Special Issue "Targeted Topical Drug Delivery: Improving the Efficacy of Local Therapy and Decreasing the Risk of Off-Target Side-Effects"

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (20 February 2020).

Special Issue Editors

Prof. Dr. Yogeshvar N. Kalia
Website
Guest Editor
School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU-1 rue Michel Servet, 1211 Geneva 4, Switzerland
Interests: targeted drug delivery; minimally invasive drug delivery; fractional laser ablation; iontophoresis; development of innovative formulations; nanoformulations; design of novel biological barrier models
Special Issues and Collections in MDPI journals
Dr. Maria Lapteva
Website
Guest Editor
School of Pharmaceutical Sciences, University of Geneva & University of Lausanne, CMU-1 rue Michel Servet, 1211 Geneva 4, Switzerland
Interests: development of novel strategies to optimize the topical skin bioavailability of already marketed and new low- and high-molecular-weight drugs in order to offer better therapeutic solutions to patients with dermatological conditions; expression, purification, formulation, and delivery of proteins using iontophoresis
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colelagues,

Parts of the body directly in contact with the external environment (e.g., skin, eyes, nails, the buccal cavity or lungs) are often host to local diseases, e.g., viral, fungal, and bacterial infections and autoimmune conditions, to name but a few. Progress in modern evidence-based medicine and pharmaceutical research has enabled the successful management of these conditions and undeniably led to improvement in patients’ quality of life. Nevertheless, despite the accessibility of these regions, too many drugs are still administered far from the diseased site, i.e., orally or parenterally. Only a small fraction of the administered dose reaches the peripheral target site, and even then, it can be at suboptimal concentrations.

Topical drug delivery allows the API to be conveyed directly to its site of action, providing relevant therapeutic concentrations and avoiding unnecessary systemic circulation, first-pass hepatic metabolism, and off-target side-effects. Nevertheless, topical delivery is often challenging because organs exposed to the environment possess effective barrier functions that hinder the entry of xenobiotics.

This Special Issue aims to reflect the ongoing research effort in the field of topical drug delivery and how this might positively influence the benefit/risk ratio and thus improve patient care. We invite articles on all aspects of targeted topical drug delivery, with an emphasis on improving efficacy and safety.

Prof. Dr. Yogeshvar N. Kalia
Dr. Maria Lapteva
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • topical skin delivery
  • topical ocular delivery
  • topical pulmonary delivery
  • nose to brain delivery
  • topical buccal delivery
  • ungual delivery
  • wound healing

Published Papers (8 papers)

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Research

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Open AccessArticle
Improved Diabetic Wound Healing by EGF Encapsulation in Gelatin-Alginate Coacervates
Pharmaceutics 2020, 12(4), 334; https://doi.org/10.3390/pharmaceutics12040334 - 08 Apr 2020
Cited by 2
Abstract
Topical imageplication of epidermal growth fctor (EGF) has been used to accelerate diabetic foot ulcers but with limited efficacy. In this study, we selected a complex coacervate (EGF-Coa) composed of the low molecular weight gelatin type A and sodium alginate as a novel [...] Read more.
Topical imageplication of epidermal growth fctor (EGF) has been used to accelerate diabetic foot ulcers but with limited efficacy. In this study, we selected a complex coacervate (EGF-Coa) composed of the low molecular weight gelatin type A and sodium alginate as a novel delivery system for EGF, based on encapsulation efficiency and protection of EGF from protease. EGF-Coa enhanced in vitro migration of keratinocytes and accelerated wound healing in streptozotocin-induced diabetic mice with increased granulation and re-epithelialization. While diabetic wound sites without treatment showed downward growth of hyperproliferative epidermis along the wound edges with poor matrix formation, EGF-Coa treatment recovered horizontal migration of epidermis over the newly deposited dermal matrix. EGF-Coa treatment also resulted in reduced levels of proinflammatory cytokines IL-1, IL-6, and THF-α. Freeze-dried coacervates packaged in aluminum pouches were stable for up to 4 months at 4 and 25 °C in terms of appearance, purity by RP-HPLC, and in vitro release profiles. There were significant physical and chemical changes in relative humidity above 33% or at 37 °C, suggesting the requirement for moisture-proof packaging and cold chain storage for long term stability. We propose low molecular weight gelatin type A and sodium alginate (LWGA-SA) coacervates as a novel EGF delivery system with enhanced efficacy for chronic wounds. Full article
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Open AccessArticle
Topical Pioglitazone Nanoformulation for the Treatment of Atopic Dermatitis: Design, Characterization and Efficacy in Hairless Mouse Model
Pharmaceutics 2020, 12(3), 255; https://doi.org/10.3390/pharmaceutics12030255 - 12 Mar 2020
Cited by 3
Abstract
Pioglitazone (PGZ) is a drug used to treat type 2 diabetes mellitus that has been reported to show additional therapeutic activities on diverse inflammatory parameters. The aim of this study was to optimize a topical PGZ-loaded nanoemulsion (PGZ-NE) in order to evaluate its [...] Read more.
Pioglitazone (PGZ) is a drug used to treat type 2 diabetes mellitus that has been reported to show additional therapeutic activities on diverse inflammatory parameters. The aim of this study was to optimize a topical PGZ-loaded nanoemulsion (PGZ-NE) in order to evaluate its effectiveness for treating atopic dermatitis (AD). The composition of the nanoformulation was established by pseudo-ternary diagram. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined. The efficacy study was carried out using oxazolone-induced AD model in hairless mice. PGZ-NE released the drug following a hyperbolic kinetic. Additionally, its properties provided high retention potential of drug inside the skin. Therapeutic benefits of PGZ-NE were confirmed on diverse events of the inflammatory process, such as reduction of lesions, enhancement of skin barrier function, diminished infiltration of inflammatory cells, and expression of pro-inflammatory cytokines. These results were reinforced by atomic force microscope (AFM), which demonstrated the ability of the formulation to revert the rigidification caused by oxazolone and consequently improve the elasticity of the skin. These results suggest that PGZ-NE may be a promising treatment for inflammatory dermatological conditions such as AD. Full article
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Open AccessArticle
Preparation, Characterisation, and Topical Delivery of Terbinafine
Pharmaceutics 2019, 11(10), 548; https://doi.org/10.3390/pharmaceutics11100548 - 22 Oct 2019
Cited by 5
Abstract
Terbinafine (TBF) is commonly used in the management of fungal infections of the skin because of its broad spectrum of activity. Currently, formulations containing the free base and salt form are available. However, there is only limited information in the literature about the [...] Read more.
Terbinafine (TBF) is commonly used in the management of fungal infections of the skin because of its broad spectrum of activity. Currently, formulations containing the free base and salt form are available. However, there is only limited information in the literature about the physicochemical properties of this drug and its uptake by the skin. In this work, we conducted a comprehensive characterisation of TBF, and we also examined its percutaneous absorption in vitro in porcine skin. TBF-free base was synthesised from the hydrochloride salt by a simple proton displacement reaction. Both the free base and salt form were further analysed using Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Delivery of TBF-free base in excised porcine skin was investigated from the following solvents: Isopropyl myristate (IPM), propylene glycol monolaurate (PGML), Transcutol® (TC), propylene glycol (PG), polyethylene glycol 200 (PEG 200), oleic acid (OL), ethanol (EtOH), and isopropyl alcohol (IPA). Permeation and mass balance studies confirmed that PG and TC were the most efficacious vehicles, delivering higher amounts of TBF-free base to the skin compared with a commercial gel (p < 0.05). These preliminary results are promising and will inform the development of more complex formulations in future work. Full article
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Open AccessArticle
Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence
Pharmaceutics 2019, 11(10), 503; https://doi.org/10.3390/pharmaceutics11100503 - 01 Oct 2019
Cited by 5
Abstract
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment [...] Read more.
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters were calculated with parametric and non-parametric approaches. Both methods conclude that equivalent microstructure between batches cannot be demonstrated with a reasonable sample size when the acceptance range was set at ±10%, since several physical parameters exhibit inter-batch variability >10%. An acceptance range of ±10% is therefore too strict to conclude equivalence in the microstructure of semisolid dosage forms, given the inter-batch variability observed between batches of the reference product. A wider fixed acceptance range or an acceptance range widened based on the inter-batch variability of the reference product would be advisable. Full article
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Open AccessArticle
Cutaneous Biodistribution: A High-Resolution Methodology to Assess Bioequivalence in Topical Skin Delivery
Pharmaceutics 2019, 11(9), 484; https://doi.org/10.3390/pharmaceutics11090484 - 18 Sep 2019
Cited by 1
Abstract
A draft guideline from the European Medicines Agency (EMA) highlights the need for methods to assess the quality/equivalence of topical drug formulations. The “cutaneous biodistribution method”, which provides insight into a drug’s spatial distribution in the epidermis/dermis, was used to compare cutaneous bioavailability [...] Read more.
A draft guideline from the European Medicines Agency (EMA) highlights the need for methods to assess the quality/equivalence of topical drug formulations. The “cutaneous biodistribution method”, which provides insight into a drug’s spatial distribution in the epidermis/dermis, was used to compare cutaneous bioavailability of econazole nitrate (ECZ) from a reference medicinal product (RMP) and two approved bioequivalent generic creams under finite dose conditions. Statistically significant differences between the ECZ biodistributions from the RMP/Generics were determined and used with acceptance criteria based on those from the EMA to evaluate bioequivalence. In porcine skin, ECZ deposition in total skin, epidermis, upper and lower dermis from Generic 1 was within the acceptance interval, contrary to Generic 2, which was marginally below it. For human skin, Generic 1 deposition was marginally above the acceptance interval and not bioequivalent. The results were consistent with those using the EMA’s acceptance intervals using the ratio of the mean ECZ depositions of Generic 1 and the RMP. Differences identified using this data-rich technique may not translate to observable differences in clinical efficacy; however, generics with non-statistically different biodistributions to the RMP should have a comparable clinical effect. The cutaneous biodistribution method could benchmark the development of topical generic products. Full article
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Open AccessArticle
Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles
Pharmaceutics 2019, 11(9), 476; https://doi.org/10.3390/pharmaceutics11090476 - 14 Sep 2019
Cited by 1
Abstract
This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a [...] Read more.
This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles. Full article
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Review

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Open AccessReview
An Update on Antimicrobial Peptides (AMPs) and Their Delivery Strategies for Wound Infections
Pharmaceutics 2020, 12(9), 840; https://doi.org/10.3390/pharmaceutics12090840 - 02 Sep 2020
Cited by 1
Abstract
Bacterial infections occur when wound healing fails to reach the final stage of healing, which is usually hindered by the presence of different pathogens. Different topical antimicrobial agents are used to inhibit bacterial growth due to antibiotic failure in reaching the infected site, [...] Read more.
Bacterial infections occur when wound healing fails to reach the final stage of healing, which is usually hindered by the presence of different pathogens. Different topical antimicrobial agents are used to inhibit bacterial growth due to antibiotic failure in reaching the infected site, which is accompanied very often by increased drug resistance and other side effects. In this review, we focus on antimicrobial peptides (AMPs), especially those with a high potential of efficacy against multidrug-resistant and biofilm-forming bacteria and fungi present in wound infections. Currently, different AMPs undergo preclinical and clinical phase to combat infection-related diseases. AMP dendrimers (AMPDs) have been mentioned as potent microbial agents. Various AMP delivery strategies that are used to combat infection and modulate the healing rate—such as polymers, scaffolds, films and wound dressings, and organic and inorganic nanoparticles—have been discussed as well. New technologies such as Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated protein (CRISPR-Cas) are taken into consideration as potential future tools for AMP delivery in skin therapy. Full article
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Open AccessReview
Targeted Topical Delivery of Retinoids in the Management of Acne Vulgaris: Current Formulations and Novel Delivery Systems
Pharmaceutics 2019, 11(10), 490; https://doi.org/10.3390/pharmaceutics11100490 - 24 Sep 2019
Cited by 13
Abstract
Acne vulgaris is a common inflammatory pilosebaceous condition that affects 80–90% of adolescents. Since the introduction of tretinoin over 40 years ago, topical retinoid products have been a mainstay of acne treatment. The retinoids are very effective in addressing multiple aspects of the [...] Read more.
Acne vulgaris is a common inflammatory pilosebaceous condition that affects 80–90% of adolescents. Since the introduction of tretinoin over 40 years ago, topical retinoid products have been a mainstay of acne treatment. The retinoids are very effective in addressing multiple aspects of the acne pathology as they are comedolytic and anti-inflammatory, and do not contribute to antibiotic resistance or microbiome disturbance that can be associated with long-term antibiotic therapies that are a common alternative treatment. However, topical retinoids are associated with skin dryness, erythema and pain, and may exacerbate dermatitis or eczema. Thus, there is a clear need to target delivery of the retinoids to the pilosebaceous units to increase efficacy and minimise side effects in surrounding skin tissue. This paper reviews the current marketed topical retinoid products and the research that has been applied to the development of targeted topical delivery systems of retinoids for acne. Full article
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