(M1430-07-38) Capmul-Based Formulations for Topical Delivery of Prodrugs Derived from Methotrexate and 5-Aminolevulinic Acid

Purpose: The aim of this project is to develop stable and effective topical formulations for delivery of novel prodrugs and co-drugs derived from methotrexate (MTX) and 5-aminolevulinic acid (ALA) for the treatment of skin diseases such as psoriasis. Previous studies support the combination of MTX with ALA-photodynamic therapy as an option for treating psoriasis effectively, as these drugs work together to increase PpIX and suppress keratinocyte proliferation. Optimizing this drug combination requires efficient topical delivery and localization of MTX and ALA in the skin. Prodrugs of MTX and ALA as well as novel MTX-ALA codrugs can mask their hydrophilic properties, improving their localization and simultaneous delivery. Upon metabolism of the prodrugs and codrugs in the skin, optimum efficacy, could be achieved through development of suitable topical formulations.

Methods: Capmul-based microemulsions (ME) and optimized microemulsions (OMEs) were prepared using the titration method with the following composition: the oil phase (Capmul MCM C8), surfactant blend (Tween 20 and PEG 400), and aqueous phase (deionized water). MEs were loaded with MTX disodium salt (MTX DSS), ALA hydrochloride (ALA HCl), and 1:1 molar combination of both; OMEs were loaded with methotrexate dimethyl ester (MTX DME), aminolevulinic acid benzyl ester (ALA BE), and 1:1 molar combination of both. Loaded and unloaded MEs and OMEs were monitored for thermodynamic stability,. Particle size, particle distribution index (PDI), and zeta potential were determined with Malvern Zetasizer Nano ZS90 (Malvern Instruments; Worcestershire, UK) at timepoints 24 hours, 48 hours, 7 days and 14 days.

Results: MEs loaded with MTX DSS, ALA HCl, and OMEs of MTX DME, and ALA BE individually, and 1:1 molar combinations of MTX DSS and ALA HCl were stable for more than 14 days, with no change in clarity. OME of 1:1 molar combinations of MTX DME and ALA BE were stable for 48 hours, with a similar particle size, PDI, and zeta potential profile as the previous MEs and OMEs.

Conclusion: The final products were stable, clear MEs and OMEs with uniform particle size and PDI. These MEs and OMEs, loaded with MTX, ALA, prodrugs MTX DME and ALA BE, and combinations of MTX DME and ALA BE are suitable vehicles to assess topical delivery of these compounds and combinations. Future studies will include characterization of ME rheological properties. Ex vivo penetration studies using porcine skin are planned to determine the efficacy of the topical formulations in delivering the drugs into the viable epidermis. The use of these ME for topical delivery of investigational co-drugs derived from MTX and ALA will also be explored.


Figure 1: I: Photographic images of stable (A) ALA, (B) ALA BE, (C) MTX DSS, and (D) ALA+MTX DSS MEs, respectively, and unstable (E) MTX DME Capmul-based ME.II: Photographic images of stable (A) blank, (B) ALA BE, (C) MTX DME, (1D) stable ALA BE+MTX DME OMEs (after 48 hours) and (2D) unstable ALA BE+MTX DME OMEs (after 7 days)


Table 1. Particle size, PDI and zeta potential measurements of MEs OMEs after 14 days (n=9). All values are written as average ± standard deviation. #= after 48 hours;TBD = to be determined.