A cochleate formulation optimized by D-optimal mixture design enhances oral bioavailability of Revaprazan.

A cochleate formulation was developed to enhance the oral bioavailability of revaprazan (RVP). Dimyristoyl phosphatidylcholine (DMPC) liposome containing dicetyl phosphate (DCP) successfully formed a cochleate after treatment with CaCl2, whereas that containing sodium deoxycholate did not. Cochleate was optimised using a D-optimal mixture design with three independent variables-DMPC (X1, 70.58 mol%), cholesterol (X2, 22.54 mol%), and DCP (X3, 6.88 mol%)-and three response variables: encapsulation efficiency (Y1, 76.92%), released amount of free fatty acid at 2 h (Y2, 39.82%), and released amount of RVP at 6 h (Y3, 73.72%). The desirability function was 0.616, showing an excellent agreement between the predicted and experimental values. The cylindrical morphology of the optimised cochleate was visualised, and laurdan spectroscopy confirmed the dehydrated membrane interface, showing an increased generalised polarisation value (approximately 0.5) over small unilamellar vesicle of RVP (RVP-SUV; approximately 0.1). The optimised cochleate showed greater resistance to pancreatic enzyme than RVP-SUV. RVP was released in a controlled manner, achieving approximately 94% release in 12 h. Following oral administration in rats, the optimised cochleate improved the relative bioavailability of RVP by approximately 274%, 255%, and 172% compared to RVP suspension, a physical mixture of RVP and the cochleate, and RVP-SUV, respectively. Thus, the optimised cochleate formulation might be a good candidate for the practical development of RVP.

Soft-capsule formulation of a re-esterified triglyceride omega-3 employing self-emulsifying technology and bioavailability evaluation in healthy volunteers.

Despite the superior clinical efficacy of the re-esterified triglyceride (rTG) form compared to the ethylester form, few studies have been conducted on improving the bioavailability of the rTG form of omega-3 oil. The aim of study was to evaluate the effect of self emulsifying formulation on the improvement of bioavailability of rTG form of omega-3 oil. To develop a re-esterified triglyceride (rTG) soft capsule, an rTG-loaded self-emulsifying delivery system (SEDS) was designed using coconut oil, polysorbate 80, and lecithin. Candidate formulations were designed from a phase-diagram study and optimal SEDS formulations containing 85% of high omega-3 (ω-3) oils were screened from the evaluation of droplet size distribution, measurement of oil floating area and emulsion turbidity. The selected, optimized rTG SEDS formulation was filled into a soft capsule (NOVASEDS) and applied to a sequence-randomized, double-blind, single-dose, and two-way crossover clinical study (n = 44), and the the bioavailability of NOVASEDS was compared with that of a 'raw' rTG capsule (rTG OMEGA3) as control. The droplet size (D50) formed from the candidate formulations was approximately 30-45 µm, and the optimal formulation showed a unimodal particle distribution with the smallest oil floating area and small changes in turbidity after 24 h. Cmax and AUC from 0 to 24 h for NOVASEDS, calculated from docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and as the sum of DHA and EPA, were significantly higher (P < 0.05) than corresponding values for rTG OMEGA3. In conclusion, NOVASEDS formulated by SEDS technology enabled the manufacture of a high rTG payload soft capsule with improved bioavailability in human subjects.

Optimization of a solidified micelle formulation for enhanced oral bioavailability of atorvastatin calcium using statistical experimental design.

To enhance the oral bioavailability of atorvastatin calcium (ATV), a novel solidified micelle (S-micelle) was developed. Two surfactants, Gelucire 48/16 (G48) and Tween 20 (T20), were employed for micelle formation, and two solid carriers (SC), Florite PS-10 (FLO) and Vivapur 105 (VP105), were selected as solid carriers. The S-micelle was optimized using a Box-Behnken design with three independent variables, including G48:T20 (X1, 1.8:1), SC:G48 + T20 (X2, 0.65:1), and FLO:VP105 (X3, 1.4:0.6), resulting in a droplet size (Y1) of 198.4 nm, dissolution efficiency at 15 min in the pH 1.2 medium (Y2) of 47.6%, Carr's index (Y3) of 16.9, and total quantity (Y4) of 562.5 mg. The optimized S-micelle resulted in good correlation showing percentage prediction values less than 10%. The optimized S-micelle formed a nanosized dispersion in the aqueous phase, with a higher dissolution rate than raw ATV and crushed Lipitor®. The optimized S-micelle improved the relative bioavailability of oral ATV (25 mg equivalent/kg) in rats by approximately 509 and 271% compared to raw ATV and crushed Lipitor®, respectively. In conclusion, the optimized S-micelle possesses great potential for the development of solidified formulations for improved oral absorption of poorly water-soluble drugs.

Immediate-release tablet formulation of rebamipide and a pharmacokinetic study in healthy human subjects.

OBJECTIVE: To develop an immediate-release tablet preparation containing rebamipide (RBM) and perform the bioavailability assessment in the healthy human subjects. MATERIALS AND METHODS: Raw RBM powder was characterized using differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy (SEM). RBM tablets were manufactured by the wet granulation method, and their dissolution behavior was compared with the reference tablet (Mucosta). A phase I study (n = 47; sequence-randomized, open-label, single-dose, and two-way cross-over design) was designed for oral administration of a test formulation (F4) and Mucosta to healthy human male subjects, and pharmacokinetic parameters including the maximum plasma concentration (Cmax) and area under the curve from 0 to 12 hours (AUC0-12h) were compared. RESULTS: RBM powder had a multimodal size distribution with typical crystallinity, and the needle-like and elongated morphologies of RBM were visualized using SEM. Various tablet formulations (F1 - F6) were successfully manufactured using wet granulation method. F4 formulation was selected based on the dissolution profile most equivalent to that of Mucosta. F4 was stable for 6 months under accelerated and long-term storage conditions. Based on one-way analysis of variance, the AUC0-12h (F(1,92) = 2.40, p = 0.13) and tmax (F(1,92) = 0.04, p = 0.85) were not significantly different; however, the Cmax (F(1,92) = 5.45, p = 0.022) showed significant difference between F4 and reference tablets. CONCLUSION: Despite similar in vitro dissolution profiles, in vivo pharmacokinetic results revealed a partial difference between F4 and reference tablets. Thus, further study on formulation development is still needed.

Enhanced oral absorption of insulin: hydrophobic ion pairing and a self-microemulsifying drug delivery system using a D-optimal mixture design.

The lipophilicity of a peptide drug can be considerably increased by hydrophobic ion pairing with amphiphilic counterions for successful incorporation into lipid-based formulations. Herein, to enhance the oral absorption of insulin (INS), a self-microemulsifying drug delivery system (SMEDDS) formulation was developed. Prior to optimization, INS was complexed with sodium n-octadecyl sulfate (SOS) to increase the loading into the SMEDDS. The INS-SOS complex was characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and its dissociation behavior. The SMEDDS was optimized using a D-optimal mixture design with three independent variables including Capmul MCM (X1, 9.31%), Labrasol (X2, 49.77%), and Tetraglycol (X3, 40.92%) and three response variables including droplet size (Y1, 115.2 nm), INS stability (Y2, 46.75%), and INS leakage (Y3, 17.67%). The desirability function was 0.766, indicating excellent agreement between the predicted and experimental values. The stability of INS-SOS against gastrointestinal enzymes was noticeably improved in the SMEDDS, and the majority of INS remained in oil droplets during release. Following oral administration in diabetic rats, the optimized SMEDDS resulted in pharmacological availabilities of 3.23% (50 IU/kg) and 2.13% (100 IU/kg). Thus, the optimized SMEDDS is a good candidate for the practical development of oral delivery of peptide drugs such as INS.

Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system.

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.