S130 Asian Pacific Journal of Tropical Disease (2012)S130-S135

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Asian Pacific Journal of Tropical Disease

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Document heading

Formulation and evaluation of sublingual tablets of losartan potassium

Nikunj J. Aghera*, Suresh D. Shah, Kantilal R. Vadalia
Shree H. N. Shukla Institute of Pharmaceutical Education and Research, Rajkot-360002, Gujarat, India

ARTICLE INFO ABSTRACT

Article history: Objective: Sublingual tablets of Losartan Potassium were prepared to improve its bioavailability,
Received 5 June 2012 to avoid pre-systemic metabolism in the gastrointestinal tract and hepatic first pass elimination.
Received in revised form 27 July 2012 Methods: The Sublingual tablets were prepared by direct compression procedure using
Accepted 18 October 2012
different concentration of Starch 1500 and microcrystalline cellulose. Compatibility studies of
Available online 28 October 2012
drug and polymer were performed by FTIR spectroscopy and DSC. Preformulation property of
API was evaluated. Postcompressional parameters such disintegration time, wetting time, water
Keywords: absorption ratio, in vitro drug release and in vivo bioavailability study of optimized formulation
Sublingual tablet were determined. Results: FTIR spectroscopy and DSC study revealed that there was no possible
Losartan Potassium interaction between drug and polymers. The precompression parameters were in acceptable
Hypertensio range of pharmacopoeial specification. The disintegration time of optimized formulation (F3) was
Starch 1500 upto 48 sec. The in vitro release of Losartan Potassium was upto 15 min. The percentage relative
microcrystalline cellulose bioavailability of Losartan Potassium from optimized sublingual tablets was found to be 144.7 %.
In vivo study Conclusions: Sublingual tablets of Losartan Potassium were successfully prepared with improved
bioavailability.

1. Introduction enzyme degradation in the gut and liver. These formulations

are particularly beneficial to pediatric and geriatric
Development of a formulation involves a great deal of study patients. In addition sublingual mucosa and abundance of
and experimental work to get optimum results. While doing blood supply at the sublingual region allow excellent drug
so we have to keep in mind various factors are considered penetration to achieve high plasma drug concentration with
like choice of excipients, drug bioavailability, drug stability rapid onset of an action [1, 2].
in required dosage form , cost effectiveness , manufacturing Hypertension is defined as a systolic blood pressure of 140
aspects i.e. scale-up and last but not the least we have to mmHg or greater and / or a diastolic blood pressure of 90
consider the patients compliance and convenience. mmHg or greater. Losartan potassium is an angiotensin II
Now a day’s formulation research is breaking barriers of receptor antagonist. It suppresses the effects of angiotensin
conventional methods. Today, active ingredients can be II at its receptors, thereby blocking the rennin angiotensin
delivered with a level of convenience, performance and system. The rennin angiotensin system plays a crucial role
bioavailability. in the control of blood pressure, and in particular it is felt
First pass metabolism can be overcome by sublingual to play crucial role in hypertension. Losartan has been
drug delivery, and quick drug delivery into the systemic demonstrated to be superior to previous peptide receptor
circulation can be obtained. Sublingual administration can antagonists and angiotensin converting enzyme ( ACE )
offer an attractive alternative route of administration. The inhibitors because of its enhanced specificity, selectively,
advantage of the sublingual drug delivery is that the drug and tolerability. Generally, losartan potassium is employed
can be directly absorbed into systemic circulation bypassing in the management of essential hypertension with lower
incidence of side effects like cough. It is readily absorbed
*Corresponding author: Nikunj J. Aghera Shree H.N.S.I.P.E.R., C/o B.M. Kyada and undergoes rapid hepatic metabolism to an active
Campus, Nr. LalPari Lake, B/H Marketing Yard, Amargardh - Bichari, Rajkot, 360002
(Gujarat) India.
metabolite, EXP-3174, via cytochrome P-450 system [3].
Contact no: 9586973378
E-mail: [email protected]
 Nikunj J. Aghera et al./Asian Pacific Journal of Tropical Disease (2012)S130-S135
S131

2. Material and methods pharmacopoeia.Tablets are placed in the disintegration

tubes and time required for complete disintegration, that is
2.1 Material without leaving any residues on the screen is recorded as
disintegration time.
Losartan Potassium (Alembic Pharmaceutical Pvt. Ltd,
Baroda), Pearlitol SD 200, Sucrose DC (Nir Life Healthcare 2.2.8 Wetting Time
Pvt. Ltd., Ahmedabad), Starch 1500 (Mepro Pharmaceutical A piece of tissue paper folded twice was placed in a small
Pvt. Ltd., Surendranagar), Sucralose (JK Sucralose, Mumbai) Petri dish (ID = 6.5 cm) containing 6 mL of simulated saliva
the above were the gift sample. pH, a tablet was put on the paper containing amaranth
powder on the upper surface of the tablet, and the time
2.2 Methods required for formation of pink color was measured as
wetting time. Three trials for each batch were performed and
2.2.1 Formulation of Tablets standard deviation was also determined.
Composition of preliminary trials for Sublingual Tablet of
Losartan Potassium by direct compression is shown in table 2.2.9 Water Absorption Ratio
1. All the ingredients were passed through 80# mesh sieve. A piece of tissue paper folded twice was kept in a Petri dish
Required quantity of drug and excipient mixed thoroughly in (internal diameter 6.5cm) containing 6 mL of purified water.
a polythene bag. Finally the talc and aerosil was added and The tablet was placed on the tissue paper and allowed to wet
mixed thoroughly to get free flowing powder. The blend is completely. The wetted tablet was removed and reweighted.
compressed using rotary tablet compression machine with 6
mm tooling punch. 2.2.10 Drug Content Uniformity
T wenty tablets were accurately weighed and finely
2.2.2 Compatibility Study powdered. A quantity equivalent to 25 mg of L osartan
The pure drug Losartan Potassium and the solid admixture Potassium was transferred to a 100 mL volumetric flask. To
of drug and various excipients used in the preparation of it, 50 mL of Phosphate buffer 6.8 was added and shaken for 1
sublingual tablet formulations were characterized by FT-IR hour to dissolve drug. The solution was filtered and residue
spectroscopy and DSC to know the compatibility [4]. was washed with 25 mL of Phosphate buffer 6.8. The washing
obtained was added to initial filtrate and volume was made
2.2.3 Evaluation of Tablets upto 100 mL with Phosphate buffer 6.8. From above solution 1
All the tablets were evaluated for different parameters as, mL of stock solution was diluted to 10 mL. The drug content
hardness, friability, weight variation, disintegration time, was determined spectrophotometrically at 250 nm.
wetting time, water absorption ratio, drug content uniformity,
dissolution study, stability study and in vivo study [5]. 2.2.11 Dissolution Studies
Dissolution studies were carried out for all the formulation
2.2.4 Hardness in USP paddle method (Apparatus 2) using Phosphate buffer
Hardness was measured using the Monsanto hardness 6.8, in the dissolution medium (300 mL) at 50 Rpm and 37
tester. Measured the pressure required to break diametrically 依 0.5 曟. Samples were periodically withdrawn at suitable
placed matrix tablet, by a coiled spring. time intervals and volume replaced with equivalent amounts
of plain dissolution medium. The samples were analyzed
2.2.5 Friability spectrophotometrically at 250 nm [6].
20 tablets were weighed and placed in the roche friabilator 2.2.12 Stability Study
test apparatus, the tablets were exposed to rolling and T he storage conditions used for stability studies were
repeated shocks, resulting from free falls within the accelerated condition (40 曟依 2 曟/ 75 %依 5 % RH) and Room
apparatus. After 100 evolutions the tablets were de-dusted temperature (30 曟依 2 曟 / 65 % RH依 5 %).
and weighted again. The friability was determined as the S tability study was carried out for the optimized
percentage loss in weight of the tablets. formulations. Tablets of optimized formulation were striped
packed and kept in humidity chamber for 30 days on above
2.2.6 Weight Variation mention temperature [7, 8].
It was performed as per the method given in the united
state pharmacopoeia. Tablets were randomly checked to Test performed
ensure that uniform weight tablets were being made. Twenty a.Dissolution profile.
tablets were selected randomly from each formulation, b.Assay
weighed individually and the average weight and % variation c. T est for other physical parameters ( H ardness and
of weight was calculated. Friability).

2.2.7 Disintegration Time 2.2.13 In vivo Study

The disintegration time for sublingual tablets was measured Testing of sublingual tablet, rabbit sublingual cavity serves
using the conventional test for tablets as described in the same purpose as of human. Rabbit having non keratinized
S132 Nikunj J. Aghera et al./Asian Pacific Journal of Tropical Disease (2012)S130-S135

sublingual mucosa as human to correlate in vivo bio- • AUC and percentage relative bioavailability was
availability study of given formulation with conditions calculated. [10, 13]
persisting in the human beings before performing the clinical
trials in the human. For the assessment of the bioavailability % R elative bioavailability was calculated by following
of sublingual tablet Comparative review of several species equation
demonstrate that non keratinized oral mucosa from rabbits, AUC Sublingual Dose Oral
伊100%
% Relative bioavailability = 伊
is acceptable model, yielding permeability values similar AUC Oral Dose Sublingual
to those found for humans. Rabbit and dog are generally ….. (3)
regarded as suitable animal models since the oral cavity of
both are histologically similar to humans. The thickness of
the rabbit mucosa (600 mm) is comparable to humans and 3. Results
offers adequate surface area for experimental work [9 - 11].
Rabbits were used as an animal model for in vivo study and The different batches of Losartan potassium sublingual
permission for laboratory animal was approved by IAEC tablets were prepared by direct compression method
(IAEC/HNSIPER/RJK/13/2011). using various ingredients like Pearlitol SD 200, starch 1500,
HPLC analysis was performed on a reversed-phase column microcrystalline cellulose, sucrose DC, PVP, sucralose etc
using phosphate buffer (pH 4.3), acetonitrile (750:250, v/v) (Table 1).
as mobile phase with a flow rate of 1 mL/min. The limit of
determination with UV detection was at 225 nm. Table 1
Formulation of Batch F1-F5 by Direct Compression Method
Calculation for drug dose for laboratory animals [12] Formulation code (Quantity in mg/Tablet)
HED (mg/kg) = Animal dose (mg/kg) [Animal weight (kg) / INGREDIENTS
F1 F2 F3 F4 F5
Human weight (kg)] ….. (1) Losartan Potassium 25 25 25 25 25
Pearlitol SD 200 65 65 65 65 65
Animal dose = Human dose [Animal weight (kg) / Human Starch1500 0 5 10 15 20
weight (kg)] ….. (2) MCC 22 17 12 7 2
Procedure for tablet administering in rabbit Sucrose DC 10 10 10 10 10
• For sublingual tablet administration, the rabbit’s mouth PVP 2 2 2 2 2
was opened, and a wooden rod was inserted between the Sucralose 3 3 3 3 3

jaws. Aerosil 1 1 1 1 1

• The tongue was elevated by using flat forcep, and the Talc 2 2 2 2 2
Total weight(mg) 130 130 130 130 130
tablet was placed underneath by using another pair of
forceps.
The FT-IR and DSC study did not show any possibility
• The mouth was gently but firmly holds shut for 5 min. with
the wooden rod. of interaction between Losartan Potassium and excipients
(Figure 1 and 2).
• Wooden rod was placed to prevent chewing or swallowing
The Hardness of tablets was determined and was found to
the tablet.
• Water 0.3 to 0.5 mL was administered immediately after be in the range of 3.8 to 4.1 kg/cm2. Percentage Friability was
dosing to facilitate tablet disintegration. observed between 0.58 to 0.72 %, which was in the limit of
• Additional 0.5 to 0.7 mL water was administered at the end range. Weight variation of all the formulations was observed
of the 5 min. immobilization time to remove any remaining which were within the acceptable limit as per United States
Pharmacopoeia (Table 2).
drug from under the tongue.
The wetting time for all the formulations was found to be
• A 0.5-1 mL blood samples were withdrawn before dosing
(18依 2.08) to (25依 3.12) seconds. The water absorption ratio
and immediately after dosing at 30, 60, 120 and 240 min.
• Afterward Blood samples were refrigerate within 1 h of for all formulations was found to be (37.65依 1.97) to (43.31
sampling and centrifuged at 4 oC. 依 3.62). The tablets were subjected for evaluation of in
• Losartan Potassium concentrations were measured by vitro disintegration time. In vitro disintegration time for
using HPLC. formulations F1 to F5 was 48 to 58 seconds. The formulation

Table 2
Hardness, Thickness, Diameter, Percentage Friability and Weight variation of Batch F1-F5
Batch Hardness(kg/cm ) Thickness(mm) Diameter(mm) Percentage Friability Weight variation (mg
2

F1 3.8依 0.25 3.4依 0.04 6.04依 0.02 0.58依 0.03 129.76依 1.3
F2 3.9依 0.38 3.6依 0.02 6.07依 0.01 0.79依 0.04 131.61依 1.4
F3 4.1依 0.47 3.5依 0.03 6.03依 0.03 0.66依 0.03 130.29依 1.1
F4 3.9依 0.36 3.4依 0.01 6.06依 0.07 0.78依 0.07 132.17依 1.3
F5 4.1依 0.33 3.5依 0.02 6.03依 0.03 0.72依 0.01 132.46依 1.8
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F3 showed rapid disintegrating time of 48 seconds this is due

to rapid uptake of water from the medium and burst effect Table 3
(Table 3). Disintegration Time, Drug Content Uniformity, Wetting Time and
Water Absorption ratio of Batch F1-F5
20 Batch Disintegration Drug Content Wetting Time Water Absorption
18
16 Time (sec) Uniformity (sec) Ratio
14
12 F1 57依 3.10 98.76依 1.20 25依 3.12 38.16依 2.12
54依 2.24 99.83依 2.21 21依 2.78 37.65依 1.97
10
8 F2
48依 2.22 99.32依 1.30 18依 2.08 41.63依 2.34
6
4 F3
F4 55依 2.01 98.51依 0.98 22依 1.93 43.31依 3.62
2
0

F5 58依 1.58 99.01依 1.37 25依 2.26 40.12依 1.28

-2
-4
3500 3000 2500 2000 1500 1000 500
Wavenumbers (cm )
-1

Percentage drug content of all the formulations was found

14
12
10
8
to be 98.51 to 99.83 of Losartan Potassium which was within
6
4
the acceptable limit.
2 It was observed that batch F3 showed faster drug release
than all other batch (figure 3). Batch F3 showed 99.13 %
0
-2

cumulative drug release in 15 minute. t50 % of batch F3

-4

was found to be 3 min. Batch F3 was formulated with 10 mg

3500 3000 2500 2000 1500 1000 500
Wavenumbers (cm )
-1

30
25
starch 1500 and 12 mg MCC. Batch F3 was considered as an
20 optimized formulation because of rapid disintegration time
and dissolution profile.
15
10
5
0
-5
-10 120
3500 3000 2500 2000 1500 1000 500
Wavenumbers (cm )
-1

100
Figure 1: FTIR spectrum of Losartan potassium, Excipients and
Physical Mixture of Drug+Excipients
cumulative drug release

80

F1
60 F2
F3

40 F4
%

F5

20

0
0 5 10 15 20

Time (min)

Figure 3: Drug Release Profile of Batch F1-F5

Stability study was performed on batch F3. Various evaluated
parameter is shown in table 4 and figure 4.
141.38C 164.72C

120
142.82C
184.72C
100
cumulative drug release

148.13C
80

60
intial
40
after one month
20
%

188.09C
0
50.00 100.00 150.00 200.00 250.00 300.00
0 5 10 15 20
Temp [C]
Time (min)

Figure 2: DSC Study of Losartan potassium, Excipients and Physical Fig 4: Comparison of Drug Release Profile of Batch F3 for Stability
Mixture of Drug+Excipients Study
S134 Nikunj J. Aghera et al./Asian Pacific Journal of Tropical Disease (2012)S130-S135

Table 4
Comparision of Various Parameters for Stability Study 60

Evaluation Parameter Initial After One month 50

Hardness 4.10依 0.47 4.30依 0.36

Plasma cone. (毺g/mL)

Percentage Friability 0.66依 0.03 0.64依 0.06 40

Disintegration Time (sec) 48.00依 2.22 51.00依 1.47

30
Drug Content 99.32依 1.30 98.00依 1.12 sublingual
20 oral

In vivo study was also performed by taking optimized 10

formulation F3 and result was compared with oral Losartan
Potassium tablet. Rabbit was used as animal model for
0
0 1 2 3 4 5

in vivo studies. The blood samples were withdrawn Time (h)

at different time intervals were analyzed for the drug

content by HPLC. AUC for plasma concentration time Figure 7: Plasma Concentration Time Profile of Oral and Sublingual
profile of sublingual and oral Losartan Potassium are shown Losartan Potassium Tablets

in figure 5 - 8 . C max and T max for sublingual L osartan

Potassium was found to be 51.25 毺g/mL and 2 h respectively.
The percentage relative bioavailability was calculated by 60

equation 3 and was found to be 144.7 %. Results of in vivo 50

sublingual
study showed that sublingual Losartan Potassium have 40
oral
Cone (毺g/mL)
improved bioavailability.
30

20

10
60

0
50
0 0.5 1 2 4
Cone (毺g/mL)

40
Time (h)
30
oral
Figure 8: Comparison for Plasma Concentration Time Profile of
20
Sublingual and Oral Losartan Potassium Tablets
10

0
0 1 2 3 4 5 4. Discussion
Time (h)

The different batches of Losartan potassium sublingual

Figure 5: AUC for Plasma Concentration Time Profile of Oral Losartan
Potassium Tablet tablets were prepared by direct compression method
using various ingredients like Pearlitol SD 200, starch 1500,
microcrystalline cellulose, sucrose DC, PVP, sucralose
60 etc. T otal number of five formulations with different
50 concentration of starch 1500 and MCC were prepared and
40
evaluated. Result are shown in Table 2, 3 and 4
The FT-IR and DSC study revealed that there was no any
Cone (毺g/mL)

30
sublingual
possibility of interaction between Losartan Potassium and
20
excipients. Pearlitol SD 200 act as a diluents and it also
10 act as a sweetener. There was direct correlation between
0 wetting time and disintegration time. S tarch 1500 and
0 1 2 3 4 5 microcrystalline cellulose act as a disintegrating agent.
Time (h) B atch F 3 was considered as a optimized formulation.
Figure 6: AUC for Plasma Concentration Time Profile of Sublingual Disintegration of batch F3 was less than all other batch.
Losartan Potassium Tablet H ardness and F riability of batch F 3 were also good.
Stability study and in vivo study were performed on Batch
F3. Stability study indicated that there was no any change
after one month. In vivo study was performed on rabbits. In
vivo study revealed that sublingual tablets have improved
 Nikunj J. Aghera et al./Asian Pacific Journal of Tropical Disease (2012)S130-S135
S135

bioavailability A.K. Recent Trends of Fast Dissolving Tablet - An Overview of

Formulation Technology. International Journal of Pharmaceutical
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sublingual tablets prepared by direct compression with different
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in serving the desired objective of management of [3] S angeetha, V enkatesh D . N , K rishan P . N and S araswathi R .
H ypertension. T he excipients used in the formulation Mucosa as a route forsystemic drug delivery. Research Journal
were inexpensive and are easily available. Most of the of Pharmaceutical, Biological and Chemical Sciences July -
excipients used in formulation are water-soluble September 2010; 1: 178-187.
and hence have a better patient acceptability. The [4] Pandya V.M, Patel D.J, Patel J.K and Patel R.P. Formulation,
present work of formulating a sublingual tablet containing Characterization, and Optimization of Fast-Dissolve Tablets
Losartan potassium was successful in terms of reducing Containing Celecoxib Solid Dispersion. Dissolution Technology
manufacturing difficulties, cost and providing a better November 2009; 22-27.
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