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Development of Solid Self Micro Emulsifying Drug Delivery System
with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Bhagwat Durgacharan A*, D’Souza John I
*Research Scholar, JJT University, Jhunjhunu, Rajasthan, India
Dept. of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Warananagar, Kolhapur, MS. India. 416113
Key words:
Telmisartan, S-SMEDDS, Neusilin US2, Pseudo
ternary phase diagram
How to Cite this Paper:
Bhagwat Durgacharan A*, D’Souza John I
“Development of Solid Self Micro Emulsifying Drug
Delivery System with Neusilin US2 for Enhanced
Dissolution Rate of Telmisartan” Int. J. Drug Dev. &
Res., October-December 2012, 4(4): 398-407.
Copyright © 2012 IJDDR, Bhagwat
Durgacharan A et al. This is an open access paper
distributed under the copyright agreement with
Serials Publication, which permits unrestricted use,
distribution, and reproduction in any medium,
provided the original work is properly cited.
INTRODUCTION
The poor solubility and low dissolution rate of poorly
water soluble drugs in the aqueous gastro-intestinal
fluids frequently cause deficient bioavailability.
Particularly for BCS class II substances, the
bioavailability may be enhanced by increasing the
International Journal of Drug Development & Research
| October-December 2012 | Vol. 4 | Issue 4 | ISSN 0975-9344 |
Available online http://www.ijddr.in
Covered in Official Product of Elsevier, The Netherlands
SJR Impact Value 0.03 & H index 2
©2012
IJDDR
Abstract
Aim of present study was to develop solid self micro
emulsifying drug delivery system (S-SMEDDS) with
Neusilin US2 for enhancement of dissolution rate of
Telmisartan (TEL). SMEDDS was prepared using Oleic
acid, Tween 80 and PEG 400 as oil, surfactant and co-
surfactant respectively. For formulation of stable SMEDDS,
micro emulsion region was identified by constructing
pseudo ternary phase diagram containing different
proportion of surfactant: co-surfactant (Km value 1:1, 2:1
and 3:1), oil and water. Prepared SMEDDS was evaluated
for thermodynamic stability study, dispersibility tests,
globule size and zeta potential. S-SMEDDS was prepared by
adsorption technique using Neusilin US2 as solid carrier.
Prepared S-SMEDDS was evaluated for flow properties,
drug content, reconstitution properties, FTIR, SEM, DSC
and in-vitro dissolution study. Results showed that
prepared liquid SMEDDS passed dispersibility test with
good thermodynamic stability. Globule size was found to be
30.2 nm with polydispersity index 0.116 and -5.80 mV zeta
potential. S-SMEDDS showed good flow property and drug
content. Reconstitution properties of S-SMEDDS showed
spontaneous micro emulsification with globule size 32.4 nm
and polydispersity index 0.219 and -6.32 mV zeta potential.
Results of in-vitro dissolution showed that there was
enhancement of dissolution rate of TEL as compared with
that of plain TEL. From the results study concluded that,
Neusilin US2 can be used to develop S-SMEDDS by
adsorption technique to enhance dissolution rate of poorly
water soluble drug such as TEL.
*Corresponding author, Mailing address:
Bhagwat Durgacharan A
E-mail: durgapharma@gmail.com
Article History:
------------------------
Date of Submission: 12-11-2012
Date of Acceptance: 22-11-2012
Conflict of Interest: NIL
Source of Support: NONE
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Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
398
solubility and dissolution rate of the drug in the
gastro-intestinal fluids.
[1]
Self micro emulsifying drug
delivery systems (SMEDDS) are isotropic mixtures of
drug, lipids and surfactants, usually with one or more
hydrophilic cosolvents or coemulsifiers. Upon mild
agitation followed by dilution with aqueous media,
these systems can form fine (oil in water) emulsion
instantaneously.
[2]
SMEDDS are generally
encapsulated either in hard or soft gelatin capsules.
Lipid formulations however may interact with the
capsule resulting in either brittleness or softness of
the shell.
[3]
To overcome this problem SMEDDS need
to convert into Solid SMEDDS. The major techniques
for converting SMEDDS to S-SMEDDS are spray-
cooling, spray drying, adsorption onto solid carriers,
melt granulation, melt extrusion, super-critical fluid
based methods and high pressure homogenization.
But adsorption process is simple and involves simply
addition of the liquid formulation to solid carriers by
mixing in a blender.
[4]
TEL is 2-(4-{[4-methyl-6-(1-methyl-1H-1,3-
benzodiazol-2-yl)-2-propyl-1H-1,3-benzodiazol-1-yl]
methyl} phenyl) benzoic acid with log P value 3.2. It
belongs to class II drug in BCS classification. TEL is
Angiotensin II receptor antagonist, which is used in
the prevention and treatment of hypertension. The
solubility of TEL in aqueous medium is very low.
Absolute bioavailability of the TEL is 42-58% and
biological half-life is 24 hours that results into poor
bioavailability after oral administration. Hence it is
necessary to increasing aqueous solubility and
dissolution of TEL.
[5,6,7]
Figure 1: Chemical structure of Telmisartan
Neusilin US2 is a fine ultra light granule of
magnesium aluminometasilicate and is widely
accepted as a multifuntional excipient that improves
the quality of pharmaceuticals. Due to its large
surface area and porous nature, Neusilin US2
adsorbs high loads of oils or water and can be
mechanically compacted into high quality tablets.
[8]
It exhibit high adsorbing capacity and can be used to
convert SMEDDS to S-SMEDDS.
[9, 10]
Hence in this
study S-SMEDDS of TEL was prepared using
Neusilin US2 by adsorption technique for
enhancement of dissolution rate.
MATERIALS AND METHODS
MATERIALS:
TEL was obtained as a gift sample from Glochem
Industries Ltd. Vishakhapatnam, AP, India. Neusilin
US2 was gifted by Fuji chemicals Japan. Oleic acid
was obtained from Loba Chemie Pvt. Ltd., Mumbai.
PEG 400, Tween 80 were obtained from S. D. Fine
Chem., Mumbai. All other chemicals were of reagent
grade.
METHODS:
Identification of micro emulsion region by
constructing pseudo ternary phase diagram:
From solubility study Oleic acid, Tween 80 and PEG
400 were selected as oil, surfactant and co-surfactant
respectively and for preparation of stable SMEDDS,
micro emulsion region was identified by constructing
pseudo ternary phase diagram containing different
proportion of surfactant: co-surfactant (Km value 1:1,
2:1 and 3:1), oil and water. In brief S
mix
and oil were
mixed at ratio of 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2
and 9:1 in pre-weighed test tube. To the resultant
mixtures, double distilled water was added drop wise
till the first sign of turbidity in order to identify the
end point and after equilibrium; if the system became
clear then the water addition was continued.
[11, 12, 13]
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Bhagwat Durgacharan A
et al:
Development of
Solid Self
Micro Emulsifying Drug Delivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
399
Preparation of Liquid SMEDDS
The phase diagrams were constructed at different Km
values and the Km value at which high micro
emulsion region obtained was selected for
formulation of Liquid SMEDDS. In brief TEL (20
mg/10gm) was placed in glass vial. To this Oleic acid
(10 % w/w) added and warmed on water bath. To this
oily mixture Tween 80 and PEG 400 in the
proportion of 3:1 (40 % w/w) was added. Then the
components were mixed by gentle stirring and vortex
mixing at 37 ºC until TEL was completely dissolved.
Then the mixture was sealed in glass vial and stored
at room temperature until used.
[14]
Evaluation of Liquid SMEDDS
[15, 16, 17, 18]
Thermodynamic Stability Studies
Thermodynamic stability study of prepared SMEDDS
was determined by carrying heating cooling cycle,
centrifugation test and freeze thaw cycle.
Heating cooling cycle
Six cycles between refrigerator temperatures 4ºC and
45ºC with storage at each temperature for not less
than 48 hours was studied. If SMEDDS stable at
these temperatures was subjected to centrifugation
test.
Centrifugation test
Passed SMEDDS was centrifuged at 3500 rpm for 30
min using digital centrifuge (Remi motors Ltd.). If
SMEDDS did not show any phase separation was
taken for freeze thaw stress test.
Freeze thaw cycle
Three freeze thaw cycles between -21ºC and +25ºC
with storage at each temperature for not less than 48
hours was done for SMEDDS.
Robustness to dilution
Robustness to dilution was studied by diluting Liquid
SMEDDS to 50, 100 and 1000 times with water,
buffer pH 1.2 and buffer pH 7.5. The diluted
SMEDDS were stored for 12 h and observed for any
signs of phase separation or drug precipitation.
Assessment of Efficiency of self-
emulsification
Efficiency of self-emulsification was assessed by
procedure used by Khoo Shui-Mei et.al. (1998) using
USP- type-II dissolution test apparatus (Veego VDA-
8DR). 1 mL of Liquid SMEDDS was added drop wise
to 200 ml of 0.1 N HCl at 37°C. Gentle agitation was
provided by a standard stainless steel dissolution
paddle rotating at 60 rpm. SMEDDS assessed
visually according to the rate of emulsification and
final appearance of the emulsion.
% Transmittance
1 mL of Liquid SMEDDS was diluted to 100 mL
distilled water and observed for any turbidity and %
transmittance was measured at 650 nm using UV–vis
spectrophotometer (Shimadzu-1800, Japan) against
distilled water as a blank.
Globule size, PDI and Zeta potential
Liquid SMEDDS was diluted to 10 times with
distilled water and globule size, PDI and zeta
potential were determined using Malvern Zetasizer
(Nano ZS90).
Dye solubilization test
So as to confirm the oil in water nature of SMEDDS a
water soluble dye Eosin was sprinkled onto the
surface of prepared microemulsion and observed for
spontaneous dispersion.
Cloud point measurement
Liquid SMEDDS was diluted with distilled water in
the ratio of 1:250, placed in a water bath and its
temperature was increased gradually. Cloud point
was measured as the temperature at which there was
a sudden appearance of cloudiness visually.
Formulation of S-SMEDDS
S-SMEDDS was prepared by mixing liquid SMEDDS
containing TEL with Neusilin US2 in 1:1 proportion.
In brief liquid SMEDDS was added drop wise over
Neusilin US2 contained in broad porcelain dish. After
each addition, mixture was homogenized using glass
rod to ensure uniform distribution of formulation.
[20]
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Bhagwat Durgacharan A
et al:
Development of
Solid Self
Micro Emulsifying Drug D
elivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
400
Evaluation of S-SMEDDS
Micromeritic properties of S-SMEDDS
[21, 22]
Prepared S-SMEDDS was evaluated for micromeritic
properties such as angle of repose, bulk and tapped
density, compressibility index and Hausner ratio.
Determination of drug content
Drug content was estimated by extracting TEL from
S-SMEDDS. In brief S-SMEDDS was dissolved in
sufficient quantity of methanol. Solution was
sonicated for 10-15 min for extraction of the TEL in
methanol and filtered. The absorbance of filtrate was
read at 296 nm on UV- Visible Spectrophotometer
(Shimadzu-1800, Japan).
[23]
Reconstitution properties of S-SMEDDS
Dilution study by visual observation
Dilution may better mimic the condition of stomach
after oral administration. Hence effect of dilution on
S-SMEDDS was studied. S-SMEDDS (100 mg) was
introduced into 100 mL of double distilled water in a
glass beaker that was maintained at 37ºC and the
contents mixed gently using a magnetic stirrer. The
tendency to emulsify spontaneously and progress of
emulsion droplets were observed with respect to
time. The emulsification ability of S-SMEDDS was
judged qualitatively “good” when clear
microemulsion formed and “bad” when there was
turbid or milky white emulsion formed after stopping
of stirring.
[24]
% Transmittance, Globule size, PDI, Zeta
potential
Reconstituted S-SMEDDS were also characterized for
% Transmittance, Globule size, PDI, Zeta potential as
described for liquid SMEDDS.
FTIR study of S-SMEDDS
FTIR spectrum was recorded for TEL, TEL: Neusilin
US2 physical mixture and prepared S-SMEDDS using
Agilent Cary 630 FTIR spectrometer.
Scanning electron microscopy
Scanning electron micrographs for TEL, Neusilin
US2 and prepared S-SMEDDS was taken using
Scanning electron microscope (JEOL, Japan) at
accelerating voltage at 3-5 kV to study surface
topography.
Differential scanning calorimetry
Physical state of TEL in S-SMEDDS was
characterized using differential scanning calorimeter.
Thermograms of TEL, Neusilin US2 and S-SMEDDS
were obtained using differential scanning
calorimeter. (TA Instruments SDT-2960, USA)
In-vitro dissolution study
The in-vitro dissolution study of S-SMEDDS and
plain TEL were carried out using USP- type-II
dissolution test apparatus in pH 1.2 and pH 7.5
buffer solutions at 37±0.5
0
C with 50 rpm rotating
speed. Samples of 5 mL were withdrawn at regular
time interval of 5, 10, 15, 30, 60 and 120 min and
filtered using 0.45 µm filter. An equal volume of
respective dissolution medium was added to
maintain the volume constant. Drug content from
sample was analyzed using UV-spectrophotometer at
296 nm. All measurements were done in triplicate
from three independent samples.
[23]
RESULTS AND DISCUSSION
Identification of micro emulsion region by
constructing pseudo ternary phase diagram
Nine different potential combination of surfactant
mixture to oil at different Km values (1:1, 2:1 and 3:1)
were used for construction of pseudo ternary phase
diagram which is presented in Figure 2. Shaded area
in phase diagram shows micro emulsion region.
Phase behavior examination of this system
established an appropriate approach to determine
concentration of oil, surfactant: co-surfactant and
water so that transparent, monophasic low viscous
micro emulsion can be formed. Phase diagram at Km
value 3:1 showed maximum micro emulsion
region.
[12]
So that maxium proportion of oil can be
incorporate in the system which will helpful for
solubalization of TEL, hence selected for further
study. Hence optimum formulation of micro
F u l l
L e n gth R es e a r ch P a p er
C o v ere d i n I n dex C o pe r n i cus w ith I C V a l u e 4 . 6 8 f o r 20 1 0
Bhagwat Durgacharan A
et al:
Development of
Solid Self
Micro Emulsifying Drug Delivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
401
emulsion contained Oleic acid (10 %), Tween 80:PEG
400 (40%) and Water 50 %
(A)
(B)
(C)
Figure 2: Pseudo ternary phase diagram at different
Km value: (A) Km value 1:1,
(B) Km value 2:1 and (C) Km value 3:1
Evaluation of Liquid SMEDDS
Thermodynamic Stability Studies
Physical stability of SMEDDS was essential to its
performance, which can be ominously affected by
precipitation of the drug. In addition, the
formulation having poor physical stability can affects
the formulation performance and it also leads to
phase separation. Hence thermodynamic stability
studies were performed by performing heating
cooling cycle, centrifugation test and freeze thaw
cycle. It was observed that, formulation was passed
the heating cooling cycle test hence, further exposed
to centrifugation test. SMEDDS did not show any
phase separation after centrifugation test hence; was
taken for freeze thaw stress test. After freeze thaw
stress test, it was found that SMEDDS showed good
stability with no phase separation, creaming or
cracking.
Robustness to dilution
After diluting Liquid SMEDDS to 50, 100 and 1000
times with water, buffer pH 1.2 and buffer pH 7.5 and
storing for 12 h it was observed that there was no any
signs of phase separation or drug precipitation.
Assessment of Efficiency of self-
emulsification
The in-vitro performance of SMEDDS was visually
assessed using the grading system used by Khoo
Shui-Mei et.al. (1998) and it was found that,
SMEDDS rapidly formed micro emulsion within 1
min which was clear and slightly bluish in
appearance as per grade A.
% Transmittance, Globule size, PDI and Zeta
potential:
Percent transmittance of reconstituted liquid
SMEDDS was found to be 88.7 ±0.67. Globule size
was found to be 30.2 nm with polydispersity index
0.116. Zeta potential of liquid SMEDDS was found to
be -5.80 mV.
F u l l
L e n gth R es e a r ch P a p er
C o v ere d i n I n d ex C o pe r n i cus w i th I C V a l u e 4 . 6 8 f o r 201 0
Bhagwat Durgacharan A
et al:
Development of
Solid Self
Micro Emulsifying Drug Delivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
402
Dye solubilization test and Cloud point
measurement
The type of emulsion was confirmed by using dye
solubilization test. Rapid incorporation of the water-
soluble dye (eosin) into the system was observed
which indicate that the continuous phase was water,
which signified the formation of o/w micro emulsion.
Cloud point of prepared liquid SMEDDS was found
to be higher than 85
o
C, which indicate that micro
emulsion will be stable at physiological temperature
without risk of phase separation.
Micromeritic properties and drug content of
S-SMEDDS
Micromeritic properties such as angle of repose, bulk
and tapped density, compressibility index, Hausner
ratio, etc and drug content of S-SMEDDS are shown
in Table:1. Results showed that prepared S-SMEDDS
shows good flow properties and drug content.
Table 1: Micromeritic properties and drug content
of S-SMEDDS of TEL
Properties of
S-SMEDDS Results
*
Angle of Repose (degree)
27.63 ± 0.04
LBD (g/ml) 0.30 ± 0.02
TBD (g/ml) 0.35±0.06
Carr’s Index (%) 14.28± 0.12
Hausner Ratio 1.16± 0.03
Drug content (%) 99.82 ± 0.36
*
Values expressed as Mean ± SD (n=3)
Reconstitution properties of S-SMEDDS
Dilution study by visual observation
S-SMEDDS showed spontaneous micro
emulsification and there was no sign of phase
separation or phase inversion of micro emulsion after
storage of 2 h.
% Transmittance, Globule size, PDI, Zeta
potential
Percent transmittance of reconstituted S-SMEDDS
was found to be 92.8 ±0.32. It indicates that
reconstituted S-SMEDDS was found to be clear.
Results Globule size with PDI and Zeta potential are
shown on Figure 3 and 4 respectively. Globule size
was found to be 32.4 nm with polydispersity index
0.219 and zeta potential was found to be -6.32 mV.
F u l l
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C o v ere d i n I n d ex C o pe r n i cus w i th I C V a l u e 4 . 6 8 f o r 201 0
Bhagwat Durgacharan A
et al:
Development of
Sol
id Self
Micro Emulsifying Drug Delivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
403
Figure 3: Globule size and PDI of reconstituted S-SMEDDS
Figure 4: Zeta potential of reconstituted S-SMEDDS
FTIR study of S-SMEDDS
Figure 5 shows FTIR spectrum of TEL, TEL:Neusilin
US2 physical mixer and S-SMEDDS. Results showed
that deformation of characteristic peaks of TEL in S-
SMEDDS which may be due to formation of
amorphous state of TEL.
Figure 5: FTIR spectra of A: Plain TEL, B: TEL: Neusilin US2 physical mixture C: S-SMEDDS
F u l l
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C o v ere d i n I n d ex C o pe r n i cus w i th I C Va l u e 4 . 6 8 f o r 201 0
Bhagwat Durgacharan A
et al:
Development of
Solid Self
Micro Emulsifying Drug Delivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
404
Scanning electron microscopy
Scanning electron micrograph of plain TEL, Neusilin
US2 and S-SMEDDS are shown in Figure 6. This
indicate that S-SMEDDS appeared as smooth
surfaced particles, indicating that liquid SMEDDS is
adsorbed or coated inside the pores of Neusilin US2
without agglomeration.
Figure 6: SEM: A: Plain TEL, B: Neusilin US2, C: S-SMEDDS
Differential scanning calorimetry
Figure 7: DSC thermogram of A: Plain TEL, B: Neusilin US2, C: S-SMEDDS
DSC curves of TEL, Neusilin US2 and S-SMEDDS is
shown in Figure 7. TEL shows sharp endothermic
peak at near about 267.1-269.6
o
C. Neusilin US2
shows peak at 201.2-231.8
o
C The S-SMEDDS exhibit
retained small endothermic peak for TEL at 268.4
o
C
and it may be due to solubilization of TEL in
SMEDDS.
In-vitro dissolution study
Figure 8 shows cumulative percent drug release of S-
SMEDDS and Plain TEL in pH 1.2 and 7.5.
Cumulative % drug release of TEL in pH 1.2 and 7.5
was found to be 95.35± 2.25 and 99.78± 2.34
respectively and that of plain TEL was found to be
29.35± 1.36 and 31.47± 2.06 respectively. This
showed that drug releases from S- SMEDDS was
found to be significantly higher as compared to plain
TEL and it was also found that, dissolution of TEL is
pH independent.
Figure 8: Cumulative % drug release of S-SMEDDS
and Plain TEL in pH 1.2 and 7.5
F u l l
L e n gth R es e a r ch P a p er
C o v ere d i n I n d ex C o pe r n i cus w i th I C V a l u e 4 . 6 8 f o r 201 0
Bhagwat Durgacharan A
et al:
Development of
Solid Self
Micro Emulsifying Drug Delivery
System with Neusilin US2 for Enhanced Dissolution Rate of Telmisartan
Int. J. Drug Dev. & Res., October-December 2012, 4 (4): 398-407
Covered in Scopus & Embase, Elsevier
405
CONCLUSION
From study it was concluded that, prepared liquid
SMEDDS was thermodynamically stable with good
self emulsification efficiency and having globule size
in nanometric range which may be physiologically
stable. Study also concluded that, S-SMEDDS of TEL
prepared with Neusilin US2 by adsorption technique
have good flow property and drug content. After
reconstitution S-SMEDDS formed clear micro
emulsion with nanometric size. Results of SEM
demonstrate that spherical S-SMEDDS can be
obtained without agglomeration. In-vitro drug
release of S-SMEDDS was much higher than that of
plain TEL. Hence it was concluded that S-SMEDDS
can be efficiently formulated by adsorption technique
using Neusilin US2 as solid carrier to enhance
dissolution rate of poorly soluble drug such as TEL.
ACKNOWLEDGEMENT:
Authors would like to thank Hon. Shri. G. D. Patil,
Secretary, Shree Warana Vibhag Shikshan Mandal,
Warananagar, Kolhapur, MS India, for constant
inspiration and making available the necessary
facilities and Fuji Chemicals, Japan for providing gift
sample of Neusilin US2.
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aran A
et al:
Development of
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Micro Emulsifying Drug Delivery
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