(M1530-03-15) Monitoring of Lidocaine Transport through Dermis and Subcutis into Muscle Tissue after Application via Topical Delivery Systems

Purpose: Topical application of analgesics has become increasingly popular in treating local pain as they ensure site-specific drug delivery, pain relief at lower daily doses, and avoidance of first-pass effect. For the treatment of lower back pain and other musculoskeletal pains, clinicians frequently use prescription lidocaine-containing topical delivery systems (TDS, “patches”). Because there is a lack of data regarding drug concentrations directly in the muscle data after TDS use, this study aimed to assess if using a TDS can increase drug concentration via direct diffusion of the drug into the muscle.

Methods: The first study (ex-vivo) was done in porcine tissue to assess drug diffusion through skin and subcutaneous adipose tissue (SAT) into muscle tissue. The study used an investigational TDS containing 5.4% lidocaine (SP-103, SCILEX Pharmaceuticals Inc., Palo Alto, CA, USA; 15 mg lidocaine per application site) and a topical pain-relief gel with 2% diclofenac (Pennsaid 2 g/100 g Gel, Gebro Pharma AG, Switzerland). 12 application sites were used on freshly explanted tissue from 2 pigs and tested in a climate chamber with controlled temperature and humidity. The second study (in-vivo) used a similar setup to assess drug diffusion in 4 pigs with six application sites each. The investigational TDS product (SP-103) was compared to a commercially available lidocaine-containing TDS (ZTlido® 1.8%). Each product was tested on 2 application sites on each pig and compared to a control site with no lidocaine application. Blood samples were taken from all pigs concurrent with interstitial fluid sampling. Both studies used open flow microperfusion (OFM) to sample interstitial fluid from skin, SAT, and muscle tissue to monitor lidocaine and diclofenac concentrations. At each application site, 2 OFM probes were inserted in skin tissue (dermis), 2 probes in SAT, and 2 probes in muscle tissue. At t=0 all products were applied, at t=12 h SP‑103 and ZTlido TDS were removed, and OFM sampling was continued until t=48 h in the first (ex-vivo) study and until t=24 in the second (in-vivo) study. Lidocaine and diclofenac concentrations were analyzed by using HPLC‑MS/MS.

Results: In the first (ex-vivo) study, data were a result of only diffusive transport due to the lack of blood circulation in explanted tissue. We found decreasing concentrations of lidocaine and diclofenac following the concentration gradient through dermal tissue and SAT into muscle tissue (Fig. 1). The lidocaine concentration was >1000 nM in muscle tissue while the diclofenac concentration in the muscle tissue was below LLOQ. In the second (in-vivo) study, drug transport via blood circulation was present in addition to diffusive transport. Four hours after drug application, lidocaine was detected in all tissues and serum (416.8 ± 641.3 nM) with the highest concentration in the dermis (3071.1 ± 4067.7 nM (SP-103) and 813.8 ± 930.6 nM (ZTlido); Fig. 2). After ZTlido application, lidocaine concentration in muscle decreased slightly over 24 hours while for SP-103 application, lidocaine muscle concentrations remained stable and surpassed lidocaine serum levels (Fig. 2). At 24 hours, lidocaine muscle concentration was 46.9 ± 63.4 nM (SP-103), 9.8 ± 2.7 nM (ZTlido®), and 27.4 ± 26.7 nM (serum). The area under the concentration curves (AUC) over 24 hours showed significantly higher lidocaine concentrations in muscle tissue for SP-103 sites compared to ZTlido® sites (P = 0.008, Fig. 3).

Conclusion: The use of TDS SP-103 led to higher lidocaine concentrations in the muscle due to a successful combination of drug delivery by blood circulation and direct drug diffusion through dermal and SAT into muscle tissue. Thus, when SP-103 is applied directly on the skin above the site of musculoskeletal pain, SP-103 utilizes an additional pharmacokinetic path for more effective drug delivery.

Acknowledgements: This research was supported by Scilex Holding, Palo Alto, CA, USA.

Figure 1: First study (ex-vivo) lidocaine and diclofenac concentrations (logarithmic scale) over 24 hours in the dermis (short dash), SAT (long dash), muscle tissue (solid). Each data point represents the mean concentration from 8 application sites for lidocaine and 4 application sites for diclofenac with standard deviations.

Figure 2: In-vivo study: lidocaine concentration (logarithmic scale) over time in dermal tissue (short dash), SAT (long dash), muscle (solid line) and serum (red). Each data point represents the mean concentration from 4 pigs with standard deviation

Figure 3: Median area under the lidocaine concentration curves (AUC) over 24 hours in muscle tissue and serum. (*P < 0.05, Wilcoxon signed rank exact test) All results are presented as mean ± standard deviation.