Isely Christopher, Stevens Alexandra C, Tate Gregory L, Monnier John R, Gower R Michael
Department of Chemical Engineering, University of South Carolina, Columbia, SC 29208, USA.
Biomedical Engineering Program, University of South Carolina, Columbia, SC 29208, USA.
Int J Pharm. 2020 Nov 30;590:119917. doi: 10.1016/j.ijpharm.2020.119917. Epub 2020 Oct 3.
Particles for biomedical applications can be produced by emulsifying biocompatible polymers dissolved in an organic solvent in water. The emulsion is then transferred to an extraction bath that removes the solvent from the dispersed droplets, which leads to polymer precipitation and particle formation. Typically, the particles are smooth and spherical, likely because the droplets remain fluid throughout the solvent extraction process allowing minimization of surface area as the volume decreases. Few modifications to this technique exist that alter the spherical geometry, even though particle performance, from drug delivery to engaging cells of the body, can be tuned with morphology. Here we demonstrate that incorporation of resveratrol, with the aid of ethanol, into the oil phase of an emulsion of poly(lactide-co-glycolide) and dichloromethane in aqueous poly(vinyl alcohol) leads to a crumpled particle morphology. Video microscopy of particle formation revealed that during solvent extraction the droplet crumples in on itself, which does not occur when only ethanol is added to the emulsion. It is unclear why this occurs with resveratrol, but its hydroxyl groups appear to be optimally positioned because removal of the 4' hydroxyl or addition of a 3' hydroxyl resulted in a loss of crumpled particle morphology. We demonstrate that particle morphology can be tuned from that of a crumpled sheet of paper to a deflated sphere by switching out ethanol for a different cosolvent. We quantify the degree of particle deformation with surface area calculated from krypton adsorption isotherms and BET theory and find surface area correlates with resveratrol loading in the particle. Furthermore, spherical particles are achieved when ethyl acetate is used in lieu of dichloromethane and a cosolvent. We propose that during solvent extraction, resveratrol accumulates at the droplet surface where it inhibits polymer chain motion necessary to maintain a spherical geometry and the role of cosolvent is to redistribute resveratrol from the droplet bulk to its surface. This method of producing nonspherical particles extends to polycaprolactone and poly(L-lactic acid) and is compatible with the encapsulation of a hydrophobic fluorescent dye, suggesting hydrophobic bioactive agents could be encapsulated. Taken together, we demonstrate an ability to control morphology of biocompatible polymer particles produced by the widely practiced oil-in-water/solvent extraction protocol via the addition of resveratrol and a cosolvent to the oil phase. The methodology reported is straight forward, and scalable, and expected to be of utility in applications in which a deviation from the default smooth, spherical morphology is desired.
用于生物医学应用的颗粒可以通过将溶解在有机溶剂中的生物相容性聚合物在水中乳化来制备。然后将乳液转移到萃取浴中，以从分散的液滴中去除溶剂，这会导致聚合物沉淀和颗粒形成。通常，颗粒是光滑的球形，这可能是因为在整个溶剂萃取过程中液滴保持流体状态，随着体积减小，表面积最小化。即使从药物递送作用于身体细胞等颗粒性能可以通过形态进行调节，但对该技术进行很少的修改就可以改变球形几何形状。在这里，我们证明在乙醇的辅助下，将白藜芦醇加入聚（丙交酯 - 乙交酯）与二氯甲烷在水性聚乙烯醇中的乳液的油相中会导致颗粒形态皱缩。颗粒形成的视频显微镜观察表明，在溶剂萃取过程中，液滴自身皱缩，而仅向乳液中添加乙醇时不会发生这种情况。尚不清楚白藜芦醇为何会导致这种情况发生，但其羟基似乎处于最佳位置，因为去除4'羟基或添加3'羟基会导致皱缩颗粒形态消失。我们证明通过用不同的共溶剂替代乙醇，可以将颗粒形态从皱缩的纸张状调整为瘪球。我们用根据氪吸附等温线和BET理论计算的表面积来量化颗粒变形程度，发现表面积与颗粒中的白藜芦醇负载量相关。此外，当使用乙酸乙酯代替二氯甲烷和共溶剂时可得到球形颗粒。我们提出，在溶剂萃取过程中，白藜芦醇在液滴表面积累，在那里它抑制维持球形几何形状所需的聚合物链运动，共溶剂的作用是将白藜芦醇从液滴主体重新分布到其表面。这种制备非球形颗粒的方法可扩展到聚己内酯和聚（L - 乳酸），并且与疏水性荧光染料的包封兼容，这表明疏水性生物活性剂可以被包封。综上所述，我们证明了通过向油相中添加白藜芦醇和共溶剂，能够控制通过广泛应用的水包油/溶剂萃取方案制备的生物相容性聚合物颗粒的形态。所报道的方法简单且可扩展，预计在需要偏离默认的光滑球形形态的应用中具有实用性。
