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Mechanistic understanding and dosage form design of solubilization and controlled release of poorly water-soluble drugs

  • JIN GANG (JIN GANG, 아주대학교 일반대학원)

초록/요약

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).

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목차

Chapter I. Role of micellized sodium lauryl sulphate in dissolution medium or solid dispersion systems to improve dissolution rate of poorly soluble cilostazol 1
1. Introduction 1
2. Materials and Methods 4
2.1. Materials 4
2.2. Preparation of CLT-SDs 4
2.2.1. Solvent evaporation method 4
2.2.2. Fusion method 4
2.2.3. Anti-solvent method 4
2.3. Solubility study 7
2.4. In vitro dissolution studies 7
2.5. HPLC analysis 7
2.6. Thermal analysis 8
2.7. Chemical interaction studies 8
2.8. Crystal form transition studies 8
2.9. Surface morphology studies 8
2.10. Particle size distribution analysis 9
2.11. Measurement of the contact angle 9
3. Results and Discussion 10
3.1. Excipients screening 10
3.2. Understanding the mechanism of SLS micellization on dissolution profiles of CLT 12
3.3. DSC 19
3.4. FTIR 21
3.5. PXRD 23
3.6. FE-SEM 25
3.7. Particle size distribution analysis 27
3.8. The role of the incorporation of micellized SLS in the SDs 29
3.9. Wettability analysis 31
3.10. Commentary for mechanistic roles of micellar SLS 33
4. Conclusions 35
Chapter II. Electrostatic interaction of cationic and anionic surfactant for modified release of negatively charged poorly water-soluble rebamipide in nanosuspension 36
1. Introduction 36
2. Materials and methods 40
2.1. Materials 40
2.2. Preparation of NSP and physical mixture (PM) 40
2.3. Drug content in NSPs during preparation process 42
2.4. In vitro release studies 42
2.5. High-performance liquid chromatography (HPLC) analysis 42
2.6. Cd analysis 43
2.7. Particle size analysis 43
2.8. Chemical interaction studies 43
2.9. Crystal form transition studies 43
2.10. Surface morphology studies 43
2.11. Field-emission transmission electron microscopy (FE-TEM) 44
3. Results and discussion 45
3.1. The influence of different types and concentrations of surfactants on the drug content in NSPs during the preparation process 45
3.2. Effect of charged surfactants on particle size of NSPs 47
3.3. Understanding the mechanism of dissolution reduction based on charge density studies 49
3.4. FTIR 57
3.5. PXRD 59
3.6. FE-SEM 61
Chapter Ⅲ.Characterization of once a day bilayered tablet containing immediate and sustained release of poorly water-soluble rebamipide 65
1. Introduction 65
2. Materials and methods 68
2.1. Materials 68
2.2. Preparation of NSPs 68
2.3. Formulation and preparation of bilayer tablet 68
2.4. Micromeritic properties of powder and granules 74
2.5. In vitro release studies 74
2.6. HPLC analysis 74
2.7. Hydrodynamic behavior studies 75
2.8. Evaluation of the physical properties of the bilayered tablet 75
2.8.1. Disintegration test of IR layer 75
2.8.2. Determination of hardness, thickness and diameter of bilayer tablet 76
3. Results and discussion 77
3.1. Analysis of the micromeritics properties of powders and granules 77
3.2. Dissolution studies 79
3.3. Swelling and erosion studies 88
3.4. Disintegration time of IR layer and physical properties of bilayered tablet 90
4. Conclusion 95
5. References 97

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