I J P B C S Original Research Article · Ramya Krishna. T1*, Suresh. B2, Jaswanth. A3 1 Talla Padmavathi Pharmacy College, Orus, Warangal, Telangana, India 2 St. Peter’s Institute

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

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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.

mailto:[email protected]

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



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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



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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



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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.



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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


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



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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.


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.


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



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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


Figure 2: In vitro drug release profile of formulations containing sodium alginate (LSA1 TO LSA4)


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

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TA

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DR

UG

RE

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TIME (HRS)

LSA1

LSA2

LSA3

LSA4

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60.00

80.00

100.00

120.00

0 2 4 6 8 10 12

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MM

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DR

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TIME (HRS)

LHPC1 LHPC2 LHPC3 LHPC4



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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

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TA

GE

DR

UG

RE

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TIME (HRS)

LSCMC1

LSCMC2

LSCMC3

LSCMC4



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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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*Corresponding author Email address:

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Documents

I J P B C S Original Research Article · Ramya Krishna. T1*, Suresh. B2, Jaswanth. A3 1 Talla Padmavathi Pharmacy College, Orus, Warangal, Telangana, India 2 St. Peter’s Institute