Development and Evaluation of Transdermal Drug Delivery System of Ivabradine
Hydrochlride
Samir
Gaur1*, Dr. Ashish Kumar Sharma2
1Research Scholar, Gyan
Vihar School of Pharmacy; SGVU; Jaipur
2Professor, Gyan Vihar
School of Pharmacy; SGVU; Jaipur,
ABSTRACT:
Transdermal patches are designed to slowly deliver the drug
substance(s) through the intact skin; resulting in a prolonged and adequately
constant systemic absorption rate after passing through the skin barriers, and
it avoid first pass effect. Through a diffusion process, the drug enters the
bloodstream directly though the skin. For this studies design the transdermal drug delivery system of Ivabradine
hydrochloride with ERS100 and Hydroxy propyl methyl cellulose polymer in various concentrations.
Propylene glycol was used as a plasticizer and dimethyl
sulphoxides used as permeation enhancer.
Characterization of transdermal patch is use to check
it’s quality, thickness, weight of patch, uniformity and
in vitro permeation studies. The
market for transdermal products has been in a
significant upward trend that is likely to continue for the foreseeable future.
It was observed that the formulation containing ERS100: HPMC K100M (4:6) showed
ideal higuchi release kinetics. On the basis of in vitro drug release through skin
permeation performance, Formulation A2 was found to be better than other formulations
and it was selected as the optimized formulation. An increasing number of TDD
products continue to deliver real therapeutic benefit to patients around the
world.
KEYWORDS: Ivabradine hydrochloride, HPMC, ERS100, Transdermal patch, permeation studies.
INTRODUCTION:
Novel drug delivery is geared towards
developing friendly dosage forms of various formulations with the ultimate aim
of increasing their dosing convenience to the patient. The NDDS may involve a
new dosage form e.g., from thrice a day dosage to once a day dosage form or
developing a patch forms in place of injections. Today, about 74% of drugs are
taken orally and are found not to be as effective as desired. Thus, various
forms of NDDS such as transdermal delivery systems,
controlled release systems; transmucosal delivery
systems etc. emerged (1).
The transdermal route now ranks with oral treatment as the most
successful innovative research area in drug delivery, with around 40% of the
drug delivery candidate products under clinical evaluation related to transdermal or dermal system. The worldwide transdermal patch market approaches £ 2 billion, based on
only ten drugs including scopolamine, nitroglycerine, clonidine,
estrogen, testosterone, fentanyl, and nicotine, with
a lidocaine patch soon to be marketed (2).
Recently, safety
concerns have arisen regarding the continued application of transdermal
patches during magnetic resonance imaging (MRI) procedures. Case reports have
revealed that serious burns may occur in patients undergoing MRI who have transdermal patches with metallic content applied to their
skin. The metallic component of these patches acts as a conductor for the radio
frequency pulses of the MRI, inducing an electric current and thereby resulting
in intense heat and burns (3).
OBJECTIVES:
To
design and develop transdermal therapeutic system of
a model antihypertensive drug, Ivabradine
hydrochloride using matrix devices.
MATERIALS AND METHODS:
Ivabradine
hydrochloride (Ind-Swift Ltd ,Panchkula) and ethylcellulose-
45 cps (Colorcon Asia pvt Ltd,Goa), were received as a gift samples. Hydroxy Propyl Methyl Cellulose
(HPMC) and Eudragit RS 100 were gift samples from Akums Drugs and Pharmaceutical LTD, Haridwar.
Propylene glycol and Dimethyl sulfoxide
(Qualigens Lab., Mumbai) were purchased. All other
reagents used were of analytical grade (AR Grade).
Compatibility studies of Drug and Polymer:
The physicochemical compatibility between Ivabradine
hydrochloride and polymers used in the films was studied by using fourier transform infrared (FTIR-
8300, Shimadzu Co., Kyoto, Japan) spectroscopy. The infrared (IR) spectra were
recorded using an FTIR and spectra were recorded in the wavelength region
between 4000 and 400 cm–1. The spectra obtained for Ivabradine hydrochloride, polymers, and physical mixtures
of Ivabradine hydrochloride with polymers were
compared.
Preparation of transdermal
films:
In the present study, drug loaded matrix type transdermal
films of Ivabradine hydrochloride were prepared by
solvent casting method (4) using different ratios
of ERS-100 and HPMC K100M polymers (Table 1). The polymers were weighed in
requisite ratios by keeping the total polymer weight at 1.0 gm added in solvent
mixture (3:2 ratio of methanol, chloroform). Propylene glycol was incorporated
as plasticizer and DSMO as penetration enhancer were used. The drug was added slowly to the solution
and dissolved by continuous stirring for 30 min. For the formulation of transdermal patch, the aluminums foil was spread uniformly
on a glass petri dish. The mould was kept on a
horizontal surface. The solution was poured on the foil into a petri dish of about 50 cm2. The rate of evaporation was controlled by
inverting a funnel over the mould. Aluminum foil was used
as backing film. The solvent was allowed to evaporate for 24 hrs. The polymer
was found to be self adhesive due to the presence of Eudragit
polymer along with plasticizer. The patches were cut to give required area and
used for evaluation.
Physicochemical evaluation:
1. Physical appearance:
All the prepared patches were visually inspected for color, clarity, opaque, transperancy, flexibility and
smoothness.
2.
Thickness of the films:
Patch thickness was measured using screw
gauge at three different places and the mean value was calculated (5).
3.
Weight uniformity:
The films of different batches were dried at 60oC for 4
hours before testing. Five patches from each batch were accurately weighed in a
digital balance. The average weight and the standard deviation values were
calculated from the individual weights (6).
4.
Folding endurance:
A strip of film (2× 2 cm) was cut evenly and repeatedly folded at
the same place till it broke. The number of times the film could be folded at
the same place without breaking gave the value of the folding endurance (7,
8).
5. Drug content:
Transdermal system of specified area (1 cm2)
was cut into small pieces and taken into a 50 ml volumetric flask and 25 mL of phosphate buffer pH 7.4 was added, gently heated to
45oC for 15 minutes, and kept for 24 hours with occasional shaking.
Then, the volume was made up to 50 ml with phosphate buffer of pH 7.4.
Similarly, a blank was carried out using a drug-free patch. The solutions were
filtered and the absorbance was measured at 286 nm (9).
6. Animals:
For the research study white Wistor
albino rats were taken
and the experiments were conducted according to the protocol approved by the
institutional animals ethics committee . The experiments were conducted
according to the guidelines of CPCSEA.
7.
In-vitro permeation study:
The in-vitro permeation study of fabricated transdermal
patches of Ivabradine hydrochloride was carried out
by using excised rat abdominal skin as diffusion cell (5).
The skin was sandwiched between donor and receptor compartments of the
diffusion cell. The patch of per cm2
was placed in intimate contact with the stratum corneum
side of the skin; the top side was covered with aluminum foil as a backing
membrane. Teflon bead was placed in the receptor compartment filled with 12 ml
of normal saline. The cell contents were stirred with a magnetic stirrer and a
temperature of 37 ± 0.5°C was maintained throughout the experiment. Samples of
2 ml were withdrawn through the sampling port at different time intervals for a
period of 48 h, simultaneously replacing equal volume by phosphate buffer pH
7.4 after each withdrawal. The samples were analyzed spectrophotometrically at
286 nm. Based on the results of in-vitro permeation profiles of
preliminary batches of Ivabradine hydrochloride transdermal patches the optimum composition of checkpoint
batches of Ivabradine hydrochloride transdermal patch was optimized.
RESULTS AND DISCUSSION:
Evaluation
of transdermal patch11
The
prepared transdermal patches were evaluated for their
physicochemical characteristics such as appearance, weight variation,
thickness, folding endurance, drug content (Table 2) and in vitro drug
permeation through albino rat skin (Table 3). The physical appearance of the
various formulations in terms of their transparency, smoothness, flexibility,
stickiness, homogenicity and opaque properties were
recorded. The formulation A-1 was found to be thin, transparent and flexible,
formulation A-2 was found to be thin, transparent and flexible,
formulation A-3 was found to be thin, opaque and flexible and formulation A-4
was found to be thick, not flexible and opaque. The formulation A-2 gave
the most suitable transdermal film with all desirable
physico-chemical properties. The thickness of the
patches was varied from 0.14±0.068
mm to 0.31±0.034 mm.
The weights
ranged between 22.61±0.85 mg and
34.92±0.64 mg, which indicates
that different batches patch weights, were relatively similar.
Polymers HPMC K100M and ERS-100 were selected on the basis of
their adhering property and non toxicity. The result of the finding showed
excellent adhering property and controlled release. Result from present study
concluded that Ivabradine hydrochloride in
combination with HPMC K100M, ERS-100 and with incorporation of PEG 400 (20%)
and DMSO (15%) produced smooth, flexible and transparent film. FT-IR studies
showed characteristic peaks of Ivabradine
hydrochloride, confirming the purity of the drug. FT-IR spectral studies
indicated there was no interaction between Ivabradine
hydrochloride and polymers used (Fig. no. 1).
Ivabradine hydrochloride patches were prepared with
combination of these polymers and evaluated it for physical parameters such as
thickness, drug content, weight variation. From the results, it was observed
that thickness, drug content, weight variations were suitable for maximum
stability of the prepared formulations. The drug content of TDDS patches ranged
from 2.07±0.24 to 2.37±0.33 mg. The cumulative percentage
drug release for A2 was found to be 98.45±1.34 % at 48 h and for A4 it was
found 92.01±3.47 % at 24 h. The formulation, A2 [ERS100:HPMC K100M (4:6)] is
considered as a best formulation, since it shows maximum in vitro drug
release as 98.45±1.34 % at 48 h shown in
figure no. 2.
The drug release kinetics studies showed that the majority of formulations
were governed by Higuchi model and mechanism of release was Fickian
mediated. Higuchi developed an
equation for the release of a drug from a homogeneous-polymer matrix-type
delivery system that indicates the amount of drug releases is proportional to
the square root of time (10). If the release of drug from the transdermal film, when plotted against square root of time,
shows a straight line, it indicates that the release pattern is obeying
Higuchi’s kinetics. In our experiments, in
vitro release profiles of all the different formulations of transdermal patches could be best expressed by Higuchi’s
equation, for release of drug from a homogeneous-polymer matrix–type delivery
system that depends mostly on diffusion characteristics.
From the in vitro permeation
profile data of all the formulations through rat skin, kinetics of drug release
were found for zero-order, first-order, Higuchi-type release kinetics and Korsmeyer-Peppas-type release
kinetics. The coefficient of correlation (R2) of each of these
release kinetics were calculated and compared (Table no.3). The data revealed
that the release pattern of selected formulations was best fitted for Higuchi
kinetics, as the formulation coefficient values predominate over zero-order,
first-order and Korsmeyer-Peppas-type
release kinetics, which again confirmed with Higuchi’s equation for the drug
release from matrix. Thus, a slow and controlled release as observed is
indicating that the drug release mechanism is Fickian
model, as proposed by Higuchi.
The regression
analysis of the in vitro permeation curves were carried out for in
vitro permeation studies in rat skin. Among all these formulations, the
formulation A-2 showed the maximum % drug cumulative release i.e. 98.45 % up to
48 hours of the study. All the formulations showed Higuchi-type release
kinetics, which was diffusion mediated. Regression analyses of the in vitro
permeation curves were carried out. The slope of the straight line obtained
after plotting the mean cumulative amount released per Cm. Square patch vs.
square root of time was taken as the experimental flux for Ivabradine
hydrochloride.
Table 1 Composition of transdermal patches
|
Formulation code |
Drug (mg) |
Polymer |
Polymers ratio |
DMSO |
PEG 400 |
Solvents ratio (Methanol : Chloroform) |
|
A1 |
100 |
ERS:HPMC HPMC |
2:8 |
15% |
20% |
3:2 |
|
A2 |
100 |
ERS:HPMCK100M |
4:6 |
15% |
20% |
3:2 |
|
A3 |
100 |
HPMCK100M:K15M |
5:5 |
15% |
20% |
3:2 |
|
A4 |
100 |
HPMCK100M:K15M |
6:4 |
15% |
20% |
3:2 |
Table 2. The drug content
uniformity, thickness variations, weight variations and appearance of the various
formulations
Formulation Code
|
A-1 |
A-2 |
A-3 |
A-4 |
|
Appearance |
+ |
*** |
** |
* |
|
Thickness
(mm)± SD |
0.14±0.068 |
0.19±0.059 |
0.32±0.081 |
0.31±0.034 |
|
Weight/cm2
(mg)± SD |
22.61±0.85 |
26.40±0.67 |
31.16±0.83 |
34.92±0.64 |
|
Average drug
content (mg)/cm2± SD |
2.17±0.30 |
2.08±0.18 |
2.07±0.24 |
2.37±0.33 |
|
Comments |
Suitable |
Very suitable |
Suitable |
Suitable |
Figure 1 FTIR Spectra of transdermal film of Ivabradine
Hydrochloride
Figure 2 Comparative in vitro drug permeation profile of
different film
CONCLUSION:
In conclusion, controlled
release TDDS patches of Ivabradine hydrochloride can
be prepared using the polymer combinations, ERS100:HPMC
K100M (4:6) with PEG 400 and DMSO as plasticizer and enhancer, respectively.
The release rate of drug through patches increased when the concentration of
hydrophilic polymer was increased. Whereas, the mechanism of drug release of
all formulations were Fickian. The properties of film
did not change during the period of study. Further, in vivo studies have
to be performed to correlate with in vitro release data for the
development of suitable controlled release patches for Ivabradine
hydrochloride.
ACKNOWLEDGEMENT:
The Authors are grateful
to In-Swift Ltd, Panchkula (Haryana) for providing
the gift sample of Ivabradine hydrochloride (Pure Drug)
for the research project . The authors are also
grateful to Gyan Vihar
School of Pharmacy, S.G.V.U., Jaipur
for providing all facilities and encouragement to them.
Table 3. The regression co-efficient values obtained from
different kinetics plots of the formulations
|
Formulation code |
Zero Order (r2) |
First order (r2) |
Higuchi kinetic (r2) |
Korsmeyer kinetic (r2) |
|
A1 |
0.911 |
0.997 |
0.984 |
0.988 |
|
A2 |
0.904 |
0.918 |
0.997 |
0.994 |
|
A3 |
0.951 |
0.974 |
0.991 |
0.997 |
|
A4 |
0.851 |
0.990 |
0.997 |
0.984 |
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Received on 22.06.2013
Modified on 10.07.2013
Accepted on 15.07.2013
© A&V Publication all right reserved
Research Journal of Pharmaceutical Dosage
Forms and Technology. 5(4): July-August, 2013, 237-241