Enteric-coated alendronate sodium solid lipid nanoparticles; a novel formula to overcome barriers for the treatment of osteoporosis By Funded Project by DSR at King Abdulaziz Uiversity DR. KHALED MOHAMED HOSNY Associate Professor of Pharmaceutics and Industrial pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia -Department of Pharmaceutics and Industrial Pharmacy, Beni Suef University, Egypt

3 Alendronate sodium is a most common oral bisphosphonate use for treatment of osteoporosis. There are many challenges for its use including; extremely low bioavailability 0.6 – 0.7% so given with higher doses, and oesophageal side effects as ulceration or erosion mostly occur with bleeding (1-3). As a result of these constraints, the drug gives under complicated instructions, as the elderly patient after taking the dose should be at least 30 minutes upstanding before any food or beverages. Up to 60% of the patient stops taking alendtonate during the first year of therapy (3). WHY ALENDRONATE SODIUM ???

In order to alleviate patients suffering specially elderly patient: The main objective of the present research project was to utilize nanotechnology for oral alendronate sodium (ALS) delivery, wherein ALS is incorporated within an enteric coated solid lipid nanoparticles (EC-SLNs). The putative advantages are enhancing the absorption and bioavailability, controlling the release, and preventing the free ALS from coming in direct contact with the GI mucosa thereby reducing the possibility of side effects. RESEARCH AIM 4

METHODOLOGY 1. Preparation and Optimization of Alendronate Sodium solid lipid nanoparticles 2. Evaluation of the prepared ALS-SLN: 2.1. Particle size 2.2. Zeta potential 2.3. Entrapment efficiency 3. Coating of ALS-SLN with Eudragit S Release in 0.1N HCl 3.2. Release in Phosphate Buffer 4. Scanning Electron microscope 5. In vivo Pharmacokinetic study 5

6 Design and optimization of alendronate sodium in situ gel -A Box-Behnken design was constructed to evaluate the effects of the independent variables on the particle size of ALS-SLN (Y 1 ) and entrapment efficiency (Y 2 ) from the prepared SLN in 15 runs. -The studied variables in this work were the percentage of Precirol ATO5 as solid lipid (X 1 ) in three different levels (1-3%), the percentage of Gelucire (X 2 ) in three different levels (1–3%), and the ultrasonication time (X 3 ) in three different levels (3-7 minutes). -The levels of the factors were selected according to preliminary studies carried out before implementing the experimental design. -Optimization of the ALS-SLN was carried out by the statistical package Statgraphics® Centurion XV Software, Version (StatPoint, Inc., USA).

7 Composition of alendronate sodium SLN and their observed response RunPrecirol ATO5 %Gelucire % Ultrasonication Time (minutes) Particle Size (nm)EE (%)

8 Estimated response surface with contours plots (3D) showing the effect of X1,X2 and X3 on the particle size (Y1)

9 Estimated response surface with contours plots (3D) showing the effect of X1,X2 and X3 on the Entrapment Efficiency % (Y2)

ComponentsOptimum Precirol ATO5 %, (X 1 )2.7 Gelucire %, (X 2 )1.8 Ultrasonication Time (X 3 )7 ResponsePredictedObservedResidual Particle Size (nm) EE% Composition of the optimized ALS-SLN formula with the predicted, observed and residual values

11 In vitro release of ALS from optimized EC-SLN formulae and marketed ALS product in N HCl (pH 1.2) 2- Phosphate buffer (pH 7.4)

12 Pharmacokinetic parameters after oral administration of EC-ALS-NLS and marketed ALS tablet (n = 6). FormulationT max (hr)C max (ng/ml) AUC 0-t (ng.hr/ml) K (hr -1 )AUC 0-∞ (ng.hr/ml) Eudragit coated ALS-SLN 3.5± ± ± ± ±407.2 Marketed ALS Tablet 0.75 ± ± ± ± ±43.15

13 CONCLUSION -Formulation of alendronate sodium as enteric coated solid lipid nanoparticles, as a novel drug delivery system, provided the maximum gastro-resistant ALS release. -The oral bioavailability of ALS was enhanced by > 14-fold in relation to the commercially available product. -The improved formula of ALS could eliminate the major drawbacks of conventionally used tablets, and allow osteoporotic patients to tolerate the drug without fear of esophageal inflammation and/or bleeding. -Of course, it will not obviate the need for further clinical evaluation for this novel formula, which may inform clinicians of other important data.

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