Keywords

1 Introduction

Drugs permeate intact skin as single molecules. When drug products are applied to the skin surface, dissolved drug molecules diffuse through the vehicle to the skin where the molecules partition from the vehicle into the skin and then permeate the skin barrier, stratum corneum, into the more permeable inner skin layers. Most penetration enhancers, chemical as well as physical, enhance drug delivery by making the skin barrier more permeable. Cyclodextrins are different. They enhance drug delivery into and through the skin by increasing the availability of dissolved drug molecules right at the skin surface. However, cyclodextrins can also hamper dermal and transdermal drug delivery by preventing drug molecules from partitioning from the surface into the skin. Thus, successful employment of cyclodextrins in topical drug formulations requires good understanding of their physicochemical properties and the way they enhance topical drug bioavailability.

Numerous books and reviews have been written on cyclodextrins, their industrial applications, and usage in drug formulations (Loftsson and Brewster 1996; Dodziuk 2006; Douhal 2006; Brewster and Loftsson 2007; Loftsson and Brewster 2010; Loftsson and Duchêne 2007; Stella and He 2008; Uekama et al. 2006; Hedges 1998; Kurkov and Loftsson 2013; Bilensoy 2011). In this chapter, the effects of cyclodextrins on drug delivery through biological membranes are discussed with emphasis on dermal and transdermal drug delivery.

1.1 Cyclodextrins and Their Properties

Cyclodextrins are cyclic oligosaccharides containing 6 (αCD), 7 (βCD), 8 (γCD), or more glucopyranose monomers linked via α-1,4-glycoside bonds (Table 14.1). These parent cyclodextrins are natural products formed by microbial degradation of starch. The outer surface of the doughnut-shaped cyclodextrin molecules is hydrophilic, bearing numerous hydroxyl groups, but their central cavity is somewhat lipophilic. Although the parent cyclodextrins and their complexes are hydrophilic, their aqueous solubility is somewhat limited. This is thought to be due to relative strong intermolecular binding in their crystal state. Partial random substitution of the hydroxy groups will result in significant improvements in their solubility (Table 14.1). Cyclodextrins possess many of the same physicochemical and biological properties as their corresponding linear dextrins. In their solid state, cyclodextrins are as stable as starch and can be stored for a number of years at room temperature without any detectable degradation (Szejtli 1988). In aqueous solutions, their degradation follows specific acid-catalyzed hydrolysis of the glycoside bonds to form glucose, maltose, and linear dextrins. In pure aqueous solution, the half-life for ring opening of βCD was determined to be approximately 15 h at pH 1.1 and 70 °C (Hirayama et al. 1992). αCD is somewhat more stable and γCD somewhat less than βCD (Schönberger et al. 1988). Cyclodextrins are stable towards β-amylases, but γCD is degraded by salivary α-amylase (Szejtli 1987; Munro et al. 2004). αCD, βCD, and γCD, as well as their derivatives that are currently used in pharmaceutical products, undergo bacterial digestion in the gastrointestinal tract (Irie and Uekama 1997; Kurkov and Loftsson 2013). Formation of inclusion complexes increases the stability of cyclodextrins, both towards nonenzymatic and enzymatic degradation. There are no reports of transporter-mediated permeation of cyclodextrins across biological membranes, and in general, the oral bioavailability of cyclodextrins is well below 4 % (Kurkov and Loftsson 2013). After parenteral administration, cyclodextrins are, like low-molecular-weight dextrins, mainly excreted unchanged with urine. In humans, their biological half-life is about 1.9 h and volume of distribution about 0.2 L/kg (Kurkov and Loftsson 2013). The safety and toxicology of cyclodextrins have recently been reviewed (Stella and He 2008; Arima et al. 2011).

Table 14.1 Characteristics of the most common natural cyclodextrins and some of their derivatives that are of pharmaceutical interest
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The regulatory status of cyclodextrins is slowly evolving as more and more cyclodextrin-containing products are being approved (Hincal et al. 2011). All three parent cyclodextrins and many of their derivatives can be found in US Pharmacopeia/National Formulary (USP/NF), the European Pharmacopoeia (Ph.EUR.), and the Japanese Pharmaceutical Codex (JPC). The parent cyclodextrins have been included in the “generally recognized as safe” (GRAS) list of the FDA, and they are commonly found in both food and toiletry products throughout the world. Worldwide cyclodextrins can be found in about 40 marketed pharmaceutical products (Loftsson and Brewster 2010; Hincal et al. 2011).

1.2 Cyclodextrin Complexes

Cyclodextrins are able to form drug-cyclodextrin inclusion complexes by taking up somewhat lipophilic drug moieties (or even small lipophilic molecules) into the central cavity (Fig. 14.1). No covalent bonds are formed or broken during the complex formation, and drug molecules bound in the complex are in very dynamic equilibrium with free drug molecules in solution. Thus, cyclodextrin complexes dissociate readily upon simple dilution, for example, upon injection into liquid chromatographic system or after parenteral administration.

Fig. 14.1
figure 1

Formation of one-to-one (i.e., 1:1) drug-cyclodextrin inclusion complex

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The main purpose for adding cyclodextrins to percutaneous drug formulations is to enhance aqueous solubility of poorly soluble drugs and, thus, increase their topical bioavailability. Higuchi and Connors’ phase-solubility method is used to study the effect of cyclodextrin concentrations on drug solubility (Fig. 14.2) (Higuchi and Connors 1965; Loftsson et al. 2005; Loftsson and Hreinsdóttir 2006). The complex formation is a reversible process:

Fig. 14.2
figure 2

Phase-solubility diagrams. A-type diagrams are due to formation of water-soluble complexes and are usually associated with the water-soluble cyclodextrin derivatives. B-type diagrams indicate formation of poorly soluble complexes that are usually associated with the poorly soluble parent cyclodextrins. S0 is the intrinsic drug solubility, i.e., the solubility of the drug in the complexation media when no cyclodextrin is present

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$$ m\cdot D+n\cdot CD\overset{K_{m:n}}{\rightleftarrows }{D}_m{CD}_n $$
(14.1)

where m drug molecules (D) associate with n cyclodextrin (CD) molecules to form a complex of m:n stoichiometry. K m:n is the observed stability constant of the complex, also known as the binding constant, formation constant, or association constant. The stability constant can be written as follows:

$$ {K}_{m:n}=\frac{\left[{D}_mC{D}_n\right]}{{\left[D\right]}^m\cdot {\left[CD\right]}^n} $$
(14.2)

where the brackets denote the molar concentrations. Most commonly, one drug molecule forms a complex with one cyclodextrin molecule:

$$ {K}_{1:1}=\frac{\left[D/CD\right]}{\left[D\right]\cdot \left[CD\right]} $$
(14.3)

where, in saturated drug solutions, [D] is the intrinsic solubility of the drug (S 0), i.e., the solubility when no cyclodextrin is present in the aqueous complexation media. The total drug solubility ([D]T) in a given media is then:

$$ {\left[D\right]}_T={S}_0+\left[D/CD\right] $$
(14.4)

assuming 1:1 D/CD complex formation according to Eq. 14.3. A plot of [D]T versus [CD]T for the formation of a 1:1 D/CD complex should give a straight line (i.e., AL-type phase-solubility diagram, Fig. 14.2) with the y-intercept representing S 0 and K 1:1 defined as (Higuchi and Connors 1965):

$$ {K}_{1:1}=\frac{\mathrm{Slope}}{S_0\cdot \left(1-\mathrm{Slope}\right)} $$
(14.5)

where Slope is the slope of the linear AL diagram. The slope is always less than unity when 1:1 complex is being formed. Complexes of other stoichiometry are less common (Brewster and Loftsson 2007; Loftsson and Brewster 2010). AP-type profile can indicate formation of a complex that is second or higher order with respect to cyclodextrin or that cyclodextrin complex aggregates (nanoparticles) are being formed. The complexation efficiency (CE) is calculated from the slope of the phase-solubility diagram. It is independent of the intercept (or S 0) and frequently used when the influence of various pharmaceutical excipients on the solubilization is investigated (Loftsson and Brewster 2010, 2012). For 1:1 D/CD complexes, the CE is calculated as follows:

$$ CE=\frac{\left[D/CD\right]}{\left[CD\right]}={S}_0\cdot {K}_{1:1}=\frac{\mathrm{Slope}}{\left(1-\mathrm{Slope}\right)} $$
(14.6)

The drug:CD molar ratio in a particular complexation media saturated with the drug can thus be calculated from the CE:

$$ D:CD\; molar\; ratio=1:\frac{\left(CE+1\right)}{CE} $$
(14.7)

For a more detailed mathematical description of the complex formation, the reader is referred to recent reviews (Brewster and Loftsson 2007; Loftsson and Brewster 2010) and the original publication by Higuchi and Connors (1965). Additionally, the effects of various pharmaceutical excipients on K 1:1 and CE and how they can enhance the solubilizing effects of cyclodextrins have been reviewed (Loftsson and Brewster 2012).

2 Cyclodextrins as Permeability Enhancers

In general, chemical penetration enhancers, such as sulfoxides, fatty acids, fatty acid esters, alcohols, amides, and surfactants, enhance drug permeation into and through the skin by permeating into the skin barrier where they temporarily decrease its barrier properties. These penetration enhancers enhance membrane permeation of both hydrophilic and lipophilic drugs and, in most cases, from both nonaqueous and aqueous vehicles. Studies have shown that the permeation-enhancing properties of cyclodextrins are quite different from these chemical permeation enhancers (Masson et al. 1999; Loftsson and Masson 2001; Loftsson et al. 2004; Dahan et al. 2010; Dahan and Miller 2012; Hymas et al. 2012). For example, only negligible amounts of cyclodextrins are able to permeate intact skin and, thus, they do not directly affect the skin barrier. In one study only 0.02 % of topically applied HPβCD was absorbed into intact hairless mouse skin over 24 h period, whereas 24 % was absorbed into stripped skin where stratum corneum had been removed (Tanaka et al. 1995). Another study showed that only 0.3 % of the more lipophilic dimethyl-β-cyclodextrin was absorbed into intact rat skin after topical application (Gerlóczy et al. 1988). In addition, cyclodextrins are only able to enhance drug permeation from aqueous vehicles and in most cases they are only able to enhance permeation of lipophilic poorly water-soluble drugs (Loftsson et al. 2007b, 2008; Loftsson and Brewster 2011; Loftsson 2012).

There are numerous reports on the effects of cyclodextrins on dermal and transdermal drug delivery (Table 14.2). Depending on the experimental conditions and vehicle composition, cyclodextrins either increase or decrease drug permeation through the skin. Still more studies can be found on the effects of cyclodextrins on drug absorption from the gastrointestinal tract and the buccal cavity through the nasal mucosa as well as through other mucosal membranes, all of which can give us some insight into how cyclodextrins act as penetration enhancers (Loftsson et al. 2007b, 2008; Loftsson and Brewster 2011; Loftsson 2012).

Table 14.2 Examples of cyclodextrin-containing dermal formulations and transdermal drug delivery studies
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2.1 Theoretical Background

Drugs permeate the skin via passive diffusion. The driving force for passive diffusion through an aqueous vehicle into the skin and then through the skin is the gradient of chemical potential (μ) (Higuchi 1960; Idson 1971). Likewise, the partitioning of drug molecules from the skin exterior into the outermost skin layer is controlled by the chemical potential. High chemical potential of the drug in topical vehicle is a prerequisite for its good dermal bioavailability:

$$ {\mu}_2={\mu}_2^{\theta }+RT\; \ln {a}_2={\mu}_2^{\theta }+RT\; \ln \left({\gamma}_2{m}_2\right) $$
(14.8)

and

$$ {a}_2={\gamma}_2\;{m}_2 $$
(14.9)

where μ 2 is the chemical drug potential in the vehicle, μ θ2 is the chemical potential in a given standard state, a 2 is the thermodynamic drug activity, R is the gas constant, T is the temperature in Kelvin, γ 2 is the activity coefficient, and m 2 is the molality of the drug. The thermodynamic definition of the partition coefficient (K o/w) of a drug between organic (o) and aqueous (w) phases is:

$$ \frac{\mu_w^{\theta }-{\mu}_o^{\theta }}{RT}= \ln \frac{a_o}{a_w}\approx \ln \frac{\gamma_o\cdot {C}_o}{\gamma_w\cdot {C}_w}= \ln \frac{\gamma_o}{\gamma_w}+ \ln {K}_{o/w} $$
(14.10)

Equation 14.10 states that equilibrium between the two phases is attained when the chemical potential of the drug in one phase (e.g., in water or the aqueous membrane exterior (μ w)) is equal to the chemical potential in the other phase (e.g., the oil phase or the membrane itself (μ o)). Thermodynamic activity is equal to unity in saturated solutions, and, thus, many ointments and creams consist of finely divided drug suspensions. Under such conditions, the vehicle is saturated with drug, and dissolved drug molecules are at their highest potential to leave the vehicle and partition into the skin. Addition of solubilizers, such as cyclodextrins, to an aqueous drug solution will lower the drug activity (i.e., lowers γ w in Eq. 14.10), and, thus, under normal conditions, cyclodextrins lower the potential of the drug to exit the formulation (Másson et al. 2005). However, addition of cyclodextrin to aqueous drug suspension, increasing the amount of dissolved drug while keeping the solution saturated with drug, will not lower the drug activity as long as solid drug is present in the aqueous suspension. Under such condition, the thermodynamic activity (a w in Eq. 14.10) will remain equal to unity, and, thus, dissolved drug molecules are at their highest “exiting” potential, while total amount of dissolved drug is increased. Adding too much cyclodextrin to an aqueous dermal formulation will, on the other hand, decrease the activity (a w) below unity and, consequently, result in less than optimum topical bioavailability. Although passive diffusion is driven by the gradient of chemical potential, it is common to replace it by the concentration gradient. For example, according to Fick’s first law, the driving force for steady-state drug diffusion between two points (i.e., from point 1 to point 2) in a solution is the concentration gradient:

$$ J=\frac{D\cdot \left({C}_1-{C}_2\right)}{h} $$
(14.11)

where J is the drug flux, D is the drug diffusion constant, C 1 and C 2 are the drug concentrations at point 1 and point 2, respectively, and h is the distance between the two points.

Most biological membranes are multilayer membrane barriers, and most contain various diffusion pathways and transport systems. Higuchi described passive drug transport through multilayer barriers as series of additive resistances analogous to electric circuits (Higuchi 1960). Later drug permeation through biological membranes was described mathematically as drug permeation through a lipophilic membrane sandwiched between unstirred water layers (UWLs) emphasizing that the UWL must be treated as a part of the total membrane barrier (Zwolinski et al. 1949; Flynn et al. 1972; Flynn and Yalkowsky 1972; Loftsson et al. 2007b). Here a simple two-barrier model will be used to explain how cyclodextrins affect drug permeation from an aqueous vehicle into and through the skin or other biological membranes (Fig. 14.3) (Loftsson and Brewster 2011). In this model, the drug molecules encounter two barriers on their way from the vehicle through a lipophilic membrane. The first one is the aqueous boundary layer at the membrane surface, the UWL. The second one is the lipophilic membrane itself, frequently identified as the outermost layer of the skin, stratum corneum. The total skin barrier towards drug permeation consists of the UWL and the lipophilic membrane. Assuming independent and additive resistances of the two layers, the total drug permeation resistance (R T) of this simple membrane can be defined as:

Fig. 14.3
figure 3

Drug permeation through a simple two-layer barrier where an unstirred water layer (UWL) forms an aqueous diffusion barrier at the vehicle – skin surface and a skin barrier (stratum corneum) that is a lipophilic membrane barrier. The vehicle contains the dissolved drug; R D, h D, R M, and h M are the resistance and the thickness of the UWL (D) and the membrane (M), respectively. C V is the drug concentration in the vehicle, C D is the drug concentration in the UWL immediate to the membrane surface, C 1 and C 2 are the drug concentrations within the membrane, and K M/D is the drug partition coefficient between the membrane and the UWL

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$$ {R}_T={R}_D+{R}_M $$
(14.12)

where R D and R M are the drug permeation resistances in the UWL at the exterior and within the lipophilic membrane, respectively. Since the permeability constants (P) are the reciprocals of the resistances, the following equation is obtained assuming sink conditions (i.e., C V – C D ≈ C V and C 1 – C 2 ≈ C 1 in Fig. 14.3):

$$ J={P}_T\cdot {C}_V={\left({R}_D+{R}_M\right)}^{-1}\cdot {C}_V={\left(\frac{1}{P_D}+\frac{1}{P_M}\right)}^{-1}\cdot {C}_V $$
(14.13)

where J is the drug flux from the aqueous vehicle through the membrane, P T is the overall permeability coefficient, C V is the concentration of the compound in the aqueous vehicle, and P D and P M are the permeability coefficients in the UWL and within the membrane, respectively. Rearranging Eq. 14.13 gives:

$$ J=\left(\frac{P_D\cdot {P}_M}{P_D+{P}_M}\right)\cdot {C}_V $$
(14.14)

If permeation is much slower through the membrane itself than the UWL (i.e., P D > P M), then:

$$ J\approx \left(\frac{P_D\cdot {P}_M}{P_D}\right)\cdot {C}_V={P}_M\cdot {C}_V $$
(14.15)

In that case, stratum corneum is the main barrier, and the UWL has negligible effect on the drug permeation through the membrane and can be ignored (i.e., R M > R D). If, on the other hand, permeation through the lipophilic membrane, i.e., the skin itself, is much faster than permeation through the UWL (i.e., P M > P D), then:

$$ J\approx \left(\frac{P_D\cdot {P}_M}{P_M}\right)\cdot {C}_V={P}_D\cdot {C}_V $$
(14.16)

In this case, the UWL is the main barrier (i.e., R D > R M), and drug permeation through the membrane becomes aqueous diffusion layer controlled. The relationship between the permeation coefficient (P) and the diffusion coefficient (D) is given by Eq. 14.17:

$$ P=\frac{D\cdot K}{h} $$
(14.17)

where h is the thickness of the UWL (h D) or the lipophilic membrane (h M) and K is either the partition coefficient between the membrane and the UWL (K M/D) or equal to unity (i.e., K = 1.00) as in the case of the UWL. Finally, D can be estimated from the Stokes-Einstein equation:

$$ D\approx \frac{R\cdot T}{6\pi \cdot \eta \cdot r\cdot N} $$
(14.18)

where R is the molar gas constant, T is the absolute temperature, η is the apparent viscosity within the UWL or the lipophilic membrane, r is the radius of the permeating drug molecule, and N is Avogadro’s number. Thus, the diffusion constant within the UWL (D D) will decrease with increasing viscosity of the layer as well as with increasing molecular weight of the drug.

2.2 Cyclodextrins and Biological Membranes

The effects of cyclodextrins on drug permeation through the skin, mucus membranes, and various artificial and biological membranes have been thoroughly reviewed (Matsuda and Arima 1999; Loftsson and Masson 2001; Loftsson et al. 2007b; Cal and Centkowska 2008; Loftsson and Brewster 2011). Based on these studies, some general remarks can be made on how and when cyclodextrins enhance drug delivery into and through biological membranes.

2.2.1 The Drug Molecules Have to Be Released from the Complex

Hydrophilic cyclodextrins and their complexes do not, in general, permeate lipophilic biomembranes (i.e., their K M/D ≈ 0; Fig. 14.3 and Eq. 14.17). The LogK o/w of cyclodextrins that are currently used in pharmaceutical formulations is very low (≤ −6; Table 14.1 and Eq. 14.10), and, thus, these cyclodextrins and their complexes have virtually no tendency to partition from the aqueous exterior into lipophilic membrane. There are no reports of transporter-mediated permeation of cyclodextrins across biological membranes, and in general, the oral bioavailability of cyclodextrins is well below 4 % (Kurkov and Loftsson 2013). Only about 0.02 % of topically applied HPβCD (calculated LogK o/w ≈ −11) is absorbed into intact hairless mouse skin (Tanaka et al. 1995). Consequently, the drug molecules have to be released from the complexes before they can permeate biological membranes (Loftsson and Brewster 2011). Some lipophilic cyclodextrin derivatives are, however, able to penetrate into lipophilic membranes (e.g., the nasal mucosa) and act as conventional chemical penetration enhancers, increasing drug permeation by reducing the lipophilic membrane barrier.

2.2.2 Cyclodextrins Can Prevent Drug Permeation

Cyclodextrins can prevent drug permeation through biological membranes. For example, tablets containing large amounts of αCD (calculated LogK o/w ≈ −13) are used to complex triglycerides in the gastrointestinal tract and prevent their absorption (Comerford et al. 2011; Artiss et al. 2006). Hydrophilic cyclodextrins have been added to sunscreen formulations to reduce absorption of lipophilic sunscreen agents into the skin (Felton et al. 2002, 2004; Sarveiya et al. 2004; Yang et al. 2008). Cyclodextrins, like HPβCD and γCD (calculated LogK o/w ≈ −17), have been used to reduce absorption of the mosquito repellent N,N-diethyl-3-methylbenzamide (DEET) through the skin (Proniuk et al. 2002). Cyclodextrins can likewise be used to decrease dermal and transdermal uptake of sunscreen agents (Cal and Centkowska 2008; Berbicz et al. 2011). The key factor here is to use excess amounts of cyclodextrins in the aqueous vehicle, i.e., more than what is needed to solubilize the poorly soluble lipophilic agent. This is done to reduce the amount of free agent (i.e., drug, mosquito repellent, and sunscreen agent) present in the formulation, thus reducing its partition into the skin. In other words, addition of excess cyclodextrin to the vehicle will lower the potential of the drug to exit the formulation (Eq. 14.10).

2.2.3 Cyclodextrins Only Enhance Drug Permeation from Aqueous Vehicles

In general, cyclodextrins are unable to enhance drug delivery from nonaqueous vehicles through biomembranes but enhance delivery of lipophilic drugs when an aqueous phase is in contact with the lipophilic membrane surface. Hydrophilic cyclodextrins can enhance drug release from hydrophilic creams, i.e., oil-in-water emulsions, but frequently decrease drug release and permeation from lipophilic creams, i.e., water-in-oil emulsions (Preiss et al. 1994, 1995; Loftsson and Brewster 2011). Thus, cyclodextrins can be good permeation enhancers for dermal drug delivery from hydrophilic creams, hydrophilic ointments, hydrophilic gels, aqueous lotions, foams, shampoos, and solutions, but they will most likely have no effect when included in lipophilic creams, hydrophobic ointments, and lipophilic gels. For definition of these pharmaceutical vehicles, see the European Pharmacopoeia, 8th Edition, 2014.

There are few examples where cyclodextrins can enhance drug delivery to the skin from nonaqueous vehicles. Such effects are usually related to increased chemical (e.g., prevention of drug degradation) or physical (e.g., inhabitation of crystal growth) drug stability within the vehicles (Frömming and Szejtli 1994).

2.2.4 Cyclodextrins Do Not Enhance Delivery of Hydrophilic Drugs

In general, hydrophilic water-soluble drugs have little tendency to form hydrophilic cyclodextrin complexes, and, in general, cyclodextrins do not enhance transmembrane delivery of water-soluble drugs. However, cyclodextrins can form complexes with lipophilic moieties of water-soluble drugs, and, thus, in some cases cyclodextrin can reduce topical availability of water-soluble drugs. For example, cyclodextrins form complexes with water-soluble β-blockers (Gagyi et al. 2008), and HPβCD has been shown to reduce ocular bioavailability of the water-soluble β-blocker timolol maleate in aqueous eye drop formulation (Loftsson and Stefánsson 1997). The HPβCD complexation of timolol does increase the hydrophilicity of timolol (i.e., lowers K M/D in Fig. 14.3) and increases the hydrodynamic radius (i.e., r in Eq. 14.18) of the permeating species, both of which will result in lower membrane and transmembrane diffusion of timolol. Few studies have indicated that the somewhat lipophilic methylated cyclodextrins (like RMβCD in Table 14.1) are, under certain conditions, able to act as conventional chemical penetration enhancers, that is, by penetrating into the skin, and decrease its membrane barrier towards drug penetration (Babu and Pandit 2004; Babu et al. 2008).

2.2.5 Cyclodextrins Can Enhance Transmembrane Delivery of Drugs by Increasing Their Chemical Stability

Cyclodextrins are able to increase chemical stability of drugs in aqueous solutions and prevent enzymatic degradation of drugs at aqueous membrane exterior (Loftsson 1995; Loftsson and Brewster 1996, 2010). The enzymatic activity at some mucosal membranes can be quite high, and, thus, the observed permeation enhancement is sometimes due to enhanced drug stability through complexation, especially in the case of proteins and peptides (Irie and Uekama 1997; Loftsson and Brewster 2011).

2.2.6 In Combination with Conventional Penetration Enhancers Cyclodextrins Can Have Additive Effect

Cyclodextrins and conventional penetration enhancers, like fatty acids, or mechanical enhancers, like iontophoresis, can have additive or synergistic effect on drug delivery through biological membranes (Adachi et al. 1992, 1993; Uekama et al. 1992; Loftsson et al. 1998; Sinha et al. 2003; Karandea and Mitragotri 2009). Most often the cyclodextrins increase drug availability at the skin surface, while the other enhancers decrease the membrane barrier itself. In some cases, cyclodextrins increase delivery of a lipophilic penetration enhancer to the skin surface (Adachi et al. 1993). In other cases, cyclodextrin complexation of a penetration enhancer decreases its skin-irritating effect without decreasing its penetration-enhancing property (Martini et al. 1996).

3 Formulation Optimization

In general, stratum corneum is the main barrier towards drug permeation into and across the skin, and the UWL at the skin surface is very thin. Thus, drug permeation from topically applied drug formulations through intact skin most often follows Eq. 14.15. However, under certain conditions, cyclodextrins are able to enhance dermal and transdermal drug delivery. Furthermore, since cyclodextrin complexes tend to self-assemble in aqueous solutions to form nanoparticles, they are known to target drug delivery to the sweat ducts, hair follicles, and sebaceous glands (i.e., drug delivery via shunt route penetration) (Konrádsdóttir et al. 2009).

3.1 When Can Cyclodextrin Help?

Cyclodextrins only enhance drug delivery from aqueous vehicles and only when a UWL presents a barrier towards uptake of drug molecules into the skin. Frequently, dermal formulations contain little or no water (e.g., hydrophobic ointments and lipophilic gels), and sometimes the water domains are not in contact with the skin surface (e.g., in lipophilic creams that consist of water-in-oil emulsions). Under such conditions, the UWL is very thin (h D in Fig. 14.3) and, thus, does not present a barrier (i.e., the skin permeation follows Eq. 14.15). However, many aqueous dermal formulations, such as hydrophilic creams (i.e., oil-in-water emulsions) and hydrophilic gels, increase the thickness of the UWL in which case the resistance of the UWL (R D in Eq. 14.12 and Fig. 14.3) can become comparable or greater than the resistance of stratum corneum (R M in Eq. 14.12 and Fig. 14.3). Under such conditions, cyclodextrins can enhance drug permeation from the surface into the skin. Sweat can also increase the thickness of the UWL between a water-free drug donor, such as dermal patch, and the skin surface (i.e., increasing R D).

Skin damage due to disease or injury can reduce its barrier function (i.e., R M in Eq. 14.12) and increase drug permeation through the skin (i.e., increase P M in Eqs. 14.13 and 14.14). Under such conditions, permeation through UWL might be the main barrier towards dermal and transdermal drug delivery (i.e., P M > P D) in which case the drug flux into and through the skin follows Eq. 14.16, creating conditions where cyclodextrins are known to act as penetration enhancers of lipophilic and poorly water-soluble drugs.

3.2 What Is the Desired Effect?

Most often the aim is to deliver drug molecules from the vehicle into and through the skin. In that case, it is important to include in the vehicle sufficient amount of cyclodextrin to enhance drug delivery to the skin surface and into the skin but to avoid excess amounts. For shunt delivery, the total cyclodextrin concentration, or rather the total concentration of drug-cyclodextrin complexes, has to be sufficient for formation of nanoparticles (Messner et al. 2011; Kurkov and Loftsson 2013). Still in other cases the target is the skin surface itself, and then cyclodextrins can be used to prevent drug partition into the skin adding excess amounts of cyclodextrins to the aqueous vehicle, more than what is needed to solubilize the drug (i.e., excess cyclodextrin lowers the value of K M/D in Eq. 14.17; Fig. 14.3).

3.3 How to Optimize the Formulation?

It is important to optimize cyclodextrin-containing vehicles with regard to the vehicle composition and the desired effect. Too little or too much cyclodextrin will result in less than optimum effect (Loftsson and Brewster 2011). Here we describe step by step the formulation of hydrophilic hydrocortisone gel. The hydrophilic gel (hydrogel) vehicle consists of water within a starch matrix (0.5–2 %) containing HPβCD as a solubilizer/penetration enhancer. Similar methods are used to optimize other aqueous skin preparations.

3.3.1 Phase-Solubility Study

One hydrocortisone molecule (MW 362.5 Da) forms an inclusion complex with one HPβCD molecule (MW 1400 Da). In aqueous solutions, the inclusion complexes are constantly being formed and dissociated at rates close to the diffusion-controlled limit, and, thus, the complexes are in dynamic equilibrium with free hydrocortisone and HPβCD molecules (Fig. 14.1) (Stella et al. 1999). The first step is to determine how much HPβCD is needed to dissolve given amount of hydrocortisone. This is done by determining the phase solubility of the drug in aqueous solution (Higuchi and Connors 1965; Loftsson et al. 2007a; Loftsson and Brewster 2010; Loftsson and Hreinsdóttir 2006). The aqueous solubility of hydrocortisone is determined as the function of HPβCD concentration. From the linear phase-solubility (i.e., AL-type) diagram in Fig. 14.4, we see that we will need about 7 % (w/v) HPβCD to dissolve 10 mg/ml (i.e., 1 % w/v) of hydrocortisone, about 11 % to dissolve 15 mg/ml, and about 14 % to dissolve 20 mg/ml. To calculate the stability constant (K 1:1) and the complexation efficiency (CE), we need to determine the phase-solubility diagram using molar concentrations (Fig. 14.5). From the slope (0.5432), we can determine the CE according to Eq. 14.6 (CE = 1.19) and the hydrocortisone/HPβCD molar ratio in the aqueous HPβCD solution saturated with hydrocortisone from Eq. 14.7 (about 1:2). Thus, in aqueous HPβCD solution at room temperature, at least two HPβCD molecules are needed to dissolve one molecule of hydrocortisone. Then according to Eq. 14.5, we can calculate K 1:1 from the slope and the hydrocortisone solubility in the aqueous complexation media when no HPβCD is present (1.15·10−3 M), the observed K 1:1 = 1,030 M−1.

Fig. 14.4
figure 4

The phase-solubility diagram of hydrocortisone in pure water-containing HPβCD at room temperature (22–23 °C)

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Fig. 14.5
figure 5

The phase-solubility diagram of hydrocortisone in pure water-containing HPβCD at room temperature (22–23 °C)

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3.3.2 The Amount of Cyclodextrin and Drug Availability

The starch (e.g., hydroxypropyl cellulose) used to form the matrix might decrease or increase the amount of HPβCD needed to solubilize hydrocortisone (Loftsson and Brewster 2012). However, it can be difficult to determine hydrocortisone solubility in a viscous gel. Alternatively, one can determine the effect of HPβCD concentration on hydrocortisone release. The phase-solubility study shows that about 11 % (w/v) HPβCD will be needed to dissolve 15 mg/ml (1.5 % w/v) hydrocortisone in the hydrophilic gel. To determine the exact amount of HPβCD needed, a series of gels are prepared, all of which contain the same amount of starch and hydrocortisone (1.5 % w/v) but different amounts (5–15 % w/v) of HPβCD, and the hydrocortisone permeation from the gels through an artificial membrane was determined (Fig. 14.6). The membrane consisted of semipermeable cellophane membrane with an octanol/nitrocellulose membrane fused to the receptor side. Only the free drug is able to permeate the octanol layer (Fig. 14.7). Permeation of hydrocortisone molecules from the gel is at its maximum when just enough HPβCD is present to dissolve all hydrocortisone. At lower HPβCD concentration, the permeation is lower, and the gel is turbid due to undissolved hydrocortisone. At higher HPβCD concentrations, the gel is clear, but excess amounts of HPβCD will decrease the concentration of free hydrocortisone at the surface of the lipophilic membrane (Fig. 14.7) resulting in decreased hydrocortisone flux through the membrane. However, to avoid drug precipitation during storage, the gel should contain a small excess of HPβCD. Maximum flux (Fig. 14.6) is obtained at 10 % (w/v) HPβCD. Increasing the concentration to 12 % (w/v) (20 % excess HPβCD) only reduces the flux from 205 to 203 mg h−1 cm−2. The final composition of the hydrophilic gel will then be 1.5 % (w/v) hydrocortisone and 12 % (w/v) HPβCD in a hydrophilic gel.

Fig. 14.6
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Effect of HPβCD concentration on the hydrocortisone flux from a hydrophilic gel vehicle through an artificial biomembrane at room temperature (22–23 °C). The membrane consisted of semipermeable cellophane membrane (MWCO 12,000–14,000) with an octanol/nitrocellulose membrane fused to the receptor side. The gel contained fixed amount of hydrocortisone, 1.5 % (w/v). Both free hydrocortisone and the hydrocortisone/HPβCD complex were able to permeate the cellulose membrane, but only the drug was able to permeate the octanol/nitrocellulose membrane

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Fig. 14.7
figure 7

Permeation of hydrocortisone from a hydrophilic gel containing hydrocortisone/HPβCD complex through a cellophane-octanol membrane. HPβCD is very hydrophilic (K M/D = K O/W ≈ 10−11; see Table 14.1) and, thus, is unable to permeate into the octanol membrane, while hydrocortisone is much more lipophilic (K M/D = K O/W ≈ 40) (Másson et al. 2005) and is able to permeate the octanol membrane. The observed K 1:1 = 1,030 M−1

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3.3.3 What Happens on the Skin?

The gel contains about 85 % water. The water content of the gel will decrease relatively rapidly after its application to the skin surface, due to both evaporation and water absorption into the skin. However, since hydrocortisone displays AL-type phase-solubility diagram in aqueous HPβCD solutions, decreased amount of water will not result in hydrocortisone precipitation. The gel will become stiffer, and the increased viscosity (η) might decrease hydrocortisone permeation from the gel to the skin surface (see Eq. 14.18), but increased hydrocortisone concentration could, on the other hand, result in increased hydrocortisone permeation. Hence, decreased water content might have less effect than expected.

4 Conclusions

Cyclodextrins can under certain conditions act as percutaneous penetration enhancers. In general, cyclodextrins can only enhance drug delivery through the skin from aqueous vehicles and only when an aqueous diffusion barrier at the skin exterior contributes to the overall skin permeation barrier. Cyclodextrins do not enhance drug penetration from lipophilic vehicles or when the skin barrier, i.e., stratum corneum, is the main permeation barrier. Cyclodextrins are able to prevent drug partition from an aqueous exterior into the skin. It is of uttermost importance to optimize composition of cyclodextrin-containing drug vehicles with regard to drug release and permeation.