Biorelevant In Vitro Skin Permeation Testing and In Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System.

Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.8% or 5.4% lidocaine were applied to healthy volunteers' backs (n = 15) for 12 h in a single-center, open-label, four-treatment, four-period crossover pharmacokinetic study. Subjects were dosed with either three 1.8% systems or one, two, or three 5.4% systems in each period. Blood was collected for up to 48 h, and plasma lidocaine levels were measured with a validated HPLC method. In parallel, human and mouse skin models characterized the in vitro skin permeation profile. The pharmacokinetic profile was linear between one, two, and three lidocaine 5.4% applications. Application of three lidocaine 1.8% systems (108 mg lidocaine) was bioequivalent to one lidocaine 5.4% system (108 mg lidocaine). Both topical systems remained well adhered to the skin and irritation was mild. The 5.4% system had approximately threefold higher skin permeability than the 1.8% system in the mouse and human skin models. The results indicate increasing the drug load by three times results in triple the drug delivery both in vivo and in vitro. The relationship between the in vitro permeation and in vivo absorption correlates and is nonlinear.

A randomized, placebo-controlled trial of long-acting dexamethasone viscous gel delivered by transforaminal injection for lumbosacral radicular pain.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03372161.

Topical Delivery Systems Effectively Transport Analgesics to Areas of Localized Pain via Direct Diffusion.

Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido®, 1.8% lidocaine), and a topical pain relief gel (Pennsaid®, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido® (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain).

Open-Label Adhesion Performance Study of a Prescription Lidocaine Topical System 1.8% versus Three Lidocaine-Containing Over-the-Counter Patches in Healthy Subjects.

Purpose: This study evaluates and compares the clinical adhesion performance of a prescription lidocaine topical system 1.8% versus two different over-the-counter (OTC) lidocaine patches 4% and an OTC combination menthol and lidocaine patch 1%/4% in human subjects. Patients and Methods: This study was an open-label, randomized, four-treatment, four-sequence, Phase 1 adhesion performance study in healthy adult volunteers (N = 24). Lidocaine topical system 1.8% (R) and the three OTC patch products (T1, T2, and T3) were separately applied for 12 hours. Adhesion of all products was scored at 0, 3, 6, 8, and 12 hours post-application. Results: There were no issues with the conduct of the study. Overall, the majority (≥59.1%) of subjects treated ("patched") with the lidocaine topical system 1.8% (R) demonstrated ≥90% adhesion (FDA adhesion score 0) throughout the 12-hour administration period versus 27.3% of subjects treated with OTC lidocaine patch 4% (T1), 22.7% of subjects treated with OTC lidocaine patch 4% (T2), and 18.2% of subjects treated with OTC menthol/lidocaine patch 1%/4%. Only one subject (4.5%) treated with lidocaine topical system 1.8% was observed with <75% adhesion (FDA adhesion score <2) versus 11 (50.0%) and 10 (45.5%) for the two OTC lidocaine patches 4% (T1 and T2), respectively, and 13 (59.1%) subjects for the OTC menthol/lidocaine patch 1%/4%. There were no complete detachments observed for lidocaine topical system 1.8%, whereas 50.0% and 31.8% complete detachments were observed for the two OTC lidocaine patches 4% (T1 and T2), and 27.3% complete detachments were observed for the OTC menthol/lidocaine patch 1%/4%. No adverse events were observed for any of the treatments. Conclusion: Lidocaine topical system 1.8% demonstrated superior adhesion relative to the three lidocaine-containing OTC products over the 12-hour treatment period.

Safety of Epidural Steroid Injections for Lumbosacral Radicular Pain: Unmet Medical Need.

OBJECTIVE: Epidural steroid injections (ESIs) are a commonly utilized treatment for lumbosacral radicular pain caused by intervertebral disc herniation or stenosis. Although effective in certain patient populations, ESIs have been associated with serious complications, including paralysis and death. In 2014, the US Food and Drug Administration (FDA) issued a safety warning on the risk of injecting corticosteroids into the epidural space. The aims of this article were to review the neurological complications associated with ESIs and to compare the formulations, safety, and effectiveness of commercially available corticosteroids given by transforaminal, interlaminar, or caudal injection. METHODS: Serious adverse events associated with ESIs were identified by a search of the FDA Adverse Event Reporting System (FAERS) database. A MEDLINE search of the literature was conducted to identify clinical trials comparing the safety and effectiveness of nonparticulate and particulate corticosteroid formulations. RESULTS: Neurological complications with ESIs were rare and more often associated with the use of particulate corticosteroids administered by transforaminal injection. Among the 10 comparative-effectiveness studies reviewed, 7 found nonparticulate steroids had comparable efficacy to particulate steroids, and 3 studies suggested reduced efficacy or shorter duration of effect for nonparticulate steroids. DISCUSSION: The risk of complications for transforaminal ESI is greater with particulate corticosteroids. Nonparticulate corticosteroids, which are often recommended as first-line therapy, may have a short duration of effect, and many commercial formulations contain neurotoxic preservatives. The safety profile of ESIs may continue to improve with the development of safer, sterile formulations that reduce the risk of complications while maintaining efficacy.

A Randomized, Crossover, Adhesion Performance and Pharmacokinetic Study of a Lidocaine Topical System Under Conditions of Water Exposure in Healthy Subjects.

PURPOSE: This study compares the adhesion performance, pharmacokinetic profile, and safety of lidocaine topical system 1.8%, which is approved to treat postherpetic neuralgia, under conditions of swimming and showering versus normal conditions. PATIENTS AND METHODS: This open-label, 3-period, 3-treatment crossover study randomized 24 healthy adults to receive one lidocaine topical system during each of three treatment periods; subjects either swam in a heated swimming pool for 15 minutes 4.0 hours post-product application (swimming), showered for 10 minutes 8.0 hours after product application (showering), or the product remained dry throughout the treatment period (normal conditions). The product was applied to the mid-upper back and was removed after 12 hours. The pharmacokinetic profile of each subject under water exposure conditions was compared to subjects under normal conditions. Skin irritation, adhesion, and adverse events were assessed. RESULTS: Twenty-four (24) subjects enrolled and 23 completed the study. Exposure to water resulted in lifting of the topical systems. There were two complete detachments, as well as seven occurrences of major lifting (more than 50% detached) after water exposure. The topical systems were immediately pressed down and/or reapplied after observing lifting and remained adhered to for the rest of the 12-hour application period. No clinically relevant differences in systemic absorption were observed under either showering or swimming conditions. The topical systems were well tolerated, with only mild adverse events, none leading to discontinuation. CONCLUSION: These data show that while water exposure can cause the topical system to lift or detach, the lidocaine topical system 1.8% is capable of being reapplied and maintains adhesion for up to 12 hours of wear with no clinically significant changes in drug delivery. CLINICALTRIALSGOV: NCT04784728.

Open-Label Adhesion Performance Studies of a New Lidocaine Topical System 1.8% versus Lidocaine Patches 5% and Lidocaine Medicated Plaster 5% in Healthy Subjects.

PURPOSE: The primary objective was to evaluate adhesion performance of the lidocaine topical system 1.8% for 12 hours in healthy human subjects in three studies: as a single product (Study 1) and versus other lidocaine topical products (lidocaine patch 5% and lidocaine medicated plaster 5% [Study 2] and generic lidocaine patch 5% [Study 3]). Safety of the lidocaine topical system 1.8%, with a skin irritation focus, was a secondary objective. PATIENTS AND METHODS: All three studies were open-label, randomized, Phase 1 adhesion performance studies in healthy adult volunteers (N=125). Lidocaine topical products were applied for 12 hours per test, per study arm. Adhesion of all test products was scored at 0, 3, 6, 9, and 12 hours post-application. Skin irritation was scored after product removal or when a product detached. RESULTS: Overall, the majority (≥75%) of subjects treated with the lidocaine topical system 1.8% demonstrated ≥90% adhesion (FDA adhesion score 0) throughout the 12-hour administration period versus 13.6% of subjects treated with lidocaine patch 5%, 15.9% of subjects treated with lidocaine medicated plaster 5%, and 0% of subjects treated with the generic lidocaine patch 5%. There were no complete detachments with the lidocaine topical system 1.8%, whereas 4.5% of lidocaine patch 5% and lidocaine medicated plaster 5% detached, and 29% of generic lidocaine patch 5% detached. Minimal skin irritation was observed with each lidocaine topical product. CONCLUSION: Across three studies, lidocaine topical system 1.8% demonstrated superior adhesion performance versus the three other products tested. Skin irritation was minimal across products and studies. CLINICALTRIALSGOV: NCT04312750, NCT04320173, NCT04319926.

A Randomized, Crossover, Pharmacokinetic and Adhesion Performance Study of a Lidocaine Topical System 1.8% During Physical Activity and Heat Treatment in Healthy Subjects.

PURPOSE: This study compares the pharmacokinetic (PK) profile, adhesion, and safety of lidocaine topical system 1.8%, a novel lidocaine topical system approved to treat postherpetic neuralgia, under conditions of heat and exercise vs normal conditions. MATERIALS AND METHODS: This open-label, 3-period, 3-treatment crossover study randomized 12 healthy adults to receive three lidocaine topical systems 1.8% during each of three treatment periods, with 7-day washouts between treatments. The product was applied to the mid-lower back and was removed after 12 hours. During Treatment A, subjects exercised on a bicycle for 30 minutes at 0, 2.5, 5.5, and 8.5 hours. During Treatment B, heat (temperature set at 36.7-40.3°C) was applied at 0 and 8.5 hours. Treatment C was normal conditions. The PK profile of each subject under exercise and heat conditions was compared to normal conditions. Skin irritation, adhesion, and adverse events were assessed. RESULTS: Twelve subjects completed the study. Exposure to external heat resulted in increased peak plasma concentration of lidocaine with a mean Cmax of 160.3±100.1 ng/mL vs 97.6±36.9 ng/mL under normal conditions, with no effect on the extent of exposure (AUC). Concentrations returned to normal within 4 hours after the heat was removed. No clinically relevant differences in absorption were observed under exercise conditions with a mean Cmax of 90.5±25.4 ng/mL and no effect on the extent (AUC) of lidocaine exposure was observed relative to normal conditions. No systems detached during the study. Adverse events were mild, with none leading to discontinuation. CONCLUSION: Transient heat exposure resulted in increased lidocaine plasma concentrations compared to normal conditions, whereas exercise had no effect. The effects of heat appear to be immediate, reversible, and below systemic therapeutic threshold in antiarrhythmic treatment (1000-1500 ng/mL), and well below the safe systemic threshold of 5000 ng/mL. Lidocaine topical system 1.8% remained adhered to the skin and was well tolerated under all conditions. ClinicalTrials.gov: NCT04150536.

A Randomized, Open-Label, Bioequivalence Study of Lidocaine Topical System 1.8% and Lidocaine Patch 5% in Healthy Subjects.

PURPOSE: This study was designed to characterize drug delivery with lidocaine topical system 1.8% vs lidocaine patch 5% through 2 PK studies. PATIENTS AND METHODS: Two Phase 1, single-center, open-label, randomized PK studies were performed in healthy adults. In Study 1, 56 subjects received a single intravenous bolus of 0.7 mg/kg of lidocaine as a lead-in to allow for the accurate determination of apparent dose of both products. After a 7-day washout period, subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours followed by another 7-day washout period, after which subjects crossed over to receive the other treatment for 12 hours. In Study 2, 54 subjects were randomized to receive either lidocaine topical system 1.8% or lidocaine patch 5% for 12 hours. After a 7-day washout period, subjects crossed over to receive the other treatment. Adhesion and skin irritation assessments were performed after application of the products in Study 2. In both studies, serial blood samples were collected to measure the plasma concentration of lidocaine after product application. Safety assessments and adverse events were monitored in both studies. RESULTS: The comparative PK analysis demonstrated that the two products, despite their difference in drug load and strength, are bioequivalent. Both products were well tolerated. In Study 2, dermal response scores (skin tolerability after removal) were similar between lidocaine topical system 1.8% and lidocaine patch 5%, with a mean irritation score per patch <1 (barely perceptible erythema), which is not considered to be clinically significant. CONCLUSION: Bioequivalence was demonstrated between lidocaine topical system 1.8% and lidocaine patch 5%. A comparison of the single-time adhesion scores at 12 hours in Study 2 favored lidocaine topical system 1.8% over lidocaine patch 5%. Both products were well tolerated as a single application in healthy adult human subjects. CLINICALTRIALSGOV: NCT04144192, NCT04149938.