Cyclodextrins

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Cyclodextrins Sergey V. Kurkov, Thorsteinn Loftsson ∗ Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, IS-107 Reykjavik, Iceland

a r t i c l e

i n f o

Article history: Received 15 May 2012 Received in revised form 25 June 2012 Accepted 26 June 2012 Available online xxx Keywords: Cyclodextrins Aggregates Nanoparticles Pharmacokinetics Metabolism Ternary complexes

a b s t r a c t Although cyclodextrins (CDs) have been studied for over 100 years and can be found in at least 35 pharmaceutical products, they are still regarded as novel pharmaceutical excipients. CDs are oligosaccharides that possess biological properties that are similar to their linear counterparts, but some of their physicochemical properties differ. CDs are able to form water-soluble inclusion complexes with many poorly soluble lipophilic drugs. Thus, CDs are used to enhance the aqueous solubility of drugs and to improve drug bioavailability after, for example, oral administration. Through CD complexation, poorly soluble drugs can be formulated as aqueous parenteral solutions, nasal sprays and eye drop solutions. These oligosaccharides are being recognized as non-toxic and pharmacologically inactive excipients for both drug and food products. Recently, it has been observed that CDs and CD complexes in particular self-assemble to form nanoparticles and that, under certain conditions, these nanoparticles can self-assemble to form microparticles. These properties have changed the way we perform CD research and have given rise to new CD formulation opportunities. Here, the pharmaceutical applications of CDs are reviewed with an emphasis on their solubilizing properties, their tendency to self-assemble to form aggregates, CD ternary complexes, and their metabolism and pharmacokinetics. © 2012 Published by Elsevier B.V.

1. Introduction Currently, it is difficult to imagine a world without cyclodextrins (CDs). Unwittingly, everyone uses CDs in their daily life as invisible constituents of common food products as well as in numerous cosmetic and toiletry goods, textiles, and as enabling excipients in various medical products. As frequently occurs, the dawn of the CD era began with a fortuitous observation by a curious researcher. The CD era began in the late 19th century when beautiful crystals were observed by the French scientist Villiers in alcohol waste left after the production of dextrins from starch with an impure bacterial culture (Villiers, 1891). Villiers determined the chemical composition and some chemical properties of the unknown crystals. Another prominent figure in CD science is Schardinger, who in the early 20th century isolated and named the strain of bacteria, Bacillus macerans, responsible for CD synthesis. He also performed a series of experiments with CDs and won fame as the founder of CD chemistry (Schardinger, 1903a,b, 1911; Szejtli, 1998). These and other milestones of CD science are provided in Table 1. A more detailed historical analysis of CD science can be found elsewhere (Szejtli, 1998; Loftsson and Duchêne, 2007).

∗ Corresponding author. Tel.: +354 525 4464; fax: +354 525 4071. E-mail address: [email protected] (T. Loftsson).

Like crown ethers and calyx[n]arenes, CDs are cyclic organic compounds that are of special interest in supramolecular chemistry. As soon as the cyclic structure of CD molecules was disclosed, it was proposed that CDs should be able to include molecules in their cavity (Table 1). The fact that oligomeric CD molecules are formed by six to eight glucopyranose units, bound via ␣-1,4glycosidic linkages, gives this class of supramolecular compounds incredible advantages. The arrangement of monomers in the CD molecules is such that it can be visualized as a ring, a doughnut, a cylinder or, more precisely, a truncated cone with a hydrophilic exterior. The inner walls of CD are formed by the hydrophobic carbon backbones of glucopyranose monomers, making the interior somewhat hydrophobic. This structural feature predetermined the application of CD as a solubilizer for poorly water-soluble chemicals. An important aspect resting on the saccharide nature of CDs is their non-toxicity toward humans. However, due to an unfortunate misunderstanding, this fact was not immediately recognized and postponed CD usage for decades (Szejtli, 1998). Nevertheless, CDs are now actively used in pharmaceutical products including formulations intended for injection, which have strict requirements regarding tolerance by humans. Several publications report complete lists of CD-containing pharmaceuticals that have successfully been approved by regulatory agencies in the USA, the EU and Japan (Szejtli, 2004; Loftsson and Duchêne, 2007; Loftsson et al., 2005b). The purpose of the present review is to disclose the present state-of-the-art in CD science from the viewpoint of

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Kurkov,

S.V.,

Loftsson,

T.,

Cyclodextrins.

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Pharmaceut

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Table 1 Historical milestones in cyclodextrin science (Furue et al., 1975; Szejtli, 1998, 2004; Buschmann and Schollmeyer, 2002; Del Valle, 2004; Loftsson and Duchêne, 2007; Messner et al., 2010). Historical period

Investigator

Event or achievement

1891

A. Villiers

Discovery of ␣ and ␤ cyclodextrins; pioneering study on composition and chemical properties

1903–1911

F. Schardinger

Isolation of bacteria responsible for CD synthesis; first attempts to distinguish between different CDs Maltose units bound via ␣-1,4-glycosidic linkages are found to be building blocks for CD molecule; first isolation of pure CDs

1930s 1935

␥CD is discovered

K. Freudenberg

CD cyclic structure is disclosed

1936 1940s

F. Cramer

Idea of inclusion complex formation is suggested

1948

K. Freudenberg W. Borchert

␥CD structure is clarified Structures of ␣, ␤ and ␥CD are determined by X-ray diffraction

1950s

D. French F. Cramer

Discovery of CDs with larger rings Study of inclusion complexation properties of CDs

K. Freudenberg F. Cramer H. Plieninger D. French

First patent on CDs

1953

1957

First fundamental review on CDs containing first misinformation on toxicity of ␤CD

1965

T. Higuchi K. Connors

Development of a mathematical model describing inclusion complexation mechanism

1975

M. Furue

First publication on CD polymers

1976

Ono Pharmaceutical Co.

Release of the first medicine, prostarmon E, from CD

1980s

Beginning of industrial application of CDs in food and cosmetics HP␤CD is patented in Europe and the USA

1981

U. Brauns B. Müller J. Pitha J. Szejtli

1983

K. Miyajima

First suggestion of self-association of parent CDs

1991

V. Stella R. Rajewski A. Harada M. Kamachi

SBE␤CD is patented

1990s 2000s

The First International Cyclodextrin Symposium is organized; the first cyclodextrin book is published

Intensive research activity on CD catenanes and rotaxanes Intensive research activity on CD aggregation

M. Bonini A. Coleman G. Gonzalez-Gaitiano T. Loftsson L. Szente A. Wu

pharmaceutical scientists engaged in formulation development. First, the basis of CD chemistry is recounted followed by a brief overview of CD complexation properties. Recent achievements in the study of CD aggregation phenomena are also given. The second half of the review is devoted to various aspects related to the pharmaceutical applications of CDs. 2. Cyclodextrins and cyclodextrin derivatives CDs are presently manufactured globally on an industrial scale. The raw material for CD production is the readily available carbohydrate polymer starch. Exposure of starch to an enzyme called cyclomaltodextrin glucanotransferase, naturally excreted by B. macerans, yields a mixture of six-, seven- and eight-member rings corresponding to ␣CD, ␤CD and ␥CD, respectively. The structural features of these parent CDs can be found elsewhere (Dodziuk, 2006).

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CDs possess many of the same physicochemical and biological characteristics as their analogous water-soluble linear dextrins. In linear dextrins, the ␣-acetal linkages (i.e., the glycosidic bonds) of the terminal glucose units are hydrolyzed faster than those of nonterminal units. Thus, due to their cyclic structure, CDs are three to five times more resistant to non-enzymatic hydrolysis compared with linear dextrins (Frömming and Szejtli, 1994; Saenger, 1980; French et al., 1950). In the solid state, CDs are at least as stable as sucrose or starch and can be stored for several years at room temperature without any detectable degradation (Szejtli, 1988). Non-enzymatic degradation of CDs in aqueous solutions follows specific acid-catalyzed hydrolysis of the ␣-acetal linkages to form glucose, maltose and non-cyclic oligosaccharides containing as many glucose units as the original CD. In pure aqueous solutions, the half-life (t1/2 ) for ring-opening of ␤CD was determined to be approximately 15 h at 70 ◦ C and a pH of 1.1 (Hirayama et al., 1992). ␣CD is approximately 1.5-times more stable and ␥CD is

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bonding, the release of conformational strain and charge-transfer interactions (Liu and Guo, 2002; Brewster and Loftsson, 2007). Based on some thermodynamic observations, it has been argued that release of water molecules from the cavity is not a driving force for cyclodextrin complex formation (Liu and Guo, 2002). This finding is based on the fact that although the water molecules located in the cavity are of higher energy (i.e., enthalpy rich), they have more conformational freedom (i.e., fewer hydrogen bonds). Thus, although the expulsion of water molecules from the cavity is accompanied by a negative enthalpy change, the free energy change of the overall process is not necessarily negative. When one drug molecule forms a complex with one CD molecule, the following equation is obtained:

Fig. 1. Relative distribution of cyclodextrins used in marketed medicines.

approximately 1.5-times less stable than ␤CD (Schönberger et al., 1988). However, the formation of inclusion complexes significantly enhances the chemical stability of CDs (Vaitkus et al., 2008, 2011). ␤CD derivatives are hydrolyzed at approximately the same rate, with ring opening being the dominant degradation pathway. In aqueous solutions, CDs are essentially chemically stable under neutral and basic conditions. A comparative analysis of more than 30 currently known CDcontaining pharmaceutical formulations shows that ␤CD is the most commonly employed (Fig. 1). The reason for this lies in the ease of its production and subsequent low price (more than 10,000 tons produced annually with an average bulk price of approximately 5 USD per kg). However, ␤CD has some drawbacks, mainly its relatively poor aqueous solubility. Its linear counterpart is freely soluble in water. It is believed that the low solubility of ␤CD is caused by its structure; its molecular dimensions are optimal for the formation of a ring of intramolecular hydrogen bonds that counteract the hydration of ␤CD, thus reducing its solubility. Due to its low aqueous solubility, ␤CD is unsuitable for parenteral administration. A universal solution to this problem was found in the substitution of multiple ␤CD hydroxyls on both rims of the molecule (i.e., random attachment of organic moieties caused breakage of intramolecular hydrogen bond construction which, in conjunction with crystallinity reduction, resulted in a notably improved aqueous solubility). Moreover, some derivatives, such as 2-hydroxypropyl (HP␤CD and HP␥CD) and sulfobutylether (SBE␤CD), possess improved toxicological profiles in comparison to their parent CDs. Due to these advantages, substituted CDs cover more than 1/3 of all CD-containing medicines, whereas a high tolerance in the human body opened new doors in the development of injectable formulations with improved efficiency. 3. Cyclodextrin complexes CD inclusion complexes are molecular complexes characterized by entrapment of a lipophilic drug molecule or, more frequently, a lipophilic moiety of a poorly water-soluble drug molecule in the somewhat hydrophobic CD central cavity. Almost without exception, CD complex (Dm CDn ) formation is a reversible process: Km:n

m · D + n · CD  Dm CDn

(1)

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

[Dm CDn ]

(2)

[D]m · [CD]n

where the brackets denote the molar concentrations. The driving forces responsible for complex formation include electrostatic interactions, van der Waals contributions, hydrogen

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K1:1 =

[D/CD] [D] · [CD]

(3)

The intrinsic drug solubility (S0 ) is defined as the drug solubility in the aqueous complexation media when no cyclodextrin is present: [D] = S0

(4)

[D]T = S0 + [D/CD]

(5)

where [D]T represents the total drug solubility in the aqueous CD media assuming 1:1 D/CD complex formation according to Eq. (3). A plot of [D]T versus [CD]T for the formation of a 1:1 D/CD complex should give a straight line with the y-intercept representing S0 and the slope defined as (Higuchi and Connors, 1965): K1:1 =

slope S0 · (1 − slope)

(6)

Dissolved drug molecules can form water-soluble dimers, trimers and higher order aggregates, as well as be associated with other excipients present in the aqueous complexation media. Frequently, only individual drug molecules can form complexes with dissolved cyclodextrin molecules. Dimers, trimers and watersoluble oligomers are often unable to form cyclodextrin complexes (Loftsson et al., 2005a). Under such conditions, the y-intercept will not be equal to S0 , which can cause considerable error in the determination of the value of K1:1 . A more accurate method for the determination of the solubilizing effect of cyclodextrins is to determine their CE (i.e., the concentration ratio between cyclodextrin in a complex and free cyclodextrin). CE is calculated from the slope of the phase-solubility diagram, is independent of both S0 and the intercept, and is more reliable 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 =

[D/CD] slope = S0 · K1:1 = [CD] 1 − slope

(7)

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 :

CE + 1 CE

(8)

A more detailed mathematical description of the complex formation has been previously published (Higuchi and Connors, 1965; Repta, 1985; Brewster and Loftsson, 2007; Loftsson and Brewster, 2010). Additionally, the effects of various pharmaceutical excipients on K1:1 and CE, and how they can enhance the solubilizing effects of CD have recently been reviewed (Loftsson and Brewster, 2012).

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4. Ternary cyclodextrin complexes Ternary complexes are supramolecular systems composed of three different molecular entities. In pharmaceutical applications, two out of the three are the active drug and CD, while the third component can have various origins and purposes. Often, it represents an auxiliary substance that, in conjunction with CD, further improves the desired physicochemical, chemical and transport properties of a given drug. In this case, the third component improves the efficiency of drug delivery and reduces the amount of CD needed in a given formulation, thereby optimizing the cost, toxicity and/or formulation bulk of the final product (Loftsson and Brewster, 2012). Sometimes, ternary complexation enables local drug administration, as in the case of acetazolamide, where topical administration excludes a wide array of side effects including dyscrasia, acidosis and diuresis as well as gastrointestinal, kidney and liver stress associated with oral administration of the drug (Santiago, 2009). 4.1. Drug/CD/metal ion Some of the simplest third components in CD complexation are metal ions, which improve drug solubility. For example, it was recently reported that addition of 0.5% (w/v) Mg2+ to an aqueous solution containing the antibiotic drug doxycycline and HP␤CD led to powerful solubilization of the drug via fourfold strengthening of the doxycycline/HP␤CD 1:1 complex (He et al., 2011). Moreover, decreased hydrolysis of this antibiotic was also disclosed. The mechanism of metal ion action is multifaceted. First, metal ions form chelates with appropriate moieties of the guest (e.g., drug) molecule, causing salting-in and sometimes preventing degradation. Second, metal ions are able to coordinate water molecules, thus significantly changing the bulk water structure. Third, metal ions are usually not included in the host cavity but may coordinate hydroxyls of the CD molecules (Dodziuk, 2006). However, this interaction is very weak and becomes strong covalent binding only under highly alkaline conditions where CD molecules exist in their deprotonated (i.e., anionic) form (Norkus, 2009). Thus, the allied action of CD via inclusion complexation and metal ions via chelation on dissolved drugs results in synergetic effects observed in ternary complexes (Yamakawa and Nishimura, 2003). 4.2. Drug/CD/organic ion Organic ions, whose structural diversity predetermines the breadth of their effect upon drug/CD solution interactions, are widely used as third components. They are mostly used when drugs are ionized. In such systems, electrostatic forces play a notable role in the overall interaction pattern. A good example illustrating this type of ternary system is shown in a recent study performed by Hamai (2009), where complexation of ␥CD with the acidic substrate sodium 1-pyrenesulfonate (SPS) was studied in the presence of cationic and anionic organic additives. SPS possesses a massive hydrophobic backbone built of four fused benzene rings, which perfectly fits within the ␥CD cavity, forming a 1:1 complex. The presence of the negatively charged sulfonate moiety diminished the hydrophobicity of the given guest molecule, resulting in a twofold weaker inclusion complexation compared with unsubstituted pyrene. When the cationic component trimethyloctylammonium bromide (TMOA), with a quaternary ammonium function and a long hydrocarbon tail, was added to the SPS/␥CD solution, a 1:1:1 ternary inclusion complex was formed. The ␥CD cavity is large enough to accommodate hydrophobic constituents of both guests, whereas oppositely charged ionized moieties of substrate and

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additive reside in the aqueous environment outside of the CD cavity and likely interact electrostatically, forming an ion pair and strengthening the ternary construction. These charge interactions are essential when TMOA is replaced by alkylsulfonate, which bears a negative charge and has a comparable hydrophobic fragment. A 1:1:1 ternary inclusion complex was still formed but revealed weaker stability by several orders of magnitude. An interesting “acidic guest/CD/basic additive” system was studied by Granero et al. (2008). The acidic carbonic anhydrase inhibitor acetazolamide was studied in a ternary complex with HP␤CD and the basic surfactant triethanolamine (TEA). In this case, HP␤CD lost its ability to solubilize acetazolamide in the presence of TEA, and the drug was only solubilized by the ternary component. This phenomenon might be explained by competition between CD and TEA for the drug. The architecture (branched skeleton) and chemical composition (multiple hydrophilic moieties at both the periphery and center of the molecule) of TEA make its encapsulation by HP␤CD problematic, which is why TEA competition with acetazolamide for the CD cavity seems to be unrealistic. However, TEA is known to be an effective surfactant (i.e., able to bind lipophilic substances and solubilize them). Thus, TEA appeared to capture acetazolamide via a double effect: interaction with the lipophilic portion as a surfactant and ion pairing as a basic agent. This behavior made TEA a successful competitor for HP␤CD. The above example demonstrates the flexibility and diversity of interactions among three coexisting components; they can either act in concert, yielding synergetic effects, or compete with each other, neutralizing favorable effects. It is worth considering a system where the substrate is basic and the third component is acidic (Pokharkar et al., 2009). In this work, the ␤-blocker carvedilol was shown to form a ternary complex with ␤CD and citric acid in a 1:2:2 stoichiometry. This complexation resulted in synergetic improvement of carvedilol physicochemical and transport characteristics. In the case of basic drugs, polycarboxylic and/or hydroxy acids, such as citric, tartaric or gluconic acid, are typically used to improve the physicochemical properties of these drugs in pharmaceutical formulations. The mechanism of action of these acids is similar to previously described mechanisms: ion pairing between oppositely charged substrate and additive stabilizes the supramolecular construction. In contrast to hydrophobic organic ions, these acids do not have an affinity for the CD cavity due to multiple hydrophilic moieties being distributed along their molecular backbone. Consequently, they do not participate in inclusion and instead interact with the host via the formation of numerous hydrogen bonds with hydroxyls on the CD exterior. Thus, acidic additives act as cross-linkers between basic guests and CD molecules, resulting in improved substrate solubility. In addition, the presence of this ternary component decreases the crystallinity of the drug and accelerates its dissolution rate. To understand the role of organic ionized ternary components, solutions containing non-ionizable guest compounds must be mentioned. For example, the steroid dexamethasone in conjunction with CD (␥CD or HP␥CD) and an organic ionized additive (acidic EDTA or basic benzalconium chloride, BAC) were studied by Jansook and Loftsson (2008). In a situation when coulombic interactions between drug and the third component are not possible, the effect of the ionized additive is not obvious and depends on the composition of the solution. Based on experimental results, when diluted solutions of ␥CD were used, a relatively weak solubilization effect for dexamethasone was observed. This effect was slightly decreased by the chelating agent EDTA and was notably increased by the surfactant BAC. When HP␥CD was used, a relatively strong solubilization effect was equally improved by both additives. In view of the work by Granero et al. (2008), electrostatic interactions of the surfactant with the substrate did not seem to play a critical role,

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Table 2 Polymers commonly used as ternary components. Polymer name

Polymer structure

Drug

Cyclodextrin

Reference

Chitosan

Finasteride

HP␤CD

Asbahr et al. (2009)

Hydroxypropylmethylcellulose

Nimesulide

␤CD HP␤CD M␤CD

Alexanian et al. (2008)

Dexamethasone

␥CD HP␥CD ␤CD ␤CD

Jansook and Loftsson (2009)

Plasdone

Itraconazole Gemfibrozil

Polyethylene glycol

Salicylic acid Nimesulide

Polyvinylpyrrolidone

Gemfibrozil Finasteride Nimesulide

Sodium carboxymethyl-cellulose

Nimesulide

as uncharged lipophilic drugs were still strongly solubilized. The action of the acidic cross-linker seemed to be dependent on charge interactions and may decrease when interactions are not available. However, salting out effects, steric hindrance and the number of hydrogen bonding centers should also be accounted for in such interpretations. To summarize this discussion of the role played by ionized organic additives, ternary complexes with basic or acidic third components are based on a combination of hydrophobic (inclusion complexation), electrostatic (ion pairing) and hydrogen bonding (non-inclusion complexation) interactions dependent on the nature and structural peculiarities of the participating compounds. 4.3. Drug/CD/polymer Polymers are most likely the most used ternary components in drug/CD systems (Loftsson and Másson, 2004; Loftsson and Brewster, 2012). Their addition leads to decreased drug crystallinity and synergetic effects on the solubilizing action of CDs. Thus, polymers are able to effectively improve solubility and the dissolution rate of poorly soluble drugs. The most commonly used polymers as ternary components are provided in Table 2. It must be emphasized that the same polymer may have different molecular weights and substitution degrees and that its chains may be either separate or interlinked, all of which can affect their interactions with drug/CD complexes. 4.4. Drug1 /CD/drug2 The third component in CD complexes may have similar physicochemical properties as the substrate. This case is nicely exemplified by ternary systems consisting of CD and two drugs

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Kumari et al. (2010) Sami et al. (2010)

␥CD ␤CD HP␤CD M␤CD ␤CD HP␤CD ␤CD HP␤CD M␤CD

Higashi et al. (2009) Alexanian et al. (2008)

␤CD HP␤CD M␤CD

Alexanian et al. (2008)

Sami et al. (2010) Asbahr et al. (2009) Alexanian et al. (2008)

with similar pharmaceutical properties. Such systems have notable practical importance because they are often used in drug formulations with improved therapeutic applications. In this context, a series of studies by Higashi et al. seem to be illustrative. In particular, these authors studied a ternary complex containing ␥CD and two nonsteroidal anti-inflammatory drugs, naproxen and flurbiprofen, in a 1:1:1 ratio (Higashi et al., 2010). Using the sealedheating method, a cocrystalline ternary complex was prepared from flurbiprofen/␥CD in a 1:1 inclusion complex with naproxen as a third component. Powder X-ray diffraction showed that naproxen was monodispersed in the intermolecular spaces between ␥CD columns bearing a flurbiprofen molecule in each CD cavity. This assembly yielded accelerated dissolution of naproxen due to the loss of its crystal packing energy as a result of non-inclusion complexation, while flurbiprofen demonstrated suppressed dissolution from the ternary system due to the presence of a hydrophobic neighbor. To understand the mechanistic foundations of the observed dissolution changes, another crystalline ternary complex made of flurbiprofen/␥CD (1:1) with salicylic acid as a third component in 1:1:2 stoichiometry was investigated by the same research team (Higashi et al., 2011). It was disclosed that non-inclusion complexation of salicylic acid caused collapse of its hydrogen-bonded dimeric structures and led to the formation of hydrogen bonds between monomeric salicylic acid and ␥CD hydroxyls. However, in the case of flurbiprofen, it dimerized but remained incorporated in the ␥CD cavity. All of these changes balanced to lead to the simultaneous release of two active ingredients, which appears to be a promising application in combination therapy. Studies on “drug1 /CD/drug2 ” ternary systems carried out in solution are also known (Jansook and Loftsson, 2009). The authors intended to detect and discuss the competing effects between dexamethasone and a series of drug additives such as hydrocortisone,

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indomethacin and amphotericin B in the presence of ␥CD or HP␥CD. Mutual negative effects of the coexisting drugs dexamethasone and hydrocortisone on the solubilizing efficiency of CDs were detected and could be explained by competition for the excipient cavity. However, drugs with poor affinity for the CD cavity favored solubilization of lipophilic dexamethasone, likely via ternary complexation. Insignificant improvement in the permeability of the guest drug was observed in some cases, although the transport properties of competing drugs appeared to be independent. The conclusions drawn from “drug1 /CD/drug2 ” ternary systems once again demonstrate the complicated mutual influence of ternary complex components. Introduction of another active component causes structural changes in the environment involving the reordering of hydrogen bonds between all participants, affecting their energetic state and impacting their physicochemical and transport properties.

The significance of electrostatic interactions is demonstrated by consideration of a basic anesthetic prilocaine (PLC) in conjunction with ␤CD and phosphatidylcholine (EPC3) (Cabeca et al., 2011). In this system, no evidence of ternary complexation was found. Moreover, NMR studies showed that at pH 10, when PLC is neutral and non-specific interactions prevail between dissolved entities, liposomes successfully compete with CD for the drug, decreasing the amount of PLC/␤CD inclusion complex in solution. At pH 5.5, however, PLC is positively charged, and repulsive forces between the choline moiety of EPC3 and the positive charge on PLC weakened the drug/liposome interaction and shifted the equilibrium toward the PLC/␤CD complex.

4.5. Drug/CD1 /CD2

One of the first observed phenomena that indicated selfassembly of CD molecules in aqueous solutions was observed for ␥CD. Researchers observed that freshly prepared aqueous solutions of ␥CD were initially transparent but became turbid after standing for several days and then revealed a slight sedimentation. This behavior was observed even at concentrations far below the intrinsic solubility of ␥CD and was disappointing because ␥CD demonstrated the lowest toxicity, good complexing ability, that is frequently comparable to that of ␤CD and better than that of ␣CD, and the highest aqueous solubility among the parent CDs. Further study concluded that ␥CD molecules agglomerated through intermolecular hydrogen bonds (Szente et al., 1998). Moreover, these aggregates were believed to serve as nuclei for crystallization, which could have explained the observed sedimentation. Later studies were published on different aspects of CD aggregation. For example, Miyajima et al. suggested dimerization of parent ␣CD, dimethyl-␤CD and ␥CD based on the CD activity coefficients in aqueous solutions (Miyajima et al., 1983, 1986). In addition, Coleman et al. measured hydrodynamic diameters of aggregates of all parent CDs and confirmed the dimerization of dimethyl-␤CD (Coleman et al., 1992). Furthermore, several hydrophobically modified CD derivatives were shown to possess surface activity and weak or strong tendency for self-aggregation dependent on both the CD structure and the sample solution (Witte and Hoffmann, 1996; Mcalpine and Garcia-Garibay, 1998; Lemos-Senna et al., 1998). The first evidence for aggregation of inclusion complexes of CDs with lipophilic guests was published in 1998 (Mele et al., 1998). Subsequent contradictory results caused confusion within the CD society and gave powerful impulse to further study and gain insight into CD science. Employment of several independent techniques, among which dynamic light scattering (DLS) and transmission electron microscopy (TEM) were the most popular and illustrative, gave rise to reliable recognition of aggregation phenomena in CD solutions. It was thus convincingly shown by several teams that parent CDs were able to form aggregates of different shapes, including spherical and elongated particles as well as such abnormal welded fibers and rods (Polarz et al., 2001; González-Gaitano et al., 2002; Rossi et al., 2007) and even extensive micro-scale sheets (Bonini et al., 2006), presumably formed by fused two-dimensional objects. Attempts to create novel CD-based nanocarriers resulted in the emergence of remarkable structures such as nanotubular suprastructures (Das et al., 2008; Wu et al., 2006), nanofibrils (Chung et al., 2007), beads (Bochot et al., 2007) and nanocapsules (Memis¸o˘gluBilensoy et al., 2006). An array of experimental data generated on CD aggregation resulted in a number of reviews (He et al., 2008; Trichard et al., 2006; Messner et al., 2010). However, the mechanism of CD aggregation and CD complex aggregation has not yet been fully explained.

The third component may also be represented by another CD entity. A series of publications by Jansook et al. were devoted to this issue. The first synergetic action of ␥CD and HP␥CD on dexamethasone and hydrocortisone was published in 2008 (Jansook and Loftsson, 2008). The authors tested mixtures of related CDs, namely natural ones with their 2-hydroxypropyl derivatives. In the case of ␣CD + HP␣CD and ␤CD + HP␤CD, the solubilizing effect was additive, whereas when ␥CD + HP␥CD was used, a notable synergistic effect was detected, resulting in a 30–50% increase in dexamethasone solubilization. This study was later expanded to other drugs and revealed the importance of drug affinity for the coexisting CDs (Jansook and Loftsson, 2009). Specifically, dexamethasone and hydrocortisone were synergistically solubilized by ␥CD + HP␥CD mixtures, whereas weakly complexed indomethacin and amphotericin B did not give such an effect. Finally, ternary dexamethasone/␥CD/HP␥CD solutions were found to be flexible, promising systems for eye drop formulations with improved physicochemical, transport and biological characteristics (Jansook et al., 2010). The drug clearly plays a central role in “drug/CD1 /CD2 ” complexation. Consequently, non-specific van der Waals interactions underlying inclusion complexation represent the main force driving ternary complex formation. Apparently, hydrogen bonding between appropriate moieties of all participants may contribute to this type of supramolecular construction. 4.6. Drug/CD/liposomes Several recent studies were devoted to ternary systems where a phospholipid played the role of the third component. Phospholipids have elongated hydrophobic tails and a phosphate hydrophilic head, which gives this class of lipids marked surface activity. Phospholipids are known to form bilayers, which in turn form vesicles called liposomes. Based on published studies, the structure of the phospholipid is crucial for mutual interactions in a ternary system. Cirri et al. (2009) reported that microwave treatment of an aqueous solution containing ketoprofen, ␤CD (or M␤CD) and phosphatidylcholine (EPC3) resulted in synergetic enhancement of the ketoprofen dissolution properties, while phosphatidylglycerol (EPG) did not show any notable effect. Apparently, interplay of electrostatic interactions between the positively charged choline moiety and the ionized carboxyl of ketoprofen from one side and non-specific host–guest interactions between the hydrophobic backbone of ketoprofen and the CD cavity from the other side were responsible for ternary complex formation. In this regard, the action of phospholipids resembles organic ions.

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S.V.,

5. Cyclodextrin aggregates

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T.,

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Table 3 Pharmacokinetic parameters after parenteral administration of cyclodextrins and fluorescein-labeled dextrans to rats.a CP = A · e−a·t + B · e−b·t . Parameter

␤CDb

HP␤CDb

SBE␤CDb

FD-4

FD-20

FD-40

Molecular weight (kDa) a (h−1 ) b (h−1 ) t1/2 (h) VD (L/kg)c VDss (L/kg)d funchanged with urine

1.1 – 1.7 0.4 0.2

1.4 – 1.7 0.4 0.2

2.1 – 1.2 0.6 0.3

4 13 2.5 0.28

20 5.7 1.4 0.48

40 1.0 0.36 1.9

70 1 0.31 2.2

150 0.77 0.23 3.0

0.9

0.9

0.9

0.2 0.8

0.1 0.6

0.1 0.3

0.06 0.08

0.04 0.01

FD-70

FD-150

a Based on the following references: Mehvar and Shepard (1992), Luke et al. (2010), Mehvar et al. (1995), Deux et al. (2001), Loftsson and Brewster (2010), Peeters et al. (2011), Gould and Scott (2005), De Bie et al. (1998b), Van Ommen et al. (2004), Stella and He (2008). b Very short distribution phase, and thus, the data followed an apparent one-compartment open model. c Volume of distribution (liters per kg body weight) calculated according to a one-compartment model. d Volume of distribution at steady state.

6. Drug release from cyclodextrin complexes Simple dissolution of solid drug/CD complexes and dilution of aqueous complexation media are the major driving forces for drug release from the CD complex. However, processes such as drug–protein binding, direct drug partitioning from the complex to tissue and competitive binding contribute to rapid drug release from the complexes (Uekama, 2004; Stella and Rajewski, 1997; Stella and He, 2008; Kurkov et al., 2010; Loftsson and Brewster, 2010). Only with a few exceptions does the administration of drugs in the form of drug/CD complexes not hamper their therapeutic effect. In the majority of cases, CDs increase the oral absorption of drugs. Furthermore, it has been shown that the binding constant of drug/CD complexes must be greater than approximately 105 M−1 to have any effect on the drug pharmacokinetics after parenteral administration (Stella and He, 2008). 7. Metabolism and pharmacokinetics The digestion of simple linear dextrins as well as starch after oral administration proceeds mainly through a stepwise enzymatic hydrolysis process into glucose (Dona et al., 2010). Salivary ␣amylase hydrolyzes dextrins quite readily, but orally administered dextrins are rapidly carried into the stomach where the enzyme is inactivated. Some non-enzymatic specific acid hydrolysis of the dextrins occurs in the stomach, but the formation of complexes with food lipids may delay the hydrolysis (Singh et al., 2010). From the stomach, the dextrins proceed to the neutral environment of the small intestine, where pancreatic fluid containing ␣-amylase is released. Here, the enzymatic hydrolysis of dextrin continues. Dextrin substrates not digested by ␣-amylase undergo bacterial digestion in the lower sections of the digestion system. Linear dextrins and other water-soluble polymers are commonly used in parenteral solutions. The most important pharmacokinetic parameters for such macromolecules are urinary clearance and hepatic uptake (Nishikawa et al., 1996). Dextrans, linear chains of ␣-1,6 linked glucose units, have been used in parenteral solutions as plasma expanders for over 60 years. Monographs are shown for four different dextrans used for injection in the European Pharmacopoeia (7th edition, 2012), namely, dextran 1, dextran 40, dextran 60 and dextran 70, of approximate molecular weight 1, 40, 60 and 70 kDa, respectively. Urinary clearance of dextrans decreases with increasing molecular weight (Table 3). In humans, dextrans with a molecular weight below 15 kDa are mainly excreted unchanged in the urine with a renal clearance close to the glomerular filtration rate, whereas dextrans with a molecular weight above 50–60 kDa are mainly degraded in the liver to lower molecular weight products before being excreted from the body (Arturson et al., 1971; Mehvar and Shepard, 1992; Mehvar et al., 1995). Small amounts of parenterally administered dextrans are

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excreted with the bile or by other means via the gastrointestinal tract (Kaneo et al., 1997). After parenteral administration, dextrans follow a pharmacokinetic two-compartment open model with a short distribution phase and a much longer elimination phase. The numerical values of the rate constants (a and b) and some other pharmacokinetic constants decrease with increasing molecular weight (Table 3). Thus, in rats, the terminal half-life (t1/2 ), volume of distribution (VD ) and fraction excreted unchanged in urine (funchanged with urine ) are 0.28 h, 0.2 L/kg and 0.8, respectively, for the 4 kDa dextran and 3.0 h, 0.04 L/kg and 0.001, respectively, for the 150 kDa dextran. Similar observations have been made in humans, where t1/2 and the fraction excreted unchanged in the urine decrease with increasing molecular weight (Arturson and Wallenius, 1964; Terg et al., 1996). After parenteral administration of dextran (molecular weight 1 and 60 kDa) to humans, the plasma concentration–time profile can be described by a two-compartment open model with a mean t1/2 for the elimination phase of 1.9 h (dextran 1 kDa) and 42 h (dextran 60 kDa) (Schwarz et al., 1981). CDs possess many of the same physicochemical and biological characteristics as water-soluble linear dextrins. However, due to their cyclic structure, they are more resistant to both enzymatic and non-enzymatic hydrolysis than linear dextrins (Frömming and Szejtli, 1994). CDs are resistant to ␤-amylases that hydrolyze starch from the non-reducing end, but they are slowly hydrolyzed by ␣amylases that hydrolyze starch from within the carbohydrate chain. The hydrolytic rate depends on the ring size and fraction of free CD. The mechanism by which CDs resist hydrolysis includes burying all bridge oxygens within the central cavity. Therefore, free CD is hydrolyzed more rapidly than CD bound in an inclusion complex, with the rate of hydrolysis increasing with increasing cavity size (Buedenbender and Schulz, 2009). For example, ␣CD and ␤CD are essentially stable toward ␣-amylase in saliva whereas ␥CD is rapidly digested by salivary and pancreatic ␣-amylase (Szejtli, 1987; Munro et al., 2004). All of the natural CDs and their previously mentioned derivatives are susceptible to bacterial digestion in the gastrointestinal tract (Irie and Uekama, 1997; Stella and He, 2008; Antlsperger and Schmid, 1996; Antlsperger, 1992; De Bie et al., 1998a; Van Ommen et al., 2004; Zhou et al., 1998). After oral administration, ␥CD is almost completely digested in the gastrointestinal tract, whereas both ␣CD and ␤CD are predominantly digested by bacteria in the colon (Fig. 2). ␣CD is digested more slowly than ␤CD. CDs are mainly (more than 90%) excreted unchanged in the urine via glomerular filtration after parenteral administration. Most likely, any remaining CD is eliminated by other pathways, such as liver metabolism and biliary excretion via the gastrointestinal tract, which is analogous to excretion of the low molecular weight dextrans. The pharmacokinetics of HP␤CD, SBE␤CD and sugammadex have been studied in humans and shown to be mainly (i.e.,

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Table 4 Pharmacokinetic parameters after parenteral administration of cyclodextrins and dextrans to humans.a Parameter

Dextran 1b

Molecular weight (Da) t1/2 (h) VD (L/kg)c VDss (L/kg)d funchanged with urine Max parenteral dose in marketed product (g/day) Max oral dose in marketed product (g/day) Fraction absorbed after oral administration

1000 1.9

Dextran 60b 60,000 42

HP␤CD

SBE␤CD

Sugammadex

1400 1.9 0.2

2163 1.4–1.8 0.2

2178 1.7

0.14 0.8

0.93–1.0 16 8 ≤0.03

Very low

0.2 ∼1.0 1.6 – –

0.95 14 – –

a

Based on the following references: Schwarz et al. (1981), De Zwart et al. (2011), Hafner et al. (2010), Zhou et al. (1998), De Repentigny et al. (1998), Kleijn et al. (2011), Mohr et al. (2004), Loftsson and Brewster (2010). b The data followed a two-compartment open model. c Volume of distribution (liters per kg body weight) calculated according to a one-compartment model. d Volume of distribution at steady state.

αCD

βCD

2.0

γCD

Buccal

α-Amylase

Esophagus Stomach Linear oligomers, Maltose, Glucose

α-Amylase and Bacterial digeson

Cecum

Bacterial digeson

Column

Bacterial digeson CO2 H2 CH4

CO2 H2 CH4

CO2 H2 CH4

Unmetabolized cyclodextrin in feces

0.3%

> 4%

0% (even at very high doses)

Oral bioavailability

2 to 3%

Approx. 0.3%

< 0.1%

ClCr = 10 ml/min

ClCr = 100 ml/min

Gas and so stools

0.0 0

20

40

60

80

100

120

Time (h)

Fig. 2. Schematic comparison of the digestion of natural ␣CD, ␤CD and ␥CD after oral administration. Cyclodextrins are slowly hydrolyzed by ␣-amylases but relatively rapidly digested by bacteria.

93–100%) excreted unchanged by glomerular filtration (Szathmary et al., 1990; Zhou et al., 1998; De Repentigny et al., 1998; Hafner et al., 2010; Abel et al., 2008; Mohr et al., 2004; Loftsson and Brewster, 2010; Kleijn et al., 2011; Mcdonagh et al., 2011). After parenteral administration to humans, CD pharmacokinetic parameters are frequently determined by non-compartmental methods. However, the CD plasma concentration–time profiles do show a brief distribution phase that is followed by an elimination phase, and the pharmacokinetics of sugammadex has been shown to follow a three-compartment open model after parenteral administration to humans (Kleijn et al., 2011). The pharmacokinetics of the three CDs are very similar to each other and to those of linear dextrins of comparable molecular weights (Table 4). The t1/2 of the elimination phase ranges from approximately 1.4 to 2 h, and the VD is approximately 0.2 L/kg for all three CDs. The pharmacokinetic studies showed that over 90% of parenterally administered CD will be eliminated from the body within approximately 6 h and over 99.9% within 24 h. Thus, no accumulation of CD will be observed in individuals with normal kidney function, even at high doses (Figs. 3 and 4). However, CD accumulation will be observed in severely renally impaired patients, i.e., individuals with renal clearance (ClCr ) below approximately 10 ml/min. Sugammadex is a ␥CD derivative specifically designed to tightly bind the neuromuscular blocking agent rocuronium and some ozonide drug candidates have been shown to be tightly bound to SBE␤CD (Adam et al., 2002; Welliver, 2006; Perry et al.,

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ClCr = 5 ml/min

1.0

0.5

Kurkov,

S.V.,

Fig. 3. Predicted plasma cyclodextrin concentrations (CP ) after intravenous bolus administration of 10 g of cyclodextrin every 12 h (D0 = 10 g,  = 12 h) in patients with normal kidney function (ClCr = 100 ml/min) and severely decreased kidney function (ClCr = 10 and 5 ml/min). Volume of distribution (VD ), 16 L; half-life (t1/2 ) in patients with normal kidney function, 1.8 h; and fraction of cyclodextrin excreted unchanged in urine, 95% (fe = 0.95).

2006). The values of the equilibrium constants for these drug/CD complexes are greater than about 106 M−1 or large enough to affect the pharmacokinetics of the drugs after parenteral administration. As mentioned previously, the stability constants of drug/CD 1.4 1.2 1.0

CP (mg/ml)

Small intesne

CP (mg/ml)

1.5

0.8 0.6

D0 = 20 grams D0 = 10 grams

0.4

∆ D0 = 1 gram

0.2 0.0

0

20

40

60

80

100

120

Time (h) Fig. 4. Predicted plasma cyclodextrin concentrations (CP ) after intravenous bolus administration of 1, 10 and 20 g of cyclodextrin every 12 h (D0 = 1, 10 and 20 g,  = 12 h) in patients with normal kidney function (ClCr = 100 ml/min). Volume of distribution (VD ), 16 L; half-life (t1/2 ), 1.8 h.

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Table 5 Natural ␣-cyclodextrin (␣CD), ␤-cyclodextrin (␤CD) and ␥-cyclodextrin (␥CD) can all be found in marketed pharmaceutical products, as well as some of their derivatives such as 2-hydroxypropyl-␤-cyclodextrin (HP␤CD), sulfobutylether ␤-cyclodextrin sodium salt (SBE␤CD), randomly methylated ␤-cyclodextrin (RM␤CD) and 2-hydroxypropyl␥-cyclodextrin (HP␥CD). Drug/cyclodextrin ˛CD Alprostadil ˇCD Cetirzine Dexamethasone Nicotine Nimesulide Piroxicam HPˇCD Indomethacin Itraconazole Mitomycin SBEˇCD Aripiprazole Maropitant Voriconazole Ziprasidone mesylate HPCD Diclofenac sodium salt Tc-99 Teoboroxime

Therapeutic usage

Formulation

Trade name

Treatment of erectile dysfunction

Intracavernous solution

Caverject Dual

Antibacterial agent Anti-inflammatory steroid Nicotine replacement product Non-steroidal anti-inflammatory drug Non-steroidal anti-inflammatory drug

Chewing tablets Ointment, tablets Sublingual tablets Tablets Tablets, suppository

Cetrizin Glymesason Nicorette Nimedex Brexin

Non-steroidal anti-inflammatory drug Antifungal agent Anticancer agent

Eye drop solution Oral and IV solutions IV infusion

Indocid Sporanox MitoExtra

Antipsychotic drug Anti-emetic drug (motion sickness in dogs) Antifungal agent Antipsychotic drug

IM solution Parenteral solution IV solution IM solution

Abilify Cerenia Vfend Geodon

Non-steroidal anti-inflammatory drug Diagnostic aid, cardiac imaging

Eye drop solution IV solution

Voltaren Ophtha CardioTec

complexes must be greater than 105 M−1 to have a significant effect on the drug pharmacokinetics after parenteral administration. 8. Toxicological considerations The safety and toxicology of CDs have recently been reviewed (Stella and He, 2008; Arima et al., 2011). CDs that can currently be found in marketed pharmaceutical products are mentioned in Table 5. These CDs are hydrophilic oligosaccharides (molecular weight (MW) between 973 and 2163 Da) with very low octanol–water partition coefficients (log Ko/w between −8 and −12) and numerous hydrogen bond donors and acceptors, all of which are characteristics of molecules that do not readily permeate biological membranes via passive diffusion (Lipinski, 2000, 2004; Lipinski et al., 2001; Loftsson and Brewster, 2010, 2011). There are no reports of transporter-mediated permeation of CDs across biological membranes, and in general, the oral bioavailability of CD is well below 4% (Fig. 2 and Table 4). Only the somewhat lipophilic randomly methylated ␤CD (RM␤CD, log Ko/w approximately −6) has greater oral bioavailability (as high as 12%) in rats (Loftsson and Brewster, 2011). Studies have shown that orally administered CDs of pharmaceutical interest are practically nontoxic due to their lack of absorption from the gastrointestinal tract (Irie and Uekama, 1997; Arima et al., 2011). Furthermore, ␣CD, HP␤CD, SBE␤CD, ␥CD and HP␥CD can all be found in marketed parenteral formulations. Parenteral administration of ␣CD, ␤CD or methylated ␤CD can result in renal toxicity, and thus, both the parent ␤CD and methylated ␤CDs, such as RM␤CD, are not used in parenteral formulations. Although ␣CD can be found in parenteral formulations, its concentrations are very low. RM␤CD is currently only used in topical or nasal drug formulations and only at relatively low concentrations.

usage in marketed pharmaceutical products or usage in the food industry. A full safety evaluation may not be needed if a given excipient has previously been used, especially if it is being used at the same levels and administration routes as in marketed products. Additionally, excipients recognized by the authorities as food additives are, in general, also accepted as pharmaceutical excipients, for example, if they have a generally recognized as safe (GRAS) status by the FDA, are recommended by the Joint FAO/WHO Committee of Food Additives (JECFA) or approved by other agencies. Furthermore, compendial excipients that have monographs published in the European Pharmacopoeia (Ph Eur), the United States Pharmacopeia and National Formulary (USP/NF), or the Japanese Pharmaceutical Codex (JPC), for example, are favored over non-compendial excipients. The regulatory status of CDs in pharmaceutical products has recently been reviewed (Hincal et al., 2011). The regulatory status of CDs has been evolving over the past 30 years. Monographs for natural ␣CD, ␤CD and ␥CD can be found in the JPC and the USP/NF, and monographs for ␣CD and ␤CD are in the Ph Eur. The monograph for HP␤CD can be found in the Ph Eur and USP/NF, and the monograph for SBE␤CD can be found in the USP/NF. In addition, ␥CD, HP␤CD and SBE␤CD are cited in the FDA’s list of Inactive Pharmaceutical Ingredients. The JECFA has a recommended Acceptable Daily Intake (ADI) of 5 mg/kg/day for ␤CD in food products, but due to their favorable toxicological profile, no ADI was defined for ␣CD and ␥CD. This “not specified” ADI for ␣CD and ␥CD is considered the most desirable value and is limited to low toxicity compounds. In the United States, ␣CD, ␤CD and ␥CD have been included in the GRAS list of the FDA. Furthermore, ␣CD, ␤CD, HP␤CD, RM␤CD, SBE␤CD, ␥CD and HP␥CD can be found in at least 35 different marketed pharmaceutical products as well as in numerous food products (Table 5).

10. Cyclodextrin as penetration enhancer 9. Regulatory issues Although pharmaceutical excipients are characterized as pharmacologically inactive compounds, from a regulatory standpoint, they are treated as active compounds, especially if they are being used for the first time in humans (Demerlis et al., 2009; Osterberg et al., 2011; Koo, 2011). Unlike drugs, excipients do not have regulatory status but are reviewed in the context of new drug applications containing a given excipient. Acceptance is often based on previous

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In general, biological membranes consist of an aqueous exterior and a lipophilic membrane barrier. Drugs are mainly transported through membranes via passive diffusion that follows Fick’s first law (Fig. 5). Drug permeation from an aqueous vehicle through such a barrier can be described as a series of additive resistances (Loftsson et al., 2007; Loftsson and Brewster, 2011). Assuming independent and additive resistances of the individual layers, the total resistance (RT ) of a simple bilayer membrane can be defined as Loftsson,

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follows:

Drug concentration

Aqueous Aqueous Lipophilic Vehicle Exterior Membrane

RD

CV

 J = PT · CV =

RM

RT−1

· CV = (RAq + RM )

−1

· CV =

1 1 + PAq PM

−1 · CV (9)

C1 = KM/D ·CD

where J is the flux of the drug through the membrane, PT is the overall permeability coefficient, CV is the drug concentration in the aqueous vehicle, and RD /RM and PD /PM are the resistance and the permeability coefficients, respectively, in the aqueous exterior (D) and within the lipophilic membrane (M). Eq. (9) can thus be rewritten as follows:

CD

hD

hM



C2 J=

Direction of drug permeation Fig. 5. Schematic of drug permeation through a simple biological membrane consisting of an aqueous exterior (i.e., an unstirred water layer, UWL) and a lipophilic membrane. The aqueous vehicle contains dissolved drug, RD , hD , RM and hM are the resistance and the thickness of the UWL (D) and the membrane (M). CV is the concentration of dissolved drug in the vehicle, CD is the drug concentration in the UWL immediate to the membrane surface, C1 and C2 are the drug concentrations within the membrane at the outer and inner surface, respectively, and KM/D is the drug partition coefficient between the membrane and the aqueous exterior.

PAq · PM PAq + PM



· CV

(10)

The aqueous exterior layer consists of a stagnant water layer that is frequently referred to as the unstirred water layer (UWL). Mucus membranes, for example, consist of an inner connective tissue layer and an outer epithelial layer that is most often covered by mucus. Mucus is present as either an aqueous gel layer attached to the mucosal surface or as an aqueous luminal component in soluble or suspended form (Smart, 2005). The thickness of the mucus layer that represents the UWL depends on its location, varying from 50 to 450 ␮m in thestomach to less than 1 ␮m in the

Table 6 Enhancement of the complexation efficiency (CE) (Loftsson and Brewster, 2012). CE = S0 × K1:1 = [D/CD]/[D] = slope/(1 − slope). The CE is enhanced by increasing S0 , K1:1 or both. Method

Description

Preparation of aqueous solutions Ionization will increase the value of S0 Drug ionization

Examples

Reference

Solubilization of weak acids and bases by cyclodextrin complexation

Loftsson and Bodor (1989), Krishnamoorthy and Mitra (1996), Li et al. (1998), Loftsson and Brewster (2012)

Salt formation

Different salts of a given drug have different S0 values

Solubilization of carvedilol and ziprasidone

Kim et al. (1998), Loftsson et al. (2008), Loftsson and Brewster (2010)

Formation of amorphous forms

In general, amorphous forms of a drug have higher aqueous solubility (i.e., larger S0 ) than crystalline forms Formation of drug/CD/acid and drug/CD/base complexes can increase the values of both S0 and K1:1

Solubilization of itraconazole by HP␤CD

Loftsson and Brewster (2010)

Solubilization of hydrocortisone in aqueous ␤CD solutions containing salicylate Solubilizing effects of hydroxy acids and bases

Loftsson et al. (2003)

Ternary complexes containing organic acids or bases

Selva et al. (1998), Fenyvesi et al. (1999), Redenti et al. (2000), Mura et al. (2003)

Ternary polymer complexes

Water-soluble polymers form ternary complexes with drug/CD complexes increasing the observed K1:1 values

Various drug/CD complexes and numerous polymers

Loftsson et al. (1994), Loftsson (1998), Loftsson and Másson (2004), Chowdary and Srinivas (2006), Loftsson and Brewster (2012)

Cosolvents

Cosolvents can increase S0 but they simultaneously decrease K1:1

For example, ethanol can both increase and decrease the CE

Li et al. (1999), He et al. (2003), Viernstein et al. (2003), Loftsson and Brewster (2012)

Charge–charge interactions

Frequently, the negatively charged SBE␤CD forms more stable complexes (i.e., have larger K1:1 values) with positively charged drugs than the neutral CDs Some drugs are able to form water-soluble metal complexes (i.e., increase the S0 value) that are again able to form complexes with CDs

Solubilization of ziprasidone and other positively charged drugs by SBE␤CD

Zia et al. (2001), Okimoto et al. (1996), Kim et al. (1998)

Formation of quinolone/magnesium ion complex followed by further solubilization of this complex through HP␤CD complexation

Yamakawa and Nishimura (2003)

The heating and enhanced solubility enhance the complexation process

Loftsson and Brewster (2012)

Preparation of piroxicam/␤CD complexes in the presence of ammonia

Redenti et al. (1996), Wenz (2000), Loftsson et al. (2004), Loftsson and Brewster (2010)

Double complexes

Preparation of solid complexes Heating Heating of aqueous complexation media increases both the drug solubility and solubility of poorly soluble CDs such as ␤CD Formation of Temporary increase in S0 of ionizable drugs metastable through addition of volatile bases (e.g., ammonia) or acids (e.g., acetic acid) that complexes are removed during drying

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oral cavity (Loftsson et al., 2007; Cu and Saltzman, 2009; Loftsson and Brewster, 2011). Conventional penetration enhancers, such as fatty acids and surfactants, enhance drug delivery by decreasing the barrier properties of the lipophilic membrane (i.e., by increasing PM ). In contrast, hydrophilic CDs, such as the parent ␣CD, ␤CD and ␥CD, and CD derivatives, such as HP␤CD and SBE␤CD, increase drug delivery through biological membranes by enhancing drug permeation through the UWL (i.e., by increasing PAq ). In general, hydrophilic CDs can only enhance drug delivery through biological membranes when PAq is relatively small compared to PM . Hydrophilic CDs do not enhance drug delivery through membranes if the lipophilic membrane barrier is the main permeation barrier (Loftsson and Brewster, 2011). When aqueous vehicles, such as hydrogels and oil-in-water (o/w) creams are applied to membranes, the UWL is extended into the vehicle, and under such conditions, CDs can increase drug delivery from the vehicle through the membrane. The principal mechanism of CD permeation enhancement appears to be an increase in drug solubility and enhanced drug permeation through the aqueous mucus upon the formation of water-soluble drug/CD complexes. The Biopharmaceutics Classification System (BCS) for oral drug delivery classifies drugs according to their aqueous solubility and ability to permeate the intestinal mucosa (Amidon et al., 1995). Class I comprises relatively water-soluble drugs that are well absorbed from the gastrointestinal tract and, in general, possess preferred physicochemical properties for optimum oral bioavailability. Class II consists of relatively water-insoluble drugs (i.e., aqueous solubility ≤0.1 mg/ml) that, when dissolved, are well absorbed from the gastrointestinal tract. Class III consists of watersoluble drugs that do not readily permeate mucus membranes and thus have low oral bioavailability. Finally, Class IV consists of waterinsoluble drugs that do not easily permeate mucus membranes. CDs have little effect on or even decrease the oral bioavailability of BCS Class I drugs. They frequently enhance the oral bioavailability of Class II drugs and Class IV drugs; however, they have a negligible effect on Class III drugs. CDs can elicit other effects, such as on the generation and stabilization of supersaturated drug solutions, prevention of drug metabolism and inhibition of drug efflux. Thus, these general guidelines do not apply to all reported studies. CDs have also been used to reduce bioavailability after oral administration where a large excess of CD is used to prevent compounds from being absorbed from the gastrointestinal tract (Loftsson and Brewster, 2011).

11. Formulation with cyclodextrins In aqueous CD solutions, the bioavailability of a drug depends on the ability of the drug molecules to interact with CD molecules and the drug:CD concentration ratio. The bioavailability of drugs that do not interact with CDs will not be significantly affected by the presence of CDs, whereas the bioavailability of drugs that show a strong CD interaction can be either increased or decreased depending on the drug:CD concentration ratio. Too much or too little CD will result in a less than optimal drug bioavailability. Furthermore, because the drug–CD interaction is affected by other excipients present in the drug formulation, it is of the utmost importance to optimize the final drug formulation with regard to the amount of CD (Loftsson and Brewster, 2011, 2012). Molecular weights of CDs are relatively high, ranging from 973 (␣CD) to 2163 (SBE␤CD) Da, and therefore, the formation of drug/CD complexes results in significant enhancement in the formulation bulk, especially if the CE is low. Several methods that can be applied to enhance the CE and lower the formulation bulk are described in Table 6. In all cases, the methods increase, at least temporary, the S0 and K1:1 (Loftsson and Brewster, 2012).

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12. Conclusions CDs are an important tool in pharmaceutical formulation to improve the apparent solubility, rate of dissolution and chemical stability of poorly water-soluble drugs. The simplistic view of CD complex formation, where a lipophilic moiety of a drug molecule enters the hydrophobic cavity of the CD molecule, is gradually being replaced by a much more complex model where individual CD molecules, complexes and complex aggregates coexist in aqueous solution. Furthermore, it is now known that various pharmaceutical excipients participate in the complex formation and can influence the solubilizing effect of the CDs. The current information on the metabolism and pharmacokinetics of CDs shows that these cyclic oligosaccharides are excreted from the body in much the same way as their linear counterparts. CDs can currently be found in over 35 pharmaceutical products as well as in a large number of food products.

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