Chetan M Patel*, Sejal N Patel, Nikhil
P Patel, DM Patel and CN Patel
epartment of Pharmaceutics and
Pharmaceutical Technology, Shri Sarvajanik
Pharmacy College, Near Arvind Baug,
Mehsana-384 001, Gujarat, India
ABSTRACT:
The purpose of this
research was to study buccal adhesive drug delivery
system (BADDS) of Lercanidipine using the bioadhesive polymers sodium alginate (Na-alginate) and HPMC
K4M along with ethyl cellulose as an impermeable backing layer. BADDS was
evaluated by weight uniformity, thickness, drug content, mucoadhesive
strength, swelling, in vitro drug release and in vitro drug permeation studies.
Mucoadhesive strength (MS) was measured by using a
modified apparatus. BADDSs containing Sodium alginate and HPMC K4M at the ratio
of 1:2 showed higher MS (34.15 g) with chicken mucosa when compared with 1:1
(28.69 g), 2:1 (24.69 g), ratios,
respectively. The swelling index was proportional to Na-alginate content and
inversely proportional to HPMC K4M content. The formulation F4 was optimized
based on good bioadhesive strength (28.69 g) and
sustained in vitro drug permeation (99.04 for 12 hours).It can be concluded
that BADDS is a superior, novel system that overcomes the drawback associated
with the conventional buccal adhesive tablet.
KEYWORDS: Mucoadhesion, buccal
drug delivery, lercanidipine, sodium alginate, HPMC
K4M
INTRODUCTION:
The focus of
pharmaceutical research is being steadily shifted from the development of new
chemical entities to the development of novel drug delivery system (NDDS) of
existing drug molecule to maximize their effective in terms of therapeutic
action and patent protection.1, 2 Moreover the developments of NDDS
are going to be the utmost need of pharmaceutical industry especially after
enforcement of Product Patent.3, 4 Buccal
delivery of drugs provides an attractive alternative to the oral route of drug
administration. It provides direct entry into the systemic circulation, thus
avoiding the hepatic first-pass effect, ensuring ease of administration, and
making it possible to terminate delivery when required.5 A suitable buccal drug delivery
system should possess good bioadhesive properties, so
that it can be retained in the oral cavity for the desired duration. In
addition, it should release the drug in a unidirectional way toward the mucosa,
in a controlled and predictable manner, to elicit the required therapeutic
response. This unidirectional drug release can be achieved using bilayer devices.6-8
Lercanidipine is a vasoselective
dihydropyridine calcium channel blocker (CCB) that
causes systemic vasodilation by blocking the influx
of calcium systemic vasodilation by blocking the
influx of calcium ions through L-type calcium channels in cell membranes. It is
a highly lipophilic drug that exhibits a slower onset
and longer duration of action than other calcium channel antagonists.9
Lercanidipine has been shown to be effective in a
wide range of hypertensive patients including mild to moderate hypertension,
severe hypertension, the elderly and those with isolated systolic hypertension.10
Table 1:
Composition of Core Layer and Buccal Adhesive Cup
Along With Formulation Code
|
No. |
First Layer |
Second layer |
Adhesive cup Layer |
Backing Layer |
||||||
|
Drug |
Mannitol |
Filler |
Drug |
Sodium alginate |
HPMC K4M |
Filler |
Sodium alginate |
HPMC K4M |
EC |
|
|
F1 |
4 |
30 |
16(A) |
16 |
10 |
20 |
4(A) |
16.66 |
33.33 |
50 |
|
F2 |
4 |
30 |
16(B) |
16 |
10 |
20 |
4(B) |
16.66 |
33.33 |
50 |
|
F3 |
4 |
30 |
16(C) |
16 |
10 |
20 |
4(C) |
16.66 |
33.33 |
50 |
|
F4 |
4 |
30 |
16(A) |
16 |
15 |
15 |
4(A) |
25 |
25 |
50 |
|
F5 |
4 |
30 |
16(B) |
16 |
15 |
15 |
4(B) |
25 |
25 |
50 |
|
F6 |
4 |
30 |
16(C) |
16 |
15 |
15 |
4(C) |
25 |
25 |
50 |
|
F7 |
4 |
30 |
16(A) |
16 |
20 |
10 |
4(A) |
33.33 |
16.66 |
50 |
|
F8 |
4 |
30 |
16(B) |
16 |
20 |
10 |
4(B) |
33.33 |
16.66 |
50 |
|
F9 |
4 |
30 |
16(C) |
16 |
20 |
10 |
4(C) |
33.33 |
16.66 |
50 |
Where A= Lactose, B=MCC, C=Mannitol,
all weights in mg.
The drug is administered orally in a dose of
10– 20 mg daily as its hydrochloride salt, reducing significantly the diastolic
blood pressure.9 After oral administration, LER is completely and
erratically absorbed from the gastrointestinal tract.11 However,
absolute bioavailability is reduced to approximately 10% because of extensive
first pass metabolism to inactive metabolites.9
The present study examined mucoadhesive buccal tablets of Lercanidipine-HCL using hydroxy propyl methyl cellulose (HPMC K4M) and sodium alginate
(Na-alginate) as the mucoadhesive polymers, lactose,
micro crystalline cellulose, manitol as filler and
ethyl cellulose (EC) as an impermeable backing layer.
Effect of polymer type, proportion and effect
of filler type were studied on swelling, drug release rate, release mechanism
and mucoadhesive strength of the prepared
formulations.
MATERIALS
AND METHODS:
Materials:
Lercanidipine HCL was gift sample from Alembic Ltd (Baroda,
India). Na-alginate (Finar chemicals Pvt. Ltd., Ahmedabad, India), Hydroxy Propyl Methyl CelluloseK4M (Yarrow Chem. Product, Bombay),
Lactose (Chemdyes Corporation, Rajkot), Micro
Crystalline Cellulose (Chemdyes Corporation, Ahmedabad), Mannitol (Finar chemicals Pvt. Ltd., Ahmedabad,
India), Ethyl Cellulose (Chemdyes Corporation,Ahmedabad),
Magnesium Sterate (Chemdyes
Corporation,Ahmedabad) were obtained from commercial
sources. All other reagents and chemicals used were of analytical reagent
grade.
Preparation of BADDS (Buccal Adhesive Drug Delivery System):
The preparation process of BADDS mainly involves 3 steps: (1)
formation of core tablet, (2) formation of Backing layer and (3) formation of
BADDS. The composition of core (fast and sustained release layers) and adhesive
outer layer along with polymer ratios are presented in Table 1. All ingredients
were passed through American Society for Testing Materials (ASTM) sieve no. 100
and blended separately in a mortar.
1)
Formation of Core Tablet (using 7 mm punch): The core containing fast and sustained
release layers was prepared in 7 mm punch size using an electrically operated
single station punching machine.
2)
Formation of Backing Layer (using 11 mm punch): Then backing
layer material was inserted in 11-mm die cavity and uniformly distributed in
11-mm die cavity by single rotation.
3)
Formation of BADDS (using 11 mm punch): Then on prepared backing
layer put core tablet of 7 mm sized in centre and buccal
adhesive polymeric material inserted around the core tablet and then compressed
using 11-mm flat-faced upper and lower punches to obtain BADDS.
Content
Uniformity:
Drug content uniformity was determined by dissolving the tablets
in acetone and filtering with Whatman filter paper
(0.45 μm, Whatman).
The filtrate was evaporated and the drug residue dissolved in 100 mL of phosphate buffer (pH 6.8) containing 2.5% w/w of Polysorbate 80. The 10 mL
solution was then diluted with phosphate buffer (pH 6.8) containing 2.5% w/w of
Polysorbate 80 up to 100 mL,
filtered through 0.45-μm Whatman filter paper,
and analyzed at 350 nm using a UV spectrophotometer (Shimadzu 1800, Japan). The
experiments were performed in triplicate, and average values were reported
(Table 2).
Table 2:
Physicochemical Properties of BADDS of Lercanidipine
|
Formulation |
Weight a(mg) |
Thickness b(mm) |
% Drug Content b |
|
F1 |
195.8±1.40 |
1.94±0.01 |
99.03±0.35 |
|
F2 |
193.68±1.53 |
1.93±0.01 |
98.17±0.28 |
|
F3 |
192.9±1.33 |
1.94±0.01 |
97.67±0.23 |
|
F4 |
191.8±1.60 |
1.94±0.01 |
99.23±0.25 |
|
F5 |
190.8±1.64 |
1.93±0.02 |
100.17±0.47 |
|
F6 |
190.1±1.68 |
1.94±0.01 |
96.67±1.02 |
|
F7 |
188.7±2.02 |
1.94±0.01 |
97.9±0.78 |
|
F8 |
187.4±1.63 |
1.93±0.01 |
97.57±0.97 |
|
F9 |
187.55±1.70 |
1.95±0.01 |
95.07±0.41 |
Where M.S. = mucoadhesion strength,
a Mean (± SD) of 20 tablets,
b Mean (± SD) of 3 tablets.
In Vitro MS Measurement:
Mucoadhesion Strength (MS) of
BADDS with chicken intestinal mucosa was measured using a modified 2-arm
balance. The design of apparatus used while measuring the mucoadhesive
strength is shown in (Figure 1) chicken intestinal mucosa was obtained from a
local slaughterhouse. The chicken intestinal mucosa was fixed to the small
beaker with cynoacrylate adhesive and then placed in
a large beaker. Phosphate buffer solution was added into the large beaker up to
the upper surface of the buccal mucosa to maintain buccal mucosal viability during the experiments. The BADDS
was attached to the upper clamp of the apparatus and then the beaker was raised
slowly until contact between chicken intestinal mucosa and BADDS was
established. A preload of 50 g was placed on the clamp for 5 minutes (preload
time) to establish adhesion bonding between BADDS and chicken intestinal
mucosa. The preload and preload time were kept constant for all the
formulations. After completion of the preload time, preload was removed from
the clamp, and water was then added into the Petri dish from the burette at a
constant rate of 100 drops per minute. The addition of water was stopped when
BADDS was detached from chicken intestinal mucosa. The weight of water required
to detach BADDS from buccal mucosa was noted as Mucoadhesion Strength (Table 3).
Figure
1: Mucoadhesive Strength Measurement Device
Table 3:
In Vitro Mucoadhesive Study of BADDS of Lercanidipine
|
Formulation |
Mucoadhesion Strength(gram
force) |
|
F1 |
34.15 |
|
F2 |
-- |
|
F3 |
-- |
|
F4 |
28.69 |
|
F5 |
-- |
|
F6 |
-- |
|
F7 |
24.69 |
|
F8 |
-- |
|
F9 |
-- |
Swelling
Studies:
BADDS was weighed individually (recorded as W1) and placed
separately in Petri dish containing 5 mL of phosphate
buffer (pH 6.8) solution. At regular intervals (1, 2, 3, 4 and 5 hours), the
BADDS was removed from the Petri dish and excess surface water was removed
carefully using the filter paper. The swollen BADDS was then reweighed (W2),
and swelling index (SI) was calculated using formula as
Swelling Index = (W2–W1)
W1
Swelling index for all batches given in table
4.
Table 4:
Swelling Index of BADDS Tablets of Batches from F1 TO F9
|
Formulation |
swelling Index at |
||||
|
1 hr. |
2 hr. |
3 hr. |
4 hr. |
5hr. |
|
|
F1 |
0.94 |
1.47 |
1.82 |
2.023 |
2.42 |
|
F2 |
0.96 |
1.48 |
1.79 |
2.28 |
2.36 |
|
F3 |
0.94 |
1.42 |
1.78 |
2.32 |
2.40 |
|
F4 |
1.052 |
1.526 |
2.25 |
2.83 |
2.86 |
|
F5 |
1.128 |
1.496 |
2.28 |
2.64 |
2.68 |
|
F6 |
1.12 |
1.51 |
2.18 |
2.76 |
2.8 |
|
F7 |
2 |
2.78 |
3.21 |
|
|
|
F8 |
2.2 |
2.82 |
3.20 |
|
|
|
F9 |
2.08 |
2.80 |
3.11 |
|
|
In Vitro
Drug Release:
In vitro drug release studies were carried
out using USP II (rotating paddle) dissolution apparatus (Elecrolab
TDT 08L) with minor modifications. The dissolution medium consisted of 200 mL of phosphate buffer pH 6.8 with 2.5 % polysorbate 80. The release study was performed at 37°C ±
0.5°C, with a rotation speed of 25 rpm. The backing layer of the buccal tablet was attached to the glass disk with cyanoacrylate adhesive. The disk was placed at the bottom
of the dissolution vessel. Samples of 5 mL were
withdrawn at predetermined time intervals and replaced with fresh medium. The
samples were filtered through 0.2-μm Whatman
filter paper and analyzed after appropriate dilution by UV spectrophotometer
(Shimadzu, 1800) at 350 nm. CPR value of factorial batches was given in table 5
and CPR Value of theoretical profile was also given table 6.Then compare the
factorial batches with theoretical profile (Figure 2) and found the similarity
factor F2 value (Table 7).
In Vitro
Drug Permeation:
The in vitro buccal
drug permeation study of Lercanidipine-HCL through
the Chicken mucosa was performed using a modified diffusion cell at 37°C ±
0.2°C. Fresh Chicken mucosa was mounted between the donor and receptor
compartments. The tablet was placed with the core facing the mucosa, and the
compartments were clamped together. The donor compartment was filled with 1 mL of phosphate buffer pH 6.8 with 2.5 % polysorbate 80. The receptor compartment was filled with
phosphate buffer pH 6.8 with 2.5 % polysorbate 80 and
the hydrodynamics in the compartment was maintained by stirring with a magnetic
bead at uniform slow speed. 5 mL samples were
withdrawn at predetermined time intervals and analyzed for drug content by UV
spectrophotometer (Table 8).
RESULTS
AND DISCUSSION:
Tablets were found to be satisfactory when
evaluated for average weight, thickness and drug content.
The average weight of the tablet was found to
be between 187.55 mg to 195.8 mg and maximum % deviation was found to be 2.02
from all formulations. The thickness of all tablets
was found to be between 1.93 mm to 1.95 mm and % deviation in thickness was
found to be 0.01 to 0.02.Percent drug content was found to be 95- 100%(table
2).
HPMC
K4M and Na-alginate were selected as the bioadhesive
polymers because of their excellent bioadhesive
properties. EC has recently been reported to be an excellent backing material,
given its low water permeability, hydrophobicity, and
moderate flexibility. So it was chosen as an impermeable backing layer. D-mannitol was used to
improve the release of drug from polymer matrices, and the concentration was
optimized during the preliminary trial to find the best formulation of buccal tablets.
The ex vivo mucoadhesive
strength of the tablets was determined for using chicken intestinal mucosa.
Tablets containing a higher proportion of Na-alginate showed higher mucoadhesion at initial stage. This finding is owing to the
hydrophilic nature of Na-alginate; it is hydrated easily with less contact time
and forms a strong gel that entangles tightly with the mucin
molecules. This high mucoadhesive strength of HPMC K4M
may be due to formation of secondary mucoadhesive
bonds with mucin because of rapid swelling and
interpenetration of the polymer chains in the interfacial region, while other
polymers undergo only superficial bioadhesion.
Formulation F4 showed good mucoadhesive strength
(28.69 g). The effect of HPMC K4M was more significant than the effect of Na
alginate. The increase in concentration of HPMC K4M in series from formulation
F9 to F1, showed a gradual rise in mucoadhesion time,
while Na-alginate, which is also a good mucoadhesive
polymer, showed a decrease in mucoadhesion time.
Table 5:
CPR Value of Factorial Batches
|
Time(hr) |
CPR of |
||||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
|
|
0 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
|
1 |
25.93 |
33.13 |
35.56 |
19.39 |
28.46 |
31.26 |
27.33 |
28.64 |
29.58 |
|
2 |
28.07 |
35.17 |
40.46 |
25.77 |
35.62 |
35.41 |
38.11 |
37.77 |
38.73 |
|
3 |
29.51 |
37.15 |
43.23 |
33.31 |
40.88 |
40.95 |
44.46 |
46.92 |
48.46 |
|
4 |
31.25 |
38.24 |
46.74 |
42.51 |
46.20 |
45.54 |
53.08 |
55.38 |
54.13 |
|
5 |
32.71 |
40.25 |
48.92 |
56.27 |
53.82 |
52.03 |
62.76 |
63.63 |
69.25 |
|
6 |
35.68 |
42.66 |
51.49 |
60.85 |
64.04 |
54.54 |
79.37 |
78.42 |
80.21 |
|
7 |
40 |
45.61 |
53.47 |
67.17 |
74.66 |
59.33 |
83.47 |
85.43 |
85.98 |
|
8 |
44.75 |
47.75 |
55.82 |
75.64 |
79.27 |
63.24 |
86.17 |
95.76 |
91.89 |
|
9 |
52.35 |
50.86 |
58.54 |
83.66 |
85.98 |
71.58 |
100.78 |
101.07 |
97.67 |
|
10 |
61.91 |
55.58 |
61.28 |
88.17 |
90.64 |
77.67 |
-- |
-- |
--- |
|
11 |
68.3 |
65.39 |
62.9 |
93.69 |
93.24 |
82.69 |
-- |
-- |
--- |
|
12 |
71.21 |
69.67 |
66.75 |
97.85 |
96.03 |
90.61 |
-- |
--- |
--- |
Table 6:
CPR Value of Theoretical Profile
|
Time (hr.) |
CPR of Theoretical |
|
0 |
0 |
|
1 |
19.4 |
|
2 |
26.72 |
|
3 |
34.04 |
|
4 |
41.36 |
|
5 |
48.68 |
|
6 |
56 |
|
7 |
63.32 |
|
8 |
70.64 |
|
9 |
77.96 |
|
10 |
85.28 |
|
11 |
92.6 |
|
12 |
100 |
Table 7:
Similarity Factor Value of Factorial Batches
|
Formulation |
F2 value |
|
F1 |
35.22 |
|
F2 |
35.23 |
|
F3 |
37.23 |
|
F4 |
70.46 |
|
F5 |
56.71 |
|
F6 |
56.45 |
|
F7 |
41.31 |
|
F8 |
39.06 |
|
F9 |
30.96 |
Table 8:
In Vitro Diffusion Study of BADDS of Lercanidipine.
|
Time(hr) |
CPR(Diffusion) |
|
1 |
18.49 |
|
2 |
25.23 |
|
3 |
33.98 |
|
4 |
42.93 |
|
5 |
50.32 |
|
6 |
56.37 |
|
7 |
69.58 |
|
8 |
73.83 |
|
9 |
82.08 |
|
10 |
87.22 |
|
11 |
95.56 |
|
12 |
99.04 |
Appropriate swelling behavior of a buccal adhesive system is essential for uniform and
prolonged release of the drug and effective mucoadhesion
.Swelling index was calculated with respect to time. The swelling index
increased as the weight gain by the tablets increased proportionally with rate
of hydration as shown in to the table 3.
The order of swelling observed in these
polymers could indicate the rates at which the preparations are able to absorb
water and swell. Maximum liquid uptake and swelling of sodium alginate was
achieved after 3 hours and then gradually decreased due to erosion. HPMC K4M
reached maximum swelling after 5 hours and this was maintained until the end of
the experiment. This finding may have been because of the fast-swelling
property of Na alginate compared with HPMC
K4M. The maximum swelling index was found in batch F7 (3.21), containing a
higher proportion of Na-alginate, and the lowest in F2 (2.36).
Dissolution profile is shown in Table 5. HPMC
K4M exhibited a much greater sustained effect on the release rate compared with
sodium alginate. All formulations containing 1:2 (Sodium alginate: HPMC K4M)
exhibited similar release of drug in 12 hrs up to 71.21%. In formulations
containing 2:1 (Sodium alginate: HPMC K4M) the drug was completely released
after 9 hours from tablets. But in formulation containing 1:1(Sodium alginate:
HPMC K4M) drug was completely release in 12 hrs with desired release rate.
Formulation containing 1:1(Sodium alginate:
HPMC K4M) was impressive since these formulations showed effective desired
release pattern. Furthermore, in order to compare the release behavior of Lercanidipine between BADDS (containing both fast and
sustained release layers) and theoretical profile, in vitro release study is
shown in Figure 2.
Incorporation of loading dose (2 mg) along
with sustained release dose into the BADDS resulted in faster release at the
initial period and controlled release pattern in the later period (Figure 2).
Figure
2: Comparison of Factorial Batches with Theoretical Profile
Formulation F4 was optimized based on in
vitro drug release (97.85 at 12 hours), swelling index (2.86 at 5 hours), and
ex vivo mucoadhesive strength (28.69 g); it showed
good drug release with sufficient mucoadhesion.
Formulation F4 was subjected to an in vitro buccal
permeation study using a diffusion cell (Table 8). The results showed drug permeation of 99.04% in 12 hours. The
correlation between in vitro drug release rate and in vitro drug permeation
across the chicken mucosa was found to be positive, with a correlation
coefficient (R2) of 0.9921.(Figure 3)
Figure
3: Correlation Between In Vitro Drug Release and In Vitro Permeability
CONCLUSION:
This designed BADDS can overcome the
disadvantage of poor and erratic oral bioavailability of Lercanidipine.
BADDS has also overcome the drawback associated with conventional buccal adhesive tablets. BADDS consists of fast and
sustained release layers, Lercanidipine can be
release and permeated through buccal mucosa rapidly
at the first and then continuously for prolonged period.
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Received on 05.01.2010
Accepted on 12.04.2010
© A&V Publication
all right reserved
Research
Journal of Pharmaceutical Dosage Forms and Technology. 2(2): March –April.
2010, 164-168