Purpose: Transdermal or topical delivery of analgesics is preferred to the oral route, due to possible gastrointestinal side effects associated with the latter. Trolamine salicylate (TS) is a topical analgesic used to treat muscular and joint pain. Similar to other analgesics belonging to the class of salicylates, TS inhibits cyclo-oxygenase and thus, reduces inflammation. Unlike other topical analgesics such as menthol and camphor, it offers many benefits including no distinct odor, low systemic absorption, and has low skin irritation properties. Bioadhesive films, incorporating cosmetic or therapeutic agents, are more convenient than the conventional topical drug delivery systems such as lotions, ointments, creams, and gels, with respect to application as well as due to lower potential loss of formulation by rubbing. Poly lactic-co-glycolic acid (PLGA) is one of the most promising polymeric candidates that is used to fabricate devices for drug delivery and tissue engineering applications. It is biocompatible and biodegradable, FDA approved, and its properties such as erosion time and mechanical strength can be controlled. In this study, PLGA-based in-situ bioadhesive film forming system for transdermal delivery of TS was designed and evaluated for drug permeation across dermatomed porcine ear skin.
Methods: Two different types of polymeric bases, PLGA and ethyl-2-cyanoacrylate, were used to develop the in-situ film forming liquid formulation. Polyethylene glycol 400 (PEG 400) was incorporated as a plasticizer to enhance the mechanical properties and flexibility of the film. To prepare the polymeric solution, PLGA (EXPANSORB DLG 50-2A polymer with lactic and glycolic acid as 1:1 and a molecular weight of 15-30 kDa) and ethyl 2-cyanoacrylate were weighed and dissolved in acetone, followed by addition of PEG 400. The drug was added at the end and the final blend was left overnight on a rotating rotor to allow the drug to dissolve completely. Two test formulations (group 1 and group 2) consisting of same drug concentration (1% w/w, wet weight), but different percentages of PLGA (10% w/w and 20% w/w, wet weight, respectively) were prepared. The control formulation, containing same drug concentration as the test ones, but no PLGA was prepared. PEG 400 and cyanoacrylate were added in the ratio of 1:1 in all the formulations. Blank formulation, without the drug, was also prepared. To check crystallization of the drug in the films, formulations were placed on a microscopic slide and observed under a microscope, after evaporation of acetone. In vitro drug permeation studies were performed using vertical Franz diffusion cells and dermatomed porcine ear skin. Each formulation (6.4 µL) was placed on the skin using positive displacement pipette. Phosphate buffered saline (10 mM, pH 7.4) was used as the receptor solution. Sampling of the receptor solution was performed at pre-determined time points for 72 h. Amount of TS was detected and quantified using HPLC. Statistical analysis was performed using student’s t-test and p<0.05 was considered for concluding significant difference between the groups.
Results: PLGA based bio-adhesive polymeric solution was prepared successfully. Upon application on dermatomed porcine skin, acetone evaporated and a thin transparent film was formed in-situ. The microscopic images of the blank and test formulations did not show any difference. Also, no drug precipitates or crystals were observed in the films during slide crystallization studies that depicted solubility of the drug in the film matrix after evaporation of acetone. The amount of TS delivered in the receptor solution after 24 h was found to be 0.13 ± 0.13 µg/sq.cm in the control group and 0.29 ± 0.09 µg/sq.cm in the test group 1. A significantly higher amount of trolamine salicylate was delivered from test group 2 (10.45 ± 4.65 µg/sq.cm) as compared to the control group and test group 1 (p < 0.05). In addition, the increased amount of PLGA in test group 2 significantly enhanced the drug delivery after 48 h and 72 h as well. The lag time of the drug with the control formulation was 22.91 h and 7.78 h for test group 1. A significantly shorter lag time was observed in test group 2 (0.16 h). The amount of TS observed in viable epidermis and dermis at the end of 72 h was found to be 13.48 ± 2.19 µg/sq.cm, 10.79 ± 0.53 µg/sq.cm, and 9.20 ± 3.30 µg/sq.cm in the control, test group 1, and test group 2, respectively. The amount of drug delivered in the skin was not significantly different between the three groups (p > 0.05).
Conclusion: In situ film forming bio-adhesive topical delivery system for TS was successfully prepared. Polymeric film without PLGA delivered a lower amount of TS and retarded the onset of the delivery across dermatomed porcine skin. However, increasing PLGA content enhanced and facilitated the early onset of TS delivery.