Studies On CBZ Supersaturatable Self-microemulsifying Drug Delivery System

Conventional self-microemulsifying drug delivery systerm (SMEDDS) are widely used in enhancing the oral absorption of poorly soluble drugs. The high surfactant level typically present in SMEDDS formulations can lead to gastrointestinal (GI)side-effects as well as a reduction in the free drug concentration and thus a reduced rate of intestinal absorption. The supersaturatable self-microemulsifying(S-SMEDDS) is a drug delivery system by adding the supersaturated promoter into the self-microemulsifying formulation. The S-SMEDDS approach is to generate a protracted supersaturated solution of the drug when the formulation is released into an aqueous medium. The S-SMEDDS formulations contain drugs dissolved with a reduced level of surfactant.Carbamazepine is used clinieally to treat seizeure disorders,trigeminal neuralgia,and most recently,manic depressive illness.CBZ is low solubility in water (113μg?mL-1,25℃) with polymorphs .Dissolution rate of the different crystalline form in the gastrointestinal tract is different .CBZ polymorphic transformation at high humidity and in water into the dihydrate. its gastrointestinal absorption is slow and irregular (4～12μg?mL-1)leading to incomplete bioavailability.There is also considerable variability in CBZ plasma concentration.In this study,the aim was to enhance the bioavailability of carbamazepine,and to reduce the fluctuation of its blood level,CBZ supersaturatable self-microemulsifying drug delivery system was carried out.The pre-formulation study showed that OE had the solubility of 42.43±3.87 mg·mL^-1 for CBZ,which was higher than other choosed oils.The logarithm of apparent partition coefficients of CBZ in octanol/0.l mol·L^-1 HCl,octanol/water and octanol/pH 7.4 PBS were 2.13,2.10和2.08,indicating that CBZ was a certain lipophilic.In the formulation study,OE ,which had the biggest solubility of CBZ,was used as oil.Cremophor EL-35,PEG400 and PVPK90 were selected as surfactant,cosurfactan and precipitation inhibitor respectively after the compatibility study,and drawing of the ternary phase diagrams,and the effectiveness of inhabiting the crystal growth. The optimized formulation were selected were selected after the optimization the SMEDDS and the supersaturated promoter. S-SMEDDS with high transmittance and low toxicity was selected through Caco-2 cell model.The optimized formulation of CBZ S-SMEDDS completed the self-microemulsifying in the 43.1±3.5S in simulated conditions of the gastrointestinal tract. Microemulsion was stable after twenty four hours at room temperature.The mean particle size of optimized formulation of CBZ S-SMEDDS was 33.74nm, and its Zeta potential was-17.2±5.37mv. Compared with the commercial tablet,S-SMEDDS enhanced the dissolution of carbamazepine.There was no medicine crystallized from the S-SMEDDS after thirty day at low temperature;the contents of CBZ showed no significant changes. There was no medicine crystallized from the S-SMEDDS after six months at normal temperature;the contents of CBZ showed no significant changes.Pharmacokinetics studies of CBZ supersaturatable self-microemulsifying formulation in beagle dogs were performed by two-treatment, two periods,randomize,crossover design.The reference formulation was commercial tablets.In this study, AUC(0-t) of reference formulation and test formulation were 1.67±1.19μg·h·mL^–1 and 9.83±2.47μg·h·mL^–1,and relative bioavailability was 760±335%;Cmax of reference formulation and test formulation were 0.74±0.19μg·mL^-1and 4.96±1.16μg·mL^-1。In different dose pharmacokinetics studies AUC(0-t) of reference formulation and test formulation were 1.58±0.35μg?h?mL–1and 1.30±0.25μg?h?mL–1;Cmaxof reference formulation and test formulation were 0.7±0.3μg·mL^-1 and 1.0±0.3μg·mL^-1 respectively.Thus,the test formulation enhanced the absorption of carbamazepine, a reduction of individual differences.