Development of Capsaicin-Containing Analgesic Silicone-Based Transdermal Patches

Abstract

Transdermal therapeutic systems (TTSs) enable convenient dosing in drug therapy. Modified silicone-polymer-based patches are well-controlled and cost-effective matrix diffusion systems. In the present study, we investigated the substance release properties, skin penetration, and analgesic effect of this type of TTS loaded with low-dose capsaicin. Release properties were measured in Franz diffusion cell and continuous flow-through cell approaches. Capsaicin was detected with HPLC-UV and UV spectrophotometry. Raman spectroscopy was conducted on human skin samples exposed to the TTS. A surgical incision or carrageenan injection was performed on one hind paw of male Wistar rats. TTSs were applied to the epilated dorsal skin. Patches were kept on the animals for 6 h. The thermal hyperalgesia and mechanical pain threshold of the hind paws were detected. Patches exhibited controlled, zero-order kinetic capsaicin release. According to the Raman mapping, capsaicin penetrated into the epidermis and dermis of human skin, where the target receptors are expressed. The thermal pain threshold drop of the operated rat paws was reversed by capsaicin treatment compared to that of animals treated with control patches. It was concluded that our modified silicone-polymer-based capsaicin-containing TTS is suitable for the relief of traumatic and inflammatory pain.

Keywords: addition polymer; capsaicin; silicone; transdermal therapeutic system.

Figure 1

Modified silicone-polymer-based matrix-controlled diffusion TTS.

Figure 2

Scheme of silicone polymerization by condensation.

Figure 3

Scheme of silicone polymerization by addition. The “+” sign indicates addition of the two ethenyl groups in the top and bottom left of the figure to respective silicon atoms of the polysiloxane to the right of the “+” sign. The product of the reaction is shown in the right.

Figure 4

Apparatus for single-layer spreading of the polymer (A). Two pieces of the modified silicone polymer TTS (B). On the top is the aluminum film that is included to improve mechanical properties. On the bottom is the adhesive layer that touches the skin. The punching tool used to cut the TTS to size is also visible.

Figure 5

The cumulative amount of released capsaicin in μg/cm² over 24 h (p < 0.05, *; p < 0.01, **; and p < 0.001, ***).

Figure 6

The cumulative amount of permeated capsaicin in μg/cm² over 24 h (p < 0.001, ***).

Figure 7

The released capsaicin in µg/cm² over 6 h.

Figure 8

Raman correlation maps for the distribution of capsaicin in human skin after treatment with patches. Untreated skin is also displayed as control. Color coding of drug content: red > yellow > green > blue.

Figure 9

Capsaicin-releasing dermal patch applied right after surgical incision of the hind paw relieved thermal hyperalgesia of the paw. Thermal hyperalgesia is indicated by the painful heat threshold and is shown in degrees of Celsius. * is p < 0.05; ** is p < 0.01; *** is p < 0.001; **** is p < 0.0001. n = 9–10.

Figure 10

Capsaicin-releasing dermal patch applied 18 h after surgical incision of the hind paw relieved thermal hyperalgesia of the paw. Thermal hyperalgesia is indicated by the painful heat threshold and is shown in degrees of Celsius. * is p < 0.05; *** is p < 0.001; **** is p < 0.0001. n = 9.

Figure 11

Capsaicin-releasing transdermal patch applied 18 h after challenge alleviated carrageenan-induced mechanical paw hyperalgesia. Mechanical pain threshold of the hind paws is shown in g. * is p < 0.05; *** is p < 0.001; **** is p < 0.0001. n = 9–14.

Figure 12

Schematic structures of the most frequent types of transdermal drug delivery systems. The figure shows the membrane-controlled (A), drug in adhesive (B), micro-reservoir (C), classical matrix diffusion (D) and modified silicone-polymer (E) systems.

Figure 13

Flow-through cell.