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Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 22917

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Special Issue Editors

Dr. Joana Marques Marto

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Guest Editor

Research Institute for Medicines (iMed.ULisboa), Universidade de Lisboa, 1649-003 Lisbon, Portugal
Interests: transdermal/topical systems; skin delivery; cosmetic formulations; 3D printing; quality-by-design
Special Issues, Collections and Topics in MDPI journals

Dr. Carla Vitorino

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Guest Editor

1. Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
2. Coimbra Chemistry Centre, Institute of Molecular Sciences (IMS), Faculty of Sciences and Technology, University of Coimbra, 3004-535 Coimbra, Portugal
Interests: nanotechnology; drug permeation enhancement; transdermal and oral drug delivery; brain targeting
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The development of drug products either to be delivered to and/or through the skin involves a multifactorial approach to address the challenges imposed by the skin–drug–vehicle triad. Ranging from in silico methodologies to determine skin permeation predictors, in vitro/ex vivo analytical technologies to estimate the potential impact that formulation or process parameters may exert in release–permeation behavior, to in vivo approaches to evaluate therapeutic performance, several issues are raised in this long journey that assist the pharmaceutical development of drug products directed to skin delivery. Initiatives such as quality by design and safety by design brought about by digital pharma intend to function as key enablers not only to speed up the formulation design task and boost the timely introduction of safer and quality-oriented skin products into the market, but also to harmonize and reduce regulatory requirements. Noteworthy, several efforts are being developed in this field to change the current paradigm of topical/transdermal development evaluation. This Special Issue is directed to the fundamentals of in silico, in vitro, and in vivo studies involved in the development of topical/transdermal drug products, and aspects concerning their regulatory translation to the market. It is our pleasure to invite you to submit a manuscript for this Special Issue. Full papers, communications, and reviews are all welcome.

Prof. Dr. Carla Vitorino
Prof. Dr. Joana Marto
Guest Editor

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Keywords

skin delivery
topical drug products
transdermal systems
quality by design, safety by design
regulatory aspects
pharmaceutical development

Published Papers (6 papers)

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Research

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22 pages, 18966 KiB

Open AccessArticle

Complying with the Guideline for Quality and Equivalence for Topical Semisolid Products: The Case of Clotrimazole Cream

by Teresa Alves, Daniel Arranca, Ana Martins, Helena Ribeiro, Sara Raposo and Joana Marto

Pharmaceutics 2021, 13(4), 555; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13040555 - 14 Apr 2021

Cited by 9 | Viewed by 3703

Abstract

Semisolids constitute a significant proportion of topical pharmaceutical dosage forms available on the market, with creams being considered profitable systems for releasing active substances into the skin. This work aimed at the development of a generic Clotrimazole topical cream, based on the assumptions that assist the development of such formulations. First, the critical parameters to obtain a final formulation as similar as possible to the reference product were defined. Then, the percentages of cetyl palmitate and octyldodecanol were identified as critical variables and chosen for optimization in further studies. A “quality by design” approach was then used to identify the effect of process variability on the structural and functional similarity (Q3) of the generic product qualitatively (Q1) and quantitatively (Q2). A two-factor central composite orthogonal design was applied and eleven different formulations were developed and subjected to physicochemical characterization and product performance studies. The results were used to estimate the influence of the two variables in the variation of the responses, and to determine the optimum point of the tested factors, using a design space approach. Finally, an optimized formulation was obtained and analysed in parallel with the reference. The obtained results agreed with the prediction of the chemometric analysis, validating the reliability of the developed multivariate models. The in vitro release and permeation results were similar for the reference and the generic formulations, supporting the importance of interplaying microstructure properties with product performance and stability. Lastly, based on quality targets and response constraints, optimal working conditions were successfully achieved. Full article

(This article belongs to the Special Issue Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?)

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15 pages, 1051 KiB

Open AccessArticle

Influence of Inter- and Intra-Batch Variability on the Sample Size Required for Demonstration of Equivalent Microstructure of Semisolid Dosage Forms

by Zhengguo Xu, Víctor Mangas-Sanjuán, Matilde Merino-Sanjuán, Virginia Merino and Alfredo García-Arieta

Pharmaceutics 2020, 12(12), 1159; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121159 - 28 Nov 2020

Cited by 9 | Viewed by 2268

Abstract

Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative sample size to describe accurately the in vitro properties of semisolids and to reach enough statistical power to demonstrate similarity between two semisolid topical products is currently challenging. The objective of this work is to establish the number of batches and units per batch to be compared based on different inter-batch and intra-batch variability to demonstrate equivalence in the physical characteristics of the products that ensure a similar microstructure of the semisolid. This investigation shows that the minimum number of batches to be compared of each product is 3 and the minimum number of units per batch could be 6 in the case of low intra- and inter-batch variability. If the products are not identical, i.e., 2.5–5% differences that are expected due to differences in the manufacturing process or the suppliers of excipients, 12 units and 6 batches are needed. If intra- or inter-batch variability is larger than 10%, the number of batches and/or the number of units needs to be increased. As the interplay between inter- and intra-batch variability is complex, the sample size required for each combination of inter- and intra-batch variability and expected difference between products can be obtained in the attached tables. Full article

(This article belongs to the Special Issue Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?)

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16 pages, 2650 KiB

Open AccessArticle

Quality-by-Design Approach for the Development of Nano-Sized Tea Tree Oil Formulation-Impregnated Biocompatible Gel with Antimicrobial Properties

by Thabata Muta, Ankit Parikh, Krishna Kathawala, Hanif Haidari, Yunmei Song, Jackson Thomas and Sanjay Garg

Pharmaceutics 2020, 12(11), 1091; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12111091 - 13 Nov 2020

Cited by 16 | Viewed by 3654

Abstract

Despite the promising properties of tea tree oil (TTO) as potential therapeutics for several superficial skin conditions, certain limitations such as physical instability and skin irritation have restricted its widespread use. This study focuses on developing a rationally designed lipid-based nanoformulation (TTO-LNF) in accordance with the US Food and Drug Administration standard using a well-recognized quality-by-design (QbD) approach. Using a mixture experimental design, TTO-LNF has been optimized with 5% TTO, 10% surfactant, 5% co-surfactant, and 80% water, which showed a 14.4 ± 4.4 nm droplet size and 0.03 ± 0.01 polydispersity index (PDI). To ease the topical administration, the TTO-LNF gel formulation was further developed using xanthan gum to achieve the desired viscosity and form a gel. The in vitro antibacterial tests of TTO-LNF showed promising inhibitory effects toward both Gram-negative and Gram-positive bacteria. In fact, a complete growth inhibition of S. epidermidis was observed when exposed to TTO-LNF and TTO-LNF gel for 24 h, showing better activity than antibiotic kanamycin (25 µg/mL). Additionally, the in vitro release study showed a sustained release profile with a 50% release in 24 h, which could be beneficial to reduce the toxicity and thereby improve the therapeutic efficacy for long-acting applications. Furthermore, the formulations were remarkably stable at 40 °C/75% Relative humidity (RH) for at least 4 weeks. Therefore, this study presents a promising strategy to develop a biocompatible and stable formulation that can be used for the topical treatment of skin infections. Full article

(This article belongs to the Special Issue Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?)

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27 pages, 5045 KiB

Open AccessArticle

Rheology by Design: A Regulatory Tutorial for Analytical Method Validation

by Ana Simões, Margarida Miranda, Catarina Cardoso, Francisco Veiga and Carla Vitorino

Pharmaceutics 2020, 12(9), 820; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090820 - 28 Aug 2020

Cited by 40 | Viewed by 5161

Abstract

The increasing demand for product and process understanding as an active pursuit in the quality guideline Q8 and, more recently, on the draft guideline on quality and equivalence of topical products, has unveiled the tremendous potential of rheology methods as a tool for microstructure characterization of topical semisolid dosage forms. Accordingly, procedure standardization is a dire need. This work aimed at developing and validating a methodology tutorial for rheology analysis. A 1% hydrocortisone cream was used as model cream formulation. Through a risk assessment analysis, the impact of selected critical method variables (geometry, temperature and application mode) was estimated in a broad range of rheological critical analytical attributes—zero-shear viscosity, upper-shear thinning viscosity, lower-shear thinning viscosity, infinite-shear viscosity, rotational yield point, thixotropic relative area, linear viscoelastic region, oscillatory yield point, storage modulus, loss modulus, and loss tangent. The proposed validation of the approach included the rheometer qualification, followed by the validation of numerous operational critical parameters regarding a rheology profile acquisition. The thixotropic relative area, oscillatory yield point, flow point and viscosity related endpoints proved to be highly sensitive and discriminatory parameters. This rationale provided a standard framework for the development of a reliable and robust rheology profile acquisition. Full article

(This article belongs to the Special Issue Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?)

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10 pages, 1625 KiB

Open AccessArticle

Novel In Vitro Investigational Methods for Modeling Skin Permeation: Skin PAMPA, Raman Mapping

by Stella Zsikó, Erzsébet Csányi, Anita Kovács, Mária Budai-Szűcs, Attila Gácsi and Szilvia Berkó

Pharmaceutics 2020, 12(9), 803; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090803 - 25 Aug 2020

Cited by 10 | Viewed by 3004

Abstract

The human skin is marked as a standard by the regulatory agencies in the permeation study of dermal formulations. Artificial membranes can substitute human skin to some extent. Academicians and pharmaceutical corporations are focusing their efforts on developing standardized protocols and safe, reliable options to substitute human skin for carrying out permeability studies. Our research aim was to study the applicability of new techniques in the case of different types of dermal formulations. The skin parallel artificial membrane permeability assay (PAMPA) method and Raman mapping were compared to the gold-standard Franz cell method. A hydrogel and two types of creams were investigated as the most generally used dermal preparations. The values of the diffused drug were closer to each other in PAMPA and Franz cell measurement. The diffused amount of drug showed the same order for the different formulations. These results correlate well with the results of Raman mapping. Our conclusions suggest that all early screening examinations can be performed with model tools such as skin PAMPA supplemented with methods like Raman mapping as a semi-quantitative method. Full article

(This article belongs to the Special Issue Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?)

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Review

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17 pages, 26426 KiB

Open AccessReview

NLRP3 Inflammasome and Allergic Contact Dermatitis: A Connection to Demystify

by Ana Isabel Sebastião, Isabel Ferreira, Gonçalo Brites, Ana Silva, Bruno Miguel Neves and Maria Teresa Cruz

Pharmaceutics 2020, 12(9), 867; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090867 - 11 Sep 2020

Cited by 19 | Viewed by 4314

Abstract

Allergic contact dermatitis is a common occupational disease that manifests as a cell-mediated hypersensitivity reaction following skin exposure to small reactive chemicals termed haptens. Haptens penetrate the stratum corneum and covalently modify proteins in the epidermis, inducing intracellular stress, which further leads to the release of damage-associated molecular patterns (DAMPs), such as uric acid, reactive oxygen species, hyaluronic acid fragments and extracellular adenosine triphosphate (ATP). These DAMPs are recognized by pattern recognition receptors (PRRs) in innate immune cells, namely dendritic cells (DCs), leading to their maturation and migration to the draining lymph nodes where they activate naïve T lymphocytes. Among all PRRs, several studies emphasize the role of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome on the allergic contact dermatitis (ACD) sensitization phase. However, skin allergens—danger signals—NLRP3 inflammasome axis is yet to be completely elucidated. Therefore, in this review, we sought to discuss the molecular mechanisms underlying DAMPs release and NLRP3 inflammasome activation triggered by skin allergens. The elucidation of these key events might help to identify novel therapeutic strategies for ACD, as well as the development of nonanimal alternative methods for the identification and potency categorization of skin sensitizers. Full article

(This article belongs to the Special Issue Pharmaceutical Development and Regulatory Aspects of Drug Products for Skin Delivery: What Is New?)

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