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Effect of solvent types on the formation of long acting self-assembled nanoparticles

초록/요약

The purpose of this study was to investigate the effect of solvents on the formation of self-assembled nanonization of albumin-oleic acid conjugates (AOC) via solvent exchange for in situ forming implant (ISFI) for long acting injectable (LAI). A poorly water-soluble paliperidone palmitate (PPP) was chosen as a model drug. AOC was prepared using a freeze-drying method using a 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) reaction. Then, six solvents, dichloromethane (DCM), tetrahydrofuran (THF), ethanol, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) and water were selected to investigate the formation of self-assembled AOC nanoparticles (AONs). As the polarity of the solvent increased, the AONs showed a spherical shape, and the larger the volume of the solvent, the smaller the size of the AONs. AOC was dispersed in various ratios of organic solvents to screen miscibility and in situ nanonizing formulation that forms a drug depot at the injection site. However, the AOC was aggregated immediately to form depot upon organic solvent exchange to aqueous dispersion but could not pass through the needle due to the rigid gelation. In contrast, drug-loaded AOC dispersed in water was nanonized without showing aggregation to form AONs but no drug depot. To impart AOC more ISFI for sustained release of PPP, poly(d,l-lactide-co-glycolide) (PLGA) was combined with AOC in NMP and water solution. The in vitro release profiles of AOC or AOC/PLGA formulations was conducted. The overall release rate of all formulations showed similar curve pattern but was more sustained in the decreasing order: AOC, PLGA and AOC/PLGA as compared with PPP alone for 14 days. Most of all, a combined formulation of AOC and PLGA could effectively control the initial burst release of the drug.

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초록/요약

이 연구의 목적은 장기 지속 주사를 위해 용매 교환을 이용한 현장 형성 임플란트(ISFI) 제형에 대한 알부민-올레산 접합체(AOC)의 자가 조립 나노입자 형성에 대한 용매의 효과를 조사하는 것입니다. 난용성 약물인 팔리페리돈 팔미테이트(PPP)가 모델 약물로 선택되었습니다. AOC는 이미드 커플링 반응을 통해 동결 건조 방법으로 제조되었습니다. 그 다음 6 개의 용매인 디클로로메탄(DCM), 테트라하이드로푸란(THF), 에탄올, N-메틸-2-피롤리돈(NMP), 디메틸 설폭사이드(DMSO) 및 물을 선택하여 자가 조립 AOC 나노 입자(AON)의 형성을 조사했습니다. AON은 용매의 극성이 증가함에 따라 구형의 모양을 보였고, 용매의 부피가 커질수록 크기는 작아졌습니다. AOC는 혼합성과 주사 부위에서 약물 저장소를 형성하는 현장 형성 나노제형을 평가하기 위해 다양한 비율의 유기용매에 분산되었습니다. 그러나 AOC는 수성 분산액으로 유기 용매 교환시 즉시 응집되어 데포를 형성했지만 단단한 겔화로 인해 주사바늘을 통과하지 못했습니다. 대조적으로, 물에 분산 된 약물 로딩 된 AOC는 응집을 보이지 않고 나노화되어 AON을 형성하지만 약물 저장소를 형성하지 않았습니다. PPP의 지속적인 방출을 위한 ISFI 제형을 만들기 위해 PLGA를 AOC와 함께 NMP 및 수용액에서 혼합시켰습니다. AOC, PLGA, AOC / PLGA 제형의 시험관내 방출 시험을 수행했습니다. 모든 제형의 전체 방출 속도는 유사한 패턴을 보였지만 14일 동안 PPP 단독에 비해 AOC, PLGA, AOC / PLGA의 순서로 방출이 더 지속되었습니다. 무엇보다도 AOC와 PLGA의 결합 된 제형은 약물의 초기 폭발 방출을 효과적으로 제어 할 수 있습니다.

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목차

1. Introduction 1
2. Materials and Methods 5
2.1. Materials 5
2.2. Preparation of AOC nanoparticles 6
2.2.1. Preparation of AOC 6
2.2.2. Effect of solvent types on the nanonization of AOC 6
2.3. Preparation of AOC injection formulation 9
2.3.1. Comparison of AOC injection solution in different solvents 9
2.3.2. Preparation of long-acting injectable AOC/PLGA solution 9
2.4. Characterization of AOC 12
2.4.1. Fourier transform-infrared (FT-IR) spectrometer 12
2.4.2. Field Emission Scanning Electron Microscopy (FE-SEM) 12
2.4.3. Field Emission Transmission electron microscopy(FE-TEM) 12
2.4.4. Dynamic light scattering (DLS) 13
2.5. In vitro dissolution test 13
3. Results and discussions 14
3.1. Synthesis and characterization of AOC nanonization 14
3.1.1. Identification of Albumin-oleic acid conjugates 14
3.1.2. The effect of organic solvent on nanoparticles formation 16
3.2. Solvent exchange and self-assembled nanonization of AOC formulations 19
3.2.1. Preparation and visual images of AOC solution 19
3.2.2. Preparation of long-acting AOC/PLGA solution 27
3.2.3. In vitro release profile of AOC and AOC/PLGA formulation 32
4. Conclusion 35
5. References 36

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