Preparation and Evaluation of Delayed Release Aceclofenac Microspheres

 

Radhika PR*, Luqman Moidutty and Borkhataria Chetan H

 

Nandha College of Pharmacy, Erode-638052, Tamil Nadu, India.

 

*Corresponding Author E-mail: radhi_kannan2005@yahoo.co.in

 

ABSTRACT

Delayed release microspheres of Aceclofenac were formulated using an enteric polymer, cellulose acetate phthalate prepared by solvent evaporation technique. The effects of various other modern enteric polymers such as hydroxyl propyl methyl cellulose phthalate, Eudragit L 100 and Eudragit S -100 on the release of Aceclofenac from the CAP microspheres have been evaluated. The microspheres were characterized for particle size, shape, percentage yield, drug entrapment, and for in-vitro release kinetics. The shape of microspheres was found to be spherical by SEM. The size of microspheres was found to be ranging 8.84 ± 0.14 to 11.2 ± 0.18. The study was designed in the form of a factorial design in which the effects of HPMCP, Eudragit L 100 and Eudragit S 100 on the release rate of CAP delayed release microspheres were calculated. The results revealed that the HPMCP exhibits positive influence whereas Eudragit L 100 and Eudragit S 100 exhibits negative effect on the drug release rate of CAP microspheres. In-vitro drug release from all formulations followed the first order release kinetics and erosion plot.

 

KEY WORDS Aceclofenac, CAP, Delayed Release Microspheres.

 

INTRODUCTION:

Microspheres are defined as homogeneous, monolithic particles in the size range of about 0.1- 1000 µ m and are widely used as drug carriers for controlled release. These systems have significant importance in biomedical applications. Microspheres can be produced for protection of core material, reduction of gastric irritation decrease in volatility, conversion of liquid to pseudo-solid, cell micro encapsulation and for designing pulsatile drug delivery systems. Administration of the drug in the form of microspheres usually improves the treatment by providing the localization of the active substances at the site of action and by prolonging release of drugs1.

 

Aceclofenac an non –steroidal anti- inflammatory drug is phenyl acetic acids derivative showing effective anti inflammatory and analgesic propertied mainly used in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Aceclofenac is rapidly and efficiently absorbed after oral administration but has short half life of 3-4 hrs and necessitates multiple dosing for maintaining therapeutic effect throughout the day. The most frequent adverse side effects occurring with Aceclofenac are gastro intestinal disturbances, peptic ulceration and gastro intestinal bleeding, hence there is a potential need for an enteric coated dosage form for this drug to minimize gastric erosion side effect. Its biological half life on the other hand is very short, sustaining its anti- inflammatory activity only for a few hours. The objective of the present study was to formulate a delayed release microspheres dosage form of Aceclofenac.

 

MATERIAL AND METHODS:

Aceclofenac, cellulose acetate phthalate, hydroxyl propyl methyl cellulose phthalate were obtained as a gift sample from Cee Gee Pharmaceutical Pvt–Ltd Pondicherry, Eudragit L100, Eudragit S100, Liquid paraffin, n- hexane etc were obtained from Nice Chemicals, Cochin. All other ingredients used were of analytical grade.

 

Method of Preparation for Microcapsules

Delayed release aceclofenac microspheres were prepared by dissolving the drug (100 mg) in a 10%w/v solution of cellulose acetate phthalate (in acetone: methanol 8:2 solvent mixture). The solution was then emulsified into liquid paraffin and the system was stirred continuously and the solvent was allowed to evaporate at room temperature. The microspheres were collected by filtration, washed n-hexane and dried at room temperature.2, 3

 

TABLE - 1 Composition of Different Formulation of Delayed Release Microspheres of Aceclofenac.

Formulation

Drug

CAP

HPMCP

Eudragit

L- 100

Eudragit

S- 100

F1

100

1000

-

-

-

F2

100

800

200

-

-

F3

100

800

-

200

-

F4

100

800

-

-

200

F5

100

800

100

100

-

F6

100

800

-

100

100

F7

100

800

100

-

100

F8

100

800

66.66

66.66

66.66

 

Eight different batches were formulated according to the factorial design and their composition is presented in Table1.The surface morphology of the microspheres was examined by scanning electron microscope. Particle size analysis was carried out by using sieving method to determine the size distribution of microspheres. The drug content in microspheres was determined (by taking 3 samples from each batch) and the entrapment efficiency was calculated from the delayed release aceclofenac microspheres.

 

Figure 1 Scanning Electron Microscope of Optimized Formulation F2 using Magnification of 15kv × 2000

 

The in-vitro release profiles of aceclofenac from microspheres was examined in pH 1.2 buffer from 0-2 hours and in phosphate buffer of pH 7.2 from 2-8 hours by rotating basket method specified in the USP XXIII tablet dissolution tester (TDT06P, Electro lab), following the procedure for enteric formulation. Delayed release microspheres equivalent to 100 mg of aceclofenac were accurately weighed, filled into capsules and used in this study. The dissolution medium is 0.1 N HCl for 2 hrs and phosphate buffer solution of pH 6.8 for the remaining period. The temperature of the bath was maintained at 37 ± 0.5°C and the stirring speed at 100 rpm. Samples of the dissolution medium (5 ml) were withdrawn at various time intervals. The same volume of fresh fluid was added to the test medium to maintain the volume. The collected samples were analyzed by the UV double beam Spectrophotometer at 276nm. Each experiment was carried out in triplicate. In order to characterize release of aceclofenac from microspheres, the in-vitro release data for all formulation was subjected to kinetic data treatment using mathematical models like zero order, first order, Higuchi model and Erosion model.

 

RESULT AND DISCUSSION:

The delayed release microspheres of all batches were found to be discrete, spherical and free flowing (Fig.1).The size range of different batches of microspheres was in the range of 8.84 – 14.60 µm (Table 2).The drug content analysis showed that the distribution of drug within each batch of microspheres ranges from 8.7 ± 0.14 to 11.2 ± 0.18 (Table- 2). The packing properties of the drug and the formulation widely depend upon bulk density. It has been stated that, Bulk density values less than 1.2 gm/cm3 indicate good flow and values greater than 1.5 gm/cm3 indicate Poor flow characteristic. It is seen from Table-2 that the bulk density values are less than 1.2 gm/cm3 indicating good flow characteristics of the microspheres. Angle of repose less than or equal to 40° indicates free flowing properties of the microcapsules. The angle of repose for all the formulations (F1-F8) is seen to be between 21°03’ to 23°30’ indicating good flow property.

 

In-vitro Drug release studies were carried out with formulations F1 – F8. The Gastro resistance of these formulations was confirmed to fit the USP XXIII specifications. Less than 0.5% of the drug content was released with in 2 hours in 0.1N HCl and more than 80% was released after 1 hour in the phosphate buffer of pH 6.8

 

Fig 2 and Fig 3 shows the drug release pattern of microspheres prepared with CAP and other enteric polymers. It is evident from the figures that all formulations showed delayed release property. The drug release in the acidic medium was found to be negligible. The drug release in the alkaline medium, which stimulated intestinal pH conditions, was found to be sustained. The in-vitro release data have been plotted according to the following models of data treatment, cumulative percent drug release verses time, log of cumulative drug retained verses time, and erosion plot of (1-t/m) 1/3 verses time.4

 

FIGURE- 2 RELEASE PROFILES OF DELAYED RELEASE MICROSPHERES OF ACECLOFENAC FOR FORMULATION F1 TO F8

TABLE-2 Physicochemical Properties of Different Batches of Delayed Release Aceclofenac Microspheres

Formulation

Bulk Density

Angle of Repose

Drug content

% of Drug entrapped

Particle Size (µm)

F1

0.592 ± 0.10

23°30’

8.9 ± 0.21

77.39

8.40-14.50

F2

0.624 ± 0.18

21°29’

8.7 ± 0.14

75.65

8.78-14.60

F3

0.624 ± 0.12

21°17’

11.2 ± 0.18

96.52

8.50-14.60

F4

0.596 ± 0.10

22°20’

9.2 ± 0.7

79.13

8.49-14.30

F5

0.622 ± 0.18

29°24’

10.5 ± 0.52

93.04

8.45-14.35

F6

0.610 ± 0.12

21°29’

9.5 ± 0.37

84.34

8.60-14.32

F7

0.598 ± 0.15

21°03’

10.7 ± 0.96

94.78

8.84-14.20

F8

0.622 ± 0.12

23°09’

10.6 ± 0.34

91.30

8.65-14.00

 

TABLE- 3 IN-VITRO DRUG ANALYSIS FOR FORMULATION OF DELAYED RELEASE MICROSPHERES OF ACECLOFENAC

 

S.No.

Formulation

first order kinetic model r2

Erosion

plot r2

1

F1

-0.957

-0.970

2

F2

-0.955

-0.981

3

F3

-0.965

-0.977

4

F4

-0.976

-0.980

5

F5

-0.979

-0.982

6

F6

-0.972

-0.967

7

F7

-0.978

-0.972

8

F8

-0.982

-0.979

 

The in-vitro drug release from all formulation was found to follow first order release kinetics. The linearity of the first order plots was assessed by correlation coefficient values (Table 3). The delayed release microspheres formulated in this study contain drug dissolved in a polymer matrix which is soluble in the dissolution medium (pH 6.8) considered as bioerodible device. The plot of (1-Mt/M)1/3 verses time was found to the linear for all the eight formulations that indicates the drug release occurs mainly by erosion. The linearity of the erosion plot was assessed by correlation co-efficient values (Table 4).

 

It is seen that hydroxyl propyl methyl cellulose phthalate has an increasing effect on drug release rate, whereas Eudragit L100, Eudragit S100 have decreasing effect on drug release rate. Among the eight formulation, the formulation F2 was considered best because it showed delayed release and the drug release in pH 6.8 buffer was found to be almost complete and sustained.

 

CONCLUSION:

From the study done above we can conclude that incorporation of Eudragit L100 and Eudragit S100 in aceclofenac microspheres decreases the rate of release. The formulation F2 was found to be the best formulation as shown by the in-vitro studies and other evaluations of the formulation.

 

REFRENCES:

1.      Bolton S. In: Pharmaceutical statistics, Marcel Dekker Inc., New York, 1984, 266.

2.      Lorenzo-Lamosa ML, Remunan-Lopez C, Vila-jato JL, Alonso MJ, Design of microencapsulated chitosan microspheres for colonic drug delivery. J Control Release. 1998; 52:109-118.

3.      Mutalik S, Naha A,. Usha AN,. Ranjith AK, Musmade P, Manoj K, Anju P and Prasanna S. Preparation, In-vitro, Preclinical and Clinical Evaluations of Once Daily Sustained Release Tablets of Aceclofenac. Arch Pharm Res. 2007; 30(2): 222-234.

4.      Banker GS and Rhodes CT. Eds; Modern pharmaceutics, 2nd edn, Marcel Dekker Inc., New York, 1990, 654.

 

Received on 24.03.2008    Modified on 06.05.2008

Accepted on 10.05.2008   © RJPT All right reserved

Research J. Pharm. and Tech. 1(3): July-Sept.. 2008;Page  270-272