Development of a 3D-printed gastroretentive system for riboflavin by applying design of experiment approach

다국어 초록 (Multilingual Abstract)

This study aims to develop a new device-based gastroretentive system that consists of a 3D-printed capsular device and conventional tablets. The gastroretentive system was designed to be expandable in the gastric cavity to prevent passage through a pylorus during the drug release from the inner tablet, and to be back to its original shape to escape the stomach after completing drug release. The device was printed with poly lactic acid by using a fused deposition modeling printer. A sustained release (SR) tablet containing riboflavin 20 mg was inserted inside of the device. Definitive screening design and Box-Behnken design were used to design a gastroretentive device for desired drug release characteristics and gastric retention time. The in vitro dissolution was determined by the paddle method. Concentrations of riboflavin in the dissolution medium were determined by high-performance liquid chromatography. Following oral administration in Beagle dogs, the in vivo gastric retention was monitored by X-ray images, and the pharmacokinetics was evaluated. Plasma concentrations of riboflavin was determined by a validated liquid chromatography-tandem mass spectrometry method. The abdominal X-ray images showed the extended gastric residence of more than 12 h and the transit of the gastroretentive device as its original form to the intestine. Compared to the reference SR tablet, the gastroretentive system showed the higher maximum plasma concentration (Cmax) and the area under the plasma concentration (AUC) by 1.96 and 3.19 folds, respectively. Taken together, this study suggested that the oral bioavailability of SR tablets of a drug with a narrow absorption window could be improved by combining gastroretentive device. This approach may provide a promising approach for various drugs to develop gastroretentive systems.

국문 초록 (Abstract)

본 연구의 목표는 3D 프린팅 된 캡슐형태의 장치와 내부 정제로 구성된 새로운 장치 기반 위체류 시스템을 개발하는 것이다. 개발된 위체류 시스템은 위내에서 팽창하여 내부 정제의 약물이 방출되기 전까지 위의 유문을 통과하지 못하게 하고 약물 방출이 완전히 방출된 후 원래 형태로 되돌아가 위장관을 통과할 수 있도록 설계되었다. 위체류 장치는 융합적층모델링 (FDM) 방식의 프린터를 사용하여 poly lactic acid (PLA) 재질로 제작되었다. 리보플라빈 20 mg의 서방정제를 장치 내부에 삽입하였다. 확정선별설계 및 Box-Behnken 설계는 약물방출 특성 및 위체류 시간을 설계하는 데 사용되었다. 시험관 내 용출시험은 패들 법을 이용하여 측정하였으며 용출액 중 리보플라빈의 농도는 고성능액체크로마토그래피 (HPLC)를 이용하여 정량하였다. 위체류 시스템은 비글견에 경구로 투여한 후 위에 머무는 시간과 방출되는 리보플라빈의 약물동태를 확인하였다. 복부 X-선 촬영을 퉁해 위체류 시스템이 12 시간 이상 위내에 머무는 것을 확인하였으며 약물이 완전히 방출된 이후 위체류 시스템의 구조변화를 통해 소장으로 배출되었다. 대조 SR 정제와 비교할 때, 위체류 시스템의 최대혈중농도 (Cmax)와 혈중농도곡선하면적 (AUC)은 각각 1.96 및 3.19 배 더 높아졌다. 종합하면, 개발된 위체류 시스템을 이용하여 좁은흡수 부위를 갖는 약물의 생체이용률과 혈중농도의 지속성을 개선할 수 있었으며 이는 개발된 위체류 시스템을 다양한 약물에 적용하여 새로운 위체류 제형을 개발할 수 있는 가능성을 보여준다.

목차 (Table of Contents)

• Chapter 1. Introduction 1
• 1.1. Gastroretentive system 1
• 1.2. Riboflavin 3
• 1.3. Three-dimensional printing technology 5
• 1.4. Design of experiments 7
• Chapter 2. Rationale and aims of the research 9
• 2.1. Rationale of the research 9
• 2.2. Aims of the research 11
• Chapter 3. Materials and methods 12
• 3.1. Materials 12
• 3.1.1. Reagents and chemicals 12
• 3.1.2. Instruments 14
• 3.1.3. Animals 15
• 3.2. Design of the gastroretentive system 16
• 3.2.1. Design of a gastroretentive capsular device 16
• 3.2.2. Design of inner tablets 20
• 3.3. Experimental design of the gastroretentive system 22
• 3.3.1. Screening design 22
• 3.3.2. Optimization design 26
• 3.4. Preparation of the gastroretentive system 31
• 3.4.1. Preparation of a gasroretentive capsular device 31
• 3.4.2. Preparation of inner tablets 32
• 3.4.3. Assembly of the gastroretentive system 33
• 3.5. In vitro evaluation of the gastroretentive system 35
• 3.5.1. Instruments and dissolution test condition 35
• 3.5.2. Evaluation of in vitro gastroretentivity 36
• 3.5.3. HPLC analysis 37
• 3.5.4. Kinetic analysis 38
• 3.6. Quantitative analysis of riboflavin in dog plasma 40
• 3.6.1. Instruments and LC-MS/MS analysis conditions 40
• 3.6.2. Sample preparation 44
• 3.6.3. Assay validation 46
• 3.7. In vivo evaluation of the gastroretentive system 52
• 3.7.1. Pharmacokinetic study 52
• 3.7.2. Evaluation of in vivo gastroretentivity 53
• 3.7.3. Data analysis 54
• Chapter 4. Results and discussion 55
• 4.1. Development of analytical methods 55
• 4.1.1. Quantitative analysis of riboflavin in dissolution medium 55
• 4.1.2. Quantitative analysis of riboflavin in dog plasma 58
• 4.2. Design of the gastroretentive system 72
• 4.3. Optimization of the gastroretentive system by DoE 75
• 4.3.1. Initial evaluation of control factors in screening design 75
• 4.3.2. Effect of control factors in optimal design 78
• 4.3.3. Optimization of the gastroretentive system 85
• 4.4. In vitro evaluation of the gastroretentive system 90
• 4.5. In vivo evaluation of the optimal gastroretentive system 93
• 4.5.1. In vivo gastroretentivity 93
• 4.5.2. Pharmacokinetics of the gastroretentive system 95
• Chapter 5. Conclusions 99
• Chapter 6. References 102
• 국문초록 108