Sustained Release Oral Dosage Form with Enhanced Dissolution and Bioavailability

다국어 초록 (Multilingual Abstract)

Poorly water-soluble drugs such as IDP ( 1μg/ml) offer challenging problems in the formulation of drugs since poor solubility is generally associated with low dissolution and bioavailability. Solid dispersions (SD) of IDP were manufactured by the melt method. The dissolution behaviors, in vivo pharmacokinetics of solid dispersion and its controlled release matrix tablet in healthy human volunteers were investigated. The physical properties of solid dispersed IDP were also examined using differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD). It was shown that structure of IDP was amorphous in the solid dispersion. The dissolution rate of IDP from solid dispersions was markedly enhanced. The increased dissolution rate was attributed to increased solubility and improved wetting of IDP crystals. The IDP controlled release (CR) tablets were prepared by directly compressing the powder mixtures composed of IDP SD, HPMC and Avicel using a single punch press. The controlled release (CR) tablet showed significantly increasedoral bioavailability compared with the marketed reference capsule. The stability of IDP controlled release (CR) tablets was also stable during storage over 3 months at 40℃/75% RH. The IDP controlled release (CR) tablet could be used as an alternative to the current marketed capsule.

국문 초록 (Abstract)

본 연구의 목적은 난용성 약물인 IDP의 용출율 및 생체이용율을 향상시킬 수 있는 고체분산체를 함유한 서방성 정제를 개발하는 것이다. 즉 고체분산체 제조 기술을 이용하여 약물의 용출율 및 생체이용율을 높이고 제제의 안정성 및 약물동태학적 거동을 평가하고자 하였다. IDP약물은 물에서 극히 난용성인 고혈압 치료제이다. IDP의 용출율 및 생체이용율 향상을 위하여 폴록사머을 이용하여 여러 가지 방법으로 고체분산체를 제조하였다. 제조된 고체분산체는 인공 위액 및 장액에서 높은 용출율을 나타내었다. 전자현미경(SEM)을 통해 본 고체분산체는 특정한 형태없이 100µm 내외의 분말상이었다. DSC를 사용하여 열분석을 한 결과 IDP의 성상이 많이 변한 것을 알 수 있었고, 분말 X-ray을 통해서 약물은 고체분산체에서 무정형으로 존재하고 있음을 알았다. 제조된 서방성정제는 H4의 종류와 그 양에 따라 다양한 용출 양상을 나타내었으며 또한 가혹조건에서 3개월동안 안정한 성상을 보여주었다. 최적 처방으로 만든 정제를 사람에게 투여하여 혈중 농도를 정량한 결과 시판 제제인 캡슐보다 아주 높은 Cmax와 AUC를 나타내었다. 이상의 결과로부터 폴록사머를 기제로하여 부동한 온도에서 제조한 고체분산체 제제는 수용액에 난용성인 여러 약물의 용출율과 생체이용율을 개선하는데 유용하게 응용될 것으로 기대된다.

목차 (Table of Contents)

• Abstract = 1
• 1. Introduction = 2
• 2. Materials and Methods = 5
• 2.1. Materials = 5
• 2.2. Method = 5
• 2.2.1. Solubility study = 5
• 2.2.2. Preparation of various carrier based solid dispersions = 6
• 2.2.3. Thermal analysis (DSC) = 6
• 2.2.4. Powder X-ray diffraction (PXRD) = 6
• 2.2.5. Scanning electron microscope (SEM) = 7
• 2.2.6. Preparation of enzyme-free simulated gastric and intestinal fluid = 7
• 2.2.7. Stability study = 9
• 2.2.8. HPLC analysis of IDP = 9
• 2.2.9. In vitro dissolution study = 9
• 2.2.10. Preparation of controlled released (CR) tablet containing SD = 10
• 2.2.12. Friability measurement = 12
• 2.3. In vivo bioequivalence of controlled released (CR) tablet and reference capsule in human volunteers = 14
• 2.3.1. Study design for bioequivalence = 14
• 2.3.2. Assay of IDP in human plasma = 14
• 2.3.3. Pharmacokinetic analysis = 15
• 2.3.4. Statistical analysis = 15
• 3. Results and Discussion = 16
• 3.1. Solubility study = 16
• 3.2. Effect of formulation compositions in solid dispersions = 16
• 3.2.1. Effect of carriers = 16
• 3.2.2. Effect of surfactant concentration = 17
• 3.2.3. Effect of fatty acid concentration =17
• 3.2.4. Effect of temperature = 17
• 3.3. Physical characterization of solid dispersions = 19
• 3.4. Effect of H4 quantity on dissolution rate of controlled released tablet = 27
• 3.5. Stability study of the controlled released tablet = 36
• 3.6. Pharmacokinetic behaviors of CR tablet in human = 36
• 4. Conclusions = 37