Effect of Moisture and Formulation Ingredients on the Release of Lamotrigine Immediate-Release Tablet

U radu je primenom eksperimentalnog dizajna urađeno ispitivanje uticaja različitih formulacijskih komponenti i njihovog variranja na karakteristike tableta sa lamotriginom (LMT) kao model supstancom. Ispitivan je uticaj faktora povišene i snižene vlage u periodu od sedam dana i četiri nedelje kao uslova čuvanja na kinetiku oslobađanja lekovite supstance iz tableta LMT-a sa trenutnim oslobađanjem. Izvršeno je međusobno poređenje karakteristika tableta LMT koje se nalaze na tržištu i njihovo variranje u brzini oslobađanja lekovite supstance nakon izlaganja uslovima povišene i snižene vlage. U formulacijama tableta korišćeni su različita sredstava za dopunjavanje [mikrokristalna celuloza (MKC) ili anhidrovana laktoza (LAK)]; kao sredstvo za raspadanje korišćen je natrijum-skrobglikolat (NaSG) u koncentracijama od 0,5% i 4%; kao sredstvo za klizanje i lubrikant je korišćen magnezijum-stearat (MgST) u koncentraciji od 0,25% i 5%. Za procenu uticaja sastava ispitivanih formulacija primenio se pun faktorski dizajn 2³ gde su praćena navedena tri faktora kao sastojci formulacije, na oba udela. Tablete su izrađivane direktnom kompresijom pomoću ekscenter mašine za tabletiranje. Tabletabilnost formulacija i pojedinačnih sastojaka je ispitivana putem multifunkcionalnog uređaja za simulaciju kompakcije – Gamlen uređaj. Karakteristike ispitivanih faktora u direktno kompresibilnim formulacijama tableta procenjivane su preko fizičkih karakteristika tabletnog materijala, mehaničkih karakteristika tableta, kao i uticaja karakteristika na kinetiku oslobađanja lekovite supstance iz formulacija tableta. Pareto dijagrami su korišćeni da se prikažu procene uticaja određenih efekata na ispitivane karakteristike formulacija. Primenom multifunkcionalnog Gamlen uređaja i analizom dobijenih rezultata za formulacije tableta, značajan pozitivan uticaj na tabletabilnost pokazala je interakcija MgST sa NaSG kada se nalaze u većem udelu. Utvrđeno je da se korišćenjem MKC kao sredstva za dopunjavanje dobijaju znatno bolje protočne karakteristike tabletnog materijala u formulacijama sa isptivanim opsegom udela lubrikanta i sredstva za dezintegraciju, u odnosu na tabletni materijal sa MKC. Potvrđeno je da dodatak LMT u placebo masu smanjuje neto rad, a povećava elastični oporavak kompresije u odnosu na placebo formulacije, čime negativno utiče na tabletabilnost formulacija. Visok udeo NaSG i veća sila kompresije uticala je na smanjenje elastičnog oporavka kod tabletnih formulacija. Značajan uticaj na protočna svojstva tabletnog materijala ima udeo MgST u formulacijama sa MKC, dok u formulacijama sa LAK pored udela MgST i udeo NaSG ima značajan uticaj. Sve formulacije tableta sa MKC su pokazale generalno zadovoljavajuće ispitivane mehaničke karakteristike zbog dobrih tabletabilnih i kompresibilnih karakteristika MKC. Dodatak LMT u placebo tabletni materijal doveo je do značajnih promena u karakteristikama formulacija kao što je smanjena otpornost na lomljenje, povećana frijabilnost i smanjeno vreme dezintegracije. Ispitivanjem profila oslobađanja LS kod formulacije sa MKC nakon izlaganja tableta uslovima povišene i snižene vlage, pokazale su nestabilne profile oslobađanja na osnovu čega je potvrđen značajan uticaj uslova čuvanja na formulacije tableta sa MKC. U medijumu pH 6,8 kod formulacija sa MKC, uslovi snižene, a posebno povišene vlage su uticali na usporavanje oslobađanja LMT. Na osnovu rezultata istraživanja, analizom faktora uticaja pomoću Design-Expert softvera zaključeno je da na oslobađanje LMT iz formulacija tableta statistički najveći uticaj ima sredstvo za dopunjavanje. U medijumu pH 6,8 statistički značajan uticaj na oslobađanje LS pokazao je i NaSG nakon izlaganja uslovima povišene i snižene vlage, kao i njegova interakcija sa LAK i MKC. U disolucionom medijumu pH 1,2 u uslovima povišene vlage značajan uticaj pokazuje udeo MgST, udeo NaSG i njihova međusobna interakcija. Kinetički parametri oslobađanja LMT su dobijeni matematičkom obradom podataka uz pomoć softvera DDSolver koristeći različite modele oslobađanja. Promena uslova izlaganja povišenoj i sniženoj vlagi uticala je na izmenjenu kinetiku oslobađanja LMT iz formulacija tableta. Značajnija promena uočena je u disolucijonom medijumu pH 6,8 u odnosu na medijum pH 1,2. Podaci dobijeni za profil oslobađanja LMT u komercijalnim tabletama izloženih uslovima povišene i snižene vlage su bili prema profilima oslobađanja LMT iz analiziranih formulacija sa MKC. U formulacijama tableta sa MKC je potvrđen uticaj povišene i snižene vlage u medijumu pH 6,8 koja utiče na usporavanje oslobađanja LMT. Zaključeno je da postoji značajan uticaj sastojaka formulacije na karakteristike tableta i brzinu oslobađanja LMT, posebno kada su izloženi uslovima povišene i snižene vlage. Rezultati su ukazali na potrebu za edukacijom pacijenata koji koriste tablete LMT sa trenutnim oslobađanjem vezano za način čuvanja i mogućim posledicama prilikom izdvajanja nedeljne i/ili mesečne terapije u dozatore za lekove.Using experimental design, the effects of different formulation components and their variations on the properties of lamotrigine tablets (LMT) as a drug model were investigated. The influence of increased and decreased moisture factors as storage conditions on the kinetics release of the immediate-release LMT tablets during a period of 7 days and 4 weeks was investigated. The characteristics of LMT tablets on the market and their variations in drug release rate after exposure to high and low humidity conditions were compared. Various types of fillers [microcrystalline cellulose (MCC) or anhydrous lactose (LAC)] were used in the tablet formulations; sodium starch glycolate (NaSG), in concentrations of 0.5% and 4%, was used as a disintegrant; Magnesium stearate (MgST), in concentrations of 0.25% and 5%, was used as a glidant and lubricant. To assess the influence of the composition of the tested formulations, a three-factor two-level full factorial design 2³ was applied. The tablets were produced by direct compression using an eccentric tablet machine. The tabletability of formulations and individual ingredients of tablets were analysed using a compaction simulator - Gamlen tablet press. The characteristics of the investigated factors in directly compressible tablet formulations were evaluated according to the physical characteristics of the tablet material, the mechanical characteristics of the tablets, as well as the influence of the properties on the drug release kinetics from the tablet formulations. Pareto diagrams were used to present estimates of the influence of certain effects on the examined formulation characteristics. Use of a compaction simulator - Gamlen tablet press, and the analysis of the results obtained for tablet formulations showed a significant positive effect of the interaction of MgST with NaSG on tableting, when present in a higher percentage. It was determined that the use of MCC as a filler in formulations enables significantly better flow properties of the tablet material in formulations with a tested concentration of lubricant and solvent content, compared to the MCC of tablets. It has been confirmed that the addition of LMT to placebo formulations reduces the net work of compression and the rate of elastic recovery increased relative to placebo formulations, which negatively affects the tabletability of formulations. High concentration of NaSG and higher compression force reduced the elastic recovery of tablet formulations. The concentration of MgST in formulations with MCC significantly affects the flow properties of tablets, while it has a significant effect in formulations with LAC, in addition to the concentration of MgST and the concentration of NaSG. All MCC tablet formulations showed generally satisfactory mechanical properties, due to good compressible properties of MCC. The addition of LMT to the placebo tablet material led to significant changes in the characteristics of the formulations such as reduced fracture toughness, increased brittleness, and reduced disintegration time. Examination of the release profile of the MCC formulation after the exposure of the tablets to high and low humidity conditions showed unstable release profiles, which confirms the significant influence of storage conditions on the MCC tablet formulations. iI the dissolution media pH 6.8 in formulations with MCC, conditions of reduced, and especially increased moisture, slow down the release of LMT. Based on the results of the research, the analysis of impact factors using Design-Expert software concluded that in addition to the influence of fillers on pH 6.8, NaSG has a significant impact after exposure to high and low humidity, as well as its interaction with LAC and MCC. In the dissolution media pH 1.2, under conditions of high humidity, the MgST content, the NaSG content and their interaction show a significant influence. The kinetic parameters of release LMT tablets were obtained by mathematical data processing using DDSolver software using different release kinetic models. Changes in conditions of exposure to elevated and decreased humidity affected the kinetics of lamotrigine. The most significant change was recorded in the dissolution media pH 6.8. Data obtained for releasing LMT in commercial tablets exposed to high and low humidity conditions were consistent with the data on LMT release from MCC formulations where the effect of moisture in pH 6.8 medium on reducing LMT release was confirmed. The results indicate a significant impact of the formulation ingredients, especially when exposed to high and low humidity conditions, as well as the need to educate patients using direct release LMT tablets about storage and the possible consequences of weekly and/or monthly dosing therapy

Effect of Moisture and Formulation Ingredients on the Release of Lamotrigine Immediate-Release Tablet

U radu je primenom eksperimentalnog dizajna urađeno ispitivanje uticaja različitih formulacijskih komponenti i njihovog variranja na karakteristike tableta sa lamotriginom (LMT) kao model supstancom. Ispitivan je uticaj faktora povišene i snižene vlage u periodu od sedam dana i četiri nedelje kao uslova čuvanja na kinetiku oslobađanja lekovite supstance iz tableta LMT-a sa trenutnim oslobađanjem. Izvršeno je međusobno poređenje karakteristika tableta LMT koje se nalaze na tržištu i njihovo variranje u brzini oslobađanja lekovite supstance nakon izlaganja uslovima povišene i snižene vlage. U formulacijama tableta korišćeni su različita sredstava za dopunjavanje [mikrokristalna celuloza (MKC) ili anhidrovana laktoza (LAK)]; kao sredstvo za raspadanje korišćen je natrijum-skrobglikolat (NaSG) u koncentracijama od 0,5% i 4%; kao sredstvo za klizanje i lubrikant je korišćen magnezijum-stearat (MgST) u koncentraciji od 0,25% i 5%. Za procenu uticaja sastava ispitivanih formulacija primenio se pun faktorski dizajn 2³ gde su praćena navedena tri faktora kao sastojci formulacije, na oba udela. Tablete su izrađivane direktnom kompresijom pomoću ekscenter mašine za tabletiranje. Tabletabilnost formulacija i pojedinačnih sastojaka je ispitivana putem multifunkcionalnog uređaja za simulaciju kompakcije – Gamlen uređaj. Karakteristike ispitivanih faktora u direktno kompresibilnim formulacijama tableta procenjivane su preko fizičkih karakteristika tabletnog materijala, mehaničkih karakteristika tableta, kao i uticaja karakteristika na kinetiku oslobađanja lekovite supstance iz formulacija tableta. Pareto dijagrami su korišćeni da se prikažu procene uticaja određenih efekata na ispitivane karakteristike formulacija. Primenom multifunkcionalnog Gamlen uređaja i analizom dobijenih rezultata za formulacije tableta, značajan pozitivan uticaj na tabletabilnost pokazala je interakcija MgST sa NaSG kada se nalaze u većem udelu. Utvrđeno je da se korišćenjem MKC kao sredstva za dopunjavanje dobijaju znatno bolje protočne karakteristike tabletnog materijala u formulacijama sa isptivanim opsegom udela lubrikanta i sredstva za dezintegraciju, u odnosu na tabletni materijal sa MKC. Potvrđeno je da dodatak LMT u placebo masu smanjuje neto rad, a povećava elastični oporavak kompresije u odnosu na placebo formulacije, čime negativno utiče na tabletabilnost formulacija. Visok udeo NaSG i veća sila kompresije uticala je na smanjenje elastičnog oporavka kod tabletnih formulacija. Značajan uticaj na protočna svojstva tabletnog materijala ima udeo MgST u formulacijama sa MKC, dok u formulacijama sa LAK pored udela MgST i udeo NaSG ima značajan uticaj. Sve formulacije tableta sa MKC su pokazale generalno zadovoljavajuće ispitivane mehaničke karakteristike zbog dobrih tabletabilnih i kompresibilnih karakteristika MKC. Dodatak LMT u placebo tabletni materijal doveo je do značajnih promena u karakteristikama formulacija kao što je smanjena otpornost na lomljenje, povećana frijabilnost i smanjeno vreme dezintegracije. Ispitivanjem profila oslobađanja LS kod formulacije sa MKC nakon izlaganja tableta uslovima povišene i snižene vlage, pokazale su nestabilne profile oslobađanja na osnovu čega je potvrđen značajan uticaj uslova čuvanja na formulacije tableta sa MKC. U medijumu pH 6,8 kod formulacija sa MKC, uslovi snižene, a posebno povišene vlage su uticali na usporavanje oslobađanja LMT. Na osnovu rezultata istraživanja, analizom faktora uticaja pomoću Design-Expert softvera zaključeno je da na oslobađanje LMT iz formulacija tableta statistički najveći uticaj ima sredstvo za dopunjavanje. U medijumu pH 6,8 statistički značajan uticaj na oslobađanje LS pokazao je i NaSG nakon izlaganja uslovima povišene i snižene vlage, kao i njegova interakcija sa LAK i MKC. U disolucionom medijumu pH 1,2 u uslovima povišene vlage značajan uticaj pokazuje udeo MgST, udeo NaSG i njihova međusobna interakcija. Kinetički parametri oslobađanja LMT su dobijeni matematičkom obradom podataka uz pomoć softvera DDSolver koristeći različite modele oslobađanja. Promena uslova izlaganja povišenoj i sniženoj vlagi uticala je na izmenjenu kinetiku oslobađanja LMT iz formulacija tableta. Značajnija promena uočena je u disolucijonom medijumu pH 6,8 u odnosu na medijum pH 1,2. Podaci dobijeni za profil oslobađanja LMT u komercijalnim tabletama izloženih uslovima povišene i snižene vlage su bili prema profilima oslobađanja LMT iz analiziranih formulacija sa MKC. U formulacijama tableta sa MKC je potvrđen uticaj povišene i snižene vlage u medijumu pH 6,8 koja utiče na usporavanje oslobađanja LMT. Zaključeno je da postoji značajan uticaj sastojaka formulacije na karakteristike tableta i brzinu oslobađanja LMT, posebno kada su izloženi uslovima povišene i snižene vlage. Rezultati su ukazali na potrebu za edukacijom pacijenata koji koriste tablete LMT sa trenutnim oslobađanjem vezano za način čuvanja i mogućim posledicama prilikom izdvajanja nedeljne i/ili mesečne terapije u dozatore za lekove.Using experimental design, the effects of different formulation components and their variations on the properties of lamotrigine tablets (LMT) as a drug model were investigated. The influence of increased and decreased moisture factors as storage conditions on the kinetics release of the immediate-release LMT tablets during a period of 7 days and 4 weeks was investigated. The characteristics of LMT tablets on the market and their variations in drug release rate after exposure to high and low humidity conditions were compared. Various types of fillers [microcrystalline cellulose (MCC) or anhydrous lactose (LAC)] were used in the tablet formulations; sodium starch glycolate (NaSG), in concentrations of 0.5% and 4%, was used as a disintegrant; Magnesium stearate (MgST), in concentrations of 0.25% and 5%, was used as a glidant and lubricant. To assess the influence of the composition of the tested formulations, a three-factor two-level full factorial design 2³ was applied. The tablets were produced by direct compression using an eccentric tablet machine. The tabletability of formulations and individual ingredients of tablets were analysed using a compaction simulator - Gamlen tablet press. The characteristics of the investigated factors in directly compressible tablet formulations were evaluated according to the physical characteristics of the tablet material, the mechanical characteristics of the tablets, as well as the influence of the properties on the drug release kinetics from the tablet formulations. Pareto diagrams were used to present estimates of the influence of certain effects on the examined formulation characteristics. Use of a compaction simulator - Gamlen tablet press, and the analysis of the results obtained for tablet formulations showed a significant positive effect of the interaction of MgST with NaSG on tableting, when present in a higher percentage. It was determined that the use of MCC as a filler in formulations enables significantly better flow properties of the tablet material in formulations with a tested concentration of lubricant and solvent content, compared to the MCC of tablets. It has been confirmed that the addition of LMT to placebo formulations reduces the net work of compression and the rate of elastic recovery increased relative to placebo formulations, which negatively affects the tabletability of formulations. High concentration of NaSG and higher compression force reduced the elastic recovery of tablet formulations. The concentration of MgST in formulations with MCC significantly affects the flow properties of tablets, while it has a significant effect in formulations with LAC, in addition to the concentration of MgST and the concentration of NaSG. All MCC tablet formulations showed generally satisfactory mechanical properties, due to good compressible properties of MCC. The addition of LMT to the placebo tablet material led to significant changes in the characteristics of the formulations such as reduced fracture toughness, increased brittleness, and reduced disintegration time. Examination of the release profile of the MCC formulation after the exposure of the tablets to high and low humidity conditions showed unstable release profiles, which confirms the significant influence of storage conditions on the MCC tablet formulations. iI the dissolution media pH 6.8 in formulations with MCC, conditions of reduced, and especially increased moisture, slow down the release of LMT. Based on the results of the research, the analysis of impact factors using Design-Expert software concluded that in addition to the influence of fillers on pH 6.8, NaSG has a significant impact after exposure to high and low humidity, as well as its interaction with LAC and MCC. In the dissolution media pH 1.2, under conditions of high humidity, the MgST content, the NaSG content and their interaction show a significant influence. The kinetic parameters of release LMT tablets were obtained by mathematical data processing using DDSolver software using different release kinetic models. Changes in conditions of exposure to elevated and decreased humidity affected the kinetics of lamotrigine. The most significant change was recorded in the dissolution media pH 6.8. Data obtained for releasing LMT in commercial tablets exposed to high and low humidity conditions were consistent with the data on LMT release from MCC formulations where the effect of moisture in pH 6.8 medium on reducing LMT release was confirmed. The results indicate a significant impact of the formulation ingredients, especially when exposed to high and low humidity conditions, as well as the need to educate patients using direct release LMT tablets about storage and the possible consequences of weekly and/or monthly dosing therapy

Energy drink consumption among medical high school students in Serbia

Energetska pića postala su vrlo popularna među adolescentima. Cilj ovoga istraživanja bio je utvrditi učestalost uzimanja energetskih pića samih ili u kombinaciji s alkoholom među učenicima srednje medicinske škole prema spolu i razredu te procijeniti njihovo poznavanje štetnih učinaka ove navike. Ovo poprečno istraživanje provedeno je pomoću anonimne ankete, a obuhvatilo je 258 polaznika srednje medicinske škole, odnosno 162 učenica i 96 učenika. Razlike u potrošnji energetskih pića prema dobi i spolu ispitane su pomoću χ2-testa. Rezultati istraživanja su pokazali da gotovo polovica učenika pije energetska pića, a 1,56% njih radi to svakodnevno. Visok postotak učenica (54%) ne uzima ova pića, dok je 32% učenika navelo da pije ova pića jedanput na tjedan. Isto tako, 28% onih koji piju energetska pića navelo je da uzima alkohol pomiješan s energetskim pićima. U zaključku, značajan dio učenika srednje medicinske škole pije energetska pića. Potrebna su daljnja istraživanja kako bi se procijenio učinak dugotrajnog uzimanja energetskih pića. Također je potrebno usredotočiti se na problem miješanja energetskih i alkoholnih pića te provesti odgovarajuće školske programe za promicanje zdravlja među učenicima srednjih medicinskih škola i tako im pomoći steći potrebna znanja i vještine u promicanju zdravlja u njihovom budućem medicinskom zvanju.Energy drinks have become very popular among adolescents. The aim of this study was to determine the frequency of energy drink consumption alone and in combination with alcohol among medical high school students according to gender and grade, as well as to evaluate their knowledge of its adverse eff ects. The cross-sectional survey was conducted using an anonymous questionnaire. A total of 258 medical high school students, 162 female and 96 male, were surveyed. The χ2-test was used to test age and gender diff erences in energy drink consumption. Study results showed nearly half of the students to take energy drinks, 1.56% of them taking these beverages every day. A higher percentage of female students did not take these drinks (54%), while 32% of male students reported taking these drinks once a week. Also, 28% of consumers of these beverages reported taking alcohol mixed with energy drinks. In conclusion, a signifi cant proportion of medical high school students used energy drinks. Further studies are needed to evaluate the impact of long-term energy drink consumption. It is also necessary to focus on the problem of mixing energy drinks with alcohol and to implement appropriate school based health promotion programs among medical high school students that will help them gain knowledge and skills for applying health promotion in their future medical profession

The Effect of Humidity on the Dissolution Kinetics and Tablet Properties of Immediate-Release Tablet Formulation Containing Lamotrigine

This study aims to find the effects of high (75%) and low (30%) humidity conditions and its correlation with formulation composition on dissolution kinetics of lamotrigine (LMT) from prepared immediate-release tablets during one- and four-week periods. Two types of fillers microcrystalline cellulose (MCC) or anhydrous lactose (LAC), disintegrant sodium starch glycolate (NaSG, 0.5% or 4%), and lubricant magnesium stearate (MgST, 0.25% or 5%) were used. A three-factor two-stage complete factorial design (23) was used to assess the influence of the composition of the tested formulations. The tablets were produced by direct compression and characterized using a disintegration test, a resistance to crushing test, and dissolution tests (pH 1.2 and pH 6.8). Using Design Expert software, it was concluded that in addition to the effect of fillers on pH 6.8, NaSG has a significant impact after exposure to high and low humidity, as well as its interaction with LAC and MCC. In the dissolution medium pH 1.2, under conditions of high humidity, the content of MgST and NaSG and their interaction show a significant influence. The release rate of LMT was affected by humidity as well as type of excipients and their interactions