الفهرس | Only 14 pages are availabe for public view |
Abstract A large proportion of the marketed drugs are poorly-water soluble. This is frequently associated with poor oral bioavailability, high intra-subject and inter-subject variability. Self-nanoemulsifying drug delivery systems (SNEDDS) have the potential to overcome these challenges due to their ability to enhance gastrointestinal solubilization and absorption of poorly water-soluble drugs. However, the stability of liquid SNEDDS could be a major issue (e.g. chemical instability, leaching, evaporation of solvents, rancidity and formulation discoloration). To overcome these limitations, the current dissertation aims to investigate and optimize the solidification of cinnarizine (CN) liquid SNEDDS into solid self-nanoemulsifying pellets (SNEP) via fluid bed coating. CN suffers poor aqueous solubility and chemical instability and hence it is an attractive candidate for the current dissertation. Methods The current study involved comprehensive optimization of CN liquid SNEDDS using equilibrium solubility studies, self-emulsification assessment, experimentally designed phase diagrams and cross polarizing light microscopy. Further, optimized liquid SNEDDS were solidified using fluid bed coating. The solidification process was designed to produce single-layer and multi-layer self-nanoemulsifying pellets (SLSNEP and ML-SNEP, respectively). In CN SL-SNEP, the drug was incorporated within the SNEEDS layer. While in CN ML-SNEP, an inner drug-free SNEDDS layer was isolated from the drug layer via a protective layer. Moisture sealing and silicon dioxide layers were also applied in some ML-SNEP batches. Process and formulation variables were optimized to ensure minimal agglomeration and minimal spray drying in each coating layer. The obtained SNEP were further characterized using scanning electron microscopy, pellet sizing, differential scanning calorimetry (DSC), x-ray diffraction (XRD), reconstitution study, and droplet size analysis. SL-SNEP and ML-SNEP were evaluated against liquid SNEDDS based on in-vitro dissolution studies. Finally, comprehensive stability studies were conducted to evaluate these formulations at accelerated, intermediate and long-term storage conditions. The formulations were evaluated based on the % of intact CN remaining, in-vitro dissolution along with physical appearance. Results CN solubility was greatly enhanced upon external and internal acidification of the formulation. Among various fatty acids, oleic acid (OL) based-formulations exhibited superior self-emulsification in water, pH 1.2 and even at pH 6.8. Surprisingly, experimentally designed phase diagrams showed significant decrease in formulation turbidity and droplet size upon equilibration with CN. Further, CN solubility was significantly increased upon increasing OL in the formulation. The design was optimized and validated using oleic acid/Imwitor308/Cremophor El (25/25/50) which exhibited excellent self-nanoemulsification, 43 nm droplet size (for CN-equilibrated formulations) and 88 mg/g CN solubility. In contrast to CN-free formulations, CNloaded SNEDDS presented lamellar liquid crystals upon 50% aqueous dilution. This finding confirm the enhanced SNEDDS efficiency upon CN incorporation in the formulation. Regarding solidification into SL-SNEP, higher spray air/microclimate air pressure ensured minimal agglomeration with no spray drying. While slight increase in inlet air volume above 35 m3/h led to remarkable spray drying. With respect to formulation variables, HPMC E3 reduced the pellet tackiness compared to Polyvinylpyrrolidone K30. OL showed higher drug loading and less agglomeration compared to medium chain triglycerides. In contrast to talc, plasacrylTMT20 didn`t hinder the complete dissolution of CN. The optimum concentration of coating solution was 15% and the optimum SNEDDS proportion in the coating layer was 40%. The optimized CN SL-SNEP were free-flowing, well-separated with excellent content uniformity and high yield. DSC and XRD studies showed complete absence of CN crystallinity within the drug-loaded SNEDDS layer. The droplet size of reconstituted SL-SNEP was significantly (p < 0.05) higher than liquid SNEDDS, yet the SNEP aqueous dispersion was still within the nano-metric scale. Pure CN showed sharp precipitation upon shifting the media from pH 1.2 to 6.8. In contrast, Both SL-SNEP and liquid SNEDDS maintained >85% CN in solution, even at pH 6.8. This confirm that ability of SNEDDS to enhance CN aqueous solubility at different pH. Further, the solidification process had no considerable negative influence on the SNEDDS efficiency. Regarding ML-SNEP, the inner layer involved similar composition of SLSNEP except that it lacks CN. HPMC E3 (5% solution) exhibited the highest coating recovery (CR) and mono-pellets%, hence it was selected as the optimum formula for protective layer coating. With respect to drug layering, the acidic solution of PVP/CN (4/1) showed excellent coating outcomes. CR%, monopellets% and drug loading efficiency were above 95% without any nozzle clogging. Further, DSC and XRD studies confirmed CN transformation into amorphous state within the PVP solid dispersion. Regarding moisture sealing, both HPMC E3 and Kollicoat smartseal 3D® showed acceptable coating outcomes. In particular, Kollicoat smartseal 3D® could be efficiently coated at high spray rates with minimal agglomeration allowing for very short process time. On general basis, ML-SNEP showed superior dissolution compared to SLSNEP and liquid SNEDDS. However, moisture sealing with Kollicoat smartseal 3D® decreased CN dissolution efficiency. No crucial influence on CN dissolution profile was observed in case of drug supersaturation or upon applying silicon dioxide layer. The chemical stability study revealed significant CN degradation in liquid SNEDDS, SL-SNEP, and ML-SNEP1 (lacking moisture seal) in all the storage conditions. However, both ML-SNEP2 and ML-SNEP3 (moisture sealed) showed significant enhancement of CN stability. CN degradation rate was in the following order: liquid SNEDDS > SL-SNEP > ML-SNEP1 > ML-SNEP2 > ML-SNEP3, respectively. At the end of the stability studies, ML-SNEP3 (coated with Kollicoat smartseal 3D®) maintained ≥ 95% of intact CN initial amount. Upon storage, liquid SNEDDS, SL-SNEP and ML-SNEP2 showed significant decrease of CN dissolution within all the tested conditions. However, the formulations retained their general pattern with no aggressive precipitation after shifting to pH 6.8. These findings ensure that the formulations retained their emulsification efficiency and the DROP in CN dissolution is mostly due to the decrease of intact CN remaining in formulation. Regarding in-vitro dissolution studies, ML-SNEP3 showed the best stability profile since it did not show any significant DROP in CN dissolution efficiency in all the tested conditions. Regarding the physical appearance, liquid SNEDDS experienced sharp discoloration within all the storage conditions. On the other hand, SL-SNEP showed no significant change in physical appearance within all the storage conditions. In addition, ML-SNEP experienced significant discoloration only at accelerated conditions. Among different ML-SNEP, only the unsealed ML-SNEP1 showed significant pellet adherence. This would be mostly associated with unsuccessful dissolution profile. On the other hand, the moisture sealed ML-SNEP2 and ML-SNEP3 showed significant improvement of the latter adherence problem. The incorporation of silicon dioxide layer had no crucial influence on the chemical stability or in-vitro dissolution of ML-SNEP. However, it had an important role in inhibiting pellet agglomeration and minimizing discoloration upon storage. ML-SNEP3 showed no significant decrease in the amount of intact CN remaining or dissolution efficiency within all the storage conditions. Furthermore, these pellets maintained acceptable physical appearance at intermediate and long-term conditions. Therefore, ML-SNEP3 showed the best stability profile and could be efficiently used for CN stabilization. Conclusion Fluid bed coating presents a competent technology to solidify CN liquid SNEDDS into SNEP. Optimized SNEP offer an efficient dosage form that combine the solubilization benefits of liquid SNEDDS, avoid their limitations in addition to solid dosage form superiority. In fact, ML-SNEP is an innovative technique that could enhance CN dissolution by dual mechanisms; self-nanoemulsification and solid dispersion. In particular, ML-SNEP coated with Kollicoat smartseal 3D® showed superior chemical and physical stability profile. Accordingly, ML-SNEP coated with Kollicoat smartseal 3D® could be an excellent dosage form that combine both enhanced CN solubilization and stabilization. |