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 25 OC), 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.
------ (1)
Flowability of
Microcapsules7:
The static angle
of reposewas measured according to the fixed funnel
and free standing cone method. the bulk density of the
mixed microcapsules was calculated by determaining
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 37 OC ± 1 OC 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 µm) 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
b) Emulsification
ionotropic Gelation Technique
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)
Figure3: Release Profile of Glipizide
Mucoadhesive MicrocapsulesPrepared
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
Figure
4. Release Profile of Glipizide
Mucoadhesive Microcapsule 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
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.bAND2.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.
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 3 and 4 ). 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 follows 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.
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(Table 2)
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.
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
|
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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