Title Page
Contents
Abstract 18
I. INTRODUCTION 20
I-1. Pramipexole 20
I-1-1. Physicochemical properties 20
I-1-2. Pharmacology 22
I-1-3. Pharmacokinetics 25
I-2. Orally disintegrating drug delivery system 26
I-2-1. Advantages of Orally disintegrating tablet (ODT) 28
I-2-2. Considerations of orally disintegrating delivery system 29
I-2-3. Formulation process for making ODTs 30
I-3. Controlled release microparticles 37
I-3-1. Spray drying 37
I-3-2. Fluid bed coating 39
I-3-3. Resin exchange 42
I-4. Excipients 43
I-4-1. Ethyl 43
I-4-2. Methacrylic acid copolymer 44
I-4-3. Coating solution 45
II. OBJECTIVES 47
III. EXPERIMENTAL METHODS 49
III-1. Materials 49
III-2. Quantitative analysis of pramipexole 51
III-2-1. HPLC method 51
III-2-2. HPLC system 51
III-2-3. Preparation of stock solution 52
III-2-4. Preparation of standard solution 52
III-2-5. Validation of pramipexole HPLC analysis 52
III-3. Formulation of pramipexole ODT containing sustained release microparticles 54
III-3-1. Preparation of microparticles by spray drying method 54
III-3-2. Preparation of ODT using spray dried microparticles 56
III-3-3. Preparation of microparticles by fluid bed coating method 56
III-3-4. Preparation of ODT containing coated microparticles 59
III-4. Evaluation of microparticles and tablets 61
III-4-1. In vitro release study 61
III-4-2. Determination of pramipexole contents 62
III-4-3. Determination of disintegration time of the tablet 62
III-5. Determination of particle morphology 63
III-5-1. Characterization of microparticles using digital Microscope 63
III-5-2. Characterization of microparticles using scanning electron microscope (SEM) 64
III-6. Data analysis 64
III-6-1. Zero-order model 65
III-6-2. Higuchi model 66
III-6-3. Statistics 66
IV. RESULTS AND DISCUSSION 68
IV-1. Quantitative analysis of pramipexole 68
IV-1-1 . Validation of pramipexole analysis method using HPLC 68
IV-2. Formulation of ODT containing sustained release microparticles made by spray drying method 72
IV-2-1. Effect of the type of spray drying mixtures 72
IV-2-2. Effect of the viscosity grade of ethyl cellulose 72
IV-2-3. Effect of the ratio of drug and polymer 83
IV-2-4. Effect of the type of polymers 88
IV-3. Formulation of sustained release microparticles using fluid bed coating method 88
IV-3-1. Drug layering 88
IV-3-2. Effect of the coating material and coating level on dissolution profile 93
IV-3-3. Characterization of the coated beads using digital microscope 100
IV-3-4. Characterization of the coated beads using SEM 100
IV-3-5. Evaluation of the effect of curing 106
IV-4. Formulation of ODT containing sustained release microparticles made by fluid bed coating method 110
IV-4-1. Effect of tablet compression on dissolution profile 110
IV-4-2. Determination of freeze drying formulation 113
IV-4-3. Effect of the freeze drying on tablet dissolution profile 116
V. Conclusion 123
VI. References 125
국문요약 132
Table IV-1. Accuracy and precision of the HPLC analysis of pramipexole 71
Table IV-2. Formulations of ODT containing spray dried microparticles with different grade of ethyl cellulose (drug : EC=1:10) 77
Table IV-3. Formulations of ODT containing spray dried microparticles with different grade of ethyl cellulose (drug : EC=1:30) 79
Table IV-4. Release kinetics of pramipexole ODT containing spray dried microparticles 81
Table IV-5. Formulations of ODT containing spray dried microparticles with different ratio of drug and polymer 84
Table IV-6. Release kinetics of pramipexole ODT containing spray dried microparticles 87
Table IV-7. Formulations of ODT containing spray dried microparticles with different polymers 89
Table IV-8. Formulation of layering solution 91
Table IV-9. Formulations of coating solution I 94
Table IV-10. Formulations of coating solution II 95
Table IV-11. Release kinetics of microparticles made by fluid bed coating method 99
Table IV-12. Size of microparticles made by fluid bed coating method 102
Table IV-13. Release kinetics of uncured or cured microparticles made by fluid bed coating method 108
Table IV-14 . Formulations of ODT containing SureleaseR coated microparticle (compression method)(이미지참조) 111
Table IV-15 . Formulations of ODT containing SureleaseR coated microparticle (compression method)(이미지참조) 112
Table IV-16. Formulations for freeze dryied ODT 115
Table IV-17. Viscosity and disintegration time of freeze drying ODT 117
Table IV-18. Formulations of ODT containing sureleaseR coated microparticle (freeze drying method)(이미지참조) 119
Figure I-1. The structure of pramipexole 21
Figure IV-1. Representative chromatograms, (A) mobile phase, (B) pramipexole 69
Figure IV-2. Standatd calibration curve for the HPLC analysis of pramipexole(r²〉0.9999) 70
Figure IV-3. Effect of the type of spray drying mixtures, Key: (●) emulsion type, (○) suspension type, (▼) solution type 74
Figure IV-4. Scanning electron microscope images of microparticles made by spray drying method, (A) emulsion type (×5000), (B) emulsion type (×11000), (C) suspension type (×3000), (D) solution type (×3000) 75
Figure IV-5. Effect of the grade of ethyl cellulose (drug : EC=1:10), Key: (●) A1, (○) A2, (▼) A3. 78
Figure IV-6. Effect of the grade of ethyl cellulose (drug : EC=1:30), Key: (●) A4, (○) A5, (▼) A6, (△) A7. 80
Figure IV-7. Effect of the ratio of EC grade on the T50% of pramipexole ODT(이미지참조) 82
Figure IV-8. Effect of the ratio of drug and polymer, Key: (●) A1, (○) A8, (▼) A9, (△) A5. 85
Figure IV-9. Effect of the ratio of drug and polymer on the T50% of pramipexole ODT(이미지참조) 86
Figure IV-10. Effect of the type of polymers, Key: (●) A5, (○) A10, (▼) A10, (△) S19. 90
Figure IV-11. Dissolution profile of drug layered microparticle 92
Figure IV-12. Effect of the type of coating solutions and coating level, Key: (●) KollicoatR 30% coating, (○) KollicoatR 50% coating, (▼) EudragitR 50% coating(이미지참조) 96
Figure IV-13. Effect of the type of coating solutions and coating level, Key: (●) EC 30% coating, (○) EC 50% coating, (▼) SureleaseR 30% coating, (△) SureleaseR 50% coating(이미지참조) 97
Figure IV-14. Effect of type of coating solutions and coating level on the T50% of pramipexole ODT(이미지참조) 98
Figure IV-15. Digital microscope images of microparticles made by fluid bed coating method (×200), (A) CelletR, (B) KollicoatR 30% coating, (C) SureleaseR 30% coating, (D) EC 30% coating(이미지참조) 101
Figure IV-16. Size of microparticles made by fluid bed coating method 103
Figure IV-17. Scanning electron microscope images of microparticles made by fluid bed coating method, (A) CelletR (×370), (B) drug layered microparticle (×370), (C) and (D) microparticle coated with KollicoatR (×370 and ×2000)(이미지참조) 104
Figure IV-18. Scanning electron microscope images of microparticles made by fluid bed coating method, (A) and (B) microparticle coated with EC (×370 and ×2000), (C) and (D) microparticle coated with SureleaseR (×370 and ×2000)(이미지참조) 105
Figure IV-19. Effect of the curing of coated beads and coating level, Key: (●) SureleaseR 30% coating, naive, (○) SureleaseR 30% coating, curing, (▼) SureleaseR 30% coating, naive, (△) SureleaseR 50% coating, curing(이미지참조) 107
Figure IV-20. Effect of type of curing on the T50% of pramipexole ODT(이미지참조) 109
Figure IV-21. Effect of the compression on dissoultion of pramipexole ODT 114
Figure IV-22. Apparent shape of freeze drying ODTs and their image in dissolution tester, (A) and (B) V1, (C) and (D) V4. 118
Figure IV-23. Effect of the freeze drying method on dissolution of pramipexole ODT, Key: (●) T5, (○) T6, (▼) SureleaseR 30% coating in capsule, (△) SureleaseR 50% coating in capsule(이미지참조) 121
Figure IV-24. Effect of the tabletting by freeze drying method on the T50% of pramipexole ODT(이미지참조) 122
Scheme III-1. Manufacturing process of pramipexole ODT (spary drying method) 55
Scheme III-2. Manufacturing process of pramipexole ODT (fluid bed coating method) 58
Scheme IV-1. Type of spray drying solvent mixtures 73