Table of contents 1.0 Introduction 1.1 Oral multiparticulate drug delivery system...2 1.2 Methods of preparing pellets...3 1.3 Extrusion-spheronization...3 1.4 Theory of pellet formation and growth...4 1.5 Pellets as a controlled drug delivery system...5 1.6 Tuberculosis...6 1.6.1 Pathogenesis of TB...6 1.6.2 Tuberculosis in the world of today...7 1.6.3 Treatment of TB...10 1.6.4 Fixed Dose Combination (FDC) for the treatment of TB...12 1.6.5 Problems associated with anti-tb FDCs...12 1.6.5.1 Impaired and variable bioavailability of rifampicin from the FDCs...13 1.6.5.2 Instability of the rifampicin in FDC formulations...15 1.6.6 Factors responsible for the impaired bioavailability and instability rifampicin FDC...16 1.7 Rationale of developing the novel FDC of rifampicin and isoniazid...18 1.8 Formulation Design...19 1.9 Objectives of the study...23 References...24 2.0 Development and evaluation of rifampicin formulation 2.1 Introduction...32 2.2 Floating drug delivery system (FDDS)...33 2.2.1 Hydrodynamically balanced systems (HBS)...33 2.2.2 Gas-generating systems...34 2.2.3 Raft-forming systems...34 2.2.4 Low-density systems...35 2.3 Drug Profile- Rifampicin...35 2.4 Formulation design...39
2.0 A Formulation development and evaluation of immediate release rifampicin pellets 2.5 Materials...40 2.6 Methods...40 2.6.1 Preliminary screening of the excipients...40 2.6.2 Material characterization...40 2.6.2.1 Loss on drying...40 2.6.2.2 Bulk and tapped density...41 2.7 Method of preparation of rifampicin pellets...41 2.7.1 Granulation...41 2.7.2 Extrusion...41 2.7.3 Spheronization...41 2.7.4 Drying...41 2.7.5 Experimental design...41 2.8 Statistical analysis of the data and validation of the model...42 2.9 Characterization of rifampicin pellets...43 2.9.1 Particle size distribution...43 2.9.2 Usable yield (% theoretical)...43 2.9.3 Pellet sphericity and shape analysis...43 2.9.4 Friability...44 2.9.5 Mechanical crushing force...44 2.9.6 Densities and angle of repose...44 2.9.7 Porosity...44 2.9.8 Moisture content...44 2.9.9 Surface characterization...45 2.9.10 Drug content...45 2.9.11 Drug release study...45 2.10 Stability of immediate release rifampicin pellets...45 2.11 Results and Discussion...46 2.11.1 Preliminary experiments...46 2.11.1.1 Selection of formulation variables...46
2.11.1.2 Selection of process variables...48 2.11.2 Optimisation of immediate release rifampicin pellets...49 2.11.2.1 Porosity...50 2.11.2.2 Friability...52 2.11.2.3 Pellet sphericity...53 2.11.2.4 Drug release...55 2.12 Validation of multiple response optimization model...57 2.13 Stability studies...59 2.14 Conclusions...61 2.0 B Formulation development and evaluation of FDDS of rifampicin 2.15 Materials...62 2.16 Methods...62 2.16.1 Approach I- Preparation of rifampicin floating pellets using extrusionspheronization...62 2.16.1.1 Granulation...62 2.16.1.2 Extrusion...63 2.16.1.3 Spheronization...63 2.16.1.4 Drying...63 2.16.2 Approach II- Preparation of rifampicin multiple-unit FDDS based on effervescent technique...63 2.16.2.1 Preparation of Core rifampicin pellets...63 2.16.2.1.1 Granulation...63 2.16.2.1.2 Extrusion...63 2.16.2.1.3 Spheronization...63 2.16.2.1.4 Drying...64 2.16.2.2 Coating of the core rifampicin pellets...64 2.16.3 Approach III- Preparation of floating rifampicin tablet...64 2.16.3.1 Method of preparation...65 2.16.3.2 Experimental design...65 2.16.3.3 Evaluation of granules...66 2.16.3.4 Evaluation of floating property of rifampicin formulation...66 2.16.3.4.1 In vitro floating duration...66
2.16.3.4.2 In vitro floating lag time determination...66 2.16.3.4.3 In vitro release studies...67 2.16.3. 5 Statistical analysis of the data and validation of the model...67 2.17 Assessment of in vivo gastroretention using Gamma-scintigraphic study...67 2.17.1 Subjects...68 2.17.2 Method of radiolabelling...68 2.17.3 Study procedure...68 2.17.4 Data analysis...69 2.18 Stability of floating rifampicin tablet...69 2.19 Results and Discussion...70 2.19.1 Preliminary studies...70 2.19.2 Selection of variables...71 2.19.2.1 Formulation variables...71 2.19.2.2 Process variables...71 2.19.3 Optimisation of floating rifampicin tablet...72 2.19.3.1 Floating lag time...73 2.19.3.2 Floating duration...74 2.19.3.3 In vitro drug release...76 2.19.3.4 Validation of multiple response optimization model...78 2.20 In vivo gastroretention using gamma-scintigraphic study...79 2.21 Stability studies...83 2.22 Conclusions...85 3.0 References Formulation development and evaluation of isoniazid delayed release pellets...86 3.1 Introduction...94 3.2 Proposed formulation design of anti-tb FDC...95 3.3 Drug profile-isoniazid...96 3.4 Formulation development and evaluation of delayed release multiparticulate system of isoniazid...100 3.4.1 Materials...100 3.4.2 Methods...100
3.4.2.1 Preparation of core isoniazid pellets...100 3.4.2.1.1 Granulation...100 3.4.2.1.2 Extrusion...100 3.4.2.1.3 Spheronization...100 3.4.2.1.4 Drying...100 3.4.2.2 Coating of core isoniazid pellets...100 3.4.3 Optimization of core isoniazid pellets using response surface methodology...101 3.4.3.1 Statistical analysis of the data and validation of the optimization model...102 3.5 Evaluation of isoniazid pellets...103 3.5.1 Particle size distribution...103 3.5.2 Usable yield (% theoretical)...103 3.5.3 Sphericity and shape analysis...103 3.5.4 Surface characterization...103 3.5.5 Abrasion resistance...104 3.5.6 Mechanical crushing force...104 3.5.7 Densities and angle of repose...104 3.5.8 Porosity...104 3.5.9 Residual moisture...104 3.5.10 Drug content...105 3.5.10.1 Gastric acid resistance test...105 3.5.10.2 Drug release...105 3.6 Stability studies...105 3.7 Results and discussion...106 3.7.1 Pellet yield and size distribution...107 3.7.2 Shape analysis...110 3.7.3 Pellet porosity...111 3.7.4 Friability and mechanical crushing force...113 3.7.5 Residual moisture...115 3.7.6 Drug release...116 3.8 Validation of multiple response optimization model...118
3.9 Coated delayed release isoniazid pellets...120 3.10 Stability studies...122 3.10 Conclusion...124 References 4.0 Human bioavailability study of novel rifampicin and isoniazid FDC...125 4.1 Introduction...130 4.2 Stability studies of rifampicin and isoniazid FDC...131 4.2.1 Methods...131 4.3 Bioavailability studies of rifampicin and isoniazid FDC in human volunteers...132 4.3.1 Materials...132 4.3.2 Methods...132 4.3.2.1 Clinical protocol...132 4.3.3 Determination of rifampicin in plasma...134 4.3.4 Determination of isoniazid in plasma...134 4.3.5 Statistical analysis...135 4.3.5.1 Pharmacokinetic analysis...135 4.3.5.2 Descriptive statistics...135 4.3.5.3 Analysis of variance...136 4.3.5.4 90% Confidence interval...136 4.3.5.5 Bioequivalence criteria...136 4.4 Results and discussion...136 4.4.1 4.4.2 Stability studies of rifampicin and isoniazid FDC Bioavailability studies...136...142 4.5 Conclusion...150 References...152 5.0 Summary and Conclusions...157 Annexure1 Patent, Publications & Presentations