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Improved solubility and bioavailability of poorly water soluble drug by mesoporous silica/self-nanoemulsion complex
- Author(s)
- 신혜원
- Alternative Author(s)
- Hey Won, Shin
- Advisor
- 박영준
- Department
- 일반대학원 약학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2021-02
- Language
- eng
- Keyword
- bioavailability; dutasteride; lipophilic drug; mesoporous silica; self-nanoemulsion; solubility
- Alternative Abstract
- 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.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Pharmacy > 4. Theses(Ph.D)
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