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난용성 약물을 위한 신규 용해보조제로서 패티게이션 플랫폼의 활용

Utilization of a fattigation platform conjugate as a novel solubilizing adjuvant for poorly water-soluble drugs

초록/요약

Solubilizing adjuvants are commonly used to dissolve insoluble drugs. However, the application of solubilizing adjuvants has many disadvantages, such as biocompatibility, biodegradability, toxicity, irritation, and environmental problems. To overcome these problems, gelatin and oleic acid sodium salt (OAS), a generally recognized as safe-listed material were chosen to develop a natural solubilizing adjuvant using the fattigation platform technology when simply mixed with poorly water-soluble drugs. We synthesized the gelatin and OAS conjugates (GOC) at three different ratios (1:1, 1:3, 1:5; GOC 1, GOC 2, and GOC 3, respectively) via the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide reaction using a spray dryer. This amphiphilic micronized GOC was self-assembled into nanoparticles. The synthesis of new amphiphilic conjugates was identified through fourier transform-infrared (FT-IR) spectroscopy. All GOCs showed good wettability, indicating that their amphiphilic nature. GOCs were also found to be non-porous. The powder properties of the GOCs, such as angle of repose, bulk density, and tapped density were varied with the oleic acid bonding ratio. Then, GOCs were utilized to investigate the enhanced solubility and dissolution rate of various poorly water-soluble drugs such as cilostazol (CSZ), coenzyme Q10, ticagrelor, telmisartan, aprepitant and itraconazole as model drugs. Based on the solubility studies by concentration and type of GOCs, 3% GOC 2 was selected. When this GOC mixed with these model drugs by a physical mixture, the wet method and by hot melting, the solubility was highly enhanced compared to the pure control drug, ranging from 20-150,000 times. In case of CSZ, all formulations significantly improved dissolution rate compared to the CSZ alone and the reference tablet, cilostan® (Korea United Pharm) in simulated intestinal fluid containing 0.2% sodium lauryl sulfate. Differential scanning calorimetry and powder X-ray diffraction were conducted to confirm the crystal polymorphic structure of CSZ, and as a result they changed to diminutive peak intensity compared to CSZ alone. Field-emission scanning electron microscopy indicated that GOC was spherical with a reduced size of about 100 nm. The reduction of drug particles via nanonization and self-assembly of amphiphilic GOC in an aqueous media could be a key factor to improve poor water solubility by providing a favorable dispersion of drug molecules in an amphiphilic network.

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목차

1. Introduction 1
2. Materials and Methods 5
2.1. Materials 5
2.2. Synthesis of GOCs 5
2.2.1. Activation of OAS 5
2.2.2. Conjugation of gelatin with OAS 7
2.2.3. Preparation of GOCs using spray dryer 7
2.3. Fourier transform-infrared spectroscopy 7
2.4. Surface properties 7
2.5. Micromeritic properties 9
2.6. Powder properties 9
2.7. Preparation of the drug formulation 10
2.8. Solubility study 10
2.8.1. Initial dissolution 11
2.8.2. Solubilizing adjuvant screening 11
2.9. In vitro dissolution studies 11
2.10. Physicochemical properties 11
2.10.1. Differential scanning calorimetry 12
2.10.2. Powder X-ray diffraction 12
2.10.3. Field-emission scanning electron microscopy 12
2.10.4. Field-emission transmission electron microscopy 12
2.10.5. Particle size during dissolution 13
2.11. HPLC analysis 13
3. Results and discussions 15
3.1. Synthesis of GOCs 15
3.2. Physicochemical properties of the GOCs 15
3.2.1. Contact angle 15
3.2.2. Pore size and porosity 20
3.2.3. Flowability 20
3.3. Solubility study 22
3.3.1. The effect of GOC type 22
3.3.2. The effect of GOC concentration 25
3.4. In vitro dissolution study 28
3.5. Physicochemical properties of the CSZ formulation 32
3.5.1. Crystallinity reduction effect 32
3.5.2. Morphology and nanonization process 35
3.5.3. Correlation between particle size and dissolution rate 38
4. Conclusions 43
5. References 44
국문초록 49

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