Development and Evaluation of Sustained Release Matrix Tablets Using Natural Polymer as Release Modifier
LP Hingmire*, VN Deshmukh and DM Sakarkar
Department of Industrial Pharmacy, S. N. Institute of Pharmacy, Pusad. Dist: Yavatmal- 445 204. MS. India.
* Corresponding Author E-mail: firstname.lastname@example.org
In the present investigation, an attempt has been made to increase therapeutic efficacy, reduce frequency of administration, and improve patient compliance, by developing sustained release matrix tablets of diclofenac sodium using natural polymers such as Xanthan gum, locust bean gum, sodium alginate. Sustained release matrix tablets of diclofenac sodium, were developed by using different drug: polymer ratios, such as 1:0.5; 1:1 and 1:1.5. Xanthan gum, locust bean gum, sodium alginate, combination of locust and xanthan, locust and sodium alginate were used as matrix former, the tablets were compressed by direct compression method using 8 mm flat faced punches. Compressed tablets were evaluated for uniformity of weight, content of active ingredient, friability, hardness, thickness, swelling index and in vitro dissolution using paddle method, and swelling index. All the formulations showed compliance with pharmacopoeial standards. Among these formulations, formulation containing combination of locust bean gum and Xanthan gum (6:4) showed sustained release of drug for 12 hours with release of 98.95 %. Optimized formulation was subjected toaccelrated stability studies. Thus, locust bean and Xanthan gum combination can be used as an effective matrix former, to extend the release of diclofenac sodium.
KEY WORDS Sustained release, Xanthan gum, locust bean gum, sodium alginate, diclofenac sodium.
Matrix system is the most innumerable method used in the development of Sustained release formulations. It is the release system, which prolongs and control release of drug that is dissolved or dispersed. In fact, a matrix is defined as a well-mixed composite of one or more drugs with a gelling agent i.e. hydrophilic polymers.1 the natural polymers are been extensively used in the field of drug delivery because they are readily available, cost effective, eco-friendly, capable of multitude of chemical modifications, potentially degradable and compatible due to their natural origin. Past research was done on various natural gums like agar agar, guar gum, chitosan, for potential pharmaceutical and biomedical applications.
Diclofenac sodium is a most widely used NSAID, useful in the treatment of rheumatic disorders, and is characterized by rapid systemic clearance, and thus warrants the use of a Sustained Release formulation for prolonged action, and to improve patient compliance.2,3
Various experimental reports such as solubility, pH, half life, indicated diclofenac sodium as a good candidate for SR formulation.4,5 Few SR formulations of diclofenac sodium (100 mg) are also available commercially.
In this study locust, Xanthan gum, Sodium alginate were used alone and combination of locust bean gum with xanthan and sodium alginate were used as a hydrophilic matrix polymers for controlling release of sparingly water soluble diclofenac sodium was studied, together with different factors affecting drug release, from the hydrophilic matrix tablets.
MATERIAL AND METHODS:
Diclofenac sodium (DS) was obtained as gift sample from Alkem Laboratories Mumbai. The Locust bean gum, Xanthan gum, was obtained from Crystal colloids Ltd. Mumbai. Sodium alginate Sulbha gums Bangalore other materials used was of analytical grade, and procured from commercial sources.
Determination of Viscosity of combination of different gums by brook field viscometer
Before using the combination of gums the viscosity of 0.5%w/v solution of gums individuals and in combinations were determined, Using brook field viscometer with spindle No.3 at 37 o C. The highest viscosity combination was considered suitable for good polymer for dosage form. (Fig-1)
Preparation of sustained release matrix tablet using natural gums6
Matrix tablets were prepared by direct compression method. Table-1 shows composition of each tablet formulation. The formulations are composed of various concentrations of natural gum in the ratios as drug and polymers 1: 0.5, 1: 1 and 1: 1.5 in various percentages. The drug and excipients weighed separately and passed through 100- mesh sieve. Drug was added to the lactose and the polymer mixture and then blended for 20 min. at last the lubricants were added and subjected to compression using 8 mm standard flat punch (single punch tablet machine) in to tablets.
Figure:1 Viscosity of various gums in combination with Locust bean gum, AA: Agar agar, SA: Sodium alginate, GG: Guar gum, GGh: Gum Ghutti.
Evaluation of post compression parameters7, 8
All prepared matrix tablets were evaluated for uniformity of weight and drug content, as per I.P. Friability, hardness, thickness, was determined.
In-vitro dissolution study 9
In-Vitro drug release studies for all formulations as well as marketed formulation were carried out using dissolution test apparatus USP Type-II at 50 rpm. The dissolution medium consisted of 900 ml of Standard buffer pH 1.2 for the first 2 hrs, followed by pH 6.8 for remaining period of time. Temperature maintained at 37°C ± 0.5°C. Aliquots of 5ml were withdrawn at predetermined time intervals and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced. Aliquots withdrawn were diluted up to 50 ml with buffer, filtered and analysed by measuring the absorbance at 278 nm.
Kinetic treatment to dissolution data
In order to investigate the mode of release from tablets, the release data of optimized formulation was analyzed with the following mathematical models: Q = Kot (Zero order kinetic), ln (100-Q) = lnQo-K 1 t (First order kinetic) and Q = Kptn (Korsmeyer and Peppas equation), where, Q is the percent of drug released at time t and Ko and K 1 are the coefficients of the equations. Kp is constant incorporating structural and geometric characteristics of the release device, and n is the release exponent indicative of mechanism of release
Figure 2: Viscosity of various gums in combination with Locust bean gum, GA: Gum Acacia, GT: Gum tragacanth, XG: Xanthan gum, GK: Gum karaya.
Swelling study 10, 11
As the release of drug is proportionate to matrix form, the swelling index was determined by equilibrium weight gain method. The study was carried out in the USP/NF dissolution apparatus I. The polymer matrices were accurately weighed, placed in dissolution baskets, immersed in pH 6.8 phosphate buffers and maintained at 37± 0.50C in the dissolution vessels. At regular intervals of 2, 4, 6, 8, 10 and 12 hours, the pre-weighed basket matrix system was withdrawn from the dissolution vessels, lightly blotted with a tissue paper to remove excess test liquid and re-weighed. The swelling index was estimated at each time point using following equation:
(Ws – Wi)
Swelling Index = X 100
Where, Ws is the weight of the swollen matrix at time t, Wi is the initial weight of matrix.
Accelerated Stability Study: 12
For determination of stability of prepared different formulations, accelerated stability studies were carried out on optimized formulation. Tablets were stored at 40 ± 2°C/75 ± 5 % RH for duration of one month. After completion of one month sample was withdrawn and tested for different tests such as thickness, hardness, drug content and in-vitro drug release.
RESULTS AND DISCUSSION:
The formulated matrix tablets met the pharmacopeial requirement of uniformity of weight. All the tablets conformed to the requirement of assay, as per I.P. Hardness,
% friability, and thickness, drug content were well within acceptable limits.
Table 1: Matrix tablet Formulation table.
In-vitro dissolution study:
All the formulations were subjected to in-vitro dissolution studies and results are shown in Fig 3-7. From dissolution study it revealed that the formulation F1, F2 and F3 containing Xanthan gum alone showed 101.05±0.65 for 7 hours, 102.43±0.32 for 9 hours and 98.12±0.45 for 10 hours respectively. This showed that as concentration of natural gum as release modifier increases the rate of drug release from tablet decreases.
This may be because of an increase in polymer concentration causes an increase in the viscosity of the gel as well as the formation of gel layer with a longer diffusional path. This may cause as decreased in the effective diffusion co-efficient of the drug and therefore a reduction in the drug release rate.
Similarly formulation F4, F5 and F6 containing Locust bean gum alone showed 94.37±0.12, 92.67±0.52 and 87.34±0.21 in 12 hours respectively. Formulation F7, F8 and F9 containing Sodium alginate alone showed 102.34±0.78 for 9 hours, 99.24±0.78 for 9 hours and 104.74±0.96 for 11 hours respectively.
From this result it was found that Locust bean gum retard more drug as compared to Xanthan gum and Sodium alginate. Hence drug release retardation from these three gums was found to be in following order.
Locust bean gum > Sodium alginate > Xanthan gum
Results also showed that, formulation F10, F11 and F12 containing combination of Locust bean gum and Xanthan gum in the ratio of 6:4 showed 103.85±0.15 for 11 hours, 98.95±0.42 for 12 hours and 87.64±0.85 for 11 hours. Similarly, formulation F13, F14 and F15 containing combination Locust bean gum and Sodium alginate in the ratio of 9:1 showed 107.64±0.23 for 11 hours, 90.24±0.42 for 12 hours and 85.12±0.17 for 12 hours. This showed that combination of Locust bean gum and Xanthan gum showed more drug retardation than that of combination of Locust bean gum and sodium alginate. Hence drug release retardation from these combinations of gums was found to be in following order
(Locust bean gum+ Xanthan gum) > (Locust bean gum+ Sodium alginate)
Figure 3: Dissolution profile of formulation F1, F2, F3 and marketed product
Figure 4: Dissolution profile of formulation F4, F5, F6 marketed product
Figure 5: Dissolution profile of formulation F7, F8, F9 marketed product
In-vitro drug release of all formulations (F1-F15) was also compared with the marketed preparation. The results showed that the drug release profile of formulation F11 resembles with that of marketed formulation. Hence formulation F11 containing combination of Locust bean gum and Xanthan gum in the ratio of 6:4 was considered as optimized formulation used for further study.
Figure 6: Dissolution profile of formulation F10, F11, F12 and marketed product
The kinetic treatment reflected that release data of F11 showed R2 value of 0.9542 and 0.9920 for first order, and zero order equation respectively, indicating that release of drug follows zero order kinetic Further Korsmeyer and Peppas equation resulted into the value of n = 0.3490, which is close to 1, indicating that the drug release was approaching zero order kinetics. Accelerated stability study on F11 formulation showed that there was no considerable change in thickness, hardness and drug content also there was no any difference found between dissolution profile before and after stability. Hence tablet prepared by using natural gums as release modifier was found to be stable.
The authors are grateful to Alkem Laboratories Mumbai
providing gift sample of diclofenac sodium. Crystal colloid, for locust bean gum, xanthan gum, sulbha gums and sodium alginate.
Figure7: Dissolution profile of formulation F13, F14, F15 and marketed product
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Accepted on 25.08.2008 © RJPT All right reserved