ABSTRACT
Nose-to-brain delivery allows the direct targeting of drug molecules bypassing the Blood Brain Barrier and systemic effect. Nanoemulsion is one of the novel strategies to deliver drug in this route due to its simplicity in manufacturing, long-term stability, and strong solubilization property for drug. The anticancer drug lomustine had poor oral bioavailability in addition to its serious side effect, therefore, developing more effective drug delivery with direct targeting towards the brain through intra-nasal administration applying nanoemulsion technology is a promising alternative. The work involved lomustine solubility screening in oils, surfactants and cosurfactants as well as emulsifier ratio (Smix) nanoemulsion area was identified using pseudo-ternary phase diagrams. Eighteen nanoemulsion formulas were produced for optimization, then characterized for droplet size, polydispersity index, zeta potential, entrapment efficiency, conductivity, transmittance, dilution, visual transparency, physical stability and in vitro release. The optimum NE formula showed droplet size, zeta potential, polydispersity index, entrapment efficiency, %transmittance, conductivity of 31.31 nm, -30.65 mV, 0.159, 98.12%, 99.08%, and 951 us/cm, respectively. The best formula released 100% lomustine within 15 min which is a promising potential drug delivery system that may deliver the drug quickly and directly to the brain as a safe and effective alternative to oral delivery.
ABSTRACT
Background: Vemurafenib (VEM) was a licensed drug for the treatment of skin melanoma and is available only in the market as oral tablets prescribed in huge doses (1920 mg/day). One reason for the high dose is vemurafenib's low oral bioavailability. Methods: VEM-lipid complex (DLC) was predicted based on Conquest and Mercury programs and prepared using the solvent evaporation method using the lipid (phosphatidylethanolamine). DLC was subjected to characterization (FT-IR, Raman spectroscopy, DSC, TGA, P-XRD, and FESEM) to confirm complexation. DLC was used to prepare solid in oil nanodispersion (DLC-SON) and subjected to in vitro, ex vivo, and in vivo evaluation in comparison to our recently prepared conventional SON (VEM-SON) and DLC-control. Results: Conquest and Mercury predict the availability of intermolecular hydrogen bonding between VEM and phosphatidylethanolamine (PE). All characterization tests of DLC ensure the complexation of the drug with PE. Ex vivo studies showed that the drug in DLC-SON has significantly (P<0.05) higher skin permeation than DLC-control but lower drug permeation than conventional SON but it has a higher % skin deposition (P<0.05) than others. The half-maximal inhibitory concentration (IC50) of the prepared DLC-SON is significantly high (P<0.05) in comparison to the conventional SON and pure VEM. In vivo permeation using confocal laser scanning microscopy (on the rat) results indicated that both conventional SON and DLC-SON can cross the SC and infiltrate the dermis and epidermis but DLC-SON has a higher luminance/gray value after 24 h in the dermis in comparison to the conventional SON. Conclusion: The novel lipid complex for VEM prepared using PE as a lipid and enclosed in SON showed higher anticancer activity and topical permeation as well as sustained delivery and good retention time in the dermis that localize the drug in a sufficient concentration to eliminate early diagnosed skin melanoma.
