Quality by Design (QbD) for Topical Dermatological and Transdermal Product Development

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (15 August 2020) | Viewed by 44343

Special Issue Editors


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Guest Editor
School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, GPO Box U 1987, Perth, WA 6845, Australia
Interests: topical and transdermal drug delivery; penetration enhancement; nanotechnology; skin permeation mechanisms
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Guest Editor
Diamantina Institute, The University of Queensland, Translation Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia
Interests: topical and transdermal drug delivery; penetration enhancement; nanotechnology; skin permeation mechanisms

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Guest Editor
Therapeutics Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, 37 Kent St, Woolloongabba, QLD 4102, Australia
Interests: topical and transdermal drug delivery; penetration enhancement; nanotechnology; dermatopharmacokinetics; skin permeation mechanisms

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Guest Editor
1. Diamantina Institute, The University of Queensland, Translation Research Institute, 37 Kent St, Woolloongabba, QLD 4102, Australia
2. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia and, Therapeutic Research Centre, Basil Hetzel Institute for Translational Medical Research, The Queen Elizabeth Hospital, Adelaide, Australia
Interests: topical and transdermal drug delivery; penetration enhancement; nanotechnology; dermatopharmacokinetics; skin permeation mechanisms

Special Issue Information

Dear Colleagues,

The Quality by Design (QbD) approach can make the drug development and regulatory pathway more efficient, leading to the availability of high quality topical dermatological and transdermal products more quickly and reducing cost for the health care system and individual consumers. Implementation of the QbD approach involves the definition of the quality target product profile (QTPP) and critical quality attributes (CQAs) of a drug product, and the accomplishment of risk assessment to identify critical material attributes (CMAs) and critical process parameters (CPPs), the definition of a design space through design of experiments (DoEs), the establishment of a control strategy, and the continual improvement and innovation throughout the product life cycle. One of the critical areas of research is the definition of CQAs, the experimental models to evaluate those CQAs, and their application in the drug development process. This Special Issue is focused on the development and evaluation of CQAs for topical and transdermal products, ranging from simple semisolids and patches to nanotechnology formulations. Understanding the interrelationships between formulation components and CQAs, and their effect on efficacy and safety is critical to good topical or transdermal product design and performance.

Prof. Dr. Heather Benson
Dr. Yousuf Mohammed
Dr. Jeffrey E. Grice
Prof. Dr. Michael Roberts
Guest Editors

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Keywords

  • Quality by design
  • Critical quality attributes
  • Topical formulation
  • Transdermal formulation
  • Skin delivery
  • In vivo in vitro correlation
  • Formulation–drug–skin interactions

Published Papers (9 papers)

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Editorial

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4 pages, 153 KiB  
Editorial
Reconciling Quality by Design and Transdermal Product Development
by Kenneth Miller II
Pharmaceutics 2020, 12(3), 273; https://doi.org/10.3390/pharmaceutics12030273 - 17 Mar 2020
Cited by 1 | Viewed by 1911
Abstract
Since my first exposure to the acronym ‘QbD’ more than ten years ago, I have been trying to understand exactly what QbD is and how I might incorporate its teachings into my twenty-odd years of experience developing transdermal systems. I feel I have [...] Read more.
Since my first exposure to the acronym ‘QbD’ more than ten years ago, I have been trying to understand exactly what QbD is and how I might incorporate its teachings into my twenty-odd years of experience developing transdermal systems. I feel I have made little progress since then. Eventually, I came to realize that while QbD has its merits, it is not a guide for (transdermal) product development, despite so often being described as such. Instead, I have come to consider QbD as a language useful for organizing and presenting the array of data supporting the approval of a new product, but it still leaves the experimental approach entirely up to the developer. What QbD does provide to the development community is a means of conveying product information through a consistent framework facilitating both internal and regulatory review. As a result, new ‘QbD’ product applications tend to be more uniform and complete than the applications that preceded the initiative. Full article

Research

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28 pages, 3496 KiB  
Article
Physiologically Based Pharmacokinetic Modeling of Transdermal Selegiline and Its Metabolites for the Evaluation of Disposition Differences between Healthy and Special Populations
by Santosh Kumar Puttrevu, Sumit Arora, Sebastian Polak and Nikunj Kumar Patel
Pharmaceutics 2020, 12(10), 942; https://doi.org/10.3390/pharmaceutics12100942 - 30 Sep 2020
Cited by 22 | Viewed by 3450
Abstract
A physiologically based pharmacokinetic (PBPK) model of selegiline (SEL), and its metabolites, was developed in silico to evaluate the disposition differences between healthy and special populations. SEL is metabolized to methamphetamine (MAP) and desmethyl selegiline (DMS) by several CYP enzymes. CYP2D6 metabolizes the [...] Read more.
A physiologically based pharmacokinetic (PBPK) model of selegiline (SEL), and its metabolites, was developed in silico to evaluate the disposition differences between healthy and special populations. SEL is metabolized to methamphetamine (MAP) and desmethyl selegiline (DMS) by several CYP enzymes. CYP2D6 metabolizes the conversion of MAP to amphetamine (AMP), while CYP2B6 and CYP3A4 predominantly mediate the conversion of DMS to AMP. The overall prediction error in simulated PK, using the developed PBPK model, was within 0.5–1.5-fold after intravenous and transdermal dosing in healthy and elderly populations. Simulation results generated in the special populations demonstrated that a decrease in cardiac output is a potential covariate that affects the SEL exposure in renally impaired (RI) and hepatic impaired (HI) subjects. A decrease in CYP2D6 levels increased the systemic exposure of MAP. DMS exposure increased due to a reduction in the abundance of CYP2B6 and CYP3A4 in RI and HI subjects. In addition, an increase in the exposure of the primary metabolites decreased the exposure of AMP. No significant difference between the adult and adolescent populations, in terms of PK, were observed. The current PBPK model predictions indicate that subjects with HI or RI may require closer clinical monitoring to identify any untoward effects associated with the administration of transdermal SEL patch. Full article
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38 pages, 4545 KiB  
Article
Progressing Towards the Sustainable Development of Cream Formulations
by Ana Simões, Francisco Veiga and Carla Vitorino
Pharmaceutics 2020, 12(7), 647; https://doi.org/10.3390/pharmaceutics12070647 - 09 Jul 2020
Cited by 14 | Viewed by 4451
Abstract
This work aims at providing the assumptions to assist the sustainable development of cream formulations. Specifically, it envisions to rationalize and predict the effect of formulation and process variability on a 1% hydrocortisone cream quality profile, interplaying microstructure properties with product performance and [...] Read more.
This work aims at providing the assumptions to assist the sustainable development of cream formulations. Specifically, it envisions to rationalize and predict the effect of formulation and process variability on a 1% hydrocortisone cream quality profile, interplaying microstructure properties with product performance and stability. This tripartite analysis was supported by a Quality by Design approach, considering a three-factor, three-level Box-Behnken design. Critical material attributes and process parameters were identified from a failure mode, effects, and criticality analysis. The impact of glycerol monostearate amount, isopropyl myristate amount, and homogenization rate on relevant quality attributes was estimated crosswise. The significant variability in product droplet size, viscosity, thixotropic behavior, and viscoelastic properties demonstrated a noteworthy influence on hydrocortisone release profile (112 ± 2–196 ± 7 μg/cm2/√h) and permeation behavior (0.16 ± 0.03–0.97 ± 0.08 μg/cm2/h), and on the assay, instability index and creaming rate, with values ranging from 81.9 to 120.5%, 0.031 ± 0.012 to 0.28 ± 0.13 and from 0.009 ± 0.000 to 0.38 ± 0.07 μm/s, respectively. The release patterns were not straightforwardly correlated with the permeation behavior. Monitoring the microstructural parameters, through the balanced adjustment of formulation and process variables, is herein highlighted as the key enabler to predict cream performance and stability. Finally, based on quality targets and response constraints, optimal working conditions were successfully attained through the establishment of a design space. Full article
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16 pages, 1432 KiB  
Article
Evaluations of Quality by Design (QbD) Elements Impact for Developing Niosomes as a Promising Topical Drug Delivery Platform
by Parinbhai Shah, Benjamin Goodyear, Anika Haq, Vinam Puri and Bozena Michniak-Kohn
Pharmaceutics 2020, 12(3), 246; https://doi.org/10.3390/pharmaceutics12030246 - 09 Mar 2020
Cited by 43 | Viewed by 5020
Abstract
Topical corticosteroids are used to treat a variety of skin conditions such as allergic reactions, eczema, and psoriasis. Niosomes are a novel surfactant-based delivery system that may be used to deliver desoximetasone via topical product application in order to mitigate common side effects [...] Read more.
Topical corticosteroids are used to treat a variety of skin conditions such as allergic reactions, eczema, and psoriasis. Niosomes are a novel surfactant-based delivery system that may be used to deliver desoximetasone via topical product application in order to mitigate common side effects associated with traditional oral delivery routes. The aim of this research was to identify the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of drug-loaded niosomes using a systematic quality by design (QbD) approach. An organic phase injection method was developed and used to manufacture the niosomes. The CMAs were identified to be drug amount, concentrations of surfactant and cholesterol, and types of lipids. The CPPs were phase volumes, temperature, mixing parameters, and addition rate based on previous research. The quality attributes measured were entrapment efficiency, particle size distribution, PDI, and zeta potential. These were used to determine the quality target product profile (QTPP) of niosomes. The experimental data indicate that the critical impacting variables for niosomes are: surfactant and cholesterol concentrations, mixing parameters, and organic-phase addition rate. Based on the experimental results of this study methanol:diethyl ether (75:25) as the organic system, drug:surfactant:cholesterol in 1:2:1 concentration, stearic acid as the charge-inducing material, 20 mL external phase and 10 mL internal phase volume, 65 °C external phase temperature, 60 min mixing time, 650 RPM mixing speed and 1 mL/ml addition rate is the ideal combination to achieve desirable desoximetasone niosomes with optimum entrapment efficiency and particle size for topical application. Full article
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15 pages, 1821 KiB  
Article
Novel Nanocarriers for Targeted Topical Skin Delivery of the Antioxidant Resveratrol
by Christofori M. R. R. Nastiti, Thellie Ponto, Yousuf Mohammed, Michael S. Roberts and Heather A. E. Benson
Pharmaceutics 2020, 12(2), 108; https://doi.org/10.3390/pharmaceutics12020108 - 29 Jan 2020
Cited by 33 | Viewed by 3793
Abstract
Resveratrol (RSV) is a potent lipophilic antioxidant with a low aqueous solubility. Novel nanoformulations have been successfully developed and evaluated to increase the potential of resveratrol as a skin targeting antioxidant. Nanoformulations were prepared using a spontaneous emulsification method, and characterized and evaluated [...] Read more.
Resveratrol (RSV) is a potent lipophilic antioxidant with a low aqueous solubility. Novel nanoformulations have been successfully developed and evaluated to increase the potential of resveratrol as a skin targeting antioxidant. Nanoformulations were prepared using a spontaneous emulsification method, and characterized and evaluated for their capabilities to penetrate/permeate the skin. In nanoformulations, the thermodynamic activity of the RSV penetration into/permeation through the skin was correlated with the thermodynamic activity of the RSV in the formulations. When terpenes were incorporated into the nanoformulations, the permeation of RSV through the skin increased and correlated with an increasing lipophilicity of the terpene. The nanoemulsion containing eugenol showed the highest RSV penetration into the stratum corneum (SC) and the epidermis-dermis-follicle region, whereas the limonene containing nanoemulsion had the highest RSV permeation through the skin (the enhancement ratios, compared to a saturated solution of RSV, were (i) 9.55 and (ii) 12.61, respectively, based on the average RSV amount (i) in each skin region and (ii) permeation through skin). Full article
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13 pages, 1372 KiB  
Article
Monitoring the Clinical Response to an Innovative Transdermal Delivery System for Ibuprofen
by Anthony Wright, Heather A. E. Benson, Penny Moss and Rob Will
Pharmaceutics 2019, 11(12), 664; https://doi.org/10.3390/pharmaceutics11120664 - 09 Dec 2019
Cited by 4 | Viewed by 2993
Abstract
We present a phase 1 study that utilizes a crossover design that provides a rapid and relatively inexpensive methodology for evaluating a new transdermal product. The treatment for osteoarthritis (OA) aims to reduce pain and improve function. An innovative magnetophoresis technology has been [...] Read more.
We present a phase 1 study that utilizes a crossover design that provides a rapid and relatively inexpensive methodology for evaluating a new transdermal product. The treatment for osteoarthritis (OA) aims to reduce pain and improve function. An innovative magnetophoresis technology has been developed that facilitates transdermal delivery of ibuprofen. The study used measures that were taken over a relatively short time period to monitor the pharmacodynamic response to ibuprofen. Each participant received magnetophoresis-enhanced transdermal ibuprofen or placebo in randomised order, with a five-day washout period. The participants were 24 volunteers with medically diagnosed, painful knee OA. The primary outcome measures were VAS rating of pain on movement and Western Ontario and McMaster Universities (WOMAC) pain and function scores. VAS for pain on movement (p < 0.001), WOMAC pain score (p = 0.004), and WOMAC function score (p = 0.004) were all significantly improved. There was a significant reduction in movement-related pain (p < 0.05) during the first patch application and for the remainder of the study period. The number needed to treat for a 50% reduction in movement related pain was 2.2. The study showed a rapid and significant analgesic effect in response to transdermal ibuprofen. A short trial of this nature can be used for informing the parameters that are required for a major randomised controlled trial. Full article
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19 pages, 4017 KiB  
Article
Investigation of Silicone-Containing Semisolid in Situ Film-Forming Systems Using QbD Tools
by Nikolett Kis, Anita Kovács, Mária Budai-Szűcs, Attila Gácsi, Erzsébet Csányi, Ildikó Csóka and Szilvia Berkó
Pharmaceutics 2019, 11(12), 660; https://doi.org/10.3390/pharmaceutics11120660 - 07 Dec 2019
Cited by 13 | Viewed by 3003
Abstract
The aim of our research work was to develop dermally applicable, semisolid film-forming systems (FFSs) containing silicones, which form a film on the skin in situ, with suitable mechanical properties for skin application. FFSs were developed and investigated by means of the Quality [...] Read more.
The aim of our research work was to develop dermally applicable, semisolid film-forming systems (FFSs) containing silicones, which form a film on the skin in situ, with suitable mechanical properties for skin application. FFSs were developed and investigated by means of the Quality by Design (QbD) methodology. With this QbD approach, the initial risk assessment defines the critical quality attributes (CQAs), the critical material attributes (CMAs) and the critical process parameters (CPPs) to ensure the required quality. Different semisolid systems were formed with or without silicones. During the initial risk assessment, three CQAs, namely skin adhesion, film flexibility and burst strength, were found to be critical attributes, while film appearance, film integrity and the drying time of the semisolid system, were found to be medium attributes. These parameters were investigated. The initial risk assessment also showed that there are three high CMAs: the type of silicones, film-forming excipients, drying excipients, and that there was one medium CMA: viscosity-enhancing excipients. Based on our results, the silicone content had a great effect on the film-forming systems. Different silicones affected the mechanical properties of the films in varying ways, decreased the drying time and showed promising results regarding the drying mechanism. Full article
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20 pages, 2238 KiB  
Article
Mechanistic Evaluation of Enhanced Curcumin Delivery through Human Skin In Vitro from Optimised Nanoemulsion Formulations Fabricated with Different Penetration Enhancers
by Shereen A. Yousef, Yousuf H. Mohammed, Sarika Namjoshi, Jeffrey E. Grice, Heather A. E. Benson, Wedad Sakran and Michael S. Roberts
Pharmaceutics 2019, 11(12), 639; https://doi.org/10.3390/pharmaceutics11120639 - 01 Dec 2019
Cited by 38 | Viewed by 3989
Abstract
Curcumin is a natural product with chemopreventive and other properties that are potentially useful in treating skin diseases, including psoriasis and melanoma. However, because of the excellent barrier function of the stratum corneum and the relatively high lipophilicity of curcumin (log P 3.6), [...] Read more.
Curcumin is a natural product with chemopreventive and other properties that are potentially useful in treating skin diseases, including psoriasis and melanoma. However, because of the excellent barrier function of the stratum corneum and the relatively high lipophilicity of curcumin (log P 3.6), skin delivery of curcumin is challenging. We used the principles of a Quality by Design (QbD) approach to develop nanoemulsion formulations containing biocompatible components, including Labrasol and Lecithin as surfactants and Transcutol and ethanol as cosurfactants, to enhance the skin delivery of curcumin. The nanoemulsions were characterised by cryo-SEM, Zeta potential, droplet size, pH, electrical conductivity (EC) and viscosity (η). Physicochemical long-term stability (6 months) was also investigated. The mean droplet sizes as determined by dynamic light scattering (DLS) were in the lower submicron range (20–50 nm) and the average Zeta potential values were low (range: −0.12 to −2.98 mV). Newtonian flow was suggested for the nanoemulsions investigated, with dynamic viscosity of the nanoemulsion formulations ranging from 5.8 to 31 cP. The droplet size of curcumin loaded formulations remained largely constant over a 6-month storage period. The inclusion of terpenes to further enhance skin permeation was also examined. All nanoemulsions significantly enhanced the permeation of curcumin through heat-separated human epidermal membranes, with the greatest effect being a 28-fold increase in maximum flux (Jmax) achieved with a limonene-based nanoemulsion, compared to a 60% ethanol in water control vehicle. The increases in curcumin flux were associated with increased skin diffusivity. In summary, we demonstrated the effectiveness of nanoemulsions for the skin delivery of the lipophilic active compound curcumin, and elucidated the mechanism of permeation enhancement. These formulations show promise as delivery vehicles for curcumin to target psoriasis and skin cancer, and more broadly for other skin delivery applications. Full article
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Review

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12 pages, 883 KiB  
Review
Quality by Design: Development of the Quality Target Product Profile (QTPP) for Semisolid Topical Products
by Sarika Namjoshi, Maryam Dabbaghi, Michael S. Roberts, Jeffrey E. Grice and Yousuf Mohammed
Pharmaceutics 2020, 12(3), 287; https://doi.org/10.3390/pharmaceutics12030287 - 23 Mar 2020
Cited by 54 | Viewed by 14152
Abstract
In recent years, the “quality by design” (QbD) approach has been used for developing pharmaceutical formulations. This is particularly important for complex dosage forms such as topical semisolid products. The first step for developing a product using this efficient approach is defining the [...] Read more.
In recent years, the “quality by design” (QbD) approach has been used for developing pharmaceutical formulations. This is particularly important for complex dosage forms such as topical semisolid products. The first step for developing a product using this efficient approach is defining the quality target product profile (QTPP), a list of quality attributes (QAs) that are required to be present in the final product. These quality attributes are affected by the ingredients used as well as manufacturing procedure parameters. Hence, critical material attributes (CMAs) and critical process parameters (CPPs) need to be specified. Possible failure modes of a topical semisolid product can be determined based on the physiochemical properties of ingredients and manufacturing procedures. In this review, we have defined and specified QTPP, QAs, CMAs and CPPs that are required for developing a topical semisolid product based on the QbD approach. Full article
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