Enteric coated mucoadhesive micropellets in rotary agglomeration process for wet spheronization [Elektronische Ressource] / Marcus Hans Knöll

ENTERIC COATED MUCOADHESIVE
MICROPELLETS IN ROTARY
AGGLOMERATION PROCESS FOR WET
SPHERONIZATION


Dissertation zur Erlangung des Grades
„Doktor der Naturwissenschaften“



am Fachbereich Chemie und Pharmazie und Geowissenschaften
der Johannes Gutenberg-Universität
Mainz




Marcus Hans Knöll
geb. in Frankfurt / Main




Mainz 2006














D 77




































Tag der mündlichen Prüfung: 8. Dezember 2006













To


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ACKNOWLEDGEMENTS
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TABLE OF CONTENTS
DEDICATION ……………………………………………………………………………………………………..I
ACKNOWLEDGEMENTS...................................................................................................................... III
TABLE OF CONTENTS..........................................................................................................................V
LIST OF TABLES ..................................................................................................................................IX
LIST OF FIGURES.................................................................................................................................XI
ABBREVIATIONS.................................................................................................................................XV
INTRODUCTION..................................................................................................................................... 1
AIMS ....................................................................................................................................... 1
CHAPTER I BACKGROUND............................................................................................................. 3
I.1. Basis for Drug Delivery to the Gastrointestinal Tract............................................................... 3
I.1.1. Anatomy and Physiology of the Gastrointestinal Tract........................................................ 3
I.1.2. Secretions of the Mucosa of the Gastrointestinal Tract....................................................... 5
I.2. Transit of Dosage Forms.......................................................................................................... 6
I.2.1. Oesophageal Transit............................................................................................................ 6
I.2.2. Gastric Emptying of Liquid Dosage Forms .......................................................................... 6
I.2.3. Gastric Emptying of Non-Digestible Solids (Solid Dosage Forms and Drug Particles)....... 7
I.2.4. Small Intestinal Transit......................................................................................................... 7
I.2.5. Large Intestinal Transit ........................................................................................................ 8
I.2.6. Prolongation of Gastrointestinal Transit Time...................................................................... 8
I.3. Mucoadhesion.......................................................................................................................... 9
I.3.1. Mechanisms of Mucoadhesion .......................................................................................... 10
I.3.2. Mucoadhesive Polymer Types........................................................................................... 11
I.3.3. Challenges to the Concept of Mucoadhesion .................................................................... 15
I.4. Mucoadhesive Polymers........................................................................................................ 16
I.4.1. Natural Polymers................................................................................................................ 16
I.4.2. Semi-Synthetic Polymers................................................................................................... 19
I.4.3. Synthetic Polymers ............................................................................................................ 21
I.5. Granulation Processes........................................................................................................... 28
I.5.1. Binding Forces of Granules ............................................................................................... 28
I.5.2. Growth Mechanisms of the Particles ................................................................................. 29
I.5.3. Fluidized Bed Technology.................................................................................................. 30
I.5.4. Rotary Processor ............................................................................................................... 34
CHAPTER II MATERIALS AND EQUIPMENT................................................................................. 40
II.1. Materials ........................................................................................................................... 40
II.2. Equipment / Software............................................................................................................. 41
CHAPTER III METHODS................................................................................................................... 43
III.1. Manufacturing of Pellets Using the GPCG1 Rotary Processor.............................................. 43
III.1.1. Na-CMC Micropellets Production....................................................................................... 43
III.1.2. Na-Alginate Micropellets Production.................................................................................. 48
III.1.3. Chitosan Micropellets Production ...................................................................................... 50
®
III.1.4. Carbopol Micropellets Production .................................................................................... 53
III.1.5. Noveon Micropellets Production ........................................................................................ 53
III.2. Characterization of Micropellets............................................................................................. 54
III.2.1. Particle Size Distribution .................................................................................................... 54
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III.2.2. Tapped Density.................................................................................................................. 55
III.2.3. Friability Testing................................................................................................................. 55
III.2.4. Water Content at the End of the Spraying Period.............................................................. 55
III.2.5. Drying Kinetics of the Micropellets..................................................................................... 55
III.2.6. Scanning Electron Microscopy (SEM) ............................................................................... 55
III.2.7. True Density....................................................................................................................... 55
III.2.8. Estimation of the Surface Area with the Modified Blaine Method...................................... 56
III.2.9. NMR for Acetic Acid Content in the Chitosan Micropellets................................................ 57
III.2.10. Content Uniformity of Theophyllin within Micropellets by HPLC........................................ 57
III.2.11. Statistical Analysis ............................................................................................................. 58
III.3. Enteric Coating of the Micropellets ........................................................................................ 58
III.3.1. Terminology ....................................................................................................................... 58
III.3.2. Formulation of the Spraying Suspension........................................................................... 58
III.3.3. Enteric Coating using the Mini-Glatt .................................................................................. 60
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III.3.4. Enteric Coating using the Hüttlin Mycrolab ...................................................................... 63
III.4. Dissolution Testing................................................................................................................. 66
III.4.1. Screening of Dissolution Methods for Mucoadhesive Micropellets ................................... 66
III.4.2. Dissolution of the Developed and Manufactured Micropellets using App. 2 and App. 4... 69
III.4.3. Dynamic Hydration Properties of Excipients for Mucoadhesive Micropellets.................... 71
III.4.4. Electron Dispersive X-Ray Method for Proving the Separation of an Enteric Coating Layer
from a Mucoadhesive Matrix Layer.................................................................................... 73 <