RESUMO
Primaquine (PMQ) is an effective antimalaria drug with several limitations. We report the combinatorial approach of thermoresponsive hydrogels and Dermarollers® for transdermal delivery of PMQ to overcome these limitations. The hydrogels were prepared using Pluronic F127 (PF127) and F68 (PF68). Specifically, HPMC was added into the formulation to improve the bioadhesive properties. Numerous formulations were prepared, showing that formulation comprising 15 % PF127, 3 % PF68 and 0.4 % HPMC with 1 % PMQ was selected as the optimum formulation. The formulation showed the gelation temperature around 35 °C with bioadhesive strength of 26.43 ± 2.31 dyne.cm2. Importantly, the pH of the formulation was suitable for skin application with the percentage of PMQ recovery of 99.57 ± 3.23 %. Moreover, the hydrogels exhibited free-flow liquid at storage and room temperature and high viscosities in the skin temperature. In vitro release experiments showed that the release of PMQ was sustained for 24 h. Evaluated in extensive ex vivo studies, the treatment with Dermarollers® improved the skin permeation and retention of PMQ for 3 days. In combination with Dermarollers®, the ex vivo permeation of PMQ was sustained and the localization of PMQ in the skin was improved over 72 h.
RESUMO
Malaria caused by various types of Plasmodium has become a global health problem. One of the drugs used as the first line of malaria therapy is primaquine (PMQ). PMQ is generally administered through the oral route. However, the use of PMQ orally could potentially cause some side effects and undergo the first-pass metabolism in the liver, reducing its effectiveness. Therefore, it is necessary to develop another drug administration route to avoid this effect. In this study, for the first time, PMQ was formulated into a transdermal patch for transdermal delivery, combined with solid microneedles, Dermaroller®. Following several optimizations, HPMC and glycerin were used as the main polymer and plasticizer, respectively. Specifically, the concentration of PEG 400 as a permeation enhancer was also optimized. The transdermal patches were evaluated for weight uniformity, thickness, surface pH, folding endurance, moisture content, moisture absorption ability, bioadhesive evaluation, and drug content recovery. PMQ release and permeation were also investigated through in vitro and ex vivo tests on rats' skin tissue. Importantly, the safety of the transdermal patch was also evaluated through in vitro hemolytic and in vivo irritation tests which were confirmed by histopathological examinations. The results showed that all formulations showed desired physical and bioadhesive properties with a folding endurance of >300 folds. The results exhibited that 31.31 ± 5.25% and 22.55 ± 4.35% of primaquine were released from transdermal patches following the in vitro and the ex vivo permeation studies. Combined with Dermaroller®, the ex vivo permeation study showed an improved permeation profile with 45.89 ± 5.00% of primaquine permeated after 24 h with a zero-order kinetic during the first 8 h. Hemolysis percentage was found to be <5%, indicating the non-toxic of this approach. Finally, the histopathology study showed that there was no severe tissue damage following the administration of our approach. Further in vivo evaluations should be performed.
