Application of the central composite design to optimize the preparation of novel micelles of harmine

Yong-Yan Bei,^1,* Xiao-Feng Zhou,^2,3,* Ben-Gang You,¹ Zhi-Qiang Yuan,¹ Wei-Liang Chen,¹ Peng Xia,¹ Yang Liu,¹ Yong Jin,⁴ Xiao-Juan Hu,¹ Qiao-Ling Zhu,¹ Chun-Ge Zhang,¹ Xue-Nong Zhang,¹ Liang Zhang<sup>5

1</sup>Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People’s Republic of China; ²College of Radiological Medicine and Protection, Soochow University, Suzhou, People’s Republic of China; ³Changshu Hospital of Traditional Chinese Medicine, Changshu, People’s Republic of China; ⁴Invasive Technology Department, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; ⁵Department of Biopharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, People’s Republic of China
^*These authors contributed equally to the paper

Abstract: Lactose–palmitoyl–trimethyl–chitosan (Lac-TPCS), a novel amphipathic self-assembled polymer, was synthesized for administration of insoluble drugs to reduce their adverse effects. The central composite design was used to study the preparation technique of harmine (HM)-loaded self-assembled micelles based on Lac-TPCS (Lac-TPCS/HM). Three preparation methods and single factors were screened, including solvent type, HM amount, hydration volume, and temperature. The optimal preparation technique was identified after investigating the influence of two independent factors, namely, HM amount and hydration volume, on four indexes, ie, encapsulation efficiency (EE), drug-loading amount (LD), particle size, and polydispersity index (PDI). Analysis of variance showed a high coefficient of determination of 0.916 to 0.994, thus ensuring a satisfactory adjustment of the predicted prescription. The maximum predicted values of the optimal prescription were 91.62%, 14.20%, 183.3 nm, and 0.214 for EE, LD, size, and PDI, respectively, when HM amount was 1.8 mg and hydration volume was 9.6 mL. HM-loaded micelles were successfully characterized by Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and a fluorescence-quenching experiment. Sustained release of Lac-TPCS/HM reached 65.3% in 72 hours at pH 7.4, while free HM released about 99.7% under the same conditions.

Keywords: harmine, chitosan derivate, self-assembled micelle, central composite design, response surface methodology, characterization