(M1030-01-02) Development of Tretinoin-loaded Lipid Nanoparticles for Topical Drug Delivery

Purpose: This study aims to provide a solution by developing a novel Tretinoin-loaded lipid nanoparticle (TRA-LNP) formulation to reduce the skin irritation and enhance the skin permeation by remaining the drug in epidermis layer. Tretinoin (all-trans retinoic acid, TRA), the first generation of retinoids, is the most common therapeutic agent used topically to treat acne, with promising efficacy. We have developed a formulation in good stability and low toxicity with the skin irritation test on rabbits

Methods: TRA-LNP was prepared by using hot melt emulsification and sonication. The developed formulations contain TRA and cetyl alcohol (oil), cetyl palmitate (oil), MCT oil (oil), lecithin, polysorbate 80 (surfactant), sorbitan monolaurate (co-surfactant), and BHT (antioxidant). Composition of these formulations are shown in Table 1. Particle size (PS), polydispersity index (PI), assay and encapsulation efficiency (EE) were determined with various instruments. Stability of these formulations was evaluated at room temperature (25±2 °C) over 4 weeks. Comparison of skin irritation between TRA-LNP and TRA cream (commercial drug) was evaluated on New Zealand rabbits.

Results: From Table 1, the appearance of TRP026 and TRP028 (cetyl alcohol-based nanoparticles) changed on day 3 and day 11 at 25±2°C, respectively and both formulations have poor stability. We speculated that hydrophilic OH group in cetyl alcohol could destabilize the structure by attracting water into the interior of nanoparticles. Therefore, cetyl alcohol-based nanoparticles were not suitable in TRA-LNP formulation. On the other hand, TRP045 showed a smaller particle size (PS: 72.3nm) among the formulations due to the polysorbate 80 formed micelles by self- assembling. This formulation also has a higher PI (PI: 0.291) because of the steric hindrance of polysorbate 80 on the surface of LNP. TRP046 demonstrated a smaller PI (0.141) due to narrow distribution of particle size in this formulation. According to the stability results in Figure 1, TRP045 and TRP046 remained good stability in PS and PI up to 4 weeks. TRP045 has also demonstrated higher encapsulation efficiency (EE) (100%) comparing to TRP046 (95%) during 4-weeks period. We concluded that TRP045 is the most promising candidate for TRA-LNP compared to other listed formulations. TRA-LNP formulation also demonstrated the superiority in reducing skin irritation comparing to the commercial Tretinoin cream from an In vivo skin irritation test on New Zealand rabbits (Table 2).

Conclusion: We have successfully developed a novel TRA-LNP formulation with high encapsulation efficiency and good stability. In comparison to commercial Tretinoin cream, our TRA-LNP formulation demonstrated effective mitigation of skin irritation. Overall, we are confident that this formulation holds significant potential for advancement into clinical study and commercialization for the treatment of acne in the near future.

References: 1. Ahmad Nasrollahi S, Koohestani F, Naeimifar A, Samadi A, Vatanara A, Firooz A. Preparation and evaluation of adapalene nanostructured lipid carriers for targeted drug delivery in acne. Dermatologic Therapy. 2021; 34:e14777. doi: 10.1111/dth.14777.
2. Chinsriwongkul A, Chareanputtakhun P, Ngawhirunpat T, Rojanarata T, Sila-on W, Ruktanonchai U, Opanasopit P. Nanostructured lipid carriers (NLC) for parenteral delivery of an anticancer drug. AAPS PharmSciTech. 2012, 13(1):150-8. doi: 10.1208/s12249-011-9733-8.


Table 1. Composition of different TRA-LNP formulations.


Figure 1. Stability of EE between TRP045 and TRP046 was evaluated at 25±2 °C


Table 2. In vivo skin irritation test (n=3)