High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

PURPOSE: To design a high drug loading formulation of self-microemulsifying/micelle system. METHODS: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). RESULTS: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. CONCLUSIONS: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

Design of self-microemulsifying drug delivery systems using a high-throughput formulation screening system.

PURPOSE: A high-throughput formulation screening (HTFS) system that enabled to rapidly and efficiently select self-microemulsifying drug delivery system (SMEDDS) formulations has been developed in our previous study. The purpose of this study was to investigate the applicability of the HTFS system to SMEDDS designs. METHODS: A poorly soluble drug (Nilvadipine), an oil (Sefsol-218), 11 hydrophilic surfactants (HS), and 10 lipophilic surfactants (LS) were used. Formulations were prepared and SMEDDS formulations were chosen by the HTFS system. A HS with the largest number of SMEDDS formulations was selected. In the selected HS system, a LS with the largest number of SMEDDS formulations was selected. Formulations with minimum turbidity at each ratio of the selected HS/LS were chosen as optimized formulations. RESULTS: A total of 2455 formulations were prepared and SMEDDS formulations were selected using the HTFS system. From the screening data, HCO60 was selected as a superior emulsifiable HS, and Plurol (PLUROL OLEIQUE CC497) was selected as a suitable LS to HCO60. Five optimized formulations were chosen from the HCO60/Plurol system. The formulations formed fine microemulsions (<33.6 nm) without phase separation and drug precipitation. These formulation designs were conducted using 600 mg of the drug at a rate of 400 formulations/person/day. CONCLUSION: SMEDDS formulations could be rapidly and efficiently designed using the HTFS system.

High-throughput formulation screening system for self-microemulsifying drug delivery.

PURPOSE: To develop a high-throughput formulation screening (HTFS) system for self-microemulsifying drug delivery system (SMEDDS) formulations. METHODS: Formulations were prepared by dispensing surfactants and a model compound (Nilvadipine) dissolved in ethanol and oil with a robotic liquid dispenser. Screenings of emulsion particle size and phase stability were conducted for selecting SMEDDS formulations by a turbidity assay. RESULTS: Formulations were prepared at 40 minute/96-formulation. Both the screenings were conducted at 1 minute/96-formulation. SMEDDS formulations and the most suitable hydrophilic surfactant (HS)/lipophilic surfactant (LS) combination, which formed the largest SMEDDS area on its corresponding phase diagram, were selected by SMEDDS-HTFS system with minimal manpower (one person) and compound consumption (0.2 mg/formulation). CONCLUSIONS: SMEDDS-HTFS system enabled rapid and efficient selections of SMEDDS formulations and the most suitable HS/LS combination for SMEDDS.

Prediction of oral drug absorption in humans by theoretical passive absorption model.

The purpose of the present study was to examine the oral drug absorption predictability of the theoretical passive absorption model (TPAM). As chemical descriptors of drugs, the octanol/buffer distribution coefficient at pH 6.0 (D(ow)), intrinsic octanol-water partition coefficient (P(ow)), pK(a), and molecular weight (MW) were calculated from the chemical structure. Total passive intestinal membrane permeation consists of transcellular, paracellular and unstirred water layer (UWL) permeation. Transcellular permeation was modeled based on the pH-partition hypothesis with correction for cationic species permeation, and the independent variables were D(ow), P(ow), and pK(a). Paracellular permeation was modeled as a size-restricted diffusion within a negative electrostatic field-of-force, and the independent variables were MW and pK(a). UWL permeation was modeled as diffusion across a water layer, and the independent variable was MW. Cationic species permeation in the transcellular permeation model and the effect of a negative electric field-of-force in the paracellular permeation model were the extensions to the previous TPAM. The coefficients of the paracellular and UWL permeation models were taken from the literature. A data set of 258 compounds with observed values of Fa% (the fraction of a dose absorbed in humans) taken from the literature was employed to optimize four fitting coefficients in the transcellular permeation model. The TPAM predicted Fa%, with root mean square errors of 15-21% and a correlation coefficient (CC) of 0.78-0.88. In addition, the TPAM predicted the effective human intestinal membrane permeability with a CC of 0.67-0.77, as well as the contribution of paracellular permeation. The TPAM was found to predict oral absorption from the chemical structure of drugs with adequate predictability for usage in drug discovery.

Biopharmaceutics classification by high throughput solubility assay and PAMPA.

The purpose of the present study was to examine the relevancy of the high throughput solubility assay and permeability assay to the biopharmaceutics classification system (BCS). Solubility and permeability were measured by high throughput solubility assay (HTSA) and parallel artificial membrane permeation assay (PAMPA), respectively. High throughput solubility assay was performed using simulated gastric fluid (SGF, pH 1.2) and simulated intestinal fluid without bile acid (SIF, pH 6.8). We categorize 18 drugs based on the BCS using HTSA and PAMPA. Fourteen out of 18 drugs were correctly classified (78% success rate). The result of the present study showed that HTSA could predict BCS class with a high success rate, and PAMPA could also be useful to predict the permeation of drugs.