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Formulation and characterization of semisolid self-microemulsifying drug delivery system as potencial new generation carriers for oral delivery of aciclovir
Универзитет у Београду Фармацеутски факултет, 2020Co-Authors: Janković JovanaAbstract: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 kritičnog značaja bili su vrsta i koncentracija surfaktanta, maseni odnos surfaktanta i ko-surfaktanta (Km), i vrsta i koncentracija korastvarača. U nastavku istraživanja je razmotrena mogućnost formulacije polučvrstih SMEDDS upotrebom makrogola 8000 kao sredstva za modifikaciju viskoziteta tečnih SMEDDS. Kod sistema ispitano je reološko ponašanje, disperzibilnost u kiselom i alkalnom vodenom medijumu, kapacitet za inkorporiranje aktivne supstance i kinetika njenog oslobađanja difuzijom, u cilju identifikacije polučvrstog SMEDDS sa optimalnim karakteristikama kao nosača za peroralnu primenu aciklovira u obliku tvrdih kapsula. Utvrđeno je da su formulisani SMEDDS bili polučvrsti na temperaturama do 50 ºC i fizički stabilni i kompatibilni sa tvrdim kapsulama od hipromeloze (HPMC) tokom tromesečnog čuvanja na temperaturama 25 °C/60% RH, odnosno, na 5±3 °C. Rezultati in vitroispitivanja oslobađanja aktivne supstance su pokazali da se brzina difuzije aciklovira povećava sa povećanjem sadržaja aciklovira u formulaciji, pri čemu polučvrsti SMEDDS sa terapijskom dozom od 200 mg aciklovira omogućava kontrolisanu raspodelu supstance iz in situformiranog nosača tipa ulje-u-vodi mikroemulzije, što smanjuje rizik od smanjenja rastvorljivosti i potencijalno poboljšava njenu dostupnost za apsorpciju. U završnoj fazi istraživanja izvedeni su invivobiološkitestovinapacovimaWistarsoja za polučvrstiSMEDDS sa acikloviromsastava: trigliceridi srednje dužine lanaca (10%), makrogol glicerol hidroksistearat (56,25%), poligliceril-3-dioleat (6,25%), glicerol (20%), makrogol 8000 (7,5%) i aciklovir (2,5 mgml). armakokinetički profil aciklovira je praćen na tri grupe životinja nakon primene vodenog rastvora aciklovira (intravenski), suspenzije aciklovira (peroralno) i polučvrstog SMEDDS (peroralno), redom. Ispitani su sledeći farmakokinetički parametri: maksimalna koncentracija aciklovira u serumu (Cmax), vreme potrebno za postizanje Cmax(Tmax), površine ispod krive zavisnosti koncentracija/vreme (AUC0-t i AUC0-∞),konstanta brzine eliminacije (kel), poluvreme eliminacije (t1/2), volumen distribucije (Vd), srednje vreme zadržavanja (MRT), klirens (Cl), nulta koncentracija (C0), volumen raspodele stacionarnog stanja (Vss) i apsolutna biološka raspoloživost (BA). Dodatno, za procenu neškodljivosti, urađena suispitivanjabiohemijskihparametara(aktivnostjetrenihtransaminaza, koncentracijamokraćnekiseline, ureeikreatinina) uuzorcimakrviživotinjanakonprimene oralnog rastvoraaciklovira, polučvrstogSMEDDS,sai bez aciklovira.Primenom polučvrstog SMEDDS sa aciklovirom postignuta je dvostruko veća Cmax(0, 20,21 mgml) i značajno kraći Tmax(14 10,84 min) u poređenju sa suspenzijom aciklovira (Cmax0,29±0,09 mg/ml i Tmax 26,005,48 min). BA je značajno povećana primenom polučvrstog SMEDDS, dok je analiza biohemijskih parametara isključila mogućnost oštećenja funkcije jetre i bubrega primenom SMEDDS.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 with aciclovir of critical importance were the type and concentration of surfactants, the mass ratio of surfactant and co-surfactant (Km), and the type and concentration of the cosolvent. Further research has been considered the possibility of formulating semisolid SMEDDS using Macrogol 8000 as a viscosity modifier of liquid SMEDDS. The system was tested for rheological behavior, dispersibility in acid and alkaline aqueous medium, capacity for incorporation of the active substance and its release by diffusion, in order to identify semisolid SMEDDS with optimal characteristics as the carrier for the oral delivery of aciclovir in the form of hard capsules. It has been established that the SMEDDSs were semisolids at temperatures up to 50 ºC and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C/60% RH and 5±3 °C, respectively. The results of in vitrorelease study revealed that the designed solid dosage form based on the semisolid SMEDDSs loaded with the therapeutic dose of 200 mg, may control partition of the solubilized drug from in situformed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation and potentially enhance availability of the drug for absorption. In vivobiological tests were also performed on Wistar rats for semisolid SMEDDS with acyclovir consisted of medium chain length triglycerides (10% w/w), Macrogolglycerol hydroxystearate (56,25% w/w), polyglyceryl-3-dioleate (6,25% w/w), glycerol (20% w/w), Macrogol 8000 (7,5% w/w), and acyclovir (2,5 mg/ml). The pharmacokinetics of acyclovir was monitored in three groups of animals after administration of drug solution (intravenously), drug suspension (orally) and semisolid SMEDDS (orally), respectively. The determined pharmacokinetic parameters were: maximum concentration of acyclovir in serum (Cmax), time taken to reach Cmax (Tmax), areas under time-concentration curves (AUC0–t and AUC0–∞), terminal elimination rate constant (kel), t1/2, volume of distribution (Vd), mean residence time (MRT), clearance (Cl), zero concentration (C0), steady state volume of distribution (Vss), and BA. Additionally, for safety evaluation, animals were treated orally with aqueous solution of acyclovir, drug-free semisolid SMEDDS and acyclovir-loaded semisolid SMEDDS. 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 Cmax (0,92±0,21 μg ml) andhas significantly shorter Tmax (14±10,84 min) compared to the suspension of acyclovir (Cmax 0,2 0,0 μg ml and Tmax 26,00 5,48 min). BA of the drug was significantly increased by semisolid SMEDDS, while the analysis of biochemical parameters excluded damage on function of liver and kidneys caused by the investigated drug delivery system
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Formulation and characterization of semisolid self-microemulsifying drug delivery system as potencial new generation carriers for oral delivery of aciclovir
Универзитет у Београду Фармацеутски факултет, 2020Co-Authors: Janković JovanaAbstract: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 kritičnog značaja bili su vrsta i koncentracija surfaktanta, maseni odnos surfaktanta i ko-surfaktanta (Km), i vrsta i koncentracija korastvarača. U nastavku istraživanja je razmotrena mogućnost formulacije polučvrstih SMEDDS upotrebom makrogola 8000 kao sredstva za modifikaciju viskoziteta tečnih SMEDDS. Kod sistema ispitano je reološko ponašanje, disperzibilnost u kiselom i alkalnom vodenom medijumu, kapacitet za inkorporiranje aktivne supstance i kinetika njenog oslobađanja difuzijom, u cilju identifikacije polučvrstog SMEDDS sa optimalnim karakteristikama kao nosača za peroralnu primenu aciklovira u obliku tvrdih kapsula. Utvrđeno je da su formulisani SMEDDS bili polučvrsti na temperaturama do 50 ºC i fizički stabilni i kompatibilni sa tvrdim kapsulama od hipromeloze (HPMC) tokom tromesečnog čuvanja na temperaturama 25 °C/60% RH, odnosno, na 5±3 °C. Rezultati in vitroispitivanja oslobađanja aktivne supstance su pokazali da se brzina difuzije aciklovira povećava sa povećanjem sadržaja aciklovira u formulaciji, pri čemu polučvrsti SMEDDS sa terapijskom dozom od 200 mg aciklovira omogućava kontrolisanu raspodelu supstance iz in situformiranog nosača tipa ulje-u-vodi mikroemulzije, što smanjuje rizik od smanjenja rastvorljivosti i potencijalno poboljšava njenu dostupnost za apsorpciju. U završnoj fazi istraživanja izvedeni su invivobiološkitestovinapacovimaWistarsoja za polučvrstiSMEDDS sa acikloviromsastava: trigliceridi srednje dužine lanaca (10%), makrogol glicerol hidroksistearat (56,25%), poligliceril-3-dioleat (6,25%), glicerol (20%), makrogol 8000 (7,5%) i aciklovir (2,5 mgml). armakokinetički profil aciklovira je praćen na tri grupe životinja nakon primene vodenog rastvora aciklovira (intravenski), suspenzije aciklovira (peroralno) i polučvrstog SMEDDS (peroralno), redom. Ispitani su sledeći farmakokinetički parametri: maksimalna koncentracija aciklovira u serumu (Cmax), vreme potrebno za postizanje Cmax(Tmax), površine ispod krive zavisnosti koncentracija/vreme (AUC0-t i AUC0-∞),konstanta brzine eliminacije (kel), poluvreme eliminacije (t1/2), volumen distribucije (Vd), srednje vreme zadržavanja (MRT), klirens (Cl), nulta koncentracija (C0), volumen raspodele stacionarnog stanja (Vss) i apsolutna biološka raspoloživost (BA). Dodatno, za procenu neškodljivosti, urađena suispitivanjabiohemijskihparametara(aktivnostjetrenihtransaminaza, koncentracijamokraćnekiseline, ureeikreatinina) uuzorcimakrviživotinjanakonprimene oralnog rastvoraaciklovira, polučvrstogSMEDDS,sai bez aciklovira.Primenom polučvrstog SMEDDS sa aciklovirom postignuta je dvostruko veća Cmax(0, 20,21 mgml) i značajno kraći Tmax(14 10,84 min) u poređenju sa suspenzijom aciklovira (Cmax0,29±0,09 mg/ml i Tmax 26,005,48 min). BA je značajno povećana primenom polučvrstog SMEDDS, dok je analiza biohemijskih parametara isključila mogućnost oštećenja funkcije jetre i bubrega primenom SMEDDS.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 ratio of surfactant and co-surfactant (Km), and the type and concentration of the cosolvent. Further research has been considered the possibility of formulating semisolid SMEDDS using Macrogol 8000 as a viscosity modifier of liquid SMEDDS. The system was tested for rheological behavior, dispersibility in acid and alkaline aqueous medium, capacity for incorporation of the active substance and its release by diffusion, in order to identify semisolid SMEDDS with optimal characteristics as the carrier for the oral delivery of aciclovir in the form of hard capsules. It has been established that the SMEDDSs were semisolids at temperatures up to 50 ºC and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C/60% RH and 5±3 °C, respectively. The results of in vitrorelease study revealed that the designed solid dosage form based on the semisolid SMEDDSs loaded with the therapeutic dose of 200 mg, may control partition of the solubilized drug from in situformed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation and potentially enhance availability of the drug for absorption. In vivobiological tests were also performed on Wistar rats for semisolid SMEDDS with acyclovir consisted of medium chain length triglycerides (10% w/w), Macrogolglycerol hydroxystearate (56,25% w/w), polyglyceryl-3-dioleate (6,25% w/w), glycerol (20% w/w), Macrogol 8000 (7,5% w/w), and acyclovir (2,5 mg/ml). The pharmacokinetics of acyclovir was monitored in three groups of animals after administration of drug solution (intravenously), drug suspension (orally) and semisolid SMEDDS (orally), respectively. The determined pharmacokinetic parameters were: maximum concentration of acyclovir in serum (Cmax), time taken to reach Cmax (Tmax), areas under time-concentration curves (AUC0–t and AUC0–∞), terminal elimination rate constant (kel), t1/2, volume of distribution (Vd), mean residence time (MRT), clearance (Cl), zero concentration (C0), steady state volume of distribution (Vss), and BA. Additionally, for safety evaluation, animals were treated orally with aqueous solution of acyclovir, drug-free semisolid SMEDDS and acyclovir-loaded semisolid SMEDDS. 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 Cmax (0,92±0,21 μg ml) andhas significantly shorter Tmax (14±10,84 min) compared to the suspension of acyclovir (Cmax 0,2 0,0 μg ml and Tmax 26,00 5,48 min). BA of the drug was significantly increased by semisolid SMEDDS, while the analysis of biochemical parameters excluded damage on function of liver and kidneys caused by the investigated drug delivery system
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Na spor. nasl. str.: Formulation and characterization of semisolid self-microemulsifying drug delivery system as potencial new generation carriers for oral delivery of aciclovir
Универзитет у Београду Фармацеутски факултет, 2020Co-Authors: Janković JovanaAbstract: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 kritičnog značaja bili su vrsta i koncentracija surfaktanta, maseni odnos surfaktanta i ko-surfaktanta (Km), i vrsta i koncentracija korastvarača. U nastavku istraživanja je razmotrena mogućnost formulacije polučvrstih SMEDDS upotrebom makrogola 8000 kao sredstva za modifikaciju viskoziteta tečnih SMEDDS. Kod sistema ispitano je reološko ponašanje, disperzibilnost u kiselom i alkalnom vodenom medijumu, kapacitet za inkorporiranje aktivne supstance i kinetika njenog oslobađanja difuzijom, u cilju identifikacije polučvrstog SMEDDS sa optimalnim karakteristikama kao nosača za peroralnu primenu aciklovira u obliku tvrdih kapsula. Utvrđeno je da su formulisani SMEDDS bili polučvrsti na temperaturama do 50 ºC i fizički stabilni i kompatibilni sa tvrdim kapsulama od hipromeloze (HPMC) tokom tromesečnog čuvanja na temperaturama 25 °C/60% RH, odnosno, na 5±3 °C...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 ratio of surfactant and co-surfactant (Km), and the type and concentration of the cosolvent. Further research has been considered the possibility of formulating semisolid SMEDDS using Macrogol 8000 as a viscosity modifier of liquid SMEDDS. The system was tested for rheological behavior, dispersibility in acid and alkaline aqueous medium, capacity for incorporation of the active substance and its release by diffusion, in order to identify semisolid SMEDDS with optimal characteristics as the carrier for the oral delivery of aciclovir in the form of hard capsules. It has been established that the SMEDDSs were semisolids at temperatures up to 50 ºC and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C/60% RH and 5±3 °C, respectively..
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Formulation and characterization of semisolid self-microemulsifying drug delivery system as potencial new generation carriers for oral delivery of aciclovir
Универзитет у Београду Фармацеутски факултет, 2020Co-Authors: Janković JovanaAbstract: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 kritičnog značaja bili su vrsta i koncentracija surfaktanta, maseni odnos surfaktanta i ko-surfaktanta (Km), i vrsta i koncentracija korastvarača. U nastavku istraživanja je razmotrena mogućnost formulacije polučvrstih SMEDDS upotrebom makrogola 8000 kao sredstva za modifikaciju viskoziteta tečnih SMEDDS. Kod sistema ispitano je reološko ponašanje, disperzibilnost u kiselom i alkalnom vodenom medijumu, kapacitet za inkorporiranje aktivne supstance i kinetika njenog oslobađanja difuzijom, u cilju identifikacije polučvrstog SMEDDS sa optimalnim karakteristikama kao nosača za peroralnu primenu aciklovira u obliku tvrdih kapsula. Utvrđeno je da su formulisani SMEDDS bili polučvrsti na temperaturama do 50 ºC i fizički stabilni i kompatibilni sa tvrdim kapsulama od hipromeloze (HPMC) tokom tromesečnog čuvanja na temperaturama 25 °C/60% RH, odnosno, na 5±3 °C...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 ratio of surfactant and co-surfactant (Km), and the type and concentration of the cosolvent. Further research has been considered the possibility of formulating semisolid SMEDDS using Macrogol 8000 as a viscosity modifier of liquid SMEDDS. The system was tested for rheological behavior, dispersibility in acid and alkaline aqueous medium, capacity for incorporation of the active substance and its release by diffusion, in order to identify semisolid SMEDDS with optimal characteristics as the carrier for the oral delivery of aciclovir in the form of hard capsules. It has been established that the SMEDDSs were semisolids at temperatures up to 50 ºC and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C/60% RH and 5±3 °C, respectively..
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Semisolid self-microemulsifying drug delivery systems (SMEDDSs): Effects on pharmacokinetics of acyclovir in rats
'Elsevier BV', 2018Co-Authors: Đekić Ljiljana, Janković Jovana, Rasković Aleksandar, Primorac MarijaAbstract: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 min). BA of the drug was significantly increased by semisolid SMEDDS, while the analysis of biochemical parameters excluded damage on function of liver and kidneys caused by the investigated drug delivery system
Primorac Marija - One of the best experts on this subject based on the ideXlab platform.
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Semisolid self-microemulsifying drug delivery systems (SMEDDSs): Effects on pharmacokinetics of acyclovir in rats
'Elsevier BV', 2018Co-Authors: Đekić Ljiljana, Janković Jovana, Rasković Aleksandar, Primorac MarijaAbstract: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 min). BA of the drug was significantly increased by semisolid SMEDDS, while the analysis of biochemical parameters excluded damage on function of liver and kidneys caused by the investigated drug delivery system
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Development of semisolid self-microemulsifying drug delivery systems (SMEDDSs) filled in hard capsules for oral delivery of aciclovir
'Elsevier BV', 2017Co-Authors: Đekić Ljiljana, Janković Jovana, Čalija Bojan, Primorac MarijaAbstract:The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six selfdispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), Macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and Macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 degrees C and physically stable and compatible with HPMC capsules for 3 months storage at 25 degrees C and 4 degrees C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200 mg, may control partitioning of the solubilized drug from in situ formed oil-inwater microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug
Đekić Ljiljana - One of the best experts on this subject based on the ideXlab platform.
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Semisolid self-microemulsifying drug delivery systems (SMEDDSs): Effects on pharmacokinetics of acyclovir in rats
'Elsevier BV', 2018Co-Authors: Đekić Ljiljana, Janković Jovana, Rasković Aleksandar, Primorac MarijaAbstract: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 min). BA of the drug was significantly increased by semisolid SMEDDS, while the analysis of biochemical parameters excluded damage on function of liver and kidneys caused by the investigated drug delivery system
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Development of semisolid self-microemulsifying drug delivery systems (SMEDDSs) filled in hard capsules for oral delivery of aciclovir
'Elsevier BV', 2017Co-Authors: Đekić Ljiljana, Janković Jovana, Čalija Bojan, Primorac MarijaAbstract:The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six selfdispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), Macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and Macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 degrees C and physically stable and compatible with HPMC capsules for 3 months storage at 25 degrees C and 4 degrees C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200 mg, may control partitioning of the solubilized drug from in situ formed oil-inwater microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug
Marija Primorac - One of the best experts on this subject based on the ideXlab platform.
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development of semisolid self microemulsifying drug delivery systems smeddss filled in hard capsules for oral delivery of aciclovir
International Journal of Pharmaceutics, 2017Co-Authors: Ljiljana Djekic, Jovana Jankovic, Bojan Calija, Marija PrimoracAbstract:Abstract The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six self-dispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), Macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and Macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 °C and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C and 4 °C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200 mg, may control partitioning of the solubilized drug from in situ formed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug.
Ljiljana Djekic - One of the best experts on this subject based on the ideXlab platform.
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development of semisolid self microemulsifying drug delivery systems smeddss filled in hard capsules for oral delivery of aciclovir
International Journal of Pharmaceutics, 2017Co-Authors: Ljiljana Djekic, Jovana Jankovic, Bojan Calija, Marija PrimoracAbstract:Abstract The study aimed to develop semisolid self-microemulsifying drug delivery systems (SMEDDSs) as carriers for oral delivery of aciclovir in hard hydroxypropylmethyl cellulose (HPMC) capsules. Six self-dispersing systems (SD1-SD6) were prepared by loading aciclovir into the semisolid formulations consisting of medium chain length triglycerides (lipid), Macrogolglycerol hydroxystearate (surfactant), polyglyceryl-3-dioleate (cosurfactant), glycerol (hydrophilic cosolvent), and Macrogol 8000 (viscosity modifier). Their characterization was performed in order to identify the semisolid system with rheological behaviour suitable for filling in hard HPMC capsules and fast dispersibility in acidic and alkaline aqueous media with formation of oil-in-water microemulsions. The optimal SMEDDS was loaded with aciclovir at two levels (2% and 33.33%) and morphology and aqueous dispersibility of the obtained systems were examined by applying light microscopy and photon correlation spectroscopy (PCS), respectively. The assessment of diffusivity of aciclovir from the SMEDDSs by using an enhancer cell model, showed that it was increased at a higher drug loading. Differential scanning calorimetry (DSC) analysis indicated that the SMEDDSs were semisolids at temperatures up to 50 °C and physically stable and compatible with HPMC capsules for 3 months storage at 25 °C and 4 °C. The results of in vitro release study revealed that the designed solid dosage form based on the semisolid SMEDDS loaded with the therapeutic dose of 200 mg, may control partitioning of the solubilized drug from in situ formed oil-in-water microemulsion carrier into the sorrounding aqueous media, and hence decrease the risk for precipitation of the drug.
