Transcript 3 - Pharmaceutics & Novel Drug Delivery Systems

Enteric-coated alendronate sodium solid lipid
nanoparticles; a novel formula to overcome
barriers for the treatment of osteoporosis
By
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
Funded Project by DSR at King Abdulaziz Uiversity
WHY ALENDRONATE SODIUM ???
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.
3
Up to 60% of the patient stops taking alendtonate during the
first year of therapy (3).
RESEARCH AIM
In order to alleviate patients suffering specially elderly
patient:
4
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.
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 S100
3.1. Release in 0.1N HCl
3.2. Release in Phosphate Buffer
4. Scanning Electron microscope
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5. In vivo Pharmacokinetic study
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 (Y1) and entrapment
efficiency (Y2) from the prepared SLN in 15 runs.
-The studied variables in this work were the percentage of Precirol ATO5 as solid
lipid (X1) in three different levels (1-3%), the percentage of Gelucire (X2) in three
different levels (1–3%), and the ultrasonication time (X3) 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.
6
-Optimization of the ALS-SLN was carried out by the statistical package
Statgraphics® Centurion XV Software, Version 15.2.05 (StatPoint, Inc., USA).
Run
Precirol ATO5 %
Gelucire %
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
3
2
2
3
1
2
1
3
1
2
2
2
2
1
3
1
3
2
2
2
1
1
2
3
2
2
3
Ultrasonication Time
(minutes)
7
3
5
5
3
5
3
3
7
5
7
5
5
5
7
Particle Size (nm)
EE (%)
95
65
115
75
115
100
105
100
80
70
85
110
100
90
115
40
10
60
20
60
45
40
35
25
15
50
55
45
41
65
7
Composition of alendronate sodium SLN and their observed response
Estimated response surface with contours plots (3D) showing the effect of
X1,X2 and X3 on the particle size (Y1)
Surface Plots of Particle Size (nm)
Contour Plots of Particle Size (nm)
Hold Values
Precirol ATO5
2
Gelucire
2
Ultrasonication Time 5
110
110
article Size (nm) 100
article Size (nm)
90
3
80
2
1
2
Precirol ATO5
3
Gelucire
1
100
90
6.0
1
2
Precirol ATO5
3
4.5
Ultrasonication
Time
3.0
3.0
Gelucire*Precirol ATO5
7
Ultrasonication Time*Precirol ATO5
2.5
6
2.0
5
1.5
4
1.0
1.0
3
1.0
7
1.5
2.0
2.5
3.0
Ultrasonication Time*Gelucire
1.5
2.0
2.5
3.0
Particle
Size (nm)
< 80
80 – 90
90 – 100
100 – 110
110 – 120
> 120
Hold Values
Precirol ATO5
Gelucire
Ultrasonication Time
2
2
5
6
120
5
100
80
6.0
1
2
Gelucire
3
Ultrasonication
4.5
Time
3.0
4
3
1.0
1.5
2.0
2.5
3.0
8
article Size (nm)
Estimated response surface with contours plots (3D) showing the effect of
X1,X2 and X3 on the Entrapment Efficiency % (Y2)
Surface Plots of EE%
Contour Plots of EE%
Hold Values
Precirol ATO5
2
Gelucire
2
Ultrasonication Time 5
3.0
Gelucire*Precirol ATO5
7
2.5
6
2.0
5
1.5
4
Ultrasonication Time*Precirol ATO5
80
EE%
80
60
40
3
20
2
1
2
Precirol ATO5
3
Gelucire
1
EE% 70
60
50
6.0
1
2
Precirol ATO5
3
4.5
Ultrasonication
Time
3.0
1.0
1.0
7
1.5
2.0
2.5
3.0
Ultrasonication Time*Gelucire
3
1.0
1.5
2.0
2.5
3.0
EE%
< 20
20 – 30
30 – 40
40 – 50
50 – 60
60 – 70
70 – 80
> 80
Hold Values
Precirol ATO5
Gelucire
Ultrasonication Time
2
2
5
6
75
5
60
45
6.0
30
1
2
Gelucire
3
Ultrasonication
4.5
Time
3.0
4
3
1.0
1.5
2.0
2.5
3.0
9
EE%
Composition of the optimized ALS-SLN formula with the predicted, observed
and residual values
Components
Optimum
Precirol ATO5 %, (X1)
2.7
Gelucire %, (X2)
1.8
Ultrasonication Time (X3)
Response
7
Predicted
Observed
Residual
Particle Size (nm)
73.4
74
0.6
EE%
56.4
56
-0.4
Marketed ALS Product
70
Optimized EC-ALS-SLN
60
50
40
30
20
10
0
0
30
60
100
90
80
70
60
50
40
30
20
10
0
90
Time (Minutes)
120
150
Marketed ALS Product
Optimized EC-ALS-SLN
0
30
60
90
120
150
180
Time ( Minutes)
11
80
% of ALS Released
% ALS Released In Acidic Medium
In vitro release of ALS from optimized EC-SLN formulae and
marketed ALS product in 1- 0.1N HCl (pH 1.2)
2- Phosphate buffer (pH 7.4)
Pharmacokinetic parameters after oral administration
of EC-ALS-NLS and marketed ALS tablet (n = 6).
Eudragit coated
ALS-SLN
Marketed ALS
Tablet
Tmax (hr)
Cmax (ng/ml)
K (hr-1)
(ng.hr/ml)
AUC0-∞ (ng.hr/ml)
3.5±0.61
24.76±4.43
4280±304.5
0.187±0.02
6875.4±407.2
0.75 ±0.09
5.43±2.54
340.6±31.23
0.672±0.12
570.2±43.15
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Formulation
AUC0-t
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.
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-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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