Current Drug Discovery Technologies, 2007, 4, 31-38 31

Controlled Release of the Pineal Hormone Melatonin from Hydroxypro-

pylmethylcellulose/Sodium Alginate Matrices in Aqueous Media Contain-
ing Dioctyl Sulfosuccinate

Marilena Vlachou*, Athanasia Tsiakoulia and Aphrodite Eikosipentaki

Faculty of Pharmacy, Department of Pharmaceutical Technology, University of Athens, Panepistimioupoli-Zografou,

157 71 Athens, Greece

Abstract: An investigation of the controlled release profile of mono-layered formulations of the hormone melatonin in
modified aqueous media is described. The tablets used were comprised of hydroxypropylmethylcellulose (HPMC K15M)
and sodium alginate with melatonin (fully soluble in the dioctyl sulfosuccinate (DSS) containing simulated intestinal solu-
tion). Three different sets of tablets (diameters 7.5, 10.0 and 13.0 mm) were tested with respect to the influence of their
sizes on the hormone’s release; the general trend observed was that tablets with larger surface area values had lower % re-
lease. A decrease in the value of Wo, obtained from the ratio [H2O]/[DSS], results to the predominance of DSS conformers
in the aqueous media, which are less likely to solubilize melatonin effectively.

Key Words: Melatonin, hydroxypropylmethylcellulose (HPMC K15M) / sodium alginate matrices, dioctyl sulfosuccinate
(DSS), controlled release, gastrointestinal pH.

INTRODUCTION secreted melatonin concentration versus time model, are thus

The pineal gland neurohormone melatonin (N-acetyl 5-
methoxytryptamine, 1) is synthesized and secreted mainly at
night. It regulates seasonal changes in various aspects of
physiology in photoperiodic species such as sheep, and, act-
ing on specific receptors in the suprachiasmatic nucleus
(SCN) of the hypothalamus, can entrain the circadian clock.
Considerable interest has been focused on its potential in
treating the disordered circadian rhythms which occur in
shift-work, jet-lag and sleep disorders in the elderly [1]. Hu-
man studies have also indicated that increasing serum mela-
tonin concentrations can trigger the onset of sleep [2].
NHCOCH3
CH3
O
N
H enhanced. Conversely, in simulated gastric fluid, the pres-
1 ence of DSS in the release of the hormone was less impor-
Scheme 1. Structure of melatonin.
Furthermore, due to its hydrophobic and hydrophilic na-
ture [3, 4] melatonin can easily enter cells and partition itself
between "shallow subsurface" and intracellular compart-
ments, where it can effectively scavenge both water–soluble
peroxyl (ROO·) [5] and lipoperoxy (LOO·) radicals [6, 7].
However, the use of melatonin as a drug is hampered by
its short biological half-life and poor bioavailability [8]. In-
exorably, dosage forms, which mimic the physiologically
*Address correspondence to this author at the Department of
Pharmaceutical Technology, University of Athens, Panepistimioupoli-
Zografou, 157 71 Athens, Greece; Tel: +302107274674; Fax:
+302107274027; E-mail: vlachou@pharm.uoa.gr
limited. In an attempt to investigate the poor bioavailability
of the hormone, we recently experimented with the solubility
of certain quantities of melatonin, which are commonly used
for tablet preparation in the pharmaceutical industry, and
found that independently of the quantity used, the hormone
is efficiently solubilized by the anionic surfactant, dioctyl
sulfosuccinate (DSS). This was attributed to the characteris-
tic features of the chemical structure of DSS and its favor-
able interaction with certain parts of the skeleton of mela-
tonin [9].
As an extension of this work, we report herein on the
controlled release of the hormone from hydroxypropylmeth-
ylcellulose (HPMC) and sodium alginate matrices in aqueous
media. The results suggest that in simulated intestinal aque-
ous environments containing DSS (in quantity < LD50
maximum toxicity), the release of melatonin is drastically
tant. Besides DSS, the type of the diluent/binder (Avicel PH
101 or PH 102), embedded in the aforementioned formula-
tions, has a profound influence on the release profile of
melatonin. Thus, unlike PH 101, the presence of Avicel PH
102 in the tablets enhances the percentage of drug release,
whilst, during the first two hours of the experiment, it retards
the release rate.
The effect of different tablet diameter on the hormone’s
release follows a general trend, which implies that tablets
with larger surface area (SA) values have lower % release.
On the other hand, when the diameter of the tablet is kept
constant (10 mm), the determining factor responsible for the
release of melatonin is found to be the volume of the dissolu-
tion medium.

1570-1638/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd.

32 Current Drug Discovery Technologies, 2007, Vol. 4, No. 1
Table 1. Composition of Controlled Release Melatonin Tablets
Materials
Melatonin
HPMC K15M
Sodium alginate
Avicel PH 101
Avicel PH 102
Magnesium Stearate
2. MATERIALS AND METHODS
2.1. Materials
Melatonin (>99% Sigma, lot 12K1471), sodium alginate,
Avicel PH 101 and dioctyl sulfosuccinate sodium salt (DSS)
were purchased from Sigma and used as received. Avicel PH
102 was offered by ELPEN S.A. Pharmaceutical Industry.
Magnesium stearate (BDH) was used as a lubricant.
2.2. Methods
2.2.1. Preparation of Melatonin Slow Release Tablets
The slow release melatonin tablets were prepared by di-
rectly compressing melatonin with HPMC K15M (30%
w/w), sodium alginate (16% w/w) on a single punch tablet
instrument (Carver 3393, Fred S. Carver, Inc., Menomonee
Falls, WI) using 7.5, 10.0 and 13.0 mm diameter matrices;
pressure 44.44, 150.02 and 295.89 kPa, respectively. Di-
rectly compressible microcrystalline cellulose (Avicel PH
101 or Avicel PH 102, 52% w/w) was used as diluent. Mag-
nesium stearate (1% w/w) was used as lubricant. Tablet
weight was kept at 200 mg and the melatonin content was 2
mg (1%) per tablet (Table 1).
2.2.2. Drug Release Studies
Tablets of each formulation were subjected to dissolution
studies at 37 ± 0.5
C using the USP apparatus II—paddle
method (Pharma Test type PTW SIII) at a stirring rate of 50
rpm. 200 and 450 ml of aqueous media of gastrointestinal
pH, in the absence and presence of DSS was used. 5 ml of
dissolution samples were withdrawn at specified intervals,
every 30 min, for up to 8 hr and an equivalent volume of
medium was added at each sampling to maintain a constant
volume. The drug concentration was determined spectropho-
tometrically at 278 nm using a Lambda 6 Perkin Elmer UV-
VIS spectrophotometer. All experiments were carried out in
triplicate.
2.2.3. Reference Curve-Melatonin Standard Solution (0.5
mg/ml)
Melatonin (25 mg) was accurately weighed and trans-
ferred to a 50 ml volumetric flask. The respective solvent
(depending on the experimental conditions) was added to
bring the volume to 2/3 of the capacity of the flask. This
standard solution was sonicated for 30 min and then the dis-
Vlachou et al.
Quantity in mg per Tablet (%)
F(I) F(II)
2 (1%) 2 (1%)
60 (30%) 60 (30%)
32 (16%) 32 (16%)
104 (52%) -
- 104 (52%)
2 (1%) 2 (1%)
solution medium was added to final volume. Several aliquots
of the standard solution of melatonin were transferred with a
volumetric pipette to 10 ml volumetric flasks and the con-
tents of each flask were diluted to volume with the appropri-
ate solvent. These solutions were transferred to the sample
cell of the spectrophotometer and the absorption values were
measured and recorded. These values versus concentration of
the respective aliquots gave a linear squared regression coef-
ficient (r2) of 0.99, which meets the relevant requirements
established for the standards of quality.
2.2.4. Preparation of the Simulated Gastric Fluid Solution
The simulated gastric fluid solution was prepared accord-
ing to USP (enzyme – free S.I.G.: HCl /NaCl solution: pH ±
1.2).
2.2.5. Preparation of the Monobasic Potassium Phosphate
Buffer Solution
The monobasic potassium phosphate buffer solution was
prepared according to USP:
(enzyme – free S.I.F : KH2PO4 /NaOH buffer: pH ± 7.8).
2.2.6. Preparation of the Dioctyl Sulfosuccinate Sodium
Salt (DSS) Solution
The required amount of DSS was added to the appropri-
ate volume of the buffer solution and the mixture was stirred
at 100 rpm at 37 ± 0.5°C in the dissolution apparatus for 24 h
prior to the experiment.
3. RESULTS AND DISCUSSION
Only scarce reports, which probe the release profile of
melatonin in aqueous media were apparently available when
this work began. Although the methodologies proposed in
most of the following articles for the preparation of water
soluble melatonin tablets and beads are elegant, their appli-
cation to facile industrial formulations would be laborious in
that they simultaneously use slow and fast release compo-
nents [8] or drug-loaded sugar beads and spheres [10,11].
The work by Lee et al., [12], is the first attempt towards the
development of HPMC sustained-release orally administered
melatonin tablets.
In the present work, we investigated the controlled re-
lease of the hormone from mono-layered hydroxypropyl
methylcellulose (HPMC K15M)/sodium alginate matrices
Controlled Release of the Pineal Hormone Current Drug Discovery Technologies, 2007, Vol. 4, No. 1 33

Table 2. Formulations F(I) and F(II): % Release of Melatonin Versus Time in 450 ml of Intestinal Dissolution Medium in the Ab-
sence and Presence of DSS (0.1 mg)

% Release of
% Release of Compo- % Release of Composition F(I) % Release of
Time (min) Composition F(II) in the Pres-
sition F(I) in the Presence of DSS Composition F(II)
ence of DSS

30 15.3 30.4 6.2 25.4

60 16.5 33.9 10.0 35.6

90 19.4 36.8 15.3 38,8

120 22.4 39.9 20.7 43.0

150 24.3 40.1 26.5 46.6

180 26.9 42.1 33.3 49.8

210 28.0 43.2 40.4 57.2

240 30.3 48.5 47.9 59.9

270 32.7 52.8 51.9 64.6

300 36.4 56.6 57.0 65.7

330 44.2 65.8 63.1 66.6

360 47.7 74.5 66.2 71.0

390 55.6 78.5 69.2 79.4

420 56.1 84.3 73.9 84.7

450 58.0 90.9 78.2 87.8

480 58.9 99.6 83.6 93.2

100
90
80
70
drug released (%)

60
50
40 F(I) in the absence of DSS

30 F(I) in the presence of DSS

20 F(II) in the absence of DSS

10
F(II) in the presence of DSS
0
0 100 200 300 400 500 600
time (min)

Fig. (1). Formulations F(I) and F(II): % release of melatonin versus time in 450 ml of intestinal dissolution medium in the absence and pres-
ence of DSS (0.1 mg).

(Table 1) in aqueous media, in the presence and absence of
the surfactant, dioctyl sulfosuccinate sodium salt (DSS).
The choice of a low viscosity HPMC was based on ear-
lier findings, according to which the drug release rate in-
creases as the viscosity and particle size of the HPMC poly-
mer decreases [13].
Among the plethora of surfactants routinely used in in vi-
tro pharmaceutical studies, DSS, a poorly water soluble ani-
onic surfactant, was chosen because it can form direct and
reverse micelles [14] (cmc in water = 2.56 mM) [15].
Moreover, it can solubilize considerable water accommo-
dated in the region near the centre of the micelle, which is
34 Current Drug Discovery Technologies, 2007, Vol. 4, No. 1 Vlachou et al.

Table 3. Formulation F(II): % Release of Melatonin Versus

100
Time in 450 ml of Gastric Dissolution Medium in the
Absence and Presence of DSS (0.1 mg) 90
80
70
Time

drug released (%)

F(II): Absence of DSS F(II): Presence of DSS 60
(min)
50
30 9.9 15.4 40
30
60 11.3 25.6
20 absence of DSS

90 12.3 24.7 10 presence of DSS

120 16.2 29.4 0

0 100 200 300 400 500 600
150 17.5 31.6
time (min)
180 21.0 32.2

210 20.4 33.8 Fig. (2). Formulation F(II): % release of melatonin versus time in
450 ml of gastric dissolution medium in the absence and presence
240 25.3 34.7 of DSS (0.1 mg).
270 27.5 37.9 Conversely, in simulated gastric fluid, the influence of
300 28.9 42.7 DSS on the release of the hormone, albeit being statistically
very important (ANOVA P value < 0.0001), was less obvi-
330 29.0 45.2 ous (49.5% in the absence of DSS vs. 64.4% in the presence
360 30.0 48.3
of DSS, after 8 hours; Table 3, Fig. (2)).
This is probably due to the fact that in the acidic envi-
390 47.1 48.5
ronment DSS adopts a less folded conformation (structure B,
420 48.0 58.2 Scheme 2); in lieu of this, melatonin and especially its indole
N-H moiety, is not in close proximity with the DSS polar
450 48.8 63.0 head group in order to form polar complexes with the surfac-
480 49.5 64.4 tant.
Moreover, the rest of the molecule of melatonin and
surrounded by the polar head group of the surfactant [16]. mainly the lipophilic benzene nucleus cannot align itself in
The structure of this solubilizing agent is different to the an effective way along the extended hydrophobic side chains
other commonly used surfactants in that the polar head group of DSS.
is located towards the centre and the side chains are pro- It is apparent from Fig. (1) that besides DSS, the type of
jected outwards (structures A and B, Scheme 2). Recently, the diluent/binder (Avicel PH 101 or PH 102), present in the
we found that due to these unique features of DSS, the aque- aforementioned formulations, has a noteworthy influence on
ous solubility of melatonin in its presence is augmented by the release profile of melatonin, as well. Thus, conversely to
23% [9]. PH 101 (formulation F(I)), the presence of Avicel PH 102 in
The results obtained in the present study suggest that in the tablets of type F(II) enhances the percentage of drug re-
simulated intestinal aqueous environments containing DSS lease, whilst, during the first two hours of the experiment, it
(in quantity < LD50 maximum toxicity), the release of mela- retards the release rate (ANOVA P value > 0.05). This could
tonin is drastically enhanced (58.9% in the absence of DSS be possibly ascribed to the difference between the mean par-
vs. 99.6% in the presence of DSS, after 8 hours; Table 2, Fig. ticle sizes of Avicel PH 102 and Avicel PH 101; the particles
(1)); this constitutes a statistically significant difference of the former, being larger, allow the formation of channels
(ANOVA P value < 0.05) [17]. within its matrix structure, which facilitate drug’s solubiliza-

O O
+Na-O S +Na-O S
3 3
O O
O O

O O

A B

Scheme 2. A: structure of folded conformer of dioctyl sulfosuccinate sodium salt (DSS); B: structure depicting the extended conformation of
DSS.
Controlled Release of the Pineal Hormone Current Drug Discovery Technologies, 2007, Vol. 4, No. 1 35

Table 4. Formulation F(II): % Release of Melatonin Versus Time from Tablets of Different Diameter in 450 ml of Intestinal Dissolu-
tion Medium in the Absence and Presence of DSS (0.1 mg)

Absence of DSS Presence of DSS

Time
(min) 7.5 mm 10 mm 13mm 7.5 mm 10 mm 13 mm

30 19.0 6.2 7.6 21.7 25.4 18.5

60 24.4 10.0 15.7 35.6 35.6 39.4
90 27.8 15.3 24.1 37.3 38.8 42.3
120 31.4 20.7 30.8 38.6 43.0 43.5
150 35.0 26.5 36.6 40.6 46.6 45.6
180 39.6 33.3 40.3 42.7 49.8 47.8
210 44.3 40.4 44.8 47.9 57.2 52.1
240 50.3 47.9 49.9 55.4 59.9 58.5
270 56.4 51.9 52.1 65.0 64.6 62.7
300 62.1 57.0 55.5 76.3 65.7 63.3
330 72.7 63.1 58.3 76.8 66.6 68.1
360 76.4 66.2 60.2 78.5 71.0 71.8
390 85.4 69.2 62.0 79.7 79.4 78.3
420 89.1 73.9 63.5 79.8 84.7 83.2
450 91.2 78.2 64.6 81.7 87.8 83.9
480 91.8 83.6 66.5 82.2 93.2 85.5

100

90

80

70
drug released (%)

60
absence of DSS (7.5mm)
50
absence of DSS (10mm)

40
absence of DSS (13mm)

30
presence of DSS (7.5mm)

20 presence of DSS (10mm)

10 presence of DSS (13mm)

0
0 100 200 300 400 500 600
time (min)

Fig. (3). Formulation F(II): % release of melatonin versus time from tablets of different diameter in 450 ml of intestinal dissolution medium
in the absence and presence of DSS (0.1 mg).

tion [18]. This possibility is corroborated by the n value (re-
lease exponent) [19] of the power law (equation 1):
Mt n
= kt
M

where, Mt and M
are the absolute cumulative amount of
drug released at time t and infinite time, respectively; k is a
constant incorporating structural and geometric characteris-
tics of the device (e.g. thin film, cylinder etc).
Thus, for F(II) (Avicel PH 102), in the presence of DSS,
n was found to be 0.41, indicative of a Fickian diffusion re-
lease. However, when this formulation was solubilized in the
same dissolution medium, but in the absence of DSS, the n
value was 1.09; this is clearly a zero order release, i.e. an
Equation 1. ideal kinetic behavior. Conversely, the respective n figures in
the case of the F(I) (Avicel PH 101) formulation were 0.28
and 0.75; the latter value suggests an anomalous transport,
while the former is outside the acceptable limits for a release
mechanism prediction [19]. It is interesting to note that it has
36 Current Drug Discovery Technologies, 2007, Vol. 4, No. 1 Vlachou et al.

Table 5. Formulation F(II): % Release of Melatonin Versus Time in 200 ml and 450 ml of Simulated Intestinal and Gastric Dissolu-
tion Media in the Presence of DSS (0.1 mg)

Simulated Intestinal Solution Simulated Intestinal Solution Simulated Gastric Solution Simulated Gastric Solution

Time (min) 200 ml 450 ml 200 ml 450 ml

30 25.6 25.4 17.6 15.4

60 29.2 35.6 18.4 25.6

90 31.8 38.8 19.6 24.7

120 34.2 43.0 22.0 29.4

150 38.9 46.6 24.2 31.6

180 41.1 49.8 25.9 32.2

210 42.9 57.2 28.9 33.8

240 47.4 59.9 30.3 34.7

270 52.6 64.6 31.1 37.9

300 56.5 65.7 33.0 42.7

330 63.1 66.6 34.7 45.2

360 65.7 71.0 35.4 48.3

390 67.9 79.4 36.7 48.5

420 70.8 84.7 37.4 58.2

450 71.7 87.8 38.2 63.0

480 73.9 93.2 38.9 64.4

been reported that the presence of Avicel in melatonin con-
taining HPMC matrix tablets retards the swelling and hydra-
tion process and this leads to a decrease in the hormone’s
release rate [12]. According to the authors, this could be due
to the increased hardness of the tablets caused by Avicel,
although they admit that tablet hardness had little effect on
the swelling and erosion of the HPMC matrices.
Apart from the aforementioned studies we also probed
the effect of different tablet diameter on the hormone’s re-
lease; three different sets of tablets (diameters 7.5, 10.0 and
13.0 mm) were tested. From the release profiles of melatonin
depicted in Fig. (3) and Table 4, it is deciphered that in 450
ml of simulated intestinal fluid containing DSS, the optimum
release is attained in the case of the 10 mm diameter tablets.
Conversely, in the absence of DSS the highest release was
observed in the 7.5 mm tablets. Interestingly, the percentage
of melatonin released from the 13 mm tablets was essentially
the same, both in the presence and absence of DSS. How-
ever, it has to be mentioned that all of the aforementioned
differences are not statistically important (ANOVA P value
> 0.05). In an attempt to elaborate on these observations, the
effect of tablet surface area (SA), SA = 2
r(r + t), on drug
release was monitored; r is the radius of the flat-faced round
tablet and t is the band thickness [20]. The general trend was
that tablets with larger SA values had lower % release. In
detail, the 7.5 mm diameter tablets with an SA value of 96.3
mm2 exhibited a 91.8% release of melatonin in the 450 ml
intestinal dissolution medium. The respective figures for the
10 mm and 13 mm diameter tablets were SA = 164.2 mm2 ,
release = 83.6% and SA = 272.3 mm2, release = 66.5%.
These findings are also in agreement with the release data
obtained from analogous formulations containing a sparingly
soluble drug [21].
On the other hand, when the diameter of the tablet was
kept constant (10 mm), the determining factor responsible
for the release of melatonin seemed to be the volume of the
dissolution medium. Thus, while in 450 ml of simulated gas-
tric fluid containing DSS, the release of the hormone reached
64.4%, in the respective 200 ml solution this figure dropped
to 38.9% (ANOVA P value > 0.05).
Likewise, in a DSS enriched intestinal environment, the
aforementioned figures were 93.2% and 73.9%, respectively
(Fig. (4), Table 5) (ANOVA P value > 0.05). It seems, there-
fore, that a decrease in the value of Wo, obtained from the
ratio [H2O]/[DSS], results to the predominance of DSS con-
formers [22], which are less likely to solubilize melatonin
effectively (structure B, Scheme 2).
4. CONCLUSIONS
It has been concluded that the solid mono-layer
HPMC/sodium alginate formulations of melatonin employed
in this study, exhibit a desirable drug release profile in the
presence of the anionic surfactant, DSS. However, release
kinetics data show that a zero order profile is attained in the
absence of DSS in the dissolution medium, but in the pres-
ence of the diluent/binder, Avicel PH 102, in the
Controlled Release of the Pineal Hormone Current Drug Discovery Technologies, 2007, Vol. 4, No. 1 37

100

90

80

70

drug released (%)

60

50

40
200 ml intestinal solution
30
450 ml intestinal solution
20
200 ml gastric solution
10
450 ml gastric solution

0
0 100 200 300 400 500 600
time (min)

Fig. (4). Formulation F(II): % release of melatonin versus time in 200 ml and 450 ml of simulated intestinal and gastric dissolution media in
the presence of DSS (0.1 mg).

HPMC/sodium alginate matrix. Independently of the pH of
the aqueous media, the concentration of DSS seems to influ-
ence the release of melatonin in a reversely proportional
manner. The in-vivo bioavailability of melatonin from the
developed formulations F(I) and F(II) is to be determined.
ACKNOWLEDGEMENTS
The authors are indebted to the EPEAEK II Program Py-
thagoras II - Support of Universities Research Groups (K.A.
70/3/7993) for financial support.
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