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Journal of Controlled Release 123 (2007) 78–99 www.elsevier.com/locate/jconrel

Review The utility of cyclodextrins for enhancing oral bioavailability ⁎ Rebecca L. Carrier a, , Lee A. Miller b,1, Imran Ahmed c,2

a Department of Chemical Engineering, Northeastern University, 457 Snell Engineering Center, Boston, Massachusetts 02115, United States b Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105, United States c Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340, United States Received 18 April 2007; accepted 30 July 2007 Available online 16 August 2007

Abstract

Cyclodextrins (CD) have been utilized extensively in pharmaceutical formulations to enhance oral bioavailability. A critical review of the literature in which cyclodextrins were utilized for this purpose was conducted. The goal of this review was to determine if quantitative guidelines for drug and cyclodextrin properties necessary for bioavailability enhancement using cyclodextrins could be extracted. Twenty-eight studies were examined in which the focus was on the use of cyclodextrins as solubilizers to enhance bioavailability. Commonly observed factors included: utilization of pre-formed complex rather than physical mixtures, drug hydrophobicity (logP N 2.5), low drug solubility (typicallyb 1 mg/ml), moderate binding constant (b 5000 M− 1), low dose (b 100 mg), and low CD:drug ratio (b 2:1). These general guidelines, however, did not apply to all studies. Quantitative guidelines useful to a formulation scientist considering the use of cyclodextrins were difficult to develop due to missing information and the complicated manner in which drug and cyclodextrin properties interact to influence key drug delivery processes (e.g., dissolution, absorption). The mechanisms by which cyclodextrins influence these processes, again emphasizing solubilization capabilities, are discussed to provide further insight into why cyclodextrins will increase bioavailability in certain cases but not influence or possibly decrease bioavailability in others. © 2007 Elsevier B.V. All rights reserved.

Keywords: Cyclodextrins; Solubilization; Bioavailability; Modeling; Formulation

Contents

1. Introduction ...... 79 2. Characteristics of studies utilizing cyclodextrins to enhance oral bioavailability ...... 80 2.1. Reported influence of cyclodextrins ...... 80 2.2. Properties of compounds whose bioavailability is enhanced using cyclodextrins...... 81 2.3. Use of complex vs. physical mixture of drug and cyclodextrin ...... 81 2.4. Complex formation methodology ...... 86 2.5. Immediate vs. controlled release ...... 87 2.6. Ionized vs. neutral drugs ...... 88 2.7. Dose and molar CD:drug ratio ...... 88 2.8. Type of CD used ...... 89 2.9. Binding constant magnitude ...... 90 2.10. Interaction with polymers and other formulation components ...... 90

⁎ Corresponding author. Tel.: +617 373 7126; fax: +617 373 2209. E-mail addresses: [email protected] (R.L. Carrier), [email protected] (L.A. Miller), [email protected] (I. Ahmed). 1 Tel.: +734 622 3628; fax: +860 686 6209. 2 Tel.: +860 441 4281; fax: +860 715 9575.

0168-3659/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2007.07.018 Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 79

3. Explanations for ability of cyclodextrins to enhance bioavailability ...... 91 3.1. Significance ...... 91 3.2. Enhancement in dissolution kinetics ...... 91 3.3. Increase in solubility ...... 92 3.4. Decrease in degradation kinetics ...... 93 3.5. Change in intestinal membrane properties ...... 93 3.6. Shuttling and enhancement of drug concentration at the intestinal wall ...... 94 4. When cyclodextrins do not enhance bioavailability ...... 94 4.1. Binding constant magnitude and amount of dosed cyclodextrin ...... 94 4.2. Degradation of cyclodextrins in the intestinal environment ...... 94 5. Conclusions ...... 95 ReferencesNomenclature...... 96 References ......

1. Introduction attribute the influence on bioavailability to the solubilizing capabilities of cyclodextrins, although some also discuss other Cyclodextrins have been used extensively in pharmaceutical cyclodextrin effects, such as effects on physical or chemical research and development, and there are currently over 30 stability [12–15]. Typically, the complex or physical mixture of marketed cyclodextrin-containing pharmaceutical products drug and cyclodextrin is dosed, and the resulting pharmacoki- worldwide [1,2]. Cyclodextrins possess a special ability to netic parameters are compared to those resulting when the drug complex with drugs enabling them to increase solubility, reduce alone or in a commercial formulation is dosed. Given the wide bitterness, enhance stability, and decrease tissue irritation upon range of experimental parameters utilized in these studies and dosing [3]. One of the most common applications of the fact that most of them report positive results, the question cyclodextrins cited in the pharmaceutical literature is the arises: Is it possible to gain insight into the important parameters enhancement of bioavailability. When can cyclodextrins be that determine the success or failure of bioavailability used to enhance oral bioavailability of a given compound? One enhancement with cyclodextrins from reviewing a finite number approach to addressing this question, taken in the present of studies? review, is to seek guidance by examining the vast body of In this critical review, a survey of the literature reporting use literature in which cyclodextrins have been utilized to enhance of cyclodextrins to enhance oral bioavailability is conducted. bioavailability. There are numerous excellent reviews on the use Some of the important attributes of these studies are discussed of cyclodextrins in oral dosage forms, and many which to give insight into key physical and chemical properties of the specifically address the effect of cyclodextrins on oral drug, cyclodextrin, and dosage form that allow bioavailability absorption and/or bioavailability [1–11]. One recent review enhancement to occur. Physical mechanisms of bioavailability by Loftsson et al. examines over 80 publications on the effect of enhancement using cyclodextrins are then discussed to provide cyclodextrins on oral bioavailability of 50 different drugs using further understanding of why these parameter values are 17 different cyclodextrins in the context of the Biopharmaceu- important and how successful bioavailability enhancement tical Classification System [1]. The importance of drug using cyclodextrins can be achieved. It should be noted that solubility and permeability is emphasized. Here, multiple while recent applications of cyclodextrins have included their aspects of studies in which cyclodextrins were utilized to use for stabilizing protein, peptide, and nucleic acid therapeu- enhance bioavailability were analyzed to gain further insight tics [2,8,11], the focus in this review is on the exploitation of into which physical and chemical properties of drug, cyclodex- the solubilizing capacity of cyclodextrins for the delivery of trin, dosage form, and delivery environment are suitable to small molecular weight (typically b 500 Da) compounds. allow enhancement of bioavailability. The specific values of However, much of the discussion of the influence of drug and cyclodextrin properties as well as experimental cyclodextrins on the bioavailability of low molecular weight parameters (e.g., drug to cyclodextrin ratio, animal species compounds generally applies to biomolecules, with certain used) were studied for apparent trends. additional mechanisms of action on biomolecules (e.g., As indicated by the large number of reviews on this topic, the prevention of protein aggregation or enhancement of endoso- literature affords an abundance of references demonstrating the mal membrane disruption in gene delivery) not emphasized in use of cyclodextrins to enhance oral bioavailability of active this review [11]. In addition, cyclodextrins have been utilized compounds. These studies have utilized a range of natural for a number of different drug delivery routes, and there has cyclodextrins and cyclodextrin derivatives, numerous animal been a large amount of recent investigation into cyclodextrin species (including human), and various dosing vehicles, dose polymers and cyclodextrins conjugated to other delivery levels, and cyclodextrin-to-drug ratios. The vast majority of vehicles (e.g., nanoparticles, liposomes) [9]. However, the these studies demonstrate a positive affect of inclusion of current discussion is focusedonoraldrugdeliveryusing cyclodextrin in a dosed formulation. Most of the studies cyclodextrin monomers. Author's personal copy

80 R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99

2. Characteristics of studies utilizing cyclodextrins to summarizes these same factors for experiments where it was enhance oral bioavailability indicated that cyclodextrins were not successful in enhancing bioavailability. The discussion below is focused on observations 2.1. Reported influence of cyclodextrins resulting from the review of these articles, although many of the comments apply to the cyclodextrin literature in general, and Most of the literature on bioavailability enhancement using several articles in addition to the twenty-eight studied in detail cyclodextrins includes similar data [5]. Phase-solubility dia- are referenced. Again, it is emphasized that the articles examined grams are often used to determine the stoichiometry of binding focused mainly on the solubilizing capabilities of cyclodextrins and the equilibrium binding constant. NMR-spectra, X-ray for small molecular weight compounds. In other words, their diffraction patterns, and DSC thermograms are typically used to focus was not on other possible mechanisms of bioavailability measure changes in the characteristic analytical features of a enhancement using cyclodextrins (discussed below) or the use of drug molecule upon complexation as an indication that a cyclodextrins to influence delivery of peptides, proteins, or complex has been formed. Dissolution profiles for the drug, nucleic acids, as has been the focus of much recent literature. physical mixture of drug and cyclodextrin, and/or complex of The studied articles contained a total of 58 comparisons made drug and cyclodextrin are often presented to demonstrate the between a dosed formulation containing cyclodextrins and one influence of cyclodextrin on dissolution kinetics and the total that did not. Of these comparisons, 52 showed evidence of amount of drug in solution [16]. In addition, pharmacokinetic bioavailability enhancement using cyclodextrins (as indicated parameters resulting from dosing a physical mixture of drug and by a change in AUC or a similar parameter as noted in Table 1), cyclodextrin or a pre-formed complex in comparison to drug while 6 showed no change with inclusion of cyclodextrins. The alone are often presented to demonstrate an overall improvement prominence of studies showing bioavailability enhancement in bioavailability upon dosing with cyclodextrin. These studies using cyclodextrins may be related to the tendency for positive often involve compounds with poor or variable bioavailability results to be reported more frequently than negative results. It is and cite low solubility or slow dissolution kinetics as reasons for also likely that drugs selected for studies with cyclodextrins tend bioavailability issues [16–24]. The variability of pharmacoki- to possess qualities which make them candidates for solubili- netic and pharmacodynamic responses to drugs has been zation (i.e. low solubility). reported to decrease with the inclusion of cyclodextrins in As can be seen in Table 1, about half of the increases in AUC dosage forms [25,26]. Pharmacokinetic responses to low- values were less than 100% increases. Of 47 studies where a solubility compounds are characteristically highly variable in change in AUC (or a similar parameter as noted in Table 1) was the absence of a solubilizing agent [17], and the ability of reported, 24 of those studies resulted in a ratio of AUC with cyclodextrins to solubilize drugs probably contributes to lower cyclodextrin to AUC without cyclodextrin between 1 and 2, response variability. Some studies also include information on while 22 resulted in a ratio of 2–8 and one resulted in a ratio of degradation rate of the studied compound and how it is 46. Increases in AUC brought about by utilizing cyclodextrins influenced by cyclodextrin. The reported increase in bioavail- with drug are accompanied by both increases and decreases in ability is typically expressed as a change in an area under the Tmax and Cmax values [24,25,28]. This implies that when the plasma concentration vs. time curve (AUC) value, a change in overall exposure to a compound is increased by inclusion of the time to reach maximum plasma levels of the given compound cyclodextrin in a dosage form, the accompanying kinetics of (Tmax), and/or the maximum plasma level achieved (Cmax) drug absorption in the intestine may increase or decrease. In [23,24,26–28]. In some studies, the pharmacodynamics are Table 1 there are 28 reported decreases in Tmax, 5 reported reported in addition to or in place of the pharmacokinetic increases, and 6 reports of no change. Most of the increases in changes brought about by inclusion of cyclodextrin in a dosage Tmax were of less than 3h. The fact that most studies reported a form, demonstrating that cyclodextrins can improve the efficacy decrease in Tmax with inclusion of cyclodextrin is logical in of a given dose of a therapeutic agent [25,29,30]. light of the fact that cyclodextrin speeds up dissolution kinetics, For the current review, twenty-eight randomly selected as described in more detail later in this review. An increase in articles from the literature in which cyclodextrins were utilized Tmax could be due to precipitation of a low solubility dosed to enhance bioavailability were examined in an effort to develop complex or decrease in free drug concentration in the intestinal a greater understanding of when cyclodextrins can be used for lumen because of binding to cyclodextrin. In Table 1 there are bioavailability enhancement [12,17,18,20,22–28,30–46]. Spe- 38 reported increases in Cmax and one reported decrease. Most cifically, the different properties of these studies were compared, increased Cmax values were less than double the control value, including the properties of the drug compounds utilized, the and all except for two reported increases were less than ten properties of the cyclodextrins, the design of the dosage forms, times the control value. There was no clear correlation between and the details of the experiment (e.g., animal species used, magnitude of increase in Cmax or change in Tmax and magnitude manner in which material was dosed). The studies were selected of increase in AUC (data not shown). The increase in Cmax is based on the information they provided and/or the ability to logical as cyclodextrins speed up dissolution, and higher levels obtain missing information from other literature sources so that of drug in solution in the intestine typically result in greater drug all studies could be compared [5,15,16,19,21,35,47–62]. Table 1 absorption. It has been noted that when an increase in blood compares some of the key aspects of studies conducted in which plasma levels for a given compound is not desired, cyclodextrin cyclodextrins were used to enhance bioavailability, and Table 2 can be used to decrease the required dose [63]. Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 81

2.2. Properties of compounds whose bioavailability is constant, cyclodextrin:drug ratio, dose, possible influence of enhanced using cyclodextrins cyclodextrin on intestinal permeability or efflux, etc.).

An obvious requirement for cyclodextrins to be a suitable 2.3. Use of complex vs. physical mixture of drug and cyclodextrin technology for bioavailability enhancement is the formation of a complex between drug and cyclodextrin. Specific exceptions As can be seen in Table 1, the vast majority of studies in include cases where cyclodextrins such as dimethyl beta- which cyclodextrins are utilized to enhance oral bioavailability cyclodextrin (DM-β-CD) inhibit efflux by P-glycoprotein (P- have employed the complex rather than the physical mixture of gp) or metabolism by multi-resistant protein 2 (MRP2) or the given drug with cyclodextrin. When the physical mixture proteolytic enzymes [64], or cases where drug is covalently bound was used, it typically resulted in a significantly lower level or to cyclodextrin for site-specific delivery [65,66], but these complete lack of bioavailability enhancement. Of the six studies specific effects were not discussed in any of the studies presented reviewed in which physical mixtures of drug and cyclodextrin in Table 1. General guidelines on what molecules will complex were dosed, two did not show bioavailability enhancement with cyclodextrin based on molecular properties are given in the [26,46], and bioavailability enhancement was moderate (1.1× to literature [67]. Drug-cyclodextrin complexation usually involves 1.5× increase in AUC) for the other studies [18,20,36,41]. AUC interaction of hydrophobic moieties on drugs and the pocket of the increases were approximately doubled for complexes vs. cyclic cyclodextrin molecule. Consideration of the calculated physical mixtures of single compounds, and this is often octanol–water partitioning coefficient (clogP)valuesofthe accompanied by greater decreases in Tmax and greater increases compounds in Table 1 and examination of their structures (Fig. 1) in Cmax. This is likely related to decreased enhancement in demonstrates the predominance of hydrophobic compounds dissolution kinetics observed when the physical mixture rather employed in studies reporting enhanced oral bioavailability than the complex is utilized (see “Explanations for the ability of using cyclodextrins. 18 of the 29 studies examined involved cyclodextrins to enhance bioavailability” below). Several compounds with logP values greater than 2.5. In addition to studies have shown that a physical mixture of cyclodextrin having a greater likelihood of complex formation, hydrophobic and drug exhibits dissolution kinetics either similar to or only compounds generally have low solubility and are more likely to slightly greater than those of drug alone, and almost always be dissolution rate-limited (as opposed to absorption rate-limited) slower than those of the complex [23,69–71]. It has been in overall absorption kinetics. The formulator should keep in mind documented that physical mixing of drug and cyclodextrin, that if a factor other than dissolution kinetics is resulting in poor especially with addition of energy (e.g. from grinding) can bioavailability (e.g., low permeability of the intestinal membrane result in some complex formation [72,73]. However, it is clear to the compound being studied), it is unlikely that formulation upon analysis (e.g., via DSC) that the majority of the mixed with cyclodextrins will result in bioavailability enhancement. material is still pure parent substances (rather than complex) Most of the compounds listed in Tables 1 and 2, although [20,24,36]. Thus, there is still likely to be a difference between they are not salt forms, will be ionized during at least a portion physical mixtures and pre-formed complex formations. of gastrointestinal (GI) transit, as indicated by their pKa values. The much more common use of complexes rather than This is important as the charge on the drug molecule can physical mixtures indicates that it is generally expected that influence its binding with cyclodextrin. Thus, the cyclodextrin formulations of physical mixtures will not enhance oral may influence the dissolution and solubility of the compound to bioavailability to the same extent as formulations of complexes. different extents in different areas of the GI tract. This fact An exception comes in the patent literature, where Stella et al. increases the complexity of comparing studies as listed in claim that sulfoalkyl ether cyclodextrins formulated as both Tables 1 and 2. If two compounds were used in the exact same physical mixtures with drug and complexes can be used to study and all properties of the compounds were identical except equivalently enhance dissolution, solubility, and/or bioavail- for pKa values, they may achieve different bioavailability due to ability [74,75]. These patents as well as published papers [76– variable binding with cyclodextrin during GI transit. The pKa 80] give several examples of controlled-release tablet formula- value will also influence the solubility of the compound at a tions containing physical mixtures with dissolution kinetics given pH, influencing the total amount of drug that can be in similar to those containing complexes. However, they do not solution in both free and complexed forms. Thus, both present actual in vivo bioavailability data to support the unbuffered water solubilities and solubilities at specific pH equivalence of physical mixtures and complexes in vivo. In values, when available, are listed for the compounds in Tables 1 addition, it is stated in these papers and patents that an and 2. Most of the compounds have water solubilities of less appropriate dosage form will allow hydration of the drug- than 0.1 mg of drug/ml, indicating that dissolution may be a cyclodextrin physical mixture within the dosage form to ensure limiting factor in drug absorption, but greater than 1 μg/ml. The adequate formation of the complex. It is possible that the high critical solubility for drugs to exhibit dissolution limited drug solubilities of sulfoalkyl ether cyclodextrins allow substantial absorption from the GI tract has been reported as 0.1 mg/ml amounts of cyclodextrin to be in solution in the hydrated oral [68]. The fact that some of the drugs listed in Table 1 have controlled-release drug delivery device (e.g., matrix or osmotic solubilities greater than 0.1 mg/ml emphasizes the importance tablet). If the hydrated cyclodextrin and drug are present at of considering the complex interaction of multiple factors that sufficiently high concentrations, there could be appreciable could determine the influence of cyclodextrins (e.g., binding complex formation prior to release from the drug delivery Author's personal copy 82

Table 1 Summary of drug, cyclodextrin, and dosage form parameters for studies in which cyclodextrins were successfully utilized to enhance bioavailability ..Crire l ora fCnrle ees 2 20)78 (2007) 123 Release Controlled of Journal / al. et Carrier R.L. – 99 Author's personal copy ..Crire l ora fCnrle ees 2 20)78 (2007) 123 Release Controlled of Journal / al. et Carrier R.L. – 99

(continued on next page) 83 Author's personal copy 84

Table 1 (continued) ..Crire l ora fCnrle ees 2 20)78 (2007) 123 Release Controlled of Journal / al. et Carrier R.L. – 99

A = Acidic, B = basic, soln. = solution, clogP = calculated logP value, calculated using Advanced Chemistry Development (ACD/Labs) Software Solaris V4.67 (data from SciFinder®). * = Calculated using Advanced Chemistry Development (ACD/Labs) Software Solaris V4.67 (data from SciFinder®). ** = Apparent 1:1 binding constant. Unless otherwise noted, the comparison and test dosage forms were the same with the complex or physical mixture replaced by drug. UCD CD:drug is based on water solubility, unless otherwise specified, and on 1:1 complex formation and apparent 1:1 binding constants. Lines separating rows separate studies. Shaded rows correspond to reports that explicitly mentioned the influence of CD on the stability of the compound. Author's personal copy

Table 2 Summary of drug, cyclodextrin, and dosage form parameters for studies in which cyclodextrins were not successfully utilized to enhance bioavailability

Drug (species) pKa clogP Water Buffered solubility Dosage Complex Dose Dosed UCD CD: CD type, Binding Other Comparison AUC increase Tmax Cmax MW solubility (mg/mL) form formation (mg) CD: Drug CD:Drug constant formation dosage form (x AUC change change −1

(mg/mL) method Drug (molar) (M ) components control) (hr) (μg/ml) 78 (2007) 123 Release Controlled of Journal / al. et Carrier R.L. (molar) − Glibenclainide 5.3 (A) 3.93 6.18e 3 (pH 7.4); Physical – 3 29:1 β-CD 827 Gelatin Drug (in No change 4.5– 0.084– − [26] (dog) 494 2.3 4 (pH 3.0) mixture 1:1 (pH 7.4) capsule, capsule, 3.5 0.12 dosed with with water) water Indomethacin 4.2⁎(A) 3.11 0069 b3.578 (pH 1,4); N3.578, Complex Freeze- 50 1:1 10.8 β-CD 5300 Dosed with Freeze- No change [38] (rabbit) 358 [49] b35.78 (pH 7,8), drying (K=5300), 1:1 [51], water dried drug N35.78,b357.8 (pH 10)⁎ 100.1 [56] 523 [57] (with water) (K=523) Naproxen [19] 44⁎ (A) 3.0 0.04 b2.30 (pH 1,4); N23.03, Complex Freeze- 200 1:1 5.2 β-CD 1378 Gelatin Drug (in No change (human) 230 (pH 4) b230.3 (pH 7,8); N230.3 drying 1:1 (pH=1, capsule gelatin capsule) (pH 10)⁎ 25 °C) Freeze-dried No change drug (in gelatin capsule) Rutin [12] 6.8⁎(A) 2.23 .045 [59] b6.11 (pH 1,4,7,8); Complex Slurry 200 1:1 52.0 β-CD 266 Starch Tablet No change (dog) 611 N61.05,b610.5 (pH 10)⁎ (tablet) (ethanol– 1:1 (complex water)/ replaced by drug) kneading/ drying – Tolbutamide 2.34 0.1053 b2.70 (pH 1,4); N2,70, Physical – 100/ 1:1 β-CD 196 [45] Drug No change 99 [46] (rabbit) 270 [49] b27.04 (pH 7); N27.04, mixture kg 2:1 [45] (serum b270.4 (pH 8); N270.4 glucose (pH 10)⁎ variation coefficient) Notations are the same as those described for Table 1. 85 Author's personal copy

86 R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99

Fig. 1. Structures of compounds used in studies, summarized in Tables 1 and 2, where cyclodextrins were employed to enhance bioavailability. device, and it would thus be likely that devices formulated with 2.4. Complex formation methodology physical mixtures of these highly soluble cyclodextrins would perform in vivo in a similar fashion to devices formulated with While most studies utilizing cyclodextrins to enhance complexes. It should be noted that formulation with a physical bioavailability employ a drug-cyclodextrin complex, the mixture rather than a complex is desirable from a processing method of preparation of the complex varies, as can be seen viewpoint, since the steps involved in making the complex in Table 1. Investigators have used freeze-drying, spray-drying, could be skipped in the manufacturing process. and co-precipitation of a cyclodextrin/drug solution, as well as Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 87 simple grinding with a mortar and pestle of a slurry of drug and through the matrix of hydrophilic polymer chains in the cyclodextrin [81]. The method of preparation of the complex hydrated HPMC tablet. In one study, the gel-forming properties can greatly influence the dissolution kinetics, and, presumably, of HP-β-CD were utilized to design a controlled-release matrix the bioavailability enhancement obtained with a complex for metoprorol [85]. [23,39,40,71]. This is logical in light of the fact that certain Cyclodextrins have also been used in osmotic systems to methods of preparation can result in more or less complex enable delivery of low solubility compounds. In a patent of formation, a factor that is rarely quantified, as well as changes in Stella et al., examples of controlled-release formulations the particle size and degree of amorphous nature of the resulting containing cyclodextrins, including multilayer tablets and material, although the cyclodextrin-drug complex is often osmotic formulations, are presented [75]. This same patent amorphous. Material with a smaller particle size (greater surface provides examples from the literature of the use of cyclodextrins area per unit volume of material) and amorphous material will in controlled-release formulations. In a separate reference, generally have faster dissolution kinetics. These differences in Stella et al. discuss the relative importance of osmotic and complex formation methodology, therefore, make it somewhat diffusional components of release kinetics in osmotic pump difficult to make clear comparisons between studies. In some tablets containing cyclodextrins [86]. It has been demonstrated studies, the particulate matter resulting from complex formation that certain cyclodextrins, especially sulfobutyl ether cyclodex- has been sieved so that only a specific particle size was used in trins, can have sufficient osmolality to act as osmotic agents in the study [12,38–40]. Care has been taken in some studies to an osmotic tablet, and the factors affecting release in subject the comparator formulation (e.g., drug alone) to the cyclodextrin-containing osmotic tablets have been studied same processing as the complex, minimizing effects of [76–78,87,88]. Hydrophobic cyclodextrins have been utilized processing on any observed increases in dissolution kinetics in controlled-release formulations mainly as the controlled- or bioavailability [38]. release agent, as they slow the release of soluble active components [13,63,66]. Enteric type cyclodextrins have been 2.5. Immediate vs. controlled release used to prevent drug release in the stomach [89]. Covalent linkage with hydrophilic cyclodextrins (as opposed to non- All studies referenced in Tables 1 and 2 and most studies covalent interactions typically involved in complex formation) employing CD to enhance bioavailability in general have has been used to provide site-specific release in the cecum and involved immediate release dosage forms. There are several colon, where the covalent cyclodextrin-drug link is broken by examples of the use of cyclodextrins in controlled-release microflora enzymatic activity [66,90]. For example, covalent dosage forms in the literature, but unfortunately very little bonding of α-cyclodextrin has been utilized to target drug information on their affect on bioavailability. Cyclodextrins release to the colon [90]. have been shown to both increase and decrease the rate of drug Special consideration of the use of cyclodextrins in oral release from controlled-release devices. Increases in release rate controlled-release dosage forms is warranted as they are could be due to increase in solubility of the complex relative to typically designed to release drug throughout a portion of GI the drug alone and associated increase in drug in solution in the transit, and the variable GI environment can alter the influence releasing device. Decreases have been attributed to the that cyclodextrin ultimately has on drug solubility. As a dosage decreased diffusivity of the bulky complex relative to the form travels through the GI tract, the changes in physiological drug alone. Giunchedi et al. used complexation of the insoluble environment (e.g., pH, water content, bile salt concentration, drug naftazone with beta-cyclodextrin (β-CD) and hydroxy- motility) can influence the dissolution kinetics and solubility of propyl beta-cyclodextrin (HP-β-CD) to enhance dissolution drugs, cyclodextrins, and complexes, especially, as mentioned kinetics from hypromellose matrix tablets [82]. The influence of above, if the drug and/or cyclodextrin is likely to change its cyclodextrin on prednisolone and carbamazepine release from ionization state with the changes in physiological pH that occur hydroxypropylmethylcellulose (HPMC) matrix tablets has been in the GI tract. The stability constant of the complex is also investigated [21,79], and it was found that cyclodextrin dependent on pH, especially if the drug is ionizable [26,30,63]. increased drug dissolution rate, with the increase being greater A charge on a drug can offset the affinity of the hydrophobic when the drug and cyclodextrin were formulated as a complex portion of the molecule for the cyclodextrin cavity. Thus, the rather than a physical mixture. Quaglia et al. [83] reported that change in pH during GI transit can influence the strength of inclusion of cyclodextrin in a formulation of nicardipine in drug interaction with cyclodextrin and ability of cyclodextrin to crosslinked polyethylenglycol (PEG) hydrogels decreased solubilize the drug. It is therefore expected that a dosage form release rate. The authors attributed this result to the decrease that slowly delivers drug during GI transit may demonstrate in the diffusivity of drug when it is complexed to cyclodextrin different pharmacokinetic changes with the inclusion of (due to increase in effective molecular size), and quantitative cyclodextrin than a dosage form that delivers all drug treatment of this phenomenon was presented. Similarly, effectively at one time to the upper GI tract. Supporting Sangalli et al. [84] found that inclusion of β-CD hindered evidence for this statement is found in comparing bioavailabil- release of poorly soluble drugs from hydrophilic matrices ity enhancement observed with dosing to different areas of the (HPMC) relative to matrices containing drug and lactose, while GI tract. When carmofur complexed with DM-β-CD, trimethyl it increased release rate from inert matrices (acrylic resins). This beta-cyclodextrin (TM-β-CD), and β-CD was dosed orally to result was attributed to the complex having difficulty diffusing rabbits, increases in AUC of 7.5, 3, and 3 times, respectively, Author's personal copy

88 R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 were seen over the AUC resulting from drug dosed alone. been demonstrated that a salt form of a compound can exhibit a However, when the same complexes were dosed rectally, only greater binding constant with cyclodextrin than the free base the DM-β-CD showed a dramatic increase in AUC over drug drug, and it is believed this is due to the association of the alone (3.3, 1.4, and 1.2 times the control for DM-β-CD, TM-β- counterion with the charged drug in the complex [94]. In the case CD, and β-CD, respectively) [28]. The change in magnitude of of ziprasidone, the binding constant of the complex of the bioavailability enhancement could be related to the lower water ziprasidone mesylate ion pair with SBE-β-CD was 7892 M− 1 content or higher pH in the rectum compared to the upper compared to 957 M− 1 for the complex with the dissociated ionic intestine altering the amount of complex formation. In a compound. A lower binding constant due to charge does not different study, indomethacin labeled with 14C was dosed alone necessarily mean that cyclodextrins cannot be used to solubilize or as a complex with β-CD. When dosed to the small intestine, a compound. In fact, a combination of pH adjustment (used to 56% of a dose of indomethacin alone was absorbed in the small deliver drug in an ionized and more soluble state) and intestine, while 6% was absorbed when dosed to the large complexation with cyclodextrin has been used to successfully intestine. However, in the case of complexed indomethacin, solubilize compounds [96]. absorption values were 68 and 66%, respectively, demonstrat- Quantitative consideration has been given to the influence of ing a more pronounced influence of complexation on absorption the ionized state of the drug on binding constant and utility of in the lower GI tract [91]. In a study aimed at improving oral cyclodextrin to solubilize the drug [93,96]. Rao and Stella [93] bioavailability of artemisinin through complexation with β- and demonstrate theoretically that the decrease in binding constant γ-cyclodextrin, the statement was made that colonic absorption associated with charge on a compound relative to the binding was “poor and negligible” regardless of whether or not the constant with the neutral compound (ranging in the studies compound was complexed [27]. It was clear in the cited study considered from 40-fold to no appreciable decrease [95–99])is that the comparator for the dosed complexes, the commercial often outweighed by the accompanying increase in solubility of formulation Artemisinin 250®, stopped being absorbed approx- the ionized compound. Another consideration of the synergism of imately at the time it reached the colon, with percent absorption ionization and complexation is given by Li et al. [97]. The authors leveling off at 60% of the dose. However, in the cases of the derive the theoretical increase in total drug solubility with ion- complexes, nearly 100% of the dose was absorbed by the time ization and complexation and provide experimental validation. the dosage form reached the colon, making it difficult to draw any conclusions regarding the influence of cyclodextrin on 2.7. Dose and molar CD:drug ratio absorption in the colon. Several other studies have demonstrat- ed enhanced bioavailability using cyclodextrins of rectally Examination of the typical drug and cyclodextrin properties dosed compounds [5,63,92]. It is evident from the studies cited and doses used in studies where cyclodextrins were shown to above that there is not a clear understanding of the relative enhance bioavailability reveals that the majority of the doses ability of cyclodextrins to enhance bioavailability in the lower used were relatively low (b 100 mg in 25 out of 29 studies). GI compared to the upper GI. Such information, especially for Many of the studies dosed drug as a suspension or a powder with compounds that have very different solubilities at the pH of the water, enabling a greater dose than would be possible in a lower and upper GI, would be particularly useful to the conventional oral dosage form such as a tablet or capsule. The formulation scientist attempting to formulate controlled-release use of cyclodextrins in solid oral dosage forms, in particular, is dosage forms containing cyclodextrins. limited to low doses with relatively large stability constants due to the relatively large size of cyclodextrin molecules and mass 2.6. Ionized vs. neutral drugs and size limitations of oral dosing [5,6,67]. For example, in the cases of α-, β-, and γ-cyclodextrins (MW = 972, 1132, and As demonstrated in Table 1, most studies to date utilizing 1297 g/mol, respectively), 100 mg of 1:1 molar complex cyclodextrin to enhance oral bioavailability did not utilize salt contains only approximately 5–25 mg of a drug with a molecular forms of active compounds or consider the ionized state of the weight of 500. Most probably for similar reasons, the molar ratio compound upon dosing. This statement is based, however, on of cyclodextrin:drug utilized was low in most of the formula- lack of mentioning in the references of the use of a salt form, and tions studied, with more than half of the comparisons involving a it is possible that specific information related to use of salt forms molar ratio of cyclodextrin to drug of 2:1 or less. The amount of may have been omitted from some references where they were cyclodextrin necessary to create a desired increase in bioavail- actually used. It is noted that all compounds listed in Table 2 will ability for a given dose of drug is dependent on a number of be ionized in the small intestines (pH 5 to 7), while only a portion factors including the binding constant and the physicochemical of those listed in Table 1 will be. As described above, the ionized properties of the drug and cyclodextrin (e.g., solubility), all of state of the active compound and the presence of counterions are which influence the various processes occurring during delivery likely to affect the drug's binding constant with cyclodextrin of the drug in the GI environment (e.g., dissolution and [93–95], and a decrease in binding constant with ionization of absorption), as described below (See “Section 3 Explanations drug is often observed. An opposite effect can be observed, for ability of cyclodextrins to enhance bioavailability”). however, in cases where a charged cyclodextrin derivative (e.g., Most of the literature concerning the use of cyclodextrins to anionically charged sulfobutyl ether beta-cyclodextrin (SBE-β- enhance bioavailability does not discuss the required amount of CD)) interacts with a drug of opposite charge [95]. It has also cyclodextrin in quantitative terms. In the previously mentioned Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 89 patents of Stella et al. [74,75], it is stated for the particular types a given dose of drug to be delivered based on solubility. It can be of cyclodextrins and drug delivery devices discussed that the assumed to be much less than one in cases where cyclodextrins are molar ratio of CD:drug should be in the range of 1:1 to 20:1. being used to enhance solubility and dissolution. The second term Rao and Stella presented a theoretical consideration of the is the UCD defined by Rao and Stella. Thus, the ability of a given appropriateness of cyclodextrins as a solubilizing technology in amount of cyclodextrin to solubilize a dose of drug is dependent which the ability of a given amount of cyclodextrin to on the drug's solubility and the binding constant with cyclo- adequately solubilize a given drug dose was determined by dextrin. A less obvious but still important factor is the solubility of whether or not a dimensionless parameter, “cyclodextrin utility the cyclodextrin, which is assumed in the analysis not to be a number,” (UCD) was greater than or less than one [93]. This limiting factor. treatment is based on the fact that a UCD number greater than It is interesting to compare the theoretical ratio of CD:drug one indicates that the cyclodextrin amount is sufficient to required according to the UCD with what has actually been used solubilize the entire dose of drug. In order for this condition to in the literature. In Table 1, the molar ratio of CD:drug be met, the dose per unit available volume of solution must be necessary for a UCD of one has been calculated for studies in less than or equal to the total solubility of the drug in the which the necessary information was able to be obtained. The presence of the cyclodextrin. Here “solubility” refers to the water solubility, when available, was used to calculate the UCD. maximum amount of drug that can be in solution at equilibrium, If the water solubility was not available, the solubility at a including both free and complexed drug. Therefore, the specific pH, as indicated in the table, was used. It is evident that solubility in the presence of cyclodextrin is the sum of the enhancement in bioavailability has been reported when a level free drug solubility and the maximum equilibrium concentration of cyclodextrin below the UCD-predicted amount has been of complex in solution. To determine an expression for this utilized. Of the studies in Table 1 about which enough solubility, first consider the definition of the binding constant information was able to be obtained to compare a CD:drug (K). The binding constant describes the equilibrium between molar ratio necessary for a UCD of one and the dosed CD:drug drug and cyclodextrin. For a 1:1 complex: molar ratio, 20 utilized a CD:drug ratio less and 5 utilized a CD: drug ratio greater than that predicted to be necessary by the ½ ¼ com ð Þ UCD. There appears to be no clear correlation of the difference K ½½ 1 CD f drug f between the utilized and UCD-predicted CD:drug molar ratio with the magnitude of the AUC increase. It should be noted that The binding constant can also be expressed in terms of the considerable error can be introduced into the UCD CD:drug total molar amount of both bound and free cyclodextrin, CDtotal, molar ratio calculation by the variation that is seen in reported for a given volume V: solubility and binding constant values, making it possible that the values calculated are not exactly those relevant to the study ½ ¼ com ð Þ at hand. For example, the binding constants reported for β-CD K ðÞ= ½½ 2 CDtotal V com drug f and piroxicam in two different studies were 101 and − 1 Rearranging and solving for [com], 28,000 M , leading to UCD-predicted necessary CD:drug molar ratios of 1.9 and 103, respectively [23,41]. However, it K½drug CD appears that it is not always necessary for the cyclodextrin ½¼com ÀÁf total ð3Þ þ ½ amount in a given formulation to be adequate to solubilize the 1 K drug f V entire dose for enhancement of bioavailability. A very high CD: The maximum complex concentration is present when the drug molar ratio, in fact, can lead to a decrease in bioavailability drug concentration is equal to the free drug solubility, So. due to a decreased free drug concentration in the intestinal Making this substitution, the maximum solubility of a drug in lumen when a very large amount of drug is bound to the presence of a given molar quantity of cyclodextrin is: cyclodextrin.

½¼ þ KSo CDtotal ð Þ drug total So 4 2.8. Type of CD used 1 þ KSo V Thus, the requirement described by Rao and Stella for a Both natural cyclodextrins and cyclodextrin derivatives have given molar dose of drug (Dtotal) is: been used to enhance bioavailability, as can be seen in Table 1. Cyclodextrin derivatives often have a higher solubility than Dtotal V þ KSo CDtotal ð Þ natural cyclodextrins, and they may have different binding So þ 5 V 1 KSo V constants with a given compound, as well. This can result in This can be rearranged to: different levels of bioavailability enhancement using natural cyclodextrins vs. derivatives [44,45]. For example, when the β- β β SoV KSo CDtotal CD and HP- -CD complexes of rutin were dosed, -CD had no þ z1 ð6Þ β Dtotal 1 þ KSo Dtotal influence on bioavailability, while HP- -CD resulted in a 2.9 times increase in the AUC [12]. Similarly, when salbutamol was The first term is the inverse of the dose number, a dosed as the perbutanoyl-β-CD (TB-β-CD) complex, the AUC dimensionless number that has been used to assess the ability of was increased 4.6 times in comparison to dosing of drug alone, Author's personal copy

90 R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 while it was only increased 1.7 times when dosed as the β-CD and a large molar excess of cyclodextrin to obtain a lower complex [13]. bioavailability in a system containing cyclodextrin than if drug alone were dosed [5,104]. If a complex with a very high binding 2.9. Binding constant magnitude constant is dosed, the complex may not dissociate appreciably, and the complex itself is not absorbed [63]. Complexation with A range of binding constant values of 0 to approximately agents other than cyclodextrin is known to be able to decrease 100,000 M− 1 have been reported for cyclodextrin complexes in absorption if the complexed species is not able to be absorbed the literature, with 0 corresponding to absence of binding [6]. [105,106]. Very weak binding is roughly characterized by a binding One strategy for displacing drug that is tightly bound to constant less than 500 M− 1, while weak, moderate, strong, and cyclodextrin is to co-dose a competitive binding agent. For ex- very strong binding are characterized by binding constants in ample, complexation of cinnarizine with β-CD resulted in AUC the ranges of 500–1000 M− 1, 1000–5000 M− 1,5000– values 8.0 and 1.4 times that of drug when dosed with and without 20,000 M− 1, and greater than 20,000 M− 1, respectively. The phenylalanine, respectively [34,107]. Interestingly, dosing of mean binding constant values of pharmaceutical compounds uncomplexed drug with phenylalanine resulted in a decrease in and α, β, and γ-CD were determined to be 129, 490, and AUC and Cmax and an increase in Tmax relative to dosing drug 355 M− 1 when a large number of complexes were statistically alone. It has been demonstrated that drug can also be displaced analyzed [93,100,101]. Of the 46 comparison for which binding from a complex by lipids in the rectum, mucus, and bile [63]. constant magnitudes were able to be found (Table 1), 23 had very weak binding constants, while 5, 5, 10, and 3 had weak, 2.10. Interaction with polymers and other formulation components moderate, strong, and very strong binding constants, respec- tively. It has been suggested in the literature that error may exist While most of the studies surveyed in Table 1 involved dosing in reported binding constants, for example if they are measured a complex of drug and cyclodextrin as a powder alone or in a assuming 1:1 binding when a different stoichiometry actually gelatin capsule with water, some also included other excipients. exists in the complex [101–103]. As the presence of other excipients, including polymers, is The AUC increase is plotted vs. the binding constant in known to possibly influence the interaction between drug and Fig. 2. It is clear that there is no correlation between binding cyclodextrins, it is important to take these factors into constant and increase in AUC for the studies examined. The consideration when reviewing the literature in search of guide- majority of the studies surveyed involved lower binding constant lines for using cyclodextrins to enhance bioavailability. The values. It also appears that as the binding constant increases, ability of water-soluble polymers to enhance the solubilizing there may be a decrease in the maximum AUC increase that can effect of cyclodextrins and thus possibly reduce the amount of be achieved. It has been reported in the literature that the cyclodextrin necessary in a given dosage form has been magnitude of binding constants is similar to molar ratios of CD: demonstrated [14,26,108–110]. Formulations containing a drug in that if it is too big, a decrease in bioavailability over drug water-soluble polymer (e.g., HPMC or polyvinylpyrrolidone, dosed alone can actually result, while if it is too small, there may PVP) have been able to achieve bioavailability enhancement not be any effect of cyclodextrin [7]. A theoretical model of a equivalent to formulations containing up to 80% less cyclodex- cyclodextrin-drug system developed by Szejtli predicts that trin [26]. Such results are generally attributed to a synergistic dosing a complex of cyclodextrin and drug at a 1:1 molar ratio solubilizing effect of polymer and cyclodextrin believed to be should result in increased blood plasma levels of the drug over a due to formation of ternary complexes or co-complexes between reasonable range of binding constants (500–10,000 M− 1). The drug, cyclodextrin, and polymer [110]. Polymers such as water- model also predicts, however, that it is possible with a high soluble cellulose derivatives can form complexes with cyclo- binding constant (e.g., greater than approximately 10,000 M− 1) dextrin that have different physicochemical properties than those of the cyclodextrin alone. For example, the solubility of the cyclodextrin and/or the apparent binding constant between drug and cyclodextrin can be changed in this manner [108]. It should be noted that formulations of drugs alone with these polymers also often lead to enhancement in bioavailability, and these polymers are known to interact with and solubilize drugs. For example, when tacrolimus was dosed to rats in a commercial PROGRAF tablet containing HPMC and compared to drug alone, it resulted in an AUC0–12 increase of 3.6 times, an increase in Cmax from 1.6 to 11.2 ng/ml, and a decrease in Tmax from 0.5 to 1.3h, effects comparable to those observed when tacrolimus was dosed with a 50:1 molar ratio of DM-β-CD [44]. Formulation of cyclodextrins with hydroxy acids or salts of Fig. 2. Plot of AUC increase vs. binding constant. The y-axis represents the basic drugs can also enhance their solubilizing effects [14,111]. factor by which the AUC was increased over the AUC when cyclodextrins were There is often a synergistic effect observed in dosing an acid not used (i.e., the ratio of these two AUC values). with a cyclodextrin, such that the total solubility enhancement Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 91 observed via dosing with both acid and cyclodextrin is greater are described below. The text is organized according to common than the predicted combined effect from dosing with each alone. explanations for bioavailability enhancement provided in the There are several examples in the literature of using cyclo- literature followed by theoretical consideration of these dextrins together with acids to enhance solubility, dissolution explanations. This theoretical consideration could provide the kinetics, and bioavailability, and several theories of possible basis for quantitative analysis of the simultaneous influence of interactions between drug, acid, and cyclodextrin have been the properties of the cyclodextrin-drug-dosage form system on proposed [111]. Other formulation components, including salts, key processes in the drug delivery environment that determine surfactants, preservatives, and organic solvents are known to bioavailability enhancement. influence and often reduce the efficiency of binding between drug and cyclodextrin. For example, the inclusion of non-ionic 3.2. Enhancement in dissolution kinetics surfactants has been shown to decrease binding of cyclodextrin to diazepam due to competitive binding of the surfactant to the The main cited reasons for enhancement in bioavailability cyclodextrin [112]. Formulation component effects can be with inclusion of cyclodextrins in a dosage form are increase in related to change in charge on the drug or cyclodextrin, as dissolution kinetics and increase in solubility, and it is often described above, as well. stated that cyclodextrins will increase bioavailability when the rate-limiting step in drug absorption is dissolution rather than 3. Explanations for ability of cyclodextrins to enhance permeation through the intestinal membrane [7,20,66]. Most of bioavailability the compounds listed in Table 1 have low solubility, and, as discussed above, most of the studies cited specifically refer to 3.1. Significance the low solubility and slow dissolution of the compound as motivating factors for studying the influence of cyclodextrin on What are the properties of drug, cyclodextrin, delivery bioavailability. Many of the compounds listed in Table 1 are device, and/or physiological environment necessary for cyclo- reported to have both low and variable absorption, character- dextrins to enhance oral bioavailability? Answers to this istics associated with low solubility and slow dissolution question in the form of general guidelines are found in kinetics [18,22,26,37]. In many of the studies cited, the reviewing the literature, as described above and demonstrated influence of cyclodextrin on the dissolution kinetics of the in Table 1 for cases where the solubilization properties of compound is measured in vitro. cyclodextrins were specifically utilized. For example, it is As depicted in Fig. 3, once solid drug is delivered to the evident that most studies in which cyclodextrins have been used gastrointestinal tract as either free drug, physical mixture with to enhance oral bioavailability involve hydrophobic (logP N cyclodextrin, or complex with cyclodextrin, dissolution and 2.5), low solubility (1 μg/ml–1 mg/ml) compounds with a dose permeation across the intestinal membrane must occur in order of less than 100 mg and a CD:drug ratio of 2:1 or less. Similar for the drug to be absorbed. If the dissolution kinetics are general guidelines were outlined above for binding constant limiting in the overall absorption process, enhancement of magnitude and dosing of a physical mixture vs. a complex. However, these are rough guidelines true of most studies, but it is evident from the discussion above that there are many exceptions to these general rules. In the limited range of studies reviewed, there was no clear correlation between properties of drug (e.g., solubility, binding constant with cyclodextrin) or experimental parameters (e.g., type of cyclodextrin used, dose) that could give definitive, quantitative guidance regarding when and how cyclodextrins can be used for bioavailability enhancement. This is likely related to the lack of information regarding failed attempts to use cyclodextrin to enhance oral bioavailability and the wide range of variables associated with each study performed (method of preparation of complex, type of cyclodextrin used, type of dosage form, animal species, etc.) that make it difficult to assign boundaries to key parameters based on available data. In addition, the drug and cyclodextrin Fig. 3. Diagram of the processes in the intestinal drug delivery system when a properties and experimental parameters interact to simulta- drug is dosed either as a physical mixture or a complex with cyclodextrin. neously influence processes in the intestinal drug delivery Processes occurring that are influenced by the presence of cyclodextrin include environment, so that looking at one parameter of this system in dissolution of drug and/or complex, precipitation of drug (if free drug isolation provides limited information. concentrations exceed equilibrium solubility), complexation of drug and Further insight can be found in consideration of what cyclodextrin, and absorption of drug. These processes interact to determine the change with time in amount of solid (drug or complex); drug, cyclodextrin, phenomena in the drug delivery environment are affected by the and complex in solution; and absorbed drug. The properties of the drug, presence of cyclodextrin and how, ultimately, overall drug cyclodextrin, and intestinal environment determine the kinetics of these absorption is influenced by these changes. These phenomena processes and their effects on overall component absorption. Author's personal copy

92 R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 dissolution kinetics via dosing a physical mixture with tend to precipitate, however, especially if formed from one of cyclodextrin or dosing a complex will likely increase the parent cyclodextrins [14,24]. This type of behavior gives bioavailability. The enhancement in dissolution kinetics rise to what Higuchi defined as a B-type phase-solubility brought about by dosing a physical mixture of drug and diagram [115]. cyclodextrin is related to the fact that the dissolution of drug will Enhancement in dissolution kinetics is not always accom- involve the flux of both free drug and complexed drug away panied by enhancement in bioavailability. For example, in a from the drug particle surface if cyclodextrin is present in the study in which the β-CD and HP-β-CD complexes of rutin were immediate environment [63]. In the classical Noyes–Whitney studied, both cyclodextrins had comparable affects on dissolu- dissolution expression for a drug particle in the absence of tion kinetics and stability, but only HP-β-CD increased cyclodextrin, dissolution rate is proportional to the concentra- bioavailability [12]. When indomethacin was processed as a tion gradient across the unstirred boundary layer surrounding a freeze-dried complex with β-CD, it showed increased dissolu- dissolving particle in a well-mixed compartment. For a neutral tion kinetics over freeze-dried drug alone. However, when the compound: complex and drug were dosed to rabbits, there was no increase in percent drug recovered in urine with dosing of the complex ÂÃÀÁ ddrugf [38]. These results highlight the importance of gaining ¼kdis So ½drug ð7Þ dt f understanding of all the interconnecting factors influencing absorption when a cyclodextrin-drug system is dosed. It is important to determine what the rate-limiting step is in ¼ ADdrug ð Þ kdis 8 absorption of the compound when cyclodextrin is not present lbl and then assess the ability of cyclodextrin to influence this rate- The concentration of drug at the drug particle surface is taken limiting step. as its solubility (So), and the concentration at the edge of the boundary layer is taken as the concentration of drug in the well- 3.3. Increase in solubility stirred intestinal lumen ([drug]f). The rate constant is equal to the ratio of the product of the diffusivity of the drug (Ddrug) and Along with an increase in dissolution kinetics, increase in the surface area (A) to the length of the unstirred boundary layer solubility is often cited as being responsible for enhanced (lbl). When cyclodextrin is present in the environment of the bioavailability when dosing drug with cyclodextrins [24]. dissolving drug particle, the rate of dissolution is now Solubility can be a key factor in kinetics of dissolution (Eq. proportional to an additional “driving force”: the difference in (7)) and can also influence permeation through the intestinal complex concentration at the particle surface and in the bulk membrane by influencing the concentration of drug in solution intestinal fluid [113]: in the intestinal lumen. Thus, low solubility is often blamed for low bioavailability. It is useful to clarify what is meant by the ÂÃÀÁÀÁ“ ” ddrugf ¼A ½þ ½ ½ increase in solubility brought about by cyclodextrins, Ddrug So drug f Dcom com surface com dt lbl however, in order to evaluate their ability to enhance ð9Þ bioavailability. In the presence of cyclodextrin, the total amount of drug in solution is equal to the sum of free drug and complex Dissolution kinetics of complex are usually enhanced over in solution. As described above in “Dose and molar CD:drug those of both the drug alone and the physical mixture [70,71]. ratio” in the discussion of the cyclodextrin utility number [93], For some drugs, the dissolution of drug alone or as a physical the maximum value that this total amount of drug in solution mixture with β-CD is indistinguishable, while the complex of can have is the sum of the solubility of the drug itself and the drug and β-CD demonstrate much faster dissolution kinetics amount of complex formed when the free drug concentration in (e.g., 90% vs. 25% dissolved in water in 10 min) [29,35,114]. solution is the drug solubility. Thus, for a neutral compound: This is related to the physical properties of the complex. The complex of a low solubility drug typically is more hydrophilic ½¼ ½þ ½V þ KSo CDtotal ð Þ drug total drug f com f So 10 and has a higher solubility than the free drug itself. In addition, ðÞ1 þ KSo V in the case of the derivatized cyclodextrins, the complex is usually amorphous. Water molecules break up amorphous Similar expressions can be written for the total amount of material with relative ease in comparison to crystalline drug ionizable compound in solution in the presence of cyclodextrin [25]. Replacement of the first term in Eq. (7), So, with the based on the binding constant with ionized drug [96]. This total enhanced solubility of the complex results in a much greater amount of free drug and complex is typically referred to as driving force for dissolution. It is possible that the method of “enhanced solubility.” For example, the solubility of prednis- formation of the complex will also result in an increased surface olone in water at room temperature is 0.25 mg/ml, while the area in relation to the surface area of dissolving drug alone or solubilities in the presence of 15 mg/ml β-CD and DM-β-CD physical mixture, increasing the dissolution rate constant in Eq. are 3.4 mg/ml and 3.3 mg/ml, respectively [5]. This enhanced (7). As a result of these various factors, the complex will solubility forms the basis for the theoretical treatment of amount dissolve faster than the drug alone or the physical mixture [63]. of cyclodextrin required in a formulation provided by Rao and There are reports of low solubility inclusion complexes that will Stella [93]. It is important to note, however, that the value of the Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 93 free drug concentration at equilibrium will not exceed the dispersed drug is released rapidly from the nanospheres, solubility of the free drug. This is a key point as the rate of enhancing dissolution rate for low-solubility compounds. permeation through the intestinal membrane is dependent on the free drug concentration in the intestinal lumen: 3.4. Decrease in degradation kinetics ddrug Stability of many compounds has been enhanced via abs ¼ k ½drug V ð11Þ dt a f lumen complexation with cyclodextrins, as has been extensively reviewed in the literature. Stability can be enhanced either in Although there are studies in which transport of cyclodex- the dosage form itself, by inhibiting polymorphic transitions, for trins across the intestinal membrane has been reported [116],it example [121], or once the drug is actually dosed. Of the studies is generally accepted that neither the complex nor free presented in Table 1, reports in which explicit mention was cyclodextrin are absorbed to an appreciable extent [7,66,117]. made of compound stability issues are highlighted. In these Thus, based on the dependence of absorption on free drug highlighted studies, the bioavailability of the drug molecule is concentration (Eq. (11)), the equilibrium “enhanced solubility” generally known to be influenced by its degradation rate, and in brought about by cyclodextrins described by Eq. (10), on its some studies bioavailability enhancement using cyclodextrins own, will not enhance rate of permeation through the intestinal was at least partially attributed to the stabilizing effect of membrane. In fact, it is possible that complexation with cyclodextrin on the drug molecule. As many of these studies cyclodextrin, especially in cases where the binding constant is involve low-solubility compounds, it is difficult to determine if high, will reduce the absorption rate due to the fact that the the bioavailability enhancement is due to the effect of complex is not absorbed and the free drug concentration can be cyclodextrins on dissolution, degradation, or both. Binding of reduced by binding [34]. cyclodextrin can reduce the reactivity of a drug by shielding the In spite of the apparent inability of cyclodextrins to increase drug molecule from attack and/or changing the chemical and the equilibrium free drug solubility, there are ways that physical stability of the molecule itself via conformation cyclodextrins can result in free drug concentration greater than changes, for example. Thus, if a compound is prone to the solubility in the intestinal lumen for a transient period of hydrolysis at intestinal pH or intestinal enzymatic degradation, time. For example, if the complex is dosed, it will disassociate as complexation with cyclodextrins can aid in maintaining it goes into solution to an extent determined by the binding intestinal drug concentrations and thus absorption through the constant and concentrations of drug, cyclodextrin, and complex intestinal membrane according to Eq. (11) [12–15].For in the intestinal lumen. Association and disassociation are often example, complexation of salbutamol with β-CD and TB-β- assumed to be instantaneous in comparison to the kinetics of CD was used to increase the bioavailability relative to dosing dissolution and permeation through the intestinal membrane, drug alone 1.7 and 4.6 times, respectively [13]. This was and free drug molecules can be considered to be in pseudo- attributed to decreased biotransformation (mainly glucuronida- equilibrium with molecules bound in the cyclodextrin cavity at tion) in the intestine. In vitro tests demonstrated that all times [14,118]. Free drug and cyclodextrin will precipitate if complexation led to decreased dissolution rate for this highly their concentrations in solution, as dissolution and decomplexa- soluble drug, especially in the case of complexation with the tion are taking place, are higher than their equilibrium hydrophobic cyclodextrin derivative TB-β-CD. Such protection solubilities [119]. However, if dissolution of the complex and may be particularly useful in oral delivery of peptides that are disassociation are rapid enough relative to precipitation, dosing particularly susceptible to physicochemical and enzymatic of a complex can result in free drug concentration higher than the degradation in the intestine [122]. It is also possible, however, solubility of the drug for a period of time [5,7,63,104]. This can that changes in physical or chemical drug properties brought lead to increased drug absorption through the intestinal about by complexation with cyclodextrins enhance the membrane. Water soluble polymers (e.g., hydroxypropyl degradation of a given drug molecule [123]. cellulose (HPC) or PVP) have been used to prolong the supersaturated state brought about by complex dissolution [7]. 3.5. Change in intestinal membrane properties A second way that cyclodextrins may enhance free drug concentration is by slowing the precipitation of free drug [5]. The interaction of cyclodextrins with biological membranes Precipitation kinetics are proportional to the drug concentration and possible associated changes in permeability have been and thus are reduced when some of the drug is bound by investigated [8,9,11,124]. The nature and extent of interaction of cyclodextrin. In addition to dosing a complex, dosing a salt form cyclodextrins with the intestinal membrane is not completely of the drug can result in transient concentrations of free drug understood, but appears to depend on the type of cyclodextrin higher than the equilibrium solubility. present. Free cyclodextrin may remove membrane components. Another cited method of using cyclodextrins to enhance For example, in a rat intestinal model, α-CD was shown to bioavailability related to dissolution kinetics and solubility is preferentially release phospholipids, and β-CD selectively re- through the formation of nanospheres. Amphiphilic CDs, such leased cholesterol. An influence of cyclodextrins on P-glycopro- as native CDs derivatized on secondary hydroxyl groups with tein (P-gp) and multidrug resistance-associated protein 2 (MRP2) alkyl chains, are capable of self-assembling into nanospheres has also been reported and investigated [11,64,125].Certain that can be loaded with drug [66,120]. The molecularly cyclodextrins (e.g., DM-β-CD) inhibited these efflux proteins in Author's personal copy

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Caco-2 cell monolayers, while other cyclodextrins (e.g., HP-β- ionized to a certain extent at the pH of the small intestines, which CD) had little effect. It was hypothesized that the P-gp inhibition can lead to a decreased binding constant. However, some of the brought about by DM-β-CD is due to its solubilizing effect on compounds listed in Table 1 will also be ionized at the pH of the cholesterol, an abundant component of the caveolae where P-gp is small intestines, yet still experienced enhanced bioavailability localized. It has been shown that methylated cyclodextrins can using CD. In some studies, the lack of bioavailability enhance- extract lipids from the nasal mucosa, possibly enhancing ment has been attributed to the magnitude of the binding constant paracellular transport via this mechanism, and a similar mech- with cyclodextrin. The reasoning is that a binding constant that is anism may apply to the GI tract [11]. Interaction of cyclodextrins “too small” does not lead to enough complexation for the with calcium ions has also been implicated in loosening of tight dissolution kinetics or solubility to be influenced significantly, junctions [9]. Peracylated β-cyclodextrins have been shown to and a binding constant that is “too big” may lead to decreased free have mucoadhesive properties [13,126]. Cyclodextrins can also drug concentration in the intestine, lowering overall absorption reduce local irritation of the GI tract that would occur if the drug (Eq. (11) and Fig. 2) [5,63]. For example, the low level of were dosed alone [39], and thus possibly influence absorption in bioavailability enhancement observed when cinnarizine was this manner. In general, the possible interaction between dosed with β-CD was attributed to a relatively high binding solubilizing capabilities, degradation inhibition, and/or changes constant (6200 M−1) [34,129]. However, similar increases in in intestinal properties make it difficult to develop quantitative bioavailability were seen when cinnarizine complexed with HP- guidelines on the use of cyclodextrins to enhance bioavailability β-CD and SBE-β-CD was dosed in spite of very different binding based on reports in the literature, such as those summarized in constants with these two cyclodextrins (2242 and 4276 M−1, Tables 1 and 2. respectively) [33,129]. A clear method does not currently exist for determining the range of appropriate binding constant values for a 3.6. Shuttling and enhancement of drug concentration at the given compound due to the complexity of the interaction of intestinal wall processes occurring in the intestinal drug delivery environment and their dependence on the properties of the drug, drug delivery The intestine is often modeled as a well-mixed compartment device, and cyclodextrin. These results again highlight the (i.e., uniform concentrations of all species) [127].However,in importance of understanding the interacting processes involved reality, there is an “unstirred” boundary layer near the intestinal in dosing a drug to the intestinal environment with a complexing wall as well as other solid species present, and there are con- agent such as cyclodextrin as opposed to focusing on the centration gradients within these boundary layers. There may be a influence of a single parameter, such as binding constant. An decreasing concentration of drug in the boundary layer adjacent to excess of cyclodextrin can have the same effect as a high binding the intestinal membrane due to the fact that drug is being depleted constant with regards to potentially decreasing bioavailability. by absorption and may not be replenished quickly enough by Both factors result in shifts in the equilibrium between drug, diffusion through the boundary layer. It is possible that com- cyclodextrin, and complex toward complexation. plexing agents diminish this effect. As free drug is depleted in the vicinity of the intestinal wall, disassociation of complex occurs to 4.2. Degradation of cyclodextrins in the intestinal environment re-establish equilibrium, potentially replenishing free drug concentration faster than it can be replenished via diffusion. While not explicitly mentioned in the studies presented in This phenomenon could be aided by the use of amphiphilic Table 2, one factor to consider when assessing the utility of derivatives of natural cyclodextrins formed by grafting aliphatic cyclodextrins to enhance bioavailability of orally delivered chains to the glucopyranose units. These hydrophobic moieties compounds, especially in the case of controlled-release may aid in intimate contact of cyclodextrins with biological formulations, is the stability of cyclodextrins in the intestinal membranes [120,128]. It has also been hypothesized that environment. Cyclodextrins are resistant to the enzymes that components of the intestinal wall (mucus, lipids) displace the hydrolyze starch. They are completely resistant to β-amylase drug from the complex, leading to an elevated drug concentration attack, in fact. α-amylases attack the inside of the cyclodextrin at the intestinal wall [63,92]. molecule at a relatively slow rate [130]. γ-CD is metabolized by enzymes in the saliva, while α-CD and β-CD are not [3]. α-CD 4. When cyclodextrins do not enhance bioavailability and β-CD are not believed to be hydrolyzed during transit through the small intestine, but are degraded by colonic flora. 4.1. Binding constant magnitude and amount of dosed Cyclodextrin metabolism was investigated by Anderson et al. by cyclodextrin orally administering 14C-labeled β-CD to rats [131]. The rats exhaled approximately 55% of the radioactivity within 24 h, The majority of the literature deals with successful use of with maximum radioactivity observed at 4–8 h. In a similar cyclodextrins to enhance bioavailability, but there are reports of study, Gerloczy et al. administered 14C-labeled cyclodextrin and no improvement or decreases in bioavailability with use of glucose to rats [132]. Radioactivity was apparent in the respired cyclodextrins, as well. There are no clear differences between air from rats administered glucose only 2 h after feeding, while it parameters of studies in Table 2, where cyclodextrins were not appeared 4–8 h after feeding in rats administered cyclodextrin. successful in increasing bioavailability, and those in Table 1.As In both cases, approximately 60% of the administered mentioned above, all of the compounds listed in Table 2 will be radioactivity was accounted for in respired air. These results Author's personal copy

R.L. Carrier et al. / Journal of Controlled Release 123 (2007) 78–99 95 indicate that cyclodextrins are metabolized in the rat. It has been In spite of these general guidelines, many studies reported suggested based on these and similar studies that absorption of parameters outside of these guidelines, and it was difficult to cyclodextrin does not occur in the small intestine, but rather in distinguish between parameters of studies in which success or the colon where cyclodextrin is metabolized by colonic bacteria. lack thereof in bioavailability enhancement was reported. There- In fact, as described above, the use of cyclodextrins as pro-drugs fore, it was not possible to develop clear quantitative guidelines for colon-targeted delivery of compounds has been investigated for what drug and cyclodextrin properties are key to enabling oral [65,66,90]. The kinetics of degradation of α- and β-CDs by bioavailability enhancement using cyclodextrins. This is likely human colon anaerobes was studied by Antenucci et al. [133].It partially due to complicating factors (method of complex form- was found that degradation is well under way in as little as 1–2h, ation, charge of drug during GI transit) and variability in reported and most of the Bacteroides strains studied were shown to parameters (e.g., binding constant). It is also partially due to the degrade the cyclodextrins. Extensive degradation was observed other effects of cyclodextrins in certain dosage forms, such as within 18 h, suggesting that colonic transit time may be adequate decreasing degradation kinetics or inhibiting compound efflux, to cause extensive deterioration of dosed cyclodextrins. The which were not taken into consideration in comparing studies. degradation observed is attributed mainly to cyclomaltodex- However, even in cases where adequate information regarding trinase (CDase), an enzyme that hydrolyzes cyclic dextrins and experimental parameters are supplied and other effects of linear maltodextrins [134,135]. CDase is known to rapidly cyclodextrin in addition to solubilization are not believed to hydrolyze cyclodextrins. Characterization of the influence of play a role, it is difficult to correlate a single parameter to the such degradation on the performance of a controlled-release ability of cyclodextrins to enhance bioavailability. The mechan- dosage form is important for formulation development. isms of bioavailability enhancement using cyclodextrins were therefore discussed to provide further insight. The influence of 5. Conclusions cyclodextrins on the dissolution of drug in the intestinal lumen as well as the absorption of drug, a process proportional to the free A survey of the literature related to use of cyclodextrins for drug concentration in the intestinal lumen, were considered. It is enhancing oral bioavailability was conducted in order to gain evident that the physical and chemical properties of a given drug, understanding of when cyclodextrins can be used for this purpose. cyclodextrin, and dosage form interact to influence kinetics of key The focus of the literature reviewed was on the solubilizing processes of oral drug delivery, including dissolution and capabilities of cyclodextrins and their contribution to bioavail- absorption. These interactions create difficulty in precisely ability enhancement, as is the focus of most literature on the use of specifying one range of values for one parameter (e.g., binding cyclodextrins in oral pharmaceutical formulations. General constant, solubility) that will result in successful bioavailability guidelines were evident from examining the studies, including enhancement using cyclodextrins. A more comprehensive information related to “typical” affect on bioavailability. For theoretical analysis of the influence of cyclodextrins on the example, most studies report successful improvement in bioavail- kinetics of simultaneous processes occurring in the drug delivery ability. Of these studies, the majority report an increase in AUC environment may provide further guidance. between 0 and 100% (1 to 2 times). Most studies (72% of those examined) report a decrease in Tmax of less than 3 h, while the vast Nomenclature 2 majority (98%) report an increase in Cmax, most often to a value A Surface area of dissolving particle, dm less than double that when drug is dosed alone. Regarding the CDtotal Total molar amount of free and bound cyclodextrin, properties of the compounds utilized in these studies, they were moles 2 generally hydrophobic (18 out of 29 studies involved compounds Dcom Complex diffusivity, dm /s 2 with logPN2.5) and poorly soluble (most with a solubility of 1 μg/ Ddrug Drug diffusivity, dm /s ml–1 mg/ml). This is expected, as cyclodextrins enhance overall Dtotal Molar dose of drug, moles absorption by influencing dissolution kinetics. The complex of the K Cyclodextrin complexation constant, M− 1, assuming drug rather than a physical mixture is typically dosed, and in 1:1 binding comparing studies in which both complex and physical mixture So Free drug solubility, M were used, the AUC approximately doubled with the complex V Total volume, L compared to the physical mixture. This phenomenon is related to Vlumen Volume of the intestinal lumen, L the high solubility of most cyclodextrin complexes. Most studies drugabs Moles of drug absorbed, moles involved low doses (b100 mg in 25 out of 29 studies) and low CD: drugf Moles of free drug in solution, moles − 1 drug ratios (more than half with 2:1 or less), with very weak to ka Absorption rate constant, min −1 − 1 moderate binding constants (b5000 M in 33 out of 46 studies kdis Dissolution rate constant, Ms reporting the constant values). Low doses are required for kpre Precipitation rate constant, units depend on specific practical use of cyclodextrins in traditional oral dosage forms kinetics (tablets, capsules). CD:drug ratios are also limited by practical lbl Boundary layer thickness, dm dosage form sizes. Low to moderate CD:drug ratios and binding [drug]f Molar concentration of free drug in solution, M constants are also important as a negative affect of cyclodextrin on [drug]total Total molar concentration of free and bound drug in bioavailability can be related to a high percentage of bound drug solution, M limiting the free drug in solution available for absorption. [com] Molar concentration of complex in solution, M Author's personal copy

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