Getting under the skin

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Getting under the skin: Cyclodextrin inclusion for the controlled delivery of active substances to the dermis

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Susana S. Braga and Joana Pais University of Aveiro, Aveiro, Portugal

CHAPTER OUTLINE 10.1 Introduction ...............................................................................................407 10.2 Cyclodextrins in Skin Formulations ..............................................................409 10.2.1 Origins and Uses .....................................................................409 10.2.2 Regulatory Status and Safety ...................................................412 10.2.3 Cyclodextrins as Active Ingredients ...........................................413 10.2.4 Modulation of Skin Function by Cyclodextrins ............................415 10.2.5 Iontoforesis With Cyclodextrins .................................................419 10.2.6 Cyclodextrins in Microneedle Arrays ..........................................420 10.3 Molecular Encapsulation With Cyclodextrins ................................................421 10.3.1 Preparation of Inclusion Complexes ..........................................421 10.3.2 Properties and Advantages of Cyclodextrin Inclusion Compounds ..............................................................422 10.3.3 Inclusion Complexes as Formulation Ingredients ........................425 10.4 Skin Products Containing Cyclodextrins .......................................................431 10.5 Conclusions and Future Perspective ............................................................435 Acknowledgments ...............................................................................................436 References ..........................................................................................................436

10.1 INTRODUCTION Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides of 1,4-linked α-D-glucose, formed by the bacterial degradation of starch (Villiers, 1891). The bacillus with the ability to form CDs was first studied by Schardinger, who

Design of Nanostructures for Versatile Therapeutic Applications. DOI: http://dx.doi.org/10.1016/B978-0-12-813667-6.00010-3 © 2018 Elsevier Inc. All rights reserved.

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isolated them from cereal-based foodstuff. They can feed on an aqueous suspension containing only starch to produce, in 24 h at 50 C, a clear solution that easily forms CD crystals as the water evaporates (Schardinger, 1903). In a follow-up study, Schardinger perfected the crystallization process and isolated the strain that produces the CDs, naming it Bacillus macerans (Schardinger, 1904, 1905). A recent taxonomical revision has changed this microorganism’s name to Bacillus firmus. Current production of CDs relies on the action of the enzyme responsible for starch fragmentation and cyclization, named cyclodextringlycosy ltranferase (CGTase) (Biwer et al., 2002). Corn is the most commonly used source of starch for the production of CDs, but alternative sources, such as sago palm (Charoenlap et al., 2004; Rauf et al., 2008), amaranth (Urban et al., 2012), and tapioca (Sakinah et al., 2014) are under research. The main products of the CGTase enzyme are named native CDs. They consist of three molecules with different sizes as the result of having six, seven, or eight α-D-glucose units. CDs are named according to the number of glucose units by following the Greek alphabet. Native CDs are thus named alpha, beta, and gamma (α-CD, β-CD, and γ-CD), respectively. CDs with higher number of glucose units, named large ring cyclodextrins (LR-CDs), are less common, although some may also be formed in trace amounts through the action of CGTase, namely rings with 9 (δ-CD), 10 (ε-CD) or more glucose units (Pulley and French, 1961). Currently, LR-CDs with up to 54 glucose units can be produced using a different enzyme, 4-α-glucanotransferase, and pea starch as the substrate (Vongpichayapaiboon et al., 2016). Native CDs preset their glucopyranose units in the 4C1 chair conformation, which, in combination with the α-(1,4) linkage, gives them the shape of a shallow truncated cone. The cavity of the CD, lined with hydrogen atoms and the glucosidic oxygen bridges, is hydrophobic. In turn, the rims are lined with hydroxyl groups that render CDs water soluble (Szejtli, 1998), with values of 15%, 1.9% and 24% (m/v), respectively, for α-CD, β-CD and γ-CD. CDs are thus able to solubilize hydrophilic compounds by including them into their ring cavities, and for this reason, they are considered molecular capsules. Chemical modification of the native CDs affords a variety of derivatives with different physicochemical and biological properties. Of the existing derivatives, there are now more than 1500 (Nitalikar et al., 2012). The most relevant for human use is 2-hydroxypropyl-β-cyclodextrin (HPβCD), which combines excellent aqueous solubility and solubilizing properties with a good tolerability in vivo, being an Food and Drug Administration (FDA)-approved inactive ingredient. Another hydroxyalkylated derivative, 2-hydroxyethyl-β-cyclodextrin (HEβCD), is also approved as a cosmetic ingredient. Recently, 2-hydroxypropyl-γ-CD has also been approved by the FDA as an inactive ingredient, but it is limited to the topical route and to a concentration of 1.5% (w/v) (FDA, 2016). Methylated CDs, such as permethylated β-CD (TRIMEB), heptakis-2,6-di-O-methyl-β-CD (DIMEB) and several randomly methylated β-CD derivatives with different

10.2 Cyclodextrins in Skin Formulations

degrees of methylation, are also under study for human use. The host RAMEB receives its name from the initials in RAndomly Methylated and it may also be referred to as simply “methylated β-CD”. The degree of methylation for RAMEB is defined at 1.8 methyl groups per glucose unit. Another noteworthy randomly methylated derivative of β-CD is CRYSMEB, named after the fact that is a crystalline solid. CRYSMEB has a very low substitution degree, with an average of 0.56 methyl groups per glucose unit (that makes only four methyl groups in each CD molecule). Concerning safety, RAMEB is an approved ingredient for cosmetics and CRYSMEB is quite a safe CD, designed to have good compatibility with the human body because it does not cause hemolysis. For the other methylated CDs, further data on safety is still lacking. Also worth highlighting is sulfobutyl ether β-CD (SBEβCD), a polyanionic variably substituted derivative, developed to be non-nephrotoxic and already marketed in several FDA-approved compositions for both oral and intravenous administration (Captisol, 2017). The solubilizing, stabilizing and protecting actions of CDs on the included guests make them useful for several applications and currently ubiquitous in a variety of products, including foodstuff (Pereira and Braga, 2015), pharmaceuticals (Agrawal and Gupta, 2012) and cosmetics (Buschmann and Schollmeyer, 2002).

10.2 CYCLODEXTRINS IN SKIN FORMULATIONS 10.2.1 ORIGINS AND USES 10.2.1.1 Early applications, decades of 1970 and 1980 The use of native CDs in industrial applications started when these materials became commercially available from production sites in Japan and Hungary (Shahidi and Pegg, 2007). From the late 1970s to the early 1980s, four Japanese companies established processes for the large-scale production of native CDs, using only water as a solvent, and introduced these products to supply the markets (Hashimoto, 1988). The native CDs produced in this way are recognized in Japan as natural products and thus they can be used without restrictions, except for considerations of purity. At that time, Japan was the leading country in the market of CDs. In the 1980s, CDs were used mainly to stabilize aromatic compounds, with various applications in foodstuff (Szejtli, 1982). This property was also considered useful for cosmetics and toiletries and, according to the report by Szejtli (1982), several prospect products, including toothpaste, deodorants, cosmetic bases, solid perfumes, and bath preparations, were under patent application in Japan (where the application document receives the specific denomination of “Japan Kaiku”). Nevertheless, a recent search on the Japanese patent website has revealed that these patent applications did not get approved. The dawn of CD application in cosmetics was yet to come.

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FIGURE 10.1 Evolution of the number of publications on the topics of cosmetic, topical or skin uses of cyclodextrins.

Research on CDs and skin was still very scarce in this decade, comprising just a few papers and short communications (Fig. 10.1). Reports included studies on the skin tolerability of CDs and their ability to reduce drug-induced skin irritation (Uekama et al., 1982) or photosensitivity (Uekama and Irie, 1985; Hoshino et al., 1987; Ishida et al., 1987).

10.2.1.2 Consolidation decade: the 1990s In the 1990s, research grew steadily (Fig. 10.1) and more of the effects of CDs on the skin became known. Native CDs and HPβCD were demonstrated to enhance the transdermal permeability of various drugs (Xu et al., 1991; Adachi et al., 1992; Vollmer et al., 1993, 1994; Loftsson et al., 1995; Tanaka et al., 1995; Legendre et al., 1995; Arima et al., 1996, 1998; Tenjarla et al., 1998). In turn, DIMEB was shown to afford high concentrations of active ingredients in skin, available for local efficiency and/or a reservoir effect (Vollmer et al., 1993). Such findings have triggered the development of a variety of pharmaceutical dermal formulations containing CD inclusion compounds with various drugs (Matsuda and Arima, 1999). Cosmetic products with CD inclusion compounds also became available on the market. In cosmetics, CDs were used with two main purposes: one as masking agents for components with unpleasant aroma, and another as

10.2 Cyclodextrins in Skin Formulations

stabilizers of active ingredients. In sun lotions, CDs protect and stabilize the chemicals against precocious degradation from light; and in fragranced products, CDs stabilize the aromatic compounds, thus bringing a sustained-release effect (Szejtli, 1997). The ability of CDs to act as formulation helpers was also investigated. Even though β-CD is not regarded as a surfactant, i.e., it was not shown to have an effect on the surface tension of the water/air interface, it can stabilize emulsions through the formation of inclusion compounds with lipidic molecules at the water/oil interface. In this way, β-CD can be used to produce stable emulsions starting from simple ternary systems of water 1 oil 1 β-CD. This effect was demonstrated with paraffin oil (Laurent et al., 1999), coconut oil, and soybean oil (Shimada et al., 1992). β-CD was also shown to facilitate the loading of poorly soluble drugs, such as piroxicam into microemulsions for topical delivery (Dalmora and Oliveira, 1999). Native CDs were shown to help stabilize oil/water/ oil multiple emulsions; the stability increasing in direct proportion to the cavity size of the CD (Yu et al., 1999).

10.2.1.3 Cyclodextrins as the functional excipients of the 21st century The decade of the 2000s and the present one mark the definitive affirmation of CDs as technological solutions for dermopharmaceutical, cosmetic, and even cosmetoceutical products (Draelos, 2014). In parallel with market expansion, the research activities continue to grow at a steady pace. CDs are presently used in a variety of functions, from solubilizing agents to formulation helpers. In formulations, CDs bring several advantages: •

•

• •

modulation of the rheological properties of creams and gels (Cal and Centkowska, 2008); dissolution of oily compounds to form aqueous transparent formulations, whereas other dissolution agents typically cause cloudiness (Numano˘glu et al., 2007); compatibilization of otherwise non-compatible components by inclusion and “masking” of one of these components, thus allowing the preparation of stable solutions; increase of the loading ability of liposomes (Cal and Centkowska, 2008); reduction of skin irritation caused by active compounds, e.g., celecoxib (Ventura et al., 2006) and tretinoin (Miura et al., 2012).

Research and development of new CD derivatives continues to grow, which allows to expand even further their range of activities. In 2016, a new molecule, octenyl succinic-β-CD, demonstrated good surface tension properties and kept test emulsions stable during an observation time of 30 months, thus opening the door for CDs to act as emulsifying agents (Cheng et al., 2016).

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10.2.2 REGULATORY STATUS AND SAFETY 10.2.2.1 Regulation on the use of cyclodextrins in topical products The products conceived to be applied topically on the skin can be classified as cosmetics or topical drugs. Cosmetics are defined by the US FDA as products which “intend to clean or to enhance the beauty” (FDA, 2015). A topical drug refers to pharmaceutical compositions and also products such as sunscreens, antiperspirants, diaper ointments, and treatments for dandruff or acne, which are cosmetic drugs and need to obtain cosmetic and drug approval. In the United States, cosmetics do not need FDA approval to be marketed, except if they contain color additives. Cosmetics are, nevertheless, regulated by the Federal Food, Drug, and Cosmetic Act (FD&C Act) and it is required that “every cosmetic and personal care product and its ingredients be substantiated for safety before going to the market, and that they contain no prohibited ingredients” (Cosmeticsinfo.org, 2016). The ingredients approved for use in cosmetics are under the scrutiny of the Cosmetic Ingredient Review Expert Panel, an independent, non-profit scientific body established in 1976 (Cosmetic Ingredient Review, 2016) that regularly examines and establishes the safety of ingredients. This entity has approved native CDs, HPβCD, HEβCD, RAMEB, and blends of native CDs with laureate and hydroxypropyltrimonium chloride as safe ingredients for cosmetics (Cosmetic Ingredient Review, 2015). In Canada, native CDs are classified as synthetic duplicates of natural products and they have been approved as “natural medicinal ingredients” since 2011, with the function of “controlled release vehicle” and are currently registered as emulsifying, sequestering, stabilizing, and encapsulating agents (Health Canada, 2016a). HPβCD is registered as an emulsion stabilizer and sequestering agent, and DIMEB as a sequestering, stabilizing, and encapsulating agent (Health Canada, 2016b). In the European Union, CDs are regulated as excipients and their use is approved by the European Medicines Agency according to the delivery route. For dermal products, native CDs are considered safe at concentrations up to 0.1%, and HPβCD is considered safe without mention of a dose restriction (European Medicines Agency, 2014). In Japan, native CDs are regarded as natural products (Pereira and Braga, 2015) and listed in the Japanese Pharmaceutical Codex (Devi et al., 2010). They are used without restriction and have made their way into a very large number of products (Loeve and Normand, 2011).

10.2.2.2 Safety of topical products with cyclodextrins CDs, as any exogenous substances applied on the skin, are likely to cause irritation or contact dermatitis at sufficiently high concentrations. To determine such concentration limits, preliminary studies were conducted on guinea pigs, using increasing concentrations of native CDs (Uekama et al., 1982). Application of

10.2 Cyclodextrins in Skin Formulations

β-CD at the concentration of 16 mM produced a slight irritation, 0.1 on the Draize scale, which ranges from 0 to 4.0 (European Comission Joint Research Centre, 2009). No irritation response was observed with 16 mM of α-CD and γ-CD. At the highest concentration tested, 80 mM, the irritation scores were 0.4 for α-CD and 0.8 for β-CD, while γ-CD continued to produce no response, thus suggesting a very high skin safety level for this molecule. Furthermore, different independent in vitro tests have confirmed that α-, β- and γ-CDs in concentrations up to 0.1% (w/v) do not show any antiproliferative influence on HaCaT keratinocytes (European Medicines Agency, 2014). Studies in human volunteers have shown that native CDs have a significant safety margin in dermal application. No irritating effect was observed for these CDs after application for 24 h and on 1 cm2 of skin, on healthy volunteers, of equivalent quantities of 2 mg of CD dissolved in water or dispersed in vaseline (Bochot Piel, 2011). The effects on cutaneous microcirculation were evaluated by laser Doppler velocimetry (European Medicines Agency, 2014). Corneoxenometry, a bioassay named after a combination of the words corneocyte, xenobiotic, and metrics, was introduced as a convenient approach to explore the effect of chemical xenobiotics other than surfactants on human stratum corneum (Pie´rard et al., 2014). This assay was used to evaluate the skin irritation ability of chemically modified CDs, namely RAMEB, DIMEB, TRIMEB, HPβCD, and HPγCD (Babu and Pandit, 2004). The results of the study, expressed as colorimetric index of mildness (CIM), suggested that all tested CD are globally well tolerated by the skin because the median values were above the threshold value of 30, indicating that a substance is mild on the skin. For comparison, the CIM value for water (mildness reference) is around 64 while that of sodium laurylsulfate, a reference irritating product, may be as low as 5 15 (Goffin et al., 1996).

10.2.3 CYCLODEXTRINS AS ACTIVE INGREDIENTS CDs were regarded in the early years of their industrial use as inert components or formulation helpers, and their current use remains mainly within this scope. Nonetheless, research has demonstrated that CD inclusion of molecules such as cholesterol or malodorous compounds generated on the human skin offers interesting benefits. This makes CDs suitable to function as the main active ingredients of a formulation in niche applications such as deodorants, skin whiteners, and HIV-prevention creams or lotions.

10.2.3.1 Cyclodextrin-based deodorants The fatty acids present on the skin by secretion of the sebaceous glands are metabolized by bacterial flora into malodorous compounds, thus causing the development of body odor (Trinh et al., 1998). Given the quasi-linear shape of these molecules, they are suitable for inclusion into the narrow cavity of α-CD, whereas substituted fatty acids are better accommodated by β-CD. Indeed, β-CD

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showed good affinity to include 3-mercaptohexanol, with a Kapp 5 407 M21, and a moderate affinity for androsterone (Kapp 5 233 M21) and two organic acids, isovaleric and 3-hydroxi-3-methylhexanoic (Kapp 5 407 M21 respectively). With malodorous molecules of smaller dimensions, such as acetic, L(1)-lactic and isobutyric acids, the affinity constant values are much lower, ranging between 11 and 50 M21 (Lopedota et al., 2015). Native CDs were also shown to sequester the aldehyde pentenal, with α-CD having the highest rate of inclusion complex formation. The inclusion of aldehydes with longer aliphatic chains using native CDs is quasi-ineffective and thus chemically modified CDs are needed. HPβCD and RAMEB include the linear aldehydes (pentenal through octenal) in very good rates (Hara et al., 2003). CDs can thus be used as active components in deodorants as well as in other personal care formulations. A few of these formulations are already patented. A set of aqueous compositions based on CDs (and polymers as thickeners), which may or may not contain adjuvant adsorbent and antimicrobial agents, is claimed to reduce body odors (Trinh et al., 1998). In another patent, compositions based on CDs and surfactants are claimed to entrap odors by spraying on surfaces (Woo et al., 1998). In a toothpaste formulation, β-CD is used in tandem with papain to achieve “rapid removal of bad breath” (Yantai Dayang Pharmaceutical Co., 2014). CDs are also used as active ingredients for the entrapment of odors in the household deodorant spray, Febreze (Procter and Gamble, 2017), launched in 1998, and in the laundry dryer sheets, Bounce (Wang, 2008), introduced in 1975. These two product lines have come to grow into the largest market applications for CDs in the cosmetics and toiletries branch.

10.2.3.2 Cyclodextrins and human immunodeficiency virus prophylaxis Most CDs have a strong affinity towards cholesterol. RAMEB was shown to selectively sequester it from biological membranes of P1798 lymphoma cells (Ilangumaran and Hoessli, 1998). On endothelial cells (HUVEC line) treated with various CDs, high extraction levels were also observed; up to almost half of cholesterol content (for a CD concentration of 10 μM). The cholesterolremoving properties of CDs on this cell line followed the order β-CD  RAMEB . DIMEB  HPβCD . TRIMEB (Castagne et al., 2009). CCR5, a chemokine receptor in macrophage cells, acts as the primary coreceptor for macrophage-tropic HIV type 1 (HIV-1). It is found on the surface of cells at specific cholesterol-rich micro-domains, named lipid rafts. Cholesterol depletion by RAMEB interferes with the expression of CCR5 at the surface of the macrophage cells, decreasing it by 100%, that is, causing its complete disappearance from the cell surface (Carter et al., 2009). RAMEB also decreases the expression of the other coreceptors, such as CD4 (by 35%) and CXCR4 (by 59%), that, along with CCR5, are vital to the process of entry of HIV-1 into the macrophages. In this way, RAMEB severely inhibits the early steps of productive HIV infection of macrophages.

10.2 Cyclodextrins in Skin Formulations

β-CD was also proposed as a suitable topical agent for the prophylaxis of HIV infection, due to its ability to remove cholesterol not only from human cells but also from the free virion particles of both HIV and simian immunodeficiency virus (SIV). This causes an effect called virion permeabilization, which consists of the reduction of the capsid proteins as well as a few matrix proteins, ultimately leading to viral inactivation (Graham et al., 2003). Further investigations by the same research team have demonstrated that HIV virions treated with β-CD did not fuse to the membrane of susceptible cells. Dequenching was restored by replenishing virion-associated cholesterol, thus indicating that cholesterol in HIV particles is strictly required for fusion and infectivity. Removing the cholesterol from infected cells of the human host, by action of β-CD or HPβCD, also had positive results, dramatically lowering the virus release and causing the virions released from cholesterol-depleted cells to be minimally infectious (Liao et al., 2003). These findings demonstrate that β-CD, RAMEB and HPβCD are excellent candidates for use as a chemical barrier for AIDS prophylaxis.

10.2.3.3 Randomly methylated β-cyclodextrin as a potential skin-lightening agent The cholesterol-binding ability of RAMEB makes it a potential skin-lightening agent. In a study conducted in vitro on human melanocytes, a solution containing 1 mM of RAMEB significantly reduced the intracellular melanin content, by 35% after 5 days of incubation (Jin et al., 2008). This decrease in pigmentation shows that cholesterol is related to modulation of skin pigmentation and that its depletion by RAMEB leads to a downregulation of the expression of tyrosinase, the enzyme that initiates the biosynthetic cascade of melanin. By acting on the synthesis of the melanin pigment itself, RAMEB provides an alternative to chemical bleaching agents, that reverse the oxidation state of the melanin present in the skin.

10.2.4 MODULATION OF SKIN FUNCTION BY CYCLODEXTRINS Skin works as the body’s frontier and protection against external aggressions. It is therefore provided with an excellent barrier function by means of its outer layer, the stratum corneum. The corneocytes of hydrated keratin form a brick-like structure embedded in an extracellular “mortar” matrix composed of highly organized, multiple lipid bilayers of ceramides, fatty acids, cholesterol and its esters (Donnelly et al., 2012) that keeps away exogenous substances, drugs included (Wiechers, 1989). In this way, a compound intended for transdermal delivery must first cross the stratum corneum and the viable epidermis, and only then can it be taken up by blood vessels in the upper papillary dermis and enter the systemic circulation. There are three possible pathways leading to the capillary network: (1) through hair follicles with associated sebaceous glands, for lipophilic

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compounds; (2) via sweat ducts, for hydrophilic compounds; or (3) across continuous stratum corneum between these appendages, for compounds with low molecular weight (,600 Da) (Larran˜eta et al., 2016). CDs are macromolecules with molecular weight . 1000 Da and for this reason it is generally accepted that they are too large to be able to penetrate deeply into the stratum corneum (Barry, 1987; Legendre et al., 1995). Nevertheless, the presence of CDs often allows for optimizing the transdermal delivery of drugs intended either for local or systemic use, by making them more soluble and creating an in situ reservoir effect. In addition, a few methylated CDs can change the skin barrier function by interacting with skin lipids or even cell membrane lipidic components like phospholipids or cholesterol. This changes the properties of the skin tissue and ultimately leads to increased drug permeation. Although methylated CDs bring positive results for drug transdermal delivery, they are also associated with skin irritancy and cracking, meaning that they must be used in low concentrations to ensure they are well tolerated.

10.2.4.1 Native cyclodextrins as skin permeation enhancers Enhancement of drug permeability by native CDs has been under study since the 1990s. The first model drugs included antiinflammatory drugs, both steroidal and non-steroidal. α-CD was able to increase the in vitro transdermal permeability of dehydroepiandrosterone without modifying the permeation coefficient of the drug in the stratum corneum (Ceschel et al., 2002, 2005). β-CD was shown to increase the in vivo skin permeation of flurbiprofen, measured by the reduction of paw edema in rats, having, in the same conditions, no effect on piroxicam (Reddy and Udupa, 1993). β-CD increased the in vitro skin permeation of betamethasone (Otagiri et al., 1984) and of 4-biphenylacetic acid, a non-steroidal antiinflammatory drug (Arima et al., 1996), but, interestingly, it had no effect on the permeability of its prodrug, ethyl-4-biphenyl acetate (EBA) (Arima et al., 1990). Furthermore, β-CD was demonstrated to enhance the in vitro permeation of dexamethasone (Lopez et al., 2000) and hydrocortisone (Preiss et al., 1995). β-CD promoted the accumulation of hydrocortisone in the dermis rather than at the upper skin layers, and, based on this observation, it was postulated that the “preferred penetration route for the easily soluble inclusion complexes (ICs) is transappendageal diffusion” (Preiss et al., 1995). In the case of ICs, which are hydrophilic, transappendageal difusion will occur essentially through the sweat glands (Fig. 10.2). Regarding γ-CD, in vitro studies show that low concentrations (0.1%) do not affect the barrier function of skin (Sclafani et al., 1995). The effect of γ-CD on skin permeation was studied mostly on steroidal antiinflammatory drugs. It promotes the permeability of beclomethasone dipropionate (Uekama et al., 1985) and it allows increasing the permeation of fludrocortisone acetate in a skin-friendly way (Klang et al., 2011).

10.2 Cyclodextrins in Skin Formulations

FIGURE 10.2 Schematic representation of the possible skin permeation routes for a drug when included into a cyclodextrin: the inclusion complex, hydrophilic in nature, is postulated to enter via the sweat duct; part of the complexes dissociate to afford the free drug that is able to cross the stratum corneum due to its lower molecular weight (model valid for molecules under 300 Da).

10.2.4.2 Skin permeation enhancement with 2-hydroxypropyl-β-cyclodextrin HPβCD behaves similarly to the native CDs in terms of skin absorption. Its absorption from aqueous solution applied to the skin of hairless mice is vestigial, with a percutaneous absorption rate after 24 h of B0.02% of the amount applied. Under the same experimental conditions, and changing the test skin to takestripped skin, the amount of HPβCD absorbed is around 24%, suggesting that the stratum corneum acts as a barrier to the penetration of HPβCD through the skin (Tanaka et al.,1995). The effect of HPβCD on skin permeability was studied with a large variety of drugs, with γ-CD having a promoting action for the majority. However, in a reduced number of cases, it was ineffective or it reduced the permeability (Bochot and Piel, 2011). A few in vivo studies in rats have demonstrated the positive effects of HPβCD, which increased the skin permeation of EBA by more than two-fold (Arima et al., 1990), of ketoprofen by up to 5.4-fold (Sridevi and Diwan, 2002) and of the flavonoids from milk thistle extract (Spada et al., 2013). In vitro, HPβCD is typically used in concentrations of 5% or 10% (m/v) and it was shown to increase the permeability of estradiol by two-fold (De Paula et al., 2007), of both dexamethasone (Lopez et al., 2000) and curcumin (Ghanghoria et al., 2013)

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by six-fold, of avobenzone by 7.3-fold (Yang et al.,2008), of celecoxib by 8-fold (Ventura et al., 2006), and also the solubility of oxybenzone (Felton et al., 2002; Sarkeiya et al., 2004). Transdermal films for the delivery of active substances, having a composite of HPβCD, polyvinyl alcohol, and chitosan as the main ingredients, are already patented in China (Yunli et al., 2012). The proposed mechanism for the increase in the skin permeability of drugs brought about by HPβCD is linked, as with native CDs, to the increased aqueous solubility of the drug by inclusion complexation, with consequent preferential transappendageal diffusion (Preiss et al., 1995). Nevertheless, the dissociation of the complex must occur prior to drug absorption. In fact, in certain instances, increasing the concentration of HPβCD to 20% or 30% (m/v) was reported to result in a poorer permeation, because the excess of host lowers the rate of dissociation of the inclusion complex and there is less free drug available (Loftsson and Siguroardottir, 1994; Felton et al., 2002). HPβCD can also be used to lower the skin uptake of toxic ingredients such as the preserving agent methylparaben. In the presence of HPβCD, the in vitro cutaneous permeation of methylparaben was strongly reduced. Furthermore, the lower concentrations facilitated the metabolic process that is active in the skin, converting methylparaben to p-hydroxybenzoic acid, a less toxic metabolite (Tanaka et al.,1995).

10.2.4.3 Methylated cyclodextrins interfere with the stratum corneum Methylated CDs have a somewhat more lipophilic profile than the native or hydroxypropylated CDs, meaning that they can be absorbed into the skin to a larger extent. It should be noted, however, that this amount is still low, according to the levels of methylated CDs detected in the blood and urine. For example, a study in rats using a 5% (w/v) methylcellulose solution of radio-labeled DIMEB showed that only about 0.3% of the dose was absorbed through the skin during the 24 h observation period and any intact DIMEB absorbed was quickly removed via the kidneys, urine levels being roughly 0.2% (Gerlo´czy et al., 1988). DIMEB has, however, the ability to interfere with the stratum corneum, as demonstrated by studies in vitro. When isolated human stratum corneum is heated and its energy transfer with the surrounding medium is measured using differential scanning calorimetry, a well-defined endothermic transition can be observed. The presence of DIMEB changed the temperature of this event, thus indicating alteration of the structure of the stratum corneum (Vollmer et al., 1994). DIMEB, in a concentration of 5% (m/v), was shown to increase the in vitro permeability of celecoxib by roughly nine-fold (Ventura et al., 2006). Concerning RAMEB, it was shown to extract all the major lipid classes from isolated stratum corneum of hairless rats and to reduce the barrier function of the skin (Legendre et al., 1995). Further in vitro studies, using caco-2 cells as an epithelial model, showed that RAMEB depletes cholesterol from cholesterol-rich cell membrane domains and that this depletion interferes with proteins in these domains. These proteins are an important part of membrane structures called tight junctions. They are multiprotein complexes that “physically link adjacent cells

10.2 Cyclodextrins in Skin Formulations

within an epithelium/endothelium but also form a semi permeable barrier between the cells that defines the permeability characteristics of the paracellular pathway” (Lambert et al., 2007). In summary, it can be concluded that exposure of the cells to RAMEB leads to the displacement of certain proteins in the tight junctions. With less proteins, there is a reduced intercellular interaction and thus the permeability is altered. An in vitro study using the RAMEB-estradiol inclusion complex gives a good illustration of this effect. The permeability of the complex was roughly twice that of free estradiol; the permeability of free estradiol also doubled when the stratum corneum was removed by tape-stripping, meaning that RAMEB can be used to create a similar effect (without having to remove one’s outer skin layer) (De Paula et al., 2007). Other in vitro studies show how RAMEB increases the permeation of drugs. With tenoxicam, the presence of RAMEB results in a permeability increase by 1.5-fold (Larrucea et al., 2002) With metopimazine hydrochloride (MPZ), simple addition of 20% RAMEB to a 2.2 mg/ml solution brings a permation increase of 2.7-fold whereas, when the RAMEB
MPZ inclusion complex is used, permeation of MPZ is 3.2-fold higher (Bounoure et al., 2007) With haloperidol, addition of 0.01M of RAMEB increases permeability by roughly sevenfold (Azarbayjani et al., 2010). A pre-clinical study on the effect of RAMEB on dermal delivery was carried out using the inclusion complex RAMEB
4-MBC (4-MBC 5 4-methylbenzylidene camphor). The complex or pure 4-MBC were formulated into emulsions and tested on six healthy female volunteers. Following this, the stratum corneum was removed by tape-stripping and the amount of 4-MBC available in these samples was quantified (Scalia et al., 2007). The study showed that complexation with RAMEB did not alter significantly the amount of sunscreen agent, 4-MBC, that penetrated into the stratum corneum. DIMEB and RAMEB are patented for promoting the penetration of vitamin A or its esters in compositions intended for cosmetics or dermatology care, to “regulate the cell metabolism of the skin, and/or preserve or restore a good physiological skin condition, and/or improve the tone, firmness and elasticity of the skin, and/or delay the appearance of wrinkles or reduce their depth” (Archambault et al., 2005).

10.2.5 IONTOFORESIS WITH CYCLODEXTRINS Iontophoresis facilitates the migration of charged compounds across a skin area which is subject to a low-intensity continuous electrical current. When the drug is lipophylic and non-charged, the use of the anionic host, such as SBEβCD, is quite advantageous as it protects the drug while allowing it to become electrically charged. Indeed, SBEβCD was shown to render the model drug, propofol, amenable to iontophoresis (Juluri and Murti, 2014). In the case of ionizable drugs, CDs allow loading higher quantities of the drug into the formulations for iontoforetic delivery, due to their solubilizing effect (Carter and Kalamasz, 2007). This was demonstrated in vitro using HPβCD as a

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solubilizing agent for the iontoforetic delivery of hydrocortisone (Chang and Banga, 1998) and piroxicam (Doliwa et al., 2001a). The practical utility of iontoforetic-delivered formulations containing HPβCD was also studied in vivo in rats. These compositions were shown to be suitable alternatives for administering indomethacin in the treatment of osteoarthritis (Nagai et al., 2015).

10.2.6 CYCLODEXTRINS IN MICRONEEDLE ARRAYS One of the newest systems for systemic delivery through the skin is the microneedle array. These devices are produced by microfabrication techniques and comprise a set of very small needles that are applied to the skin surface and pierce the epidermis, creating microscopic aqueous pores through which drugs diffuse to the dermal microcirculation. The process is claimed to be painless, because the needles are short and narrow enough to avoid stimulation of dermal nerves or the puncture of dermal blood vessels (Larran˜eta et al., 2016). The drug formulation is applied either as a coating on the microneedles or as a hydrogel on the skin site that has been pierced. CDs are often employed to help solubilize drugs in the hydrophilic pores created by the microneedles. CDs are patented for use in a variety of patch microneedle delivery systems (Wong and Daddona, 2005; Cormier et al., 2006; Singh et al., 2008; Zhang et al., 2012; Determan et al., 2013; McAllister, 2014; Stinchcomb and Ghosh, 2014; Lee and Kim, 2016) and they are also patented as ingredients for the preparation of biodegradable microneedle systems (Takada and Ono, 2013; Singh et al., 2015). Microneedle arrays are quite useful in the field of pharmaceutics. βCD, HPβCD and SBEβCD are patented in microneedle delivery of benzodiazepines (Stonebanks, 2008). Native CDs, their sulfobutylethylated derivatives, RAMEB, HEβCD, glycosyl-α-CD, and maltosyl-α-CD are patented for use in microneedle delivery of fentanyl-based opioids (Ameri et al., 2005), of epoetin-based erytropoietic agents (Ameri et al., 2006) and of peptide therapeutic agents (Zhang et al., 2013). Biodegradable microarrays for the delivery of anthrax vaccine can be prepared using native CDs, HPβCD, and RAMEB (Ghartey-Tagoe et al., 2014). Another patent describes an alternative and more patient-friendly method for the delivery of the influenza vaccine, relying on HPβCD-containing microneedles (Mistilis et al., 2015). In the field of cosmetics, a few products based on the technology of the microneedle arrays are starting to make their first steps into the market, as demonstrated by a few patents in this field. One example is the claim of a biodegradable microneedle array specifically designed for the delivery of substances for the treatment of skin ageing or scarring (Takada and Ono, 2013). Another interesting and innovative patent claims the use of CD-containing microneedles for the application of permanent or semi-permanent markings on the skin, such as subcutaneous makeup or other cosmetic compounds, or even tattoos which will have high resolution since

10.3 Molecular Encapsulation With Cyclodextrins

“the preferred inks contain particles of a certain minimum size that will not diffuse too far through the skin”. The markings are made from substances that will disappear from the skin after a time period (Yuzhakov et al., 2001).

10.3 MOLECULAR ENCAPSULATION WITH CYCLODEXTRINS CDs are often used in cosmetic and topical formulations for the wide range of technical advantages that they bring, such as helping to emulsify basic compositions, solubilizing hydrophobic substances without causing cloudiness, and helping substances permeate the skin. These properties were described in previous subsections. Nevertheless, the most important feature of CDs is their chemical ability to form ICs with less polar molecules, rendering them more resistant to degradation by oxidation, heat, and exposure to visible and ultraviolet light, and, in the case of volatile compounds, to losses by evaporation. The ICs are formed by replacement of hydration waters in the cavity of the CD by the guest molecule, which has a higher affinity towards this apolar site. They are stabilized by van der Waals forces or, when adequate functional groups are available, by hydrogen bonds. The inclusion process is always driven by a higher affinity of the apolar guest to the cavity of the CD in regard to the hydration waters. It is a competitive association. The most energetically favored fit leads to the formation of a complex with the most stability and, therefore, less likely to be disrupted in the presence of a competing molecule. In this process, besides the polarity and possibility of hydrogen bonding, the dimensional fit also plays a key role. In this way, α-CDs, with a narrower cavity, will tend to include only guest molecules of small dimensions or aliphatic compounds, whereas β-CDs are able to accommodate aromatic and heterocycles compounds; γ-CDs can include larger molecules such as steroids and flavonoids.

10.3.1 PREPARATION OF INCLUSION COMPLEXES The preparation of CD ICs typically involves a co-dissolution or suspension step, using as solvent water or a water/cosolvent mixture. For industrial purposes, and particularly when concerning human use, the co-solvent must be safe, i.e., ethanol, isopropanol or a mild organic acid. Following the co-dissolution step, the solution is stirred for some time and then the complex is isolated by means of a drying step, typically using spray-drying or freeze-drying procedures. For a couple of examples, refer to the preparations of CD-artemisin complexes, with CD 5 β-CD, HPβCD, SBEβCD (Plaizier-Vercammen and Gabriels, 2004) and CD-perindopril complexes, with CD 5 β-CD, HPβCD, γ-CD, ε-CD (Ruckman, 2005). An alternative, innovative, and environmentally friendly method for the preparation of ICs is to use supercritical CO2 as a green solvent. The thermodynamic

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conditions of supercritical fluids provide densities which are between those of liquids and gases and they allow for fine-tuning the physical properties of substances, such as the solubility, by applying smooth changes in the density of the medium (Ingrosso et al., 2016). Supercritical CO2 is a technique that can be adapted to the preparation of ICs, particularly with methylated CDs, because they are freely soluble in apolar media. Successful results, at the laboratory scale, are reported for RAMEB with flurbiprofen (Rudrangi et al., 2016), ketoprofen (Banchero et al., 2013), olanzepine (Rudrangi et al., 2015), and borneol (He and Li, 2009), and for TRIMEB with benzoic acid (Ingrosso et al., 2016) and omeprazole (Sultana et al., 2012), to name a few. Inclusion into β-CD by means of supercritical CO2 procedures requires the use of an auxiliary cosolvent in order to help solubilize the host, which typically is water or ethanol. Recent reports on ICs prepared using this technique comprise β-CD
safranal (Abbaszadegan et al., 2015) and β-CD-piroxicam (Grandelli et al., 2012). Noteworthy is the fact that supercritical CO2 procedures are already being used at full industrial scale in the preparation of ICs by the company Pierre Fabre. The procedure has the tradename Formulplex and it is described as “a cyclodextrin complexation procedure in a supercritical medium [for the] improvement of solubility and/or bioavailability of an active substance” (Pierre Fabre S.A., 2017).

10.3.2 PROPERTIES AND ADVANTAGES OF CYCLODEXTRIN INCLUSION COMPOUNDS Inclusion complexation affects the physicochemical properties of the entrapped guest molecules, mainly by disrupting the intermolecular interactions that exist when the guest is in its pure form. In the inclusion complex, the guest molecules are wrapped individually or in pairs (depending on the stoichiometry of inclusion) by the CD cavity and therefore their behavior is dramatically altered. Here are a few examples: •

• •

•

Compounds having a very high affinity towards the CD cavity will dissociate at a very slow rate from the complex and these ICs will thus exhibit sustained release of the drug or active ingredient when applied on the skin. Liquid compounds, such as plant essential oils and botanical extracts, can be turned into powders, and volatility is strongly reduced. Molecules that are sensitive to ultraviolet and visible radiation are protected by inclusion, since CDs can themselves act as filters against radiation and avoid photodegradation of the guest. For this reason, CDs are often employed in sunscreen compositions to protect the active ingredients (Perassinoto et al., 2016). Included guest molecules are protected from the attacks of several reactive substances and in this way the hydrolysis, oxidation, racemization, isomerization, polymerization, and enzymatic decomposition reactions are eliminated or minimized, which results in extended shelf-life for the products containing ICs (Tarimci, 2011).

10.3 Molecular Encapsulation With Cyclodextrins

Liquid or oily substances as powders

Improvement of handling

Increased dissolution rate Increased solubility Change in the viscosity Avoidance of organic solvents

Increase in the stability of emulsions

Solubilization of the guest in water

Advantages of cyclodextrins in cosmetics

Decomposition reactions induced by light or heat Oxidation or hydrolysis Protection of the guest from

Elimination of

Undesired odors or tastes

Loss by evaporation Chemical reactions with other compounds

Hygroscopicity

FIGURE 10.3 Advantages of the use of cyclodextrins and their inclusion complexes in cosmetic and dermal compositions.

•

Pharmaceutical products that act via the transdermal route can have CDs in their composition, with an aim to improve the release and/or penetration, the stability, and reduce the local irritation.

A summary of the various advantages brought about by the inclusion of actives into CDs is schematized in Fig. 10.3.

10.3.2.1 Advantages of inclusion complexes with fragrances Inclusion of aromatic molecules is one of the earliest applications of CDs. To date, these ICs remain among the most widely used, as demonstrated by the large variety available from commercial sources (for details, refer to the Section 10.3.3 and Table 10.2). The hydrophilicity, small size, and adequate geometry of the fragrance molecules make them excellent guests for CDs, affording ICs with strong affinity constants. β-CD has the cavity with the most adequate size for most of these guests. In a comparative study with α- and β-CDs, β-CD was shown to form more stable complexes with maltol, furaneol, methyl cinnamate, cineole, citral, menthol, geraniol, camphor, eugenol, guaiacol, and limonene. It should be noted, however, that the values of the affinity constants (Kapp) therein determined were lacking units (Astray et al., 2010). Vanillin also forms the most stable IC with β-CD, followed by γ-CD and lastly α-CD. The Kapp value of β-CD-vanillin is 270 M21, being interpreted as evidence of moderate affinity (Ishikawa et al., 2007). Much stronger affinities were observed for β-CD complexes with transanethole (Zhang et al., 2015) and α-terpineol (Mazzobre et al., 2011), having Kapp values of 1195 and 1360 M21 respectively. Within the chemically modified CDs, HPβCD is the most popular and suitable for the inclusion of fragances. The ICs with camphor, linalool (Tanaka et al., 1996), eucalyptol, geraniol, limonene,

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α-pinene, β-pinene, and thymol have reported Kapp values ranging between 1200 and 2000 M21 (Kfoury et al., 2014). With l-menthol and eugenol, HPβCD forms remarkably stable complexes, with Kapp values of 4000 and 4600 M21, respectively (Tanaka et al., 1996). When ICs are used to prepare fragranced compositions, the time of permanence of the fragrance molecules in the product is usually increased, in comparison to that obtained using only the pure fragrance. In hydrophilic formulations, such as gels, the permanence of the fragrance can be increased by several months. In a case study, HPβCD complexes with linalool, the main terpenic compound associated with lavender fragrance, and benzyl acetate, an aromatic compound associated with jasmine fragrance, were incorporated into hydrophilic gels and retained the fragrance for over 6 months, whereas the same compositions, having only linalool or benzyl acetate, lost the fragrance after 2 months (Numano˘glu et al., 2007). Another important consequence of the strong host guest affinity occurring in complexes with fragrances is that these guests are released in a very slow manner and thus the compositions that contain these ICs will exhibit sustained-release activity. In vitro tests showed that the quantity of eugenol that was able to permeate excised mouse skin 24 h after application was roughly five times lower for HPβCD
eugenol than for pure eugenol (Tanaka et al., 1996). Sustained release properties were also reported for β-CD
trans-anethole (Zhang et al., 2015), HPβCD
ionone (sweet osmanthus flower fragrance) (Li et al., 2014), and HPβCD
geraniol (Aytac et al., 2016).

10.3.2.2 Practical applications and benefits of inclusion complexes in sunscreens Sunscreen compositions benefit greatly from the use of active ingredients in the form of ICs, for two main reasons. The first and most obvious advantage is the aforementioned protection against early photodegradation of the sunscreen agent, which allows increased stability and shelf-life. In some instances, reduction of interaction with other components in the composition is also observed. The second advantage is the odor-masking effect of the CDs on these substances. In vitro studies have demonstrated that inclusion into β-CD improves the stability of ethylhexyl-p-methoxycinnamate (Scalia et al., 2002), octyl-p-methoxycinnamate (Monteiro et al., 2012) 4-methylbenzylidene camphor (Scalia et al., 2007), oxybenzone, and octocrylene (Al-Rawashdeh et al., 2013). Other CDs, such as HPβCD, may also be used to protect sunscreen agents, namely butylmethoxydibenzoylmethane (Scalia et al., 2011). The complex HPβCD-benzophenone-3 (2:1 ratio) was demonstrated to eliminate the undesirable effects (comedogenesis and acanthosis) that this sunscreen agent has on the skin when used in the free form (Berbicz et al., 2011). When HPβCD is used to form ICs, given the high solubilizing effect brought about by this CD, the sunscreen agent is absorbed through the skin much more quickly, which is undesirable since its

10.3 Molecular Encapsulation With Cyclodextrins

action requires it to remain on the surface of the skin. To counteract the permeation effect, ICs with sunscreen agents are usually incorporated into lipophylic vehicles such as lipid micro- or nanoparticles.

10.3.3 INCLUSION COMPLEXES AS FORMULATION INGREDIENTS 10.3.3.1 Commercially available cyclodextrin inclusion complexes A selection of ICs is already commercially available for use as ingredients in the food, cosmetic, or pharmaceutical industries. One example is γ-CD
coenzyme Q10 (Wacker Chemie AG, 2017a), recommended by the manufacturer for use in nutrition, but also suitable for use in cosmetics. Indeed, γ-CD-coenzyme Q10 was demonstrated to be very well absorbed by the skin in the presence of dipotassium glycyrrhizate (Cyclochem Bio Co., 2011) and coenzyme Q10 is already a featured skin active in a few facial creams. The complex γ-CD
curcumin is only approved as dietary supplement (Wacker Chemie AG, 2017b). Specifically for cosmetic applications, this company has several complexes: β-CD
citral, used as a raw material in the perfume industry (Wacker Chemie AG, 2017c); 2γ-CD
vitamin E, which is recommended for a variety of cosmetic and pharmaceutical cosmetic products within skin care, antiaging, selftanning, shaving formulations, colored cosmetics, and sun lotions (Wacker Chemie AG, 2017d); and 2γ-CD
retinol, recommended for personal and skin care, antiaging, and suncare products (Wacker Chemie AG, 2017e). β-CD
squalene (3:2 ratio), β-CD
vitamin B7 (also referred to as β-CD
biotin), RAMEB
palmitic acid and RAMEB
sodium palmitate are available from Carbomer (2016). β-CD
retinol, RAMEB
retinol and β‑CD
β‑carotene are available from CDT holdings, but recommended by the company for research and development uses only (CTD Holdings, 2013). CD complexes of pharmaceutical interest are available in a much larger variety, as presented in Table 10.1. Also available is a selection of ICs with botanical extracts such as essential oils, oleoresins, and other extracts that may be used, for instance, in natural cosmetics and with aromatic molecules, suitable as fragrance for a variety of compositions. These materials are listed in Table 10.2.

10.3.3.2 Incorporation of inclusion complexes into elastic liposomes A growing trend in the development of skin formulations with improved performance is to incorporate ICs into molecular assemblies of larger dimensions and complexity. This way, ICs can be used as raw materials to incorporate into liposomes, building the so called ’drug-in-CD-in-liposome assemblies’ (Chen et al., 2014). Liposomes are frequently used in cosmetic and pharmaceutical preparations as transdermal drug delivery systems, due to their composition of phospholipid bilayers, similar to the cell membrane, that renders them biocompatible, biodegradable and minimally toxic (Im et al., 2016). In the most recent systems,

425

Table 10.1 Commercially Available Cyclodextrin Inclusion Complexes (ICs) With the List of Their Potential Applications in Topical Compositions IC α-CD
prostaglandin β-CD
indomethacina β-CD
piroxicamb,c β-CD
pirprofen c β-CD
salicylic acidb

a,c

DIMEB
moxidectina RAMEB
beclomethasonea RAMEB
betamethasonea RAMEB
benzocainea RAMEB
cromoglicic acida RAMEB
chloramphenicola RAMEB
diosgenina RAMEB
erithromycina RAMEB
flucinonidea RAMEB
isosorbide dinitratea RAMEB
ivermectina RAMEB
nicotinea RAMEB
propofol a RAMEB
salbutamola RAMEB
tetracaina RAMEB
theophyllinea RAMEB
triamcinolone acetonidea

Drug Type

Proposed Topical Uses

Biomolecule Antiinflammatory Antiinflammatory Antiinflammatory Antiinflammatory, peeling agent Antihelmintic Corticosteroid

Glaucoma treatment Acute pain and sport lesion treatment Analgesic with reduced drug odorb Acute and moderate pain treatment Removing acne, cleaning pores, lightening, promoting cutin renewal and killing fungib Scabies treatment (mostly veterinary) Treatment of atopic dermatitis, eczema and other inflammatory skin conditions Treatment of skin inflammation, redness, dryness and scaling Local anesthesia Antiitch Disinfectant Menopausal symptoms alleviation Skin infection treatment Treatment of atopic dermatitis and other inflammatory skin conditions Increase of peripheral circulation Lice infection treatment Tobacco discontinuation aid Local anesthesia Lupus eritematosus treatment, reduction of hyperpigmentation of scar tissued Local anesthesia Anticellulite Treatment of allergies, eczema and other inflammatory skin conditions

Corticosteroid Anesthetic agent Antihistamine agent Biocide Saponin Antibiotic Corticosteroid Vasodilator Antihelmintic Alkaloid Anesthetic agent β2-Adrenergic receptor agonist Anesthetic agent Alkaloid Corticosteroid

HPβCD
adenosinea HPβCD
ampicillina HPβCD
cinnarizinec HPβCD
chloramphenicola HPβCD
chlorhexidina HPβCD
dexamethasonea HPβCD
erithromycina HPβCD
estradiola HPβCD
hydrocortisonea HPβCD
ibuprofena HPβCD
moxidectina HPβCD
progesteronea HPβCD
salicylic acidb

Biomolecule Antibiotic Antihistamine agent Biocide Biocide Corticosteroid Antibiotic Sex steroid Corticosteroid Antiinflammatory Antiparasital Female hormone sex steroid Antiinflammatory, peeling agent

γ-CD
beclomethasonea γ-CD
ipratropium bromidea a

Vasoconstricting agent

Hair growth stimulatore Skin infection treatment Rashes, bites, and allergies treatment Disinfectant Disinfectant Treatment of inflammatory skin conditions Skin infection treatment Menopausal symptom alleviation Treatment of allergies, eczema and other inflammatory skin conditions Treatment of localized pain due to strains or arthritis Scabies treatment (mostly veterinary) Menopausal symptom alleviation Removing acne, cleaning pores, whitening, promoting cutin renewal and killing the fungib Treatment of atopic dermatitis, eczema and other inflammatory skin conditions Nasal decongestant

Compiled from the CTD online catalogue (CTD Holdings, 2013). Compiled from the Shandong Binzou Zhiyuan Biotechn. online catalogue (Shandong Binzou Zhiyuan Biotechnology Co., Ltd., 2017). Compiled from the Carbomer online catalogue (Carbomer, 2016). d Topical treatment of discoid lupus eritematosus can be achieved with salbutamol (Jemec et al., 2009); scar tissue accumulation and hyperpigmentation are reduced by local application of salbutamol (University of Leicester, 2017). e Adenosine has been proposed for the treatment of alopecia, based on results with healthy volunteers (Faghihi et al., 2013; Iwabuchi et al., 2016). b c

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Table 10.2 Commercially Available Inclusion Complexes With Botanicals and Aromatic Compounds ICs With Botanicals

Essential Oils and Oleoresins

Cyclodextrin

Guest

β-CD

Bergamot oila,c Black pepper oleoresinc; eucalyptus oila,c Jasminea Lemon oila,c Mustard oila,c Peppermint oila,c Rose oila,c Vanilla extracta,c Black pepper oleoresina Euphrasiaa

RAMEB HPβCD

ICs With Aromatic Compounds Cyclodextrin

Guest

α-CD

β-Pinene (pine tree)a Cinnamaldehyde (cinnamon)a,c Benzaldehyde (bitter almonds)a,c β-Pinenec Camphora,c Cinnamaldehydea,c Citrala,c Cherry flavora,c Eugenol (cloves)a,c Guaiacol (coffee)a,c Limonene (lemon)a,c Menthol (mint)a,b Piperonal (pepper)a,c Strawberry flavorc Thymol (thyme)a Mentholb

β-CD

HPβCD a

Compiled from the CTD online catalogue (CTD Holdings, 2013). The ICs are recommended for research purposes only. b Compiled from the Shandong Binzou Zhiyuan Biotechn. Online catalogue (Shandong Binzou Zhiyuan Biotechnology Co., Ltd., 2017). c Compiled from the Carbomer online catalogue (Carbomer, 2016).

the transdermal penetrating abilities of the liposomes are further increased by incorporation of a water-soluble surfactant and/or humectant polymer, such as polyethyleneglycol, polyglyceryl-3 methylglucose distearate (Tego care 450), or sodium deoxycholate, to create vesicles named ‘elastic liposomes’. The additive

10.3 Molecular Encapsulation With Cyclodextrins

is called an ‘edge activator’ and it has the role of destabilizing the lipid bilayers of the vesicles in order to increase their deformability. These structural features allow the elastic liposomes to have an easier penetration through the stratum corneum and to deliver bioactive compounds into the skin more efficiently (Elsayed et al., 2007). Elastic liposomes are reported to form stable, more permeable assemblies with a variety of ICs, such as HPβCD
caffeic acid (Im et al., 2016), HPβCD
quercetin, HPβCD
resveratrol (Cadena et al., 2013), HPβCD
isotretinoı´n (Kaur et al., 2010), HPβCD
betamethasone and CRYSMEB
betamethasone (Gillet et al., 2009). It must be noted, however, that the affinity between the CD and the included drug must be higher than the affinity of the CD to the phospholipidic components of the liposome. Should the CDs have lower affinity with the drug than with the lipid components, during storage, these molecules, especially cholesterol, could displace the drug molecules in the CD cavity by forming inclusion complex with CDs and thus destabilize the bilayers of the liposomes (Lapenda et al., 2013). The issue can be circumvented by coating the liposomes with polymers (Lim et al., 2008) or incorporating sphingomielyn in the liposome bilayer (Beseniˇcar et al., 2008).

10.3.3.3 Compatibility of inclusion complexes with water-based formulations The successful incorporation of ICs into a topical formulation depends strongly on the type and the composition of the vehicle. Aiming at the full dissolution of the IC, the best results are achieved with aqueous-based compositions, such as lotions, gels and emulgels. The main excipients in these skin formulations are hydrophylic polymers. Incorporation of ICs into a polymer-based composition may cause changes in its physicochemical properties because ICs are a dynamic system; in water there is always some dissociation of host and guest, leaving free CDs to thread onto the end chains of the polymers. The tight junctions occurring at polymer end chains form interactions that typically keep the gel together, which are disrupted upon threading of CD molecules. The result of this interference can be either an increase in the viscosity, by a gelation effect, or a decrease in the viscosity, by transition from a gel to a more or less viscous solution. The addition of α-CD to a poly(ethylene oxide) (PEO) solution was reported to cause a sol gel transition, due to the threading of α-CD molecules on the PEO chains in pseudopolyrotaxane arrangements, i.e., necklace-like supramolecular structures. α-CD is also capable of threading on other narrow-chained polymers, whereas β‑CD, having a slightly wider cavity diameter, threads on poly(propylene oxide) (Miro et al., 2011). γ‑CD increases the viscosity of Carbopol 974P NF gels, while RAMEB, in turn, causes the viscosity of these gels to diminish in a dose-dependent manner (Boulmedarat et al., 2003). As RAMEB is more lipophilic than γ-CD, it is likely to form stronger hydrophobic interactions with the polymer chains, lowering their unfolding abilities. Carbopol chains would consequently have less affinity towards the hydration medium and their swelling would decrease. The complex HPβCD
rhEGF (where rhEGF is the recombinant protein, epidermal growth factor)

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also caused a reduction in the viscosity of a poloxamer gel at temperatures above its critical gelation value. This was attributed to disruption of the hydrogen bonding pattern due to the presence of free HPβCD (Kim et al., 2002). The compatibility of a polymer with CDs also depends on a series of other factors, namely the viscosity, the extent of substitution, and the applied shear stress. For instance, β-CD and HPβCD were shown to have good compatibility with hydroxypropylmethylcellulose (HPMC) of the grade K4M, allowing its viscosity to remain unaltered (Pose-Vilarnovo et al., 2004). However, when similar HPMC gels are subject to increasing shear stress, the presence of β-CD and HPβCD caused its apparent viscosity to decrease (Jug et al., 2005). In summary, the addition of ICs to a polymer composition is a process that requires a careful and case-by-case compatibility study. Nevertheless, when adequately formulated, the combination of ICs with hydropolymers may bring a number of advantages, such as an easier gelation process, the formation of gels with less opacity, and a better uptake of the active by the skin (Miro et al., 2011).

10.3.3.4 Incompatibility risks CDs, in particular β-CD and its derivatives, have a strong affinity to include compounds belonging to the family of p-hydroxybenzoic esters, commonly denominated as methyl-, ethyl-, propyl-, and butyl-parabens. These substances are frequently used as preservative agents and they have both the geometry and the size to form a good fit with the cavity of β-CD. Butylparaben forms the strongest IC with β-CD, followed by methylparaben, propylparaben, and ethylparaben, in decreasing order of affinity (Chan et al., 2000). These interactions are observed for β-CD concentrations above 0.25% (m/v). Most compositions have concentrations of the IC above this threshold, and thus parabens will replace, at least partially, the drug molecule which is included in the CD. This disruption of ICs by parabens is most likely to occur when they exist concomitantly in an aqueous formulation. Additionly, the antimicrobial activity of the included paraben molecules is lost or strongly reduced due to inclusion into the CDs (Lehner et al., 1993), leaving the formulation subject to quick microbial degradation. The association of ICs and parabens in a formulation is thus to be avoided. Disruption of the ICs may also occur by the action of some solvents. Compositions containing complexes of α-CD cannot contain poly(ethylene glycol) since, over time, the molecules of α-CD will dissociate from the IC and thread onto this polymeric solvent, causing it to precipitate in the form of crystals (Harada, 1996). Glycerol can be used instead, because it has a quite low affinity constant with α-CD (Kapp 5 1.34 6 0.07 M21) (Bastos et al., 1997). With complexes of HPβCD, the presence of the solvent propylene glycol requires special attention. Partial dissociation of HPβCD-piroxicam (Doliwa et al., 2001b) and HPβCD-dexamethasone (Reer and Mu¨ller, 1993) by addition of propylene glycol was observed. Once again, this was attributed to the competiting effect of this solvent for the cavity of HPβCD.

10.4 Skin Products Containing Cyclodextrins

Surfactants are also known to cause destabilization of the ICs due to competitive binding. Complexes with β-CD can be dissociated in the presence of Cremophor 60 (polyethoxylated castor oil) (Shigeyama et al., 2000) and complexes with HPβCD are disrupted by Cremophor RH 40 and Solutol HS 15 (Reer and Mu¨ller, 1993). Good compatibility was, nevertheless, reported for Cremophor 60 with DIMEB and TRIMEB (Shigeyama et al., 2000), and for Cremophor SH with SBEβCD (Sanghvi et al., 2009). In summary, when incorporating an IC into a formulation, it is important to consider the potential competitive inclusion by the co-solvent, emulsifying agent, or preservative; the use of ingredients with reported incompatibilities is to be avoided. In any case, it is advisable to conduct a series of stability and aging tests to guarantee the compatibility of all the ingredients when a new composition is being developed.

10.4 SKIN PRODUCTS CONTAINING CYCLODEXTRINS In cosmetics, CDs are mainly used to include aromatic compounds, either for the stabilization of fragrances or for odor masking, given their odor absorption capabilities. As stabilizers that keep other ingredients from evaporating and losing efficacy, CDs are often used to protect retinoids because they are very sensitive to temperature and light. Inclusion also helps make retinoids to be better tolerated by the skin, reducing the incidence of redness and irritation (Anadolu et al., 2004). In this regard, products containing retinoids are likely to have the γ-CD inclusion complex with retinol, which is commercially available as mentioned in the Section 3.2, but this information cannot be ascertained because native CDs are generically listed in the ingredients as “cyclodextrin.” Native CDs are found in a variety of antiaging products that contain potent, yet unstable, antioxidant ingredients, such as antiaging treatments, facial moisturizers or lotions, sunscreens, cleansers, eye creams, deodorants, and self-tanners. Table 10.3 presents a compilation of products containing native CDs, HPβCD and even one product containing RAMEB. We note that, in the vast majority of the compositions presented, HPβCD is not incorporated in the pure form, but rather as part of a previously prepared formulation of excipients and actives for the skin. A known example is the combination of glycerin, water, HPβCD and the antiwrinkle agent palmitoyl tripeptide-38 (Fournial et al., 2010), which is available for cosmetic manufacturers under the tradename “Matrixyl® synthe’6t.” In this way, it is not uncommon that HPβCD is not mentioned in the ingredients list of the composition, rather mentioned as the component Matrixyl synthe’6, thus making it harder to systematize the information on CD-containing products. Novel CD-containing cosmetics are currently under development. A stateowned Russian company, Rusnano, joining entrepreneurs and scientists, is

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Table 10.3 Commercially Available Compositions Containing Cyclodextrins. Compiled From the EWG Cosmetics Database (EWG, 2016a,b) and Retailer’s Websites (Medico Beauty, 2017; Osmosis Skincare, 2017; Prai Beauty, 2017) Manufacturer

Composition Denomination

Cyclodextrin

Facial Moisturizers and Serums, With or Without SPF Absolute Care

Ahava Borghese

Clarins Derma e Dr Dennis Eminence Estée Lauder

Lab Series L’Oreal

Lumene Merle Norman MyChelle

Triple-effect day cream Triple-effect night cream Triple-effect face serum Safe and active face serum Beauty before age uplift day cream, SPF 20 CC cream age defying cellular complex, SPF 15 Protect moisture lotion with age defying cellular complex, SPF 15 Sunscreen for Face Wrinkle Control cream, SPF 30, 50 and 501 Deep wrinkle peptide moisturizer Deep wrinkle peptide serum Dark spot sun defense, SPF 50 Persimmon & cantaloupe day cream, SPF 32 Red currant day cream, SPF 30 Advanced time zone for dry skin, SPF 15 Day wear advanced multi-protection antioxidant cream, SPF 30 Daily moisture defense lotion, SPF 15 Age perfect cell renewal day cream moisturizer, SPF 15 Men expert vita lift daily moisturizer, SPF 15 Complete rewind recovery day cream, SPF 15 Complete rewind recovery night cream Antiaging complex emulsion, SPF 30 Clear skin pore refiner Remarkable retinal serum Revitalizing night cream

Naturopathica

Peptide plus antiwrinkle serum Serious hyaluronic moisturizing gel Supreme polypeptide cream Argan & retinol wrinkle repair cream Argan & retinol wrinkle repair night cream

HPβCD HPβCD HPβCD HPβCD HPβCD HPβCD HPβCD Native CD HPβCD HPβCD HPβCD Native CD Native CD Native CD Native CD Native CD Native CD γ-CD HPβCD HPβCD HPβCD β-CD and/or γ-CD β-CD and/or γ-CD β-CD and/or γ-CD HPβCD HPβCD HPβCD HPβCD HPβCD (Continued)

Table 10.3 Commercially Available Compositions Containing Cyclodextrins. Compiled From the EWG Cosmetics Database (EWG, 2016a,b) and Retailer’s Websites (Medico Beauty, 2017; Osmosis Skincare, 2017; Prai Beauty, 2017) Continued Manufacturer

Composition Denomination

Cyclodextrin

Osmosis

Relieve level 1 vitamin A serum

γ-CD and HPβCD γ-CD and HPβCD γ-CD and HPβCD γ-CD and HPβCD γ-CD Native CD γ-CD HPβCD Native CD Native CD

Calm level 2 vitamin A serum Correct level 3 vitamin A serum Renew level 4 vitamin A serum

Prai Skin Rx Clinic Tilth Beauty Vivité

Clarify vitamin A blemish serum Rescue epidermal serum 24 K gold concentrate retinol plus Peptide protection moisturizing sun protection, SPF 30 A flawless serum Daily antioxidant facial serum

Eye Contour Creams and Serums Absolute Care Derma e Jack Black Lumene Medico Beauty MyChelle Naturopathica Tilth Beauty

Safe and active eye cream Triple-effect eye cream Firming DMAE eye lift Protein booster eye rescue Complete rewind recovery eye cream Cosmedix eye genius brilliant eye complex

HPβCD HPβCD HPβCD HPβCD HPβCD HPβCD

Remarkable retinal eye cream Argan & retinol wrinkle repair eye cream Eye wondrous serum

Native CD HPβCD Native CD

Facial Cleaners, Exfoliators and Scrubs Olay Dermalogica Mad Hippie MyChelle

Daily facials deeply clean 4-in-1 water-activated cloths Total effects 7-in-1 antiaging cleanser Daily microfoliant Exfoliating serum Refining sugar cleanser

Native CD Native CD Native CD HPβCD HPβCD

Tinted Facial Moisturizer, Foundation and Concealer Derma e Merle Norman Pür. Revlon

BB cream multi-functional mineral beauty balm, SPF 25, tones light and medium Sheer defense tinted moisturizer, SPF 15, tones L10, L20, M50, MD 70, ML 30 and ML40 CC cream, SPF 40, tones light and tan ColorStay whipped creme makeup; Tones: buff, caramel, early tan, ivory, medium beige, natural beige, natural tan, nude, rich ginger, sand beige, true beige, warm golden ColorStay concealer; Tones: medium deep, deep, fair, light, light medium and medium

HPβCD Native CD HPβCD Native CD

(Continued)

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Table 10.3 Commercially Available Compositions Containing Cyclodextrins. Compiled From the EWG Cosmetics Database (EWG, 2016a,b) and Retailer’s Websites (Medico Beauty, 2017; Osmosis Skincare, 2017; Prai Beauty, 2017) Continued Manufacturer

Composition Denomination

Cyclodextrin

Plush Rush lip gloss; varieties: birthday suit, dance party, double dare, fireworks, first kiss, flash mob, flirt, free fall, in love, late night, pillow talk, siren

Native CD

Lip Gloss Butter London

Antiperspirants and Deodorants Gillette Sport Old Spice Secret

Training day invisible solid Fresher collection stick, Benali Wild collection refresh body spray, Hawkridge Clinical strength advanced solid, Marathon fresh Clinical strength smooth solid for women, powder protection Outlast clear gel, varieties completely clean and sport fresh Outlast invisible solid Varieties: active fresh, completely clean and protecting powder Outlast clear gel for women, completely clean Outlast conditioning solid Varieties: completely clean and protecting powder Scent expressions invisible for women, Va va vanilla

Native CD Native CD RAMEB Native CD Native CD Native CD Native CD Native CD Native CD Native CD

Body Moisturizers With SPF Clarins

Chantecaille

Sunscreen care milk lotion spray SPF 20 Sunscreen care cream SPF 30 Sunscreen care milk lotion spray SPF 501 Ultra sun protection sunscreen SPF 45

Native Native Native Native

CD CD CD CD

Dirt destroyer deep clean body wash, lasting legend

Native CD

Dry shampoo, varieties oat milk and nettle Bain nutri-thermique intensive nutrition shampoo Phytokeratine repairing shampoo Phytobaume repair express conditioner Phytokeratine ultra repairing mask Phytokeratine reparative serum for damaged ends Phytokeratine repairing thermal protectant spray

Native Native Native Native Native Native Native

Body Wash Old Spice Hair Care Klorane Kerastase Phyto

CD CD CD CD CD CD CD

10.5 Conclusions and Future Perspective

working on perfecting face-lifting products called “nanocosmetics.” The active principle, uronic acid, forms an inclusion complex with a non-disclosed CD, and the IC is subsequently incorporated into lipidic nanoparticles. The IC-nanoparticle technology will be used in the production of “antiaging cosmetics, skin cleansing agents, and professional agents for cosmetic salons” (Rusnano, 2017).

10.5 CONCLUSIONS AND FUTURE PERSPECTIVE This chapter compiles information on the myriad of applications of CDs, either used alone or forming ICs with active ingredients, in products to be applied on the skin that include both cosmetic and pharmaceutical compositions. The large number of academic studies and patented products, methods, and applications of dermal uses of CDs are strong evidence of the many advantages associated with these multifaceted molecules, that range from the simple solubilizing effect to the stabilization of active ingredients and otherwise incompatible formulations to prevention of side effects, odor-masking, sustained delivery, and even permeability enhancement. Such a unique set of properties of CDs has led them to grow well beyond the laboratory bench into the market, and to expand, firmly and continuously, to cosmetics, toiletries, cosmeceuticals and dermopharmaceuticals, making their way into our households and appearing ever more frequently on the labels of our skincare products. In Japan, the presence of CDs in products associated with the daily hygiene routine of the consumer is well-known and accepted for decades. In North America and Europe, the approval of CDs for human use and presence on labels using their own names (not a numeric code as happens with some additives) is quite recent (2012 for γ-CD). CDs are, accordingly, still widely unknown for the majority of the average consumer. To build the required confidence in these new ingredients, a lot more needs to be learned about them. Clinical studies are scarce and contain a reduced number of participants. Many of the derivatives of CDs, such as CRYSMEB, DIMEB and TRIMEB are not approved for skin applications, either due to either known incompatibility issues or simply by lack of clinical evidence stating their safety. New CDs with unknown effects on the human body are emerging, some of them being already under research for the inclusion of bioactives guests, as is the case of the maltosyl-β-CD complex with the antioxidant polydatin (Liu et al., 2015). Others, such as octenyl succinic-β-CD, promise new applications as emulsifying ingredients (Cheng et al., 2016). Also lacking are systematic studies on the compatibility of CDs with various excipients such as polymers, surfactants, and preservatives. So far, only a few reports are available in the literature, that are far from covering the many the possible combinations of ICs with other ingredients. A formulator trying to develop a new CD-based compositions still has to resort to exhaustive experimental work, based on the traditional trial-and-error approach.

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A comprehensive understanding of the benefits and risks of CDs and their ICs in skin care products and medications can only be attained, in our opinion, by large-scale studies combining the efforts of industry, academics, and a significant number of volunteers or consumers. Another important strategy is to continue to educate and encourage consumers towards a higher awareness on skin products, either pharmaceuticals or mere cosmetics, and to imbue in them the relevance of reporting adverse reactions. There is already a significant number of products with CDs in the market, and consumer reports on these products may provide a very relevant source of information in the near future.

ACKNOWLEDGMENTS The authors gratefully acknowledge the University of Aveiro and FCT/MEC for support for the QOPNA research project (FCT UID/QUI/00062/2013) through national funds, cofinanced by the FEDER within the PT2020 Partnership Agreement, and also to the Portuguese NMR Network.

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