European Journal of Pharmaceutics and Biopharmaceutics
Research paperPolyglycerol fatty acid ester surfactant–based microemulsions for targeted delivery of ceramide AP into the stratum corneum: Formulation, characterisation, in vitro release and penetration investigation
Graphical abstract
The different nanostructures of CER [AP] MEs as characterised by EPR and other conventional techniques as well as their in vitro release and penetration profiles into the stratum corneum in comparison with a conventional hydrophilic cream.
Introduction
Skin is the largest organ of the body and provides barrier against harmful environmental insults and loss of water and other essential components from body. The barrier function is solely founded on the SC (10–20 μm thick [1]) [2], which contains about 15 layers of corneocytes (flat dead cells filled with keratin filaments and water [3]) separated by a unique and complex mixture of highly ordered multi-lamellar lipid sheets [2], [4], [5]. The corneocytes are surrounded by a very dense corneocyte envelope, which is impermeable to most diffusing substances [6]. Thus, the main penetration pathway through the SC remains the intercellular lipid lamella [6], [7], and its main components are CERs, cholesterol and free fatty acids (FFAs), which exist nearly in equimolar amounts [2], [8].
CERs are sphingolipids that contain a sphingoid moiety (which can be sphingosine (S), dihydrosphingosine (D), phytosphingosine (P) or 6-hydroxy-sphingosine (H)), linked with a long-chain FFA moiety (which can be nonhydroxy (N), α-hydroxy (A) or ester-linked ω-hydroxy (EO)) through an amide bond [3], [9]. To date, 12 different classes of free CERs have been identified in human SC, which are named as “Ceramide XY” where “X” represents the type of FFA moiety and Y represents the type of sphingoid base [10], [11]. They play a major role in the water-retaining properties of the epidermis and are claimed to dramatically increase skin’s hydration level, repair the cutaneous barrier, prevent vital moisture loss, and contribute to reducing dry flaky skin and aged appearance [8], [10], [12]. They can also be used against some skin diseases such as atopic dermatitis [12] and psoriasis [3], [8]. Schröter et al. [13] indicated that CER [AP], with four hydroxyl groups on its head group, is capable of forming super stable membranes through formation of strong hydrogen bonds. It has also been shown to be antiproliferative and proapoptotic in numerous cancer cell types in vitro [14]. Therefore, administration of CER [AP] to the skin might help to restore the barrier function of aged and affected skin.
However, the effectiveness of CER [AP], like other CERs, is limited due to its inherent hydrophobicity and precipitation as fine lipid micellar suspensions when administered in hydrophilic formulations. From conventional dosage forms, CERs cannot penetrate the SC [14], [15] to reach the SC/SG interface, where the SC lipids are organised into meaningful lamellae [16], [17], [18], [19]. Therefore, to realise the therapeutic benefits of CER [AP], an appropriate drug delivery system that can enhance its solubility and penetration into the SC should be developed.
Microemulsions (MEs) are transparent, low-viscous, optically isotropic and thermodynamically stable colloidal dispersions of oil and water, which are stabilised by an interfacial film of a SAA, in most cases in combination with a co-SAA [20], [21]. In recent years, they have emerged as promising vehicles for dermal and transdermal delivery of drugs [22], [23], [24], [25], [26], [27], [28]. They possess large solubilisation capacity attributing to their immense interfacial area and the presence of various microdomains of different polarities [29], [30], [31], [32], [33]. They also significantly enhance penetration of hydrophilic, lipophilic and amphiphilic substances into and through biological membranes [23], [34], [35]. Besides, they are easy to formulate [29], [30], [31], [33], have relatively low viscosity [29], [30], [36] and have self-preserving property [37]. However, formulation of MEs might need high level of SAAs that might irritate the skin. Therefore, the objective of this work was to develop CER [AP] MEs that can enhance the permeability of the CER into the SC using safe and mild SAAs.
Section snippets
Materials
CER [AP] and TCPL4 were kindly donated by Evonik-Goldschmidt GmbH (Essen, Germany). HPGMO4 was a gift from Hydrior AG massgeschneiderte Tenside (Wettingen, Germany). PeG was kindly supplied by Symrise GmbH & Co KG (Holzminden, Germany). Lin A was purchased from Sigma-Aldrich Chemie GmbH (Taufkirchen, Germany). IPP and 4% collodion were obtained from Caesar & Loretz GmbH (Hilden, Germany). 14N HD-PMI (HD-PMI: 2-heptadecyl-2,3,4,5,5-pentamethyl-imidazoline-1-oxyl) was supplied by Institute of
Determination of solubility of CER [AP] in various solvents
As can be seen in Table 1, preceding development of CER [AP] MEs, the solubility of the lipid was determined in various solvents, oils and co-solvents at RT (21–23 °C) and 32 °C. The results in the table showed that solubility of CER [AP] increased considerably as the temperature increases. However, according to solubility classification, CER [AP] was practically insoluble in water, all the oils investigated and PG at both RT and 32 °C.
Formulation of CER [AP] MEs
A preliminary study was carried out to choose ME components
Acknowledgements
The authors would like to thank Manuela Woigk, Kerstin Schwarz and Adelheid Pötzsch for their excellent technical assistance. We are also grateful to Dr. Karsten Busse for his contribution during measurement and analysis of data Using PCS. Fitsum F. Sahle greatly acknowledges the financial support provided by the German Academic Exchange Service (DAAD).
References (75)
- et al.
Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs)
Int. J. Pharm.
(2011) - et al.
New acylceramide in native and reconstructed epidermis
J. Invest. Dermatol.
(2003) - et al.
Analysis of all stratum corneum lipids by automated multiple development high-performance thin-layer chromatography
J. Chromatogr. B: Biomed. Appl.
(1995) - et al.
Two new methods for preparing a unique stratum corneum substitute
Biochim. Biophys. Acta
(2008) - et al.
Modelling the stratum corneum lipid organisation with synthetic lipid mixtures: the importance of synthetic ceramide composition
Biochim. Biophys. Acta
(2004) - et al.
Epidermal sphingolipids: metabolism, function, and roles in skin disorders
FEBS Lett.
(2006) - et al.
Characterization of overall ceramide species in human stratum corneum
J. Lipid Res.
(2008) - et al.
Ceramide biosynthesis in keratinocyte and its role in skin function
Biochimie
(2009) - et al.
LC/MS analysis of stratum corneum lipids: ceramide profiling and discovery
J. Lipid Res.
(2011) - et al.
Enzymatic production of ceramide from sphingomyelin
J. Biotechnol.
(2006)
Basic nanostructure of stratum corneum lipid matrices based on ceramides [EOS] and [AP]: a neutron diffraction study
Biophys. J.
The skin barrier and use of moisturizers in atopic dermatitis
Clin. Dermatol.
The skin barrier in healthy and diseased state
Biochim. Biophys. Acta
Enhancement of transdermal delivery of theophylline using microemulsion vehicle
Int. J. Pharm.
The influence of cosurfactants and oils on the formation of pharmaceutical microemulsions based on PEG-8 caprylic/capric glycerides
Int. J. Pharm.
Microemulsion-based hydrogel formulation of penciclovir for topical delivery
Int. J. Pharm.
Terpene microemulsions for transdermal curcumin delivery: effects of terpenes and cosurfactants
Colloids Surf. B: Biointerfaces
Microemulsion formulations for the transdermal delivery of testosterone
Eur. J. Pharm. Sci.
Visualization, dermatopharmacokinetic analysis and monitoring the conformational effects of a microemulsion formulation in the skin stratum corneum
J. Colloid Interface Sci.
Linker-based lecithin microemulsions for transdermal delivery of lidocaine
Int. J. Pharm.
Formulation design of microemulsion for dermal delivery of penciclovir
Int. J. Pharm.
Self-microemulsifying and microemulsion systems for transdermal delivery of indomethacin: effect of phase transition
Colloids Surf. B: Biointerfaces
Formulation of ascorbic acid microemulsions with alkyl polyglycosides
Eur. J. Pharm. Biopharm.
Microemulsion-based media as novel drug delivery systems
Adv. Drug Deliv. Rev.
Characterization of potent anticholinesterase plant oil based microemulsion
Int. J. Pharm.
Effect of surfactant concentration on transdermal lidocaine delivery with linker microemulsions
Int. J. Pharm.
Rheological properties and microstructures of gelatin-containing microemulsion-based organogels
Colloids Surfaces A: Physicochem. Eng. Aspects
Parenteral microemulsions: an overview
Int. J. Pharm.
Profiling of human stratum corneum ceramides by liquid chromatography–electrospray mass spectrometry
Anal. Chim. Acta
A multilayer membrane system for modelling drug penetration into skin
Int. J. Pharm.
Formation and characterisation of mint oil/S and CS/water microemulsions
Food Chem.
Formulation and characterization of microemulsions based on mixed nonionic surfactants and peppermint oil
J. Colloid Interface Sci.
Formation of organic nanoparticles from volatile microemulsions
J. Colloid Interface Sci.
A new type of microemulsion consisting of two halogen-free ionic liquids and one oil component
Colloids Surfaces A: Physicochem. Eng. Aspects
The hydrophobicity of silicone-based oils and surfactants and their use in reactive microemulsions
J. Colloid Interface Sci.
Protein delivery using nanoparticles based on microemulsions with different structure-types
Eur. J. Pharm. Sci.
Conductivity study on the w/o microemulsion of a saponified mono(2-ethylhexyl) phosphoric acid extractant system
Colloids Surfaces A: Physicochem. Eng. Aspects
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