Development of locally- and systemically effective methotrexate transdermal therapeutic system: Formulation development and in vitro/in vivo evaluation

A folic acid derivative, methotrexate (MTX) solution was found to be very unstable in the hydrophilic and lipophilic vehicles with the Hildebrand solubility parameter range of 5.9–23.4 (cal/cc)1/2 and extremely impermeable through the skin because of its polar nature. In the present study, the ion-pair formation of the anionic carboxylic functionality (pK_a1 = 3.76 and pK_a2 = 4.83) of MTX in the presence of protonated counter ions of basic amino acids was studied to evaluate its effect on the chemical stability and skin transport characteristics of the immunosuppressant. The cationic counter ions examined in the study include basic amino acids such as L-arginine (pK_a1 = 2.17, pK _a2 = 9.04, pK_R = 12.48), L-lysine (pK_a1 = 2.18, pK_a2 = 8.95, pK_R = 10.53), and L-histidine (pK _a1 = 2.82, pK_a2 = 9.17, pK_R = 6.00), and an inorganic base, sodium hydroxide. The influence of various hydrophilic and lipophilic vehicles in single and binary mixtures on the epidermal permeation of MTX was also investigated in vitro using the hairless mouse (HLM) skin. Among the neat solvents examined, a lipophilic carrier, isopropyl myristate (IPM) provided the most enhancing effect on the permeation of MTX, followed by N-methylpyrrolidone (NMP), and a short-chain alkanol, isopropyl alcohol. The binary cosolvents consisting of IPM and NMP, in particular, in a 2:8 combination, produced a marked synergistic enhancement of MTX permeation, achieving the steady-state flux value of 39 μg/cm2/hr with a short lag time of 0.8 hrs. The inclusion of ion-paired MTX with a basic amino acid, in particular, with L-arginine in a 1:3 molar ratio into a simple aqueous solution and NMP/IPM cosolvent based microemulsion provided a marked improvement of chemical stability of the easily hydrolysable drug and also produced a significant enhancement of transdermal flux of a polar compound, MTX. The rank order of stabilizing and skin permeation enhancing potency of the basic amino acids obtained with aqueous MTX solutions was L-arginine > L-lysine > L-histidine, which conforms to the order of ionic strength of basic group functionality (pK_R) of the amino acids.; An attempt was made to improve the viscosity of ME reservoir systems with a view to reducing the solvent leaching effect through the microporous rate controlling membrane. The two polymer materials, i.e. methyl vinyl ether-maleic anhydride (Grantrez®/GTZ) and polyoxyethylene-polyoxypropylene-polyoxyethylene (Poloxamer®) polymers were evaluated in the study. The permeation results clearly indicated that the HLM skin was 10–12 times more permeable for MTX than the HC skin. The 3% MTX ME prepared with NMP/IPM cosolvent produced a steady state flux value of 2.4 μg/cm2/hr across human skin, which is approximately 41% greater flux than the target delivery rate of 1.7 μg/cm2/hr.; The results of skin irritation study in New Zealand white rabbits indicated that 1 MTX suspension in water appeared to be no evidence of irritation while 1% MTX solution in NMP showed a mild irritation score. In addition, 2.6% MTX gel formulation prepared with IPM-NMP-TW80-SP20-1%GTZ 139-Water exhibited a mild irritation (3.3 score) while its placebo produced an irritation score of 1.3. The formulation development studies with ion-paired MTX in microemulsion and gel structures showed the feasibility of designing a stable and effective MTX topical and transdermal therapeutic system for use in the treatment of rheumatoid arthritis, psoriasis, and other proliferative disorders of the skin. (Abstract shortened by UMI.)...