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U radu je izvršena formulacija nove generacije nosača lekovitih supstanci tipa polučvrstih samo-mikroemulgujućih sistema (SMEDDS), pogodnih za razvoj tvrdih kapsula kao finalnog čvrstog farmaceutskog oblika, kao i sveobuhvatna fizičko-hemijska, farmaceutsko-tehnološka i biofarmaceutska karakterizacija u cilju sagledavanja njihovog potencijala za peroralnu primenu aciklovira kao model aktivne supstance. Dodatno, kod sistema koji ispunjava postavljene kriterijume u pogledu fizičko-hemijskih i farmaceutsko-tehnoloških karakteristika, kao i biofarmaceutskog profila, izvršena je procena uticaja samo-mikroemulgujućeg nosača na biološku raspoloživost aciklovira i neškodljivost razvijenih sistema in vivo na animalnom modelu. U prvoj fazi istraživanja ispitan je uticaj različitih formulacionih parametara u tečnim pseudo-ternernim sistemima pripremljenim od ulja (trigliceridi srednje dužine lanaca), surfaktanata (PEG-8 kaprilno/kaprinski gliceridi, polisorbat 20, makrogol glicerol hidroksistearat), ko-surfraktanata (poligliceril-3-dioleata) i korastvarača (glicerol, makrogol 400), i procenjen je njihov potencijal kao nosača za peroralnu primenu aciklovira kao model aktivne supstance sa karakteristikama grupe 3, odnosno, 4 prema biofarmaceutskom sistemu klasifikacije (BSK). Kapacitet sistema za inkapsulaciju aciklovira iznosio je 0,18-31,66 mg/ml. Od ukupno 60 ispitanih formulacija, tri su odgovarale kriterijumima postavljenim za SMEDDS u pogledu prosečne veličine kapi (Z-ave) i polidisperziteta (PdI) (Z-ave ≤ 100 nm, PdI ≤ 0,250) nakon dispergovanja u 0,1 M HCl i fosfatnom puferu pH 7,2. SMEDDS sa najvećim kapacitetom za inkapsulaciju aciklovira (24,06 mg/ml i 21,12 mg/ml) su pokazali brzinu difuzije aciklovira 0,325 mgcm-2min-1 i 0,323 mgcm-2min-1 redom, i značajno su doveli do povećanja permeabilnosti lekovite supstance ispitane testom permeabilnosti na paralelnim veštačkim membranama (PAMPA test), u poređenju sa čistom supstancom. Za formulaciju SMEDDS sa aciklovirom od kr, The study aimed to develop the new generation of semisolid self-microemulsifying drug delivery systems (SMEDDS), suitable for the development of hard capsules as the final solid pharmaceutical form, as well as a comprehensive physico-chemical, pharmaceutical, technological and biopharmaceutical characterization in order to examine their potential for oral delivery of aciclovir as a model of active substance. Semisolid SMEDDS with optimized pharmaceutical-technological characteristics, as well as the biopharmaceutical profile, was evaluated in vivo regarding effects on pharmacokinetics of aciclovir. Additional goal of this study was evaluation of safety of this semisolid SMEDDS. In the first phase of the study it was investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides), surfactant (PEG-8 caprylic/capric glycerides, polysorbate 20, or macrogolglycerol hydroxystearate), cosurfactant (polyglyceryl-3-dioleate), and cosolvent (glycerol or macrogol 400), and evaluate their potential as carriers for oral delivery of aciclovir as a model of the active substance with the characteristics of the group 3, respectively, 4 to Biopharmaceutical Classification System (BSC). The drug loading capacity of the prepared formulations ranged from 0,18–31,66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave ≤ 100 nm, PdI ≤ 0,250) upon spontaneous dispersion in 0,1 M HCl and phosphate buffer pH 7,2. SMEDDSs with the highest aciclovir loading capacity (24,06 mg/ml and 21,12 mg/ml) provided the in vitro drug release rates of 0,325 mgcm-2min-1 i 0,323 mgcm-2min-1, respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. For the formulation of SMEDDS w

U radu je izvršena formulacija nove generacije nosača lekovitih supstanci tipa polučvrstih samo-mikroemulgujućih sistema (SMEDDS), pogodnih za razvoj tvrdih kapsula kao finalnog čvrstog farmaceutskog oblika, kao i sveobuhvatna fizičko-hemijska, farmaceutsko-tehnološka i biofarmaceutska karakterizacija u cilju sagledavanja njihovog potencijala za peroralnu primenu aciklovira kao model aktivne supstance. Dodatno, kod sistema koji ispunjava postavljene kriterijume u pogledu fizičko-hemijskih i farmaceutsko-tehnoloških karakteristika, kao i biofarmaceutskog profila, izvršena je procena uticaja samo-mikroemulgujućeg nosača na biološku raspoloživost aciklovira i neškodljivost razvijenih sistema in vivo na animalnom modelu. U prvoj fazi istraživanja ispitan je uticaj različitih formulacionih parametara u tečnim pseudo-ternernim sistemima pripremljenim od ulja (trigliceridi srednje dužine lanaca), surfaktanata (PEG-8 kaprilno/kaprinski gliceridi, polisorbat 20, makrogol glicerol hidroksistearat), ko-surfraktanata (poligliceril-3-dioleata) i korastvarača (glicerol, makrogol 400), i procenjen je njihov potencijal kao nosača za peroralnu primenu aciklovira kao model aktivne supstance sa karakteristikama grupe 3, odnosno, 4 prema biofarmaceutskom sistemu klasifikacije (BSK). Kapacitet sistema za inkapsulaciju aciklovira iznosio je 0,18-31,66 mg/ml. Od ukupno 60 ispitanih formulacija, tri su odgovarale kriterijumima postavljenim za SMEDDS u pogledu prosečne veličine kapi (Z-ave) i polidisperziteta (PdI) (Z-ave ≤ 100 nm, PdI ≤ 0,250) nakon dispergovanja u 0,1 M HCl i fosfatnom puferu pH 7,2. SMEDDS sa najvećim kapacitetom za inkapsulaciju aciklovira (24,06 mg/ml i 21,12 mg/ml) su pokazali brzinu difuzije aciklovira 0,325 mgcm-2min-1 i 0,323 mgcm-2min-1 redom, i značajno su doveli do povećanja permeabilnosti lekovite supstance ispitane testom permeabilnosti na paralelnim veštačkim membranama (PAMPA test), u poređenju sa čistom supstancom. Za formulaciju SMEDDS sa aciklovirom od kr, systems (SMEDDS), suitable for the development of hard capsules as the final solid pharmaceutical form, as well as a comprehensive physico-chemical, pharmaceutical, technological and biopharmaceutical characterization in order to examine their potential for oral delivery of aciclovir as a model of active substance. Semisolid SMEDDS with optimized pharmaceutical-technological characteristics, as well as the biopharmaceutical profile, was evaluated in vivo regarding effects on pharmacokinetics of aciclovir. Additional goal of this study was evaluation of safety of this semisolid SMEDDS. In the first phase of the study it was investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides), surfactant (PEG-8 caprylic/capric glycerides, polysorbate 20, or macrogolglycerol hydroxystearate), cosurfactant (polyglyceryl-3-dioleate), and cosolvent (glycerol or macrogol 400), and evaluate their potential as carriers for oral delivery of aciclovir as a model of the active substance with the characteristics of the group 3, respectively, 4 to Biopharmaceutical Classification System (BSC). The drug loading capacity of the prepared formulations ranged from 0,18–31,66 mg/ml. Among a total of 60 formulations, three formulations meet the limits for average droplet size (Z-ave) and polydispersity index (PdI) that have been set for SMEDDSs (Z-ave ≤ 100 nm, PdI ≤ 0,250) upon spontaneous dispersion in 0,1 M HCl and phosphate buffer pH 7,2. SMEDDSs with the highest aciclovir loading capacity (24,06 mg/ml and 21,12 mg/ml) provided the in vitro drug release rates of 0,325 mgcm-2min-1 i 0,323 mgcm-2min-1, respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. For the formulation of SMEDDS with aciclovir of critical importance were the type and concentration of surfactants, the mass r

Semisolid self-microemulsifying drug delivery system (SMEDDS) with optimized drug loading capacity, stability, dispersibility in aqueous media and in vitro drug release profile, was evaluated in vivo regarding effects on pharmacokinetics of acyclovir, an antiviral with low bioavailability (BA) and short half-life (t(1/2)). Additional goal of this study was evaluation of safety of this semisolid SMEDDS consisted of medium chain length triglycerides (oil) (10% w/w), macrogolglycerol hydroxystearate (surfactant) (56.25% w/w), polyglyceryl-3-dioleate (cosurfactant) (6.25% w/w), glycerol (cosolvent) (20% w/w), macrogol 8000 (viscosity modifier) (7.5% w/w), and acyclovir (2.5 mg/ml). The study was performed on fully mature white male Wistar rats. The pharmacokinetics of acyclovir was monitored in three groups (1-3) of animals after administration of drug solution (intravenously (IV)), drug suspension (orally) and semisolid SMEDDS (orally), respectively. The determined pharmacokinetic parameters were: maximum concentration of acyclovir in serum (C-max), time taken to reach C-max (T-max), areas under time-concentration curves (AUC(0-t) and AUC(0-infinity)), terminal elimination rate constant (k(el)), t(1/2), volume of distribution (V-d), mean residence time (MRT), clearance (Cl), zero concentration (C-0), steady state volume of distribution (V-ss), and BA. Additionally, for safety evaluation, animals were treated orally with aqueous solution of acyclovir, drug-free semisolid SMEDDS and acyclovir-loaded semisolid SMEDDS, during 21 days (groups 4-7). Serum samples of sacrificed animals were used for biochemical analysis of enzymatic activity of alanine transaminase (ALT) and aspartate transaminase (AST), urea, creatinine, and uric acid. Acyclovir administered by semisolid SMEDDS reached twice higher C-max (0.92 +/- 0.21 mu g/ml) and has significantly shorter T-max (14 +/- 10.84 min) compared to the suspension of acyclovir (C-max 0.29 +/- 0.09 mu g/ml and T-max 26.00 +/- 5.48