Formulation Design and Characterization of Fixed-Dose Combination Preparations with Controlled Release
Formulation Design and Characterization of Fixed-Dose Combination Preparations with Controlled Release
- 주제(키워드) bilayered tablet , immediate release layer , sustained release layer , alkalizer , solid dispersion , drug stability
- 발행기관 아주대학교
- 지도교수 이범진
- 발행년도 2016
- 학위수여년월 2016. 2
- 학위명 석사
- 학과 및 전공 일반대학원 약학
- 실제URI http://www.dcollection.net/handler/ajou/000000021575
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
The objective of the present study was to develop bilayered tablets of AFN that are characterized by initial burst drug release followed by sustained release of drug. The immediate-release layer of AFN bilayered tablet was formulated and optimized by investigating the amounts of the solubilizer (PLX) and the binder (HPL). The sustained-release layer was formulated by employing HM-based matrix and HF-based matrix, respectively. Micromeritic properties of lubricated granules/powder blends, tablet assay and physical evaluation were tested. Additionally, drug crystallinity and morphology of the granules and powder blends were examined by powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM). The in vitro dissolution studies of AFN 200 mg bilayered tablet and AFN 110 mg fast-release tablet were performed in intestinal fluid (pH 6.8 buffer). Stability testing of the optimized AFN bilayered tablet was finally carried out in accelerated condition (40 °C, 75% RH). For fast-release layer formulation, the percentage of binder (HPL) and the percentage of solubilizer (PLX) are two critical factors, which have significant impact on its physicochemical properties and dissolution profiles. The optimized bilayered tablets had very similar in vitro dissolution profiles to commercial reference tablet Clanza®CR according to similarity factor (f2). Carr’s index and Hausner’s ratio of lubricated granules and powder blends showed a good compressibility and flowability of all investigated samples. PXRD data indicated that the drug maintained the crystalline form after granulation and blending. SEM images showed the relatively round shapes of AFN granules and rectangular shapes of pure AFN and powder blend. The optimized bilayered tablet samples were stable during one month of stability testing based on tablet assay, related substances, and dissolution profiles. In conclusion, the double layer tablets for AFN were successfully formulated as once-a-day oral-controlled release drug delivery system. Key words: bilayered tablet, immediate release layer, sustained release layer, HM, HF, CF.
more초록/요약
The aim of this study is to investigate the effect of the pharmaceutical alkalizers on the stability of EPM which is an proton-pump inhibitor (PPI) drug in gastro-intestinal fluid. The alkalizer-added solid dispersion containing EPM were prepared by dissolving (or dispersing) EPM, alkalizer, and Opadry®, in ethanol 50% followed by spray drying. Nine different alkalizers were tested for the stability enhancement of EPM assessed by in vitro stability testing in two media, gastric fluid (pH 1.2 buffer), and intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pHM) was measured to elucidate the effect of alkalizer on pHM of solid dispersions. Drug crystallinity and morphology of pure drug and drug-loaded solid dispersion were examined by DSC, PXRD, and SEM. The interaction among the drug, carrier and alkalizer were clarified by FT-IR spectra. Alkalizer A8 was proved to be the best alkalizer to stabilize EPM in both gastric and intestinal fluids when incorporated in solid dispersion containing EPM. pHM of EPM alkalizer-containing solid dispersion were remarkably higher than that of non-alkalizer counterpart. The pHM value was in the decreasing order: A8, A1, A2, and no alkalizer. The DSC, PXRD data exhibited a change in EPM crystallinity in solid dispersion from crystalline to amorphous. FT-IR indicated a strong molecular interaction between EPM, alkalizer and Opadry®, especially A8 showed the strongest interaction with EPM. SEM data showed a relatively spherical shape of A8-incorporated solid dispersion compared to the obscure shape of pure drug. This study provides a promising approach for stabilization of acid-labile drug, thereby improving drug bioavailability. Key words: alkalizer, solid dispersion, microenvironmental pH (pHM), acid-labile drug, drug stability.
more목차
1. Introduction 4
2. Materials and Methods 11
2.1. Materials 11
2.2. Preparation of AFN 200 mg bilayered tablet 11
2.2.1. Formulation and preparation of 110 mg of AFN immediate release layer 12
2.2.2. Formulation and preparation of 90 mg of AFN sustained release layer 12
2.3. Bilayered tablet compression 13
2.4. Formulation evaluation 17
2.4.1. Micromeritic properties of lubricated granules and powder blends 17
2.4.2. Tablet assay and physical evaluation 18
2.4.3. In vitro dissolution studies 18
2.4.4. Similarity factor (f2) 19
2.4.5. Powder X-ray diffraction (PXRD) 20
2.4.6. Scanning electron microscopy (SEM) 20
2.4.7. Stability studies 21
2.5. HPLC analysis 21
3. Results and discussions 23
3.1. Micromeritic properties of lubricated granules and powder blends 23
3.2. Tablet assay and physical evaluation of AFN 110 mg immediate release tablets and AFN 200 mg bilayered tablet formulation 25
3.3. In vitro dissolution studies 27
3.3.1. AFN immediate release formulation 27
3.3.2. AFN bilayered tablet formulation 30
3.4. Characterizations of the solid states of the granules/powder blends 37
3.5. Stability study 40
4. Conclusions 44
5. References 45
Chapter II Enhanced aqueous stability of acid-labile drug EPM using alkalizer-containing solid dispersion 50
Abstract 51
1. Introduction 53
2. Materials and methods 57
2.1. Materials 57
2.2. Formulation of EPM alkalizer-containing solid dispersion 57
2.3. Preparation of EPM alkalizer-containing solid dispersion 58
2.4. In vitro stability study of EPM alkalizer-containing solid dispersion 60
2.5. Optimization of EPM solid dispersion formulations 60
2.6. Microenvironmental pH (pHM) measurement 61
2.7. Differential scanning calorimetry (DSC) 61
2.8. Powder X-ray diffraction (PXRD) 63
2.9. Fourier transform infrared spectroscopy (FT-IR) 63
2.10. Scanning electron microscopy (SEM) 64
2.11. HPLC analysis 64
3. Results and discussions 65
3.1. Screening alkalizers for stabilization of EPM in gastric fluid (pH 1.2) and intestinal fluid (pH 6.8) 65
3.2. Optimization of EPM solid dispersion formulations 66
3.3. Microenvironmental pH (pHM) measurement 69
3.4. Differential scanning calorimetry (DSC) 71
3.5. Powder X-ray diffraction (PXRD) 73
3.6. Fourier transform infrared spectroscopy (FT-IR) 73
3.7. Scanning electron microscopy (SEM) 77
4. Conclusions 80
5. References 81
