(M1130-01-02) Preparation and Evaluation of Pramipexole Transdermal Patch: In Vitro and In Vivo Study

Purpose: Pramipexole is available orally for the treatment of Parkinson’s disease (PD), however, patient’s compliance is poor due to gastrointestinal adverse effects that may be associated with the oral route. The transdermal delivery of daily pramipexole is advantageous in reducing the dosing frequency and improving the tolerability by reduced fluctuation of plasma levels, compared to oral route of administration. Therefore, a daily pramipexole patch currently under development to improve patient’s compliance.

Methods: The drug-in-adhesive patches containing pramipexole were prepared by solvent evaporation method. The patch formulation was optimized using Box-Behnken design to study the effect of independent variables, amount of pramipexole (X1), amount of plasticizer (X2) and amount of enhancer (X3) on dependent variables flux (Y1), adhesiveness (Y2), drug utilization (Y3) and gel strength (Y4). Physicochemical properties of the patch were characterized, including drug content, uniformity, crystal growth, adhesiveness, gel strength and stability test. In vitro skin permeation was measured using Franz diffusion cell with human skin. The cumulative amount of pramipexole in the receptor phase was analyzed by high-performance liquid chromatography (HPLC). For in vivo pharmacokinetics studies in rats, the plasma concentrations of pramipexole were quantified for single dosing of Mirapex® 0.125mg tablet through the oral route, or for 24 hours after single-application of the pramipexole patches, by LC-MS/MS. To examine the skin irritation of the application site, the pramipexole patch was applied transdermally for 24 hours in rabbits.

Results: The pramipexole patch was optimized by Box-Behnken design, and the effect of formulation factors was evaluated individually and in combination over the responses to determine the optimal composition. In optimized formulation, the pramipexole permeated through human skin over a period of 24 hours and approximately 60% of pramipexole in the patch permeated transdermally through the human skin for 24 hours at a constant rate. After application of the pramipexole patch in rats, PK profiles were observed in a dose-dependent manner. In order to examine the toxicity of application site, pramipexole patch was transdermally applied for 24 hours. As a result of skin irritation analysis on the pramipexole patch, very slight erythema was observed, and edema was not observed. There were no abnormalities or specific adverse events detected during the experiments.

Conclusion: Pramipexole patch was successfully developed and optimized using a three-factor, three level Box-Behnken design. Sustained transdermal delivery of pramipexole from nonclinical study were supported the feasibility of a convenient, safe and effective daily dosing regimen as compared to oral treatment.


Fig 1. Cumulative pramipexole permeation through human skin (means +- SD)


Fig 2. Mean pramipexole plasma concentration vs. time curve in hairless rats


Fig 3. Skin irritation study of pramipexole patch in hairless rats