Research

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12 pages, 1700 KiB

Open AccessArticle

The Usefulness of In Vitro Percutaneous Absorption Experiments Applying the Infinite Dose Technique to Predict In Vivo Plasma Levels: Comparison of Model-Predicted and Observed Plasma Concentrations of Nortriptyline in Rats

by Iris Usach, Sara Di Marco, Octavio Díez, Manuel Alós and José-Esteban Peris

Pharmaceutics 2022, 14(7), 1457; https://doi.org/10.3390/pharmaceutics14071457 - 12 Jul 2022

Cited by 1 | Viewed by 1266

Abstract

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (k_out) using the in vitro infinite dose technique to predict in vivo [...] Read more.

The aims of this study were to evaluate the feasibility of a nortriptyline (NT) formulation for transdermal administration and to assess the usefulness of an estimated kinetic parameter (k_out) using the in vitro infinite dose technique to predict in vivo plasma levels when used in combination with pharmacokinetic parameters. To do so, a simple one-compartment model was used to describe the transport of a permeant across a membrane (skin). This model provides relatively simple expressions for the amount of permeant in the skin, the cumulative amount of permeant that crosses the skin, and the flux of permeant, for both the infinite and the finite dose regimens. Transdermal administration of the formulated NT gel to rats resulted in plasma levels of approximately 150 ng/mL between 8 and 30 h post-administration. These levels were higher than the minimum concentration of 40 ng/mL recommended for smoking cessation therapy and slightly higher than the upper limit of the therapeutic range for the treatment of depression in humans. The one-compartment model used to describe transport across the skin was connected to a two-compartment pharmacokinetic model used to predict NT plasma concentrations in rats using the k_out determined in vitro and the values of other pharmacokinetic parameters obtained in vivo. The predicted concentrations were close to the observed plasma levels and the time profiles were similar for both types of data. These results show the usefulness of the k_out parameter determined in vitro to predict plasma concentrations of drugs administered percutaneously. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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13 pages, 2511 KiB

Open AccessArticle

Needle-Free Jet Injectors and Nanosuspensions: Exploring the Potential of an Unexpected Pair

by Michele Schlich, Luca Casula, Aurora Musa, Rosa Pireddu, Giulia Pitzanti, Maria Cristina Cardia, Donatella Valenti, Salvatore Marceddu, Anna Maria Fadda, Maria Antonietta De Luca, Chiara Sinico and Francesco Lai

Pharmaceutics 2022, 14(5), 1085; https://doi.org/10.3390/pharmaceutics14051085 - 19 May 2022

Cited by 3 | Viewed by 2503

Abstract

Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the [...] Read more.

Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the feasibility of using liquid jet injectors to administer nanosuspensions, assessing the impact of the jet injection on their pharmaceutical and physicochemical properties. For this purpose, the model drug diclofenac was used to prepare a set of nanosuspensions, stabilized by poloxamer 188, and equilibrated at different pHs. The hydrodynamic diameter and morphology of the nanocrystals were analyzed before and after the jet injection across porcine skin in vitro, together with the solubility and release kinetics of diclofenac in a simulated subcutaneous environment. The efficacy of the jet injection (i.e., the amount of drug delivered across the skin) was evaluated for the nanosuspension and for a solution, which was used as a control. Finally, the nanosuspension was administered to rats by jet injector, and the plasma profile of diclofenac was evaluated and compared to the one obtained by jet injecting a solution with an equal concentration. The nanosuspension features were maintained after the jet injection in vitro, suggesting that no structural changes occur upon high-speed impact with the skin. Accordingly, in vivo studies demonstrated the feasibility of jet injecting a nanosuspension, reaching relevant plasma concentration of the drug. Overall, needle-free jet injectors proved to be a suitable alternative to conventional syringes for the administration of nanosuspensions. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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22 pages, 5576 KiB

Open AccessArticle

Design, Physicochemical Characterization, and In Vitro Permeation of Innovative Resatorvid Topical Formulations for Targeted Skin Drug Delivery

by Victor H. Ruiz, David Encinas-Basurto, Bo Sun, Basanth Babu Eedara, Sally E. Dickinson, Georg T. Wondrak, H. -H. Sherry Chow, Clara Curiel-Lewandrowski and Heidi M. Mansour

Pharmaceutics 2022, 14(4), 700; https://doi.org/10.3390/pharmaceutics14040700 - 24 Mar 2022

Cited by 4 | Viewed by 2812

Abstract

Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 [...] Read more.

Nonmelanoma skin cancers (NMSCs) are the most common malignancies worldwide and affect more than 5 million people in the United States every year. NMSC is directly linked to the excessive exposure of the skin to solar ultraviolet (UV) rays. The toll-like receptor 4 (TLR4) antagonist, resatorvid (TAK-242), is a novel prototype chemo preventive agent that suppresses the production of inflammation mediators induced by UV exposure. This study aimed to design and develop TAK-242 into topical formulations using FDA-approved excipients, including DermaBase^TM, PENcream^TM, polyethylene glycol (PEG)-400, propylene glycol (PG), carbomer gel, hyaluronic acid (HA) gel, and Pluronic^® F-127 poloxamer triblock copolymer gel for the prevention of skin cancer. The physicochemical properties of raw TAK-242, which influence the compatibility and solubility in the selected base materials, were confirmed using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Raman spectroscopy, and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopic analysis. The permeation behavior of TAK-242 from the prepared formulations was determined using Strat-M^® transdermal diffusion membranes, and 3D cultured primary human-derived epidermal keratinocytes (EpiDerm^TM). Despite TAK-242′s high molecular weight and hydrophobicity, it can permeate through reconstructed human epidermis from all formulations. The findings, reported for the first time in this study, emphasize the capabilities of the topical application of TAK-242 via these multiple innovative topical drug delivery formulation platforms. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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19 pages, 5971 KiB

Open AccessArticle

Cutaneous Delivery of Cosmeceutical Peptides Enhanced by Picosecond- and Nanosecond-Domain Nd:YAG Lasers with Quick Recovery of the Skin Barrier Function: Comparison with Microsecond-Domain Ablative Lasers

by Woan-Ruoh Lee, Chien-Yu Hsiao, Zi-Yu Chang, Pei-Wen Wang, Ibrahim A. Aljuffali, Jie-Yu Lin and Jia-You Fang

Pharmaceutics 2022, 14(2), 450; https://doi.org/10.3390/pharmaceutics14020450 - 19 Feb 2022

Cited by 4 | Viewed by 2933

Abstract

Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium–aluminum–garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional [...] Read more.

Picosecond or nanosecond-domain non-ablative lasers generate faster photothermal effects and cause less injury than microsecond lasers. In this study, we investigated the enhancing effect of 1064 nm picosecond- and nanosecond-domain neodymium (Nd):yttrium–aluminum–garnet (YAG) lasers on the cutaneous delivery of cosmeceutical peptides. Microsecond-domain fractional ablative CO₂ and fully ablative erbium (Er):YAG lasers were also used for comparison. In the Franz diffusion cell study, pig or mouse skin was treated with a laser before exposure to palmitoyl tripeptide (PT)-1, PT-38, and copper tripeptide (CT)-1 at a concentration of 150 μM. Psoriasiform, atopic dermatitis (AD)-like, and photoaged skins were also developed as permeation barriers. The non-ablative laser elicited the ultrastructural disruption of the stratum corneum and epidermal vacuolation. All laser modalities significantly increased the skin permeation of peptides in vitro. The non-ablative laser chiefly enhanced peptide delivery to the receptor compartment, whereas the ablative laser mainly increased the intracutaneous peptide deposition. The picosecond- and nanosecond-domain Nd:YAG lasers elevated the amount of PT-1 in the receptor up to 40- and 22-fold compared with untreated skin, respectively. Laser treatment promoted peptide delivery in barrier-deficient and inflamed skins, although this enhancement effect was less than that observed in healthy skin. Fluorescence microscopy indicated the capability of the non-ablative laser to deliver peptides to deeper skin strata. The ablative laser confined the peptide distribution in the epidermis. Confocal microscopy showed that peptides penetrated the skin along the microdots created by the fractional Nd:YAG and CO₂ lasers. The skin barrier function determined by transepidermal water loss suggested quick recovery when using a nanosecond-domain laser (within 4 h). A longer period was needed for the skin treated with the fully ablative Er:YAG laser (76−84 h). Nanosecond non-ablative laser-facilitated peptide delivery may become an efficient and safe approach for cosmeceutical applications. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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12 pages, 1883 KiB

Open AccessArticle

Immune Response after Skin Delivery of a Recombinant Heat-Labile Enterotoxin B Subunit of Enterotoxigenic Escherichia coli in Mice

by Melibea Berzosa, Alzbeta Nemeskalova, Amaia Zúñiga-Ripa, Miriam Salvador-Bescós, Eneko Larrañeta, Ryan F. Donnelly, Carlos Gamazo and Juan M. Irache

Pharmaceutics 2022, 14(2), 239; https://doi.org/10.3390/pharmaceutics14020239 - 20 Jan 2022

Cited by 5 | Viewed by 1885

Abstract

Enterotoxigenic Escherichia coli (ETEC) infections have been identified as a major cause of acute diarrhoea in children in developing countries, associated with substantial morbidity and mortality rates. Additionally, ETEC remains the most common cause of acute diarrhea of international travellers to endemic areas. [...] Read more.

Enterotoxigenic Escherichia coli (ETEC) infections have been identified as a major cause of acute diarrhoea in children in developing countries, associated with substantial morbidity and mortality rates. Additionally, ETEC remains the most common cause of acute diarrhea of international travellers to endemic areas. The heat-labile toxin (LT) is a major virulence factor of ETEC, with a significant correlation between the presence of antibodies against LT and protection in infected patients. In the present work, we constructed a recombinant LTB unit (rLTB) and studied the capacity of this toxoid incorporated in microneedles (rLTB-MN) to induce a specific immune response in mice. MN were prepared from aqueous blends of the polymer Gantrez AN^® [poly (methyl vinyl ether-co-maleic anhydride)], which is not cytotoxic and has been shown to possess immunoadjuvant properties. The mechanical and dissolution properties of rLTB-MNs were evaluated in an in vitro Parafilm M^® model and in mice and pig skin ex vivo models. The needle insertion ranged between 378 µm and 504 µm in Parafilm layers, and MNs fully dissolved within 15 min of application inside porcine skin. Moreover, female and male BALB/c mice were immunized through ear skin with one single dose of 5 μg·rLTB in MNs, eliciting significant fecal anti-LT IgA antibodies, higher in female than in male mice. Moreover, we observed an enhanced production of IL-17A by spleen cells in the immunized female mice, indicating a mucosal non-inflammatory and neutralizing mediated response. Further experiments will now be required to validate the protective capacity of this new rLTB-MN formulation against this deadly non-vaccine-preventable disease. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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13 pages, 1392 KiB

Open AccessArticle

Use of an In Vitro Skin Parallel Artificial Membrane Assay (Skin-PAMPA) as a Screening Tool to Compare Transdermal Permeability of Model Compound 4-Phenylethyl-Resorcinol Dissolved in Different Solvents

by Bálint Sinkó, Vivien Bárdos, Dániel Vesztergombi, Szabina Kádár, Petra Malcsiner, Anne Moustie, Chantal Jouy, Krisztina Takács-Novák and Sebastien Grégoire

Pharmaceutics 2021, 13(11), 1758; https://doi.org/10.3390/pharmaceutics13111758 - 21 Oct 2021

Cited by 5 | Viewed by 2489

Abstract

Absorption through the skin of topically applied chemicals is relevant for both formulation development and safety assessment, especially in the early stages of development. However, the supply of human skin is limited, and the traditional in vitro methods are of low throughput. As [...] Read more.

Absorption through the skin of topically applied chemicals is relevant for both formulation development and safety assessment, especially in the early stages of development. However, the supply of human skin is limited, and the traditional in vitro methods are of low throughput. As an alternative, an artificial membrane-based Skin Parallel Artificial Membrane Permeability Assay (Skin-PAMPA) has been developed to mimic the permeability through the stratum corneum. In this study, this assay was used to measure the permeability of a model compound, 4-phenylethyl-resorcinol (PER), dissolved in 13 different solvents that are commonly used in cosmetic formulation development. The study was performed at concentrations close to the saturated solution of PER in each solvent to investigate the maximum thermodynamic potential of the solvents. The permeability of PER in selected solvents was also measured on ex vivo pig skin for comparison. Pig ear skin is an accepted alternative model of human skin. The permeability coefficient, which is independent of the concentration of the applied solution, showed a good correlation (R² = 0.844) between the Skin-PAMPA and the pig skin permeation data. Our results support the use of the Skin-PAMPA to screen the suitability of different solvents for non-polar compounds at an early stage of formulation development. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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14 pages, 2296 KiB

Open AccessArticle

Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes

by Javiana Luengo, Marc Schneider, Anna M. Schneider, Claus-Michael Lehr and Ulrich F. Schaefer

Pharmaceutics 2021, 13(10), 1608; https://doi.org/10.3390/pharmaceutics13101608 - 03 Oct 2021

Cited by 10 | Viewed by 2543

Abstract

The steady improvement and optimization of transdermal permeation is a constant and challenging pharmaceutical task. In this study the influence of poly(lactide-co-glycolide) (PLGA) nanoparticles on the dermal permeation of the anti-inflammatory drug flufenamic acid (FFA) was investigated. For this aim, different vehicles under [...] Read more.

The steady improvement and optimization of transdermal permeation is a constant and challenging pharmaceutical task. In this study the influence of poly(lactide-co-glycolide) (PLGA) nanoparticles on the dermal permeation of the anti-inflammatory drug flufenamic acid (FFA) was investigated. For this aim, different vehicles under non-buffered and buffered conditions and different skin models (human heat separated epidermis and reconstructed human epidermis equivalents) were tested. Permeation experiments were performed using static Franz diffusion cells under infinite dosing conditions. Already the presence of drug-free nanoparticles increased drug permeation across the skin. Drug permeation was even enhanced when applying drug-loaded nanoparticles. In contrast, buffered vehicles with different pH values (pH 5.4–7.4) revealed the influence of the pH on the permeation of FFA. The change of the surrounding pH of the biodegradable nanoparticulate system was demonstrated and visualized using pH-sensitive fluorescent probes. While a potential contribution of hair follicles could be ruled out, our data suggest that the enhanced permeation of FFA through human skin in the presence of PLGA nanoparticles is mediated by a locally decreased pH during hydrolytic degradation of this polymer. This hypothesis is supported by the observation that skin permeation of the weak base caffeine was not affected. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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13 pages, 6084 KiB

Open AccessArticle

Achyrocline satureioides (Lam.) DC (Asteraceae) Extract-Loaded Nanoemulsions as a Promising Topical Wound Healing Delivery System: In Vitro Assessments in Human Keratinocytes (HaCaT) and HET-CAM Irritant Potential

by Lucélia Albarello Balestrin, Tainá Kreutz, Flávia Nathiely Silveira Fachel, Juliana Bidone, Nicolly Espindola Gelsleichter, Letícia Scherer Koester, Valquiria Linck Bassani, Elizandra Braganhol, Cristiana Lima Dora and Helder Ferreira Teixeira

Pharmaceutics 2021, 13(8), 1241; https://doi.org/10.3390/pharmaceutics13081241 - 12 Aug 2021

Cited by 14 | Viewed by 2639

Abstract

Achyrocline satureioides (Lam.) DC Asteraceae extracts (ASEs) have been investigated for the treatment of various skin disorders. This study reports the effects of ASE-loaded nanoemulsions (NE_ASE) on the cellular viability, death by necrosis, and migration of immortalized human keratinocytes (HaCaT cell [...] Read more.

Achyrocline satureioides (Lam.) DC Asteraceae extracts (ASEs) have been investigated for the treatment of various skin disorders. This study reports the effects of ASE-loaded nanoemulsions (NE_ASE) on the cellular viability, death by necrosis, and migration of immortalized human keratinocytes (HaCaT cell line), as well as the irritant potential through the hen’s egg chorioallantoic membrane test (HET-CAM). NE_ASE exhibited a polydispersity index above 0.12, with a droplet size of 300 nm, ζ-potential of −40 mV, and content of flavonoids close to 1 mg/mL. No cytotoxicity of the ASE was observed on HaCaT by MTT assay (up to 10 µg/mL). A significant increase of HaCaT viability was observed to NE_ASE (up to 5 μg/mL of flavonoids), compared to treatment with the ASE. The necrosis death evaluation demonstrated that only NE_ASE did not lead to cell death at all the tested concentrations. The scratch assay demonstrated that NE_ASE was able to increase the cell migration at low flavonoid concentrations. Finally, the HET-CAM test proved the non-irritative potential of NE_ASE. Overall, the results indicate the potential of the proposed formulations for topical use in wound healing, in view of their promising effects on proliferation and migration in keratinocytes, combined with an indication of the absence of cytotoxicity and non-irritating potential. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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Review

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18 pages, 3994 KiB

Open AccessReview

Nanostructured Drug Delivery Systems for Targeting 5-α-Reductase Inhibitors to the Hair Follicle

by Silvia Tampucci, Valentina Paganini, Susi Burgalassi, Patrizia Chetoni and Daniela Monti

Pharmaceutics 2022, 14(2), 286; https://doi.org/10.3390/pharmaceutics14020286 - 26 Jan 2022

Cited by 8 | Viewed by 4048

Abstract

Androgenetic alopecia is a multifactorial condition characterized by noticeable hair loss, affecting both men and women and representing a debilitating and chronic disorder that considerably affects the quality of life. Available topical treatments based on minoxidil or finasteride require repeated applications and are [...] Read more.

Androgenetic alopecia is a multifactorial condition characterized by noticeable hair loss, affecting both men and women and representing a debilitating and chronic disorder that considerably affects the quality of life. Available topical treatments based on minoxidil or finasteride require repeated applications and are associated with a certain number of adverse effects. The challenges associated with current treatments pave the way for the research of new therapeutic strategies, more precise and selective, and capable of providing long-term results. In this context, the present review examines the new proposed formulation strategies to deliver 5-α-reductase inhibitors in order to obtain a targeted drug delivery, for improving drug retention at the site of action in the hair follicle, contemporaneously reducing drug systemic absorption, which is the cause of important adverse effects. In particular, the research will be focused on the several aspects that influence the performance of nanostructured drug delivery systems in creating a depot in the hair follicles, such as particle size, surface charge, excipients, and combined application with external stimuli (infrared radiation, mechanical massage, ultrasounds application). Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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39 pages, 2539 KiB

Open AccessReview

3D-Printed Products for Topical Skin Applications: From Personalized Dressings to Drug Delivery

by Rafaela Santos de Oliveira, Stephani Silva Fantaus, Antonio José Guillot, Ana Melero and Ruy Carlos Ruver Beck

Pharmaceutics 2021, 13(11), 1946; https://doi.org/10.3390/pharmaceutics13111946 - 17 Nov 2021

Cited by 31 | Viewed by 5952

Abstract

3D printing has been widely used for the personalization of therapies and on-demand production of complex pharmaceutical forms. Recently, 3D printing has been explored as a tool for the development of topical dosage forms and wound dressings. Thus, this review aims to present [...] Read more.

3D printing has been widely used for the personalization of therapies and on-demand production of complex pharmaceutical forms. Recently, 3D printing has been explored as a tool for the development of topical dosage forms and wound dressings. Thus, this review aims to present advances related to the use of 3D printing for the development of pharmaceutical and biomedical products for topical skin applications, covering plain dressing and products for the delivery of active ingredients to the skin. Based on the data acquired, the important growth in the number of publications over the last years confirms its interest. The semisolid extrusion technique has been the most reported one, probably because it allows the use of a broad range of polymers, creating the most diverse therapeutic approaches. 3D printing has been an excellent field for customizing dressings, according to individual needs. Studies discussed here imply the use of metals, nanoparticles, drugs, natural compounds and proteins and peptides for the treatment of wound healing, acne, pain relief, and anti-wrinkle, among others. The confluence of 3D printing and topical applications has undeniable advantages, and we would like to encourage the research groups to explore this field to improve the patient’s life quality, adherence and treatment efficacy. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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27 pages, 4418 KiB

Open AccessReview

Dissolving Microneedles Developed in Association with Nanosystems: A Scoping Review on the Quality Parameters of These Emerging Systems for Drug or Protein Transdermal Delivery

by Patrícia Weimer, Rochele Cassanta Rossi and Letícia Scherer Koester

Pharmaceutics 2021, 13(10), 1601; https://doi.org/10.3390/pharmaceutics13101601 - 02 Oct 2021

Cited by 8 | Viewed by 2971

Abstract

The largest organ of the body provides the main challenge for the transdermal delivery of lipophilic or high molecular weight drugs. To cross the main barrier of the skin, the stratum corneum, many techniques have been developed and improved. In the last 20 [...] Read more.

The largest organ of the body provides the main challenge for the transdermal delivery of lipophilic or high molecular weight drugs. To cross the main barrier of the skin, the stratum corneum, many techniques have been developed and improved. In the last 20 years, the association of microneedles with nanostructured systems has gained prominence for its versatility and for enabling targeted drug delivery. Currently, the combination of these mechanisms is pointed to as an emerging technology; however, some gaps need to be answered to transcend the development of these devices from the laboratory scale to the pharmaceutical market. It is known that the lack of regulatory guidelines for quality control is a hindrance to market conquest. In this context, this study undertakes a scoping review of original papers concerning methods applied to evaluate both the quality and drug/protein delivery of dissolving and hydrogel-forming microneedles developed in association with nanostructured systems. Full article

(This article belongs to the Special Issue Skin Drug Delivery: Local and Systemic Applications)

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