Design and Development of Sweet Potato Starch Blended Sodium Alginate
Mucoadhesive Microcapsules of Glipizide
N. Sandhya
Rani*, M. Teja
Krishna and V. Saikishore
Dept. of Pharmaceutics, Bapatla College of Pharmacy, Bapatla-522101, Andhra Pradesh
India.
ABSTRACT:
Mucoadhesive microcapsules of Glipizide
were prepared for reducing the dosing frequency, to improve the patience
compliance and to obtain control release. Glipizide microcapsules with a coat
consisting of alginate and sweet potato starches
were prepared by employing ionic gelation and emulsification
ionotropic gelation
techniques. The microcapsules were
evaluated for flow properties, Carr’s index, hausner
factor, microencapsulation efficiency, drug release characteristics, surface
characteristics; compatibility studies and mucoadhesive
properties. These two methods gave discrete, large sized, free flowing
spherical microcapsules without any interactions. Glipizide release from the microcapsules was slow and
followed zero order kinetics and followed non–fickian
release and depended on the coat: core ratio and the method employed in the
preparation of microcapsules. Among the two methods emulsification ionotropic gelation technique was found to be more suitable for
slow and complete release of Glipizide over a long period of time. These microcapsules
exhibited good mucoadhesive property in the in-vitro
wash-off test. These Mucoadhesive
microcapsules are, thus, suitable for oral controlled release of Glipizide.
KEYWORDS: Glipizide, microcapsules, ionic gelation, emulsification ionotropic
gelation
INTRODUCTION:
Mucoadhesion
has been a topic of interest in the design of drug delivery systems to prolong
the residence time of the dosage form at the site of application or absorption
and to facilitate intimate contact of the dosage form with the underlying
absorption surface to improve and enhance the bioavailability of drugs1. Sweet
potato (Ipomea batatas)
is an important crop in many developing countries Sweet potatoes are rich in
starch (6.9-30.7% on wet basis) and starch production is the main industrial
utilization of sweet potatoes2. Sweet potato starches have been
reported to retrograde more slowly than wheat and corn starches but similar to
potato starch. Alginate is a complex polysaccharide whose composition varies on
the basis of the proportions of its monomeric units,
namely mannuronic acid and guluronic
acid Glipizide3, an effective antidiabetic that requires controlled release owing to its
short biological half-life of 3.4 ± 0.7 hours was used as the core in micro
encapsulation.
MATERIALS
AND METHODS:
Materials:
Glipizide U.S.P was a gift
sample from M/s Orchid Pharma Ltd, Chennai, India. Girijan Co-operative Corporation Ltd (Visakhapatnam, India)
supplied Sweet potato flour (Grade 1).
Sodium alginate
(having a viscosity of 5.5 cps in a 1% w/v aqueous solution at 25ºC), calcium
chloride and Preparations of
Microcapsules:
Ionic gelation technique4:
Sodium alginate
(1.0 g) and Sweet potato flour (1.0 g) were dissolved in purified water (32 mL) to form a homogeneous polymer solution. The active
substance, Glipizide (2.0 g), was added to the
polymer solution and mixed thoroughly with a stirrer to form a viscous
dispersion. The resulting dispersion was then added manually drop wise into
calcium chloride (15% w/v) solution (40 mL) through a
syringe with a needle of size no 18. The added droplets were retained in the
calcium chloride solution for 15 minutes to complete the curing reaction and to
produce spherical rigid microcapsules having coat:core ratio 1:1 (MC1). Similarly
microcapsules with coat:core
ratio 1.5:1 (MC2) and 2:1 (MC3) were also prepared. The
microcapsules were collected by decantation and dried over night at room
temperature.
Emulsification ionotropic gelation technique5:
Sodium alginate (1.0 g) and Sweet
potato flour (1.0 g) were dissolved in 32 ml of water. Drug (2 g) was added and mixed thoroughly. The polymer
dispersion was then added in a thin strin to 50 ml of
heavy liquid paraffin contained in a 250 ml beaker, while stirring at 500 rpm
to emulsify the added dispersion as fine droplets. A Remi
make medium duty stirrer with speedometer (RQ 121/D) was used for stirring.
Then 20 ml of calcium chloride solution (15% w/v) was transferred in to the
emulsion while stirring at 500 rpm for 15 min to produce spherical
microcapsules. The microcapsules were collected by decantation and washed
repeatedly with petroleum ether. The product was then air dried to obtain
discrete micro spheres. Different proportions of coat: core materials namely
1:1 (MC4), 1.5:1 (MC5) and 2:1 (MC6) were used
to prepare microcapsules.
Evaluation of Microcapsules:
Size Distribution and Size Analysis6:
For size distribution analysis, different sizes in a batch were
separated by sieving, using a range of standard sieves. The amounts retained on
different sieves were weighed. The mean particle size of the microcapsules was
calculated by the formula.
Flowability of Microcapsules7:
The static angle
of repose was measured according to the fixed funnel and free standing cone
method. the bulk density of the mixed microcapsules
was calculated by determining the Hausner’s ratio and
Carr’s index from the pored and tapped bulk densities of a know weight of
sample using a measureing cylinder. The following
formulas were used for calculating Hausner’s Ratio = Dp ÷ Dt,
Carr’s Index = [(Dp - Dt)
÷ Dp] X 100, where Dp
(Poured density) = Weight of the microcapsules ÷ Vp(Poured
Volume), Dt (tappaed
density) = Weight of the microcapsules ÷ Vt
(tapped Volume).
Drug Content Evaluation:
Glipizide content in the microcapsules was estimated
by a UV spectrophotometric (UV-1700, Shimadzu, Japan) method based
on the measurement of absorbance at 223 nm in phosphate buffer of pH 7.48.
Microcapsules containing equivalent to 100mg of glipizide
were crushed to fine powder in a mortar and extracted with 50ml of methanol. It
was filtered and made up to the volume of 100 ml with methanol. One ml of the
sample was taken and made up the volume to 10ml with phosphate buffer pH 7.4
and the absorbance was measured at 223nm.
Microencapsulation Efficiency9:
Microencapsulation
efficiency was calculated using the following formula.
-
(2)
Scanning Electron Microscopy (SEM):
The samples for the SEM analysis were prepared by sprinkling the gel
beads on one side of the double adhesive stub. The stub was then coated with
fine gold dust. The gel beads were then observed with the scanning electron
microscope (Leica Electron Optics, Cambridge, USA) at
15kv.
Infrared Spectroscopic Studies:
Fourier–transformed infrared (FT–IR)
spectra were obtained on a Perkin Elmer 2000 FT–IR system (Perkin Elmer,
Norwalk, CT) using the KBr disk method (2 mg sample
in 200 mg KBr). The scanning range was 400 to 4000 cm-1 and the
resolution was 1 cm-1.
In Vitro Release Studies:
Release of Glipizide from the microcapsules was studied in phosphate
buffer of pH 7.4 (900 mL) using a United States Pharmacopoeia (USP) XXIII
8-station Dissolution Rate Test Apparatus (Model TDT - 08L, M/s Electrolab, Mumbai, India) with a rotating paddle stirrer
at 50 rpm and 37ºC ± 1ºC as prescribed for Glipizide
tablets in USP XXIV. A sample of microcapsules equivalent to 10 mg of Glipizide was used in each test. Samples of dissolution
fluid were withdrawn through a filter (0.45 m) at different time
intervals and were assayed at 223 nm for Glipizide content
using a Shimadzu UV-1700 double beam spectrophotometer10 (Shimadzu
Corporation, Japan). The drug release experiments were conducted in triplicate
(n = 3).
The release data
obtained were fitted to zero order, first order, Higuchi
and Korsmeyer peppas
equations to determine the corresponding release rate and mechanism of drug
release from the Mucoadhesive micro spheres11.
Mucoadhesion
Evaluation:
The mucoadhesive property of the microcapsules was evaluated by
an in vitro adhesion testing method known as the wash-off test12.
The mucoadhesiveness of these microcapsules was
compared with that of non bioadhesive material,
ethylene vinyl acetate microcapsules. Freshly excised pieces of intestinal
mucosa (2 × 2 cm) from sheep were mounted onto glass slides (3 × 1 inch) with cyanoacrylate glue. Two glass slides were connected with a
suitable support. About 50 microcapsules were spread onto each wet rinsed
tissue specimen, and immediately thereafter the support was hung onto the arm
of a USP tablet disintegrating test machine. When the disintegrating test
machine was operated, the tissue specimen was given a slow, regular up-and-down
movement in the test fluid at 37 OC contained in a 1 L vessel of the
machine. At the end of 30 minutes, at the end of 1 hour, and at hourly
intervals up to 12 hours, the machine was stopped and the number of
microcapsules still adhering to the tissue was counted. The test was performed
at both gastric pH (0.1N HCl, pH 1.2) and intestinal
pH (phosphate buffer, pH 7.4).
RESULTS
AND DISCUSSION:
Microcapsules of
glipizide could be prepared by ionic gelation process and emulsification gelation
process by employing blending pre
gelatinized sweet potato flour with sodium alginate
as the polymer. The microcapsules were found to be discrete spherical and free
flowing. The size analysis of different batches of microcapsules showed that
about 76% of the prepared microcapsules were in the size range of 920 µm (-16
to +20). The size distribution of microcapsule was found to be normal in all
the batches. The microcapsules imparted good flow ability as indicated by angle
of repose (22.38 - 25.68), the Carr’s index (11 - 15) and the Hausner Ratio (1.1 – 1.2). The SEM photographs indicated
that the microcapsules were spherical and completely covered with the coat
polymer (Fig 1).
Fig 1 : SEM Photographs of Glipizide Microcapsules
prepared by Ionic Gelation technique and Emulsification ionotropic gelation
technique.
a)
Ionic Gelation Technique
Emulsification
ionotropic Gelaon Technique
Low coefficient
of variation (< 2.0%) in percent drug content indicated uniformity of drug
content in each batch of microcapsules. The Microencapsulation efficiency was
in the range of 79% to 97%, with various products.
The IR spectrum
of Glipizide was shown in Fig 2.a and the following
characteristic bands were observed 1689
(- C=O, Amide), 1651 (- C=O, Urea), 1528 (Ar- CH,
stretching), 1433 (Ar- CH, bending), and 1333 and
1159 cm-1 (- SO2NH). The IR spectrum of Glipizide microcapsules was shown in Fig 2.b and 2.c and
the presence of characteristic bands of Glipizide
were observed. Thus, any change in the structure of Glipizide
was ruled out and it was concluded that there is no chemical incompatibility
between Glipizide and mixture of pre gelatinized sweet potato flour with sodium alginate.
Fig 2: IR Spectra of Glipizide and Microcapsules .
IR Spectra of Glipizide and Microcapsules prepared by Ionic
Gelation technique(MC3) and Emulsification ionotropic gelation technique(MC6)
Table
1: Correlation Coefficient (R) Values in Various Kinetic Models Tested to
Describe Drug Release from the Mucoadhesive
Microcapsules Formulated
|
Formulation
|
Correlation
Coefficient Values
|
n
|
|
Zero
Order
|
First
Order
|
Higuchi
model
|
Peppas Model
|
|
MC1
|
0.9967
|
0.8996
|
0.92375
|
0.99849
|
0.6836
|
|
MC2
|
0.9953
|
0.8878
|
0.92737
|
0.99951
|
0.7674
|
|
MC3
|
0.9961
|
0.8859
|
0.93800
|
0.98213
|
0.8640
|
|
MC4
|
0.9950
|
0.8849
|
0.94021
|
0.99553
|
0.6578
|
|
MC5
|
0.9934
|
0.8894
|
0.93443
|
0.99245
|
0.7696
|
|
MC6
|
0.9962
|
0.8867
|
0.92375
|
0.99849
|
0.8284
|
Table 2: Invitro
wash-off test values for the Glipizide loaded Mucoadhesive microcapsules formulations .
|
Formulation
|
Percentage of microspheres adhering to tissue at 4 times
intervals (h)
|
|
0.1 N Hydrochloric
acid
|
7.4 pH Buffer
|
|
2
|
4
|
6
|
8
|
2
|
4
|
6
|
8
|
|
MC1
|
90±0.51
|
83±0.54
|
79±0.22
|
77±0.46
|
87±0.54
|
81±0.58
|
76±0.86
|
73±0.65
|
|
MC2
|
92±0.85
|
87±0.61
|
84±0.55
|
80±0.67
|
89±0.88
|
83±0.74
|
80±0.77
|
75±0.48
|
|
MC3
|
93±0.28
|
91±0.61
|
88±0.66
|
83±0.59
|
91±0.65
|
88±0.21
|
84±0.35
|
80±0.77
|
|
MC4
|
95±0.66
|
91±0.77
|
85±0.15
|
83±0.24
|
93±0.15
|
88±0.12
|
83±0.59
|
79±0.51
|
|
MC5
|
97±0.52
|
93±0.28
|
87±0.42
|
85±0.11
|
95±0.46
|
91±0.97
|
86±0.79
|
82±0.27
|
|
MC6
|
99±0.58
|
95±0.13
|
90±0.64
|
88±0.57
|
97±0.25
|
94±0.56
|
88±0.66
|
86±0.46
|
|
EC
|
43±0.29
|
31±0.62
|
18±0.65
|
05±0.54
|
41±0.65
|
28±0.21
|
16±0.35
|
04±0.77
|
Glipizide
release from the microcapsules was studied in phosphate buffer (pH 7.4) for 12
hours as prescribed for Glipizide tablets in USP
XXIV. Glipizide release from the microcapsules was
slow, spread over extended period of time and depended on the composition of
the coat composition and method employed for the preparation of microcapsules (Figure 2 and 3). To ascertain the mechanism of drug release, the
dissolution data was analyzed by zero order, first order, and higuchi and peppas equations. The
correlation coefficient values (r) were reported in Table 1. These values
revealed that the dissolution profiles follow zero order kinetics and the
mechanism of drug release was governed by peppas
model. The n values are found to be more than 0.5 (n>0.5) indicted that the
drug release was from the microspheres followed the anomalous transport
mechanism controlled by swelling and relaxation of the polymer chains.
Figure3:
Release Profile of Glipizide Mucoadhesive
Microcapsules Prepared by Ionic gelation
technique.
MC1 -(♦)-
microcapsules having coat:core
ratio 1:1
MC2 - (¡)- microcapsules
having coat:core ratio
1.5:1
MC3 - ()-microcapsules having coat:core ratio 2:1
Figure4. Release Profile of Glipizide
Mucoadhesive Microcapsules Prepared by Emulsification ionotropic gelation technique
MC4 -(♦)-
microcapsules having coat:core
ratio 1:1
MC5 - (¡)- microcapsules
having coat:core ratio
1.5:1
MC6 - ()-microcapsules having coat:core ratio 2:1
Microcapsules with a coat consisting of blending pre gelatinized sweet potato flour with sodium
alginate exhibited good Mucoadhesive
properties in the in vitro wash-off test when compared to non-Mucoadhesive material, ethyl cellulose microcapsules. The
wash-off was slow in the case of microcapsules consisting of blending
pre gelatinized sweet potato flour with sodium alginate
as coat when compared to that of ethyl cellulose microcapsules. The wash-off was faster at simulated intestinal pH (7.4)
than that at simulated gastric pH (1.2). The rapid wash-off observed at
simulated intestinal pH may be due to the ionization of carboxyl acid group and
other functional groups in the polymers, which increase their solubility and
reduce adhesive strength. The results of the wash-off test indicated that the microcapsules had fairly
good mucoadhesive properties. The developed mucoadhesive microcapsules would adhere to the GI walls, thus resisting gastric
emptying. It would ensure the prolong residence time at the absorption site to
facilitate intimate contact with the absorption surface and thereby improve and
enhance the bioavailability.
CONCLUSION:
The data suggest that sweet
potato flour is a potentially useful natural material for making controlled
release mucoadhesive
microcapsules by ionic
gelation and emulsification gelation
techniques. Glipizide release from these Mucoadhesive microcapsules was slow and extended over
longer periods of time and depended on composition of the coat method employed
for the preparation. These Mucoadhesive microcapsules
are, thus, suitable for oral controlled release of Glipizide.
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