Abstract

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In the present investigation, an attempt has been made to reduce frequency of administration and increase therapeutic efficacy, there by improve patient compliance, by developing sustained release tablets of diclofenac sodium (DS). Sustained release tablets of DS, were developed by wet granulation method using different colonic polymers, (Guar gum, Ethyl cellulose, Acrycoat L100) with Drug: polymer ratios 1:2, which delivers the drug specifically into colonic region. Formulations were also prepared with combination polymers keeping drug: polymer ratio constant i.e. 1:2, where two polymers were used of equal proportion instead of the single polymer. All the lubricated formulations were compressed using 8 mm flat faced punches. Compressed tablets were evaluated for weight uniformity, drug content, friability, hardness, thickness, In vitro drug release study was conducted by buffer change method to mimic GIT environment. Among different formulations, F3 showed sustained release of drug for 10 hours with 67.23% release. The effect of other parameters like compression coating with Acrycoat L100, pH of dissolution medium was also studied. Pharmaco-equivalence of the prepared formulation with a standard marketed formulation was also carried out. The kinetic treatment showed that the release of drug follows zero order kinetic (R² = 0.9758). Korsmeyer and Peppas equation gave value of n = 0.9409 which was close to one, indicating that the drug was released by zero order kinetic. Thus, Guar gum, Ethyl cellulose and Acrycoat L100 can be used as an effective matrix former, to extend the release of diclofenac sodium.

Keywords: Diclofenac Sodium, Colonic polymers, Sustained release, Pharmaco-equivalence, drug release kinetics

Introduction

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The Colonic Drug Delivery Systems have recently gained importance for delivering a variety of drugs. Colonic drug delivery may be achieved by either oral or rectal administration. Rectal administrations of drugs for colon targeting always face high variability in the distribution of drug, when they are administered in form of dosage forms like enemas and suppositories, which are not always effective. Therefore, the oral route is the most preferred. Conventional oral formulations dissolve in the stomach or intestine and are absorbed from these regions. The major obstacle with the delivery of drugs by oral route to the colon is the absorption and degradation of the drug in the upper part of the gastrointestinal tract (GIT) which must be overcome for successful colonic drug delivery [1].
In conditions were localized delivery of the drugs is required in the colon or drugs which are prone to degradation in the environment of the upper GIT, colonic drug delivery may be valuable. Drug release at this site will ensure maximum therapeutic benefits. Oral delivery of drugs to the colon is valuable in the treatment of diseases of colon (ulcerative colitis, Crohn's disease, carcinomas and infections) whereby high local concentration can be achieved while minimizing side effects that occur because of release of drugs in the upper GIT or help to avoid unnecessary systemic absorption of the drug. Ulcerative colitis is the inflammatory disease of the colonic mucosa which is usually treated with salicylates or glucocorticoids. However, during the periods of remission, Ornidazole is the drug of choice. In this case it is desirable to localize the release of Ornidazole to the afflicted site in the colon. Thus, Ornidazole was used as a model drug in the present study [2].
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 SR formulation for prolonged action, and to improve patient compliance. Various experimental reports indicated diclofenac sodium as a good candidate for SR formulation. Few SR formulations of diclofenac sodium (100 mg) are also available commercially.
In this study, the use of Guar gum, Ethyl Cellulose, Acrycoat L100 polymer for controlling release of sparingly water soluble diclofenac sodium was studied, together with different factors affecting drug release, from the tablets at different pH conditions for colonic delivery [3]

Experimental methods

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1. Solubility Studies
Solubility of drug in various solvents was carried out in order to select the solvent to be used for formulation development and Analytical studies. Analysis of the drug was carried out on UV Spectrophotometer (Shimadzu) at 276nm.

2. Preparation of Sustained Release Tablets[4]
In the present study for the preparation of colonic delivery sustained release tablets the wet granulation method was used (Table 1). The formulations were prepared by wet granulation technique, using different polymers by keeping the drug polymer ratio 1:2 (Table 1). All the formulations were compared with a marketed formulation F7.

3. Evaluation of Physical Properties
A] All prepared tablets were evaluated for uniformity of weight and drug content[5], as per I.P. method. Friability was determined using Roche Friabilator. Hardness was measured by using Monsanto hardness tester. Thickness was measured by Vernier caliper.

B] In Vitro Drug Release Study[6, 7]
In vitro drug release was studied using USP paddle apparatus, with 900 ml of dissolution medium maintained at 37±1° for 10 h, at 50 rpm. 0.1 N HCl (pH 1.2) was used as a dissolution medium for the first 2 hr, followed by pH 6.8 phosphate buffer for further 4 hr, then for remaining 4hr media changed with pH 7.4 phosphate buffer. 5ml of sample was withdrawn after every hour, and was replaced by an equal volume of fresh dissolution medium of same pH. Collected samples were analyzed spectrophotometrically at 276 nm, and cumulative percent drug release was calculated. The study was performed in triplicate. Dissolution study is performed to know the in-vitro bioavailability of the drug, with respect to the In-vivo bioavailability.

C] Kinetic treatment to dissolution data[8, 9]
In order to investigate the mode of release from tablets, the release data of F3 was analyzed with the following mathematical models:

Q = K_ot (Zero order kinetic),

ln (100–Q) = lnQ_o–K₁t (First order kinetic)

Q = K_ptⁿ  (Korsmeyer and Peppas equation),

Where, Q is the percent of drug released at time t and K_o and K₁ are the coefficients of the equations. K_p is constant incorporating structural and geometric characteristics of the release device, and n is the release exponent.

Results and discussion

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The formulated tablets met the pharmacopoeial requirement of uniformity of weight. All the tablets confirmed to the requirement of assay, as per I.P. Hardness, % friability, and thickness was well within acceptable limits (Table 2). All formulations showed very low drug release in 0.1N HCl (pH 1.2). This was due to the very low solubility of diclofenac sodium at pH 1.2. Sustained, but complete drug release was displayed by all formulations in phosphate buffer (pH 6.8). Thus it can be concluded, that drug dissolution was a function of drug solubility, at various pH ranges. Indeed, pH dependent solubility of diclofenac sodium is well known. The inverse relationship was noted between amount of polymer and release rate of diclofenac sodium [10].

The kinetic treatment reflected that release data of F3 showed R² value of 0.9173 and 0.9758 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 = 0.9409, which is close to 1, indicating that the drug release was approaching zero order kinetic. When n is approximate to 0.5, a Fickian/diffusion controlled release is implied, where 0.5<n<1.0 non-Fickian transport and n=1 for zero order (case II transport). When the value of n approaches 1.0 phenomelogically, one may conclude that the release is approaching zero order.

Summary and Conclusion

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Diclofenac Sodium controlled release colonic tablets were prepared successfully utilizing ACRYCOAT L100 as a carrier For the technological point of view ,the wet granulation method enables a preparation of these controlled release tablets. It was observed that free flowing powders were obtained by using aerosil as glidant and lubricant. There was a significant difference in drug release of the tablets when the ACRYCOAT L-100 concentration is modified in high percentages. ACRYCOAT L 100 principally regulated drugs release from the controlled release tablet. Clearly each of the components was capable of interacting to some extent with each other to control the drug release. The best-fit release kinetic was achieved with zero order plots. Compared to conventional tablets release of Diclofenac sodium from this ACRYCOAT L 100 controlled release was prolonged [11]. As a result the oral release dosage forms to avoid the Gastro intestinal adverse effect was achieved. It may be also concluded that the controlled tablets gives same or almost nearly same drug release profile with that of marketed formulation of Diclofenac sustained release tablets.

References

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Source(s) of Funding

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None

Competing Interests

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None

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