Factors responsible for the impaired bioavailability and instability rifampicin FDC

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1 Table of contents 1.0 Introduction 1.1 Oral multiparticulate drug delivery system Methods of preparing pellets Extrusion-spheronization Theory of pellet formation and growth Pellets as a controlled drug delivery system Tuberculosis Pathogenesis of TB Tuberculosis in the world of today Treatment of TB Fixed Dose Combination (FDC) for the treatment of TB Problems associated with anti-tb FDCs Impaired and variable bioavailability of rifampicin from the FDCs Instability of the rifampicin in FDC formulations Factors responsible for the impaired bioavailability and instability rifampicin FDC Rationale of developing the novel FDC of rifampicin and isoniazid Formulation Design Objectives of the study...23 References Development and evaluation of rifampicin formulation 2.1 Introduction Floating drug delivery system (FDDS) Hydrodynamically balanced systems (HBS) Gas-generating systems Raft-forming systems Low-density systems Drug Profile- Rifampicin Formulation design...39

2 2.0 A Formulation development and evaluation of immediate release rifampicin pellets 2.5 Materials Methods Preliminary screening of the excipients Material characterization Loss on drying Bulk and tapped density Method of preparation of rifampicin pellets Granulation Extrusion Spheronization Drying Experimental design Statistical analysis of the data and validation of the model Characterization of rifampicin pellets Particle size distribution Usable yield (% theoretical) Pellet sphericity and shape analysis Friability Mechanical crushing force Densities and angle of repose Porosity Moisture content Surface characterization Drug content Drug release study Stability of immediate release rifampicin pellets Results and Discussion Preliminary experiments Selection of formulation variables...46

3 Selection of process variables Optimisation of immediate release rifampicin pellets Porosity Friability Pellet sphericity Drug release Validation of multiple response optimization model Stability studies Conclusions B Formulation development and evaluation of FDDS of rifampicin 2.15 Materials Methods Approach I- Preparation of rifampicin floating pellets using extrusionspheronization Granulation Extrusion Spheronization Drying Approach II- Preparation of rifampicin multiple-unit FDDS based on effervescent technique Preparation of Core rifampicin pellets Granulation Extrusion Spheronization Drying Coating of the core rifampicin pellets Approach III- Preparation of floating rifampicin tablet Method of preparation Experimental design Evaluation of granules Evaluation of floating property of rifampicin formulation In vitro floating duration...66

4 In vitro floating lag time determination In vitro release studies Statistical analysis of the data and validation of the model Assessment of in vivo gastroretention using Gamma-scintigraphic study Subjects Method of radiolabelling Study procedure Data analysis Stability of floating rifampicin tablet Results and Discussion Preliminary studies Selection of variables Formulation variables Process variables Optimisation of floating rifampicin tablet Floating lag time Floating duration In vitro drug release Validation of multiple response optimization model In vivo gastroretention using gamma-scintigraphic study Stability studies Conclusions References Formulation development and evaluation of isoniazid delayed release pellets Introduction Proposed formulation design of anti-tb FDC Drug profile-isoniazid Formulation development and evaluation of delayed release multiparticulate system of isoniazid Materials Methods...100

5 Preparation of core isoniazid pellets Granulation Extrusion Spheronization Drying Coating of core isoniazid pellets Optimization of core isoniazid pellets using response surface methodology Statistical analysis of the data and validation of the optimization model Evaluation of isoniazid pellets Particle size distribution Usable yield (% theoretical) Sphericity and shape analysis Surface characterization Abrasion resistance Mechanical crushing force Densities and angle of repose Porosity Residual moisture Drug content Gastric acid resistance test Drug release Stability studies Results and discussion Pellet yield and size distribution Shape analysis Pellet porosity Friability and mechanical crushing force Residual moisture Drug release Validation of multiple response optimization model...118

6 3.9 Coated delayed release isoniazid pellets Stability studies Conclusion References 4.0 Human bioavailability study of novel rifampicin and isoniazid FDC Introduction Stability studies of rifampicin and isoniazid FDC Methods Bioavailability studies of rifampicin and isoniazid FDC in human volunteers Materials Methods Clinical protocol Determination of rifampicin in plasma Determination of isoniazid in plasma Statistical analysis Pharmacokinetic analysis Descriptive statistics Analysis of variance % Confidence interval Bioequivalence criteria Results and discussion Stability studies of rifampicin and isoniazid FDC Bioavailability studies Conclusion References Summary and Conclusions Annexure1 Patent, Publications & Presentations