Effect
of Formulation Variables on Pharmacotechnical
Properties of Carvedilol Self-Emulsifying Drug
Delivery System
Umesh
D Shivhare*, Pushpraj T Chopkar, Kishore P Bhusari, Vijay B Mathur and Vivek I Ramteke
Sharad
ABSTRACT
In the
present work, self-emulsifying drug delivery system was formulated using Oleic
acid (oil) and Tween 80 (surfactant). Carvedilol is a poorly water soluble drug and its
bioavailability is very low. A new self-emulsifying drug delivery system
(SEDDS) has been developed to increase the solubility, dissolution rate, and
ultimately oral bioavailability of carvedilol. The
solubility of carvedilol was determined in various
vehicles. Pseudo ternary phase
diagrams were used to evaluate the self-emulsification existence area. The
developed SEDDS were evaluated for phase separation, turbidity, particle size, in
vitro dissolution study. The release rate of carvedilol was investigated. The release rate was
accelerated by decreasing droplet size, and was significantly faster as the
particle size decreased. The particle size of formulation consisting of oleic
acid 10%, Tween 80 90% and carvedilol
12.5 mg was found to be 41.72 nm and released more than 90% of drug
within 30 min. The reduced
particle size improved the self-emulsification performance of SEDDS in 0.1N
hydrochloric acid pH 1.2 and phosphate buffer solution pH 6.8. The developed SEDDS formulation can be used
as an alternative to traditional oral formulations of carvedilol to
improve its bioavailability.
KEYWORDS: Self-emulsifying, Carvedilol, Ternary phase diagram, Particle size,
Dissolution.
INTRODUCTION
As compared to other routes, oral delivery
is preferred for administration of drugs in chronic therapy and most of the
potent drugs, which are administered orally, are lipophilic
in nature, exhibiting low oral bioavailability due to their poor aqueous
solubility. To solve this problem, efforts are going on to enhance the oral
bioavailability of lipophilic drugs in order to
increase their clinical efficacy1.
Approximately 40% of new drug candidates
exhibit low solubility in water which leads to poor oral bioavailability, high
inter and intra-subject variability and lack of dose proportionality. To
overcome these problems, various formulation strategies are explored
which include modification of the physicochemical properties, such as salt
formation and particle size reduction of compound, complexation
with cyclodextrins, solid dispersion, nanoparticles, lipids.2
Self-emulsifying drug delivery systems are
mixture of oil and surfactant (especially non-ionic) which forms clear and
transparent isotropic solution known as self-emulsifying system (SES)4.
The microemulsion preconcentrate,
also known as self-microemulsifying drug delivery
system (SMEDDS)5, upon dilution with aqueous media, accompanied by
gentle agitation, spontaneously forms clear isotropic solutions or
microemulsions6. Compared to ready-to-use microemulsion,
it has improved physical stability profile upon long-term storage, and can be
filled directly into soft or hard gelatin capsules for convenient oral delivery7,8.
This mixture is known to form a fine oil-in-water
emulsion with gentle agitation, when exposed to aqueous media. This property
makes the self-emulsifying system a good vehicle for oral delivery of hydrophobic
drugs having adequate oil solubility. Soft gelatin capsules containing
self-emulsifying system readily disperse in the stomach to form a fine
emulsion; in this case, the gastrointestinal motility can provide the agitating
effect necessary for emulsification9.
Carvedilol is an aryl ethanolamine and is a racemic mixture of two enantiomers.
It has b-adrenoreceptor blocking activity and α1-receptor
blocking activity. Carvedilol has been used
extensively in patients with hypertension and has also been reported to be of
benefit in patients with angina or congestive cardiac failure. The drug is well
tolerated and has relatively few adverse effects. The drug is highly lipophilic and highly protein bound. It has a low
solubility in gastrointestinal fluids and undergoes extensive first-pass
metabolism in the liver, which leads to the low absolute oral bioavailability
which is about 20% in humans. The resulting plasma concentrations are highly
variable and often low following oral administration of the commercially
available tablet formulation due to the extensive first-pass metabolism. Ways
of avoiding the above-mentioned disadvantages are needed. This has led to the
development of self-emulsifying system of carvedilol.
In this study,
the self-emulsifying drug delivery systems (SEDDS) carvedilol
were prepared to improve the in vitro
dissolution and permeability, since this is the most outstanding property of
SEDDS. The objectives of the study were to develop an optimum formulation of
SEDDS containing carvedilol and to assess its
characteristics.
Carvedilol was obtained as a gift sample from Cipla Ltd., Patalganga. Oleic
acid and Tween 80 were purchased from SD fine
chemicals. All the other chemicals, reagents and solvents used were of AR
grade.
Solubility
studies
The solubility of
carvedilol in various oils and surfactants was
determined. An excess amount of Carvedilol was placed
in 2 ml of selected vehicles in glass vials, and mixed with glass rod for 30
min, the mixture were equilibrated at 300c for 48 h in a water bath
and then centrifuged at 3000 rpm for 20 min to separate the undissolved
drug. Aliquots of supernatant were diluted in methanol and quantified by UV
spectrophotometer at 240.5 nm.
TABLE 1: SOLUBILITY OF
CARVEDILOL IN DIFFERENT OILS.
|
Sr. No. |
Oils |
Solubility (mg/ml) |
Surfactant |
Solubility (mg/ml) |
|
1 |
Olive oil |
80.12 |
Tween 80 |
193.15 |
|
2 |
Arachis oil |
40.75 |
Tween 20 |
80.98 |
|
3 |
Sesame oil |
35.81 |
Span 80 |
61.25 |
|
4 |
Cod-liver oil |
82.43 |
Span 20 |
25.67 |
|
5 |
Oleic acid |
96.84 |
Trixon X 100 |
82.78 |
|
6 |
Sunflower
oil |
60.35 |
Triethanolamine |
86.15 |
TABLE 2: FORMULATION OF SELF-EMULSIFYING
DRUG DELIVERY SYSTEM (SEDDS) OF CARVEDILOL
|
Sr. No. |
Formulation Code |
Oleic acid (%) |
Tween 80(%) |
Carvedilol (mg) |
|
1 |
F1 |
90 |
10 |
12.5 |
|
2 |
F2 |
80 |
20 |
12.5 |
|
3 |
F3 |
70 |
30 |
12.5 |
|
4 |
F4 |
60 |
40 |
12.5 |
|
5 |
F5 |
50 |
50 |
12.5 |
|
6 |
F6 |
40 |
60 |
12.5 |
|
7 |
F7 |
30 |
70 |
12.5 |
|
8 |
F8 |
20 |
80 |
12.5 |
|
9 |
F9 |
10 |
90 |
12.5 |
Fig. 1:
Ternary phase diagram of oleic acid (Oil) and Tween
80 (Surfactant).
Ternary phase
diagram:
In order to find out the concentration range
of components for the existing range of microemulsion,
the pseudo-ternary phase diagram was constructed with different ratio of oil
(Oleic acid) and surfactant (Tween 80) using water
titration method.
The ratios of oil and surfactant were varied
as 1:9, 2:8, 3:7, 4:6, 5:5, 6:4, 7:3, 8:2 and 9:1 w/w. To oil-surfactant
mixture water was added drop wise under moderate stirring with mechanical
shaker. After being equilibrated, the samples were assessed visually and
determined as being microemulsion or coarse emulsion.
Formulation of self-emulsifying drug
delivery system (SEDDS) of carvedilol:
Self-emulsifying
drug delivery systems (SEDDS) of carvedilol were developed with varying concentration of oil
and surfactant. (Table 2) Oil and surfactant were weighed and transferred in
glass vial. Carvedilol 12.5 mg was added to the mixture and mixed with glass
rod for 30 min. The prepared SEDDS (600 µl) were filled in hard gelatin capsule
shell (size'0') with the help of micropipette.
Phase separation study:
Self-emulsifying system (0.05 ml) was added
in separate glass test tubes containing 5 ml of 0.1 N hydrochloric acid and
distilled water respectively. After inverting the test tube for 3-4 times, each
mixture was stored for a period of 2 h and phase separation was observed
visually.
Fig.2: Turbidity profile of formulation F3
to F9 with and without drug in 0.1 N Hydrochloric Acid
Fig.3: In vitro cumulative % drug release vs time profile of
SEDDS in pH 1.2
Turbidimetric evaluation of SEDDS:
Nepheloturbidimetric evaluation was done to monitor the growth
of emulsification. To observe the effect of drug loading on the turbidity,
self-emulsifying system (0.5 ml) with and without drug was added under
continuous stirring (50 rpm) on magnetic plate to 0.1 N hydrochloric acid (150
ml), and turbidity was measured using a nepheloturbidimeter.
However, since the time required for complete emulsification was too short, it
was not possible to monitor the rate of change of turbidity.
Particle size analysis:
Particle size
analysis of resultant microemulsion was determined by
photon correlation spectroscopy (Malvern Particle Size Analyser,
Nano ZS, DTS Ver: 5.03).
For the measurement samples were diluted with the 0.1 N hydrochloric acid. The
time-average intensity of light scattered by the sample at an angle of 900
was collected by averaging the individual readings of count rate obtained over
a few minutes.
In vitro dissolution of SEDDS:
A modified stainless steel disc assembly
(USP Apparatus 5, paddle over disc assembly), was used for the assessment of
the release of the drug from the SEDDS.
SEDDS containing 12.5 mg of carvedilol was filled in
hard gelatin capsule and introduced into 900ml of dissolution medium (0.1N HCl pH1.2) and maintained at 370. The revolution
speed of the paddle was kept constant at 100 rpm. The aliquot of 5ml was
withdrawn at 5 min interval upto 60 min, and filtered
with whatman filter paper. The removed volume was
replaced each time with 5 ml of fresh medium. The concentration of drug was
determined spectrophotometrically at 240.5 nm. Same procedure was adopted for
phosphate buffer pH 6.8.
TABLE 3: PARTICLE SIZE AND PHASE SEPARATION
RESULTS OF SEDDS
|
Sr. No. |
Formulation Code |
Particle size(nm) |
Phase separation |
|
|
0.1 N HCL |
D.W. |
|||
|
1 |
F1 |
- |
O |
O |
|
2 |
F2 |
- |
O |
O |
|
3 |
F3 |
- |
NO |
NO |
|
4 |
F4 |
- |
NO |
NO |
|
5 |
F5 |
- |
NO |
NO |
|
6 |
F6 |
139.6 |
NO |
NO |
|
7 |
F7 |
129.6 |
NO |
NO |
|
8 |
F8 |
104.1 |
NO |
NO |
|
9 |
F9 |
41.72 |
NO |
NO |
NOTE: - O:
Observed, NO: Not Observed, D.W.: Distilled Water
In vitro diffusion study of SEDDS:
In
vitro diffusion studies were performed using dialysis technique. Saline phosphate buffer pH 7.4 was used as dialyzing medium. One end of the
activated cellulose dialysis tubing (7cm) was tied with thread, and then 0.6 ml
self-emulsifying formulation was placed in dialysis membrane (7 cm), and
diluted 10 times with 0.1 N hydrochloric acid for formation of microemulsion. The other end of bag was tied with thread
and allowed to rotate freely in 200 ml of saline phosphate buffer. The medium
was stirred at 50 rpm with magnetic bead on magnetic plate at 370.
Aliquots of 5 ml were withdrawn after every one hour and diluted further.
Volume of aliquots was replaced with fresh dialyzing medium. Amount of drug
diffused was determined using UV-spectrophotometer at 240.5 nm.
STABILITY STUDY:
The stability study of optimized formulation F9 was
carried out at accelerated condition of 40° ± 2° at 75% ± 5% RH condition for a
period of three months.
The capsules were individually wrapped using aluminum
foil and packed in ambered colored screw capped
bottle and kept at above specified conditions in stability chamber for a period
of three months. After each month, capsules were analyzed for any change in
physical appearance and drug content.
RESULTS AND DISCUSSION:
Solubility studies were performed for selection of oil
and surfactant, which was an important for formulation of SEDDS. The solubility
of carvedilol in oleic acid and tween
80 was found to be maximum than other oils and surfactants. They were utilized
for development of self- emulsifying drug delivery system (Table 1).
Pseudo-ternary
Phase Diagram was constructed to find out the concentration range of
components for the existing range of microemulsion,
the pseudo-ternary phase diagram was constructed with different ratio of oil
(Oleic acid) and surfactant (Tween 80.) using water
titration method. The result indicateD formations of
more microemulsion region (Fig. 1)
.
TABLE 4: PHYSICAL APPEARANCE
AND DRUG CONTENT OF FORMULATION F9
|
Sr. No. |
Parameters |
Days |
|||
|
T = 0 |
T = 30 |
T = 60 |
T = 90 |
||
|
1 |
Physical appearance |
Entire Capsule without any damage |
No change |
No change |
No change |
|
2 |
Drug content |
99.76 ± 0.829 |
99.01 ± 0.987 |
95.35 ± 0.042 |
93.43 ± 0.553 |
(T = Days)
Fig.4: In vitro cumulative % drug release vs time profile of
SEDDS in pH 6.8
Phase separation studies
(Table 3) were performed and result indicated that the phase separation was observed in formulations
F1 and F2 due to less concentration of surfactant and not subjected to further
evaluation. Formulation F3 to F9 subjected to the above studies were stable and
showed no signs of phase separation within 2 h, which indicated formation of
stable emulsion.
Turbidimetric data (Fig. 2) of SEDDS indicated that turbidity of the
resultant microemulsion decreased on increase in
concentration of surfactant, which implies the formation of less turbid microemulsion having very small droplets size. However,
since the time required for complete emulsification was too short, it was not
possible to monitor the rate of change of turbidity.
Effect of drug loading was observed and it was found
that turbidity of SEDDS formulation without drug was very less as compared to
SEDDS with drug (12.5 mg) which confirms that as the drug is added in
formulation there is increase in droplet size of resultant emulsion or microemulsion. Turbidity study gives a rough idea about the
characteristics of resultant microemulsion.
The SEDDS subjected to
particle size analysis (Table 3). From the result of particle size analysis it was
observed that particle size of various formulations F6, F7, F8 and F9 decreased
with increase in concentration of surfactant.
The study of drug
release kinetics showed in (fig. 3) where majority of the formulations governed
by peppas model. Regression analysis of the in vitro permeation
curves was carried out. The slope of the curve obtained after plotting the mean
cumulative amount released per SEDDS vs. time was taken as the in vitro release
for CDL.
Formulation F9 (99.99%) showed maximum release as compared to other
formulation.
Fig. 5: In vitro cumulative % drug release vs time profile of
SEDDS in pH 7.4 (diffusion study).
SEDDS containing more than 80 % of surfactant shows
fastest release of drug within 30 min as compared to other formulation. It
could be suggested that the SEDDS formulation resulted in spontaneous formation
microemulsion with small droplet size, which permit
the faster rate of drug release. It was seen that in dissolution medium buffer
pH 6.8 (Fig.4) had no effect on drug release as compared to pH 1.2.
Drug permeation from in vitro diffusion studies are indicated in (Fig. 5). The study of
drug release kinetics showed that majority of the formulations were governed by
peppas model and mechanism of release was anomalous
mediated. Regression analysis
of the in vitro permeation curves was carried out. The slope of the
curve obtained after plotting the mean cumulative amount released per SEDDS vs.
time was taken as the in vitro release for CDL. Formulation F9 has showed maximum release (99.57%) in 9 h, and follows peppas model (k Value= 24.7770) and mechanism of release was Anomalous mediated. Thus, rate of diffusion of drug from SEDDS depends
on the droplet size of microemulsion; if the droplet
size is small the rate of diffusion of drug is fast and vice-versa.
CONCLUSION:
Stability studies of formulation F9 at 400±20
at 75±5% RH for three month concluded that the formulated self-emulsifying
capsules possess good stability as there was no significant effect on physical
properties and drug content. (Table 4)
ACKNOWLEDGEMENT:
Authors are grateful to Cipla
Ltd. Patalganga, for providing as a gift sample of
drug. And Sharad Pawar
College of Pharmacy, Hingna,
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Received on 08.11.2009
Accepted on 01.12.2009
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage
Forms and Technology. 1(3): Nov. – Dec. 2009, 275-279