目次 | Abbreviations .........1, Abstract .........2, Introduction ........4, Chapter 1 Usefulness of intracutaneous injection by 33 gauge-needles for systemic delivery of high molecular compounds........7, 1.1. Introduction .....7, 1.2. Materials and methods ........8, 1.2.1. Materials ........8, 1.2.2. Injection needles ........8, 1.2.3. Experimental animals .........9, 1.2.4. Intravenous injection (i.v.) of Evans blue with different needles .........9, 1.2.5. I.c. injection of FD-4 with different needles.........9, 1.2.6. I.v. injection of FD-4/FL-Na ........10, 1.2.7. I.c., s.c. and i.m. injection of FD-4/FL-Na with a 33 G needle .........10, 1.2.8. Assay .........10,1.2.9. Pharmacokinetic analysis method .........10, 1.2.10. Statistical analysis ........11, 1.3. Results and discussion.......11, 1.3.1. Appearance of injection site.......11, 1.3.2. Systemic disposition of FD-4 after i.c. injection using different needles....11, 1.3.3. Systemic disposition of FD-4 and FL after injection with a 33 G-needle into different sites........13, 1.4. Discussion......17, 1.5. Chapter conclusion........18, Chapter 2 Transdermal drug delivery by in-skin electroporation with microneedle array .........19, 2.1. Introduction ........19, 2.2. Materials and methods......19, 2.2.1. Chemicals and animals ........19, 2.2.2. Application of IN-SKIN EP using an MN-electrode array .......20, 2.2.3. In vitro skin permeation experiments......21, 2.2.4. Scanning electron micrographic observation......22, 2.2.5. Confocal microscopic observation of drug distribution ......23, 2.2.6. Confocal microscopic observation (Vivascope) of puncture ......23, 2.2.7. Measurement of lactate dehydrogenase (LDH) leakage from skin in vivo.......23, 2.2.8. Statistical analysis .....24, 2.3. Results and discussion......24, 2.3.1. Effect of IN-SKIN EP pretreatment on the skin permeation of FD-4 .........24, 2.3.2. Effect of voltage and pulse width in the IN-SKIN EP treatment.....29, 2.3.3. Influence of IN-SKIN EP on lactate dehydrogenase (LDH) leaching from skin .......31, 2.4. Chapter conclusion ........32, Chapter 3 Development and evaluation of the microneedle-electrode array......33, 3.1. Introduction ........33, 3.2. Materials and methods.........34, 3.2.1. Chemicals and animals ........34, 3.2.2. Configurations of MN-electrode array ........34, 3.2.3. Applications of IN-SKIN EP and ON-SKIN EP with MN-electrode array ..........35, 3.2.4. In vitro skin permeation experiments..........35, 3.2.5. Scanning electron microscopic observation ...........35, 3.2.6. Measurement of skin redness and cutaneous blood flow.........35, 3.2.7 In vivo experiment......36, 3.2.8. Statistical analysis .........37, 3.3. Results and discussion........37, 3.3.1. Effect of IN-SKIN EP pretreatment on the skin permeation of FD-4 .........37, 3.3.2. Scanning electron micrographic observation............39, 3.3.3. Influence of IN-SKIN EP to the skin redness and blood flow...........40, 3.4. Chapter conclusion ...........44, Conclusion ..........45, Acknowledgement .........46, References .........47 |