Prodrug Therapy for the Treatment of Psoriasis: Formulation, Stability and Drug Delivery to the Ski

Psoriasis is a chronic autoimmune disease that is characterized by premature maturation and hyperproliferation of keratinocytes, and inflammation. Mycophenolic acid (MPA) is an immunosuppressant that targets inflammation through inhibition of inosine monophosphate dehydrogenase (IMPDH) and other mechanisms. 5-Aminolevulenic acid (5-ALA) is a drug used in photodynamic therapy and is cytostatic towards hyperproliferating keratinocytes. We have formulated MPA, 5-ALA and methyl ester prodrugs of MPA and 5-ALA, methyl mycophenolic acid (MPA-ME) and methyl 5-aminolevulenic acid (MAL) respectively, as model compounds to develop stable microemulsions (MEs) as vehicles for topical delivery. The eventual aim is to use these MEs to deliver co-drugs of MPA and 5-ALA to the skin as novel combination therapies to treat psoriasis.;The specific aims of this project were to develop the MEs, characterize the formulations by particle size and viscosity, evaluate stability of the ME and the drugs in the ME formulations, to determine drug delivery into the viable skin layers and to monitor hydrolysis of the prodrugs in the skin. ME formulations composed of IPM as the oil phase, a mixture of Tween 80, Span 80 and 1,2-octanediol as surfactant blend, and deionized water (DI) as the aqueous phase were prepared and selected formulations were monitored for stability and characterized by particle size and viscosity. Hydrolytic stability MPA-ME was monitored in the ME formulations by HPLC. Drug delivery of the formulated drugs in MEs into the viable skin layers was assessed using intact, porcine skin specimens and drug penetration was quantified at 2, 4, 8, 12 and 24 hours using HPLC analysis. Hydrolysis of MPA-ME the skin was also monitored and quantified.;MEs used for formulating the drugs were composed of IPM as the oil phase (based solubility of the drugs) with low water content (1%) to minimize hydrolysis of prodrugs in the formulations. All of the drug-loaded ME formulations were physically stable for 24h, but ME formulations of MPA, 5-ALA and MAL phase separated, or drug precipitated from the formulation after 1 week. The MPA-ME formulation was physically stable for 1 week and no evidence of hydrolysis of the ester in the formulation was detected. The range of average particle sizes of drug-loaded ME formulations (1%) was found to be 25.7-102.9 d.nm and the viscosities ranged from 3.65- 8.88 cP.;Results from the skin penetration studies with porcine skin demonstrated that both MPA and MPA-ME penetrated into the viable layers of the skin. At 2h for 1% MPA formulation, 1.23% of drug penetrated in SC and 4.96% drug penetrated in the ED layers of the skin, as opposed to 12.41% in SC at 24h and 60.05% in ED at 24h. Complete hydrolysis of MPA-ME to MPA was observed in the ED after only 2h., suggesting that esterases in the skin are likely responsible for hydrolysis of the prodrug as the ester was hydrolytically stable in the formulation before application. Concentrations of MPA and MPA-ME in the ED layer of the skin was approximately the same at 2h-12h (37-227nmols/cm 2, but at 24h, significantly more MPA-ME was detected in the ED layer (4.2 micromols) compared with MPA concentrations (1.04 micromols). MPA-ME is 100% hydrolyzed to MPA in the ED layer, thus these data show that the prodrug, formulated in ME-A, delivers more of the active drug (MPA) to the ED layer than the parent drug formulated in the same delivery vehicle. However, skin integrity was not assessed after 24h and the significant increase in drug concentrations at the 24h timepoint may be due to deteriorating barrier function of the skin.;Overall, the drugs; MPA, 5-ALA and MAL; were successfully formulated as stable topical MEs and are stable for at least 24 hours. MPA-ME was stable for at least 1 week. No hydrolysis of the drugs was seen in the formulations. The drugs penetrated and accumulated into the skin layers in sufficient concentrations. The ester prodrug MPA-ME was hydrolyzed in the skin layers releasing the parent compound MPA possibly enabling it to exert its action. The efficacy of these formulations followed by their use for a co-drug development of MPA and 5-ALA will be explored in the future.