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BASED NASAL FORMULATIONS of LEVOTHYROXINE by Esomchukwu

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BASED NASAL FORMULATIONS of LEVOTHYROXINE by Esomchukwu DEVELOPMENT AND IN VITRO CHARACTERIZATION OF POLYMER- BASED NASAL FORMULATIONS OF LEVOTHYROXINE by Esomchukwu Vin-Boris Obinna Submitted in partial fulfilment of the requirements for the degree of Masters of Science at Dalhousie University Halifax, Nova Scotia August 2020 © Copyright by Esomchukwu Vin-Boris Obinna, 2020 TABLE OF CONTENT LIST OF TABLES……………………………………………………………………… v LIST OF FIGURES……………………………………………………………………. vi ABSTRACT………………………………………………………………………………x LIST OF ABBREVIATIONS AND SYMBOLS USED………………………………xi ACKNOWLEDGEMENTS…….………………………………………………….… xii CHAPTER 1 INTRODUCTION ............................................................................. 1 1.1 ANATOMY AND PHYSIOLOGY OF THE THYROID GLAND .............................. 1 1.2 DISEASES OF THE THYROID GLAND ............................................................. 2 1.2.1 Hyperthyroidism ................................................................................. 2 1.2.2 Hypothyroidism .................................................................................. 3 1.3 LEVOTHYROXINE REPLACEMENT THERAPY ................................................. 4 1.3.1 Chemical and Physical Properties of Levothyroxine .......................... 5 1.3.2 Current Levothyroxine Delivery Methods .......................................... 6 1.4 ANATOMY AND PHYSIOLOGY OF THE NOSE ................................................. 8 1.5 NASAL DRUG DELIVERY .............................................................................. 9 1.5.1 Mechanisms of Nasal Drug Absorption ............................................ 10 1.5.2 The Rationale for Nasal Mucoadhesive Drug Delivery .................... 11 1.6 EXPERIMENTAL MODELS FOR NASAL DRUG DELIVERY ........... 12 1.6.1 In situ models .................................................................................... 12 1.6.2 In vivo models ................................................................................... 13 1.6.3 In vitro models .................................................................................. 14 CHAPTER 2 OBJECTIVES AND SCOPE ......................................................... 17 CHAPTER 3 MATERIALS AND METHODS ................................................... 18 3.1 MATERIALS ................................................................................................ 18 3.2 INSTRUMENTS ............................................................................................ 18 3.3 CHROMATOGRAPHIC CONDITIONS ............................................................. 19 3.4 HPLC METHOD VALIDATION .................................................................... 20 ii 3.4.1 Linearity and Range .......................................................................... 20 3.4.2 HPLC Method Validation: Precision ................................................ 20 3.4.3 HPLC Method Validation: Accuracy ................................................ 21 3.4.4 HPLC Method Validation: Limit of Detection and Quantification .. 21 3.5 FORMULATION OPTIMIZATION STUDIES ..................................................... 21 3.6 PERCENTAGE YIELD ................................................................................... 22 3.7 PERCENTAGE DRUG LOADING ................................................................... 22 3.8 MORPHOLOGY (SCANNING ELECTRON MICROSCOPY) ............................... 23 3.9 PARTICLE SIZE ........................................................................................... 23 3.10 ZETA POTENTIAL MEASUREMENTS ............................................................ 23 3.11 DIFFERENTIAL SCANNING CALORIMETRY (DSC) ....................................... 24 3.12 POWDER X-RAY DIFFRACTION (PXRD)..................................................... 24 3.13 IN VITRO DRUG RELEASE ........................................................................... 24 3.14 STATISTICAL METHODS ............................................................................. 26 CHAPTER 4 RESULTS ........................................................................................ 27 4.1 HPLC VALIDATION ................................................................................... 27 4.1.1 Linearity ............................................................................................ 28 4.1.2 Accuracy ........................................................................................... 29 4.1.3 Precision ............................................................................................ 29 4.1.4 Limit of detection and limit of quantification ................................... 31 4.2 PERCENTAGE YIELD AND DRUG LOADING ................................................. 31 4.3 SURFACE MORPHOLOGY ............................................................................ 33 4.4 PARTICLE SIZE AND ZETA POTENTIAL ....................................................... 37 4.5 DIFFERENTIAL SCANNING CALORIMETRY (DSC) ....................................... 38 4.5.1 DSC for Carbopol-Levothyroxine Formulation ................................ 38 4.5.2 DSC for Polycarbophil-Levothyroxine Formulation ........................ 39 4.5.3 DSC for HPMC-Levothyroxine Formulation ................................... 40 4.5.4 DSC for Chitosan-Levothyroxine Formulation ................................ 41 4.6 POWDER X-RAY DIFFRACTION (PXRD)..................................................... 42 4.6.1 PXRD for Carbopol-Levothyroxine Formulation ............................. 42 4.6.2 PXRD for Polycarbophil-Levothyroxine Formulation ..................... 43 iii 4.6.3 PXRD for Levothyroxine-HPMC Formulation ................................ 44 4.6.4 PXRD for Levothyroxine-Chitosan Formulation ............................. 45 4.7 IN VITRO DRUG RELEASE ........................................................................... 46 4.7.1 In vitro Release of Levothyroxine-Carbopol Formulations .............. 46 4.7.2 In vitro Profile of Levothyroxine-Polycarbophil Formulations ........ 47 4.7.3 Invitro Release of Levothyroxine-HPMC Formulations .................. 48 4.7.4 Invitro Release of Levothyroxine-Chitosan Formulations ............... 50 4.8 IN VITRO RELEASE KINETICS ..................................................................... 51 CHAPTER 5 DISCUSSION .................................................................................. 53 5.1 ANALYTICAL METHOD DEVELOPMENT AND VALIDATION ........................... 53 5.2 PERCENTAGE YIELD AND DRUG LOADING ................................................. 54 5.3 SURFACE MORPHOLOGY ............................................................................ 55 5.4 PARTICLE SIZE ........................................................................................... 55 5.5 ZETA POTENTIAL ....................................................................................... 56 5.6 DIFFERENTIAL SCANNING CALORIMETRY (DSC) ....................................... 57 5.7 POWDER X-RAY DIFFRACTION ................................................................... 58 5.8 IN VITRO DRUG RELEASE AND KINETICS OF IN VITRO RELEASE ................ 58 CHAPTER 6 SUMMARY AND CONCLUSION ............................................... 61 REFERENCES………. ................................................................................................... 62 iv LIST OF TABLES Table 1. Physicochemical characteristics of levothyroxine ................................................ 5 Table 2. Nasal formulations for local and systemic effects. ............................................... 9 Table 3. Chromatographic conditions for levothyroxine detection .................................. 19 Table 4. Accuracy data for 10 µg/ml, 30 µg/ml and 70 µg/ml levothyroxine standard solutions with Varian 920 LC system (n=3). ...................................................... 29 Table 5. Intra-day and inter-day precision for 10 µg/ml, 50 µg/ml, and 100 µg/ml levothyroxine standard solutions with the Varian 920 LC system (n=3). .......... 30 Table 6. Percentage yield and percentage drug loading of levothyroxine-carbopol, levothyroxine-polycarbophil, levothyroxine-HPMC, and levothyroxine-chitosan formulations. ..................................................................................................... 32 Table 7. Particle size and zeta potential of the lyophilized levothyroxine-polymer formulations.. ...................................................................................................... 38 Table 8. Mathematical models for levothyroxine release from carbopol, polycarbophil, HPMC, and chitosan.. ......................................................................................... 51 v LIST OF FIGURES Figure 1. HPLC chromatogram for 100 µg/ml in acetonitrile and 0.1 % trifluoroacetic acid (70:30) solvent. .......................................................................................... 27 Figure 2. Linearity of levothyroxine within a concentration range of 0.5-100 µg/ml in acetonitrile and 0.1 % trifluoroacetic acid. ........................................................ 28 Figure 3. Scanning electron images of carbopol 1:1 (A), carbopol 1:3 (B), carbopol 1:5 (C), and raw levothyroxine (D) .......................................................................... 33 Figure 4. Scanning electron images of polycarbophil 1:1 (A), polycarbophil 1:3 (B), polycarbophil 1:5 (C), mannitol (D) .................................................................. 34 Figure 5. Scanning electron images
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