FORMULATION, CHARACTERIZATION AND BIOAVAILABILITY STUDY OF SOLID SELF NANOEMULSIFYING DRUG DELIVERY SYSTEM (S-SNEDDS) OF FENOFIBRIC ACID

• Main Author: Noviana Suhery, Wira
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/53021
• Institution: Institut Teknologi Bandung

Solubility is one of the critical parameters that determine the bioavailability of drugs in the blood. Nearly about 40% of new drugs on the market have low solubility in water. Therefore, this greatly affects its bioavailability. Fenofibric acid is a drug that has poorly water solubility, so its bioavailability is difficult to predict. Hence, fenofibric acid requires a technique to increase its solubility. Solid self nanoemulsifying drug delivery system (S-SNEDDS) is one of the novel techniques currently being developed to increase the solubility of drugs which have poorly water solubility. Many factors can affect the success of increasing drug solubility with this technique, such as the selection and amount of oil, surfactants, and cosurfactants components as well as adsorbents and the methods used in the solidification process to convert SNEDDS into S-SNEDDS. To date, there have been no studies regarding the increase in fenofibric acid solubility using the S- SNEDDS technique accompanied by in vivo bioavailability study. The aim of this research was to formulate fenofibric acid in the form of S-SNEDDS, by determining the right type and amount of oil, surfactants, cosurfactants, and adsorbents as well as an efficient solidification method. Furthermore, characterization was carried out to investigate and explain the effect of various S-SNEDDS components on the physical properties and dissolution of fenofibric acid in the SNEDDS formulation. The best formulation will be tested for bioavailability in vivo in healthy subjects. This study also covers the effect of S-SNEDDS on the absorption and bioavailability of fenofibric acid in the blood. The components of oil, surfactant and cosurfactant were determined by the fenofibric acid solubility test in each of these components. The highest solubility of fenofibric acid in each component was selected as a SNEDDS component. Especially in surfactant selection, the emulsification ability of the surfactant was required. Various concentration of the selected SNEDDS components were designed with oil and Smix (surfactant and cosurfactant) in the ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2, and 9:1. Those comparisons which produced nanoemulsion with globule size <100 nm after being diluted with water were then constructed in a pseudo-ternary diagram to show the nanoemulsion area. The diagram was used as a reference to optimize fenofibric acid loaded-SNEDDS formula. SNEDDS were characterized by globule size, polydispersity index, zeta potential, percent transmittance, self-emulsifying time, physical accelerated stability test, and in vitro dissolution test. The best formula was further observed for nanoemulsion globules using a Transmission Electron Microscopy (TEM) and Fourier Transform Infrared Spectroscopy (FTIR) test. The selected formula of SNEDDS was then solidified into S-SNEDDS using adsorption and freeze-dry methods with the use Neusilin® US2 as adsorbent. S-SNEDDS were physically characterized for Powder X-Ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), FTIR, Scanning Electron Microscopy (SEM), as well as globule size after reconstitution, and in vitro dissolution tests. Furthermore, bioavailability tests were carried out in healthy subjects compared to fenofibric acid tablets (innovator products). Preliminary test showed that (fenofibric acid solubility test in each component) the selected oil components; surfactant; cosurfactants were Maisine® CC, and Kollisolv® MCT 70, Kolliphor® RH 40, and PEG 400 and Transcutol® HP, respectively. Furthermore, optimization of the formulation based on the pseudoternary diagram resulted should be more than 16 formulations. The use of oil, surfactant and cosurfactant in F1-F8 were Kollisolv® MCT 70, Kolliphor® RH 40 and PEG 400, and Transcutol® HP, respectively. While Fa-Fh were consisted of Maisine® CC, Kolliphor® RH 40, PEG 400, Transcutol® HP, respectively. Fd and F1 was the best formulation of fenofibric acid SNEDDS and then solidified with Neusilin® US2 by adsorption method and freeze-dried (SSa-SSd, and SS1-SS4). Characterization of S-SNEDDS showed a change in fenofibric acid from crystalline to amorphous form after it was formulated into S-SNEDDS as indicated by the results of PXRD, DSC, and SEM. Additionally, there was no chemical interaction between the components in the formula as shown by the FTIR spectrum. As results, SSd and SS1 were selected for further optimization in weight to be more efficient so that two final formulations of fenofibric acid S-SNEDDS (FS1 and FS2) were obtained. FS1 and FS2 were tested for dissolution in vitro (n=6) in three mediums of acid medium (HCl buffer pH 1.2), acetate buffer medium pH 4.5, and phosphate buffer medium pH 6.8 with a comparison to innovator product of fenofibric acid tablets (FSt). The results showed that the dissolution of FS1 and FS2 were higher than FSt of approximately 40% and 96% in acid medium pH 1.2 and acetate buffer medium pH 4.5 within 60 minutes, respectively. In addition, the dissolution of FS1, FS2, and FSt in phosphate buffer medium 6.8 showed a high dissolution, which was 100% within 60 minutes. Furthermore, FS1, FS2, and FSt were tested for bioavailability in 12 healthy subjects by three way cross-over design. The results showed that FS1, FS2 had faster Tmax compared to FSt (p value <0.05), namely 0.96 ± 0.438 hours, 0.71 ± 0.445 hours and 1.71 ± 0.840 hours, respectively. The values of Cmax and AUC0-t FS1, FS2, and FSt were not significantly different with p values >0.05. This study provides information that S-SNEDDS increases the dissolution of fenofibric acid especially in medium pH 1.2 and pH 4.5, thereby increasing the rate of drug absorption into the blood.