Different Methods of Formulation and Evaluation of Mucoadhesive Microspheres by using Various Polymers for H2 Receptor Antagonist Drug

Gowri, R (2017) Different Methods of Formulation and Evaluation of Mucoadhesive Microspheres by using Various Polymers for H2 Receptor Antagonist Drug. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.


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BACKGROUND: Ranitidine HCl is a H2 receptor antagonist and is used in peptic ulcer disease. It is administered as conventional tablet in a dose of 150 mg and 300 mg. Although proton pump inhibitors have taken over in the treatment of peptic ulcer Ranitidine HCl is still used in clinical practice. Bioavailability of Ranitidine HCl from the conventional dosage form remains problematic in achieving successful therapeutic benefits of the drug. Ranitidine HCl is bioavailable to the extent of about 50 % owing to greater protein binding as well as first pass metabolism. Therefore an alternative drug delivery system that can overcome the disadvantages of conventional dosage form of drug is necessitated in order to achieve desired therapeutic benefits. Mucoadhesive drug delivery system is one of the approaches most preferred for drugs that are poorly bio available following oral administration. Besides mucoadhesive drug delivery system is advantageous for drugs that are primarily absorbed in stomach as the system increases the gastric retention time. AIM AND OBJECTIVES: Multifarious drugs enumerated as once a day delivery have been proclaimed to have suboptimal absorption owing to susceptibility on the dosage form transit time, accomplishing long established prolonged release. Ranitidine hydrochloride is a H2 receptor antagonist and currently used in clinical practice for the treatment of peptic ulcer as a conventional dosage form. The drug has a short half-life of 2-3 h and requires frequent dosing to maintain therapeutic efficacy, which eventually attracts poor patient compliance. Considering the above factors it is desirable that the drug be retained in the stomach for longer period of time to achieve prolonged efficacy of the drug for effective management of ulcer. Mucoadhesion is one of the successful methods of retaining the drug in the target site for prolonged release and exhibit prolonged action of the drug. METHODS: Drug-excipient interactions / incompatibility studies were utmost essential in formulation development. An imperforate characterization and conception of physicochemical interactions of an active pharmaceutical ingredient (API) in the dosage forms are intrinsic part of preformulation stage of new dosage form development as it is most captivating for consistent potency, impregnability and stability of a drug product. In a dosage form, an API comes in direct contact with other components (excipients) of the formulation that facilitate the administration and release of an active component as well as protect it from the environment. Although excipients are pharmacologically inert, they can interact with drugs in the dosage form to affect drug product stability in physical aspects such as organoleptic properties, dissolution slow down or chemically by causing drug degradation. Careful selection of the excipients is required for a robust and effective formulation of dosage forms that make administration easier, improve patient compliance, promote release and bioavailability of the drug and increase its shelf life. Thus, compatibility screening of an API with excipients or active ingredients is recognized as one of the mandatory factors and is at the fore front of drug product science and technology research. STATISTICAL ANALYSIS: Experimental results were tested by one-way analysis of variance (ANOVA). Data represented as mean values ± SEM. The values of p < 0.05 (*) were indicative of significant difference, very significant difference if p < 0.01 (**) and highly significant difference if p < 0.001 (***). SUMMARY AND CONCLUSION Ranitidine HCl is a H2 receptor antagonist administered in dose 150 – 300 mg in the treatment of gastric ulcer. The effect of the drug lasts up to 5 h and is poorly bioavailable from the conventional dosage form. A gastroretentive mucoadhesive drug delivery system of Ranitidine HCl was attempted as an alternative to conventional drug delivery system for extended release characteristics. Mucoadhesive microspheres of Ranitidine HCl was developed using Chitosan and Eudragit RS 100 as polymers at different drug to polymer ratios. The mucoadhesive microspheres were developed by different methods such as solvent evaporation, double emulsion, coacervation phase separation. The developed microspheres were screened for physiochemical and in vitro release characteristics. The performance of the microspheres in physiochemical characteristics and in vitro release behaviour were compared. The formulations were coded RCS1 – RCS6 (solvent evaporation), RCD1 – RCD6 (double emulsion), RCP1 – RCP6 (coacervation phase separation) for Chitosan microsphere and RES1 – RES6 (solvent evaporation), RED1 – RED6 (double emulsion), REP1 – REP6 (coacervation phase separation) for Eudragit RS 100 microsphere. Based on the performance of the microspheres in various characteristics as mentioned above were analyzed and the best fit formulations from among Chitosan microspheres and from among Eudragit RS 100 microspheres were RCP3 and RES3 respectively. Formulations RCP3 and RES3 were validated for reproducible results on percentage yield, particle size and entrapment efficiency. In the preformulation study the drug and polymer screened for DSC analysis to study the interaction between drug and the mixture. The results showed no change in characteristic peaks in drug and polymer and hence no interaction between them. In the micromeritics study formulations evaluated for bulk density, tapped density, Carr’s index, Hausner’s ratio and Angle of repose. The data obtained were within the pharmaceutically acceptable limit. Morphology of best formulation RCP3 and RES3 were studied by SEM analysis and the microspheres were spherical and uniform in size with smooth surfaces. Particle size and percentage yield were analyzed and the results showed all the above parameters changed with change in concentration of polymer. Percentage product yield of microsphere was chosen as the criterion for the best formulation for further studies. The formulations RCS1 – RCS4, RCD1 – RCD4, RCP1 – RCP4 RES1 – RES4, RED1 – RED4, REP1 – REP4 were selected for in vitro release study. The selected microspheres showed slow rate of release extended up to 24 h. The rate of release was influenced by particle size polymer concentration and the method of preparation of microspheres. The in vitro release data were fitted in to various kinetic model and zero order, first order, Higuchi, Korsmeyer-peppas and the exponent value were explored. The regression values obtained were compared and it was found that all formulations followed first order release kinetics and the release mechanism was found to be non-Fickian anamolous diffusion based on the exponent value. Formulations that showed highest percentage extended release up to 24 h were selected and accordingly RCP3 and RES3 were found as the best formulations. Stability study was performed on formulations RCP3 and RES3 at different storage condition as per the ICH guidelines. The formulations were found stable over storage. The swelling index and mucoadhesion formulations of Chitosan and Eudragit RS 100 were examined and high percentage swelling index and percentage mucoadhesion were found with formulation RCP3 and RES3. Antiulcer activity was performed on the best fit formulations RCP3 and RES3 in albino rats and percentage ulcer protection was calculated. Both RCP3 and RES3 showed highest percentage ulcer protection as compared to pure Ranitidine HCl. In vivo bioavailability was performed on RCP3 and RES3 and Cmax, tmax and AUC were measured. The C max of microsphere extended to 8 h and the AUC of the microspheres were greater than that of Ranitidine and the results showed improved bioavailability of the microsphere. The finding of the present study demonstrates that Chitosan as well as Eudragit RS 100 are beneficial for development of gastroretentive microspheres of Ranitidine HCl. The processing method employed for development of microspheres with best results seems dependent upon the type of polymer used. In the present study Chitosan provided desirable characteristics of mucoadhesive microspheres with coacervation phase separation method, whereas Eudragit RS 100 solvent evaporation method was found suitable. Optimization of drug to polymer ratio concentration was found to be optimum for providing desired characteristics of the gastroretentive microspheres of Ranitidine HCl. At 24 h first order release was observed with both Chitosan and Eudragit RS 100 microspheres and no significant difference in antiulcer activity was observed between Chitosan and Eudragit RS 100 microspheres. Thus it can be concluded that gastroretentive Ranitidine HCl with 24h release microspheres can be developed either with Chitosan or Eudragit RS 100 as an alternative to conventional dosage form for effective control of gastric ulcer.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Formulation, Evaluation, Mucoadhesive Microspheres, Polymers, H2 Receptor Antagonist Drug.
Subjects: PHARMACY > Pharmaceutics
Depositing User: Subramani R
Date Deposited: 24 Sep 2019 05:17
Last Modified: 24 Oct 2022 08:41
URI: http://repository-tnmgrmu.ac.in/id/eprint/11567

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