Journal of Young Pharmacists 5 (2013) 167e172

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Journal of Young Pharmacists

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Original article

Design and in vitro/in vivo evaluation of extended release matrix

tablets of nateglinide
Pushkar R. Sharma, Shaila A. Lewis*
Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India

a r t i c l e i n f o a b s t r a c t

Article history: Aim: Nateglinide is a quick acting anti-diabetic medication whose potent activity lasts for a short
Received 13 July 2013 duration. One of the dangerous side effects of nateglinide administration is rapid hypoglycemia, a con-
Accepted 16 November 2013 dition that needs to be monitored carefully to prevent unnecessary fatalities. The aim of the study was to
Available online 11 December 2013
develop a longer lasting and slower releasing formulation of nateglinide that could be administered just
once daily.
Keywords:
Methods: Matrix tablets of nateglinide were prepared in combination with the polymers hydrox-
Hydroxypropylmethylcellulose
ypropylmethylcellulose (HPMC), eudragits, ethyl cellulose and polyethylene oxide and the formulated
Matrix tablets
Nateglinide
drug release patterns were evaluated using in vitro and in vivo studies.
Sustained release Conclusion: Of the seventeen formulated matrix tablets tested, only one formulation labelled HA-2 that
contained 15% HPMC K4M demonstrated release profile we had aimed for. Further, swelling studies and
scanning electron microscopic analysis confirmed the drug release mechanism of HA-2. The optimized
formulation HA-2 was found to be stable at accelerated storage conditions for 3 months with respect to
drug content and physical appearance. Mathematical analysis of the release kinetics of HA-2 indicated a
coupling of diffusion and erosion mechanisms. In-vitro release studies and pharmacokinetic in vivo
studies of HA-2 in rabbits confirmed the sustained drug release profile we had aimed for.
Copyright Ó 2013, InPharm Association, Published by Reed Elsevier India Pvt. Ltd. All rights reserved.

1. Introduction therefore enhance the therapeutic effects of nateglinide. Oral drug

delivery system is the most accepted route for drug delivery, its
Nateglinide, a D-phenylalanine derivative is an anti-diabetic benefits being easy administration and flexibility in dosage form
drug that is quick but short acting and controls postprandial design.5 There are several approaches for retarding drug release
blood glucose (PBG) effectively. Nateglinide belongs to the megli- from dosage form.6 Matrix tablets composed of drug and release
tinide class of anti-diabetic drugs used to treat type 2 diabetes by retarding polymers offer the simplest approach in designing a
stimulation of pancreatic beta cells that results in the release of sustained release system.7 The goals of the present study were to
proinsulin. Nateglinide immediate-release tablets are administered develop a once-daily sustained-release dosage form of nateglinide
twice or thrice a day.1,2 A sustained release formulation of nate- in tablet form using different polymers in varying proportions and
glinide would enable control of both PBG and FBG (fasting blood to determine which combination best fit the desired release profile.
glucose) with the novel advantage of improving patient compliance The prepared tablets were evaluated with respect to physico-
by decreasing multiple drug administration and minimizing side chemical parameters including in-vitro drug release, stability, sur-
effects such as hypoglycemia and hepatic impairment.3,4 The usual face morphology and in vivo pharmacokinetics in rabbits.
dose of nateglinide administered is three times a day. By using a
higher 24-hr dose of nateglinide in a single matrix tablet, the drug 2. Experimental materials
is released at a slower rate thus preventing extremely high and low
concentrations of nateglinide in plasma. This helps to avoid the side Nateglinide, hydroxypropylmethylcellulose (K4M, K15M and
effects of hypoglycemia and hepatic impairment associated with K100M) and polyethylene oxide N80F were obtained from Lupin
high concentration and the lack of drug activity when its concen- Laboratories Ltd, Pune, India. Eudragit RS 100 and Eudragit RL 100
tration in plasma is low. A slower release formulation would were obtained from Vikram Thermolab Ahmedabad, India. Mag-
nesium stearate, talc, lactose, hydrochloric acid and methanol, were
purchased from S.D. Fine-Chem Limited, Merck, Loba Chemie
* Corresponding author. Tel.: þ91 820 29224842. Mumbai, India respectively. All other chemicals used were of
E-mail address: [email protected] (S.A. Lewis). analytical grade.

0975-1483/$ e see front matter Copyright Ó 2013, InPharm Association, Published by Reed Elsevier India Pvt. Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jyp.2013.11.003
168 P.R. Sharma, S.A. Lewis / Journal of Young Pharmacists 5 (2013) 167e172

3. Experimental methods paddle dissolution apparatus (Electrolab, TDL-08L, Mumbai, India)

run at 50 rpm. The temperature of the medium was maintained at
3.1. Preparation of nateglinide tablets 37  0.5  C. Samples (5 ml) were withdrawn at predetermined
intervals and read at 210 nm using a spectrophotometer.
Tablets were prepared by direct compression. The investigated
formulations are shown in Table 1. The respective powders (drug, 3.2.4. Determination of swelling:eroding behaviour
polymers and excipients) were passed through 60# sieve. The The swelling-eroding behaviour of matrix tablets was deter-
powders were blended thoroughly using a mortar and pestle after mined using the method described by Al-Taani and Tashoush.11 One
which 500 mg of each mixture were weighed and manually fed into matrix tablet was weighed and placed in a dissolution apparatus.
the die of a single punch tableting machine (Rimix tableting ma- The swollen weights of tablets were calculated after placing the
chine, Gujarat, India) equipped with 10.5 mm flat punches. mixture in a vacuum oven at 40  C for 48 h. The following formula
was used for calculating % swelling
3.1.1. Conventional tablets for rabbits
Doses for rabbits were calculated using following formula of % Swelling ¼ S=R  100
Gosh.8,9 According to the dose calculated for rabbits (48.30 mg), the
where, S is the weight of the matrix after swelling and R is the
same formula was proportionately reduced and compressed into
weight of the eroded matrix.
tablets using 2.5 mm flat punch.
% Erosion ¼ T  R=T  100%
Rabbit dose ¼ 0:07  human dose
where, R is the weight of the eroded matrix and T is the initial
where, human dose ¼ 345 mg, rabbit weight ¼ 2 kg and rabbit
weight of the matrix.
dose ¼ 48.300 mg. The rabbit dose was found to be 1.5 times the
observed value.
3.2.5. Scanning electron microscopy
A SEM study of the optimized formulation was carried out
3.2. Evaluation of prepared tablets confirming drug release mechanism. SEM photograph of the matrix
tablets were taken at 0 h, 2 h, 12 h and 24 h of dissolution.
3.2.1. Thickness and diameter
The prepared matrix tablets were evaluated for thickness, 3.2.6. Stability
hardness, friability and drug content. Thicknesses of randomly The tablets were kept under accelerated storage conditions
selected tablets were determined using screw gauge. Hardness of 40  2  C and 75  5% relative humidity according to ICH guidelines
the tablets was determined using Monsanto Hardness tester. Fria- using a stability chamber (Thermolab, Mumbai) for a period of
bility of tablets was determined using Roche Friabilator according three months. The samples were withdrawn at predetermined time
to the official method IP.10 The values are expressed as the mean of intervals and evaluated for drug content and physical parameters.
three measurements (SD).
3.2.7. In vivo pharmacokinetic study
3.2.2. Drug content An in vivo pharmacokinetic study was conducted in accordance
For determination of drug content, tablets were crushed and with the ethical guidelines for investigations in laboratory animals
100 mg of powder was dissolved in 100 ml of methanol. The filtrate and approved by the Institutional Animal Ethics Committee (IAEC),
further diluted with phosphate buffer (pH 6.8) was analyzed spec- Manipal University (MU) No.IAEC/KMC/21/2011. All procedures and
trophotometrically (UVe1601PC, Shimadzu, Japan) at 210 nm. Drug care of the rabbits were in accordance with institutional guidelines
content was calculated using a standard curve generated using for animal use in research. Twelve Rabbits (New Zealand, White)
various concentrations of nateglinide in phosphate buffer (pH 6.8). weighing 2.30  0.12 kg (divided into two groups) were fasted
overnight. Tablets were administered orally via gastric intubation.
3.2.3. In vitro dissolution study The first group received conventional tablet while the second group
An in-vitro dissolution study of formulated matrix tablets was received optimized extended release tablet of nateglinide. Rabbits
carried out in 900 ml 0.5% sodium lauryl sulphate (SLS) in 0.01 N were held in rabbit restainers during blood sampling. Blood sam-
HCl, followed by 900 ml of Phosphate buffer (pH 6.8) with type II ples were collected from ear veins at predetermined intervals of

Table 1
Formulation of different batches of matrix tablets.

Ingredients (mg/tablet) Batch code

HA-1 HA-2 HA-3 HB-1 HB-2 HB-3 HC-1 EC-1 ES-1 ES-2 ES-3 EL-1 EL-2 EL-3 PO-1 PO-2 PO-3

Nateglinide 345 345 345 345 345 345 345 345 345 345 345 345 345 345 345 345 345
Lactose 45 70 95 45 70 95 45 45 45 70 95 45 70 95 45 70 95
HPMC K4M 100 75 50 ** ** ** ** ** ** ** ** ** ** ** ** ** **
HPMC K15M ** ** ** 100 75 50 ** ** ** ** ** ** ** ** ** ** **
HPMC K100M ** ** ** ** ** ** 100 ** ** ** ** ** ** ** ** ** **
Ethyl Cellulose ** ** ** ** ** ** ** 100 ** ** ** ** ** ** ** ** **
Eudragit RS-100 ** ** ** ** ** ** ** ** 100 75 50 ** ** ** ** ** **
Eudragit RL-100 ** ** ** ** ** ** ** ** ** ** ** 100 75 50 ** ** **
Polyethylene oxide N 80 F ** ** ** ** ** ** ** ** ** ** ** ** ** ** 100 75 50
Talc 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
Mag. Stearate 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5
Total Tab. Wt. 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500 500

** Indicates that ingredient is not included.

 P.R. Sharma, S.A. Lewis / Journal of Young Pharmacists 5 (2013) 167e172 169

0.5, 1, 2, 4, 8, 12 and 24 h post dose into heparinized tubes.12 Plasma Table 2

samples were obtained following centrifugation of blood at Release data of formulations.

3500  g for 5 min at 4  C and kept frozen at 70  C until analysis. Formulation % Release at 0.5 h % Release at 24 h

HA-1 7.31  1.23 91.14  1.98

3.2.8. Analysis of plasma nateglinide concentration using HPLC13 HB-1 3.39  1.67 85.28  2.56
A sensitive HPLC (HPLC-LC-2010C HT, Shimadzu, Japan) method HC-1 1.02  3.12 64.75  3.67
was used for the estimation of nateglinide in plasma. The mobile HA-2 9.35  5.23 96.62  4.10
HA-3 10.72  0.89 97.92  2.78
phase consisted of acetonitrile and phosphate buffer (pH 3) 50:50
HB-2 5.00  4.12 94.44  2.67
v/v. The column was C18 (250 cm  4.6 mm) Hypersil BDS, The HB-3 7.14  3.90 96.12  1.78
mobile phase was delivered at a flow rate of 1.0 ml/min, the ES-1 2.27  1.56 78.22  2.13
detection wavelength was 210 nm. All assays were performed at ES-2 4.24  2.67 90.39  2.94
ES-3 4.99  4.24 97.06  3.45
ambient temperature.
EL-1 0.50  0.98 77.45  1.45
EL-2 2.53  1.56 92.53  2.15
3.2.9. Preparation of sample solutions EL-3 2.77  3.12 94.34  4.67
Rabbit plasma (100 ml) were pipetted into centrifugal tubes, PO-1 3.93  0.98 78.43  3.44
10 ml of IS (gliclazide) 500 mgmL1 was added and vortexed for 10 s. PO-2 6.32  1.67 82.39  3.14
PO-3 7.56  2.13 90.30  3.23
Then 100 ml methanol and acetonitrile 100 ml were added and
vortexed for 30 s and centrifuged at 10000 rpm for 10 min at 4  C. All values are expressed as Mean  SE, n ¼ 3. HA-1 (HPMC K4M 20%), HA-2(HPMC
K4M 15%), HA-3(HPMC K4M 10%). HB-1 (HPMC K15M 20%) HB-2(HPMC K15M 15%)
The supernatant layer (200 ml) was separated out, 100 ml of mobile
HB-3 (HPMC K15M 10%). HC-1 (HPMC K100M 20%) ES-1-(Eudragit RS-100 20%), ES-
phase was added to make up the volume to 300 ml and then 50 ml 2-(Eudragit RS-100 15%), ES-3-(Eudragit RS-100 10%). EL-1-(Eudragit RL-100 20%),
was injected into HPLC system. EL-2-(Eudragit RL-100 15%), EL-3-(Eudragit RL-100 10%). PO-1 (polyethylene oxide
Pharmacokinetic analysis was performed by means of non- 20%), PO-2 (polyethylene oxide 15%), PO-3 (polyethylene oxide 10%).
compartmental pharmacokinetic data analysis software PK Solu-
tions 2.0 TM.
tablet formulations HA-1(HPMC K4M), HB-1(HPMC K15M) and HC-
1(HPMC K100M) released 7.31, 3.39 and 1.02% at the end of 0.5 h
4. Results
and 91.14%, 85.28% and 64.75% of nateglinide at the end of 24 h. The
release profile of HC-1 was retarded when compared to the for-
4.1. Evaluation of prepared tablets
mulations HA-1 and HB-1. Hence HA-I and HB-2 were selected for
the further studies.
The tablets exhibited uniform thickness and hardness. The
In formulations HA-1, HA-2 and HA-3 containing 20%, 15% and
friability and drug content were also within the acceptable limits.
10% HPMC K4M respectively, the percentage release was 7.31, 9.35
and 10.72% respectively at the end of 0.5 h and 91.14, 96.62 and
4.2. In vitro release profile
97.92% at the end of 24 h. In the cases of formulations HB-1, HB-2
and HB-3 containing 20%, 15% and 10% HPMC K15M respectively,
Release parameters of the tablet formulations are summarized
the percentage releases were 3.93, 5.00 and 7.14% respectively at
in Fig. 1. Nateglinide release from the prepared tablets was slow,
the end of 0.5 h and 85.28, 94.44 and 96.12% at the end of 24 h.
spanning a period of 24 h and rested on the grade of the controlled
Release studies illustrate incomplete drug release with formulation
release polymer. The results of dissolution studies indicated that
HA-1 and with formulation HA-3 it was observed that tablet
HA-1, ES-1, EL-1, EC-1 and PO-1 released 7.31, 2.27, 0.50, 0.99 and
integrity was lost resulting in complete release within12 h.
3.93% of nateglinide at the end of 0.5 h; at 24 h, 91.14, 78.22, 77.45,
Since release of nateglinide with 15% of HPMC K15M and 10% of
60.40 and 78.43% of nateglinide was released. Since formulation
HPMC K15M were lower compared with same concentrations of
EC-I containing ethyl cellulose showed incomplete release in the
HPMC K4M, formulation HA-2 was selected for further studies.
24 h, further studies were discontinued.
For formulations ES-1, ES-2 and ES-3 containing 20%, 15% and
A study was undertaken to determine the release profile of
10% Eudragit RS-100, the percentage releases were 2.27, 4.24 and
nateglinide matrix tablets with different viscosity grades of HPMC
4.99% respectively at the end of 0.5 h and 78.22, 90.39 and 97.06% at
and thereby select a suitable polymer. HPMC K15M and HPMC
the end of 24 h (Table 2). For formulations EL-1, EL-2 and EL-3
K100M were selected for formulation and their release profile
compared with HPMC K4M matrix tablets. Results indicate that the

Fig. 1. Release profile of formulations containing different polymers. Fig. 2. Percentage swelling of optimized formulation HA-2.
170 P.R. Sharma, S.A. Lewis / Journal of Young Pharmacists 5 (2013) 167e172

Figs. 2 and 3 represent the percentage swelling and percentage

matrix erosion respectively as a function of time. The matrix tablets
underwent both swelling and erosion at the same time after
placement in the dissolution media. SEM study of the optimized
formulation taken at 0 h, 2 h, 12 h and 24 h of dissolution are shown
in Fig. 4.

4.3. In vivo pharmacokinetic study

The retention time of nateglinide and gliclazide was 11.5 and

7.55 min respectively (Fig. 5). The plasma concentrations of con-
ventional nateglinide and extended release formulation over time
are presented in Figs. 6 and 7 respectively. The pharmacokinetic
parameters of conventional nateglinide and extended release
formulation are presented in Table 3.
Fig. 3. Percentage erosion of optimized formulation HA-2.

4.4. Stability studies

which contain 20%, 15% and 10% Eudragit RL 100, the percentage
releases were 0.50, 2.53 and 2.77 respectively at the end of 0.5 h Accelerated stability studies conducted for the optimized batch
and 77.45, 92.53 and 94.34% at the end of 24 h (Table 2). These of nateglinide extended release matrix tablets (HA-2) showed no
results indicate that lower percentage of Eudragit exhibit satisfac- change in drug appearance and assay after storage at 40  C for 3
tory release over a period of 24 h. Eudragits were not considered for months. The drug content was 97% at the end of 90 days and
further studies since inadequate amount of nateglinide was appearance was unchanged indicating that the optimized formu-
released at 0.5 h. lation is fairly stable at accelerated storage condition.
Matrix tablets with the polymer polyethylene oxide, PO-1, PO-2
and PO-3, exhibited better release with reduction in polymer 5. Discussion
concentration. Percentage release found with 20%, 15% and 10%
polyoxyethylene were 78.43%, 82.39%, and 90.30% respectively; The results of dissolution studies indicate that release was
also, 10% polymer showed an initial release of 7.56% in 0.5 h influenced by the grade of control release polymer. Polymers ethyl
(Table 2) .The results indicate that 10% polyoxyethylene has po- cellulose, HPMC K100M, eudragits and polyethylene oxide had a
tential for extended release formulation and further trials are retarding effect compared to polymers HPMC K4M and HPMC
needed to assess this potential. Formulation HA-2 (15% HPMC K4M) K15M when used in same concentration. Hence further trials were
was selected for further studies. not undertaken with these polymers. When polymer concentration

Fig. 4. a and b SEM images of optimized formulation matrix tablet HA-2 at 0 and 2 h respectively. c and d SEM images of optimized formulation matrix tablet HA-2 at 12 and
24 h respectively.
 P.R. Sharma, S.A. Lewis / Journal of Young Pharmacists 5 (2013) 167e172 171

Fig. 5. Retention time of nateglinide and internal standard gliclazide.

is high drug release rates are too low. Once there is sufficient
polymer concentration in the matrix system a uniform barrier is
formed. This barrier protects the drug from releasing immediately
into the dissolution medium. Only formulation HA-2 followed the
desired release profile up to 24 h.
The matrix tablets underwent both swelling and erosion at the
same time after placement in the dissolution media. It has been
reported that constant release can be obtained in such type of
matrices.14 Constant release in such situations occurs because the
increase in diffusion path length due to swelling is compensated for
by continuous erosion of the matrix.15
SEM further confirmed both diffusion and erosion mechanisms
to be operative during drug release from the optimized formulation
(HA-2). Initially, tablet matrix showed swelling with pore forma-
tion that is clearly visible from SEM image. At the end of 12 h, the
matrix was intact and pores had formed through it. SEM images
also show the formation of gel structure indicating swelling and
Fig. 6. Plasma concentrationetime curve for conventional tablet.
pore formation on the tablet surface.
In case of Peppas model16; n values close to 0.64 indicate diffusion
as the mode of release. In case of Higuchi R2, the value was close to
unity indicating a linear response and clearly supporting the Peppas
model. HA-2 showed R2 value close to unity when zero order model
was applied which indicates good linearity and hence following zero
order release. Korsmeyer’s plot showed good linearity with regres-
sion value of 0.9914 and slope 0.6562 indicating that diffusion is the
dominant mechanism of drug release coupled with erosion.17
In case of conventional tablet, nateglinide was detectable in
blood within 30 min after its oral administration in rabbits. The
absorption was rapid with conventional tablets as indicated by low
tmax value (1.5 h) in comparison with HA-2 formulation which
exhibited delayed absorption as demonstrated by high tmax (4 h)
values. Cmax value of conventional tablet was high compared with
HA-2 (Table 3). In comparison, HA-2 formulation exhibited low
Fig. 7. Plasma concentrationetime curve for extended release tablet. elimination rate constant and high values of mean residential time
(MRT). The low area under the curve (AUC) was observed with
conventional tablets whereas the extended release formulation
showed high AUC values indicating increased bioavailability of the
Table 3 drug in the matrix tablet.
Pharmacokinetic parameters from the plasma concentrationetime curve (results The results of the in vivo bioavailability test indicate that drug
expressed are mean of six rabbits).
release from matrix tablet is controlled thereby providing pro-
Parameters Conventional tablet HA-2 longed drug delivery.
Cmax (ng/ml) 505.20  20.67 403.75  28.77
Tmax (h) 1.5  0.0 4.0  0.0
AUC0et (ng h/ml) 3039.1  215.98 4895.2  314.66 6. Conclusion
MRT (h) 3.5  2.67 14.3  3.59
Elimination rate 0.3649  0.09 0.08821  0.01 Extended release matrix tablets of nateglinide were prepared
constantKe (h1)
by direct compression. Various polymers in varying concentrations
172 P.R. Sharma, S.A. Lewis / Journal of Young Pharmacists 5 (2013) 167e172

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