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Mechanistic understanding and dosage form design of solubilization and controlled release of poorly water-soluble drugs
- Author(s)
- GANG JIN
- Alternative Author(s)
- JIN GANG
- Advisor
- 이범진
- Department
- 일반대학원 약학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2022-08
- Language
- eng
- Keyword
- nanosuspensions; rebamipide
- Alternative Abstract
- The aim of chapter I is to study the role of SLS in poloxamer 407-based solid dispersions (POX-based SDs) for ameliorating the dissolution rate of cilostazol (CLT). Herein, SLS was incorporated into CLT-SDs at a weight ratio of 50:50:10 between CLT, POX 407 and SLS, respectively, prepared by antisolvent, melting and solvent evaporation methods. Among them, the physicochemical characterizations of SDs evaluated by FTIR, DSC and PXRD indicated that SDs prepared by antisolvent method showed a strong interaction between micellized SLS and hydrophobic regions of POX, leading to the transformation of crystalline drug into partially amorphous state. Moreover, field emission scanning electron microscope (FE-SEM), contact angle measurement and particle size analyses confirmed that drug possessed an effective adsorption on the surface of micellized SLS, which precluded drug particles from aggregation and improved the wettability of SDs. Dissolution results showed that the incorporation of SLS into POX-based SDs significantly enhanced the dissolution rate of CLT as compared to the binary solid dispersion of CLT and POX 407. Collectively, our research highlights the solubilization mechanism of SLS in SDs and the pertinent method to incorporate effectively SLS into SDs for dissolution enhancement of poorly water-soluble drugs. In previous study, nanosuspensions (NSPs) prepared by the neutralization method significantly enhanced the pH-independent dissolution of the poorly water-soluble drug, rebamipide (RBM). For a long-term stability of NSPs, we investigated on different charged surfactants to induce a surface charge, promoting an electrostatic stabilization for preventing the agglomeration. Unexpectedly, when the cationic surfactant cetyltrimethyl ammonium bromide (CTAB) was introduced directly into the NSPs or into different dissolution media (deionized water, buffer pH 1.2 and buffer pH 6.8), the concentration of dissolved RBM from NSP was significantly reduced due to the presence of CTAB. In order to understand this surprised phenomenon, the kinetic dissolution behavior and the dynamic charge density (Cd) changed during the dissolution process were studied respectively. Furthermore, fourier transform infrared (FTIR), powder X-ray diffraction (PXRD) and field-emission scanning electron microscopy (FE-SEM) were also employed to elucidate the interaction among CTAB and RBM. Collectively, these results revealed the decrease of dissolution was mainly due to the formation of precipitates, so-called poorly soluble complexes, by the electrostatic interaction between positively charged CTAB and negatively ionized RBM. Thereby, when the charged surfactants are presented in formulations or dissolution media to modulate the dissolution of pH-dependent drugs, this unexpected negative impact on dissolution should be carefully considered to correctly couple the pertinent charged surfactant with the model drug. The purpose of chapter Ⅲ is to develop a once-daily bilayer controlled-release matrix tablet of rebamipide (RBM) with immediate/sustain dual release characteristics. Due to the pH-dependency and poor water solubility of RBM, the nanosuspensions (NSPs) consisting of RBM and poloxamer 407 (POX 407) were previously designed by acid-base neutralization method to increase successfully its dissolution rate, which was further applied to the immediate-release (IR) layer. Polyethylene oxide (PEO) with different molecular weight (PEO 100000 and PEO 5000000), and hydroxypropyl methylcellulose 4000 (HPMC 4000) were optimized as sustained release agents to incorporate into a sustained-release (SR) layer with pure RBM via a wet granulation method. In the formulation design of the immediate-release layer, the most challenging issue was the gelling property of POX 407, which hindered the penetration of water in the tablet, resulting in a slow disintegration and an insufficient release of the drug in the IR layer. Thereby, POX 188 was co-utilized during the preparation of the NSPs to elevate the gelation temperature of the POX matrix, preventing the rapid gelation of the IR layer and achieving faster disintegration. The dissolution profiles of the optimal bilayer tablet showed that the IR layer could rapidly disintegrate in pH 1.2 buffer solution within 2 hours, reaching 50% of drug release from the tablet and followed by an extended drug release from the SR layer in pH 6.8 buffer over 24 h. The design of this once-daily RBM bilayer tablet (300 mg RBM) with dual release characteristics could provide potential application for unmet medical needs as an alternative to commercial tablets (100 mg RBM).
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Pharmacy > 4. Theses(Ph.D)
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