INTRODUCTION:
Floating
microspheres are gastro-retentive drug delivery frameworks dependent on non-effervescent methodology. Gastro-retentive floating
microspheres are low-density
frameworks that have adequate buoyancy to float over gastric contents
and stay in stomach for delayed period.26 The drug is released gradually
at a ideal rate resulting in increased
gastric retention with retarded
fluctuations in plasma drug concentration. A few challenges are looked in designing controlled released systems for better absorption and improved the bioavailability1,27. Microparticles are defined as round polymeric particles with sizes ranging
from 1 to 1000 μm. There are two subtypes of microparticles. Microcapsules are vesicular systems in
which the drug molecules are surrounded by a membrane.
Microspheres
are network frameworks in which the drug molecules are scattered throughout the particle17. Microspheres constitute an important
part of these particulate drug
delivery systems by virtue of their small size
and productive transporter characteristics2. Floating drug delivery offers several applications for drugs having
poor bioavailability in view of the narrow absorption window in the upper part of the gastrointestinal
tract. It holds the dosage form at the site of absorption and thus improves the bioavailability3.
Curcumin is a
bioactive natural product. It is used in treatment of gastric and duodenal ulceration and also used as antibacterial, anti-protozoal, antiviral, hypolipemic, hypoglycemic, anticoagulant and antioxidant. It is poorly absorbed from the gastro intestinal tract and has a short elimination half- life. The goal of our research
work was to create floating microspheres of curcumin to achieve sustained
drug release in the body. The prepared
microspheres were evaluated for size, in-vitro curcumin release, and buoyancy and incorporation efficiency4. Microspheres can be defined as solid,
approximately spherical particles ranging
size from 1 to 1000μm. Polymers and modify natural items. For example, starches, gums, proteins, fats and waxes.18 Microsphere
Carrier framework comprised of naturally
occurring biodegradable polymers
have attracted significant consideration for several
years in sustained drug delivery as of late,
dosage forms that can precisely
control the release rates and target drugs to a particular body site have made an tremendous effect in the formulation and improvement of novel
drug delivery frameworks5.
MATERIAL AND METHODS:
Curcumin was
obtained as a gift sample from Marida Green and Organics Pvt. ltd. Gujrat.
Hydroxyl propylemethyle
cellulose (HPMC), Ethyl cellulose (EC), methanol
and ethanol obtained from S.D. fine chemicals
ltd. Mumbai. Eudragit
obtained from Glukem pharmaceutical
ltd. India.25 Tweens 80 and poly vinyl alcohol (PVA) obtained from Rankem Laboratory, New Delhi.
Dichloromethane provided by institution.
Preparation of microspheres:
Curcumin microspheres were prepared by solvent diffusion technique by the drug and
polymer ratio used are shown in table
1. The materials were weight and added to a mixture
of organic solvent
ethanol and dichloromethane. The emulsion was added
slowly drop wise by using a 26 G
syringe needle in prepared aqueous phase
containing 0.25% w/v 400ml solution of polyvinyl alcohol (PVA) at room temperature.19,24 The stirring slowly by using magnetic beads was
continued for 2 hrs in order to
evaporate the solvent. After 2 hrs the formed
microspheres were filtered, washed with distilled water, stored in desiccators and air-dried at room temperature.6,22,23
Table 1. Formulation chart of microspheres
|
Formula
-tion code
|
Curcumin (mg)
|
HPMC
(mg)
|
EC
(mg)
|
Eudragit RS
100
(mg)
|
Ethanol and Dichloro- methane
(%)
|
Poly vinyl
alcohol (PVA).
(%)
|
|
F1
|
100
|
100
|
300
|
-
|
1:1
|
0.25
|
|
F2
|
100
|
300
|
-
|
100
|
1:1
|
0.25
|
|
F3
|
100
|
100
|
100
|
200
|
1:1
|
0.25
|
|
F4
|
100
|
-
|
300
|
100
|
1:1
|
0.25
|
|
F5
|
100
|
300
|
100
|
-
|
1:1
|
0.25
|
|
F6
|
100
|
200
|
200
|
-
|
1:1
|
0.25
|
Evaluation Parameter:
Micrometric properties:
The prepared
microspheres are characterized by their micrometric properties, such as Bulk density, Tapped density, Carr’s compressibility index, Hausner’s ratio and
angle of repose by using standard methods.8
Yield:
The prepared microspheres of all batches
were accurately weighed. The measured amount of formulated
microspheres was divided by sum amount of all the excipients and drug utilize
in preparation of the microspheres.
Content:
The drug substance of floating microspheres was assessed by dispersing 50mg prepared (precisely weighed) in 10ml ethanol followed by agitation with a magnetic stirrer for 12 hrs to breakdown
the polymer and to separate
the drug. After filtration through
a 5μm membrane
filter (Millipore), the drug content
was estimated spectrophotometrically
at 430.4nm.
Floating Behavior:
50mg of the microspheres were placed in 100ml of simulated
gastric juice (pH 1.2) containing 0.02% w/v Tween 80. The mixed was stirred
at 100rpm on a magnetic
stirrer. After 4 hrs, the layer of floating microspheres was pipetted and detached by filtration particles
and the sinking particulate layer was like manner
confined by filtration.28 Particles of both types were dried in desiccators.20 Both the portions
of microspheres were weighed
and floatancy was directed by the
weight proportion of floating particles to the total of floating and sinking particles.9
Scanning Electron Microscopy (SEM):
The shape and exterior
morphology of drug loaded microspheres were investigated by using scanning
electron microscope. The sample was spread on stub and coated for 120 s with a layer of gold
utilizing a sputter coater. A short
time later, the stub containing the sample was
placed in the examining electron microscope (JSM 5610 LV SEM, JEOL, Japan)
chamber at the speeding up voltage of 20 kV, chamber weight of
0.6mm Hg. At that point photo micrographs were taken at various magnifications.
In-vitro Dissolution studies:
The formulated
microspheres were poured in each of the six-basket dissolution apparatus. The assembly
was maintained at a
temperature of 370C in HCl buffer, pH 1.2.10
Release kinetics:
Several
theories and kinetic models were described the
drug release characteristics of qualities of quick release and adjusted release dose forms, by utilizing
dissolution information and quantitative elucidation of qualities obtained in dissolution test.
RESULT AND DISCUSSION:
Melting point determination:
Melting point of
the Curcumin was founding the range
of 176-1790C as reported in literature, thus indicating purity
of Curcumin.29,30
Figure 1. FT-IR spectra of Curcumin
UV Spectrophotometric study:
UV Spectrophotometric studies were carried
out in different media (methanol, phosphate buffer pH 7.4 and HCl buffer pH 1.2) in the scanning range
of 200-400nm. The λmax obtained
was recorded in methanol the λmax was 417.2nm, in phosphate buffer pH 7.4 λmax was 426nm and HCl
buffer pH 1.2 λmax was 430.4nm.11
FT- IR Spectral analysis:
The FTIR
spectrum of pure Curcumin sample recorded by FTIR spectrum is shown in figure 1 which was compared
with standard functional group. Frequencies of
Curcumin as shown in table 2.12, 31
Table 2. FT-IR spectra of Curcumin
|
S. No.
|
Functional group
|
Range (cm-1)
|
Observed frequencies(cm-1)
|
|
1.
|
O-H stretching
|
3200-3600,
|
3508.97
|
|
2.
|
-CH2 stretching
|
2962 - 2853
|
2944.03
|
|
3.
|
-C=O stretching
|
1600-1850
|
1627.99
|
|
4.
|
C=C stretching
|
1600-1700
|
1509.52
|
|
5.
|
-CH2 bending
|
1480-1440
|
1428.96
|
|
6.
|
C-O stretching
|
1050-1150,
|
1115.28
|
Preparation of calibration curve:
Calibration curve of
the drug (Curcumin) was
obtained in Methanol, phosphate buffer pH
7.4 and HCl buffer pH
1.2 in concentration range 5-30 g/ml as shown in Fig 5, 6 and 7
respectively and linearity was observed with an r2=0.999 for methanol,
r2=0.998 for phosphate
buffer (pH 7.4) and an r2=0.998
for HCl buffer pH 1.2 when analyzed at 417.2nm, 426nm and 430.4nm
respectively.
Micrometrics characterization:
Various
Micrometrics characterizations were performed
for all formulation shown in
table 3 and 4.
Table 3. Micrometrics study of formulated floating microspheres
|
Formu lation code
|
Bulk density
(g/cm3)
|
Tapped density (g/cm3)
|
Carr’s Index
(%)
|
Hausner’s Ratio
|
Angle of
repose (ř)
|
Parti cle
size (µm)
|
|
F1
|
0.084±
0.006
|
0.093±
0.001
|
9.594±
0.034
|
1.101±
0.008
|
20.35±
0.777
|
578
|
|
F2
|
0.134±
0.001
|
0.146±
0.003
|
8.219±
0.015
|
1.082±
0.010
|
24.27±
0.210
|
416
|
|
F3
|
0.129±
0.001
|
0.139±
0.004
|
7.142±
0.024
|
1.076±
0.015
|
25.60±
0.617
|
565
|
|
F4
|
0.182±
0.002
|
0.196±
0.005
|
7.146±
0.043
|
1.082±
0.014
|
30.24±
1.051
|
425
|
|
F5
|
0.095±
0.003
|
0.103±
0.004
|
7.676±
0.032
|
1.084±
0.012
|
24.41±
0.330
|
618
|
|
F6
|
0.103±
0.002
|
0.109±
0.005
|
5.504±
0.040
|
1.058±
0.021
|
23.32±
0.787
|
585
|
Table 4. Percent
yield % Buoyancy, Drug Content
and Drug entrapment efficiency of microspheres
|
Formulat ion
code
|
% Yield
|
%
Buoyancy
|
Theoreti cal
Content (mg)
|
Actual Content
(mg)
|
%Drug entrapme
nt efficiency
|
|
F1
|
70.95±
0.051
|
72.00±
0.340
|
20
|
12.10±
0.363
|
60.5±
0.050
|
|
F2
|
60.27±
0.041
|
62.24±
0.161
|
20
|
9.48±
0.086
|
47.4±
0.065
|
|
F3
|
72.29±
0.056
|
86.95±
0.416
|
20
|
15.60±
0.096
|
78.0±
0.052
|
|
F4
|
68.55±
0.152
|
83.92±
0.396
|
20
|
14.96±
0.157
|
74.8±
0.025
|
|
F5
|
60.21±
0.052
|
70.72±
0.315
|
20
|
9.89±
0.135
|
49.45±
0.055
|
|
F6
|
80.87±
0.043
|
88.63±
0.413
|
20
|
15.58±
0.080
|
77.9±
0.036
|
Scanning Electron Microscopy (SEM):
The surface
morphology of enhanced formulation was inspected the SEM photo demonstrated that the microspheres was round and smoother surface
which may because
of the drug scattered at molecular level appeared
in figure 2.
Figure 2. SEM Micrograph of Microspheres
In-vitro dissolution studies:
The in-vitro
drug discharge studies were carried out in
900 ml of HCl buffer pH 1.2 by using USP XXVI six stage paddle basket type dissolution test apparatus (VEEGO). Temperature of the dissolution
medium was maintain at 37±0.50C a rotating
speed at 50rpm. The result of dissolution studies indicated
that the % drug release significantly
decrease as polymer conc. increase shown
in table 5 and % drug release graph shown in
figure 3.13
Table 5. In-vitro release profile of Curcumin
microspheres
|
Time (hrs)
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
|
|
%
Drug rel.
|
%
Drug rel.
|
%
Drug rel.
|
%
Drug rel.
|
%
Drug rel.
|
%
Drug rel.
|
|
1
|
17.19
|
13.42
|
20.64
|
17.85
|
16.25
|
20.12
|
|
2
|
22.45
|
17.22
|
26.35
|
25.16
|
24.88
|
28.55
|
|
3
|
26.36
|
22.46
|
30.32
|
33.32
|
30.45
|
35.42
|
|
4
|
35.45
|
30.24
|
37.76
|
40.76
|
37.75
|
43.65
|
|
5
|
39.25
|
38.55
|
42.63
|
47.18
|
43.52
|
50.62
|
|
6
|
52.29
|
45.35
|
55.21
|
52.48
|
49.95
|
57.08
|
|
7
|
63.84
|
52.21
|
64.39
|
58.32
|
57.35
|
62.89
|
|
8
|
70.12
|
60.18
|
73.45
|
64.81
|
62.49
|
69.24
|
|
9
|
76.11
|
64.39
|
79.71
|
70.85
|
66.05
|
76.79
|
|
10
|
79.45
|
67.85
|
82.61
|
75.28
|
70.36
|
81.40
|
|
11
|
82.33
|
70.25
|
84.09
|
78.12
|
73.48
|
85.22
|
|
12
|
83.95
|
72.13
|
85.13
|
80.12
|
74.92
|
87.13
|
Figure 3. In-vitro release profile of Curcumin
microspheres formulation F1 –F6
Release Kinetics:
In order to
find out the mechanism of drug release, the in-vitro dissolution statistical data were applied to different kinetics
models21. The best fit with highest regression coefficient value (r2) was anticipated by Higuchi model (0.987). This demonstrates that the release
pattern followed by Higuchi model.14
Table 6. Release kinetics
of Curcumin floating
microspheres
|
Formulation s
Code
|
Zero order
(R2)
|
First order
(R2)
|
Higuchi (R2)
|
Hixon
– Crowell (R2)
|
Korsmayer’s and Peppa’s (R2)
|
|
F1
|
0.967
|
0.925
|
0.947
|
0.956
|
0.811
|
|
F2
|
0.964
|
0.918
|
0.956
|
0.953
|
0.823
|
|
F3
|
0.961
|
0.917
|
0.956
|
0.957
|
0.817
|
|
F4
|
0.993
|
0.935
|
0.985
|
0.955
|
0.829
|
|
F5
|
0.971
|
0.926
|
0.986
|
0.955
|
0.879
|
|
F6
|
0.976
|
0.929
|
0.987
|
0.955
|
0.861
|
Figure 4. In-vitro release profile of Curcumin
microspheres formulation F1 –F6
(Higuchi matrix)
Stability Studies at Accelerated Conditions: Optimized formulation were packed in glass vials sealed with aluminum foil and rubber cap and
kept for 3 months at 40±5oC and 75% RH in stability
chamber. At the end of studies, microspheres were evaluated for in- vitro
drug release and drug content.
The result of stability studies
shown in table 7.15
Table 7. Stability Analysis
during Accelerated Conditions
|
Months
|
40 ± 5 0C, 75 ± 5% RH
(FORMULATION F6)
|
|
|
% Drug content
|
% Drug Release
|
|
0
|
77.9
|
87.13
|
|
3
|
76.39
|
86.48
|
|
6
|
75.95
|
85.59
|
CONCLUSION:
In the present research
work we developed floating microspheres of Curcumin. The drug identification
tests were carried out M.P.
determination, FT-IR, U.V. visible spectrophotometric
studies and the results indicated that the
drug was pure Curcumin. The compatibility between the drug and excipients was studied by FT-IR and there was no interaction between the drug and
excipients. The λmax of curcumin drug was found to be 426nm and
430.4nm in
phosphate buffer pH 7.4 and HCl buffer pH 1.2.
Floating microspheres of Curcumin were successfully formulated by solvent evaporation technique. The formulated microspheres were optimized
on the basis of
%drug release,
% entrapment efficiency and % buoyancy. The optimized formulation (F6) showed 87.13
% drug
release. It was observed that % drug release was increased as polymer (HPMC, EC) conc. increased, drug entrapment efficiency was increased as
polymer Eudragit RS100 conc.
increase and buoyancy also increased as Hydroxypropyl methyl cellulose and ethyl cellulose
(HPMC, EC) conc. increased. FTIR indicated there was no interaction between drug and polymer.
The in-vitro drug release
after 12 hrs was 72.12- 87.13%. The in-vitro drug release was found controlled during the period of analysis.
The release pattern
followed the Higuchi
model. Therefore, such dosage form is able to delay the release
and improve bioavailability and suitable for sustained
release.
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Received on 26.08.2020 Modified on
04.11.2020
Accepted on 08.12.2020 ©
RJPT All right reserved
Research J. Pharm.
and Tech. 2021; 14(10):5202-5206.
DOI: 10.52711/0974-360X.2021.00905