(M1330-03-18) Study of the Physiochemical Characteristics of Luteolin for Application in (Trans)Dermal Delivery

Purpose: Luteolin, a natural anti-inflammatory flavonoid, can be derived from a variety of plants, e.g. Reseda luteola, Chrysanthemum morifolium or Sigesbeckia pubescens. This molecule can also be found in common vegetables such as celery, pepper, carrot, onion etc. [1] Previous studies have reported that luteolin is biologically active with anti-oxidant, anti-inflammatory, anti-cancer and neuroprotective properties [2,3]. The toxicology and mechanisms underlying the compound’s pharmacological properties have also been investigated [2,3]. Thus, luteolin appears to be a promising molecule with applications in management of inflammation. However, due to its low aqueous solubility, luteolin formulation for pharmaceutical applications is challenging. In this work the physiochemical properties e.g. log D_{1-octanol/PBS}, solubility and stability in topical solvents, of luteolin were analyzed, characterized and quantified, as a preliminary step for the compound’s future use in different skin formulations. To our knowledge these properties have not been reported previously.

Methods: High performance liquid chromatography (HPLC) was used for sample analysis. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used for determining degradation temperature and melting point respectively. The Log D_{1-octanol/PBS} test was conducted according to OECD guidelines [4], using the shake flask method with PBS and 1-octanol in three different ratios (n=3). Solubility studies were conducted using the water bath method. Solubility of luteolin was determined in PBS, water, methanol, 1-octanol, 1,2-propanediol (PG), 1,2-ethanediol (EG), diethylene glycol monoethyl ether (TC), caprylocaproyl polyoxyl-8 glycerides (Labrasol) and propylene glycol monolaurate (PGML), at 32 ± 0.5 °C (n=3). The stability of 0.1% luteolin in PG and EG, and the stability of 0.05% luteolin in PBS with 5% BRIJ^®> O20, was investigated at 32 ± 0.5 °C, over 24 h, 48 h, and 72 h (n=3).

Results: Log D_{1-octanol/PBS} of luteolin at pH 7.3 ± 0.2, degradation temperature, melting point and solubility results are shown in Table 1. The stability of luteolin in PG, EG, PBS with 5% BRIJ^® O20 was evaluated by percentage recovery and all values were in the range of 80%-120%.

Conclusion: Based on the chemical structure and Log D_{1-octanol/PBS} value, luteolin is a promising active for dermal delivery. With the highest solubility of luteolin in TC and Labrasol, these two solvents are candidates for further development and formulation optimisation. The stability results of luteolin in PG, EG and PBS with 5% BRIJ^® O20 show that luteolin is stable in these solvents. Further solubility and stability tests in a wider range of solvents will be tested in the future.

References: [1] Gendrisch F, Esser PR, Schempp CM, Wölfle U. Luteolin as a modulator of skin aging and inflammation. Biofactors. 2021 Mar;47(2):170-180.
[2] Nabavi SF, Braidy N, Gortzi O, Sobarzo-Sanchez E, Daglia M, Skalicka-Woźniak K, Nabavi SM. Luteolin as an anti-inflammatory and neuroprotective agent: A brief review. Brain Res Bull. 2015 Oct;119(Pt A):1-11.
[3] Imran M, Rauf A, Abu-Izneid T, Nadeem M, Shariati MA, Khan IA, Imran A, Orhan IE, Rizwan M, Atif M, Gondal TA, Mubarak MS. Luteolin, a flavonoid, as an anticancer agent: A review. Biomed Pharmacother. 2019 Apr;112:108612.
[4] OECD Test No. 107: Partition Coefficient (n-octanol/water): Shake Flask Method, OECD Publishing.

Acknowledgments: I declare that the research described is original and all the text written herein and have clearly indicated by suitable citation any part of this dissertation that has already appeared in any publication.

Table 1. Data of Log D, degradation temperature, melting point and solubility