DSpace at VNU: Physical properties and in vivo bioavailability in human volunteers of isradipine using controlled release matrix tablet containing self-emulsifying solid dispersion

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Contents lists available at SciVerse ScienceDirect

International Journal of Pharmaceutics
journal homepage: www.elsevier.com/locate/ijpharm

Pharmaceutical nanotechnology

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Physical properties and in vivo bioavailability in human volunteers of
isradipine using controlled release matrix tablet containing
self-emulsifying solid dispersion

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Q1

Phuong Ha-Lien Tran a,1 , Thao Truong-Dinh Tran a,∗ , Zong Zhu Piao b,1 , Toi Van Vo a ,
Jun Bom Park b , Jisung Lim c , Kyung Teak Oh d , Yun-Seok Rhee e , Beom-Jin Lee b,∗
a

International University, Vietnam National University, Ho Chi Minh City, Viet Nam
College of Pharmacy, Ajou University, Suwon 443-749, Republic of Korea
c
College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea
d
College of Pharmacy, Chung-Ang University, Seoul 155-756, Republic of Korea
e
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea
b

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a r t i c l e

i n f o

a b s t r a c t

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Article history:
Received 11 November 2012
Received in revised form 24 February 2013
Accepted 8 April 2013
Available online xxx

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Keywords:
Self-emulsifying solid dispersion
Enhanced dissolution
Controlled release tablet
Physicochemical properties
In vivo bioavailability

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1. Introduction

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Poorly water-soluble drug with a short half-life such as isradipine (IDP) offer challenges in the controlled
release formulation because of low dissolution rate and poor bioavailability. Self-emulsifying solid dispersions (SESD) of IDP consisted of surfactant and fatty acid in poloxamer 407 (POX 407) as a carrier and
were manufactured by the melting method. Then, controlled release HPMC matrix tablet containing SESD
were prepared via direct compression. The dissolution behaviors and in vivo bioavailability of controlled
release matrix tablet in healthy human volunteers were investigated. The physical properties of solid
dispersion were also examined using differential scanning calorimetry (DSC), powder X-ray diffraction
(PXRD) and scanning electron microscopy (SEM). It was shown that structure of IDP was amorphous in
the solid dispersion. The dissolution rate of IDP from SESD was markedly enhanced because of increased
solubility and wetting effect. Controlled release HPMC matrix tablets containing SESD released drug in
a controlled manner and were stable during storage over 3 months at 40 ◦ C/75% RH. Furthermore, the
tablet containing 5 mg IDP SESD showed significantly increased oral bioavailability and extended plasma
concentration compared with the marketed 5 mg Dynacirc® capsule. A combined method of solid dispersion and controlled release technology could provide versatile dosage formulations containing IDP with
poor water solubility and short half-life.
© 2013 Published by Elsevier B.V.

Solubilization of poorly water-soluble drugs is very important
to overcome rate-limiting dissolution, slow absorption and low
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bioavailability of this drug type. Various solubilization strategies
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therefore, have been developed such as complexation, cosolvents,
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micelles, microemulsions, self-microemulsifying drug delivery sys31
tems or self-nanoemulsifying drug delivery systems, or solid
32
dispersion (SD) techniques (Wong and Yuen, 2001; Pouton, 2006;
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Tran et al., 2009). SD among those strategies has been considered as

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one of common methods to enhance solubility, dissolution rate and
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36Q2 bioavailability of various poorly water-soluble drugs (Vasconcelos
et al., 2007; Tran et al., 2011a).
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∗ Corresponding authors. Tel.: +82 31 219 3442; fax: +82 31 212 3653.
E-mail addresses: (T.T.-D. Tran),
(B.-J. Lee).
1
Equally contributed.

However, there are many difficulties associated with the preparation of SD dosage forms as follows: the use of unwanted organic
solvent related to the environment in the solvent evaporation
method, or the problem of drug stability related with elevated
temperatures, and the soft and tacky physical state of the SD
product to be hardly pulverized, leading to the use of more
pharmaceutical excipients as well as complicated manufacturing procedures to compensate the poor flowing characteristics
(Serajuddin, 1999).
Self-emulsifying drug delivery systems, especially in the solid
state obtained by the addition of some free-flowing adsorbents as
one of preferable methods, are in current trends to be investigated
due to their advantages over the liquid formulation for improving
the bioavailability of hydrophobic drugs and good manufacturability (Serajuddin, 1999; Tang et al., 2008). It was recently reported
that a SD utilizing a self-emulsifying carrier like Gelucire 44/14 as
exposed to aqueous media could readily modify drug crystallinity
and hence, improve drug dissolution rate of poorly water-soluble
drug, aceclofenac (Tran et al., 2009).

0378-5173/$ – see front matter © 2013 Published by Elsevier B.V.
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Table 1
Formulation compositions (weight basis) of SDs containing IDP (unit: mg).
Code

Drug

PEG 6000

SD1
SD2
SD3
SD4
SD5
SD6
SD7
SD8
SD9
SD10
SD11

5
5
5
5
5

5
5
5
5
5
5

60

a

57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75

76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95

97

2.1. Materials

100
101
102
103

POX 407

Brij 98
5
5
5
5
5
5
5
5
10
5
0

60
60
60
50
40
30
60
60
60
60

We recently published that controlled release dosage forms containing self-emulsifying or nonself-emulsifying SDs of many poorly
water-soluble drugs with short elimination half-life have been considered as effective drug delivery systems for the treatment of
diseases over a longer period of time (Tran et al., 2010, 2011a,
2011b). Advanced controlled release of SDs can be achieved by a

pertinent combination of pharmaceutical polymers (Wang et al.,
1993). Most of all, HPMC-based hydrophilic matrix tablets offer
several advantages in the development of oral sustained-release
formulations such as flexibility of release modulation, simplicity
of preparation, low production costs and ease to scalability (Cao
et al., 2005). The release behavior of both water-soluble and waterinsoluble drugs is variable with the nature of the HPMC matrices
as a consequence of the drug–polymer interaction via swelling, diffusion and erosion processes (Colombo et al., 1995; Velasco et al.,
1999).
In this study, isradipine (IDP), a calcium antagonist for treating
hypertension was chosen as a model drug (Chrysant and Cohen,
1997). IDP is known to be poorly water-soluble in aqueous solution (less than 10 ␮g/mL) (Verger et al., 1998). Moreover, IDP is
also a good candidate for controlled release dosage form due to
the short elimination half-life (Hafizullah et al., 2000). SESD of IDP
was prepared using melting method and then loaded into HPMCbased hydrophilic matrix tablet for controlled release of IDP. Here,
poloxamer 407 (POX 407), a tri-block copolymer consisting of a
central hydrophobic block of polypropylene glycol flanked by the
two hydrophilic blocks of polyethylene glycol, was used as a carrier to prepare SESD due to its low melting point, good physical
properties of facilitating the solubilization of many poorly watersoluble drugs as well as its stabilization (Shin and Cho, 1997;
Chutimaworapan et al., 2000). The surface morphology and crystal structure of SESD were characterized using DSC, PXRD and
SEM. Thereafter, release characteristics of drug from SESDs and the
HPMC matrix tablets were then evaluated in enzyme-free simulated intestinal fluid (pH 6.8). The stability of HPMC matrix tablets
containing SESD was also investigated under various storage conditions. Finally, the controlled released HPMC matrix tablet and
the commercially available Dynacirc® capsule as a reference were
compared for in vivo bioavailability studies.

2. Materials and methods

99

GUC 50/13

OA

Triacetin

Aerosil 200

BHT

3
3
3
3
3
3
3
3
3
0
0

5
5
5
5
5
5
5
0
0

0
0

17
17
17
17
17
17
17
17
17
17
17

0.1%a
0.1%a
0.1%a
0.1%a
0.1%a
0.1%a
0.1%a
0.1%a
0.1%a
0.1%a
0.1%a

w/w percent value based on OA.

96

98

PVP K30

IDP as a powder form was obtained from Daewoong Pharmaceutical Corp. (Seoul, Korea). Oleic acid (OA), Brij-98, microcrystalline
cellulose (Avicel® PH102), hydroxypropylmethylcellulose 4000
(HPMC-4000), polyvinyl pyrrolidone (PVP K30, Kollidon® 30) and
poloxamer 407 (POX 407) were obtained from Seoul Pharmaceutical Corp. (Seoul, Korea). Aerosil® 200 was purchased from Evonik

(Seoul, Korea). Butylated hydroxyl toluene (BHT) was purchased
from Sigma (Germany). Dynacirc® CR 5 mg capsule (Daewoong
Pharma, Korea) was chosen as a reference IDP formulation. All other
reagents were of reagent grade and used without further purification.
2.2. Method

104
105
106
107
108

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2.2.1. Solubility study
The solubility of IDP was determined in various solvents, surfactants, co-surfactants and oils. An excess amount of IDP was added to
1.5 mL snap-cap Eppendorf tube (Hamburg, Germany) containing
various additives. The resulting mixture was sufficiently mixed and
then placed in a constant temperature water bath at 37 ◦ C for 3 days.
Aliquots were centrifuged at 13,000 rpm for 10 min (Hanil, Korea).

The supernatant layer was carefully collected and then adjusted
with a proper dilution. The concentration of IDP was analyzed by a
HPLC system as described below.
2.2.2. Preparation of SESDs
SESDs of IDP using various carriers were prepared by melting method. The detailed formulation compositions of SESDs are
shown in Table 1 (Code: SD1-SD11). IDP, surfactant and fatty acid
were homogenously mixed together based on the formulation
compositions. The resulting mixtures were slightly heated at various temperatures and sufficiently stirred. Thereafter, the melted
solution was added to adsorbent (Aerosil® 200). After sufficiently
mixing, the mixtures were cooled at −38 ◦ C within 2 h. The solidified mass was pulverized thoroughly by a pestle and mortar and
finally, passed through a 50 mesh sieve to obtain SESD powders.
2.2.3. Preparation of controlled released tablet containing SESD
The HPMC-based matrix tablets (150 mg) were prepared by the
direct compression method. Table 2 shows compositions of the controlled release HPMC matrix tablets. The SESD, HPMC polymer and
the other excipients were mixed thoroughly with a pestle and mortar. The resulting mixtures were directly compressed into tablet
using a conventional tablet machine equipped with round punches
(8 mm diameter) and a die. The tablet hardness was in triplicate
Table 2
Formulation compositions (weight basis) for the preparation of HPMC-based controlled release matrix tablets containing SESD (unit: mg).
No.

SESD

HPMC 4000

Avicel® PH-102

Total weight

T1

T2
T3
T4
T5
T6

90.03
90.03
90.03
90.03
90.03
90.03

0
7.5
15
30
37.5
45

60
52.5
45
30
22.5
15

150.03
150.03
150.03

150.03
150.03
150.03

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measured using a hardness tester (Model SVM-12, Erweka GmbH,
Heusenstamm, Germany).

2.2.4. HPLC analysis of IDP
A reverse phase HPLC system was used for the analysis of
IDP. The HPLC system (Jasco, Tokyo, Japan) consisted of the pump
(PU-980), the UV–visible spectrophotometric detector (UV-975),
the autosampler (Jasco, AS-950-10), the degasser (DG-980-50),
the reverse phase column (Luna 5 ␮m C18 100A, 150 × 4.6 mm)
and integrator (Borwin 1.20 software). The concentration of IDP
was determined at wavelength of UV 325 nm. The mobile phase
consisted of a mixture of methanol, deionized water and acetonitrile (7:3:5, v/v ratio) was degassed under vacuum for 5 min. The

flow rate of the mobile phase was 1 mL/min. A 20 ␮l of the sample
was injected into the HPLC system. The stock solution was prepared by dissolving IDP in HPLC-grade ethanol (1 mg/10 mL) and
then further diluted with the mobile phase to prepare standard
solutions.

2.2.5. In vitro dissolution study
In vitro dissolution test of the SESD and tablet formulations
equivalent to 5 mg IDP was performed according to the USP dissolution II paddle method with a rotation speed of 50 rpm in
900 mL of the enzyme-free simulated intestinal fluid (pH 6.8 ± 0.1)
at 37 ± 0.5 ◦ C using a dissolution tester (DCM1, Anyang, Korea). Dissolution samples were collected at 5, 15, 30, 60, 90 and 120 min
and 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 h, respectively, with
replacement of equal volume of temperature-equilibrated media.
The sinker was used for dissolution of the tablets. The samples were
instantly centrifuged at 10,000 rpm for 10 min. The supernatant of
the centrifuged sample was diluted with the mobile phase. The
concentration of samples was determined by the HPLC system as
described previously.

2.2.6. Thermal analysis (DSC)
The thermal behaviors of pure drug, POX and different SESD
formulations were investigated using Dupont DSC (Dupont, USA).
About 3 mg of sample was weighed in a standard open aluminum
pan; whereas an empty pan of same type was used as reference.
The samples were heated from 20 to 200 ◦ C at a heating rate of
10 ◦ C/min under purged dry nitrogen. Calibration of temperature
and heat flow was performed with indium.

2.2.7. Powder X-ray diffraction (PXRD)
Powder X-ray diffraction patterns were obtained for the samples
of pure drug, POX and different SESD formulations using a D5005

(Bruker, Germany) with Cu-K radiation at 40 kV 50 mA. The samples
were scanned in steps of 0.02◦ from 3◦ to 40◦ with a rate of one
second per step, using a zero background sample holder.

2.2.8. Scanning electron microscope (SEM)
Scanning electron microscopy was used to characterize the surface morphology and particle shape of the samples. The samples
were examined using a JSM-5410 (Jeol, Japan), at an acceleration
voltage of 15 kV. The samples were coated with a thin layer of gold
for 10 min.

2.2.9. Stability study
The HPMC matrix tablets bearing SESD were stored for 3 months
in a plastic bottle with silica gel at 40 ◦ C/75% RH (relative humidity).
The hardness and dissolution profiles for initial and stored samples
were tested at the given period of time.

3

2.3. In vivo comparative bioavailability in healthy human
volunteers
2.3.1. Study design
Eight healthy human volunteers aged 20–30 years old and
weighing from 60 to 70 kg were participated in this study after
submitting a written informed consent. Document review and
approval from a formally constituted Institutional Review Board
in Kangwon National University were permitted. The study was
performed according to the revised declaration of Helsinki for
biomedical research involving human subjects and the rules of
Good Clinical Practice. The in vivo bioavailability was carried out
under the bioequivalence guidelines (KFDA 2008-25) according to

the Korean Food & Drug Administration. The eight volunteers were
randomly divided into two groups.
The current controlled release tablets containing SESD and
marketed Dynacicr® capsules equivalent to 5 mg IDP were orally
given to human volunteers with 250 mL of water for comparatibe
bioavailability. Food and drinks were withheld for at least 4 h after
dosing. Standardized lunch and dinner were served 5 h after dosing.
All subjects were prohibited from strenuous activity and consuming alcoholic drinks during the study. Blood samples (10 mL) were
withdrawn through an indwelling three-way catheter in the forearm and collected in heparin-loaded vacutainers at 0, 0.5, 1, 1.5, 2,
3, 4, 6, 8, 10, 12, 24 and 36 h after dosing. The blood samples were
centrifuged for 10 min at 3000 rpm. The collected samples were
kept frozen at −70 ◦ C until analysis.
2.3.2. Assay of IDP in human plasma
The LC/MS/MS system was used for the analysis of IDP. The
LC/MS/MS system consisted of the HPLC (PerkinElmer Series
200, Boston, USA), the autosampler (CTC analytic SPA, Zwingen,
Switzerland), the MS/MS (Applied Biosystems API 4000, Boston,
USA), and the column (Capcell PAK UG120, 2.0 mm × 150 mm,
5.0 ␮m pore size). The mobile phase consisted of 20% 1 mM ammonium acetate and 80% acetonitrile (pH 6.0 with acetic acid).
Felodipine was used as an internal standard. The flow rate of the
mobile phase was 0.2 mL/min
For analysis of IDP in human plasma, 300 ␮L of plasma, 50 ␮L
(20 ng/mL) of internal standard and 30 ␮L of 10% ammonium
hydroxide were put into test tube and mixed 10 s. Two millliliters
of ethyl ether was then added and mixed for 20 min. The resulting
solution was centrifuged at 1500 rpm for 5 min. The 20 ␮L of the
supernatant layer injected to the LC/MS/MS system.

2.3.3. Pharmacokinetic analysis
Non-compartmental pharmacokinetic analysis was performed.

The maximum plasma concentration of IDP (Cmax ) and time to reach
Cmax (Tmax ) after the oral administration were directly determined
from plasma concentration–time curves. The area under the plasma
concentration–time curve (AUC0–36 h ) from zero to 36 h was computed using the linear trapezoidal rule. All data were expressed as
mean ± S.D.
2.3.4. Statistical analysis
Logarithmically transformed or untransformed (arithmetic)
AUC0–36 h and Cmax was used for statistical analysis of variance
(ANOVA) using SPSS® for windows software and K-BE test® program, respectively. The drug, period, group and subject nested
within group were included in statistical model. The Tmax was also
analyzed as a reference.
All statistical calculations were performed at 5% significance
level. The confidence interval of pharmacokinetic parameters
between the two preparations was allowed within 80–125%

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100

700
600
500
400

80

200

% Released

solubility (ppm)

300

100

60

raw IDP powder
SD1: PEG-6000
SD2: PVP K30
SD3: Gelucire 50/13
SD4: poloxamer 407

40

20

0

ter 1.2 6.8 -97- 9i8j- 5i8j- 35r ELH40SLSn-80n-60n-2c0etin600400000/19334pr407r18c8elinacidacidacidacid
wapH pH BrijBrijB
r Br ho r R
ee ee ee ia G- G- e 5 ol- me me ly ic ic lic ric
p o
Tw Tw Tw tr PE PElucirboploxaloxa g olienolaeprycap
mooph
l c
Ge ca po po
crreem
c

Fig. 1. The solubility of IDP in various pharmaceutical excipients.

0
0

20

40

60

80

100

120

Time (min)

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(logarithmic value) or 80–120% (arithmetic value) for bioequivalence, respectively.

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3. Results and discussion

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3.1. Solubility study

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The effects of pH, solubilizers and fatty acid on drug solubility were investigated at 37 ◦ C as shown in Fig. 1. The solubility
of drug upon various pH conditions was very low. On the other
hand, all of the surfactants and co-surfactants in general had a tendency to enhance the drug solubility. Especially, surfactants such
as triacetin, Brij 98, SLS and POX 407 showed their potential capability of enhancing drug solubility remarkably. Because solubility
of IDP in POX 407 was about 1200 times higher than that in water,
it was included in the SESD formulations as a good carrier. Besides,
other carriers such as PEG 6000, PVP K30 and GUC 50/13 were also

compared in the SESD formulations.

3.2. Effect of formulation compositions in SESDs on drug
dissolution rate
3.2.1. Effect of carriers
The effect of carrier types on drug dissolution rate in intestinal fluid (pH 6.8) is shown in Fig. 2. Dissolution rate of pure drug
was very low (<0.1 ppm) in intestinal fluid, confirming the poor
water solubility of IDP. The POX 407 based SESD showed significantly higher drug dissolution rate as compared to PEG, PVP and
GUC-based SESDs. This result was matched with the preliminary
study in which solubility of IDP reached the highest with POX 407.
POX 407 has been widely used as a wetting and solubilizing
agent to enhance the solubility, dissolution and bioavailability of
many poorly water soluble drugs (Collett and Popli, 2000; Vyas
et al., 2009). The effect of POX content on drug dissolution rate
from SESD in intestinal fluid (pH 6.8) was also investigated (Fig. S1).
The dissolution rate of IDP significantly increased as the amount of
POX 407 increased from 30 mg to 60 mg (SD4-7) due to its high
solubilizing capability (Lee et al., 2008). For this reason, SD4 with
the highest content of POX 407 (60 mg) was selected as an optimal
formulation for further experiments.

Fig. 2. The effect of carriers on the dissolution rate of drug from SESD in simulated
intestinal fluid (pH 6.8).

3.2.2. Effect of surfactant and fatty acid
Together with the carrier, incorporating surfactants and other
solubilizers such as Triacetin, Brij 98 and oleic acid were also important components to form nanoemulsions when SESDs was exposed
to aqueous solution. Although the solubility of drug in oleic acid
was not so much high, this fatty acid was incorporated in the SESD
formulation because it has been known to be effective in increasing

in vivo absorption and bioavailability of poorly water-soluble drugs
by forming chylomicrons in the gut (Caliph et al., 2000; Porter and
Charman, 2001; Park et al., 2007). Figs. S2–S4 show drug dissolution rate in simulated intestinal fluid (pH 6.8) as the contents
of Triacetin, Brij 98 and/or oleic acid were varied into POX 407
based SESD formulations, respectively. As the amount of drug, POX,
Brij 98 and oleic acid were kept constant, there was no significant
difference in drug dissolution rate of SESDs with (SD4) or without triacetin (SD8) (Fig. S2). Thus, tricetin was not important in
increasing drug dissolution and excluded in the optimal formulation. Drug dissolution from SD8 (5 mg Brij 98) was almost identical
irrespective of the amount of Brij 98 as compared with SD9 (10 mg
Brij 98) (Fig. S3). So, the amount of Brij 98 at 5 mg was sufficient
to modulate the drug dissolution rate. Then, oleic acid was added
into SESD formulation to investigate the effect of the fatty acid.
Fig. S4 shows that the presence of oleic acid was not meaningful
because drug release rate from SD8 (with OA) and SD10 (no OA)
was almost the same. The fact that drug dissolution profiles from
those SESDs were almost identical was believed due to the great
effect of POX 407 on the enhancement of drug release. So, the contribution of varying amount of surfactants or fatty acids in SESD
formulations had a negligible effect on drug dissolution rate. Interestingly, the drug dissolution rate from POX 407 based SESD alone
without incorporating surfactant and fatty acid (SD11) was the lowest as compared with SD8 containing these two components (Fig.
S5). In other words, the drug dissolution rate was mainly governed
by incorporating surfactant in POX 407 based SESD. The dissolution rate of SD4, SD8, SD9 and SD10 except SD11 using Pox 407
were almost identical. However, the fatty acid (OA) and surfactant
(Brij 98) were combined to add into the current POX 407 based
SESD for further studies not only for enhancing dissolution rate
but also promoting in vivo bioavailability. It was also known that

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2000

0

A
B

-2

D

Endothermic

E

1000

C
500

E

(A) IDP:drug only
(B) poloxamer 407 only
(C) SD11 : IDP+poloxamer +Aerosil
(D) SD8: Low temperature
(E) SD8 : high temperature
0

20

40

60

80

100

120

140

160

180

Temperature
Fig. 3. DSC thermograms of (A) IDP, (B) poloxamer 407, (C) SD11, (D) SD9 and (E)
SD8.

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unsaturated fatty oil like oleic acid might enhance absorption and
bioavailability of drug by increasing lipophilicity of drug, or even
lymphatic absorption in Peyer’s patch by forming chylomicrons in
the gut (Porter and Charman, 2001; Park et al., 2007).

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3.2.3. Effect of temperature
In order to improve the processing of SESDs into solid dosage
form like tablet, it is desirable that SESD should possess good flowability and compressibility properties. Thus, the adsorbent Aerosil®
200 was chosen and added into the formulation of the SESD using
melting method. In addition, because temperature is an important
factor to control the physicochemical properties of SESD prepared
by melting method (Fassihi et al., 1985), SD8 was prepared at two
different temperatures: A – the temperature used in the study and
another B – lower temperature used for only comparison and abbreviated as SD8low T ◦ . Fig. S6 shows the effect of temperatures on
drug dissolution rate from SESDs (SD8 and SD8low T ◦ ) in simulated
intestinal fluid (pH 6.8). The drug dissolution rate was significantly

increased as the heating temperature increased from B to A. Therefore, the temperature A was confirmed to be the optimal one for
preparation of SESDs by melting method.

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3.3. Physical characterization of SESDs

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-10

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-4

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1500

C

In order to elucidate the enhanced drug dissolution rate from
SESDs, the physical states of the SESDs were investigated using
instrumental analysis such as SEM, PXRD and DSC (Franco et al.,
2001). It has been widely known that the SESD can improve the
dissolution rate of poorly water-soluble drugs by changing the crystalline structure of drug into a high energy state, i.e. an amorphous
state. DSC thermograms of SESDs (SD8, SD8low T ◦ and SD11) are
compared with the pure drug and POX 407 in Fig. 3. Pure IDP
and POX 407 exhibited single endothermic peaks at 169 ◦ C and
52 ◦ C, respectively, which corresponded to their intrinsic melting
points. In contrast, the thermograms of all SESDs showed that drug
characteristic peak disappeared except for that of the carrier itself
indicated that most of crystalline drug changed into its amorphous
structure (Leuner and Dressman, 2000). This fact was attributed
to be a factor enhancing drug release. However, additional peaks
were also observed around 50–55 ◦ C in case of SD8low T ◦ and SD11.
It suggested drug was not completely amorphous, giving decreased
dissolution rate as shown previously.

F

0

0

10

20

30

40

50

60

70

2 Theta
Fig. 4. The powder X-ray diffraction patterns of (A) IDP, (B) poloxamer 407, (C) SD11,
(D) SD9, (E) SD8, and (F) Aerosil® 200.

The PXRD patterns of SESDs (SD8, SD8low T ◦ and SD11) are also
compared with the pure drug and POX 407 in Fig. 4. Diffractogram
of the pure drug reveals the highly crystalline nature through its
numerous distinctive peaks. POX 407 alone exhibited two high
intensity peaks at 18◦ and 24◦ . Contrarily, numerous distinctive
peaks of the drug in the three SESDs disappeared, indicating that
a high concentration of the drug was dissolved in the solid-state
carrier matrix in an amorphous structure (Sheen et al., 1995; Hu
et al., 2003). There was no significant difference in PXRD patterns
among SESD systems (SD8, SD8low T ◦ and SD11).
In addition to physical state of drug in SESD system, either amorphous or crystalline structure, the imaging analysis using SEM was
examined to clarify the differences in dissolution profiles among
SESD formulations. The surface morphology of IDP pure material,
POX 407, Aerosil® 200, SESDs (SD8, SD8low T ◦ and SD11) is shown

in Fig. 5. IDP crystals have an acicular form whereas POX 407 and
Aerosil showed irregular granule shape and powder-like spherical
shape, respectively. The SESDs appeared to be irregularly granulated or agglomerated, depending on the preparation temperature
and formulation compositions. These differences of morphological
properties can affect physical state of drug and wettability of SESD,
varying drug dissolution rate. SD8low T ◦ , prepared by the melting
method at low temperature, or SD11 without any surfactant and
fatty acid, exhibited crystalline state of drug in the SESD, resulting
in decreased dissolution rate as discussed previously. Meanwhile,
the SD8 showed almost amorphous structure, indicating the drug
dissolution enhancement was due to the lack of crystalline state
and the better wettability.
3.4. Effect of HPMC content on dissolution rate of controlled
release tablet
The optimally formulated SD8 was used to prepare controlled
release HPMC matrix tablet. Hydrophilic swellable HPMC polymers are widely used to control the release of drugs from matrix
formulations (Alderman, 1984; Rao et al., 1990). Additionally, cellulose ethers have good compression characteristics so that they
can be directly compressed to form swellable sustained release
matrices (Doelker, 1987). The polymer content and the viscosity grade of HPMC are considered to be critical factors in the
controlled release of drugs due to the changes of swelling behaviors of HPMC matrices (Bonferoni et al., 1998; Katzhendler et al.,
2000; Cao et al., 2005). Therefore, the effect of HPMC quantity
on dissolution rate of the controlled released HPMC matrix tablet

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Fig. 5. SEM photo-micrographs of IDP (× 10k), poloxamer-407 (× 2k), Aerosol 200vv (× 10k), SD8 (× 10k), SD9 (× 10k) and SD11 (× 10k).

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in simulated intestinal fluid (pH 6.8) was investigated (Fig. 6).
The hardness and friability of HPMC matrix tablets were given
40.0 ± 5 N and 0.3 ± 0.05% respectively. The matrix tablet without HPMC (T1) or having low content of HPMC (T2) displayed a
rapid disintegration with no controlled release. The HPMC matrix
tablets showed controlled release over a period of 10–16 h depending on the HPMC content (T3–T6) because of the swelling property
of HPMC as reported on somewhere (Wan et al., 1993; Patel and
Patel, 2007). One of the most important characteristics of HPMC
is the high swellability, which has a considerable effect on the
release kinetics of incorporated drugs (Velasco et al., 1999; Cao
et al., 2005). When HPMC matrices come in contact with water

or aqueous gastro-intestinal fluids, the polymer absorbs water
and undergoes swelling and hydration. The rapid formation of
a viscous gel layer upon hydration has been regarded as the
essential step in achieving controlled drug release from HPMC
matrices. This process leads to relaxation of the polymer chains
with a reduction in the glass transition temperature of the polymer. Subsequently, the polymer undergoes a glassy to rubbery
phase transition and the polymeric chains disentangle as a result
of increased distance separation between the chains to diffuse the
drug more easily (Parakh et al., 2003). Contrarily, the marketed
Dynacirc® capsule showed very low dissolution rate (T0 ; about
20%/24 h).

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5

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60

T0:
T1:
T2:

T3:
T4:
T5:
T6:

40

Plasma conc. of IDP (ng/ml)

% Released

P.H.-L. Tran et al. / International Journal of Pharmaceutics xxx (2013) xxx–xxx

Dynacirc Capsule
HPMC 0 %
HPMC 5 %
HPMC 10 %
HPMC 20 %
HPMC 25 %
HPMC 30 %

20

7

3
Dinacirc-Reference
CR Tablet (T4)
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1

0

0
0

5

10

15

20

25

0

Time (h)

10

20

30

40

Time (h)

Fig. 6. The effects of amount of HPMC on the dissolution rate of controlled released
tablet in simulated intestinal fluid (pH 6.8).

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3.5. Stability study of controlled released matrix tablet
Drug dissolution rates from the controlled release matrix tablets
(T4–T6) are almost identical. T4 with lower amount of HPMC was
considered as the optimal formulation to avoid stickiness problem in the tableting process. The stability of HPMC matrix tablet
(T4) containing SESD was also investigated under the accelerated
storage conditions or room temperature. Release profiles of controlled released HPMC tablets in simulated intestinal fluid (pH 6.8)
as a function of time under the two different storage conditions
are shown in Fig. 7. The dissolution profiles of the tablets at two
different storage conditions were almost identical for 3 months
100

80

% Released

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60

40
Initial
1 months: 40 degree / 75% RH
1 months: Room temperature
3 months: 40 degree / 75 % RH
3 months: Room temperature

20

Fig. 8. Plasma concentration–time profiles of IDP after an oral administration of
controlled released tablet (T4) and marketed Dynacirc® capsule in healthy human
volunteers.

as compared with initial time. Moreover, the drug content was
almost unchanged during storage conditions for 3 months (data
not showed). Accordingly, the HPMC matrix tablet containing SESD
(T4) in the study has a good stability and could be used to delivery
poorly water-soluble IDP in a controlled manner.
3.6. Pharmacokinetic behaviors of controlled release tablet in
healthy human volunteers
The plasma concentration–time profiles of controlled released
HPMC matrix tablets (T4) and marketed Dynacirc® capsule equivalent to 5 mg of IDP following an oral administration to healthy
human volunteers are shown in Fig. 8. The Table 3 also compares
pharmacokinetic parameters of IDP between controlled released
matrix tablets (T4) and marketed Dynacirc® capsule. The controlled
released HPMC matrix tablets showed significantly increased Cmax
and AUC compared to the marketed dynacirc® capsule. The relative AUC and Cmax of controlled released HPMC matrix tablets

increased about 256% and 587%, respectively. Due to the solubilization effect, the Tmax of controlled released HPMC matrix tablets
was also highly advanced. The mechanism for this enhanced in vivo
bioavailability resulted from the controlled release of highly solubilizable SESD system loaded in HPMC matrix tablet. As the water
penetrates into the tablet, drug readily dissolves via emulsification
process and release through the polymeric network of HPMC in a
controlled manner. The change of drug crystal structure into amorphous form as well as the increase of wetting and solubilization
Table 3
Comparison of pharmacokinetic parameters after an oral administration of controlled released matrix tablets (T4) and marketed Dynacirc® capsule equivalent to
5 mg IDP in healthy human volunteers.

0
0

5

10

15

20

25

Time (h)
Fig. 7. Dissolution profiles of controlled released tablet in simulated intestinal fluid
(pH 6.8) as a function of time during various storage conditions.

No.
®

Dynacirc
T4
*

AUC (ng h/mL)

Cmax (ng/mL)

Tmax (h)

8.56 ± 4.28
21.98 ± 18.15*

0.48 ± 0.10
2.82 ± 2.27*

8.25 ± 3.86*
2.50 ± 1.22

p < 0.05, significantly different compared to Dynacirc® .

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capacity by incorporating excipients or their mixtures (surfactant
and fatty acid) into the SESD system could contribute the enhanced
dissolution of IDP as discussed previously.

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4. Conclusions

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The SESD prepared by melting method could be a useful formulation to enhance in vitro dissolution and in vivo bioavailability of
a poorly water-soluble drug like IDP. The dissolution enhancement
in SESD system was attributed to the change of drug crystalline
into the amorphous state and the formation of microenvironment
to dissolve IDP by incorporating formulations. This SESD system
was dispersed in HPMC-based matrix tablet to control the release
rate of drug. Interestingly, the HPMC matrix tablet containing SESD
showed good stability and enhanced in vivo bioavailability. The
drug content and dissolution profiles of the tablets were unchanged
during storage for 3 months. Oral bioavailability of the controlled
release HPMC tablet was highly increased as compared with the
reference capsule in healthy human volunteers. Therefore, solubilization method combined with controlled release technique could
provide a unique way to increase dissolution rate and bioavailability of many poorly water-soluble drugs.

490

Acknowledgements

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This work was supported by a grant from the Korean Health
Technology R&D Project, Ministry for Health and Welfare, Korea
(A092018). We would like to thank the Central Research Laboratory
for the use of the DSC, PXRD and SEM, Kangwon National University.

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Appendix A. Supplementary data

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Supplementary data associated with this article can be
found, in the online version, at />j.ijpharm.2013.04.022.

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