polimernih mikro- in nanodelcev, ki izboljšajo lastnosti raztapljanja vgrajene učinkovine, poleg tega pa delci v primerjavi s klasičnimi trdnimi disperzijami izkazujejo večjo stabilnost.A large portion of newly discovered drug substances exhibits poor solubility and dissolution in water, which reflects in poor drug bioavailability. Solubility and dissolution enhancement is therefore an important aspect in pharmaceutical industry. Electrospraying is a promising technique to increase drug solubility by preparing solid dispersions in the form of micro- or nanoparticles. In the present study we have used different mathematical models to examine interactions between clarithromycin and different polymers, which is highly important for successful preparation of solid dispersions. The latter were prepared by solvent evaporation or electrospraying method. Based on the results of interaction studies, literature sources and preliminary electrospraying experiments, polymer PVP K30 was chosen for our study. In order to achieve a stable eletrospraying process we examined different solvent mixtures. Combination of n-butanol and tetrahyrofuran proved to be optimal in aspects of process stability and solvent toxicity. We prepared 8% solution of clarithromycin and PVP K30 1:1 (m/m) using previously mentioned solvents. The solution was successfully electrosprayed by a multi-nozzle injector, resulting in 1840 nm particles. The particles and a conventional solvent evaporation solid dispersion were analysed by DSC, TGA, FTIR, XRPD and in-vitro dissolution test in deionised water and phosphate buffer (pH = 6,8) by HPLC. Clarithromycin was found to be present in amorphous form in electrosprayed particles and in n-butanol solvated crystalline form in conventional solvent evaporation solid dispersion. Both formulations exhibit superior solubility and dissolution to pure drug in water and buffer. A one month stability study of particles and solid dispersion was performed at 25°C and RH=0% using above mentioned analytical techniques. Minor solid state changes were noticed in solid dispersion while properties of particles remained the same. Electrospraying is an easy and effective method of enhancing drug dissolution by preparing solid dispersions in the form of drug-loaded polymeric micro- and nanoparticles that exhibit superior stability to conventional solvent evaporation solid dispersions