cosmetics Review Design, Preparation, and Characterization of Effective Dermal and Transdermal Lipid Nanoparticles: A Review Dima Khater 1 , Hamdi Nsairat 2 , Fadwa Odeh 3,* , Mais Saleh 4 , Areej Jaber 2, Walhan Alshaer 5 , Abeer Al Bawab 3,6 and Mohammad S. Mubarak 3,* 1 Department of Chemistry, Faculty of Arts and Science, Applied Science Private University, Amman 11931, Jordan; [email protected] 2 Pharmacological and Diagnostic Research Center, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; [email protected] (H.N.); [email protected] (A.J.) 3 Department of Chemistry, The University of Jordan, Amman 11942, Jordan; [email protected] 4 Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, The University of Jordan, Amman 11942, Jordan; [email protected] 5 Cell Therapy Center, The University of Jordan, Amman 11942, Jordan; [email protected] 6 Hamdi Mango Center, The University of Jordan, Amman 11942, Jordan * Correspondence: [email protected] (F.O.); [email protected] (M.S.M.) Abstract: Limited permeability through the stratum corneum (SC) is a major obstacle for numerous skin care products. One promising approach is to use lipid nanoparticles as they not only facilitate penetration across skin but also avoid the drawbacks of conventional skin formulations. This review focuses on solid lipid nanoparticles (SLNs), nanostructured lipid nanocarriers (NLCs), and nanoemulsions (NEs) developed for topical and transdermal delivery of active compounds. A Citation: Khater, D.; Nsairat, H.; special emphasis in this review is placed on composition, preparation, modifications, structure and Odeh, F.; Saleh, M.; Jaber, A.; Alshaer, characterization, mechanism of penetration, and recent application of these nanoparticles. The W.; Al Bawab, A.; Mubarak, M.S. presented data demonstrate the potential of these nanoparticles for dermal and transdermal delivery. Design, Preparation, and Characterization of Effective Dermal Keywords: dermal and transdermal delivery; solid lipid nanoparticles (SLN); lipid nanocarriers and Transdermal Lipid Nanoparticles: (NLC); stratum corneum (SC) A Review. Cosmetics 2021, 8, 39. https://doi.org/10.3390/ cosmetics8020039 1. Introduction Academic Editor: Enzo Berardesca In most civilizations, humans have used cosmetics for thousands of years. Their main purposes were to clean, protect, improve appearance, perfume, prevent odor, and Received: 17 April 2021 resist aging. In this regard, numerous materials used as cosmetics are either derived Accepted: 13 May 2021 Published: 18 May 2021 from synthetic materials such as vitamin A derivatives (e.g., adapalene) [1] and UV filters (e.g., avobenzone) [2], while others are considered natural, including milk, honey, flowers, Publisher’s Note: MDPI stays neutral extracts, minerals, fruit, oils, and many others [3,4]. These cosmetics were applied to with regard to jurisdictional claims in various parts of the body such as hair, nails, teeth, and skin. However, skin was (and still published maps and institutional affil- is) the main target for these products since it constitutes the largest organ of the human iations. body and its appearance, in general, reflects the beauty of the person. Active compounds in cosmetics are either hydrophilic (water-soluble compounds) or hydrophobic (lipid soluble compounds). Each type has its own shortcomings regarding use in dermal formulations, and in order to overcome such difficulties several aspects such as location of intended effect, mechanism of action, side effects, and duration of applications Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. should be considered. For example, hydrophilic active compounds suffer from their inabil- This article is an open access article ity to penetrate the SC due to their polarity. On the other hand, hydrophobic compounds distributed under the terms and suffer from their unpleasant oily texture that might be undesirable for users. Because of conditions of the Creative Commons this, several approaches such as the use of emulsions, liposomes, polymer-based carriers, Attribution (CC BY) license (https:// and lipid nanoparticles have been used to overcome the various obstacles to forming a creativecommons.org/licenses/by/ most effective formulation for dermal and transdermal applications. Naturally, each tech- 4.0/). nique has its own advantages and disadvantages. While emulsions lack thermodynamic Cosmetics 2021, 8, 39. https://doi.org/10.3390/cosmetics8020039 https://www.mdpi.com/journal/cosmetics Cosmetics 2021, 8, x FOR PEER REVIEW 2 of 45 Cosmetics 2021, 8, 39 to forming a most effective formulation for dermal and transdermal applications. Natu-2 of 43 rally, each technique has its own advantages and disadvantages. While emulsions lack thermodynamic stability [5], liposomes are expensive with difficult and complicated mass production [6]. Interestingly, lipid nanoparticles are both effective and economic with stability [5], liposomes are expensive with difficult and complicated mass production [6]. simple scale-up processes [7]. Accordingly, and owing to the wide interest of skin-related Interestingly, lipid nanoparticles are both effective and economic with simple scale-up products, this review focuses on current knowledge about methods of preparation and processes [7]. Accordingly, and owing to the wide interest of skin-related products, this characterization of lipid nanoparticles. In addition, the use of lipid nanoparticles in der- review focuses on current knowledge about methods of preparation and characterization mal and transdermal formulations will be discussed with emphasis on the last five years. of lipid nanoparticles. In addition, the use of lipid nanoparticles in dermal and transdermal For this purpose, we have obtained the most recent relevant references from known data- formulations will be discussed with emphasis on the last five years. For this purpose, we bases including Google Scholar, Science Direct, MEDLINE (PubMed), Scopus, and have obtained the most recent relevant references from known databases including Google SciFinder. We hope this review will be a great help for researchers and a valuable addition Scholar, Science Direct, MEDLINE (PubMed), Scopus, and SciFinder. We hope this review towill the be field. a great help for researchers and a valuable addition to the field. 2.2. Skin Skin 2.1.2.1. Skin Skin Structure Structure TheThe human human skin skin is is the the body’s body’s largest largest multi- multi-layerslayers organ organ that that acts acts as as a a formidable formidable barrierbarrier to to external external factors factors damaging damaging the the deeper deeper tissues tissues and and internal internal organs organs [8]. [8]. The The skin skin consistsconsists of of three three main main layers; layers; epidermis, epidermis, dermis, dermis, and and hypodermis hypodermis (or (or subcutis) subcutis) but but each each withwith different different cell cell composition composition (Figure (Figure 11).). The epidermis is the upper skin layer, which is mainlymainly composed composed of of keratinocytes keratinocytes (95%) (95%) and and th thee rest rest (5%) (5%) are are melanocytes, melanocytes, Langerhans Langerhans cells,cells, and and Merkel Merkel cells cells [9]. [9]. FigureFigure 1. 1. SchematicSchematic representation representation of human skinskin structurestructure modifiedmodified from from Saleh Saleh et et al. al. [10 [10]] (Reprinted (Reprintedwith permission, with permission, Copyright Co 2020pyright Elsevier 2020 B.V.). Elsevier B.V.). TheThe epidermis epidermis consists consists of of four four main main layers: layers: stratum stratum basale, basale, stratum stratum spinosum, spinosum, stra- stra- tumtum granulosum, granulosum, and and stratum stratum corneum corneum (SC). (SC). The The stratum stratum basale basale is is a a single single layer layer of of the the activelyactively dividing dividing keratinocytes keratinocytes as as well well as as melanocytes, melanocytes, and and Merkel Merkel cells cells [11]. [11]. These These viable viable keratinocyteskeratinocytes are are actively actively dividing dividing to to give give daughter daughter cells. cells. Some Some remain remain in in the the basal basal layer layer whereaswhereas the the rest rest undergo undergo terminal terminal differenti differentiationation and and migrate migrate upward upward in in a a 40-day 40-day trip trip thatthat ends ends in in the the formation formation of SC of SC[12]. [12 The]. rene Thewal renewal time of time normal of normal epidermal epidermal cells in cellsadults in isadults approximately is approximately 6 to 8 weeks 6 to [13,14], 8 weeks whereas [13,14], the whereas average the turn average over time turn of over SC timeis approx- of SC imatelyis approximately 2 weeks [15]. 2 weeks The activity [15]. The of the activity enzymes of the involved enzymes in involveddesquamation in desquamation is affected by is wateraffected level by and water pH. level The and water pH. level The depends water level on dependsthe presence on the of presencehygroscopic of hygroscopic molecules knownmolecules as natural known moisturizing as natural moisturizing factors (NMF) factors [16]. The (NMF) melanocytes, [16]. The which melanocytes, produce which mel- aninproduce photoprotective melanin photoprotective pigments and pigments consist andof a consistcentral of body a central and bodydendrite and tips, dendrite are also tips, foundare also in the found stratum in the basale.