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Improved solubility and bioavailability of poorly water soluble drug by mesoporous silica/self-nanoemulsion complex
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | 박영준 | - |
| dc.contributor.author | 신혜원 | - |
| dc.date.accessioned | 2022-11-29T02:32:43Z | - |
| dc.date.available | 2022-11-29T02:32:43Z | - |
| dc.date.issued | 2021-02 | - |
| dc.identifier.other | 30852 | - |
| dc.identifier.uri | https://dspace.ajou.ac.kr/handle/2018.oak/20287 | - |
| dc.description | 학위논문(박사)--아주대학교 일반대학원 :약학과,2021. 2 | - |
| dc.description.tableofcontents | 1. Introduction 1 1.1.The characterization of poorly water-soluble drugs 1 1.2. Solubilization 2 1.3. Nanocarrier system for oral delivery 6 1.4. Mesoporous silica for oral delivery 8 1.5. Dutasteride 14 2. Objectives 16 3. Materials and methods 18 3.1. Materials 18 3.2. Self-emulsion system 18 3.2.1. The Solubility effect of oil and surfactant on dutasteride 18 3.2.2. The pseudo-ternary phase diagram 19 3.3. Mesoporous carrier system 19 3.3.1. A physical mixture of silica and dutasteride (Phy) 19 3.3.2. Preparation of silica-DUT complex by solvent dropping method (SD) 19 3.3.3. The solubility of dutasteride in various silica types 20 3.4. Preparation of MS/E 20 3.4.1. The solubility of dutasteride according to the complex of silica and lipid 20 3.4.2. Preparation of MS/E by solvent dropping method 20 3.5. Characterization of MS/E 21 3.5.1. Fourier-transform infrared/Attenuated total reflection (FT-IR/ATR) 21 3.5.2. Scanning electron microscope (SEM) 21 3.5.3. Differential scanning calorimetry (DSC) 22 3.5.4. High power X-ray diffraction (HP-XRD) 22 3.5.5. Specific surface area (SSA) by the Brunauer-Emmett-Teller (BET) 22 3.5.6. Small-angle X-ray scattering (SAXS) 22 3.5.7. Dynamic light scattering (DLS) for nanoparticle size 23 3.5.8. Quantitation of dutasteride by high-performance liquid chromatography (HPLC) 23 3.5.9. Flowability 24 3.5.10. Content uniformity 25 3.6. Preparation and evaluation of MS/E tablets 25 3.6.1. MS/E tablets 26 3.6.2. Design of Experiments for MS/E formulation 26 3.6.3. Dissolution test 26 3.7. Stability of MS/E and MS/E tablets 28 3.7.1. Stability of MS/E 28 3.7.2. Humidity stress of MS/E tablets 29 3.7.3. Temperature stress of MS/E tablets 29 3.7.4. Long term and accelerated stability of MS/E tablets 29 3.8. Pharmacokinetic studies in beagle dogs 29 4. Results and discussion 31 4.1. MS/E system 31 4.1.1. Self-emulsion system 31 4.1.2. Mesoporous carrier system 35 4.1.3. MS/E complex 43 4.2. The characterization of MS/E 47 4.2.1. Encapsulation efficiency of MS/E 54 4.2.2. SAXS of MS/E 54 4.2.3. Specific surface area of MS/E 54 4.2.4. Surface morphology of MS/E particle 58 4.2.5. Interaction of silica and dutasteride by FT-IR/ATR 62 4.2.6. Crystallinity by DSC and XRD 62 4.2.7. Evaluation for the formulation of MS/E 64 4.3. Stability of the MS/E complex 67 4.4. Formulation for MS/E tablets 71 4.5. In vitro release studies 78 4.6. Stability of MS/E tablets 78 4.6.1. Humidity stress 84 4.6.2. Temperature stress 84 4.6.3. Long-term and accelerated stability of MS/E tablets 86 4.7. In vivo pharmacokinetics profile 90 5. Conclusions 96 6. References 98 | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | Improved solubility and bioavailability of poorly water soluble drug by mesoporous silica/self-nanoemulsion complex | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 일반대학원 | - |
| dc.contributor.alternativeName | Hey Won, Shin | - |
| dc.contributor.department | 일반대학원 약학과 | - |
| dc.date.awarded | 2021. 2 | - |
| dc.description.degree | Doctoral | - |
| dc.identifier.localId | 1218623 | - |
| dc.identifier.uci | I804:41038-000000030852 | - |
| dc.identifier.url | http://dcoll.ajou.ac.kr:9080/dcollection/common/orgView/000000030852 | - |
| dc.subject.keyword | bioavailability | - |
| dc.subject.keyword | dutasteride | - |
| dc.subject.keyword | lipophilic drug | - |
| dc.subject.keyword | mesoporous silica | - |
| dc.subject.keyword | self-nanoemulsion | - |
| dc.subject.keyword | solubility | - |
| dc.description.alternativeAbstract | The purpose of this study was to improve bioavailability (BA) by solubilizing lipophilic drugs using silica-based nanocarrier systems to obtain solid dosage forms. The lipophilic model drug selected in this study was dutasteride, with a log P value of 5.5. While techniques to improve solubility of lipophilic drugs have been examined, including use of large amounts of lipidic additives to produce lipid-based formulations, only a limited number of techniques have been investigated to prepare stable formulations. To address this gap, we developed mesoporous silica (MS/E) using self-emulsification technology to improve the solubility of dutasteride. The characteristics of MS/E were studied using the solvent drop method, the surface adsorption properties of dutasteride were using electron microscopy, and the pore loading type was predicted by the small-angle X-ray scattering (SAXS) analysis and specific surface area analysis. The encapsulation efficiency was found to be high (≥ 80%). X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC) confirmed the amorphous property, and dynamic light scattering (DLS) determined the size of the nanoparticles in the self-nanoemulsion to be approximately 407.8 nm. In addition, the adsorption mechanism was identified by Fourier transform infrared spectroscopy/attenuated total reflection (FT-IR/ATR) analysis. Flowability and content uniformity assessments found to be suitable for formulation. MS/E showed improved physical stability over 4 weeks at 4℃ ~ 60℃ due to the addition of lipid. This was confirmed through SAXS, specific surface area, encapsulation loading efficiency, content, and scanning electron microscopic (SEM) analyses. MS/E was formulated into solid dosage forms (tablets) at a dosage of 170 ~ 220 mg/tablet using suitable additive. These tablets demonstrated improved dissolution rate and hardness. In order to evaluate the lipid stability of the MS/E formulation, severe humidity and temperature stress tests were performed. The MS/E formulation was used to prepare; tablets with lipids (using D-α-tocopherol polyethylene glycol succinate or glyceryl caprylate/caprate) or silica (using Neusilin® US2) types. The optimum composition of the ii MS/E tablets was tested for long-term stability for 12 months and accelerated stability for 6 months and the content and dissolution rate were found to be stable. The dissolution rate of MS/E tablets was compared with those of physically mixed tablets. MS/E tablets had a higher dissolution rate, about 2 times more than the dissolution rate of physically mixed tablets. A pharmacokinetic study in beagle dogs showed bioequivalence of MS/E tablets and Avodart®. Dutasteride is a lipophilic drug with limited BA due to poor dissolution. Hence, it is a good candidate to investigate the technique to improve BA and other pharmacokinetic parameters via formulation in a solid dosage form. Further, the MS/E tablet of dutasteride using this technique could reduce its formulation weigh size by approximately four times relative to the original lipid formulation, thus increasing patient compliance and safety. | - |
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