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Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis.

ABSTRACT: A combined experimental and computational model approach was developed to assess heat effects on drug delivery from transdermal delivery systems (TDSs) in vitro and nicotine was the model drug. A Franz diffusion cell system was modified to allow close control of skin temperature when heat was applied from an infrared lamp in vitro. The effects of different heat application regimens on nicotine fluxes from two commercial TDSs across human cadaver skin were determined. Results were interpreted in terms of transport parameters estimated using a computational heat and mass transport model. Steady-state skin surface temperature was obtained rapidly after heat application. Increasing skin surface temperature from 32 to 42°C resulted in an approximately 2-fold increase in average nicotine flux for both TDSs, with maximum flux observed during early heat application. ANOVA statistical analyses of the in vitro permeation data identified TDS differences, further evidenced by the need for a two-layer model to describe one of the TDSs. Activation energies associated with these data suggest similar temperature effects on nicotine transport across the skin despite TDS design differences. Model simulations based on data obtained from continuous heat application were able to predict system response to intermittent heat application, as shown by the agreement between the simulation results and experimental data of nicotine fluxes under four different heat application regimens. The combination of in vitro permeation testing and a computational model provided a parameter-based heat and mass transport approach to evaluate heat effects on nicotine TDS delivery.

SUBMITTER: La Count TD

PROVIDER: S-EPMC7644264 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeSince electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of drugs for intra-articular indications. Our aim was to compare the anti-inflammatory and analgesic efficacy of EP-combined topical administration of diclofenac sodium hydrogel (50 mg mL-1 in 230 µL volume) with that of an equivalent dose of oral (75 mg kg-1) and simple topical administration.MethodsArthritis was induced with the injection of 2% λ-carrageenan and 4% kaolin into the right knee joints of male Sprague Dawley rats. EP was applied for 8 min with 900 V high-voltage pulses for 5 ms followed by a 20 ms break. Drug penetration into the synovial fluid and plasma was detected by high-performance liquid chromatography. Leukocyte-endothelial interactions were visualized by intravital videomicroscopy on the internal surface of the synovium. Inflammation-induced thermal and mechanical hyperalgesia reactions, knee joint edema, and inflammatory enzyme activities were assessed at 24 and 48 h after arthritis induction.ResultsEP significantly increased the plasma level of diclofenac as compared with the topical controls 10 min after the 2% λ-carrageenan and 4% kaolin injection. Increased leukocyte-endothelial interactions were accompanied by joint inflammation, which was significantly reduced by oral and EP diclofenac (by 45% and by 30%, respectively) and only slightly ameliorated by simple topical diclofenac treatment (by 18%). The arthritis-related secondary hyperalgesic reactions were significantly ameliorated by oral and EP-enhanced topical diclofenac treatments. The knee cross-section area (which increased by 35%) was also reduced with both approaches. However, simple topical application did not influence the development of joint edema and secondary hyperalgesia.ConclusionThe study provides evidence for the first time of the potent anti-inflammatory and analgesic effects of EP-enhanced topical diclofenac during arthritis. The therapeutic benefit provided by EP is comparable with that of oral diclofenac; EP is a useful alternative to conventional routes of administration.

Project description:IntroductionA mandated reduction in the nicotine content of cigarettes may decrease smoking, but also increase demand for other nicotine products. The present study tested the impact of smoking cigarettes with very low nicotine content and concurrent use of a transdermal nicotine patch.Study designA balanced 2 × 2 factorial randomized clinical trial investigating the impact of cigarette nicotine content (double-blind, very low nicotine content versus normal nicotine content) and use of a transdermal nicotine patch (open label, patch versus no patch).Setting/participantsAdult daily smokers (n=240) in the Pittsburgh, PA area.InterventionParticipants were provided with research cigarettes and transdermal nicotine patches (if assigned to patch condition) for 7 weeks. Cigarettes were Spectrum brand (National Institute on Drug Abuse) and either 15.8 mg nicotine/g tobacco (normal nicotine content) or 0.4 mg nicotine/g tobacco (very low nicotine content). In the 7th week, participants were monetarily incentivized to abstain from smoking.Main outcome measuresParticipants reported daily cigarette use throughout the trial and the primary outcome was average number of cigarettes smoked per day (study + nonstudy) during Week 6. Participants were recruited from 2015 to 2017 and data were analyzed between 2017 and 2018.ResultsAssignment to very low nicotine content cigarettes and assignment to wear a nicotine patch both reduced the number of cigarettes smoked per day during Week 6 (p=0.001 and 0.04, respectively). However, assignment to the patch along with very low nicotine content cigarettes did not significantly reduce cigarette smoking compared with assignment to very low nicotine content cigarettes alone.ConclusionsA mandated reduction in the nicotine content of cigarettes is likely to reduce the number of cigarettes smoked per day, but the added benefit of concurrent transdermal nicotine is unclear. Future studies should investigate whether alternative sources of noncombusted tobacco, such as e-cigarettes, enhance the effects of very low nicotine content cigarettes on smoking.Trial registrationThis study is registered at www.clinicaltrials.gov NCT02301325.

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Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis.

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