Structure Enhancement Relationship of Chemical Penetration Enhancers in Drug Transport across the Stratum Corneum (original) (raw)
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Design principles of chemical penetration enhancers for transdermal drug delivery
Proceedings of The National Academy of Sciences, 2005
Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro. Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future. stratum corneum ͉ spectroscopy ͉ skin irritation ͉ lipid
2015
There is considerable interest in the skin as a site of drug application for both local and systemic effect. However, the skin, in particular the stratum corneum, possesses a formidable barrier to drug penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and to increase the range of drugs for which topical and transdermal delivery is a viable option. Transdermal drug delivery system (TDDS) having objective to deliver the therapeutic moiety via the skin into the systemic circulation for its therapeutic effect. This route provides many advantages over other routes as avoiding first pass hepatic metabolism, decrease side effects, GI effects and increased bioavailability. The skin, in particular stratum corneum provides protective barrier that prevents the loss of physiologically essential substances and provide resistance to penetration and it is the rate limiting step in percutaneou...
Journal of controlled release : official journal of the Controlled Release Society, 2016
Skin is attractive for drug therapy because it offers an easily accessible route without first-pass metabolism. Transdermal drug delivery is also associated with high patient compliance and through the site of application, the drug delivery can be locally directed. However, to succeed with transdermal drug delivery it is often required to overcome the low permeability of the upper layer of the skin, the stratum corneum (SC). One common strategy is to employ so-called penetration enhancers that supposedly act to increase the drug passage across SC. Still, there is a lack of understanding of the molecular effects of so-called penetration enhancers on the skin barrier membrane, the SC. In this study, we provide a molecular characterization of how different classes of compounds, suggested as penetration enhancers, influence lipid and protein components in SC. The compounds investigated include monoterpenes, fatty acids, osmolytes, surfactant, and Azone. We employ natural abundance (13)C...
Chemical penetration enhancers for transdermal drug delivery systems
Tropical Journal of Pharmaceutical Research, 2009
Skin as an important site of drug application for both local and systemic effects. However in skin, the stratum corneum is the main barrier for drug penetration. Penetration enhancement technology is a challenging development that would increase the number of drugs available for transdermal administration. The permeation of drug through skin can be enhanced by both chemical penetration enhancement and physical methods. In this review, we have discussed the chemical penetration enhancement technology for transdermal drug delivery as well as the probable mechanisms of action.
Penetration enhancers for transdermal drug delivery system: A review
There is considerable interest in the skin as a site of drug application both for local and systemic effect. However, the skin, in particular the stratum corneum, poses a formidable barrier to drug penetration thereby limiting topical and transdermal bioavailability. Skin penetration enhancement techniques have been developed to improve bioavailability and increase the range of drugs for which topical and transdermal delivery is a viable option. This review describes enhancement techniques based on drug/vehicle optimisation such as Selection of correct drug or prodrug, Chemical potential adjustment, Ion pairs and complex Parameters Ideal limits Aqueous solubility >1mg/ml Lipophilicity 10<Ko/w<1000 Molecular weight <500 Daltons Melting point <200 0 C pH of aqueous saturated solution 5-9
Chemical and Physical Enhancers for Transdermal Drug Delivery
a r e a o f 0. 1 %. I n t h i s w a y , d i f f u s i o n t h r o u g h t h e s k i n i s c o n t r o l l e d b y t h e p a r t i c u l a r characteristics of the stratum corneum. In order to obtain a sufficient drug flux and, in turn, the therapeutical objectives in question, an alternative is to use chemical percutaneous enhancers. These substances alter some of the properties of the stratum corneum. (López-Castellano & Merino, 2010) 2.2 Direct effects on the skin due to the use of transdermal penetration enhancers The lipid-protein-partititioning theory sets out the mechanisms by which enhancers alter skin lipids, proteins and/or partitioning behaviour (Barry, 1991): i) They act on the stratum corneum intracellular keratin by denaturing it or modifying its conformation, causing subsequent swelling and increased hydration; ii) They affect the desmosomes that maintain cohesion among corneocytes; iii) They modify the intercellular lipid domains to reduce the barrier-like resistance of the bilayer lipids. Disruption to the lipid bilayers can be homogeneous when the enhancer is distributed evenly within the complex bilayer lipids, but the accelerant is more likely to be heterogeneously concentrated within the domains of the bilayer lipids and iv) They alter the solvent nature of the stratum corneum, thus aiding the partitioning of the drug or a co-solvent into the tissue.(López-Castellano & Merino, 2010) 2.3 Indirect effects on the skin due to the use of transdermal penetration enhancers Chemical enhancers can produce: a) Modification of the thermodynamic activity of the vehicle. The permeation of a good solvent from the formulation, such as ethanol, can increase the thermodynamic activity of a drug; b) It has been suggested that, by permeating through the membrane, a solvent can 'drag' the permeant with it, though this concept is somewhat controversial and requires confirmation; c) Solubilising the permeant within the donor, especially when solubility is very low, as in the case of aqueous donor solutions, can reduce depletion effects and prolong drug permeation.(López-Castellano & Merino, 2010) 2.4 Classification of percutaneous chemical enhancers The classification of percutaneous enhancers is frequently based on the chemical class to which the compounds belong. Table 1 shows the principal classes of percutaneous enhancers. CHEMICAL CLASS COMPOUNDS Water Water Sulfoxides and similar chemicals Dimethyl sulfoxide, Dodecyl methyl sulfoxide Ureas Urea Alcohols Ethanol, Caprylic alcohol, Propylene glycol Pyrrolidones and derivatives N-methyl-2-pyrrolidone, 2-pyrrolidone Azone and derivatives Azone ® (1-dodecylazacycloheptan-2-one) Dioxolane derivatives SEPA ®
Discovery of transdermal penetration enhancers by high-throughput screening
Nature Biotechnology, 2004
Skin, the largest organ of the human body, offers a painless and compliant interface for systemic drug administration 1 . As compared with injections and oral delivery routes, transdermal drug delivery increases patient compliance, avoids metabolism by the liver, and provides sustained and controlled delivery over long time periods. And yet, after nearly four decades of extensive study, the success of this technology remains limited, with only a few transdermal products available in the market, all of which are based on low molecular weight lipophilic drugs 2 . Development of transdermal products for macromolecules is hindered primarily by low skin permeability. Evolved to impede the flux of toxins into the body, skin naturally offers a very low permeability to the movement of foreign molecules across it 3 . A unique hierarchical structure of lipid-rich matrix with embedded corneocytes in the upper strata (15 µm) of skin, stratum corneum (SC), is responsible for this barrier 3 . Overcoming this barrier safely and reversibly is a fundamental problem in the field of transdermal delivery.
Journal of Pharmaceutical Research International, 2021
Skin penetration enhancement technology is a rapidly evolving area that will greatly increase the quantity of transdermal drug delivery medications. Penetration enhancers are used to facilitate the movement of drugs through the skin barrier. Numerous methods exist for extending partition enhancement. The enhancers' contact with the polar head of the lipid groups is the potential means for increasing the penetration. Penetration enhancers improve the amount of free water molecules between the bilayer, leading to an improvement of the polar drug diffusion cross section. This article focuses on the different compounds assessed for improving penetration activity like sulphoxides, azones, pyrrolidones, alcohols and alkanols, glycols, surfactants and terpenes.
The effect of penetration enhancers on drug delivery through skin: a QSAR study
Journal of Controlled Release, 2004
Skin penetration enhancers are used to allow formulation of transdermal delivery systems for drugs that are otherwise insufficiently skin-permeable. A full understanding of the mode of action could be beneficial for the design of potent enhancers and for the choice of the enhancer to be used in the topical formulation of a special drug. In this study, the structural requirements of penetration enhancers have been investigated using the Quantitative Structure-Activity Relationship (QSAR) technique. Activities of naturally occurring terpenes, pyrrolidinone and N-acetylprolinate derivatives on the skin penetration of 5-fluorouracil, diclofenac sodium (DFS), hydrocortisone (HC), estradiol and benazepril have been considered. The resulting QSARs indicated that for 5-fluorouracil and diclofenac sodium, less hydrophobic enhancers were the most active. More precisely, molecular descriptors in the corresponding QSARs indicated the possible involvement of intermolecular electron donor-acceptor interactions. This was in contrast to the skin permeation promotion of hydrocortisone, estradiol and benazepril by enhancers, where a linear relationship between enhancement activity and n-octanol/water partition coefficients of enhancers was evident. The possible mechanisms of penetration enhancement as suggested by the QSARs will be discussed. D
Therapeutic Delivery, 2017
Skin is the outermost and largest protective covering of the body. The uppermost layer of the skin, stratum corneum also called the horny layer is composed of keratin-filled cells covered by a lipid matrix which shields the skin from physical and chemical entrants. The lipid lamellar structure comprises of ceramides, cholesterol, fatty acids and proteins. Chemical enhancers that mimic the lamellar chemistry, reversibly fluidize the latter can be utilized for enhancing transport of cargo across the epidermis into the dermis. This review deals with the stratum corneum chemistry, mechanisms to modulate its packing with the aid of chemical enhancers, biophysical techniques for characterization and applications in the design of nature-inspired biocompatible lipid nanostructures for transdermal delivery of drugs and bioactive agents.