산업적 적용을 위한 나노현탁제의 유동층 과립화와 물성개선연구 = Improvement of Physical Properties of Dried Nanosuspension by Fluidized-Bed Granulation for Industrial Application

다국어 초록 (Multilingual Abstract)

The purpose of this study is to make nanosuspension granules (NSGs) with improving physical properties using fluidized-bed and to investigate the possibility of industrialization of NSGs through characterization. In general, there are spray drying and freeze drying methods for drying nanosuspension (NS). However, the NS powders obtained by these methods are difficult to develop into a tablet or capsule formulation due to its poor physical properties. Therefore, improved type of NS drying system is required. The fluidized-bed is a convenient system that can be blending with drying at the same time. In this study, NSG was prepared by fluidized-bed granulation, and the effects of stabilizers and matrix former on the properties of granules were investigated. The particle size, zeta potential, polydispersity (PDI) of NS and particle morphology, drug content, and flowability of the NSG were measured and their crystallinity, stability, dissolution rate, and pharmacokinetic study were evaluated. After preparation of the capsules with the NSGs, the formulation uniformity was examined to see if the fluidized-bed granulation of the NS has industrial applicability. SDS stabilized nanoparticles efficiently during the preparation of NS. To specify this, the particle size and absolute value of zeta potential were 249.9 ± 3.7 nm, 35.6 ± 1.2 mV, respectively. Mannitol, a matrix former, prevented the agglomeration of nanoparticles during the granulation process. The dissolution rate and flowability of the NSG were increased as the amount of mannitol increased. The dissolution rate of initial 5-minute and final were 260 and 18-fold higher than compound X. Pharmacokinetics experiments compared with market product showed that the AUC0-inf of the NSGs was about 1.32 times higher, resulting in improved bioavailability. The flowability of the NSGs was also significantly improved compared to compound X powder, and the capsule formulation prepared with NSG was satisfied with formulation uniformity. As a result, fluidized-bed granulation can be a method to improve the disadvantages of the conventional method of drying the NS, and has the possibility to be applied to industrialization.

국문 초록 (Abstract)

본 연구의 목적은 유동층을 이용하여 물성이 개선된 나노현탁제 과립을 만들고, 특성 평가를 통해 나노현탁제 과립의 산업화 가능성을 보는 것이다. 일반적으로 나노현탁제를 건조하는데 쓰이는 방법에는 분무건조와 동결건조가 있다. 하지만 이 방법으로 얻은 나노현탁제 파우더는 물성이 좋지 않아 정제나 캡슐 제형으로 개발하기 힘들다. 또한 이를 해결하기 위해 후혼합을 진행해야 한다는 번거로움을 가지고 있어, 개선된 형태의 나노현탁제 건조 시스템이 요구된다. 유동층은 건조와 동시에 혼합이 가능한 간편한 시스템으로써, 이를 이용하여 나노현탁제 과립을 제조하였다. 또, 나노현탁제의 유동층 과립화 과정에서, 안정화제의 종류와 분산제의 양이 최종 과립 특성에 미치는 영향에 대해 확인하였다. 나노현탁제의 입자크기, 제타전위, 다분산도, 나노현탁제 과립의 입자형태, 약물함량, 흐름성을 측정하고 결정성, 안정성, 용출률, 약동학을 평가하였다. 제조된 과립으로 캡슐제를 제조한 뒤 제제균일성을 확인함으로써 나노현탁제의 유동층 과립화가 산업적 적용 가능성을 가지는지 살펴보았다. 안정화제 SDS는 나노현탁제의 제조과정에서 입자들을 효율적으로 안정시켰으며, 입자크기와 제타전위 절댓값은 각각 249.9 ± 3.7 nm, 35.6 ± 1.2 mV 였다. 분산제인 만니톨은 과립 공정 중 생기는 나노입자의 응집을 방지하였으며, 만니톨의 양이 증가할수록 과립의 용출률과 흐름성이 함께 높아졌다. 제조된 나노현탁제 과립은 원료의약품인 compound X와 비교했을 때, 초기 5분 용출률이 260배까지 증가하였으며 최종용출률이 18배 까지 개선되었다. 기존 시판제제와 비교한 약동학 실험 결과, 나노현탁제 과립의 AUC0-inf가 약 1.32배 높아 생체이용률이 개선되었음을 확인하였다. 나노현탁제 과립의 흐름성 또한 compound X 파우더에 비해 상당히 개선되었고, 이를 사용하여 제조한 캡슐제형은 제제균일성을 만족하였다. 결과적으로, 유동층 과립화는 기존 나노현탁제의 건조방법이 가지는 단점들을 개선시키는 방법이 될 수 있으며 나아가 산업화에 적용시킬 수 있는 가능성을 가진다.

목차 (Table of Contents)

• 국문초록 ⅰ
• Abstract ⅲ
• 약어 ⅴ
• Ⅰ. Introduction 1
• Ⅱ. Purpose 5
• Ⅲ. Materials & Methods 6
• 1. Materials 6
• 2. Preparation of NS using bead mill 7
• 3. Fluidized-bed granulation of NS 7
• 4. Characterization of NS and NSG 9
• A. Particle size and zeta potential of NS 9
• B. Morphology of NSGs and compound X 9
• C. Drug contents of NSGs 10
• D. Flowability of NSGs and compound X 11
• E. Crystallinity of NSG 11
• 5. In vitro dissolution test of NS and NSG 12
• 6. In vivo oral pharmacokinetic studies in rats 12
• 7. Physical stability of NSG 14
• 8. Homogeneity test for NSG capsules 15
• Ⅳ. Results and Discussion 17
• 1. Effect of stabilizer on NS and NSG 17
• A. Particle size and zeta potential of NS 17
• B. Dissolution rate before and after granulation 19
• C. Flowability of NSGs depending on stabilizers 21
• 2. Effect of matrix former on NSG 23
• 3. Morphology of NSGs and compound X 25
• 4. Crystallinity of NSG 26
• 5. In vivo oral pharmacokinetic studies of NSG 28
• 6. Physical stability of NSG 30
• 7. Homogeneity test of NSG capsules 32
• Ⅴ. Conclusion 34
• Ⅵ. References 35