FORMULATION AND EVALUATION OF LORNOXICAM …ijpi.org/wp-content/uploads/march2013/4.pdf · polymer ratios on physical characteristics of the microsponges were investigated. ... a

INTERNATIONAL JOURNAL OF RESEARCH ARTICLE PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

29 | P a g e Volume 3, Issue 2, March ₋ April 2013 http://www.ijpi.org

FORMULATION AND EVALUATION OF LORNOXICAM MICROSPONGE

TABLETS FOR THE TREATMENT OF ARTHRITIS

*Karthika.R , Elango.K , Ramesh Kumar.K , Rahul.K

Department of Pharmaceutics, College of Pharmacy, Madras Medical College, Chennai, India

Abstract

The purpose of this study was to design novel drug delivery system containing Lornoxicam

microsponges. Lornoxicam is a Non-steroidal anti-inflammatory drug used for the treatment

of various inflammatory diseases. Microsponges containing Lornoxicam and Eudragit RS

100 were prepared by quasi emulsion solvent diffusion method. The effects of drug to

polymer ratios on physical characteristics of the microsponges were investigated.

Compatibility of drug with adjuncts was studied by FT-IR. Production yield, loading

efficiency, particle size analysis, surface morphology and in-vitro release studies were carried

out. The microsponges were compressed into tablets. Mechanically strong tablets were

obtained owing to the plastic deformation of sponge-like structure of microsponges. The

effects of different stirring rates, amount of solvent, amount of emulsifier used on the

physical characteristics of the microsponges were investigated. All the factors studied had an

influence on the physical characteristics of the microsponges. In-vitro dissolution studies

were done on all formulations and the results were kinetically evaluated and the release rate

of Lornoxicam was found to be modified. This study presents a new approach based on

microsponge drug delivery system.

Keywords: Microsponges, Lornoxicam, Quasi-emulsion solvent diffusion method,

Morphology, Release kinetics

INTRODUCTION

Many of conventional delivery systems

require high concentrations of active

agents to be incorporated for effective

therapy because of their low efficiency as

delivery systems. Thus novel drug delivery

systems have been increasingly

investigated to achieve targeted and

controlled release of drugs. Microsponges

are highly crosslinked, patented, porous,

polymeric microspheres that acquire the

flexibility to entrap a wide variety of

active ingredients that are mostly used for

prolonged topical administration and

recently for oral administration.

Microsponges are designed to deliver a

pharmaceutically active ingredient

efficiently at minimum dose and also to

enhance stability, elegance, flexibility in

formulation, reduce side effects and

modify drug release profiles. [1, 2]

Microsponges are prepared by several

*Corresponding author

Karthika.R



methods utilizing emulsion systems as

well as by suspension polymerization in a

liquid-liquid system. The most common

emulsion system used is Quasi-emulsion

solvent diffusion method. [2]

Lornoxicam, a congener of tenoxicam, is

a new NSAID belonging to the oxicam

class. It is a strong analgesic and anti-

inflammatory NSAID as compared to

other NSAIDs. Chemically its 6-chloro-

4-hydroxy-2-methyl-N-2-pyridyl-2H-

thieno-[2, 3-e]-1, 2-Thiazine-3-

carboxamide-1,1-dioxide. Like all

NSAIDs, it acts by inhibiting the

metabolites of COX branch of

arachidonic acid pathway. Half-life of

Lornoxicam is 3-5 hours, which increases

the dosing frequency of the drug. The

increased dosing frequency leads to side

effects. Thus the present study is aimed at

developing microsponge based novel

drug delivery system containing

Lornoxicam. The microsponges of

Lornoxicam were prepared and

characterized. They were formulated as

tablets and subjected to in-vitro

characterization for various attributes. [3]

MATERIAL AND METHODS

Lornoxicam was obtained as a gift

sample from Glenmark Pharmaceuticals

Ltd., Eudragit RS 100 was obtained from

MMC Healthcare, Chennai, Polyvinyl

alcohol was procured from S.D Fine-

Chem Limited, Mumbai, Triethyl citrate

was purchased from Himedia laboratories

Pvt.Ltd, Ethanol was from

ChangshuYangyuan Chemical, China,

Magnesium stearate from Indian

Research Products, Chennai, Micro

crystalline cellulose from Kniss

Laboratories, Chennai, Talc from S.S

Chemicals, Chennai, Lactose from

Microfine Chemicals, India. All other

chemicals and solvents were of analytical

reagent grade.

Preparation of Lornoxicam

microsponges

Lornoxicam microsponges were prepared

by quasi emulsion solvent diffusion

method. The internal phase consisted of

Eudragit RS 100 (100mg) and triethyl

citrate dissolved in 5ml ethanol. Triethyl

citrate was used as plasticizer. This was,

followed by addition of drug with gradual

stirring. The internal phase was then

poured into polyvinyl alcohol (0.5%w/v)

solution in water, the external phase.

After 2 hours of stirring the microsponges

were formed due to the removal of

ethanol from the system. The

microsponges were filtered and dried at

40˚C for 24 hours. The composition of

microsponge formulations are given in

table1.

Fourier transform infrared analysis

Infrared spectroscopy was conducted

using FT-IR spectrophotometer and the

spectrum was recorded in the wavelength

region of 4000 to 400 cm-1

. The

procedure consisted of dispersing the

sample (drug alone, mixture of drug and

excipients and the optimized formulation)

in KBr and compressed into discs by

applying a pressure of 5 tons for 5

minutes in a hydraulic press. The pellet

was placed in the light path and the

spectrum was recorded. [4]

Surface morphology of microsponges

The surface morphology of the prepared

microsponges was examined using a

scanning electron microscope, operating at



20 kV. Dried microsponges were coated

with gold–palladium alloy for 45sec under

an argon atmosphere before observation.

SEM photograph was recorded at different

magnifications using Tescan VEGA3SBU

SEM analyzer. [5]

Determination of percentage yield [5]

The production yield of the microsponges

was determined by calculating accurately

the initial weight of the raw materials and

the weight of the microsponge obtained,

WPr

Production yield = × 100

WTh

Where-

WPr = Practical mass of microsponges

WTh = Theoretical mass (polymer + drug)

Determination of loading efficiency [5]

Lornoxicam microsponges equivalent to

50 mg of the drug was taken in a 100 ml

standard flask. 25 ml ethanol and 25ml of

6.8 pH phosphate buffer were added and

shaken for about half an hour and the

volume was made upto 100 ml with 6.8 pH

phosphate buffer. 2 ml of the solution was

taken and diluted to 100 ml with 6.8 pH

phosphate buffer. The absorbance of the

resulting solution was measured at 376 nm

and the content of LOX was calculated.

The loading efficiency (%) of the

microsponges was calculated.

DCact

Loading efficiency = × 100 DCTheo.

DCact. = Actual drug content in

microsponges

DCTheo. = Theoretical drug content

Particle size analysis

Particle size and size distribution of

microsponge particles was determined

using optical microscope. The values are

given for the formulations in the form of

mean particle size.

Micromeritic properties

The drug and blend of drug with excipients

were evaluated for bulk density, tapped

density, compressibility index, Hausner’s

ratio and angle of repose. [6, 7]

Preparation of tablet formulations

After the preparation of lornoxicam

microsponges, they were formulated as

tablets by “Direct compression method”.

All the ingredients were weighed

accurately and mixed thoroughly. The

lubricated blend was then compressed

using 8 mm flat face punch. The

composition of different formulations used

in the study is shown in Table 2.

Evaluation of Lornoxicam microsponge

tablets

The tablets of lornoxicam were evaluated

for uniformity of weight. Thickness and

diameter were measured by vernier

calipers. Hardness was determined using

Monsanto hardness tester and friability of

tablets was determined by Roche

friabilator. [7]

Disintegration test

One tablet was placed in each of the six

tubes of basket, the assembly was

suspended in water, maintained at

temperature 37˚C±2˚C and the apparatus

was operated. The time taken to

disintegrate the tablet completely was

noted. [7]

Drug content

Ten tablets were weighed and ground. The

weight equivalent to 8 mg of drug was



taken and transferred to a 100 ml standard

flask. 25 ml of ethanol and 25 ml of 6.8

pH phosphate buffer were added and

shaken for about half an hour and the

volume was made up to 100 ml with 6.8

pH phosphate buffer. The above solution

was filtered and 5 ml of filtrate was taken

and diluted to 100 ml with 6.8 pH

phosphate buffer. The absorbance of the

resulting solution was measured at 376 nm

and the content of Lornoxicam was

calculated. [7, 8]

Uniformity of content

Six tablets were randomly selected and

tested for their drug content. The content

of active ingredients of various

formulations was calculated by measuring

the absorbance of diluted solutions using

UV-Visible Spectrophotometer at 376 nm. [7]

In-vitro drug release studies

Two step dissolution conditions was used

in USP Type II (paddle) dissolution

apparatus to simulate the physiological

conditions of GIT – 2 hours in 900 ml of

simulated gastric fluid (SGF, pH 1.2) and

10 hours in 900 ml of simulated intestinal

fluid (SIF, pH 6.8). The stirring rate was

100 rpm and the temperature was

maintained at 37 ± 0.5˚C. Aliquots of

dissolution medium were withdrawn at

predetermined time intervals and the same

volume of medium was replenished to

maintain the constant volume. The

absorbance of the solutions was measured

at 376 nm and the release was calculated. [8]

Drug release kinetics

The dissolution profile of optimized

formulation was subjected to various

models such as Zero order kinetics

(percentage drug release against time),

First order kinetics (log percentage drug

unreleased against time), Higuchi

(percentage drug released against square

root of time), Korsemeyer-Peppas (log

percent drug released against log of time)

and Hixson-Crowell (cube root of

cumulative percentage of drug remaining

against time) to assess the kinetics of drug

release from prepared Lornoxicam

microsponges.

RESULTS AND DISCUSSION

Compatibility studies

FT-IR spectra were recorded to assess the

compatibility of the drug and excipients.

FT-IR spectra of drug, physical mixture of

drug and excipients were examined. In FT-

IR spectra of Lornoxicam powder,

characteristic O-H stretching band at

3448.47 cm-1

, C-Cl stretching band at

794.61 cm-1

, SO2 streching band at

1427.22 cm-1

and aromatic C=S stretching

band at 1188.06 cm-1

were seen. These are

the major peaks of the spectra of the drug.

All these peaks were present in the spectra

of formulation and thus confirm that the

drug did not interact with the excipients.

Evaluation of microsponge

Particle size and shape

The SEM photographs of the

microsponges are shown in figure 4.

Particle size analysis showed the particle

size ranging from 75.6 to 45.5 µm and

spherical in shape. Mean particle size of

formulations M1 to M5 is given in table 4.

Production yield and loading efficiency

Production yield and loading efficiency of

Lornoxicam microsponge formulation are

given in table 4. Batch M1 to M5 shows

production yield in the range of 69.35 to



89.65 % and loading efficiency in the

range of 89.25 to 96.39 % as shown in

table 4.

Evaluation of tablets

Micromeritic properties

The Lornoxicam microsponge blends were

free flowing as indicated by the values of

bulk density (0.479 to 0.510 g/ml), tapped

density (0.534 to 0.585 g/ml),

compressibility index (10.29 to 12.82%)

and Hausner’s ratio (1.11 to 1.14). Angle

of repose ranged from 29.11 to 31.16. The

values are given in Table 3.

Physical evaluation and Drug content

The Lornoxicam microsponge tablets were

uniform in weight (0.178 to 0.181g). The

thickness (2.5 mm) and diameter (8.00

mm) of the tablets were uniform. The

hardness of tablets was found to be

between 4.25 and 4.75 kg/cm2, while the

friability of the tablets ranged between

0.44 and 0.6 %. The tablets have enough

hardness to withstand stress during

transport and handling. The disintegrating

time of the various formulations were

found to be between 2.12 and 3.0 min.

Disintegrating time was found to be within

the limits as the maximum time for

uncoated tablets is 30 min. The drug

content in various formulations varied

between 91.22 and 100.6% w/w. (Table 5) [8]

Uniformity of Drug content

The percentage of drug content of all the

formulations ranged from 96.85 and 100.7

% w/w. All the formulations comply with

the test for uniformity of content.

In-vitro drug release

The release profiles obtained for the

microsponge tablets are presented in figure

1. The profiles showed a bi-phasic release

with an initial burst effect. In the first 2

hrs, about 13 to 27% of the drug was

released. Cumulative release for the

microsponges after 12 hrs ranged from 86-

96%. Drug release from the formulations

decreased with increase in the amount of

polymer in the microsponges. [9]

Release Kinetics of the Optimized

formulation

The R2 values for various release models

are 0.919 for Zero order, 0.994 for First

order, 0.966 for Higuchi, 0.948 for

Korsemeyer-Peppas and 0.991 for Hixson-

Crowell kinetics. The drug release follows

first order kinetics and the mechanism

followed is Hixson-Crowell.

Effect of stirring rate on microsponges

The effect of stirring rate on the size of

microsponges was studied. As the stirring

speed was increased, microsponges of

smaller size were obtained. When the rate

of stirring was increased from 200 to 400

rpm, the mean particle size decreased from

59.67 µm to 35.81µm. It was also

observed that at higher stirring rates

employed, turbulence was created within

the external phase, polymer then adhered

to the stirrer and the production yield

decreased, but the drug content increased,

as shown in table 6. [9]

Effect of volume of internal phase on

microsponges

It was observed that on increasing the

volume of internal phase from 5 to 15 ml

microsponges were not formed. This may

be due to the decrease in viscosity of

internal phase. It was observed that the

particle size, production yield and drug

content decreased on increasing internal

phase volume. The result suggests that the



amount of ethanol need to be controlled

within an appropriate range to affect not

only the formation of quasi-emulsion

droplets at the initial stage but also the

solidification of drug and polymer in the

droplets. The good microsponges were

produced only when 5 ml of internal phase

was used, as shown in table 7. [10]

Effect of amount of emulsifying agent

on microsponges

The production yield and mean particle

size were greatly affected by the amount of

emulsifying agent. The increase in the

amount of emulsifying agent resulted in

larger microsponges. This could be due to

the increased viscosity. The increased

amount of emulsifying agent decreased the

production yield and drug content but

increased the mean particle size as shown

in the table 8. [10]

Conclusion

This study presents a new approach for the

preparation of modified microsponges with

prolonged release characteristics. The

prepared microsponges exhibited

characteristics of an ideal delivery system.

The unique compressibility of

microsponges offers a new alternative for

producing mechanically strong tablets.

References

1. Swetha A, Gopal Rao M, Venkata

Ramana K, Niyaz Basha B, Koti

Reddy V. Formulation and In-vitro

evaluation of Etodolac entrapped in

Microsponge based drug delivery

system. International Journal of

Pharmacy 2011; 1(2): 73-80.

2. Markand Mehta, Amish Panchal,

Viral H Shah, Umesh Upadhyay.

Formulation and In-vitro

evaluation of controlled release

Microsponge gel for topical

delivery of Clotrimazole.

International Journal of Advanced

Pharmaceutics 2012; 2(2): 93-101.

3. Prasad Byrav D S, Medhi B,

Prakash A, Patyar S, Wadhwa S.

Lornoxicam : A Newer NSAID.

IJPMR 2009; 20(1): 27-31.

4. Afsar C Shaikh, Sayyed Nazim,

Shaikh Siraj, Tarique Khar, Siddik

Patel M, Mohammad Zameeruddin,

Arshad Shaikh. Formulation and

evaluation of sustained release

tablets of Aceclofenac using

hydrophilic matrix system. IJPPS

2011; 3(2): 145-148.

5. Sarat Chandra Prasad M, Ajay M

B, Nagendra Babu, Prathyusha P,

Audinarayana N, Bhaskar Reddy

K. Microsponge Drug Delivery

System : A Review. Journal of

Pharmacy Research 2011; 4(5):

1381-1384.

6. Debajyoti Ray, Amresh K Prusty.

Designing and In-vitro studies of

Gastric floating tablets of Tramadol

Hydrochloride. International

Journal of Applied Pharmaceutics

2010; 2(4): 12-16.

7. Indian Pharmacopoeia (2010) :

Ministry of Health and Family

Welfare, Government of India,

Controller of Publication, New

Delhi, India.

8. Uma Maheswari A, Elango K,

Daisy Chellakumari, Saravanan K,

Anglina Jeniffer Samy.

Formulation and Evaluation of

Controlled Porosity Osmotic



Tablets of Lornoxicam. IJPSR

2012; 3(6): 1625-1631.

9. Vikas Jain, Ranjit Singh.

Dicyclomine loaded Eudragit based

Microsponge with potential for

Colonic Delivery: Preparation and

Characterization. Tropical Journal

of Pharmaceutical Research 2010;

9(1): 67-72.

10. Manoj Kumar Mishra, Mukesh

Shikhri, Rishikesh Sharma,

Mahesh Prasad Goojar.

Optimization, formulation

development and characterization

of Eudragit RS 100 loaded

Microsponges and subsequent

colonic delivery. IJDDHR 2011;

1(1): 8-13.

Table 1: Composition of Lornoxicam microsponge containing eudragit RS 100

Ingredient M 1 M 2 M 3 M 4 M 5

Lornoxicam(g) 0.1 0.3 0.5 0.7 0.9

Eudragit RS 100 (g) 0.1 0.1 0.1 0.1 0.1

Polyvinyl Alcohol (g) 0.5 0.5 0.5 0.5 0.5

Triethyl citrate (ml) 0.5 0.5 0.5 0.5 0.5

Ethanol (ml) 5 5 5 5 5

Water (ml) 200 200 200 200 200

Table 2: Composition of Lornoxicam tablets

Formulation

code

Lornoxicam

microsponges (mg)

Micro crystalline

cellulose (mg)

Magnesium

stearate (mg)

Talc

(mg)

Lactose

(mg)

F1 16.00 30 5.4 9 119.60

F2 10.66 30 5.4 9 124.94

F3 9.60 30 5.4 9 126.00

F4 9.14 30 5.4 9 126.45

F5 8.88 30 5.4 9 126.72



Table 3: Micromeritic properties of Lornoxicam and powder blend

Drug and

Blends

Bulk density*

(g/ml)

Tapped

density* (g/ml)

Compressibility

index* (%)

Hausner’s

ratio*

Angle of

repose*

Drug 0.312±0.012 0.454±0.014 31.2±0.16 1.452±0.06 47.57˚±0.34

MB1 0.51±0.006 0.585±0.004 12.82±0.21 1.14±0.03 30.2˚±0.19

MB2 0.489±0.002 0.560±0.003 12.67±0.24 1.14±0.07 29.7˚±0.69

MB3 0.479±0.003 0.534±0.006 10.29±0.28 1.11±0.05 31.16˚±0.68

MB4 0.489±0.005 0.560±0.008 12.67±0.34 1.14±0.09 30.1˚±0.83

MB5 0.492±0.04 0.558±0.017 11.82±0.19 1.13±0.05 29.11˚±0.20

* Mean of three readings

Table 4: Evaluation of Lornoxicam microsponges

Formulation Production yield (%) Loading efficiency (%) Mean particle size (µm)

M1 69.35 89.25 75.60

M2 79.3 90.00 64.20

M3 84.77 93.38 62.20

M4 78.20 96.95 54.40

M5 89.65 96.39 45.50



Table 5: Physical evaluation and drug content

Formu

-lation

Uniformity

of weight *

(g)

Diameter

# (mm)

Thickness

# (mm)

Hardness#

(kg/cm2)

Friability

^ (%)

Drug

content #

(%w/w)

Uniformity

of content ҂

(%w/w)

Disintegration

time # (min)

F1 0.179±

0.006

8±0.0 2.5±0.0 4.4±0.45 0.44±

0.023

100.6±0.02

3

100.69±0.52

3

2.12±0.06

F2 0.179±

0.005

8±0.0 2.5±0.0 4.25±0.25 0.47±

0.012

96.38±0.05

4

100.60±1.07

6

2.19±0.05

F3 0.180±

0.002

8±0.0 2.5±0.0 4.75±0.25 0.60±

0.025

91.22±0.01

8

96.85±0.859 2.78±0.01

F4 0.181±

0.003

8±0.0 2.5±0.0 4.25±0.25 0.53±

0.019

93.09±0.03

2

100.7±0.632 2.52±0.05

F5 0.178±

0.005

8±0.0 2.5±0.0 4.35±0.33 0.47±

0.015

95.9±0.027 99.76±0.927 3.0±0.02

*mean of 20 readings. # mean of 5 readings. ^mean of 3 readings. ҂mean of 6 readings

Figure1: Release study of various formulations

0

20

40

60

80

100

120

0 2 4 6 8 10 12 14

% D

RU

G R

ELEA

SE

TIME IN HOURS

F1

F2

F3

F4

F5



Table 6: Effect of stirring rate on Lornoxicam microsponges

Formulation

Internal phase composition External

phase

Stirring

rate

(rpm)

Production

yield (%)

Mean

particle

diameter

* (µm)

%Drug

content

*

F5

Drug

(g)

Polymer

(g)

Ethanol

(ml)

water PVA

(%)

0.9 0.1 5 200 0.5 200 80.07 59.67±

3.15

84.17±

1.3

0.9 0.1 5 200 0.5 300 75.18 48.19±

6.89

90.02±

2.4

0.9 0.1 5 200 0.5 400 73.96 35.81±

4.56

94.23±

1.7

* Mean of 5 readings

Table 7: Effect of internal phase composition on Lornoxicam microsponges

Formulation


phase

Stirring

rate

(rpm)

Production

yield (%)

Mean

particle

diameter

* (µm)

%Drug

content

*

F5

Drug

(g)

Polymer

(g)

Ethanol

(ml)

water PVA

(%)

0.9 0.1 5 200 0.5 300 79.29 45.5±

5.39

93.95±

1.6

0.9 0.1 10 200 0.5 300 68.34 41.99±

6.89

86.21±

0.9

0.9 0.1 15 200 0.5 300 66.85 38.25±

7.24

80.05±

0.5




Table 8: Effect of emulsifying agent on Lornoxicam microsponges

Formulation


phase

Stirring

rate

(rpm)

Production

yield (%)

Mean

particle

diameter

* (µm)

%Drug

content

*

F5

Drug

(g)

Polymer

(g)

Ethanol

(ml)

water

(ml)

PVA

(%)

0.9 0.1 5 200 0.25 300 82.3 46.49±

7.11

92.81±

0.8

0.9 0.1 5 200 0.5 300 78.69 50.17±

6.45

90.23±

0.4

0.9 0.1 5 200 0.75 300 69.05 66.25±

5.67

85.87±

0.6


Figure 2: A plot of First order kinetics

y = -0.115x + 2.057R² = 0.994

0

0.5

1

1.5

2

2.5

0 2 4 6 8 10 12

Log

Cu

m %

Dru

g R

emai

nin

g

Time



Figure 3: A plot of Hixson-Crowell kinetics

Figure 4: SEM image of Lornoxicam Microsponges

y = -0.266x + 4.628R² = 0.991

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

0 2 4 6 8 10 12 14

Cu

be

ro

ot

of

% d

rug

rem

ain

ing

Time in Hours

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