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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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Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir
'Elsevier BV', 2016Co-Authors: Janković Jovana, Đekić Ljiljana, Dobričić Vladimir, Primorac MarijaAbstract:The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol (R), polysorbate 20, or Kolliphor (R) RH40), cosurfactant (Plurol (R) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or Macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). 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 lt = 100 nm, PdI lt 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 mg cm (2) min (1) and 0.323 mg cm (2) min (1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent
Luo Zhongyang - One of the best experts on this subject based on the ideXlab platform.
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Kinetic enhancement of adsorbent for CO2 capture from atmosphere by porous material
ECI Digital Archives, 2016Co-Authors: Wang Tao, Liu Jun, Ge Kun, Luo ZhongyangAbstract:Strategies for stabilizing atmospheric greenhouse gas concentrations will need to consider future CO2 emissions from an enormous resource of worldwide fossil fuel supplies and a diverse range of mitigation technologies. In 2013, global CO2 emissions due to fossil fuel use (and cement production) were 36 gigatonnes (Gt CO2), and are projected to increase by an additional 2.5% in 2014. Even if all emissions from large fixed sources could be captured, the roughly 30-50% of global emissions due to transportation and mobile sources would still be released into the atmosphere. To ensure the concentration of atmospheric CO2 in the scope of security, CO2 air capture, which offers the potential to be a truly carbon negative technology, is urgent. The design and preparation of porous materials with controlled structures and functionalities is crucial to low concentration CO2 capture. In this work, two preparation approaches of CO2 adsorbents are explored. One is heterogeneous membrane preparation using porous supporting materials through phase inversion method, which is relatively simple, rapid, and inexpensive, and the other is to directly prepare the porous adsorbents through grafting method using a novel material—cellulose. For phase inversion method, anion exchange resin, which can absorb low concentration CO2 after ion exchange treatment, is mixed with Polyethersulfone (PES), N-Methyl pyrrolidone (NMP) and Macrogol 400(PEG-400) to form casting solution, and finally, the heterogeneous membrane is prepared for CO2 adsorption. For grafting method, the cellulos anion exchange fiber used for CO2 adsorption, is prepared by alkali pretreatment of sodium hydroxide and the grafting of epichlorohydrin and ethylenediamine onto fiber, and finally ion exchange treatment is made to introduce basic groups, such as carbonate ions and hydroxide ion. The surface properties of the prepared adsorption materials are characterized by SEM and BET, as can be seen in Figure 1, and the results reveal that the materials are porous and have large specific surface area, which is beneficial to the kinetics of CO2 adsorption. The absorption performances of the two kinds of adsorbents are tested on a self-made rotating bed reactor, and the absorption capacity and kinetics are compared. To optimize the kinetics performance of CO2 adsorption, the modified shrinking core model (SCM) is used to analyze the resistance during the reaction process according to the test results. The resistance during the mass transfer process includes physical diffusion resistance and chemical reaction resistance. For the heterogeneous membrane, the results reveal that the resistance of physical diffusion and chemical reaction is comparable when the saturation of CO2 adsorption is low (less than 0.3), and the physical diffusion resistance increases greatly and controls the kinetics performance when the saturation of CO2 is high, as can be seen in Figure 2. The influence of temperature and humidity on CO2 adsorption kinetics is also studied and the diffusion coefficient and reaction rate constant are obtained, and the activation energy of reaction can be determined
Primorac Marija - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of critical formulation parameters in design and differentiation of self-microemulsifying drug delivery systems (SMEDDSs) for oral delivery of aciclovir
'Elsevier BV', 2016Co-Authors: Janković Jovana, Đekić Ljiljana, Dobričić Vladimir, Primorac MarijaAbstract:The study investigated the influence of formulation parameters for design of self-microemulsifying drug delivery systems (SMEDDSs) comprising oil (medium chain triglycerides) (10%), surfactant (Labrasol (R), polysorbate 20, or Kolliphor (R) RH40), cosurfactant (Plurol (R) Oleique CC 497) (q.s. ad 100%), and cosolvent (glycerol or Macrogol 400) (20% or 30%), and evaluate their potential as carriers for oral delivery of a poorly permeable antivirotic aciclovir (acyclovir). 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 lt = 100 nm, PdI lt 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 mg cm (2) min (1) and 0.323 mg cm (2) min (1), respectively, and significantly enhanced drug permeability in the parallel artificial membrane permeability assay (PAMPA), in comparison with the pure drug substance. The results revealed that development of SMEDDSs with enhanced drug loading capacity and oral delivery potential, required optimization of hydrophilic ingredients, in terms of size of hydrophilic moiety of the surfactant, surfactant-to-cosurfactant mass ratio (Km), and log P of the cosolvent
Wang Chun-ren - One of the best experts on this subject based on the ideXlab platform.
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Bacterium endotoxin test of medical Macrogol 400 berberine hydrochloride
Chinese Journal of Pharmaceutical Analysis, 2009Co-Authors: Wang Chun-renAbstract:Objective:The research reviewed bacterium endotoxin test of medical Macrogol 400 berberine hydrochloride.Method:The bacterium endotoxin test were performed to detect valid dilution concentration and limit value according to the Chinese pharmacopoeia edited 2005.Result:The sample which were diluted 50 times didn't disturb the bacterium endotoxin test and the limit value accord with demand.Conclusion:The product may use bacterium endotoxin test.
Vladimir I Musatov - One of the best experts on this subject based on the ideXlab platform.
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substantiation of an approach to determination of ketoprofen and Macrogol 400 esters
ScienceRise: Pharmaceutical Science, 2021Co-Authors: Elena Bezuglaya, I A Zinchenko, Nikolay Lyapunov, Hanna Vlasenko, Vladimir I MusatovAbstract:The aim. The work is concerned with the substantiation of the approach to the identification and quantification of ketoprofen and Macrogol 400 esters. Materials and methods. Ketoprofen, Macrogol 400, ketoprofen Macrogol 400 ester (KM400E), as well as model cream-gels were investigated by the following methods: absorption spectrophotometry ultraviolet (UV) and visible, high-performance liquid chromatography (HPLC), gas chromatography (GC), GC / mass spectrometry, nuclear magnetic resonance (NMR) spectrometry and thermogravimetry. Results. It was found by GC and GC / mass spectrometry that the average molecular mass (M. m.) of the test Macrogol 400 is 383.50 and it contains oligomers with molecular masses from 150.17 to 546.65. KM400E, which is a mixture of esters of ketoprofen with Macrogol oligomers, was synthesized. The formed esters were characterized by 1H NMR spectra. It was shown that the ratio of the average molecular mass of KM400E, calculated for monoesters, and the molecular mass of ketoprofen corresponds to the ratio of specific absorbances of solutions of ketoprofen and solutions of KM400E, this fact indicated the formation of monoesters. Taking into account the risk of variability of the fractional composition of Macrogol 400 in different batches, it is advisable to quantify KM400E using ketoprofen reference standard (RS) and not KM400E RS. Using HPLC with diode array detection the peak of KM400E should be identified by the UV absorption spectrum with λmax≈255 nm, which is characteristic for ketoprofen, and the relative retention time (RRt) of the peak; KM400E should be quantified by the content of ketoprofen in this impurity. During storage of model cream-gels the content of impurity of KM400E is significantly lower than the content of ketoprofen propylene glycol ester (mixture of isomers). Conclusions. The approach to the identification and quantification of KM400E is substantiated. The analytical procedure for determination of impurity KM400E by HPLC with a diode array detection using ketoprofen RS was developed. Correctness of the procedure was proved by the results of the validation studies.
