الفهرس 
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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.