| 抄録 | Acne vulgaris is a very common skin disease, which causes a high degree of psychosocial suffering and has a detrimental effect on the quality of life in the patients irrespective of age or gender. Treatment of acne is principally directed towards these known pathogenic factors. Clindamycin and erythromycin are commonly prescribed topical antibiotics for acne vulgaris with their anti-inflammatory properties. However, the effectiveness against the acne treatments has been limited by their relative low penetration into the pilosebaceous unit, the site of acne formation.
Evaluation of skin and hair follicular concentration of the acne drugs is a key for their therapeutic and cosmeceutic effects, because their pharmacodynamics and toxicodynamics can be closely expressed by a function of these concentrations. Permeation pathwaiesof topically applied chemical compounds, i.e., stratum corneum and hair follicle (HF) are related to their skin concentrations. Then, I aimed to investigate the contribution of skin permeation of drugs through HF as well as stratum corneum to enable their selective delivery to HF.
The contribution of HF pathway on the skin permeation of chemicals was evaluated from a difference between their permeability coefficients through skin with and without HF plugging using in vitro skin permeation experiment. The obtained result revealed that the contribution of HF pathway could be predicted by lipophilicities of applied chemicals. In a hydrophilic region of chemicals (logKo/w < 0), a higher reduction ratio was observed by HF plugging compared with lipophilic chemicals (logKo/w ≥ 0). In addition, the reduction ratio was decreased with an increase in the logKo/w. This consideration on the HF pathway would be helpful to investigate usefulness and safety of chemicals after their topical application and exposure, because skin permeation and disposition must be changed among different sites of skin due to different densities of HF. Furthermore, another study was conducted to evaluate the drug disposition in HF. HF concentration of drugs with different lipophilicities was investigated to evaluate the effect of physicochemical properties on their HF disposition.
Obtained results showed that a lag time was observed in the skin permeation before obtaining a steady-state profile for hydrophilic drugs compared with that for lipophilic drugs. Hydrophilic drugs were found to be distributed through the HF as well as into the shallow part of stratum corneum, whereas lipophilic drugs distributed both into the stratum corneum and HF from a histological observation using fluorescent makers. These results suggest that lipophilic drugs could be easily delivered both into the stratum corneum and HF, whereas hydrophilic drugs were mainly delivered through HF, but not for deep layers of the stratum corneum.
Generally, stratum corneum route is the main permeation pathway for lipophilic drugs, but HF route is the main permeation pathway for hydrophilic drugs. However, lipophilic drugs show a higher amount of disposition at HF compared t hydrophilic drugs. Therefore, suitable drug delivery systems to treat acne must be considered in detail. Nowadays, formulation design of topically applied drugs is conducted to enhance the skin permeation. Only a few studies, however, have been focused on the selective drug delivery to HF. An efficient delivery to HF would be feasible in the near feature by understanding drug and vehicles characteristics through the present research. |
| 目次 | Abstract・・・1, General introduction・・・3, Chapter 1 Contribution of hair follicular pathway of topically applied and exposed chemicals for the total skin permeation, 1.1. Introduction・・・7, 1.2. Method・・・10,1.3. Results・・・19, 1.4. Discussion・・・25, 1.5. Chapter conclusion・・・29, Chapter 2
Evaluation of drug disposition in hair follicles after topical application, 2.1. Introduction・・・30, 2.2. Methods・・・31, 2.3. Results・・・38, 2.4. Discussion and chapter conclusion・・・44, General conclusions・・・46, Appendix Using nano-emulsion formulation approach to enhance the skin permeation of clindamycin and tetracycline as a new strategy for acne therapy, A.1. Introduction・・・48, A.2.
Method・・・50, A.3. Result・・・54, A.4. Discussion・・・56, A.5. Appendix conclusion・・・56, Acknowledgments・・・57, References・・・58 |
