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A study on the development of platform technology to enhance bioavailability of drug

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Author(s)
김아리
Issued Date
2017
Abstract
The aim of this study is to develop a drug platform for oral administration of rotigotine, that marketed and used as an antiparkinsonian transdermal patch, by develop the SLNs (Solid lipid nanoparticles) technology based formulation that can avoid the first-pass effect and increase the bioavailability through lipid-based absorption pathway.
Parkinson's disease (PD) is a disease caused by loss of dopaminergic neurons in the substantia nigra. As a primary treatment, dopamine agonists are considered. Since rotigotine selectively acts on dopamine receptors, especially D3 receptors, it is being seen as a promising antiparkinsonian drug.
But rotigotine is a poorly soluble drug and is known to be a drug that has a low bioavailabilty due to metabolism caused by the hepatic first-pass effect when administered orally.
In addition, in the case of the presently-marketed the transdermal patch - Neupro○R, skin reaction at the attachment site is reported to be a common side effect, and there is inconvenience because it must be applied to another site once a day. Therefore, if it is developed as an oral formulation which can increase the bioavailability, the above disadvantages can be overcome and the patient's compliance with the medicines can be improved. In order to improve the bioavailability of rotigotine, the SLN technology - based drug delivery system, which can avoid the first-pass effect by transferring drugs to the lymphatic system through the pathway such as Peyer's patch that involved in the absorption and migration in lipid-soluble compounds in the small intestine.
As a solid lipid, Precirol® ATO 5 was used because lipid such as the long chained triglyceride was advantageous to promote uptake to the lymphatic system, and TPGS and Solutol HS 15 were used as surfactants and emulsifiers. They have the effect of inhibiting the efflux by P-gp protein upon absorption of the drug and enhancing the bioavailability by facilitating the migration of poorly soluble and lipophilic substances to the lymphatic system.
The design of experiment (DoE) was applicated to find out the optimum composition. In this study, mixture designs were used among various methods of DoE and optimization process was performed through the use of an Extreme vertices design.
Physicochemical properties of rotigotine-loaded SLN prepared with optimal composition were confirmed by measuring particle diameter, PDI, EE and zeta potential. And in vitro release experiments were performed to determine if sustained release was properly controlled.
In this study, the optimal formulation was designed by analyzing the effects of the components of the formulation in a more scientific way by applying the experimental design method. Based on these results, we have developed a formulation that can maintain the concentration of rotigotine at a high level for a long time and improve the bioavailability when administered orally. In addition, it is thought to be universally applicable to other drugs which have been developed only by the route of administration other than orally because of poor solubility and low bioavailability
|본 연구의 목적은 경구 투여시 지질류 흡수 경로로 흡수되어 간 초회 효과를 회피하고 생체 이용률을 높일 수 있는 고형 지질 나노입자 (solid lipid nanoparticles, SLNs) 기술 기반 제형을 개발하여 현재 항 파킨슨 약물로 개발 되어 경피 흡수 패취제로 시판, 사용중인 로티고틴을 경구 투여용 의약품으로 개발하고자 함이다.
파킨슨병은 중뇌 흑질에 존재하는 도파민 분비 신경세포의 소실로 나타나는 질환으로서 1차적 치료제로 도파민 작용약물 (Dopamine agonists)이 고려된다. 로티고틴은 도파민 수용체 특히 D3 수용체에 선택적으로 작용하므로 항 파킨슨 약물로 각광받고 있다. 하지만 로티고틴은 난용성인 약물이며, 경구로 투여시 간 초회 효과에 의한 대사로 인해 약물의 체내 흡수율이 낮은 약물로 알려져 있다. 현재 시판중인 경피 흡수 패취제-Neoupro® 의 경우 부착 부위의 피부 반응이 흔한 부작용으로 보고 되었으며 1일 1회 매번 다른 부위에 부착해야 하는 불편함이 존재한다. 따라서, 생체이용률을 높일 수 있는 경구 제형으로 개발한다면 상기의 단점을 극복하고 환자의 복약 순응도를 높일 수 있다. 이에 경구 투여시 로티고틴의

생체 이용률을 높이기 위해 소장 내에서 지질 물질의 흡수와 이동에 관여하는 Peyer’s patch경로를 통해 림프계로 약물을 이행시켜 간 초회 통과를 회피할 수 있는 고형 지질 나노 입자 기술을 기반으로 하는 제제를 개발하고자 하였다.
고형 지질로는 Precirol® ATO 5 를 사용하였는데 이는 림프계로의 uptake를 촉진시키기 위해서는 긴 탄소 사슬의 지질이 유리하기 때문이며, 계면활성제와 유화제로는 TPGS와 Solutol® HS 15를 사용했다. 이들은 약물의 체내 흡수시 P-gp단백질에 의한 efflux를 억제하여 난용성이며 지용성인 물질의 림프계로의 이동을 용이하게 해 생체 이용률을 높이는 효과가 있다.
이들을 이용하여 제형을 설계시 최적의 조성을 알아내기 위해 실험 설계법 (Design of Experiment)을 시행하였다. 본 연구에서는 실험 설계법의 여러 방법들 중에서 혼합물 설계법 (Mixture designs)을 사용하였고, 꼭지점 설계법 (Extreme vertices design)을 통해 최적화 과정을 거쳤다. 실험 설계법에서 제시된 조성으로 제조된 로티고틴 고형 지질 나노 입자는 입자경, 다분산 지수, 봉입률 그리고 제타 전위 등을 측정함으로써 물리 화학적 성질을 확인하고, in vitro release 평가로 약물의 방출 특성을 평가하였다.
본 연구는 실험 설계법을 적용하여 보다 과학적인 방법으로 조성 성분들간 영향을 분석하여 최적의 제형을 설계하였고, 이를 바탕으로 장기간 안정적으로 높은 농도의 로티고틴을 함유하며, 경구 투여시 생체 이용률 개선의 잠재성을 갖는 제형을 개발하였다. 또한, 로티고틴 외에도 난용성이며 생체 이용률이 낮아 경구외의 투여경로로 개발되던 약물들에도 범용적으로 응용할 수 있으리라 생각된다.
Alternative Title
약물의 생체 이용률 개선을 위한 경구투여용 플랫폼 기술 개발에 대한 연구
Alternative Author(s)
Kim A Ri
Affiliation
조선대학교 대학원
Department
일반대학원 약학과
Advisor
지준필
Awarded Date
2017-08
Table Of Contents
1. Abstract ························································································8
2. Introduction ················································································10
3. Materials and methods
3-1. Materials ···············································································12
3-2. Preparation of solid lipid nanoparticles ························12
3-3. Experimental design ·························································12
3-4.Optimization and validation of solid lipid nanoparticles ···········································································································13
3-5. Quantification of rotigotine by HPLC analysis ············13
3-6. Characterization of solid lipid nanoparticles ···············14
4. Results and discussion
4-1. Preliminary experiment for experimental design ·······15
4-2. Experimental design (DoE)···············································15
4-3. Validation of the DoE model ············································17
4-4. In vitro release study··························································18
5. Conclusion··················································································19

6. References ··················································································20
Degree
Master
Publisher
조선대학교
Citation
김아리. (2017). A study on the development of platform technology to enhance bioavailability of drug.
Type
Dissertation
URI
https://oak.chosun.ac.kr/handle/2020.oak/13244
http://chosun.dcollection.net/common/orgView/200000266256
Appears in Collections:
General Graduate School > 3. Theses(Master)
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