1. Chitosan aqueous solution (0.1 mg/mL)
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Simvastatin-loaded chitosan nanocapsules for the innovative administration of statins 
Sonvico F.
Garrastazu G.
Batger M.
Introduction
Recent research indicates that statins display a wide range of anti-inflammatory and immunomodulatory effects that could be beneficial in neurodegenerative disorders.1,2 These pleiotropic effects are concentration dependent and are only observed at higher systemic concentrations.
However, current oral administration is subject to extensive first pass metabolism leading to low systemic concentrations. The purpose of the present study was to prepare and evaluate the physico-chemical properties of simvastatin (SV)-loaded nanoparticles suitable for oral and trans-mucosal deliveries. It was hypothesized that the addition of oily excipients can help to improve the encapsulation efficiency of the nanoparticles and result in prolonged release of the drug.
Methods
Nanoparticles were prepared according to an established method by Sonvico et al.3 Chitosan and lecithin nanoparticles loaded with SV (1 mg/mL final concentration) were prepared with (NCSV, nanocapsules) or without (NSSV, nanospheres) two oily excipients, medium chain triglycerides (Labrafac, Trapeze) and glycerol monolinoelate (Maisine, Trapeze). The nanoparticles were characterized for particle size and surface charge (ZetaSizer NS, Malvern), morphology (STEM, EVO Zeiss), drug encapsulation efficiency (Ultrafiltration followed by HPLC) and drug release using the dialysis bag method with a SV solution as control (HPLC, Shimadzu).
Simvastatin chemical structure and crystals
Ethanol solution of:
Lecithin (25 mg/mL)
Simvastatin (12.5 mg/mL)
Oils 1:1 (50 mg/mL) only for NCSV
Chitosan aqueous solution (0.1 mg/mL)
Nanoparticles
Results
The SV-loaded chitosan/lecithin nanospheres produced without oil (NSSV) had larger particle size. The SV-loaded oily nanocapsules (NCSV) showed particle size below 200 nm. Furthermore, formulations prepared had positive surface charge and narrow size distribution. The SV encapsulation efficiency was low (23%) in the absence of the oil components. The addition of the oily excipients resulted in a high encapsulation efficiency of over 99%.
In the electron microscopy images of NSSV, the presence of SV crystals was evidenced, while only small, spherical, mono-dispersed structures were observed in the NCSV batch.
Batch
NSSV
NCSV
Mean particle size (nm)
272.4 ± 12.7
189.2 ± 0.5
Polydispersity index
0.236 ± 0.03
0.129 ± 0.01
Zeta potential (mV)
± 2.60
± 0.13
Encapsulation efficiency (%)
22.60 ± 20.8
99.18 ± 0.72 1
NSSV
NCSV
SV Solution
NCSV
Preliminary drug release studies were carried out on the NCSV formulation as NSSV was characterized by low SV-loading. The drug release profile of NCSV in PBS (20% EtOH, 2% Tween 20) was prolonged for over 48 h. Approximately 40% of SV was released from nanoparticles after 48 h in PBS at 37oC. Although sink conditions were not maintained throughout the experiment, the release of SV from NCSV was significantly reduced compared to a SV solution.
Conclusion
References
1. BLANCO-COLIO, L. M, TUÑÓN, J, MARTÍN-VENTURA; et al Kidney Int. 63,
FASSBENDER. K, SIMONS, M, BERGMANN, C, STROICK, M, L; et al Proc. Natl Acad. Sci. USA, 98,
SONVICO, F, CAGNANI, A, ROSSI, A; et al Int J Pharm, 324, 67-73
NCSV with positive surface charge were obtained by the self-assembly of chitosan, lecithin and oily excipients. The high encapsulation efficiency nanosystem will be studied for improving statins bioavailability by oral or transmucosal routes thus avoiding the first-pass effect, e.g. nasal delivery.