Park Chun-Woong, Lee Hyo-Jung, Oh Dong-Won, Kang Ji-Hyun, Han Chang-Soo, Kim Dong-Wook
College of Pharmacy, Chungbuk National University, Cheongju, Republic of Korea.
Department of Pharmaceutical Engineering, Cheongju University, Cheongju, Republic of Korea.
Drug Des Devel Ther. 2018 Apr 5;12:711-719. doi: 10.2147/DDDT.S151437. eCollection 2018.
Norquetiapine (-desalkyl quetiapine, NQ) is an active metabolite of quetiapine with stable pharmacokinetic and pharmacological properties. However, its short half-life is a drawback for clinical applications, and long-acting formulations are required.
The objectives of this study were to prepare improved entrapment efficiency NQ freebase microspheres by the solvent evaporation method with poly(d,l-lactic-co-glycolic acid) (PLGA) as a release modulator and to evaluate their physicochemical and in vitro/in vivo release properties.
NQ freebase PLGA (1:5 w/w) formulations were prepared by the oil-in-water (o/w) emulsion-solvent evaporation method. A solution of the drug and PLGA in 9:1 v/v dichloromethane:ethanol was mixed with 0.2% polyvinyl alcohol and homogenized at 2,800 rpm. The emulsion was stirred for 3 h to dilute and evaporate the solvent. After that, the resulting product was freeze-dried. Drug-loading capacity was measured by the validated RP-HPLC method. The surface morphology of the microspheres was observed by scanning electron microscopy (SEM), and the physicochemical properties were evaluated by differential scanning calorimetry, powder X-ray diffraction, and Fourier-transform infrared spectroscopy particle size distribution. The in vitro dissolution test was performed using a rotary shaking bath at 37°C, with constant shaking at 50 rpm in sink condition.
The NQ freebase microspheres prepared by o/w emulsion-solvent evaporation showed over 30% efficiency. NQ was confirmed to be amorphous in the microspheres by powder X-ray diffraction and differential scanning calorimetry. Special chemical interaction in the microspheres was not observed by FT-IR. The in vitro dissolution test demonstrated that the prepared microspheres' release properties were maintained for more than 20 days. The in vivo test also confirmed that the particles' long acting properties were maintained. Therefore, good in vitro-in vivo correlation was established.
In this study, NQ freebase-PLGA microspheres showed potential for the treatment of schizophrenia for long-periods.
去甲喹硫平（-去烷基喹硫平，NQ）是喹硫平的一种活性代谢产物，具有稳定的药代动力学和药理特性。然而，其半衰期短是临床应用中的一个缺点，因此需要长效制剂。
本研究的目的是通过溶剂蒸发法，以聚（d，l-乳酸-共-乙醇酸）（PLGA）作为释放调节剂，制备包封率提高的NQ游离碱微球，并评估其理化性质和体外/体内释放特性。
采用水包油（o/w）乳液-溶剂蒸发法制备NQ游离碱PLGA（1:5 w/w）制剂。将药物和PLGA溶于9:1 v/v二氯甲烷：乙醇的溶液与0.2%聚乙烯醇混合，以2800 rpm的转速均质化。将乳液搅拌3小时以稀释并蒸发溶剂。之后，将所得产物冷冻干燥。通过经验证的反相高效液相色谱法测定载药量。通过扫描电子显微镜（SEM）观察微球的表面形态，并通过差示扫描量热法、粉末X射线衍射和傅里叶变换红外光谱粒度分布评估其理化性质。体外溶出试验在37°C的旋转振荡浴中进行，在漏槽条件下以50 rpm的恒定转速振荡。
通过o/w乳液-溶剂蒸发法制备的NQ游离碱微球显示出超过30%的包封率。通过粉末X射线衍射和差示扫描量热法证实NQ在微球中为无定形。傅里叶变换红外光谱未观察到微球中有特殊的化学相互作用。体外溶出试验表明，制备的微球的释放特性保持超过20天。体内试验也证实了颗粒的长效特性得以保持。因此，建立了良好的体外-体内相关性。
在本研究中，NQ游离碱-PLGA微球显示出长期治疗精神分裂症的潜力。
