Development of a Novel Controlled Release System for Gastric Retention

Jagdish Chandra Rathi, (2011) Development of a Novel Controlled Release System for Gastric Retention. Doctoral thesis, The Tamilnadu Dr.M.G.R. Medical University, Chennai.


Download (4MB) | Preview


The present study reports the development of a novel multiple-unit floating dosage form for aceclofenac based on an emulsion solvent diffusion technique. There were two principle objectives to this study. Firstly, the suitability of different polymer such as Eudragit S 100, Eudragit RL 100, ethyl cellulose and HPMC either alone or in combination for the production of floating microspheres were investigated. The second objective was to assess the effect of stirring speed on various physiochemical properties of prepared floating microspheres. The size of the microspheres formed may however be a function of many factors such as stirring speed, viscosity of the dispersed phase, dispersion medium and temperature etc. Therefore, it is possible to prepare microspheres of desired size by varying some of these parameters. From the literature review, it was found that entrapment efficiency, particle size, floating ability, and drug release of floating microspheres could be adjusted by altering the stirring rate during microencapsulation. Hence, stirring speed was kept constant in the preliminary trial and selected as a second independent variable. From the results of the preliminary studies, the concentrations of Eudragit RL 100 and stirring speed were selected as independent variables for central composite design in Eudragit floating microspheres. Similarly, in ethyl cellulose microspheres, the concentrations of HPMC and stirring speed were selected as independent variables for central factorial design. Stirring speed affected percentage yield and entrapment efficiency significantly. In general, the percentage yield increased when stirring speed increased. At low stirring speed, polymer solution was aggregated around the propeller shaft, and the resultant yield of microspheres was relatively low. The percent drug entrapment of aceclofenac in all the formulations was found to be good at all levels of drug loading Stirring speed had a negative effect on entrapment efficiency. The high entrapment efficiency of aceclofenac is believed to be due to its poor aqueous solubility of aceclofenac. The purpose of preparing floating microspheres was to extend the gastric residence time of a drug. The floating ability test was carried out to investigate the floatability of the prepared microspheres. The results also showed a tendency that the larger the particle size, the longer the floating time and stirring speed showed the negative effect on floating ability in both polymer. Release of aceclofenac from microspheres was evaluated in pH 1.2 and 6.8. Since the acrylic polymer used in formulation is not soluble in acidic pH, no significant amount of drug was released from Eudragit microspheres in pH 1.2. On the other hand, when the content of Eudragit RL 100 increased, the rate of drug release was higher from Eudragit microspheres. Aceclofenac release from ethyl cellulose microspheres decreased with increasing ethyl cellulose concentration. Increase in the content would increase polymer matrix density and thus result in increased diffusional path length, leading to a decrease in drug release from the microsphere. Another factor might be that the smaller microspheres formed at low ethyl cellulose concentration had a larger surface area exposed to the dissolution medium, thus, giving rise to faster drug release. But when HPMC was added, release was increased. Thus, by varying the ratio of HPMC and ethyl cellulose in the ethyl cellulose microspheres, and Eudragit S 100 and Eudragit RL 100 in Eudragit microspheres, the rate of release of aceclofenac can be controlled. From preliminary study, the effect of speed stirring and ratio of Eudragit RL 100 and HPMC on the release rate of floating microspheres was selected for further study for optimization of formulation. It was found that at higher stirring speed, smaller microspheres were formed and have larger surface area exposed to the dissolution medium giving rise to faster drug release. While release was retarded on decreasing the stirring speed due to formation of big particle and amount of drug present close to the surface was decreased. The results of a central composite design revealed that the concentration of polymer and stirring speed significantly affected the dependent variables such as drug entrapment efficiency, drug release at 12 h, floating ability and particle size of the microspheres. The polynomial equation based optimization model was generated and validated. The accuracy of the model was established on the basis of the magnitude of errors and R2 values. The microspheres of the optimum batch (AS3) exhibited 73.83 % drug entrapment efficiency, mean particle size of 303.35 µm, 78.74 % floating ability at 8 h and 91.92 % release at 12 h. An appropriate balance between the levels of the polymer and stirring speed was imperative to acquire maximum drug entrapment efficiency, sustained release of the drug, floating ability and adequate particle size. The SEM images showed the spherical and hollow nature of the microspheres as well as the presence of pores on their surface. The microspheres prepared with both the polymers were spherical with smooth surface. Their sphericity contributed considerably to their very good flow properties while their hollow nature would mean lower microsphere density. The presences of pores were detected on the surface of microspheres. In FT- IR study, floating microspheres showed the characteristic peaks due to pure aceclofenac without any markable change in their position after successful encapsulation, indicating no chemical interaction between aceclofenac and polymers. The thermal behavior of the prepared floating microspheres with comparison to the pure drug indicated that aceclofenac was stable in the microspheres developed without undergoing any chemical changes during particle production. In Eudragit microspheres, the major thermal change is the disappearance of the sharp characteristic melting peak of drug incorporated into floating microspheres due to the loss of the crystalline state caused by the formation of an amorphous phase of aceclofenac. In ethyl cellulose microspheres, the displaced peak of drug suggested that drug is partly dissolved in the polymer and partly in the amorphous form distributed throughout the system. The X-ray powder diffraction spectra of pure aceclofenac and optimized formulations were measured for comparison. Pure aceclofenac showed a typical pattern of crystalline substance, which showed characteristic sharp refraction peaks. From X-ray patterns, it was investigated that the pure drug exhibited crystalline characteristics, while polymers and all formulations showed amorphous pattern, peak of drug being absent or nearly so in case of the formulations. The in vitro release pattern of the optimized formulations was analyzed by fitting the dissolution data into various kinetic models. It was observed that R2 value was higher when fitted to zero order equation as compared to first order equation, which indicated a zero order release from the prepared floating microspheres. In stability study, optimized formulation was selected as a promising formulation and was found stable at 40  2C/75 % RH for 6 months. Optimized formulation AS3 had shown good in vitro buoyancy and controlled release behavior and hence was finally selected for in vivo study, In in vivo anti-inflammatory study, the floating microspheres formulation AS3 showed 62.75 % decrease in the weight of granuloma, whereas, the standard showed a decrease of 54.10 % compare to control. This indicated that the prepared microspheres exhibited a better efficacy than the standard preparation. The effect of aceclofenac and floating microspheres of aceclofenac on freund’s adjuvant model induced arthritis was investigated and it was found that both aceclofenac and floating microspheres of aceclofenac significantly decrease the chronic inflammation induced by adjuvant shown as decrease in paw volume. In stomach protective activity, there was a marked difference in the reduction of ulcer index in case of floating microspheres. The calculated percent protection was 80.53%. The pharmacokinetic parameters of the floating delivery system of aceclofenac compared with pure drug were investigated in six rabbits. Aceclofenac was detectable in plasma within 30 min after its oral administration in rabbits. Compared with pure drug, the t1/2 was increased while the Ke was reduced. The low value of area under the curve (AUC) observed with plain aceclofenac may be due to its rapid absorption and elimination from the body; on the contrary, the sustained release compositions showed high AUC values indicating increased bioavailability of drug. These results clearly demonstrated the sustained release of aceclofenac from the prepared floating drug delivery system. In vivo X-ray study was conducted to determine the gastric retention time and to assess the gastrointestinal transit of this floating controlled drug delivery system. X-ray studies revealed the location of floating microspheres in six healthy rabbits. The optimized floating formulation showed excellent in vivo buoyancy and remain float up to 6 h. CONCLUSION: The floating microspheres of aceclofenac prepared by emulsion solvent diffusion method exhibited excellent in vitro buoyancy and zero order drug release. The surface response central composite design methodology could be successfully employed for assessing the influence of formulation parameters on the desired response. The drug polymer concentration and stirring rate played a vital role in achieving the desirable designed product. In all in vivo study, formulation was found to be superior. Hence the floating hollow microspheres of aceclofenac prepared with acrylic polymers may provide a convenient dosage form for achieving better floating and drug release. From the data obtained, it can be concluded that ◈ A novel floating drug delivery system of aceclofenac can be formulated as an approach to increase gastric residence time and thereby improve its bioavailability. ◈ Among the polymers used the combination of Eudragit S 100 and Eudragit RL 100 showed better control over drug release and floating ability. ◈ Preparation formulation was optimized for particle size, floating ability, entrapment efficiency and drug release. ◈ Optimized formulation was selected for in vivo study and in all study it gave favorable result. ◈ Thus the objective of formulating a floating dosage form of aceclofenac by using optimization technique has been achieved.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Development, Novel Controlled Release System, Gastric Retention.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Subramani R
Date Deposited: 11 Jan 2022 02:13
Last Modified: 16 Nov 2022 02:43

Actions (login required)

View Item View Item