Nicotine Transdermal Systems Research Articles

Technical Note: Comparison of USP Apparatus 5 and 7 for In Vitro Drug Release from Nicotine Transdermal Systems

Technical Note: Comparison of USP Apparatus 5 and 7 for In Vitro Drug Release from Nicotine Transdermal Systems

In vitro–in vivo correlations for nicotine transdermal delivery systems evaluated by both in vitro skin permeation (IVPT) and in vivo serum pharmacokinetics under the influence of transient heat application

The in vitro permeation test (IVPT) has been widely used to characterize the bioavailability (BA) of compounds applied on the skin. In this study, we performed IVPT studies using excised human skin (in vitro) and harmonized in vivo human serum pharmacokinetic (PK) studies to evaluate the potential in vitro–in vivo correlation (IVIVC) of nicotine BA from two, matrix-type, nicotine transdermal delivery systems (TDS). The study designs used for both in vitro and in vivo studies included 1h of transient heat (42±2°C) application during early or late time periods post-dosing. The goal was to evaluate whether any IVIVC observed would be evident even under conditions of heat exposure, in order to investigate further whether IVPT may have the potential to serve as a possible surrogate method to evaluate the in vivo effects of heat on the bioavailability of a drug delivered from a TDS. The study results have demonstrated that the BA of nicotine characterized by the IVPT studies correlated with and was predictive of the in vivo BA of nicotine from the respective TDS, evaluated under the matched study designs and conditions. The comparisons of single parameters such as steady-state concentration, heat-induced increase in partial AUCs and post-treatment residual content of nicotine in TDS from the in vitro and in vivo data sets showed no significant differences (p≥0.05). In addition, a good point-to-point IVIVC (Level A correlation) for the entire study duration was achieved by predicting in vivo concentrations of nicotine using two approaches: Approach I requiring only an in vitro data set and Approach II involving deconvolution and convolution steps. The results of our work suggest that a well designed IVPT study with adequate controls can be a useful tool to evaluate the relative effects of heat on the BA of nicotine from TDS with different formulations.

A fully validated LC-MS/MS method for simultaneous determination of nicotine and its metabolite cotinine in human serum and its application to a pharmacokinetic study after using nicotine transdermal delivery systems with standard heat application in adult smokers.

A sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous determination of nicotine and its main metabolite cotinine in human serum samples. Liquid-liquid extraction using ethyl acetate was employed for serum sample extractions. Chromatographic separation was achieved on Phenomenex Luna(®) HILIC column (150 mm x 3.0mm, 5 μm). Isocratic elution was performed using acetonitrile:100mM ammonium formate buffer (pH=3.2) (90:10, v/v) as the mobile phase, at a flow rate of 0.4 mL/min. Tandem mass spectrometric detection was employed at positive electrospray ionization in MRM mode for the determination of both nicotine and cotinine and their stable isotope labeled internal standards. Analysis was carried out in 8 min over a concentration range of 0.26-52.5 ng/mL and 7.0-1500 ng/mL for nicotine and cotinine, respectively. The assay was validated according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained; the accuracy ranged between 93.39% and 105.73% for nicotine and between 93.04% and 107.26% for cotinine. No significant matrix effect was observed. Stability assays indicated both nicotine and cotinine were stable during sample storage, preparation and analytical procedures. The method was successfully applied to biological samples obtained from a pharmacokinetic study conducted in adult smokers to investigate heat effect on nicotine and cotinine serum levels after nicotine transdermal delivery system (TDS) application.

Molecularly imprinted polymers as nicotine transdermal delivery systems

Abstract The aim of the present study was to prepare molecularly imprinted polymers (MIPs) with nicotine as the template drug and to evaluate the feasibility of these materials as excipients for the controlled transdermal delivery of nicotine. To achieve this goal, MIPs were synthesised by a free radical polymerisation method using methacrylic acid as the monomer and ethylene glycol dimethacrylate as the cross-linker. Polymer particles were prepared and included in transdermal systems with vehicles of different polarities. Characterisation studies employed the appropriate techniques, such as scanning electron microscopy, infrared spectroscopy and thermal analysis, to study the morphology of the particles, drug–polymer interactions and compatibility. Based on the results, in the MIP particles, non-covalent drug–polymer interactions were established by nicotine adsorption, mainly in non-polar vehicles. The drug release kinetics was fitted to Higuchi model, indicating drug diffusion from polymer matrix. Additionally, the diffusion of the drug from the polymer matrix can be modified by selective sites in the imprinted polymer carrier. Therefore, MIPs can be considered as suitable candidates for the controlled transdermal administration of nicotine.

Semipermeable Membrane Dressings Can be Used with the Nicotine Transdermal System and Do Not Interfere with Nicotine Absorption

Adverse skin reactions as a local side effect of nicotine patches sometimes interfere with smoking cessation therapy. We studied the effects of semipermeable membrane dressings (SMD) used under nicotine patches (NP) on nicotine absorption, as assessed according to the urinary cotinine levels, and skin symptoms. First, the urinary cotinine levels were compared in eight nonsmokers that applied NP over SMD and NP without SMD (Study 1). The urinary cotinine levels were measured using a highly sensitive competitive enzyme immunoassay. Second, 28 subjects undergoing NP therapy for diagnosed nicotine dependence were randomly assigned into two groups in a crossover design to receive NP over SMD and NP without SMD. The urinary cotinine levels and skin symptoms were compared between the two treatment groups. During the follow-up period of 48 weeks, the smoking cessation rate was evaluated (Study 2). No statistical differences were observed in the urinary cotinine levels between the NP over SMD and NP without SMD groups. In Study 2, the skin symptoms improved with the use of SMD in 42.8% (6/14) of the patients and worsened in 28.5% (4/14) of the patients. No serious skin disorders were reported. The subjects followed in Study 2 exhibited smoking cessation rates of 92.8%, 78.5% and 64.2% at 12, 24 and 48 weeks, respectively. The use of NP over SMD is a safe and effective alternative application to NP treatment for preventing the skin symptoms caused by NP without interfering with nicotine absorption.

Pharmacokinetic comparison of two nicotine transdermal systems, a 21-mg/24-hour patch and a 25-mg/16-hour patch: A randomized, open-label, single-dose, two-way crossover study in adult smokers

Background: A comparison of the 21-mg NiQuitin patch with other marketed nicotine patches reported significant differences in pharmacokinetic profiles, even among patches of the identical labeled dose strength. The 25-mg Nicorette Invisi patch became available in the United Kingdom at the end of 2008. No published studies have directly compared the pharmacokinetic profile of this new patch with that of the 21-mg NiQuitin patch. Objectives: This study was conducted to compare the single-dose pharmacokinetics of the 21-mg/24-hour patch and the 25-mg/16-hour patch. To determine whether any pharmacokinetic differences might be related to differences in wear time, a post hoc exploratory analysis evaluated the nicotine delivery profiles of the patches under the assumption that the 21-mg patch was removed after 16 rather than 24 hours. Methods: This was a single-center, randomized, open-label, single-dose, 2-way crossover study in healthy adults who smoked >10 cigarettes per day in the 6 months before the study. Eligible subjects were housed at the study center for 2 baseline and 2 treatment sessions; no smoking was permitted during the baseline or treatment sessions. Subjects were allocated to receive either the 21-mg patch (removed after 24 hours) or the 25-mg patch (removed after 16 hours) during the first treatment session, after which they crossed over to the alternative sequence in the second treatment session. Blood samples were obtained at predetermined time points before and after patch application. The primary pharmacokinetic parameter was the AUC 0−∞, an indication of total nicotine exposure. Secondary pharmacokinetic parameters included AUC 0−t, C max, and T max. Post hoc exploratory parameters were the AUC 0–16 and the AUC 0−∞ assuming a 16-hour application time for the 21-mg patch. The differences in AUC 0−∞, AUC 0−t, Cmax, AUC 0−16, and AUC 0−∞ assuming a 16-hour application time for the 21-mg patch were considered significant if the lower limit of the 90% CI for the geometric mean ratio (21 mg:25 mg) was >100%. T max values were compared using a signed-rank test. Adverse events were elicited using a standard open-ended question on each day of confinement; spontaneously reported events were also captured. The topical effects of the patch (erythema; edema; extent of erythema/papules/pustules; self-reported pruritus) were assessed by study staff before patch application and 1 and 8 hours after patch application using a 4-point rating scale; any topical effects were recorded as adverse events. Results: Fifty otherwise healthy smokers (29 men, 21 women) were enrolled; 47 (94%) were white. Their mean (SD) age was 31.5 (9.57) years (range, 20–53 years), mean weight was 70.24 (9.56) kg (range, 51.0–95.9 kg), and mean height was 173.0 (8.02) cm (range, 156–194 cm). Subjects reported smoking between 11 and 40 cigarettes per day before the study. The AUC 0−∞ was significantly higher for the 21-mg patch worn for 24 hours than for the 25-mg patch worn for 16 hours (382.36 vs 243.69 ng/mL · h, respectively; geometric mean ratio: 156.90%; 90% CI, 148.10%–166.23%; P < 0.001). T max was reached significantly sooner with the 21-mg patch than with the 25-mg patch (6.0 vs 12.0 hours; P < 0.001). C max was significantly higher for the 21-mg patch compared with the 25-mg patch (18.34 vs 16.56 ng/mL; geometric mean ratio: 110.72%; 90% CI, 104.82%–116.94%; P < 0.01). The exploratory analyses suggested that the 21-mg patch applied for 16 hours may provide greater total nicotine exposure than the 25-mg patch applied for 16 hours. Although most subjects reported adverse events (75.0% with the 21-mg patch, 89.8% with the 25-mg patch), the majority of these events were mild. Conclusions: In this single-dose study in adult smokers, the 21-mg patch was associated with significantly greater nicotine exposure compared with the 25-mg patch. The 21-mg patch provided a maximal nicotine concentration faster than did the 25-mg patch.

Effects of smoking on the pharmacokinetics and pharmacodynamics of a nicotine patch

The effect of smoking on the pharmacokinetics and pharmacodynamics of a nicotine transdermal delivery system, administered as a single dose or multiple doses, was examined in smokers (n=12) and nonsmokers (n=12). The study was a two-period, parallel trial. In the first period, a single dose of the Nicotinell TTS 20 patch was administered, followed by a 1-week washout period. Then, in the second period, multiple doses of the Nicotinell TTS 20 patch were administered over 4 days. Regarding the pharmacokinetics of nicotine, the AUC(36 h) and AUC(tau) of smokers were about 20% and 40% greater, respectively, than those of nonsmokers. Significant differences in heart rate were observed between smokers and nonsmokers at 10, 12, 16 and 24 h, and significant differences in systolic blood pressure were seen between smokers and nonsmokers at 12, 30 and 36 h in the single-dose study. With multiple doses, significant differences in systolic and diastolic blood pressures were detected between smokers and nonsmokers only at 72.5 and 82 h. Here, it is demonstrated for the first time that the pharmacokinetic and hemodynamic effects of a nicotine patch are significantly different between smokers and nonsmokers.

Pharmacokinetic evaluation of a developed nicotine transdermal system

The plasma concentration time profiles for nicotine were characterized after a single application of nicotine transdermal system to the upper fore arm of healthy smokers. A 12 cm2 system was applied for 24 h. Blood samples were withdrawn at predetermined time intervals. Plasma nicotine concentrations rose rapidly and achieved a mean Cmax value of 14.5 ng/ml .The half life was estimated as 4.78 h and AUC(0-24)181.0 ng.h/ ml. The nicotine transdermal system was well tolerated. The results indicate that the system has potential usefulness in smoking cessation. The pharmacokinetic profiles of marketed patch system was compared with the developed system. Significant difference was observed in the pharmacokinetic parameters.

생체내 예측 및 흰쥐를 이용한 니코틴 패취의 약물동력학적 평가

Nicotine transdermal therapeutic systems have been regarded as an effective mean to aid smoking cessation. However, most of nicotine in the market have some problems such as unpleasant side effects and skin irritation due to the excess amount of the drug permeated and the properties of the additives employed. In order to solve these problems, new nicotine were formulated using biocompatible additives. The optimized formula of the drug layer consisted of nicotine, propylene glycol and poloxamer 188 at the ratio of 1.2: 17.0: 2.0. The drug layer had the sickness of , the pH of 8.12. The skin permeation rate of nicotine from optimized nicotine patch (NP) was . Transdermal administration of nicotine patch has been carried out for the determination of pharmacokinetic parameters in rats. Steady-state plasma concentration of nicotine following transdermal application of NP (area of patch = ) on the dorsal skin of rats was 143.2 ng/ml and AUC for 24 hrs was 3,022 ng h/ml. In case of and Nicotinell , the steady-state plasma concentration of nicotine and ACU for 24 hrs were 428.9 ng/ml, and 155.3 ng/ml, , respectively. NP showed the experimental plasma nicotine concentration profile was very similar to the simulated one and had an appropriate skin permeation rate and a steady-state concentration of nicotine, which can show therapeutic blood levels of the drug for 24 hrs without severe side effects.

Effect of exercise on transdermal nicotine release in healthy habitual smokers

Transdermal nicotine patches have become a frequently prescribed tool in smoking cessation programs during the past years. However, there is circumstantial evidence that transdermal nicotine release substantially varies with physical activity producing toxic plasma concentrations that may account for severe adverse events. We, therefore, compared nicotine release from two different transdermal nicotine systems (TDNS) at rest and during strenuous physical activity in a two-period crossover study in healthy smokers (n = 10). The subjects were randomly assigned to receive either 21 mg/day of formulation A or B on study Day 1 and 2. Patches were applied eight hours before starting standardized physical activity, and nicotine concentrations were measured in plasma and topically in the tissue layers underneath the application site by microdialysis. There was no difference between groups in the mean values for area under the time-concentration curve at rest from 0 - 8 hours AUC(0-8) (p < 0.799) and during exercise from 8 - 11 hours AUC(8-11) (p < 0.878). C(max) values between groups with C(max) values of 16.4 +/- 9.5 ng/ml and 16.0 +/- 10.7 ng/ml at rest (p < 0.919, NS) and 10.05 +/- 6.8 ng/ml and 10.2 +/- 6.9 ng/ml (p < 0.959, NS) during exercise did not differ significantly. Nicotine tissue concentrations increased two-fold during exercise versus baseline (p < 0.878). Skin blood flow increased significantly during exercise compared with baseline (p < 0.001). No adverse events were observed. The present study provides evidence that transdermal nicotine release from TDNS increases during exercise. However, this increase has no significant effect on overall plasma pharmacokinetics. Our pharmacokinetic data further indicate that the two TDNS formulations are equivalent during conditions of rest and exercise.

An In-Vitro Iontophoretic Permeation Study of Nicotine through Rat Skin

Nicotine transdermal systems are being used as an aid to smoking cessation programs. As the kinetics of nicotine delivery is important in success of a smoking cessation program, rapid and high input of nicotine is required, which is not possible by passive methods and requires enhancement strategies such as iontophoresis. Iontophoretic permeation, of nicotine looks promising, based on published data on human skin. However, to optimize this method, permeation pathways should be known and further parameters have to studied, which are the subject of the present investigation. In this study iontophoretic permeation of nicotine through rat skin was performed and the effects of different variables on this phenomenon were studied. Anodic iontophoresis of nicotine from a solution at pH 2.8, using a 0.5 mA/cm2 current density resulted in a considerable enhancement (about 3-fold) of nicotine absorption through rat skin. Nicotine concentration and current density showed a directly increasing effect on permeation of the drug, but the effect of concentration was not linear. Pulsatile current delivery was more effective in permeation of nicotine than the continuous method. Anodic iontophoresis was around 2-fold more effective than the cathodic method in increasing the flux. Post iontophoretic permeation studies showed good reversibility of the membrane barrier properties. Results were in good agreement with the reported human data and might be considered as an evidence of the ability of rat skin to model human skin and also the importance of intercellular pathway of the stratum corneum in iontophoretic delivery of nicotine and possibly other drugs. Donor's pH showed no effect on permeation of nicotine under the studied conditions, pH values of

Nicotine transdermal systems: pharmaceutical and clinical aspects.

Smoking is creating a burden on the healthcare budgets all over the world. Management of nicotine dependence is difficult due to the so-called pleasurable effects experienced by smokers. Among the various treatment approaches, nicotine replacement therapy, where nicotine from cigarettes is replaced with nicotine from a relatively safer delivery vehicle, has been successful. Transdermal delivery of nicotine is an effective type of nicotine replacement therapy due to inherent pharmacokinetic advantages over other routes of delivery. Several nicotine transdermal delivery systems are available to suit the varying needs of smokers and have been found to be clinically patient friendly and well tolerated. This review focuses on the various clinical and pharmaceutical aspects of nicotine with special emphasis on transdermal delivery systems.

Treatment of spit tobacco users with transdermal nicotine system and mint snuff.

The purpose of this study was to examine the effects of nicotine patch and mint snuff (a nonnicotine product) on craving, withdrawal symptoms, and treatment outcome. This study involved a 2 x 2 factorial design, with Active Nicotine Versus Placebo Patch as one of the factors and Mint Snuff Versus No Mint Snuff as the other factor. Spit tobacco users (N = 402, n = 100-101 in each condition) were randomly assigned to 1 of the 4 treatment conditions for a period of 10 weeks. Treatment outcome was measured up to 62 weeks. The results showed that the nicotine patch was effective in increasing short-term abstinence over the placebo patch and in reducing craving and withdrawal signs and symptoms from spit tobacco. Although mint snuff was not effective in enhancing treatment outcome, it reduced craving and withdrawal symptoms. No interaction effects were observed. At this time, the use of the nicotine patch and mint snuff should be primarily considered for the reduction of craving and withdrawal symptoms.

Treatment of spit tobacco users with transdermal nicotine system and mint snuff.

Treatment of spit tobacco users with transdermal nicotine system and mint snuff.

Does Abstinence from Smoking or a Transdermal Nicotine System Influence Atracurium-Induced Neuromuscular Block?

Does Abstinence from Smoking or a Transdermal Nicotine System Influence Atracurium-Induced Neuromuscular Block?

Does Abstinence from Smoking or a Transdermal Nicotine System Influence Atracurium-Induced Neuromuscular Block?

Does Abstinence from Smoking or a Transdermal Nicotine System Influence Atracurium-Induced Neuromuscular Block?

Transdermal nicotine system prevents the abstinence-induced sensitivity to atracurium in smokers

Transdermal nicotine system prevents the abstinence-induced sensitivity to atracurium in smokers

Pharmacokinetics of a 16-Hour Transdermal Nicotine Patch

A nicotine transdermal delivery system (NTDS) designed to deliver 15 mg/16 hours (Nicotrol®) was applied to 40 healthy smoking volunteers in 3 separate studies: A single administration to different body sites, a multiple-dose study with 16-hour repeated application for 6 days, and a single-dose study with a 16-hour versus a 24-hour application period. The resulting plasma nicotine concentration profiles were similar after application to the arm or the hip with maximum nicotine concentrations of approximately 13 µg/L attained after 8 to 10 hours. The nicotine half-life after removal of the patch was approximately 4 hours. When applying the NTDS daily for a 16-hour period, nicotine stored in a shallow skin compartment was emptied during the nonapplication night-time period, and the repeat-dose study over 6 days showed no accumulation of plasma nicotine. Compared with an average nicotine intake of 15 mg/16 hours when applying NTDS according to recommendation, wearing it for 24 hours resulted in an additional nicotine release of only 2 to 3mg. This profile of nicotine release lends support to the idea of Nicotrol® being a daytime (16-hour) delivery system. Pharmacokinetic simulation indicated that the transdermal system itself determines the flux so an increase in cutaneous blood flow would have no major influence on the nicotine plasma concentration-time profile.

Tobacco control: reducing cancer incidence and saving lives. American Society of Clinical Oncology.

The American Society of Clinical Oncology (ASCO) supports the elimination of tobacco products. Toward that goal, ASCO urges the adoption of national policy that strengthens regulation of the sale, promotion, and distribution of such products. To reduce cancer mortality, our regulatory policies must recognize that the nicotine within tobacco is an addictive substance, the use of which leads to 30% of all cancer deaths and a total of 419,000 deaths each year. Tobacco-related advertising and promotion should be banned. At a minimum, national policies should: ban billboards; limit advertising to black and white text only; prohibit the sale or giveaway of products that contain tobacco brand names or logos; prohibit brand name sponsorship of sporting or entertainment events; and require stronger and more prominent warning labels on all tobacco products. Despite existing state laws prohibiting sale of tobacco products to minors, children are able to buy such products easily. National regulation of the sale and distribution of tobacco products is necessary to eliminate children's access to tobacco. Where sales are permitted, they should be limited to face-to-face purchases by individuals 18 and older. Vending machines and other means of distributing tobacco without a face-to-face purchase should be outlawed. To the extent tobacco sales are allowed to continue, the federal government should mandate that the tobacco industry contribute substantial funds for a national public education campaign to prevent young people from smoking and other tobacco use. ASCO has long advocated a substantial increase (in the range of $2) in the federal excise tax on cigarettes and other tobacco products- a measure known to decrease consumption, particularly among children. Revenue from a tax on tobacco products should be used to support retraining for tobacco farmers, biomedical research, health care delivery, and antitobacco education. United State trade policies should discourage the export of tobacco products and manufacturing to foreign markets. At a minimum, United States tobacco companies selling or manufacturing tobacco products in foreign markets that have not developed comparable health warning labels should be required to retain United States warning labels. Physicians, nurses, and other health care professionals-especially those in primary care disciplines-have the opportunity and responsibility to assist patients' efforts to quit tobacco use and to ensure that nonsmokers continue to avoid the addiction. Oncology specialists should discuss the causal relationship between tobacco use and cancer as well as a variety of other chronic diseases and assist, as required, the patient and family members to end tobacco dependency. In addition, health care professionals must advocate that public and private insurers be required to provide health care coverage for medically necessary interventions, such as counseling and nicotine transdermal systems.

Comparison of the Nicotine Pharmacokinetics of Nicoderm (Nicotine Transdermal System) and Half‐Hourly Cigarette Smoking

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half-hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half-hourly intervals on days 1 and 5; ad libitum smoking on days 2-4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.