低温下的叶黄素临界PGSS封装包埋，实现更好的控制释放

Lutein PGSS encapsulation at low temperature for a better controlled release

M. Schneider,^a,e Y. Masmoudi,^a,* F. Matonti,^b,c,d C. Olmière,^e E.Badens ^a
aAix Marseille Univ, CNRS, Centrale Marseille, M2P2, Marseille, France
^bCentre Paradis Monticelli, 433 bis rue Paradis,,Marseille , France
^cAix Marseille Univ, CNRS, INT, Inst Neurosci Timone, Marseille, France
^dGroupe Almaviva Santé, Clinique Juge, Marseille, France
^eLaboratoires Théa, Clermont-Ferrand, France
*Corresponding author: yasmine.masmoudi@univ-amu.fr

1. Introduction
In the past decades, the pharmaceutical industry faced novel challenges linked to the increase of agerelated and chronic illness due to the ageing of the population in industrialized countries. Age related macular degeneration (AMD) is one of them. Currently, due to the availability of palliative treatments only to mitigate the progression of AMD, the pharmaceutical industry brings a particular attention to the identification and development of preventing agents. Lutein, a carotenoid with strong antioxidant properties found in the macular region was identified as a strong preventing factor of AMD. Consequently, lutein diet supplements for elderly persons were developed. Some daily recommendation intakes can be found in the literature. Some studies suggested a 4 mg per day intake to reduce risk of development of AMD. 1Another study also investigated a 20 mg daily dose and concluded to no toxicity.

2 Due to the lutein low water-solubility and consequently low bioavailability, as well as the low lutein chemical stability (photosensitive compound), some studies focused on lutein delivery optimization through encapsulation processes. In a recent review of Steiner et al., it can be seen that mainly solventbased methods have been used, suggesting the risk of hazardous solvent residues.

3 To avoid such residues, supercritical carbon dioxide (scCO2) technology, especially particles from gas saturated solution (PGSS) process, can be an alternative to solvent-based methods. De Paz et al., demonstrated the feasibility of lutein encapsulation in polycaprolactone (PCL) using scCO2 at 70 °C under 15 MPa with moderate yields (up to 44 % collected particles).

4 In this study, PGSS technology is investigated using pure PCL and PCL/polyethylene glycol (PEG) blend to entrap lutein. Thus, the lutein release could be modulated thanks to the hydrophilic behavior of PEG and the hydrophobic behavior of PCL. Regarding PGSS processing, moderate temperatures (38 to 45°C) are applied, demonstrating the ability to encapsulate thermolabile compounds, while optimizing the process yield.

在过去几十年中，由于工业化国家人口老龄化，与年龄相关的疾病和慢性病的增加，制药行业面临着新的挑战。年龄相关性黄斑变性（AMD）就是其中之一。目前，由于姑息治疗只能缓解AMD的进展，制药行业特别关注预防剂的识别和开发。叶黄素是一种在黄斑区发现的具有强大抗氧化特性的类胡萝卜素，被确定为AMD的强大预防因子。因此，为老年人开发了叶黄素饮食补充剂。一些每日推荐摄入量可以在文献中找到。一些研究建议每天摄入4毫克，以降低患AMD的风险。1另一项研究也调查了每天20 mg的剂量，得出的结论是没有毒性。

2.由于叶黄素的水溶性低，因此生物利用度低，以及叶黄素的化学稳定性低（光敏化合物），一些研究侧重于通过包封过程优化叶黄素的递送。在Steiner等人最近的一篇综述中，可以看出主要使用了基于溶剂的方法，这表明存在危险溶剂残留的风险。

3.为了避免此类残留物，超临界二氧化碳（scCO2）技术，特别是来自气体饱和溶液（PGSS）工艺的颗粒，可以替代基于溶剂的方法。De Paz等人证明了在70°C、15MPa下使用scCO2将叶黄素包埋在聚己内酯（PCL）中的可行性，产率适中（收集的颗粒高达44%）。

4.在本研究中，使用纯PCL和PCL/聚乙二醇（PEG）混合物包埋叶黄素，研究了PGSS技术。因此，由于PEG的亲水行为和PCL的疏水行为，叶黄素的释放可以被调节。关于PGSS加工，应用了中等温度（38至45°C），证明了封装不耐热化合物的能力，同时优化了工艺产率。

Conclusions
This study highlights the potentiality of applying PGSS process to encapsulate lutein in mild conditions of temperature (38°C) with good process yields (up to 80%). In addition to enhance the drug stability, the release from the polymer formulation can be modulated by adjusting the polymer blend ratio.

结论
本研究强调了应用PGSS工艺在温和的温度条件（38°C）下封装叶黄素的潜力，工艺产率高达80%。除了增强药物稳定性外，还可以通过调节聚合物共混比来调节聚合物制剂的释放。

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