i j p b c s original research article · ramya krishna. t1*, suresh. b2, jaswanth. a3 1 talla...
TRANSCRIPT
International Journal of Pharmaceutical
Biological and Chemical Sciences
ISSN: 2278-5191
International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS)
| Jan-Mar 2016 | VOLUME 5 | ISSUE 1 |05-15 www.ijpbcs.net or www.ijpbcs.com
Original Research Article
Pag
e5
DESIGN AND EVALUATION OF LOSARTAN POTASSIUM CHRONOMODULATED
DELIVERY SYSTEM FOR EFFECTIVE THERAPY OF HYPERTENSION
Ramya Krishna. T1*
, Suresh. B2, Jaswanth. A
3
1 Talla Padmavathi Pharmacy College, Orus, Warangal, Telangana, India
2 St. Peter’s Institute of Pharmaceutical Sciences, Hanamkonda, Warangal, Telangana, India
3 Procadence Institute of Pharmaceutical Sciences, Rimmanaguda, Gajwel, Medak, Telangana, India
*Corresponding Author Email: [email protected]
INTRODUCTION
Traditionally, drug delivery has meant to get a simple
chemical absorbed predictably from the gut or from
site of injection [1]. Oral controlled drug delivery
systems release the drug with constant or variable
release rates. These dosage forms offer many
advantages, such as nearly constant drug level at the
site of action, prevention of peak-valley fluctuations,
reduction in dose of drug, reduced dosage frequency,
avoidance of side effects, and improved patient
compliance. The oral controlled release system shows
the typical pattern of drug release in which the drug
concentration is maintained in the therapeutic window
for a prolonged period of time (sustained release),
there by sustained therapeutic action. But there are
certain conditions which demand release of drug after
a lag time i.e., chronopharmacotherapy of disease
which shows circadian rhythms in their
pathophysiology [2]. A number of common diseases
which shows circadian rhythms in their
pathophysiology include rheumatoid arthritis, allergic
rhinitis [3], hypertension [4, 5] and cancer [6].
ABSTRACT:
The intent of present investigation is to develop and evaluate a novel oral pulsatile drug delivery system based on a
core-in-cup dry coated tablet.
The system consists of three parts, a core tablet, containing the active ingredient acting as reservoir, an impermeable
outer shell and top cover layer barrier of hydrophilic polymer. The core containing Losartan potassium as model drug.
The impermeable coating cup consisted of cellulose acetate propionate and the top cover layer of hydrophilic
swellable materials (Sodium Alginate, HPMC K4M, Sodium carboxy methylcellulose).
The formulations were subjected to evaluation of various parameters like thickness, hardness, weight variation,
friability, disintegration time, percentage drug content, water uptake and erosion studies, in vitro drug release studies,
FTIR and stability studies. The effect of polymer properties and quantity of top cover layer, on the lag time and drug
release was investigated. The results showed that the release lag time increased when the quantity of the plug layer
increased whereas drug release decreased. Plug layer polymers showed a lag time with rank order: SA < NaCMC <
HPMC. Weight variation and percentage drug content results showed that they were within the limits of official
standards. The in vitro release studies revealed that the formulation with polymer HPMC showed better pulsatile
release property as compared to the other formulations. FTIR study showed no evidence of interaction between the
drug and polymers. Optimized formulation was stable for at least 3 months under standard long-term and accelerated
storage conditions. In conclusion, pulsatile tablets were successfully formulated which provided a desirable lag time
followed by a drug release.
KEYWORDS: Pulsatile drug delivery system; lag time; Losartan potassium; Core-in-cup tablet; swellable polymers.
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS) | JAN-MAR 2016 |VOLUME 5 | ISSUE 1 | 05-15 | www.ijpbcs.net
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Hypertension is a chronic disorder present in over 90
% of all patients with cardiovascular (CV) disease and
is a major risk factor for CV disease which sometimes
leads to sudden death [7-9]. Ambulatory blood
pressure (BP) exhibits a diurnal variation with increase
in the morning (between 6 am and noon; BP surge)
with activation of the sympathetic nervous system
prior to awakening. The morning BP surge was
reported to be associated with high risk of cardiac
death, ischemic and hemorrhagic stroke [10, 11].
These changes in blood pressure corresponds the
morning activation in catecholamines, renin, and
angiotensin [12].
Treatment of this disease condition occurring in the
early hours is not convenient by using conventional
immediate release dosage form. Hence,
chronotherapeutic drug delivery system (ChDDS) may
be useful for such patients since the drug is released at
a predetermined lag time. Chronotherapeutics refers to
a treatment method in which in vivo drug availability
is timed to match the rhythms of disease, in order to
optimize therapeutic outcomes and minimise side
effects [7, 13 & 14]. It is designed such that drug
release is modulated in a manner that ensures that
maximum concentration (Cmax) of the drug is reached
at the maximum intensity of the disease condition.
Cmax of the drug is normally reached within 1 - 2 h
for many conventional dosage forms and this may not
match with the maximum intensity of the disease state.
Hence, for effective therapy, it is always advisable to
provide maximum drug concentration at maximum
intensity of disease condition.
Angiotensin II receptor blockers selectively and
specifically antagonize the action of angiotensin II, a
potent vasoconstrictor impacting BP regulation.
Angiotensin II receptor blockers are becoming
increasingly popular for the treatment of hypertension
because they are effective and well tolerated [2].
Losartan potassium is the first orally active, highly
specific, non-peptide angiotensin II receptor antagonist
which blocks the renin–angiotensin system by
suppressing the effects of angiotensin II at its
receptors. It is a weakly acidic yellowish white
crystalline powder with a pKa of 4.9 [7, 15 & 16]. It is
a salt of 2-n-butyl-4-chloro-5- hydroxymethyl-1-[2_-
(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole
with a biological half life of 2-2.5h [7, 15 & 16].
It is used in the treatment of hypertension particularly
in diabetic patients for nephropathy [16]. Its adult dose
is 25mg, 50 mg and 100 mg once daily based on the
requirement as prophylactic, for treatment and in
severe conditions [17]. It is almost completely
absorbed from following oral administration but its
bioavailability has been limited (33%) due to
extensive first pass metabolism [10]. It can used for
the therapy of symptoms or disease that according to
circadian rhythms and chronobiology become worse
during night or in early morning (fax and
mulcuhy1991) [2]. For these cases conventional drug
delivery system are inappropriate for the delivery of
drug, as they cannot be administrated just before the
symptoms are worsened because at that time the
patients are sleeping [2]. Hence, an attempt was made
to formulate pulsatile drug delivery system of losartan
potassium which can deliver the drug after lag time of
5-6 h.
Chronomodulated drug delivery system (ChDDS) can
be defined as a system where drug is released
suddenly after a well-defined lag time according to the
circadian rhythm of the disease [18, 19]. ChDDS can
be classified according to the pulse-regulation of drug
release into three main classes; time-controlled
pulsatile release (single or multiple unit system),
internal stimuli induced release and external stimuli-
induced pulsatile release systems [20]. PDDS can also
be classified according to the dosage form into three
main types; capsules, pellets and tablets among which
the ‘core-in-cup’ tablet system.
The core-in-cup tablet system consists of three
different parts: a core tablet, containing the active
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS) | JAN-MAR 2016 |VOLUME 5 | ISSUE 1 | 05-15 | www.ijpbcs.net
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ingredient, an impermeable outer shell and a top cover
plug layer of a soluble polymer [21].
The objective of the present investigation is to design
and evaluate Losartan Potassium pulsatile core-in-cup
tablets as to optimize the drug release after a certain
lag time expecting an improvement in its
bioavailability and to meet therapeutic needs relating
to particular pathological conditions.
MATERIALS
Losartan Potassium was obtained from Cirex Pharma
Pvt Ltd, Hyderabad, India. Cellulose Acetate
Propionate was obtained from S.D. Fine Chem. Ltd.,
Mumbai. Sodium Alginate (SA, 200 cps of 1% w/v
aqueous solution), Sodium Carboxy Methyl Cellulose
(Na CMC, 1500 cps of 1% w/v aqueous solution) and
Hydroxy Propyl Methyl Cellulose K4M (HPMC 4000)
was obtained from ozone international Mumbai. All
other reagents and chemicals used were analytical
grade.
METHODS
Flowability Studies
The angle of repose of the core formulation mixture
was determined by the fixed funnel method [22]. The
fluff bulk density (FBD) and tapped bulk density
(TBD) were determined by using a tapped density
tester (Copley, UK). The Compressibility Index
(Carr’s Index) (%) and the Hausner ratio were
calculated as follows: [19]
Carr’s Index (%) = TBD – FBD ×100
Hausner Ratio = TBD
Solubility Studies
Losartan Potassium solubility was investigated in 0.1
N HCl, phosphate buffer (pH 6.8) and distilled water.
A known excess amount of Losartan Potassium was
added to a flask containing 25mLof each medium. The
flasks were shaken for 24 h in a water bath at 37°C
and then they were left to attain equilibrium for
another 24 h. Solutions were filtered, diluted and
analyzed using UV-Visible spectrophotometer (PG
Instruments limited, T-80 UV-Visible
Spectrophotometer) at 230nm [19].
Tablet Preparation
The tablets were prepared using Rimek Mini Press-I
with suitable flat face punches. The system is
consisted of a core-in-cup tablet (Figure 1). The core
tablet was made of 50 mg of Losartan Potassium using
flat punches (6mm). An impermeable coating cup
consisting of cellulose acetate propionate was applied
under the bottom and around the core tablet. The
cellulose acetate propionate powder (100mg) used in
the under bottom coating layer was filled into a die of
10mm diameter and then was gently compacted to
make a powder bed with a flat surface. The core tablet
was in turn carefully placed in the center of the
powder bed. Next, the die was filled with the
remainder of the coating powder (65 mg) so that the
surrounding surfaces of the core tablet were fully
covered. On the top was added the hydrophilic
swellable material (30, 60, 90 or 120 mg), which
consists of sodium alginate or sodium carboxy methyl
cellulose or HPMC K4M. Last, the bed was
compressed to produce the desired core-in-cup system
using Rimek Mini Press-I, (total weight 240, 270, 300
or 330 mg). The composition of core-in-cup
formulations was depicted in Table 1 [21].
TBD
FBD
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
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Figure 1: Schematic representation of core-in-cup tablet
Table 1: Composition of Losartan Potassium core-in-cup formulations
LSA: Formulation containing Sodium Alginate, LHPC: Formulation containing Hydroxy Propyl Methyl Cellulose K4M,
LSCMC: Formulation containing Sodium Carboxy Methyl Cellulose
Physicochemical Characterization of Tablets
The prepared core tablets were subjected to uniformity
of thickness and diameter using Vernier calipers. The
tests were carried out on 20 randomly selected tablets
[19].
Tablet tensile strength is the stress needed to fracture a
tablet by diametral compression. It is given by Fell
and Newton as in Equation.
T= 2P/_Dt ………………………………. (1)
Where, P is the fracture load that causes tensile failure
of a tablet of diameter D, and thickness t. The fracture
load (kg) of ten tablets was determined individually
with a Monsanto hardness tester (Tab Machines,
Mumbai, India), using the procedure of Brook and
Marshal [23]. The mean values of the fracture loads
were used to calculate T values for the various tablets
[7].
Formulation
Losartan
Potassium
(Mg)
Cellulose
Acetate
Propionate (Mg)
Sodium
Alginate
(Mg)
Hpmc
K4m
(Mg)
Sodium
Carboxymethyl
Cellulose (Mg)
Total
Weight
(Mg)
LSA-1 50 160 30 - - 240
LSA-2 50 160 90 - - 270
LSA-3 50 160 60 - - 300
LSA-4 50 160 120 - - 330
LHPC-1 50 160 - 30 - 240
LHPC-2 50 160 - 60 - 270
LHPC-3 50 160 - 90 - 300
LHPC-4 50 160 - 120 - 330
LSCMC-1 50 160 - - 30 240
LSCMC-2 50 160 - - 60 270
LSCMC-3 50 160 - - 90 300
LSCMC-4 50 160 - - 120 330
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
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Weight variation test of tablet (n=20) was carried out
as per official method [24, 25].
The disintegration time method described in the
British Pharmacopoeia [26] was followed using water
maintained at 37±2°C as the disintegration fluid. Six
tablets were placed in disintegration apparatus
(Electrolabs, Model, ED-2L Mumbai, India)) for each
determination. It was carried out in triplicate and the
mean results reported [16].
Percent drug content of Losartan Potassium can be
determined using 5 tablets which were weighed and
crushed to fine powder. The powder equivalent to 50
mg of drug was weighed out, transferred to a 100 ml
volumetric flask and made up the volume with
phosphate buffer (pH 6.8).The resulting solution was
filtered and 1ml of it diluted to 10 ml with phosphate
buffer. The absorbance of the resulting solution was
measured at 230 nm using a spectrophotometer and the
drug content was computed [7].
Lag Time
The lag time was determined by visual observation of
the pulsatile tablet in USP II paddle apparatus
(medium: 0.1 N HCl for 2 h followed by phosphate
buffer, pH 6.8, at 37°C, rotation speed 50 rpm) and
was determined as time point, when the outer coating
ruptured (n=3) [25].
In Vitro Drug Release
The in vitro dissolution study of various pulsatile
tablets was carried out in 900 ml of 0.1 N HCl for first
2 h, followed by 900 ml of phosphate buffer (pH 6.8).
The dissolution medium was maintained at
temperature 37±0.5°C. The paddle speed was set at 50
rpm. At different time intervals 5 ml of sample was
withdrawn and analysed by UV/Vis spectrophotometer
at 230 nm. At each time of withdrawal, 5 ml of fresh
corresponding medium was replaced into dissolution
vessel. The time when 10% or more of Losartan
Potassium dissolved in medium was defined as end of
lag time in this experiment. The test was performed in
triplicate [25].
Stability Studies
The selected formulations were tested for their
stability according to the International Conference of
Harmonization (ICH) guidelines under both standard
long-term and accelerated storage conditions.
Tabletswere enclosed in polyethylene Petri dishes.
Half of the tablets was loaded in a desiccator
containing anhydrous CaCl2 kept at 25°C and 60% RH
for 3 months. The other half was kept in a stability
cabinet (Climacell-MMM, Germany) adjusted at 40°C
and 75% RH for 3 months. At specified time intervals,
the tablets were examined for their physical
appearance and in vitro drug release [19].
Fourier Transform Infra Red (FTIR) Studies
The FTIR spectrum of the different samples were
recorded with an infra-red spectrometer (Shimadzu,
Model 84005, Japan) using potassium bromide discs
prepared from powdered samples. The spectrum was
recorded in the region of 4000 to 400 cm-1 [7].
RESULTS AND DISCUSSION
Flowability Studies
For direct compression of materials, it is required to
possess good flow and compacting properties.
According to USP, values for angle of repose 31-35°
generally indicate good flow property. A Hausner ratio
of less than 1.25 and Carr’s index of 16-20 indicate
fair flow [27].
Losartan potassium exhibited angle of repose, Carr’s
index and Hausner ratio 24°±1.2°, 8.336±0.58% &
1.09 ± 0.1, respectively, which indicated the good flow
property.
Solubility Studies
The available literature on solubility profile of losartan
potassium indicated that the drug is freely soluble in
water. The results of losartan potassium solubility in
water, 0.1N HCl & phosphate buffer pH 6.8 were
found to be 1.239 gm/ml, 1.377 gm/ml and 1.289
gm/ml respectively.
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
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Physico-Chemical Characterization of Tablets
The thickness of core tablet and core-in-cup tablets
was found to be 2.32±0.45mm and 3.32±0.04 to
5.83±0.09mm respectively. The diameter of core
tablets and core-in-cup tablets was found to be
6.01±0.01mm and 10.03±0.02mm to 10.04±0.01
respectively. The core tablets and core-in-cup tablets
showed a uniform thickness and diameter as shown in
Table 2 & 3.
The hardness of the core tablet and core-in-cup tablets
was found to be 2.5±025 kg/cm2 and 5.50±0.02 to
8.50±0.01 kg/cm2 respectively as shown in Table 2 &
3
The friability of core tablet and core-in-cup
formulations was found to be 0.7415% and 0.69 to
0.83% respectively which was within the
pharmacopeia limits as shown in Table 2 & 3.
The weight variation of core tablet and core-in-cup
tablets were found to be within the range of
49.16±0.47 mg and 241.5±1.3 to 335±0.08 mg as
shown in Table 2 & 3. All the tablets passed weight
variation tests as the average % weight variation was
within 7.5% i.e. in the pharmacopeia limits.
The disintegration time of core tablet was found to be
22±0.05sec as shown in Table 2.
The drug content of core-in-cup tablets was found to
be within the range of 97.23% to 99.01% 9 i.e., in the
pharmacopeia limits as shown in Table 3.
Table 2: Physico-chemical characterization of Losartan Potassium core tablet
Parameter Observation
Thickness* 2.32±0.45 mm
Diameter* 6.01±0.01 mm
Hardness* 2.50 ± 0.25 kg/cm2
Weight variation 49.16 + 0.47mg
Friability (%) 0.7415 (%)
Disintegration time 22±0.05sec
Each value represents the mean ±SD (n =3).
Table 3: Physico-chemical characterization of Losartan Potassium core-in-cup tablet formulations
Each value represents the mean ±SD (n =3).
Formulation
Hardness*
(kg/cm2)
±SD
Thickness*
(mm)±SD
Diameter*
(mm)±SD
Weight
variation
(mg)±SD
Friability
(%)
Drug content
(%)±SD
LSA-1 5.50±0.02 3.32±0.04 10.02±0.06 241.5±1.30 0.72 97.56±2.03
LSA-2 5.60±0.06 4.81±0.03 10.01±0.07 273.5±0.60 0.74 98.67±1.80
LSA-3 6.50±0.01 5.25±0.08 10.03±0.02 299.0±0.07 0.74 97.67±2.30
LSA-4 6.51±0.02 5.81±0.03 10.01±0.01 332.0±0.08 0.75 99.01±0.09
LHPC-1 6.00±0.05 4.12±0.04 10.04±0.01 243.0±0.05 0.73 97.78±1.18
LHPC-2 5.50±0.03 4.35±0.07 10.04±0.02 268.4±0.06 0.73 98.89±1.06
LHPC-3 8.00±0.05 5.22±0.03 10.03±0.06 301.8±0.70 0.77 99.01±0.25
LHPC-4 8.50±0.01 5.83±0.09 10.02±0.07 332.0±0.70 0.79 97.23±1.25
LSCMC-1 4.50±0.05 4.10±0.09 10.00±0.02 242.0±0.08 0.69 97.99±1.89
LSCMC-2 4.50±0.03 4.35±0.07 10.00±0.02 271.5±0.60 0.68 97.78±1.18
LSCMC-3 5.50±0.02 5.32±0.03 10.05±0.02 310.0±0.07 0.75 98.89±1.06
LSCMC-4 6.59±0.04 5.83±0.09 10.01±0.03 335.0±0.08 0.83 99.01±0.25
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS) | JAN-MAR 2016 |VOLUME 5 | ISSUE 1 | 05-15 | www.ijpbcs.net
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Lag Time and In Vitro Drug Release Studies
Sodium Alginate, Sodium CMC and HPMC K4M
were chosen as the most suitable plug polymers for
designing of Losartan Potassium core-in-cup tablet
formulations based on a number of preliminary
studies, as shown in Table 1. To choose the most
appropriate plug polymer among them, further release
studies were conducted.
Figure 2 shows the in vitro release profile of
formulations containing Sodium Alginate (LSA1 to
LSA4). LSA1, LSA2, LSA3 & LSA4 showed a lag
time of 1 h, 2 h, 2 h & 2 h respectively with drug
release of 97.48% at 5 h, 96% at 6 h, 98.04% at 6 h &
98.61% at 7 h, respectively.
Figure 3 shows the in vitro release profile of
formulations containing HPMC K4M (LHPC1 to
LHPC4). LHPC1, LHPC2, LHPC3 & LHPC4 showed
a lag time of 3 h, 3 h, 5 h & 7 h respectively with drug
release of 96.92% at 8 h, 97.19% at 9 h, 98.74% at 10
h & 97.96% at 11h, respectively.
Figure 4 shows the in vitro release profile of
formulations containing NaCMC (LSCMC1 to
LSCMC4). LSCMC1, LSCMC2, LSCMC3 &
LSCMC4 showed a lag time of 2 h, 3h, 3h and 3 h,
respectively with drug release of 97.7% at 7 h, 96.37%
at 7 h, 95.97% at 8 h & 98.65% at 8 h, respectively.
In all formulations containing Sodium Alginate,
NaCMC & HPMC K4M, an increase in the polymer
quantity results to a increase in lag time and decrease
of the release rate of the drug from the system [21].
Upon contact of the core-in-cup tablet with the
medium, the plug layer, consisting of SA, NaCMC or
HPMC, absorbs water. Consequently, the polymer
swells and expands. By time the swelling and
expansion of the plug increases creating a barrier
which delays the contact of liquids with the surface of
the core tablet. This process varies with the nature of
the polymer used. It is also suggested that the swelling
of the plug layer may destabilize the plug itself and
gradually leads to its erosion or removal. Therefore,
the swelling and destabilization of the plug polymer
control the rate by which the plug layer polymer
erodes. At the end, according to the properties of each
polymer, the plug is completely eroded and water
ingress into the core increases heavily resulting in
rapid drug release [19, 28].
In formulations containing LSA1 to LSA4, Sodium
Alginate shrinks at low pH. In gastric fluid the
hydrated Sodium Alginate is converted into a porous,
insoluble alginic acid skin. After passed into the
higher pH medium, the alginic acid is converted to
soluble viscous layer. The pH dependent behavior and
rapid dissolution of sodium alginate in higher pH
range results in release of Losartan Potassium at pH
6.8. Sodium Alginate can be used as a biological on-
off switch with which the release of drugs can be
controlled by the external pH change due to its
swelling behavior [19, 28].
In formulations containing NaCMC (LSCMC1 to
LSCMC4), NaCMC, as a polyelectrolyte gel, is very
sensitive to pH changes. The neutralization of charges
in acid medium affects the polymer chain
conformation and leads to a tight network structure.
The chain arrangement generates a system of
connected channels in the gel matrix that controls the
drug release process in a biological environment. In
phosphate buffer pH 6.8, NaCMC gels show a lower
dynamic viscosity in comparison with that in an acid
medium. The system has a liquid-like character and
looser structure of NaCMC. This behavior is typical
for normal solutions of conformationally disordered
(random coil) polymers interacting by physical
entanglement. The weak gel structure determines the
ability of NaCMC polymer chains to disentangle from
the polymer network and dissolve. This results in a
faster erosion of hydrogel matrix and enhances the
drug release [19, 29].
According to the previous facts, NaCMC was expected
to show faster dissolution behavior. Unexpectedly,
Sodium Alginate exhibited much faster dissolution
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
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upon elevating the pH of the medium than NaCMC.
This could be resulted from the higher viscosity of the
used grade of NaCMC relative to that of SA. NaCMC,
with the higher viscosity, displays the most rapid and
the greatest bulk swelling which lasts longer than SA.
After maximum swelling of both polymers was
achieved, a tendency to rapid decrease of swelling was
observed, which appeared to be greater for SA,
followed by NaCMC. Apparently, NaCMC, the
polymer with the maximum volume increase,
exhibited the slower drug release [19, 21].
In formulations containing HPMC K4M (LHPC1 to
LHPC4), the sensitivity of HPMC gel (plug layer) to
pH changes is not significant in comparison with the
NaCMC or SA gels. Its rheological properties are not
influenced by the medium pH. The system keeps its
elastic characteristic at pH 1.0, which determines its
ability to retain the network structure for a long period
of time. In pH 6.8, the elastic viscosity is almost the
same. This behavior indicates the absence of
entanglement coupling [29].
As HPMC K4M, was characterized by its high
viscosity, gel layer was sufficiently resistant to
extensive erosion even after thorough hydration which
was accompanied by path length increase [30].
Therefore, it was logic to get the lowest drug release in
comparison with Sodium Alginate and NaCMC which
have lower viscosities.
Accordingly, in vitro release rate of Losartan
Potassium from LHPC3 was the most convenient one
among the previously studied tablet formulations
showing an optimum lag time of 6hrs followed by a
drug release after changing pH from1.2 to 6.8
Each value represents the mean ±SD (n =3).
Figure 2: In vitro drug release profile of formulations containing sodium alginate (LSA1 TO LSA4)
Each value represents the mean ±SD (n =3).
Figure 3: In vitro drug release profile of formulations containing HPMC K4M (LHPC1 to LHPC4)
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 2 4 6 8
CU
MM
UL
AT
IVE
PE
RC
EN
TA
GE
DR
UG
RE
LE
AS
E
TIME (HRS)
LSA1
LSA2
LSA3
LSA4
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 2 4 6 8 10 12
CU
MM
UL
AT
IVE
PE
RC
EN
TA
GE
DR
UG
RE
LE
AS
E
TIME (HRS)
LHPC1 LHPC2 LHPC3 LHPC4
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Each value represents the mean ±SD (n =3).
Figure 4: In vitro drug release profile of formulations containing Sodium CMC (LSCMC1 to LSCMC4).
Stability Studies
LHPC3 tablets were kept at 25 °C and 60% RH for 3
months (standard long-term storage conditions) and
40°C and 75% RH for 3 months (accelerated storage
conditions). The rate of drug release from LHPC3 did
not change significantly (P > 0.05) after storage under
both regular and accelerated conditions. In addition,
LHPC3 did not show dramatic changes in appearance
during the study period. A slight plug layer swelling
was observed at the end of the study period under
accelerated storage conditions which did not affect the
drug release profile significantly (P > 0.05).
FTIR Studies
In order to investigate if there is any interaction
between added excipients and Losartan Potassium in
the core-in-cup tablet, the FTIR of the Losartan
Potassium, cellulose acetate propionate, HPMC K4M
and the optimized formulation LHPC3 were
determined as shown in Figure 5. All the characteristic
peaks observed for both drug and excipient remained
unchanged and the spectra data was superimposed.
This observation ruled out the possibility of chemical
interaction and modification between the Losartan
Potassium and added excipients during the production
process.
Figure 5: FTIR Spectrum of (A) Losartan Potassium (B) HPMC K4M (C) Cellulose Acetate Propionate (D)
Optimized Formulation LHPC3.
0.00
20.00
40.00
60.00
80.00
100.00
120.00
0 2 4 6 8 10
CU
MM
UL
AT
IVE
PE
RC
EN
TA
GE
DR
UG
RE
LE
AS
E
TIME (HRS)
LSCMC1
LSCMC2
LSCMC3
LSCMC4
Ramya Krishna. T et al; Design And Evaluation of Losartan Potassium Chronomodulated Delivery System……..
International Journal of Pharmaceutical, Biological and Chemical Sciences (IJPBCS) | JAN-MAR 2016 |VOLUME 5 | ISSUE 1 | 05-15 | www.ijpbcs.net
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CONCLUSION
A chronomodulated core-in-cup drug delivery system
for oral use was developed and evaluated. The
formulation consisted of a core tablet, containing the
drug, an impermeable outer shell and a top cover
swellable layer. The results suggested that the
described system released the drug after a certain lag
time, which could be modified by several factors. The
quantity of material in the top layer and polymer
characteristics are important factors in controlling the
lag time and drug release. The lag time increases by
increasing the quantity of the hydrophilic top cover
layer. In contrast, drug release was found to decrease.
Thus, we concluded that the top cover layer and
especially the erodible polymeric material, from which
this layer consists, regulate the performance of the
system. Formulation LHPC3 with a predetermined lag
time of 5 h with drug release of 98.74% was taken as
the optimized formulation and it was observed that no
modification and/ or chemical interaction throughout
the process of formulation. Hence from the above
study it was concluded that HPMC K4M is suitable for
the development of chronotherapeutic drug delivery
systems with Losartan Potassium.
Thus this approach can provide a useful means for
pulsatile/programmable release and may helpful for
patients with morning surge. This work can also be
extended for variety of drugs suitable for
chronotherapy.
ACKNOWLEDGEMENT
The author Ramya Krishna T is much thankfull to Dr.
Suresh B and Dr. Jaswanth A (guides) for his valuable
support. The author is also thankfull to Dr. Sanjeev
Kumar Subudhi, Dr. J Venkateshwar Rao, faculty and
management of Talla Padmavathi Pharmacy College
for their invaluable suggestions for improvement,
support abd constant encouragement.
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