Examination of the Rate and Extent of Drug Released from Commercial Topical Delivery Systems During Wear: An Example with Lidocaine Topical Systems.

OBJECTIVE: This study aimed to determine the extent and rate of lidocaine released in vivo from two bioequivalent topical delivery systems (TDS) by using complementary assessments: pharmacokinetic analysis in healthy human volunteers, and residual lidocaine in TDS following 12 h of wear. The goal was to explore a potentially more clinically meaningful strength presentation than percent active pharmaceutical ingredient loaded in topical systems. METHODS: A three-arm, open-label, crossover clinical study was conducted in 23 human subjects, with 5% lidocaine topical systems from two manufacturers, and intravenous lidocaine administration. Residual drug and LC-MS/MS analyses were performed on worn TDS and serum samples. The rate and extent of drug released from the TDS during wear were determined through (1) calculations of consumed lidocaine via analysis of residual drug in worn TDS, and (2) a pharmacokinetic approach via derivation of the absolute clearance and serum lidocaine concentration at steady state. RESULTS: Overall the pharmacokinetic approach underestimated the amount transferred to the subject and exhibited greater variability, which may relate to natural inter-subject variability in pharmacokinetic parameters. Further, lidocaine TDS are intended for localized, not systemic, delivery and this may also explain some of the variability seen in the systemic serum concentrations. CONCLUSIONS: The residual drug and pharmacokinetic approaches align well for transdermal formulations, but the differences in administration route (topical versus transdermal) all but eliminates the potential use of the pharmacokinetic approach unless additional compartmental modeling is explored.

Use of Artificial Intelligence to Improve the Calculation of Percent Adhesion for Transdermal and Topical Delivery Systems.

Adhesion is a critical quality attribute and performance characteristic for transdermal and topical delivery systems (TDS). Regulatory agencies recommend in vivo skin adhesion studies to support the approval of TDS in both new drug applications and abbreviated new drug applications. The current assessment approach in such studies is based on the visual observation of the percent adhesion, defined as the ratio of the area of TDS attached to the skin to the total area of the TDS. Visually estimated percent adhesion by trained clinicians or trial participants creates variability and bias. In addition, trial participants are typically confined to clinical centers during the entire product wear period, which may lead to challenges when translating adhesion performance to the real world setting. In this work we propose to use artificial intelligence and mobile technologies to aid and automate the collection of photographic evidence and estimation of percent adhesion. We trained state-of-art deep learning models with advanced techniques and in-house curated data. Results indicate good performance from the trained models and the potential use of such models in clinical practice is further explored.

Raman mapping of fentanyl transdermal delivery systems with off-label modifications.

Raman mapping is a powerful and emerging tool in characterization of pharmaceuticals and provides non-destructive chemical and structural identification with minimal sample preparation. One pharmaceutical form that is suitable but has not been studied in-depth with Raman mapping is transdermal delivery systems (TDS). TDS are dosage forms designed to deliver a therapeutically effective amount of active pharmaceutical ingredient (API) across a patient's skin. To enhance drug delivery through the skin, the API in the formulation is often close to a saturated or supersaturated state. Thus, improper use or off-label modifications can lead to occurrence of unwanted API changes, specifically, crystallization over time. Here, off-label modifications were mimicked on a set of fentanyl drug-in-adhesive TDS sold on the U.S. market by four different manufacturers via die cutting, and then the die cut TDS were investigated through confocal Raman mapping for structural and chemical changes. Using Multivariate Curve Resolution (MCR), not only was morphological and chemical characterization of transdermal systems provided, but also fentanyl crystals in certain products due to off-label modifications were identified. The chemometric model used in analysis of Raman maps allowed precise identification of fentanyl as the crystalline material as confirmed by the hit-quality-index correlation of component spectra from the chemometric model with library spectra of a fentanyl reference standard. The results show that confocal Raman mapping with MCR can be utilized in assessing pharmaceutical quality of TDS. This method has the potential to be widely used in characterization of such systems as an alternative to existing techniques.

Determination of Rate and Extent of Scopolamine Release from Transderm Scop® Transdermal Drug Delivery Systems in Healthy Human Adults.

To estimate strength of a scopolamine transdermal delivery system (TDS) in vivo, using residual drug vs. pharmacokinetic analyses with the goal of scientifically supporting a single and robust method for use across the dosage form and ultimately facilitate the development of more consistent and clinically meaningful labeling. A two-arm, open-label, crossover pharmacokinetic study was completed in 26 volunteers. Serum samples were collected and residual scopolamine was extracted from worn TDS. Delivery extent and rate were estimated by (1) numeric deconvolution and (2) steady-state serum concentration determined from graphical and non-compartmental analyses. In residual drug analyses, mean ± SD scopolamine release rate was 0.015 ± 0.002 mg/h (11% RSD), vs. 0.016 ± 0.006 mg/h (35% RSD) from numeric deconvolution, 0.015 ± 0.005 mg/h (34% RSD) from graphical analysis, and 0.015 ± 0.007 mg/h (44% RSD) from non-compartmental analysis. In residual drug analyses, total drug released was 1.09 ± 0.11 mg (10% RSD), vs. 1.12 ± 0.40 mg (35% RSD) from numeric deconvolution, 1.07 ± 0.35 mg (33% RSD) from graphical analysis, and 1.07 ± 0.45 (42% RSD) from non-compartmental analysis. Extent and rate of scopolamine release were comparable by both approaches, but pharmacokinetic analysis demonstrated greater inter-subject variability.

The Sensitivity of In Vitro Permeation Tests to Chemical Penetration Enhancer Concentration Changes in Fentanyl Transdermal Delivery Systems.

Chemical penetration enhancers (CPEs) are frequently incorporated into transdermal delivery systems (TDSs) to improve drug delivery and to reduce the required drug load in formulations. However, the minimum detectable effect of formulation changes to CPE-containing TDSs using in vitro permeation tests (IVPT), a widely used method to characterize permeation of topically applied drug products, remains unclear. The objective of the current exploratory study was to investigate the sensitivity of IVPT in assessing permeation changes with CPE concentration modifications and subsequently the feasibility of IVPT's use for support of quality control related to relative CPE concentration variation in a given formulation. A series of drug-in-adhesive (DIA) fentanyl TDSs with different amounts of CPEs were prepared, and IVPT studies utilizing porcine and human skin were performed. Although IVPT could discern TDSs with different amounts of CPE by significant differences in flux profiles, maximum flux (Jmax) values, and total permeation amounts, the magnitudes of the CPE increment needed to see such significant differences were very high (43-300%) indicating that IVPT may have limitations in detecting small changes in CPE amounts in some TDSs. Possible reasons for such limitations include formulation polymer and/or other excipients, type of CPE, variability associated with IVPT, skin type used, and disrupted stratum corneum (SC) barrier effects caused by CPEs.

Programmable transdermal drug delivery of nicotine using carbon nanotube membranes.

Carbon nanotube (CNT) membranes were employed as the active element of a switchable transdermal drug delivery device that can facilitate more effective treatments of drug abuse and addiction. Due to the dramatically fast flow through CNT cores, high charge density, and small pore dimensions, highly efficient electrophoretic pumping through functionalized CNT membrane was achieved. These membranes were integrated with a nicotine formulation to obtain switchable transdermal nicotine delivery rates on human skin (in vitro) and are consistent with a Fickian diffusion in series model. The transdermal nicotine delivery device was able to successfully switch between high (1.3 + or - 0.65 micromol/hr-cm(2)) and low (0.33 + or - 0.22 micromol/hr-cm(2)) fluxes that coincide with therapeutic demand levels for nicotine cessation treatment. These highly energy efficient programmable devices with minimal skin irritation and no skin barrier disruption would open an avenue for single application long-wear patches for therapies that require variable or programmable delivery rates.

Statistical Considerations in Assessing In Vivo Adhesion with Transdermal and Topical Delivery Systems for New Drug Applications.

Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food and Drug Administration outlines a non-inferiority comparison between a test product and its reference product for generic TDS in abbreviated new drug applications (ANDAs). However, the statistical method is not applicable for evaluating adhesion of TDS for NDAs, because no reference product exists. In this article, we explore an alternative primary endpoint and a one-sided binomial test to evaluate in vivo adhesion of TDS in NDAs. Statistical considerations related to the proposed approach are discussed. To understand its potential use, the proposed approach is applied to data sets of in vivo adhesion studies from selected NDAs and ANDAs.

Drug recrystallization in drug-in-adhesive transdermal delivery system: A case study of deteriorating the mechanical and rheological characteristics of testosterone TDS.

This study investigated the effects of drug recrystallization on the in vitro performance of testosterone drug-in-adhesive transdermal delivery system (TDS). Six formulations were prepared with a range of dry drug loading in the adhesive matrix from 1% to 10% w/w with the aim of generating TDS with various levels of drug crystals. We visually quantified the amount of crystals in TDS by polarized light microscopy. The effect of drug recrystallization on adhesion, tackiness, cohesive strength, viscoelasticity, drug release, and drug permeation through human cadaver skin were evaluated for these TDS samples. The Optical images showed no crystals in 1% and 2% testosterone TDSs; however, the amount of crystals increased by increasing testosterone loading from 4 to 10%. A proportional and significant decrease (p < 0.05) in tack, peel, and shear strength of the adhesive matrix with increasing amount of crystals in TDS was observed. The drug crystals resulted in a proportional deterioration of the viscoelastic properties of the adhesive matrix. The 2% testosterone TDS showed faster drug release rate when compared to 1% testosterone TDS. The increase in drug loading from 2% to 4% w/w slightly increased the cumulative amount of testosterone released. Further increase in drug loading in TDS to 6, 8, and 10% was nonsignificant (p > 0.05) to affect the drug release and permeation. In conclusion, this study demonstrated that the extent of drug recrystallization can be quantitatively correlated with the deterioration of performance characteristics of TDS products.

Navigating sticky areas in transdermal product development.

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form.

Programmable transdermal clonidine delivery through voltage-gated carbon nanotube membranes.

Oral dosage forms and traditional transdermal patches are inadequate for complex clonidine therapy dosing schemes, because of the variable dose/flux requirement for the treatment of opioid withdrawal symptoms. The purpose of this study was to evaluate the in vitro transdermal flux changes of clonidine in response to alterations in carbon nanotube (CNT) delivery rates by applying various electrical bias. Additional skin diffusion studies were carried out to demonstrate the therapeutic feasibility of the system. This study demonstrated that application of a small electrical bias (-600 mV) to the CNT membrane on the skin resulted in a 4.7-fold increase in clonidine flux as compared with no bias (0 mV) application. The high and low clonidine flux values were very close to the desired variable flux of clonidine for the treatment of opioid withdrawal symptoms. Therapeutic feasibility studies demonstrated that CNT membrane served as the rate-limiting step to clonidine diffusion and lag and transition times were suitable for the clonidine therapy. Skin elimination studies revealed that clonidine depletion from the skin would not negatively affect clonidine therapy. Overall, this study showed that clonidine administration difficulties associated with the treatment of opiate withdrawal symptoms can be reduced with the programmable CNT membrane transdermal system.

CDER risk assessment exercise to evaluate potential risks from the use of nanomaterials in drug products.

The Nanotechnology Risk Assessment Working Group in the Center for Drug Evaluation and Research (CDER) within the United States Food and Drug Administration was established to assess the possible impact of nanotechnology on drug products. The group is in the process of performing risk assessment and management exercises. The task of the working group is to identify areas where CDER may need to optimize its review practices and to develop standards to ensure review consistency for drug applications that may involve the application of nanotechnology. The working group already performed risk management exercises evaluating the potential risks from administering nanomaterial active pharmaceutical ingredients (API) or nanomaterial excipients by various routes of administration. This publication outlines the risk assessment and management process used by the working group, using nanomaterial API by the oral route of administration as an example.

Carbon Nanotube Membranes for use in the Transdermal Treatment of Nicotine Addiction and Opioid Withdrawal Symptoms.

Transdermal systems are attractive methods of drug administration specifically when treating patients for drug addiction. Current systems however are deficient in therapies that allow variable flux values of drug, such as nicotine for smoking cessation or complex dosing regimens using clonidine when treating opioid withdrawal symptoms. Through the use of functionalized carbon nanotube (CNT) membranes, drug delivery to the skin can be controlled by applying a small electrical bias to create a programmable drug delivery system. Clearly, a transdermal patch system that can be tailored to an individual's needs will increase patient compliance as well as provide much more efficient therapy. The purpose of this paper is to discuss the applicability of using carbon nanotube membranes in transdermal systems for treatment of drug abuse.