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Basavaraj et al.
Research Article
Central Research Laboratory, M. S. Ramaiah Medical College and Hospitals, MSRIT Post,
Bengaluru- 560 054, India.
Article Received on
12 October 2014,
Revised on 06 Nov 2014,
Accepted on 26 Nov 2014
ABSTRACT
Catechin is known for its diverse health benefits and poor
bioavailability. In the present work catechin rich extract (CRE) has
been chosen to develop sustained released nanoparticlesby solvent
evaporation technique for enhancing bioavailability. Eudragit L 100 is
*Correspondence for
Author
Department of
Pharmaceutics, M. S.
Ramaiah College of
results indicated that, nanotablets had good hardness and flow properties. The results of in
vitro release study for nanotablet showed highest drug release of 94.43 % at pH 6.8 (NF1)
and lowest of 62.20 % was observed for NF3 at pH 7.4.The in vitrorelease data of
nanoformulations showed highest correlation for Higuchi matrix, First orderand KorsmeyerPeppas,indicating that the drug release occurred via non-fickian diffusion. Thus, prepared
sustained release nanotablets with enhanced bioavailability proved to be a potential oral drug
delivery system and based on the results its worth considering it for future work.
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The potential sources of catechin include apples, oranges, pears, black grapes,
blackberries, cherries, raspberries, red wine and dark chocolate. Acacia catechu is one of the
richest sources of catechin and most widely used commercially.
Flavanoids have multitude therapeutic effects due to their possession of various biochemical
activities involved in inhibiting many enzymatic pathways and enzymes such as aldose
reductase, cyclooxygenase, xanthine oxidase, lipooxygenase and phosphodiesterase
[3]
[7]
suggested that high quantity of oral dosage of catechin is required to achieve maximum
plasma concentration, which accounts to 100 folds more than intravenous dosage. Besides
higher dosage, slow rate of absorption and rapid elimination from systemic circulation was
observed. [8] There are very few clinical studies carried out on humans, the very reason being
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its very low bioavailability which might be due to rapid elimination from liver by biliary
excretion [9] when administered in vivo.
[10]
prominent in most of the in vivo research works, but the reason for this is still not clear and
based on the existing literature, there are minimum efforts to address this issue.
Hence, the existing problem of low bioavailability, slow absorption and high first pass effect
necessitates the need to develop strategies that minimizes the dosage of catechin to achieve
maximum therapeutic activity which is a result of high absorption and higher bioavailability.
It is thus essential to make the molecule reach cells effectively and make it stay in cells for
sufficient time to execute therapeutic activity.
Several plant based bioactive compounds are formulated to overcome with these
shortcomings and drawbacks and there are several strategies involving very low quantity of
the natural plant based products to improve the above said limitations have a wide scope in
the research field. Most of the recent studies employ nanotechnology approaches to improve
the solubility, bioavailability and bioefficacy because it allows the use of biodegradable, nontoxic nanoparticles having higher surface to volume ratio to attach or encapsulate natural
plant products.
[11]
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the scanning range of 400 4000 cm-1using FT-IR spectrophotometer (FT-IR 8400 S,
Shimadzu, Japan). [12]
Development of Nanoformulation
Nanoformulations were developed by emulsion solvent evaporation technique
[13]
with some
modifications.CRE and Eudragit L 100 were finely triturated manually using a pestle and
mortar to reduce the size to nano-size. CRE and polymer in the ratios of 1:1, 1:2 and 1:3 were
dissolved separately in 15 ml of methanol. These solutions were sonicated for 30 min using
an ultrasonicator(PCI, Mumbai, India) following which were filtered separately using a
whattmans filter paper no 44 and mixed thoroughly using an electric stirrer (REMI
Instruments, India) at 3000 rpm for 20 min. 5 mg of Sodium Lauryl Sulphate (SLS) was
added to the solution. After the addition of SLS, 10 mg/ml aqueous solution of lactose
monohydrate was added and continuously stirred. The obtained solution was dried in hot air
oven (Tempo Instruments, Mumbai, India) maintained at 40 C 5 C for 8 hours.
Determination of Surface Morphology and Particle Size by Scanning Electron
Microscopy
The surface morphology and particle size of the nanoparticles was determined by Scanning
electron microscopy (SEM) (Zeiss Ultra 55, Germany).
[14]
firstly attached to a small piece of electro-conductive silicon chip, then sputter-coated with
gold using a vacuum sputter coater.
X-Ray Diffraction Studies
Physical nature of the samples was determined by X-Ray Diffractor (XRD) (Rigaku Smart
Lab, Japan). The Cu KL radiation was generated at 20 mA and 40 kV with the power of 1.2
kW. Diffraction patterns recorded the X-ray intensity as a function of 2 angle covering from
0 to 60.0. The scanning rate was 10/min. The samples characterized by XRD were CRE,
Eudragit L 100 (polymer), physical mixture of CRE and Eudragit L 100, NF1, NF2 and NF3
tablets. [15]
Differential Scanning Calorimetry Analysis
The successful formulation of a stable and effective dosage form depends on the careful
selection of the excipients, which are added to facilitate administration, promote the
consistent release and bioavailability of the drug and protect it from degradation. Differential
Scanning Calorimetry (DSC)(Mettler7, Japan) was used to investigate and predict any
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X 100
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[20]
The
nanotablets were packed in aluminium foil and then sealed with self-sealed cover. At
specified intervals of time, the samples were withdrawn and evaluated for their physical
(colour, shape and hardness) and chemical parameters (drug content and in vitro drug
release).
Statistical Analysis
All values were obtained by three independent biological replicates (n=3). The results are
represented as mean SD. Statistical analysis of in vitro drug release was performed by t
test to compare the different groups.
RESULTS AND DISCUSSIONS
The objective of the present study was to develop a pharmacologically efficient
nanoformulation of CRE. A pH-sensitive polymer Eudragit L 100 was used for the purpose
of sustained release and nanoformulation was developed using emulsion solvent evaporation
technique. The nanoformulations were further converted into convenient oral solid dosage
form such as nanotablets. Various parameters such as percentage yield, drug entrapment
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Characteristic
Frequency range
Observed
-1
functional group
(cm )
Frequency (cm-1)
1
OH stretching
3650-3590
3579
2
C-H stretch (CH3)
3000-2840
2883
3
C=C
1667-1640
1620
4
C-C stretch
1200-800
1188
5
C-O stretch
1270-1000
1251
FT-IR study was carried out by KBr disc method using Kubelka Munk function
The IR spectra of physical CRE-polymer blend (Fig. 1) showed neither significant shift nor
IR peaks disappearance of characteristic peaks when compared with IR spectrum of pure
sample suggesting that there was no physical interaction between CRE and polymer (Table
1). Hence the pure drug extract was stable without undergoing any physical changes up on it
to converting it to nanoformulation.
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(a)
(b)
(c)
Figure 1. FT-IR spectra for analysis of drug and polymer compatibility. IR spectra of
(a) CRE, (b) Eudragit L 100 and (c) physical mixture of CRE and Eudragit L 100
obtained by KBr disc method. Here drug refers to catechin (present in CRE) and
polymer refers to Eudragit L 100
Development of Nanoformulation
Nanoformulations were developed by a simple and cost effective method i.e., emulsion
solvent evaporation technique using an enteric and biodegradable polymer Eudragit L 100.
Eudragit L 100 was chosen as a polymer to obtain a sustained release of the drug and to target
the nanoformulation to colon as the polymer has a characteristic to get solubilized in alkaline
pH and has an advantage of sustained release profile. CRE and polymer in the ratios of 1:1,
1:2 and 1:3 were prepared and evaluated as NF1, NF2 and NF3, respectively throughout the
study. Other ingredient SLS was used as a detergent in small quantity to improve dissolution
rate and lactose was used as a diluent.
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(a)
(b)
Figure 2. SEM image of CRE nanoformulation obtained by drop coating method SEM
image (a) showing surface morphology (b) measuring the particle size
X-Ray Diffraction Studies : The XRD study was performed to investigate the physical
nature the samples. The XRD patterns of CRE (pure drug extract), Eudragit L 100 (polymer),
physical mixture of CRE and Eudragit L 100, NF1, NF2 and NF3 nanotablets were shown in
Figure 3. The physical mixture was prepared by mixing CRE and Eudragit L 100 directly in
the ratio of 1:1.
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Figure 3. XRD pattern of (a) CRE, (b) Eudragit L 100, (c) physical mixture of CRE and
Eudragit L 100, (d) NF1 tablet, (e) NF2 tablet and (f) NF3 tablet obtained by X-ray
intensity covering 2 angle from 0 to 60.0
As shown in Figure 3, It could be seen that the pattern of the physical mixture was simply a
superimposition of the patterns of the two raw materials showing both crystalline peak
representing the drug and amorphous nature of the polymer indicating that the crystalinity of
the drug was not changed by just blending it with polymer, while the XRD patterns of
nanoformulations showed amorphous nature. Nanoformulation process changed the
crystalline nature of the drug by totally encapsulating the drug inside the amorphous
polymeric matrix which can be evidenced from the XRD patterns of NF1, NF2 and NF3
nanotablets (Fig. 3). Amorphous nature increases the bioavailability of the drug encapsulated
in nanoformulations13. Thus, it can be concluded that the drugs bioavailability can be
enhanced to a great extent by nanoformulation of the drug using an amorphous polymer
Eudragit L100 by solvent evaporation technique.
Differential Scanning Calorimetry Analysis
DSC study was carried out to investigate and predict any physico chemical interactions
between components in a nanoformulation by thermal analysis. Figure 4 depicted the DSC
thermograms of CRE, Eudragit L 100, physical mixture of CRE and Eudragit L 100, NF1,
NF2 and NF3 nanotablets, respectively. Each of these indicates the thermal behaviour pattern
of the pure drug, polymer and drug polymer blend.
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Figure 4. DSC thermogram of (a) CRE, (b) Eudragit L 100, (c) physical mixture of CRE
and Eudragit L 100, (d) NF1 tablet, (e) NF2 tablet and (f) NF3 tablet obtained by
heating the samples from 30 C to 300 C at a rate of 10 C/min under nitrogen
atmosphere
DSC curve of CRE exhibited sharp endothermic peaks indicating its crystalline nature at
112.92 C and 108.48 C which corresponds to the lowered melting point of catechin (drug).
Since the sample of drug is a catechin rich extract which contains other minor plant
ingredients apart from catechin which is a major phenolic compound it shows decrease in
melting point. Eudragit L 100 showed a characteristic peak at 229.04 C which corresponds
to the melting point of the polymer. The CRE-polymer blend showed endothermic peaks at
105.85 C and 223.35 C for drug and polymer, respectively (Fig. 4). The presence of
endothermic signals in the physical mixture confirmed that CRE crystals still exist at physical
mixture. [21]
Figure 4 represents DSC thermograms of standardized nanotablets. NF1 showed a broad
endothermic peak at 240.38 C which corresponds to the melting point of the polymer.
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Similarly, NF2 and NF3 showed broad endothermic peaks at 241.56 C and 241.76 C,
respectively which corresponds to the melting point of polymer. In all the DSC thermograms
of nanotablets there was a small and broad endothermic peak observed at around 108 C
which corresponds to the melting point of the drug and confirms that there is a phase
transition of the drug from crystalline to amorphous state due to the disappearance of sharp
endothermic peak as observed in the DSC thermogram of pure CRE which was now observed
as broad endothermic peak as seen in the DSC thermograms of nanotablets. The broad curves
observed in the respective thermograms of NF1, NF2 and NF3 indicate the complete
encapsulation of CRE within the polymer. The absence of the sharp melting point peak for
the catechin might be attributed to its amorphous nature.
Evaluation of Standardized Nanoformulations
Parameters such as percentage yield and drug entrapment were evaluated and the results are
shown in Table 2. Percentage yield of NF1, NF2 and NF3 was found to be 79 0.86 %,
85.31 0.39 % and 91.12 0.44 %, respectively. Drug entrapment efficiency of NF1, NF2
and NF3 nanotablets was found to be 32.13 0.34 mg, 25.51 0.69 mg and 18.77 0.72 mg,
respectively. Percentage yield is directly proportional to polymer ratio whereas, drug
entrapment efficiency is inversely proportional to polymer concentration. As the polymer
concentration increased the drug entrapment efficiency decreased due to lower concentration
of drug in nanoformulation.
Evaluation of Pre-compression Parameters for Standardized Nanotablets
The standardized nanotablets were evaluated for the various pre-compression parameters.
Micromeritic studies such as bulk density, bulkiness, tapped density, Carrs index, and
Hausners ratios were determined for all the nanoformulations. The values range for Bulk
density was 0.176 0.188 g/cc, Bulkiness - 5.3195.682, Tapped density - 0.198-0.214 g/cc,
Carrs index -10.84 % 12.15 %, Hausners ratio 1.121-1.138 (Table 2). All the parameters
were within the acceptable limits for powder blend having good flow properties while
compressing the nanotablets.
Evaluation of Post Compression Parameters for Standardized Nanotablets
Weight variation study was carried out using 20 nanotablets from each nanoformulation and
no significant changes in weights were observed between average weight and individual
weights and the weight variation of the nanotablets was well within the limits of the weight
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variation test (Table 2). Hardness of the nanoformulation tablets plays an important role, which is critical for dissolution and stability of the
nanoformulation. The required hardness of the tablets was produced to ensure good handling quality. The hardness of the nanotablets ranged
between 9 to 11 kg/cm2.
Thickness of each individual nanotablet was 6 mm, respectively (Table 2). Increase in thickness induces hardness of the nanotablets. Thus,
thickness of the nanotablets was increased to get a required hardness. The percentage friability of the prepared nanotablets was well within the
acceptable limits (<1 %).
Table 2 . Pre-compression and post compression results of standardized nanotablets
Nanoformula
tion
code
NF1
NF2
NF3
CRE:
Percentage
Drug
Eudragit
yield
entrapment
L 100
efficiency
ratio
(mg)
(%)
Bulk
density
(g/cc)
Bulkiness
Tapped
density
(g/cc)
Carrs
index (%)
Hausners
ratio
Weight
variation
(mg)
1:1
790.86
32.130.34 0.1880.34 5.3190.38 0.2140.38 12.150.37 1.1380.33 0.2980.88
90.22
1:2
85.310.39 25.510.69 0.1810.57 5.5250.53 0.2030.59 10.840.52 1.1210.54 0.2991.31 100.14
1:3
91.120.44 18.770.72 0.1760.43 5.6820.41 0.1980.51 11.110.58 1.1250.51 0.2991.74 110.46
Here NF refers to nanoformulation; drug entrapment efficiency was calculated at pH 6.8 using phosphate buffer; here bulk density,
(mm)
60.12
0.10.57
60.28
0.10.87
60.17
0.30.84
bulkiness,
tapped density, carrs index and hausners ratio are pre-compression parameters whereas, weight variation, hardness, thickness and friability are
post compression parameters; carrs index and hausners ratio are indicative of flow properties which inturn is calculated based on the values of
bulk density and tapped density; weight variation was conducted for 20 nanotablets whereas, friability test was carried out with 10 nanotablets;
hardness and thickness was adjusted to obtain sufficient hardness and lesser thickness; (mean S.D., n=3)
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(a)
(b)
(c)
Figure 5. In vitro dissolution studies of nanotablets carried out at pH 6.8 and pH 7.4
using phosphate buffers by USP II dissolution apparatus for 12 hours by withdrawing 3
ml of the sample every hour. In vitro drug release graph of (a) NF1 tablet, (b) NF2 tablet
and (c) NF3 tablet (mean S.D., n=3)
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From Figure 5, it was observed that NF1 had highest percentage drug release followed by
NF2 and NF3 nanotablets showing 94.43 %, 79.40 % and 66.17 %, respectively. This
indicates that on increasing the polymer concentration the drug release was found to be
decreased due to the increase in the thickness of the outer surface coated by Eudragit L 100.
The increased drug release was recorded for NF1 due to low particle size with greater surface
area and thinner outer polymer coating. Thus in vitro percentage drug release was found to be
inversely proportional to polymer concentration at both pH 6.8 and pH 7.4.
NF1 tablet showed a low quality of sustained release pattern at both pH 6.8 and pH 7.4 (Fig.
5a). This might be due to poor or thinner layer of polymer coating which fails to release the
drug in the sustained manner. The poor and thinner polymer coating leads to greater chances
for drug leakage from the polymeric matrix. Whereas, with increase in the thickness of the
polymeric coating, the time taken for dissolution or drug release increases (Fig. 5b and 5c). In
this process initially each layer of the polymeric matrix is dissolved one by one followed by
the release of the drug in the substantial manner thus increasing the time taken for the
complete release of the drug.
Also, pH 6.8 medium (phosphate buffer) showed higher percentage drug release compared to
pH 7.4 medium (phosphate buffer) for all nanotablets due to higher solubility and dissolution
rate of Eudragit L 100 at pH 6.8 (Fig. 5a, 5b and 5c).
Drug Release Kinetics and Mechanism of Drug Release
In order to establish the mechanism of drug release at pH 6.8 and pH 7.4, the in vitro
dissolution data were fitted to Zero-order, Higuchi Matrix, KorsmeyerPeppas, First-order
and HixonCrowell models (Table 3 and 4). It was observed that highest correlation was
found for Higuchi matrix, First order and Korsmeyer- Peppas, which indicated that the drug
release occurred via non-fickian diffusion mechanism. The mechanism of drug release and
the best fit model for all three nanotablets at both pH 6.8 and pH 7.4 is shown in Table 5
Statistical analysis of in vitro dissolution data for all nanotablets was done and it was
observed that, NF1 tablet (at pH 6.8) and NF3 tablet (at pH 7.4) gave the best fit with the first
order kinetic model unlike other nanotablets. This model is applicable to study the release
profiles of pharmaceutical dosage forms such as those containing water-soluble drugs in
porous matrices. Here catechin (present in CRE) is a water soluble compound used in our
study and Eudragit L 100 is considered as a porous matrix coating the catechin molecules.
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All the nanotablets except NF3 at pH 7.4 showed the n value between 0.5 to 1, signifying
non - fickian diffusion at both pH 6.8 and pH 7.4 (Table 5). This means the drug diffuses
partly through the swollen matrix and partly by the gradually expanding hydrated matrix with
increasing diffusion path length. Case II Super transport was observed for NF3 nanotablet at
pH 7.4, in which the drug release mechanism is mainly by swelling behaviour of polymeric
matrix and non- fickian diffusion.
Table 3. Drug release kinetics of final standardized nanotablets at pH 6.8
KINETIC MODELS
Nanoformulation
code
Zero - order
First order
Korsmeyer Higuchi plot
Hixon - Crowell
plot
plot
Peppas
r2
K
r2
K
r2
K
r2
K
r2
K
NF1 tablet
0.8795 9.4381 0.9917 0.2070 0.9748 27.7132 0.9684 17.0463 0.9719 0.0512
T-test
6.130 (Passes) 25.622 (Passes) 14.484 (Passes) 12.872 (Passes) 13.706 (Passes)
NF2 tablet
0.8647 7.5318 0.9747 -0.1241 0.9905 22.1813 0.9827 18.2005 0.9505 -0.0346
T-test
5.711 (Passes) 14.459 (Passes) 23.940 (Passes) 17.623 (Passes) 10.149 (Passes)
NF3 tablet
0.9924 4.3719 0.9986 -0.0561 0.9560 12.5112 0.9988 6.0303 0.9986 -0.0172
T-test
26.702 (Passes) 62.855 (Passes) 10.807 (Passes) 67.678 (Passes) 62.908 (Passes)
Note - Bold value represents the highest r2 value of the best fit model corresponding to
the nanoformulation where, r2 is co-relation coefficient and K is release constant
Table 4. Drug release kinetics of final standardized nanotablets at pH 7.4
KINETIC MODELS
Nanoformulation
code
Zero - order
First order
Korsmeyer Higuchi plot
Hixon - Crowell
plot
plot
Peppas
r2
K
r2
K
r2
K
r2
K
r2
K
NF1 tablet
0.9265 9.8985 0.8766 -0.2217 0.9372 29.6846 0.9248 28.7123 0.8147 0.0546
T-test
2.612 (Passes) 6.042 (Passes) 8.911 (Passes) 8.061 (Passes) 4.659 (Passes)
NF2 tablet
0.8836 6.8333 0.9799 -0.1051 0.9977 20.0839 0.9976 18.3595 0.9585 -0.0301
T-test
6.258 (Passes) 16.281 (Passes) 49.222 (Passes) 48.165 (Passes) 11.150 (Passes)
NF3 tablet
0.9737 6.0425 0.9953 -0.0880 0.9553 17.3664 0.9775 5.4371 0.9914 -0.0257
T-test
14.162 (Passes) 34.144 (Passes) 10.711 (Passes) 15.362 (Passes) 25.140 (Passes)
Note - Bold value represents the highest r2 value of the best fit model corresponding to the
nanoformulation where, r2 is co-relation coefficient and K is release constant
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Table 5. Mechanism of drug release and best fit model shown by final standardized
nanotablets
Nanoformulation
code
Medium
/Buffer
NF1 tablet
NF2 tablet
NF3 tablet
pH 6.8
NF1 tablet
NF2 tablet
n value
Mechanism of drug
release
1st order
0.7481
Matrix
Korsmeyer-Peppas
0.6029
0.8539
Korsmeyer-Peppas
0.5248
Non-Fickian Diffusion
Korsmeyer-Peppas
0.5454
pH 7.4
NF3 tablet
1st order
1.0770
Case II Super transport
Comparison of mechanism of drug release at both pH 6.8 and pH 7.4. Best fit model was
decided by the highest r2 value and mechanism of drug release was determined based on n
value where, n = diffusional release exponent indicative of the mechanism of drug release for
drug dissolution. Here if n > 0.5, it is considered as non-fickian diffusion and if n > 1, it is
considered as case II super transport (mean S.D., n=3)
Stability Studies: Accelerated stability studies were performed for all final standardized
nanotablets as per standard ICH guidelines for 6 months. At an interval of 2,4 and 6 months
the samples were evaluated for physical appearance (colour, shape and hardness), drug
entrapment efficiency and in vitro drug release tests were conducted. The accelerated stability
studies data is shown in Table 6.
Table 6: Accelerated stability studies data of nanotablets
Nanoformula
tion
code
Physical appearance
2nd
4th
6th
mont mont month
h
h
tablet
0.23
0.25
0.57
0.96
73.56
NF2
24.09
79.40 77.69
++
++
+
25.51 0.69 24.14 0.39
tablet
0.75
0.37
0.08
0.84
60.56
NF3
17.43
66.17 64.2
++
++
+
18.77 0.72 17.52 0.53
tablet
0.72
0.38
0.79
0.89
Note - ++ refers to same as 0 day, + refers to reduced, physical appearance refers to colour,
shape and hardness. Both drug entrapment efficiency and in vitro drug release was
determined for final standardized nanotablets at pH 6.8 using phosphate buffer for a period of
6 months with data collected every 2 month interval (mean S.D., n=3)
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There was no appreciable change in the physical appearance and drug entrapment efficiency
of the nanotablets was decreased by 1-2 % and in vitro drug release of the nano tablet was
reduced by 3-6 % after 6 months (Table 6). In vitro drug release studies were carried out at
pH 6.8 due to higher solubility of Eudragit L 100 in this buffer and efficient dissolution rates
as compared to pH 7.4 (Fig. 5).
CONCLUSION
In the present work, nanoformulation of CRE using Eudragit L 100 was developed by
emulsion solvent evaporation technique and converted into nanotablets. FT-IR analysis
showed that the CRE was physically stable and compatible with the polymer. SEM images
showed uniformly distributed nanoparticles with spherical shape and smaller particles in the
size range of 50 nm to 150 nm. The XRD and DSC analyses revealed that CRE was
completely embedded into Eudragit L 100 and existed in an amorphous state in the
nanoformulations. Evaluation results of pre-compression and post-compression parameters
indicated that, the nanotablets had good hardness, good flow properties and were of good
quality based on the valueswhich were within the specified limits. Evaluation of other
parameters indicated that percentage yield is directly proportional to polymer concentration
whereas, drug entrapment efficiency and in vitro drug release rates is inversely proportional
to polymer concentration. It was concluded that, in vitro release of drug can be sustained with
high concentration of the polymer with maximum solubility and higher dissolution rate
observed at pH 6.8 than at pH 7.4. The statistical analysis of the in vitro dissolution data of
nanotabletsat pH 6.8 and 7.4 using phosphate buffers indicated that the highest correlation
was found for Korsmeyer- Peppas and Higuchi matrix which indicated that the drug release
occurred mainly via non-fickiandiffusion indicating the mechanism of drug release was found
to be a mixture of diffusion and swelling. These results collectively indicate that the
development of nanotablets proved to be a potential oral drug delivery system in this era of
sustained release nanoformulations known for the purpose of better patient compliance and
enhanced bioavailability. Thus, it is worth to consider further studies on catechin
nanoformulations for pilot studies, in vivo studies and for clinical applications.
ACKNOWLEDGMENT
Authors would like to acknowledge the support and motivation from Gokula Education
foundation and its institutions, specifically, Central Research Lab of M. S. Ramaiah Medical
College and Teaching Hospital, M. S. Ramaiah Institute of Technology and M. S. Ramaiah
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College of Pharmacy. Monika P. would like to acknowledge the support of Vision Group of
Science and Technology, Department of Science and Technology, Government of Karnataka
for financial support for the project through Technology Related Innovative Projects (TRIP
2013-14). Authors would like to thank Dr. Rajendran, Green Chem Herbal Pvt. Ltd.,
Bangalore, for providing Catechin Rich Extract for the study.
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