Search

Purpose: Typical clinical "in use" conditions for topical semisolids involve their application as a thin film, often with rubbing that can induce metamorphic stress. Yet, product quality and performance tests often characterize the manufactured product, and may not consider product metamorphosis (e.g., shear history) during dispensing and administration. This work sought to elucidate how such metamorphosis might alter product quality and performance., Methods: We evaluated the effect of "in use" stresses on drug crystal metamorphosis in acyclovir creams by optical microscopy. The amount of dissolved acyclovir was determined by separation of the cream base by ultra-centrifugation and quantification by HPLC. IVPT was undertaken on Zovirax ® US and Aciclostad ® comparing static and "in use" application of a finite dose. A mechanistic IVPT study was also conducted to understand the influence of acyclovir particle size reduction by "in use" rubbing on skin permeation., Results: Reduction in acyclovir particle size was seen after "in use" rubbing with increases in the amount of dissolved acyclovir after rubbing (30 and 60 s) compared to static for both products. "In use" application resulted in significantly higher acyclovir permeation from both products. The mechanistic IVPT study proved the role of product metamorphosis., Conclusion: These results highlight the role of metamorphosis of product microstructure and its influence on performance., Competing Interests: Declarations. Competing Interest: The authors declare that they have no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Obesity is associated with increased infection risk after primary total joint arthroplasty. In this retrospective cohort analysis, we sought to assess the association between body mass index (BMI) and infection recurrence after two-stage revision total joint arthroplasty for periprosthetic joint infection (PJI)., Methods: Patients were grouped by BMI (< 30, 30 to 40, and ≥ 40) as non-obese, obese, and morbidly obese, and assessed for associations and timing of PJI reinfection as well as readmissions and complications., Results: Following the two-stage revision, PJI reinfections increased from 11.5% in nonobese to 19.0% in obese and 25.9% in morbidly obese patients (P = 0.011). As BMI increased across the three groups, 90-day readmission rates following two-stage PJI revision significantly increased (8.6, 19.7, and 16.7%, respectively (P = 0.042)). The average time to reinfection decreased with obesity tercile (restricted-mean times of 4.5, 4.2, and 3.8 years with non-obese, obese, and morbidly obese, respectively (P = 0.023))., Conclusions: The success of PJI management with two-stage arthroplasty is significantly impacted by patient BMI, with morbidly obese subjects having the worst outcomes. Attempts to modify BMI before completion of two-stage PJI treatment should be considered in the morbidly obese given high rates of recurrence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: The objective of this study was to investigate whether different dispensing processes can alter the physicochemical and structural (Q3) attributes of a topical cream product, and potentially alter its performance., Methods: Acyclovir cream, 5% (Zovirax®) is sold in the UK and other countries in a tube and a pump packaging configurations. The structural attributes of the cream dispensed from each packaging configuration were analyzed by optical microscopy, confocal Raman microscopy and cryo-scanning electron microscopy. Rheological behavior of the products was also evaluated. Product performance (rate and extent of skin delivery) was assessed by in vitro permeation tests (IVPT) using heat-separated human epidermis mounted in static vertical (Franz-type) diffusion cells., Results: Differences in Q3 attributes and IVPT profiles were observed with creams dispensed from the two packaging configurations, even though the product inside each packaging appeared to be the same in Q3 attributes. Visible globules were recognized in the sample dispensed from the pump, identified as dimethicone globules by confocal Raman microscopy. Differences in rheological behaviour could be attributed to these globules as products not dispensed through the pump, demonstrated a similar rheological behaviour. Further, IVPT confirmed a reduced rate and extent to delivery across human epidermis from the product dispensed through a pump., Conclusions: Different methods of dispensing topical semisolid products can result in metamorphosis and Q3 changes that may have the potential to alter the bioavailability of an active ingredient. These findings have potential implications for product developers and regulators, related to the manufacturing and comparative testing of reference standard and prospective generic products dispensed from different packaging configurations., (© 2024. The Author(s).)

Background: Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established., Objective: To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties., Methods: The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 h. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC 0to12h and C max using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study., Results: BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible., Conclusions: dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK-based BE approach for topical lipophilic drugs, including lidocaine and prilocaine., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: To develop a toolkit of test methods for characterizing potentially critical quality attributes (CQAs) of topical semisolid products and to evaluate how CQAs influence the rate and extent of active ingredient bioavailability (BA) by monitoring cutaneous pharmacokinetics (PK) using an In Vitro Permeation Test (IVPT)., Methods: Product attributes representing the physicochemical and structural (Q3) arrangement of matter, such as attributes of particles and globules, were assessed for a set of test acyclovir creams (Aciclostad® and Acyclovir 1A Pharma) and compared to a set of reference acyclovir creams (Zovirax® US, Zovirax® UK and Zovirax® Australia). IVPT studies were performed with all these creams using heat-separated human epidermis, evaluated with both, static Franz-type diffusion cells and a flow through diffusion cell system., Results: A toolkit developed to characterize quality and performance attributes of these acyclovir topical cream products identified certain differences in the Q3 attributes and the cutaneous PK of acyclovir between the test and reference sets of products. The cutaneous BA of acyclovir from the set of reference creams was substantially higher than from the set of test creams., Conclusions: This research elucidates how differences in the composition or manufacturing of product formulations can alter Q3 attributes that modulate myriad aspects of topical product performance. The results demonstrate the importance of understanding the Q3 attributes of topical semisolid drug products, and of developing appropriate product characterization tests. The toolkit developed here can be utilized to guide topical product development, and to mitigate the risk of differences in product performance, thereby supporting a demonstration of bioequivalence (BE) for prospective topical generic products and reducing the reliance on comparative clinical endpoint BE studies., (© 2024. The Author(s).)

For proportionally formulated intermediate strengths of a topical product, the relationship of drug release across multiple strengths of a given product is not always well understood. The current study aims to assess the proportionality of tretinoin release rates across multiple strengths of tretinoin topical gels when manufactured using two different methods to understand the impact of formulation design on drug product microstructure and tretinoin release rate. Two groups of tretinoin gels of 0.04 %, 0.06 %, 0.08 % and 0.1 % strengths were manufactured. Gels in Group I were prepared by incorporating 4-10 % g/g of 1 % w/w tretinoin-loaded microparticles into a gel base. Gels in Group II were manufactured using 10 % g/g of the microparticles that were loaded with increasing amounts (0.4-1 % w/w) of tretinoin. The two groups of gels were characterized by evaluating microstructure using a polarized microscope, rheology using an oscillatory rheometer, and drug release using Vison® Microette™ Hanson vertical diffusion cells. The microscopic images were used to discriminate between the two groups of gels based on the abundance of microparticles in the gel matrix observed in the images. This abundance increased across gels of Group I and was similar across gels of Group II. The rheology parameters, namely viscosity at a shear rate of 10 s -1 , shear thinning rate, storage, and loss modulus, increased across gels of Group I, and were not significantly different across gels of Group II. The release rate of tretinoin from the drug products was proportional to the nominal strength of the drug product in both Group I and Group II, with a correlation coefficient of 0.95 in each case, although the absolute release rates differed. Overall, changing the formulation design of tretinoin topical gels containing porous microparticles may change the physicochemical and structural properties, as well as the drug release rate of the product. Further, keeping the formulation design consistent across all strengths of microparticle-based topical gels is important to achieve proportional release rates across multiple strengths of a given drug product., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Generic drugs are essential for affordable medicine and improving accessibility to treatments. Bioequivalence (BE) is typically demonstrated by assessing a generic product's pharmacokinetics (PK) relative to a reference-listed drug (RLD). Accurately estimating cutaneous PK (cPK) at or near the site of action can be challenging for locally acting topical products. Certain cPK approaches are available for assessing local bioavailability (BA) in the skin. Stimulated Raman scattering (SRS) microscopy has unique capabilities enabling continuous, high spatial and temporal resolution and quantitative imaging of drugs within the skin. In this paper, we developed an approach based on SRS and a polymer-based standard reference for the evaluation of topical product BA and BE in human skin ex vivo. BE assessment of tazarotene-containing formulations was achieved using cPK parameters obtained within different skin microstructures. The establishment of BE between the RLD and an approved generic product was successfully demonstrated. Interestingly, within the constraints of the current study design the results suggest similar BA between the tested gel formulation and the reference cream formulation, despite the differences in the formulation/dosage form. Another formulation containing polyethylene glycol as the vehicle was demonstrated to be not bioequivalent to the RLD. Compared to using the SRS approach without a standard reference, the developed approach enabled more consistent and reproducible results, which is crucial in BE assessment. The abundant information from the developed approach can help to systematically identify key areas of study design that will enable a better comparison of topical products and support an assessment of BE., Competing Interests: Declaration of competing interest CLE is an inventor on patents for CARS microscopy that were licensed to multiple microscope manufacturers. All other authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Comparative assessment of cutaneous pharmacokinetics (cPK) by dermal microdialysis (dMD) appears to be suitable to evaluate the bioequivalence (BE) of topical dermatological drug products applied to the skin (TDDPs). Although dMD studies in the literature have reported inconclusive BE assessments, we have addressed several methodological deficiencies to improve dMD's capability to assess BE between reference (R) and approved generic (referred to as test (T)) gel and cream products of metronidazole (MTZ). The 90% confidence interval (CI) of the geometric mean ratios for the Ln(AUC 0-24 ) and Ln(C max ) endpoints was centered within the BE limits of 80-125%. The CIs extended outside this range as the proof-of-principle study was not statistically powered to demonstrate BE (N = 7 rabbits). A power analysis suggests that, with the variability observed in this study, 21 rabbits for the cream and 11 rabbits for the gel would be sufficient to support an evaluation of BE with the 2 probe replicates we used, and only 10 and 5 rabbits would be sufficient to power the study for the cream and gel, respectively, if 4 probe replicates are used for each treatment per rabbit. These results indicate that dMD when properly controlling variables can be used to support BE assessments for TDDPs., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

On September 30 and October 1, 2021, the US Food and Drug Administration (FDA) and the Center for Research on Complex Generics cosponsored a live virtual workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches." The overall aims of the workshop included (i) engaging the generic drug industry and other involved stakeholders regarding how mechanistic modeling and simulation can support their product development and regulatory submissions; (ii) sharing the current state of mechanistic modeling for bioequivalence (BE) assessment through case studies; (iii) establishing a consensus on best practices for using mechanistic modeling approaches, such as physiologically based pharmacokinetic modeling and computational fluid dynamics modeling, for BE assessment; and (iv) introducing the concept of a Model Master File to improve model sharing between model developers, industry, and the FDA. More than 1500 people registered for the workshop. Based on a postworkshop survey, the majority of participants reported that their fundamental scientific understanding of mechanistic models was enhanced, there was greater consensus on model validation and verification, and regulatory expectations for mechanistic modeling submitted in abbreviated new drug applications were clarified by the workshop., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The development of a generic drug product involves demonstrating that there is no significant difference in the rate and extent to which the active ingredient becomes available at the site of action, relative to the reference listed drug product. This remains challenging for many locally acting topical dermatological products because measuring the concentration of the active ingredient at the site of action in the skin may not be straightforward, and, in most instances, there are no established relationships between skin and plasma pharmacokinetic profiles. In recent years, the Office of Generic Drugs of the US Food and Drug Administration (FDA) established scientific research programs with the goal of enhancing patient access to high quality, affordable topical dermatological generics. A key strategy of these research programs was to leverage modeling and simulation methodologies that accelerate the development of these generics by facilitating alternative bioequivalence approaches for dermatological drug products. This report summarizes relevant insights and discussions from a 2021 FDA public workshop titled "Regulatory Utility of Mechanistic Modeling to Support Alternative Bioequivalence Approaches," which illustrated how mechanistic modeling and simulation approaches can be utilized (and have been used) to inform generic drug product development and regulatory decisions during the assessment of generic drug applications submitted to the FDA., (© 2022 Bill & Melinda Gates Foundation, The Authors and Simulations Plus, Inc, et al. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Physiologically-based pharmacokinetic models combine knowledge about physiology, drug product properties, such as physicochemical parameters, absorption, distribution, metabolism, excretion characteristics, formulation attributes, and trial design or dosing regimen to mechanistically simulate drug pharmacokinetics (PK). The current work describes the development of a multiphase, multilayer mechanistic dermal absorption (MPML MechDermA) model within the Simcyp Simulator capable of simulating uptake and permeation of drugs through human skin following application of drug products to the skin. The model was designed to account for formulation characteristics as well as body site- and sex- population variability to predict local and systemic bioavailability. The present report outlines the structure and assumptions of the MPML MechDermA model and includes results from simulations comparing absorption at multiple body sites for two compounds, caffeine and benzoic acid, formulated as solutions. Finally, a model of the Feldene (piroxicam) topical gel, 0.5% was developed and assessed for its ability to predict both plasma and local skin concentrations when compared to in vivo PK data., (© 2022 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutic. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Approved generic drugs are therapeutically equivalent to a preidentified brand name product and are expected to have the same clinical effect and safety profile when administered to patients under conditions specified in the labeling. Availability of generic topical dermatologic drugs is expected to enhance patient access to such widely used drug products. Assessment of equivalence for a prospective generic product involves a systematic and rigorous comparative evaluation to ensure there is no significant difference in the rate and extent to which the active ingredients become available at the site of action for the prospective generic and corresponding brand name product., (Published by Elsevier Inc.)

The evaluation of bioequivalence (BE) involves comparing the test product to its reference product in a study whose fundamental scientific principles allow inferring of the clinical performance of the products. Several test methods have been discussed and developed to evaluate topical bioavailability (BA) and BE. Pharmacokinetics-based approaches characterize the rate and extent to which an active ingredient becomes available at or near its site of action in the skin. Such methodologies are considered to be among the most accurate, sensitive, and reproducible approaches for determining the BA or BE of a product., Competing Interests: Disclosure The information and opinions expressed in this article reflect the views of the authors and do not necessarily reflect the views or policies of the FDA or any other organizations with which the authors are affiliated., (Published by Elsevier Inc.)

Dermal microdialysis (dMD) permits the investigation of cutaneous pharmacokinetics (cPK) for topical dermatological drug products (TDDP). dMD involves probe implantation into the dermis and a sample collection system that restricts subjects' movements for the experimental duration. A truncated dose-duration, by TDDP removal at predetermined time-points, may help to adequately characterize the cPK in a relatively short time. The goals of this study were to: assess and compare the dose-duration effect on the dermal exposure of metronidazole (MTZ) containing TDDPs; and characterize MTZ dermal elimination following TDDP application and direct dermal delivery of MTZ utilizing a retrodialysis/microdialysis approach that we termed "dermal infusion." MTZ cream and gel were applied on three Yucatan mini-pigs for dose-durations of 6-hr, 12-hr, or 48-hr. The gel's dermal exposure was similar among the three dose-durations. Conversely, at the 6-hr dose-duration, the cream's dermal exposure was significantly lower than other cream dose-durations while also comparable to the gel. In comparison, the 12-hr and 48-hr cream exposures were not significantly different. Terminal-phase half-live differences between the MTZ TDDP's and dermal-infusion indicate flip/flop cPK. Truncating topical dose-duration may provide a valuable strategy to reduce experimental duration; however, dose-duration must be carefully selected if the goal is to discriminate between formulations., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Drug release from microparticle-based topical gels may affect their bioavailability, safety and efficacy. This work sought to elucidate spatial distribution of the drug within the microparticle matrix and how this impacts the product's critical performance attributes. The purpose of this research was to inform the development of in vitro characterization approaches to support a demonstration of bioequivalence. Drug-free microparticles were loaded with tretinoin or drug-loaded microparticles were separated from purchased Retin-A Micro® (tretinoin) topical gel drug products. The resultant microparticles were analyzed for tretinoin content, drug loading efficiency, morphology, surface topography, surface pore size distribution, particle size distribution and tretinoin release. The solid-state characteristics and chemical interaction of tretinoin with the microparticles were also investigated. Microparticles loaded with tretinoin made in-house and those separated from Retin-A Micro® (tretinoin) topical gel were spherical, polydisperse and free of aggregates. The surface porosity of the microparticles was ∼19.8% with an average pore size of ∼327 nm. Microparticles loaded with tretinoin in-house were smaller in size and exhibited faster drug release than those separated from Retin-A Micro® (tretinoin) topical gel. Tretinoin release was found to increase with an increase in the drug loading. Based on XRD and DSC data, tretinoin was present in an amorphous state. The FTIR spectra indicated a disappearance of carbonyl band of microparticles and shifting of the hydroxyl band of tretinoin due to hydrogen bonding. The extent of drug loading and the solid-state interaction of tretinoin with the microparticles may be critical for drug release. Additional characterization of the drug products is necessary to understand the effect of the factors examined in this work on the bioavailability and efficacy of tretinoin gels., (Published by Elsevier B.V.)

Purpose: The quality testing and approval procedure for most pharmaceutical products is a streamlined process with standardized procedures for the determination of critical quality attributes. However, the evaluation of semisolid dosage forms for topical drug delivery remains a challenging task. The work presented here highlights confocal Raman microscopy (CRM) as a valuable tool for the characterization of such products., Methods: CRM, a laser-based method, combining chemically-selective analysis and high resolution imaging, is used for the evaluation of different commercially available topical acyclovir creams., Results: We show that CRM enables the spatially resolved analysis of microstructural features of semisolid products and provides insights into drug distribution and polymorphic state as well as the composition and arrangement of excipients. Further, we explore how CRM can be used to monitor phase separation and to study skin penetration and the interaction with fresh and cryopreserved excised human skin tissue., Conclusion: This study presents a comprehensive overview and illustration of how CRM can facilitate several types of key analyses of semisolid topical formulations and of their interaction with their biological target site, illustrating that CRM is a useful tool for research, development as well as for quality testing in the pharmaceutical industry., (© 2022. The Author(s).)

The value of developing an in vitro/in vivo correlation (IVIVC) is substantial in biopharmaceutical drug development because once the model is developed and validated, an in vitro method may be used to efficiently assess and predict drug product performance in vivo. In this study, three bioequivalent, matrix-type, fentanyl transdermal delivery systems (TDS) were evaluated in vitro using an in vitro permeation test (IVPT) and dermatomed human skin, and in vivo in human pharmacokinetic (PK) studies under harmonized study designs to evaluate IVIVC. The study designs included 1 h of transient heat application (42 ± 2°C) at either 11 h or 18 h after TDS application to concurrently investigate the influence of heat on drug bioavailability from TDS and the feasibility of IVPT to predict the effects of heat on TDS in vivo. Level A (point-to-point) and Level C (single point) IVIVCs were evaluated by using PK-based mathematical equations and building IVIVC models between in vitro fraction of drug permeation and in vivo fraction of drug absorption. The study results showed that the three differently formulated fentanyl TDS have comparable (p > 0.05) heat effects both in vitro and in vivo. In addition, the predicted steady-state concentration (C ss ) from in vitro flux data and the observed C ss in vivo showed no significant differences (p > 0.05). However, the effects of heat on enhancement of fentanyl bioavailability observed in vivo were found to be greater compared to those observed in vitro for all three drug products, resulting in a weak prediction of the impact of heat on bioavailability from the in vitro data. The results from the current work suggest that while IVPT can be a useful tool to evaluate the performance of fentanyl TDS in vivo with a relatively good predictability at a normal temperature condition and to compare the effect of heat on drug delivery from differently formulated TDS, additional testing measures would enhance the ability to predict the heat effects in vivo with a lower prediction error., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Complex generics are generic versions of drug products that generally have complex active ingredients, complex formulations, complex routes of delivery, complex dosage forms, are complex drug-device combination products, or have other characteristics that can make it complex to demonstrate bioequivalence or to develop as generics. These complex products (i.e. complex generics) are an important element of the United States (U.S.) Food and Drug Administration's (FDA's) Generic Drug User Fee Amendments (GDUFA) II Commitment Letter. The Center for Research on Complex Generics (CRCG) was formed by a grant from the FDA to address challenges associated with the development of complex generics. To understand these challenges, the CRCG conducted a "Survey of Scientific Challenges in the Development of Complex Generics". The three main areas of questioning were directed toward which (types of) complex products, which methods of analysis to support a demonstration of bioequivalence, and which educational topics the CRCG should prioritize. The survey was open to the public on a website maintained by the CRCG. Regarding complex products, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and inhalation and nasal products. Regarding methods of analysis, the top three selections were locally-acting physiologically-based pharmacokinetic modeling; oral absorption models and bioequivalence; and data analytics and machine learning. Regarding educational topics, the top three selections were complex injectables, formulations, and nanomaterials; drug-device combination products; and data analytics, including quantitative methods and modeling & simulation. These survey results will help prioritize the CRCG's initial research and educational initiatives., (© 2021. The Author(s).)

The aim was to evaluate whether an in vitro release test (IVRT) could differentiate the release rates from five pharmaceutically equivalent acyclovir cream products and one ointment compared to that from a reference product, Zovirax cream (USA), to identify a test product with an inequivalent drug release rate that could serve as negative control for bioequivalence (BE) in a separate in vivo study. The reference product showed equivalent drug release rates compared to itself. The six test products failed to show equivalent drug release rates compared to the reference product. Aciclovir 1A pharma cream was selected to serve as a negative control for subsequent BE studies, since it exhibited the greatest difference in release rate among all creams, compared to the reference product. The results of this study indicate that IVRT results can be highly sensitive and may discriminate clinically relevant differences between products. Results from an appropriately validated IVRT method can support a demonstration of BE by showing that the drug release rates from test and reference products are statistically equivalent, mitigating the risk that differences may exist between the products which may influence in vivo performance of the drug product., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Increasing emphasis is being placed on using in vitro permeation test (IVPT) results for topical products as a surrogate for their in vivo behaviour. This study sought to relate in vivo plasma concentration - time pharmacokinetic (PK) profiles after topical application of drug products to IVPT findings with mechanistic diffusion and compartment models that are now widely used to describe permeation of solutes across the main skin transport barrier, the stratum corneum. Novel in vivo forms of the diffusion and compartment-in-series models were developed by combining their IVPT model forms with appropriate in vivo disposition functions. Available in vivo and IVPT data were then used with the models in data analyses, including the estimation of prediction intervals for in vivo plasma concentrations derived from IVPT data. The resulting predicted in vivo plasma concentration - time profiles for the full models corresponded closely with the observed results for both nitroglycerin and rivastigmine at all times. In contrast, reduced forms of these in vivo models led to discrepancies between model predictions and observed results at early times. A two-stage deconvolution procedure was also used to estimate the in vivo cumulative amount absorbed and shown to be linearly related to that from IVPT, with an acceptable prediction error. External predictability was also shown using a separate set of in vitro and in vivo data for different nitroglycerin patches. This work suggests that mechanistic and physiologically based pharmacokinetic models can be used to predict in vivo behaviour from IVPT data for topical products., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Dermal microdialysis (dMD) can measure the rate and extent to which a topically administered active pharmaceutical ingredient (API) becomes available in the dermis. Using multiple test-sites on the same subject, and replicate probes at each test-site, it is feasible to compare the cutaneous pharmacokinetics of an API from different topical dermatological drug products in parallel on the same subject with this technique. This study design would help to reduce variability. However, there are technical considerations related to the dMD experimental methods that must be characterized and optimized to ensure that an in vivo dMD study is selective, sensitive, discriminating, and reproducible. The goals of this study were to assess: the minimum distance required between test-sites to prevent cross-talk between probes due to potential lateral-diffusion; the sensitivity of the dMD method to detect differences in the local concentration of metronidazole (MTZ) among single escalating doses; the ability to discriminate between the two different formulations; and the stability of the dMD-probes over 48 h. Results indicate that lateral-diffusion and systemic redistribution of the API following topical application of the drug product were negligible, thus MTZ measured by dMD can be selectively attributed to the dermal bioavailability of the API from the applied topical dose. The dMD methodology was able to detect differences in the bioavailability of MTZ from the cream compared to the gel when applied at the same dose, as well as among different doses of the same formulation over a 48-hour sampling duration; therefore, the method is sensitive. The percentage loss of D 3 -MTZ from the probe compared to its original concentration in the perfusate indicates that the probe performance was stable over the 48 h., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: The in vitro permeation test (IVPT) with a new statistical approach was investigated to evaluate the utility of an IVPT methodology as a sensitive tool to support a demonstration of bioequivalence (BE) for topical dermatological drug products., Methods: IVPT experiments were performed utilizing ex vivo human skin. The initial screening tests involved four differently formulated acyclovir 5% creams: the U.S. Zovirax® as the reference product and the U.K. Zovirax®, Aciclovir 1A Pharma® and Aciclostad® as test products. Subsequently, a pivotal BE study was conducted comparing the two Zovirax® creams. The resulting data was used to evaluate BE of test (T) versus reference (R), T versus T, and R versus R, with an adaption of scaled average BE approach to address high variability in IVPT data., Results: More acyclovir permeated into and through the skin from the two Zovirax® creams compared to the two non-Zovirax® creams. The U.S. Zovirax® cream showed a significantly higher J max and total amount permeated over 48 h, compared to the U.K. Zovirax® cream. The statistical analysis indicated that the test and reference products were not bioequivalent, whereas each product tested against itself was shown to be bioequivalent., Conclusions: The current study demonstrated that the IVPT method, with an appropriate statistical analysis of the results, is a sensitive and discriminating test that can detect differences in the rate and extent of acyclovir bioavailability in the skin from differently formulated cream products.

Experimental conditions that could impact the evaluation of heat effects on transdermal delivery systems (TDS) using an in vitro permeation test (IVPT) and in vitro release testing (IVRT) were examined. Fentanyl was the model TDS. IVPT was performed using Franz diffusion cell, heating lamp, and human skin with seven heat application regimens. IVRT setup was similar to IVPT, without using skin. Dissolution study was conducted in a modified dissolution chamber. The activation energy of skin permeation for fentanyl was determined using aqueous solution of fentanyl. In IVPT, the increase of temperature from 32 °C to 42 °C resulted in a 2-fold increase in flux for fentanyl TDS, consistent with the activation energy determined. The magnitude of flux increase was affected by the heat exposure onset time and duration: higher flux was observed when heat was applied earlier or following sustained heat application. Heat induced flux increases could not be observed when inadequate sampling time points were used, suggesting the importance of optimizing sampling time points. Drug release from TDS evaluated using IVRT was fast and the skin was the rate-limiting barrier for TDS fentanyl delivery under elevated temperature., (Copyright © 2020 American Pharmacists Association®. All rights reserved.)

The cost of prescription drugs has increased at rates far exceeding general inflation in recent history, with topical drugs increasing at a disproportionate rate compared to other routes of administration. We assessed the relationship between net changes in the number of therapeutic options, defined as any approved drug or therapeutic equivalent on the market, and prescription topical drug spending. Drugs were divided based on the category of use through pairing of Medicare Part D Prescriber Public Use and Food and Drug Administration (FDA) approved drug products databases. Across drug classes, we modeled the log of the ratio of total spending per unit in 2015 to total spending per unit in 2011 as a linear function of net number of topical therapeutic options over this time period. Primary outcomes include total Medicaid Part D spending on topical drugs and net change in the number of available therapeutic options within each category of use. Total spending on topical drugs increased by 61%, while the number of units dispensed increased by only 18% from 2011-2015. The greatest total spending increases were in categories with few new therapeutic options, such as topical corticosteroid and antifungal medications. Each net additional therapeutic option during 2011-2015 was associated with an reduction in how much relative spending per unit increased (95% CI 2.5%-14.4%, p = 0.013). Stimulating greater competition through increasing the net number of therapeutic options within each major topical category of use may place downward pressure on topical prescription drug spending under medicare Part D.

Purpose: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study., Methods: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products., Results: The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject's skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability., Conclusions: Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.

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.

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. The approximately 2-fold increase of nicotine absorption with a 10°C increase in skin surface temperature was consistent with a 50-65 kJ/mol activation energy for diffusion in the stratum corneum, with this layer serving as the primary barrier for nicotine absorption. Incorporation of a dermal clearance component into the model revealed efficient removal of nicotine via the dermal capillaries at both normal and elevated temperatures. Two-compartment pharmacokinetic simulations yielded systemic drug concentrations consistent with the human pharmacokinetic data. Both in vitro skin permeation and in vivo pharmacokinetics of nicotine delivered from a marketed TDS under normal and elevated temperatures can be satisfactorily described by a simultaneous heat and mass transfer computational model incorporating realistic skin barrier properties and dermal clearance components.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Until 2016, a ratio of means (ROM) non-inferiority (NI) test was recommended in FDA product-specific guidances (PSGs) to evaluate adhesion performance for prospective generic transdermal delivery systems (TDS). However, the ROM NI test had low power for well-adhering TDS, which were becoming increasingly prevalent. Mathematical proof and simulation revealed that the low power wasn't because the non-normality of adhesion data violated the normality assumption of parametric methods; it was because the ROM NI test was coupled with an adhesion scale where scores approached 0 as adhesion got better. In June 2016, FDA published a draft general guidance on TDS adhesion and recommended a new statistical approach, replacing the ROM NI test with a difference-of-means (DOM) NI test, using the same scale and primary endpoint (mean adhesion scores). An analysis of 40 TDS adhesion studies submitted in ANDAs after the publication of the 2016 draft guidance suggests that, consistent with simulation results, the new statistical approach markedly improves the low power, and thereby reduces the sample size required by the old approach for moderately to well-adhering TDS, while retaining comparable power for poorly adhering TDS. The new statistical approach thus enhances the potential approvability and patient access to well-adhering generic TDS.

Complex regulatory and scientific considerations exist for drug-device combination products submitted under an Abbreviated New Drug Application. The Agency has published several guidances to aid industry in the development of a generic drug-device combination product: providing recommendations on the types of studies necessary to establish bioequivalence, providing considerations on product quality and performance for certain types of device constituents, and most recently, providing tools to assess the proposed user interface when compared to the user interface of the Reference Listed Drug. In addition, the Office of Generic Drugs 1 has established a regulatory science research program intended to support projects that examine scientific questions relating to the development of generic combination products and their associated regulatory review. Several research examples are described within this article, which demonstrate how equivalence can be evaluated when the function of the device could potentially impact drug delivery. Moreover, this article provides an overview of regulatory recommendations and ongoing scientific research efforts to further develop guidances and ultimately improve public access to generic combination products., (Published by Elsevier B.V.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The rate of release of an active pharmaceutical ingredient (API) from a topical semisolid dosage form can be influenced by its physical and structural properties. An In Vitro Release Test (IVRT) is an established method to characterize this rate of API release and compare the underlying sameness in product quality characteristics. The purpose of this work was to validate an IVRT method to compare acyclovir cream, 5% products. However, despite widespread use of the IVRT since 1997, there has been no established approach to validate an IVRT method. Our approach included: 1) qualification of the diffusion cell apparatus, 2) qualification of the laboratory, 3) validation of the HPLC analytical method, and 4) validation of numerous critical parameters of the IVRT method, itself, and resulted in a comprehensive and successful IVRT method validation. Subsequent to the IVRT validation work described here, the U.S. Food and Drug Administration (FDA) drafted a guidance on the development and validation of an IVRT method for acyclovir cream, 5%. Although there are notable differences between our approach and the approach in that guidance, this report illustrates how many of the same essential qualification parameters and validation concepts were considered and systematically addressed in our approach to IVRT validation., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: At elevated temperatures, the rate of drug release and skin permeation from transdermal delivery systems (TDS) may be higher than at a normal skin temperature. The aim of this study was to compare the effect of heat on the transdermal delivery of two model drugs, nicotine and fentanyl, from matrix-type TDSs with different formulations, using in vitro permeation tests (IVPT)., Methods: IVPT experiments using pig skin were performed on two nicotine and three fentanyl TDSs. Both continuous and transient heat exposures were investigated by applying heat either for the maximum recommended TDS wear duration or for short duration., Results: Continuous heat exposure for the two nicotine TDSs resulted in different effects, showing a prolonged heat effect for one product but not the other. The J max enhancement ratio due to the continuous heat effect was comparable between the two nicotine TDS, but significantly different (p < 0.05) among the three fentanyl TDSs. The J max enhancement ratios due to transient heat exposure were significantly different for the two nicotine TDSs, but not for the three fentanyl TDSs. Furthermore, the transient heat exposure affected the clearance of drug from the skin depot after TDS removal differently for two drugs, with fentanyl exhibiting a longer heat effect., Conclusions: This exploratory work suggests that an IVPT study may be able to discriminate differences in transdermal drug delivery when different TDS are exposed to elevated temperatures. However, the clinical significance of IVPT heat effects studies should be further explored by conducting in vivo clinical studies with similar study designs.

Purpose: Performance of a transdermal delivery system (TDS) can be affected by exposure to elevated temperature, which can lead to unintended safety issues. This study investigated TDS and skin temperatures and their relationship in vivo, characterized the effective thermal resistance of skin, and identified the in vitro diffusion cell conditions that would correlate with in vivo observations., Methods: Experiments were performed in humans and in Franz diffusion cells with human cadaver skin to record skin and TDS temperatures at room temperature and with exposure to a heat flux. Skin temperatures were regulated with two methods: a heating lamp in vivo and in vitro, or thermostatic control of the receiver chamber in vitro., Results: In vivo basal skin temperatures beneath TDS at different anatomical sites were not statistically different. The maximum tolerable skin surface temperature was approximately 42-43°C in vivo. The temperature difference between skin surface and TDS surface increased with increasing temperature, or with increasing TDS thermal resistance in vivo and in vitro., Conclusions: Based on the effective thermal resistance of skin in vivo and in vitro, the heating lamp method is an adequate in vitro method. However, the in vitro-in vivo correlation of temperature could be affected by the thermal boundary layer in the receiver chamber.

Background: The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products., Objective: To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product., Methods: In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum dermal concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25., Results: The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent., Conclusions: dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study)., Competing Interests: Compliance with Ethical Standards Funding Funding for this project was made possible, in part, by the FDA through research award FD004946. The views expressed in this publication do not reflect the official policies of the FDA, or the Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. Conflict of interest MB, KIT, RR, BT, TA, CD, TB, SK, DS, TRP, and FS are employees of Joanneum Research holding patents on OFM devices. SGR is an employee of US FDA. GS and IK declare that there are no conflicts of interest. Ethics, informed consent, research involving human participants The study was conducted with the full informed consent of all participating subjects, under the authority of the Ethical Committee of the Medical University of Graz, the Austrian health authority AGES, and the FDA’s Research Involving Human Subjects Committee (RIHSC) and was performed in accordance with Good Clinical Practice and the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study has been registered in the European Clinical Trials Register (EudraCT No. 2013-005062-19) and at ClinicalTrials.gov (NCT02711267).

Purpose: A study was designed to assess barrier integrity simultaneously using separate compounds (probes) for polar and non-polar pathways through the skin, 3 H 2 O and 14 C-octanol, respectively; and to determine whether the two probe approach could better define barrier integrity., Methods: A 5-min dose of water containing 3 H 2 O and 14 C -octanol was applied to ex vivo human skin mounted in Franz diffusion cells. The receptor solution was sampled at 30 min, analyzed for 3 H and 14 C content, and the correlation between water and octanol absorption was determined by statistical tests suitable for non-normally distributed data. This study was conducted on skin from 37 donors with from 3 to 30 replicate skin sections per donor (a total of 426 sections)., Results: The correlation between 3 H 2 O and 14 C-octanol absorption was low (Pearson correlation coefficient = 0.3485). The 3 H 2 O absorption cutoff used in this study to select for a normal skin barrier rejected some sections in which 14 C-octanol absorption was within normal limits and accepted others in which 14 C-octanol absorption was abnormally high. The converse was true for 3 H 2 O absorption when the 14 C-octanol-based cutoff was used., Conclusions: The results of the 3 H 2 O test or of similar tests that primarily assess the permeability of polar pathways through the skin may not necessarily provide information relevant to the absorption of highly lipophilic compounds. Octanol, or another molecule that more closely matches the physicochemical attributes of the test compound, may characterize properties of the skin barrier that are more relevant to compounds of low water solubility.

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., (Published by Elsevier B.V.)

Introduction: Exposure to heat can impact the clinical efficacy and/or safety of transdermal and topical drug products. Understanding these heat effects and designing meaningful in vitro and in vivo methods to study them are of significant value to the development and evaluation of drug products dosed to the skin., Areas Covered: This review provides an overview of the underlying mechanisms and the observed effects of heat on the skin and on transdermal/topical drug delivery, thermoregulation and heat tolerability. The designs of several in vitro and in vivo heat effect studies and their results are reviewed., Expert Opinion: There is substantial evidence that elevated temperature can increase transdermal/topical drug delivery. However, in vitro and in vivo methods reported in the literature to study heat effects of transdermal/topical drug products have utilized inconsistent study conditions, and in vitro models require better characterization. Appropriate study designs and controls remain to be identified, and further research is warranted to evaluate in vitro-in vivo correlations and the ability of in vitro models to predict in vivo effects. The physicochemical and pharmacological properties of the drug(s) and the drug product, as well as dermal clearance and heat gradients may require careful consideration.

The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products.

An in vitro human percutaneous absorption study was conducted to assess the delivery of ketoprofen and testosterone from two base formulations, a Pluronic lecithin organogel and Pentravan Cream. Each formulation was applied to ex vivo human trunk skin (from three skin donors) on triplicate sections mounted onto Franz Diffusion Cells. Following a 5-mcL/cm2 applied dose, serial dermal receptor solutions were collected over 48 hours. For both compounds, a greater rate and extent of absorption was found from the Pentravan formulation than from the Pluronic lecithin organogel formulation: 3.8-fold greater for ketoprofen, 1.7-fold greater for testosterone, for amount absorbed.

Aims: To examine the existing literature to determine the degree to which percutaneous absorption data obtained using the excised human skin model match those obtained from living man., Methods: The scientific literature was reviewed to collect data on compounds whose percutaneous absorption through human skin had been measured under both in vitro and in vivo conditions. The in vitro-in vivo (IVIV) correlation was evaluated by computing the in vitro/in vivo ratio using total absorption (percent of applied dose) as the metric for comparison., Results: A total of 92 data sets were collected from 30 published studies. The average IVIV ratio across all values was 1.6, though for any single data set there could be a nearly 20-fold difference between the in vitro and in vivo values. In 85% of the cases, however, the difference was less than 3-fold. The correlation was significantly improved when data were excluded from studies in which the protocols for both studies were not fully harmonized. For harmonized data sets the average IVIV ratio was 0.96 and there was a less than 2-fold difference between the in vitro and in vivo results for any one compound, with IVIV ratios ranging from 0.58 to 1.28. The dominant factors leading to exclusion of data were the use of skin from different anatomical sites and vehicles of differing composition., Conclusions: Percutaneous absorption data obtained from the excised human skin model closely approximate those obtained from living man when the two study protocols are appropriately matched., (Copyright © 2011 S. Karger AG, Basel.)

Although it is well documented that the immunological activity of cytosine-guanine (CpG) motifs is abrogated by 5' methylation of the cytosine residue, encapsulation within stabilized lipid nanoparticles endows these methylated cytosine-guanine- (mCpG-) containing oligonucleotides (ODNs) with potent immunostimulatory activity in murine animal models. Surprisingly, not only do liposomal nanoparticulate (LN) mCpG ODN possess immunostimulatory activity, their potency is found to be equivalent and often greater than the equivalent unmethylated form, as judged by a number of ex vivo innate and adaptive immune parameters and anti-tumor efficacy in murine models. Preliminary data indicate that both methylated and unmethylated CpG ODN act through a common receptor signaling pathway, specifically via toll-like receptor (TLR) 9, based on observations of up-regulated TLR9 expression, induction of nitric oxide and dependence on endosomal maturation. This is confirmed in TLR9 knockout animals which show no immunostimulatory activity following treatment with LN-mCpG ODN. These data, therefore, indicate that the mCpG DNA is fully competent to interact with TLR9 to initiate potent immune responses. Furthermore, this work implicates an as yet unidentified mechanism upstream of TLR9 which regulates the relative activities of free methylated versus unmethylated CpG ODN that is effectively bypassed by particulate delivery of CpG ODN.

The medical management of rosacea increasingly has involved not only the appropriate selection of topical medication but also patient education and specific recommendations regarding appropriate skin care. The recognition that epidermal barrier dysfunction and transepidermal water loss (TEWL) play a pathophysiologic role in rosacea and that skin moisturization may help to mitigate signs and symptoms of the disease has led to a deeper appreciation of the importance of proper skin care in the treatment of rosacea. Data from a percutaneous penetration study performed using human skin suggest that any of the tested moisturizer lotions may be applied either before or after azelaic acid gel 15% without a major change in the percutaneous absorption profile of azelaic acid.

Background: Establishing the bioequivalence of topical drug products is a costly and time-consuming process since, with few exceptions, clinical efficacy trials are required., Objective: To develop a surrogate for clinical bioequivalence testing through evaluation of the kinetics of drug absorption in vitro through excised human skin., Methods: The percutaneous absorption of seven approved generic topical drug products was compared with their corresponding reference products during preclinical development using the Franz diffusion cell. Thereafter, following the conduct of bioequivalence trials and regulatory approval of these products in the United States, clinical data became available to which the in vitro data were compared., Results: In six of the seven cases the in vitro test:reference ratio for total absorption was close to one and indicated that the products were equivalent, in agreement with the clinical data. Results from the seventh case, in which the test:reference ratio was only 0.63, indicated that the in vitro model actually had greater sensitivity than the clinical method to detect small differences between products., Conclusion: These data demonstrate the relevance and predictive power of the in vitro human skin model and strongly support its use as a surrogate for in vivo bioequivalence studies., (Copyright 2009 S. Karger AG, Basel.)

The encapsulation of conventional drugs in lipid nanoparticles (LNs) has been extensively utilized to enhance therapeutic activity by altering their pharmacokinetic (PK) and biodistribution (BD) properties. We have previously shown that the immunostimulatory activity of unmethylated cytidine-guanosine (CpG)-containing immunostimulatory oligodeoxynucleotides (ODN) is greatly enhanced when encapsulated in an LN (LN CpG-ODN). Here, we investigate the effect of circulation lifetime (determined by lipid composition) and drug-to-lipid (D/L) ratio of intravenously (i.v.) administered LN CpG-ODN on PK, BD, and cellular uptake and correlate these parameters with the immunostimulatory activity. Results from these studies show that despite significant differences in the circulation lifetime and the D/L ratio, the immune response is similar with respect to immune cell activation and cytolytic activity in the spleen and the blood compartments. Our findings indicate that the benefits of liposomal nanoparticles for the delivery of immunomodulatory drugs such as CpG-ODN are defined by a different paradigm than that for conventional drugs.