Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery

Pereira, Rui; Silva, Sandra G.; Pinheiro, Marina; Reis, Salette; Vale, M. Luísa C. do

doi:10.3390/membranes11050343

Cited by 34 publications

(22 citation statements)

References 114 publications

(167 reference statements)

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“…In a similar spirit, the use of conjugated antioxidants with antiretroviral drugs has been proposed to increase drug penetration into the central nervous system [599]. Additionally, peptides, including antimicrobial peptides, were proposed as an effective enhancer [600,601]. Recent MD simulations demonstrated that glycyrrhizic acid enhanced the translocation of the antiparasitic drug praziquantel through a lipid bilayer by lowering the free energy barrier associated with the hydrophobic center of the membrane along with a rearrangement of the lipid headgroups [252].…”

Section: Translocation Through the Membranementioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

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Section: Translocation Through the Membranementioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

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“…While physical and nanotechnological approaches like those addressed in previous sections undeniably lie at the forefront of dermal and transdermal drug delivery research, CPEs remain the simplest and most cost-effective way to permeate different solutes across the skin, and their use is widely disseminated [ 116 ]. This explains the strong interest towards a better understanding of their modes of action [ 10 , 117 ] and on development of novel CPEs, searching for greener and more biocompatible alternatives, such as those derived from essential oils [ 118 ] or amino acids [ 4 ].…”

Section: Overview Of Current Methods For Dermal and Transdermal Drug Deliverymentioning

confidence: 99%

“… Schematic view of skin permeation pathways: intercellular, transcellular, and transappendageal [ 4 ]. Reprinted with permission from ref.…”

Section: Figurementioning

confidence: 99%

The Emerging Role of Ionic Liquid-Based Approaches for Enhanced Skin Permeation of Bioactive Molecules: A Snapshot of the Past Couple of Years

Gomes

Aguiar

Ferraz

et al. 2021

IJMS

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Topical and transdermal delivery systems are of undeniable significance and ubiquity in healthcare, to facilitate the delivery of active pharmaceutical ingredients, respectively, onto or across the skin to enter systemic circulation. From ancient ointments and potions to modern micro/nanotechnological devices, a variety of approaches has been explored over the ages to improve the skin permeation of diverse medicines and cosmetics. Amongst the latest investigational dermal permeation enhancers, ionic liquids have been gaining momentum, and recent years have been prolific in this regard. As such, this review offers an outline of current methods for enhancing percutaneous permeation, highlighting selected reports where ionic liquid-based approaches have been investigated for this purpose. Future perspectives on use of ionic liquids for topical delivery of bioactive peptides are also presented.

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“…Another approach to lower enhancer toxicity exploits natural compounds 5,7 . Natural compounds have successfully been used as the polar heads of amphiphilic enhancers (such as α-and ω-amino acids [8][9][10][11][12][13][14][15][16] and sugars) or their lipophilic tails (e.g., terpene moieties) 17 .…”

Section: Abbreviationsmentioning

confidence: 99%

Proline, hydroxyproline, and pyrrolidone carboxylic acid derivatives as highly efficient but reversible transdermal permeation enhancers

Kopečná

Macháček

Roh

et al. 2022

Sci Rep

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Overcoming the skin barrier properties efficiently, temporarily, and safely for successful transdermal drug delivery remains a challenge. We synthesized three series of potential skin permeation enhancers derived from natural amino acid derivatives proline, 4-hydroxyproline, and pyrrolidone carboxylic acid, which is a component of natural moisturizing factor. Permeation studies using in vitro human skin identified dodecyl prolinates with N-acetyl, propionyl, and butyryl chains (Pro2, Pro3, and Pro4, respectively) as potent enhancers for model drugs theophylline and diclofenac. The proline derivatives were generally more active than 4-hydroxyprolines and pyrrolidone carboxylic acid derivatives. Pro2–4 had acceptable in vitro toxicities on 3T3 fibroblast and HaCaT cell lines with IC50 values in tens of µM. Infrared spectroscopy using the human stratum corneum revealed that these enhancers preferentially interacted with the skin barrier lipids and decreased the overall chain order without causing lipid extraction, while their effects on the stratum corneum protein structures were negligible. The impacts of Pro3 and Pro4 on an in vitro transepidermal water loss and skin electrical impedance were fully reversible. Thus, proline derivatives Pro3 and Pro4 have an advantageous combination of high enhancing potency, low cellular toxicity, and reversible action, which is important for their potential in vivo use as the skin barrier would quickly recover after the drug/enhancer administration is terminated.

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Current Status of Amino Acid-Based Permeation Enhancers in Transdermal Drug Delivery

Cited by 34 publications

References 114 publications

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

The Emerging Role of Ionic Liquid-Based Approaches for Enhanced Skin Permeation of Bioactive Molecules: A Snapshot of the Past Couple of Years

Proline, hydroxyproline, and pyrrolidone carboxylic acid derivatives as highly efficient but reversible transdermal permeation enhancers

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