INTRODUCTION:^1-5

Naproxen is a non-steroidal anti-inflammatory drug. It is chemically described as 2-naphthaleneacetic acid, 6-methoxy-a-methyl-, (S)-. It is commonly used for the reduction of moderate to severe pain, fever, inflammation and stiffness caused by conditions such as osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, bursitis, and the treatment of primary dysmenorrhea. It works by inhibiting both the COX-1 and COX-2 enzymes. It has a biological half life of 10hrs.and can be used as sustained release dosage form. Generally, primary objectives of controlled drug delivery are to ensure safety and to improve efficacy of drugs as well as patient compliance, which can be achieved by better control of plasma drug levels and less frequent dosing. The most convenient way to achieve controlled release of active agent involves physical blending of drug with polymer matrix, followed by direct compression, compression molding, injection molding, extrusion, or solvent casting which results either in monolithic device or in swellable hydrogel matrix. For any controlled-release dosage form it is very important to use minimum number of excipients with minimum processing steps in order to reduce the tablet-to-tablet and batch-to-batch variations, hence direct compression is the most suitable and easily up-scalable technique.

On contact with an aqueous medium, the hydrophilic polymer matrix gradually begins to hydrate from the periphery towards the centre forming a gelatinous swollen mass, which controls the diffusion of drug molecules through the polymeric material into the aqueous medium. On the other hand the hydrophobic polymer matrix retards the diffusion of drug molecules into the aqueous media. The objective of this study was to develop sustained-release tablets of Naproxen using suitable hydrophilic systems and comparison with the hydrophobic matrices. Hydrophilic system used was Sodium alginate and Xanthan gum, hydrophobic system used was Ethyl cellulose.

MATERIALS AND METHODS:-

Materials:

The drug Naproxen was procured as gift sample from (Ranbaxy Laboratories Ltd., New Delhi), Sodium Alginate was procured from (Loba Chemie Pvt. Ltd. Mumbai.), Xanthan Gum and Ethyl Cellulose was procured from (Research-Lab Fine Chem. Industries, Mumbai.). All other chemicals purchased and were of analytical grade.

Preparation of Matrices:

Naproxen, Sodium alginate, Ethyl cellulose and Xanthan gum were mixed separately in various ratios individually and in combinations with each other in a laboratory mixer and were passed through 10and12 mesh screen. The tablets were compressed by direct compression method by using 8 Station Tablet Punching Machine – Karnavati - Minipress D-II Link, Mumbai fitted with 11-mm diameter flat-faced punches. Powder admixtures were manually filled into the die, and 1 compaction cycle was performed. For each batch, 50 tablets were produced.

Fourier Transform Infrared Spectrometry:

Fourier Transform Infrared (FTIR) spectra of, Naproxen, Sodium alginate, Ethyl cellulose and Xanthan gum, physical mixtures, were recorded on FTIR spectrometer (model FTIR-4100 Plus, Jasco).

Figure 1: Fourier transform infrared (FTIR) spectra patterns

· Naproxen

Evaluation of Tablets:⁶

The tablets were also evaluated as per IP1996 for weight variation (n=20), hardness (n=6), thickness (n=20), and friability. Hardness was determined by using a Monsanto tablet hardness tester (Campbell Electronics, Mumbai, India). Friability test was conducted using Roche friabilator (F. Hoffmann-La Roche Ltd, Basel, Switzerland).

Thickness of the tablets was measured by digital Vernier calipers (Mitutoyo Corp, Kawasaki, Japan).

Determination of Drug Content:

0.200gms. drug was dissolved in 70ml. of alcohol and 5ml. of 0.01M HCl was added. Potentiometric titration using 0.1M NaOH and the volume added between two points of inflexion was read.

In Vitro Drug Release Studies:

The release rate of Naproxen tablets was determined using USP Dissolution Testing Apparatus II. The dissolution test was performed using 900 ml of 7.4pH phosphate buffer, at 37° ± 0.50°C and 50 rpm. A sample (5 ml) of the solution was withdrawn from the dissolution apparatus hourly for 12 hrs and the samples were replaced with fresh dissolution medium. The samples were filtered through Whatman filter paper no. 41. Absorbance of these solutions was measured at 332 nm. Cumulative percentage drug release was calculated using an equation obtained from a standard curve.

DSC studies:⁷

Naproxen along with the combination with different polymers was weighed (4-8mg) into a 40µl standard aluminum crucible and hermetically sealed with perforated aluminium lid. Sample were subjected to thermal study using model mettler Toledo 82 le .The system was purged with N₂ gas at rate of 100 ml/min to maintain inert atmosphere .Heating of samples was done from -30 to 350⁰ C at rate of 10⁰ C/min.

Figure 2: Thermal analysis

(a) Xanthan gum + Sodium alginate 1:10

(b) Xanthan gum + Sodium alginate + Ethyl cellulose 1:10+5%

Water Uptake Studies:^8-9

Water uptake studies were performed by using equation stated by Roy and Rohera et al^{8, 9}. The rate of test medium uptake by the polymer was determined by equilibrium weight gain method. The dry drug and polymer matrices were weighed, placed in dissolution baskets, and immersed in phosphate buffer (pH 7.4) maintained at 37±0.50°C in the dissolution vessels. At regular intervals, the pre-weighed basket–matrix system was withdrawn from the dissolution vessel, lightly blotted with a tissue paper to remove excess test liquid and re-weighed. The percent water uptake, i.e., degree of swelling, was estimated at each time point from using equation:

Water Uptake (%) = Ws- Wi

Where,

Ws is the weight of the swollen matrix at time t, Wi is the initial weight of the matrix and Wp is the weight of the polymer.

Drug release kinetics:¹⁰

Data from the in vitro drug release were analyzed by different equations and kinetic

models in order to evaluate the release mechanism of Naproxen from the matrices.

The kinetic models used were as follows:

(a) Korsmeyer and Peppas model

Mt / M∞ = k x tn

Where, Mt / M∞ is the fraction drug released, k is kinetic constant, t is the release time, n is the diffusional exponent for drug release.

Peppas claimed that, the above equation could adequately describe the release of solutes from slabs, spheres, cylinders, and tablets (discs), regardless of release mechanism. The value of ‘n’ gives an indication of release mechanism. When n = <0.5 the drug release follows fickian diffusion; and the value of n =>0.5<1.0 then anomalous non fickian release would be implicated. n is the slope value, of log Mt / M∞ vs log time curve.

b) Zero-Order Release:

Qt = Q0+ K0t

where Q is the amount of drug dissolved in time t, Q is initial amount of drug in the solution (most times, Q0=0) and Ko is the zero order release constant

c) First Order Kinetics:

logQt=log Q0+ K1t/2.303

d) Hixon-Crowell Model:

W₀^1/3- Wt^1/3 =Kst

e) Higuchi Model:

Qt=KHt^1/2

Stability Studies:¹¹

Stability studies were conducted on Naproxen sustained matrix tablets containing Sodium alginate, Ethyl cellulose, Xanthan gum and their various combinations to assess their stability with respect to their physical appearance, drug content, and drug release characteristics after storing them in Stability chamber (Thermolab) at 40°C/ 75%(RH) for 6 months.

RESULTS AND DISCUSSION:-

Water Uptake Study:

Swelling index of matrices comprising of Sodium alginate, Ethyl cellulose and combination of all the polymers is show in Table No. 1 (a and b) It is seen that as the amount of polymer in the matrix increases swelling increases for all the polymers. In the case of Sodium alginate maximum swelling is observed at 45% polymer concentration. Due to its excessive hydration ability with simultaneous swelling. In Sodium alginate high initial swelling is observed with erosion in the latter stages with the amount of polymer at 20%.The swelling index increases as the amount of polymer in the matrix increases. Hence a more quantity of polymer is required to achieve sustained release of drug from Sodium alginate polymer. In case of Ethyl cellulose matrices, high initial swelling is observed at polymer concentration of 5% due to its high hydration ability and forms a thick gel from which the drug diffuses. The swelling of Ethyl cellulose matrices increases as the amount of polymer in the matrix is increased with polymer concentration at 20% and the amount of drug release is reduced. When Sodium alginate and Xanthan gum are combined together swelling increases due to the amount of Xanthan gum present in the matrices increases. The matrices containing Xanthan gum and Sodium alginate in the ratio 1:10 do not swell rapidly. When Xanthan gum, Sodium alginate and Ethyl cellulose in the ratio of 1:10+5% are combined together high swelling is observed due to excessive hydration of polymers.

Table 1: Water uptake studies:

(a) Swelling Index of Drug and Polymer matrices (%)

Formulation code.	2hrs.	4hrs.	6hrs.	8hrs.
NS1	152.2	251.5	319.3	321.9
NS2	146.8	248.7	295.5	310.3
NS3	142.0	232.9	274.2	296.5
NS4	134.9	210.6	268.9	284.6
NS5	128.8	200.6	255.8	270.4
NS6	167.4	192.4	250.7	265.3
NE1	65.0	133.4	187.1	221.7
NE2	64.1	122.7	180.4	212.0
NE3	62.8	113.9	173.8	203.6
NE4	60.5	101.4	164.3	195.4

(b) Swelling Index of Drug and Combination of Polymer matrices (%)

Formulation code.	2hrs.	4hrs.	6hrs.	8hrs.
NSX1	133.8	194.6	237.1	256.2
NSX2	124.1	184.7	221.3	246.8
NSX3	118.2	170.9	210.5	240.4
NSEX1	95.4	168.4	209.2	235.7
NSEX2	90.1	163.9	204.5	230.6
NSEX3	83.7	154.3	197.4	225.7
NSEX4	75.9	142.6	183.9	215.5

Table 2 – Effect of hydrophilic polymer concentration:

(a) Tablet Formulations Containing Relative Quantities of Drug and Polymer (Naproxen & Sodium alginate)

Formulation no.	Drug (naproxen)	Polymer (sodium alginate)
NS 1	33.33%	20%
NS 2	33.33%	25%
NS 3	33.33%	30%
NS 4	33.33%	35%
NS 5	33.33%	40%
NS 6	33.33%	45%

* Formulations contains dose of drug (naproxen) i.e. 200mg (33.33%)

Weight of the polymer 120mg (20%), 150mg (25%), 180mg (30%),

210mg (35%), 240mg (40%), 270mg (45%)

Effect of Hydrophilic Polymer Concentration:-

The formulations of different ratios as depicted in Table No.2 (a) were prepared and their in-vitro studies were carried out in phosphate buffer 7.4pH.The release pattern of the drug in combination with sodium alginate (Table No.2(b)) varied with the amount of the polymer. The release varied with the amount of polymer concentration, 20%alginate showing a faster release (97.035) as compared to alginate concentration containing 45%(82.914) in 8h time interval. At a fixed Naproxen dose, the total content of sodium alginate shows a dramatic change in their dissolution profile. At lower alginate content, rapid swelling of matrices with less tight hydrogel structure resulted in higher drug release. Conversely when a natural polymer like Xanthan gum is added in different ratios it affected the release pattern (Table No.4 (a)). The ratio of 1:10 of Xanthan gum and sodium alginate showed an optimized release.

As the amount of Xanthan gum in the matrix increased, there would be a greater degree of hydration with simultaneous swelling which results in a lengthening of the drug diffusion pathway and reduction in drug release rate and the drug showed a release of 91.249% in 12h. time (Table No.4 (a)).

Effect of Hydrophobic Polymer Concentration¹²:-

The formulations of different ratios as depicted in Table No.3(a) were prepared and their in-vitro studies were carried out in phosphate buffer 7.4pH. The release pattern of the drug varied with the amount of the polymer (Table No. 3(b)). Due to it hydrophobic nature ethyl cellulose showed a greater retardation and a decrease in amount of drug release. Ethyl cellulose with 5 % concentration showed decreased drug diffusion due to less amount of swelling, and with the amount of the polymer concentration increasing 20% it retard further the drug release due to a much decreased in swelling and showed a release of 37.529% in 12h. time compared to 41.854% in 12h. time (Table No.3 (b))

Table 3 - Effect of hydrophobic polymer concentration:

(a)Tablet Formulations Containing Relative Quantities of Drug and Polymer (Naproxen & Ethyl cellulose)

Formulation no.	Drug (naproxen)	Polymer (ethyl cellulose)
NE 1	33.33%	5%
NE 2	33.33%	10%
NE 3	33.33%	15%
NE 4	33.33%	20%

* Formulations contains dose of drug (naproxen) i.e. 200mg (33.33%)

Weight of the polymer 30mg (5%), 60g (10%), 90mg (15%), and 120mg (20%)

(b) Percentage Release of Naproxen from Drug and Polymer matrices (Naproxen and ethyl cellulose)

Time (hrs.)	NE 1	NE 2	NE 3	NE 4
0	0	0	0	0
1	6.434	5.316	4.178	3.875
2	10.678	9.509	9.415	8.435
3	15.643	12.756	12.774	11.856
4	19.507	17.662	17.662	16.208
5	23.308	21.622	20.880	19.990
6	25.405	24.024	23.913	23.674
7	27.845	27.039	27.589	27.515
8	31.111	30.692	30.364	29.525
9	33.974	33.286	32.869	32.126
10	36.749	35.218	34.497	34.173
11	38.629	38.790	36.713	36.247
12	41.854	40.413	38.561	37.529

Table 4 – Effect of combination of polymer concentration:

(a) Percentage Release of Naproxen from Drug and Polymer combination matrices (Naproxen+ sodium alginate+ Xanthan gum)

Time (hrs.)	NSX 1 (1:6)	NSX 2 (1:8)	NSX 3 (1:10)
0	0	0	0
1	20.937	22.189	22.625
2	28.004	28.777	31.058
3	31.522	32.190	34.803
4	36.472	37.311	39.175
5	40.177	41.975	43.429
6	44.262	48.612	49.644
7	50.112	55.243	56.728
8	53.669	61.850	63.198
9	57.217	67.163	69.753
10	60.757	70.861	75.651
11	63.660	75.603	82.801
12	67.095	79.092	91.249

(b) Percentage Release of Naproxen from Drug and Polymer combination matrices (Naproxen+ sodium alginate+ Xanthan gum+

Ethyl cellulose)

Time (hrs.)	NSEX 1 (1:10+5%)	NSEX 2 (1:10+10%)	NSEX 3 (1:10+15%)	NSEX 4 (1:10+20%)
0	0	0	0	0
1	21.355	20.937	20.558	20.369
2	28.362	25.365	24.988	24.554
3	34.410	30.472	29.629	28.204
4	37.833	34.850	33.825	32.557
5	41.048	39.213	38.212	37.026
6	45.055	43.211	41.368	39.949
7	50.313	47.271	45.713	42.928
8	54.889	50.735	49.623	46.489
9	59.029	55.369	53.177	50.260
10	64.017	58.217	55.371	52.472
11	69.390	60.759	54.485	54.869
12	73.610	63.214	60.491	56.023

Effect of Combination of Polymer Concentration^13-14:-

Different ratio of concentrations of Sodium alginate and Xanthan gum were done to determine the optimum amount of both the polymers as shown in Table No.4 (a).for retarding the Naproxen release. Xanthan gum and Sodium alginate based formulations were screened to select those that showed slow release of Naproxen over 12 h. The ratio of 1:10 showed a greater retarding effect. Due to the presence of Xanthan gum content, the initial drug release was diminished and drug diffuses slowly continuously for more than 12 h. with the amount of Xanthan gum in the matrix, there would be a greater degree of hydration with simultaneous swelling which results in a lengthening of the drug diffusion pathway and reduction in drug release rate. A release of 91.249% was seen with 1:10 ratio compared to the other ratio which showed much less release (Table No. 4(a)). The optimized ratio of 1:10 Xanthan gum and Sodium alginate were also combined with different concentrations of Ethyl cellulose as shown in Table No.4 (b). The different ethyl cellulose concentration due to its hydrophobicity showed decreased amount of drug release with an increasing amount of polymer as seen from Table No.4(b) with the ratio 1:10+5% showing a release of 73.610% in 12h. time. Therefore a combination of Xanthan gum and Sodium alginate showed a much better release as compared to its combination with Ethyl cellulose.

Stability Studies:

At the end of the testing period, the matrix tablets were observed for changes in physical appearance, analyzed for drug content, and subjected to in vitro drug release studies. No visible changes in the appearance of the matrix tablets were observed and a significant change was not seen in the drug content and drug release at the end of the storage period.

CONCLUSION:

In Hydrophilic matrix system the amount of Sodium alginate resulted in decreasing the release rate of drug while increasing the amount of Ethyl cellulose in hydrophobic matrix did not affect the rate of drug release. The combination of Sodium alginate and Xanthan gum sustained the release of drug effectively by retarding the drug release compared to the combination of all the three polymers. Hydrophilic and Hydrophobic polymers can be effectively used in the modulation of drug release. These findings could thus be of importance in developing a suitable model for sustained release technology.

REFERENCES:

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Received on 17.08.2009 Modified on 02.03.2010

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 776-780

Time (hrs.)	ns1 (20%)	ns2 (25%)	ns3 (30%)	ns4 (35%)	ns5 (40%)	ns6 (45%)
0	0	0	0	0	0	0
1	23.250	22.644	23.023	22.833	22.340	21.923
2	36.733	34.829	34.414	33.679	33.302	30.832
3	43.577	43.221	42.696	40.896	40.203	39.621
4	53.306	51.759	51.218	49.913	48.944	48.329
5	63.071	61.254	60.902	59.067	58.733	57.751
6	72.721	72.094	71.191	70.233	69.071	68.113
7	81.670	80.589	80.076	78.206	76.117	74.633
8	97.035	94.466	91.550	89.182	86.303	82.914