Immediate- and controlled-release preparation of solid multiparticulate SMEDDS/SNEDDS for poorly soluble drugs

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Immediate- and controlled-release preparation of solid multiparticulate SMEDDS/SNEDDS for poorly soluble drugs


Quantum Structure & Nanodevices

A large number of marketed drugs available in Saudi Arabia and all over the world 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 such 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 stability, leaching, evaporation of solvents, rancidity and formulation discoloration). To overcome these limitations, the current study aims to investigate and optimize the solidification of cinnarizine (CN) liquid SNEDDS into solid self-nanoemulsifying pellets (SNEP) via fluid bed coating. CN suffers both low aqueous solubility and chemical instability and thus it was selected as model drug for the current study. Due to the criticality of this technique, very few articles worldwide have utilized fluid bed coating for SNEDDS solidification and no similar researches are yet conducted in Saudi Arabia. The current project involved comprehensive optimization of CN liquid SNEDDS using equilibrium solubility studies, self-emulsification assessment and experimentally designed phase diagrams. Further, optimized liquid SNEDDS were solidified using fluid bed coating technique. Both process and formulation variables were optimized to achieve minimal agglomeration as well as minimal spray drying in the final product. Finally, optimal SNEP were evaluated against liquid SNEDDS based on in-vitro dissolution and comprehensive stability studies that involved accelerated, intermediate and long-term storage conditions. CN solubility was greatly enhanced upon external and internal acidification. Among various fatty acids, oleic acid (OL) based-formulations exhibited superior self-emulsification in all the tested media. 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 OL-I308-Cr-El (25/25/50), which exhibited excellent self-emulsification along with 43nm droplet size (for CN-equilibrated formulations) and 88 mg/g CN solubility. Regarding solidification process optimization, 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. Regarding formulation variables, HPMC E3 reduced the pellet tackiness compared to PVP 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%. In contrast to CN powder, SNEP presented similar dissolution behavior to liquid SNEDDS holding high CN% in solution even at pH 6.8. Fluid bed coating offers an effective technology to solidify CN liquid SNEDDS into SNEP. Optimized SNEP offer an efficient dosage form that combine the solubilzation benefits of liquid SNEDDS, avoid their limitations in addition to solid dosage form superiority. CN-SNEP showed superior chemical and physical stability profile, compared to liquid SNEDDS. Further research should be conducted in the near future to minimize CN degradation within SNEP by altering SNEDDS composition or minimizing their contact with the drug.

1. Designing liquid lipid formulations (SMEDDS/SNEDDS) utilizing new lipid formulation classification systems and selecting a model drug from among poorly soluble compounds (BCS class II drugs, highly lipophilic compounds with low solubility and high permeability) 2. Converting liquid lipid formulation into solid multiparticulate and/or single unit dosage form to enhance oral delivery and thereby improve physical stability (e.g. leaching, evaporation of solvents, phase changes, oxidation etc) and chemical stability issues. 3. Developing technology platform based on lipid-carrier systems (formulations) that can carry different drugs with different physicochemical properties and enhance solubility in vitro/in vivo and bioavailability 4. Developing immediate or controlled-release delivery of poorly soluble drugs by final drug-retarding film coating over solid SMEDDS/SNEDDS layer 5. Filling solid multiparticulates into soft/hard gelatin capsules or developing single-unit dosage form by compressing into fast-disintegrating tablets, which can lead to patented products.

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