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Encapsulation of Ibuprofen in CD-MOF and Related Bioavailability Studies Karel J. Hartlieb,† Daniel P. Ferris,† James M. Holcroft,† Irawati Kandela,∥ Charlotte L. Stern,† Majed S. Nassar,⊥ Youssry Y. Botros,‡ and J. Fraser Stoddart*,† †
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States Chemistry of Life Processes Institute, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States ⊥ Joint Center of Excellence in Integrated Nano-Systems (JCIN), King Abdul-Aziz City for Science and Technology (KACST), P.O. Box 6068, Riyadh 11442, Kingdom of Saudia Arabia ‡ PanaceaNano, Inc., 2265 East Foothill Boulevard, Pasadena, California 91107, United States
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∥
S Supporting Information *
ABSTRACT: Although ibuprofen is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs), it exhibits poor solubility in aqueous and physiological environments as a free acid. In order to improve its oral bioavailability and rate of uptake, extensive research into the development of new formulations of ibuprofen has been undertaken, including the use of excipients as well as ibuprofen salts, such as ibuprofen lysinate and ibuprofen, sodium salt. The ultimate goals of these studies are to reduce the time required for maximum uptake of ibuprofen, as this period of time is directly proportional to the rate of onset of analgesic/anti-inflammatory effects, and to increase the half-life of the drug within the body; that is, the duration of action of the effects of the drug. Herein, we present a pharmaceutical cocrystal of ibuprofen and the biocompatible metal−organic framework called CD-MOF. This metal−organic framework (MOF) is based upon γ-cyclodextrin (γ-CD) tori that are coordinated to alkali metal cations (e.g., K+ ions) on both their primary and secondary faces in an alternating manner to form a porous framework built up from (γ-CD)6 cubes. We show that ibuprofen can be incorporated within CD-MOF-1 either by (i) a crystallization process using the potassium salt of ibuprofen as the alkali cation source for production of the MOF or by (ii) absorption and deprotonation of the free-acid, leading to an uptake of 23−26 wt % of ibuprofen within the CD-MOF. In vitro viability studies revealed that the CD-MOF is inherently not affecting the viability of the cells with no IC50 value determined up to a concentration of 100 μM. Bioavailability investigations were conducted on mice, and the ibuprofen/CD-MOF pharmaceutical cocrystal was compared to control samples of the potassium salt of ibuprofen in the presence and absence of γ-CD. From these animal studies, we observed that the ibuprofen/ CD-MOF-1 cocrystal exhibits the same rapid uptake of ibuprofen as the ibuprofen potassium salt control sample with a peak plasma concentration observed within 20 min, and the cocrystal has the added benefit of a 100% longer half-life in blood plasma samples and is intrinsically less hygroscopic than the pure salt form. KEYWORDS: cyclodextrin, drug delivery, ibuprofen, metal−organic framework
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as cyclodextrins.9,10 The macrocyclic nature of cyclodextrins (CDs), which consist of a central lipophilic cavity and a hydrophilic outer surface, in addition to the truncated cone or “bucket” shape of this class of molecules, facilitates the binding and solubilization of hydrophobic guest molecules in hydrophilic media. The ability of CDs to form inclusion complexes with APIs is not only of interest for the development of pharmaceutical formulations of poorly water-soluble drugs in order to improve solubility and bioavailability, but additionally, CDs (i) act as masking agents in oral formulations to disguise
INTRODUCTION The development of new formulations that enhance water solubility and bioavailability of active pharmaceutical ingredients (APIs) is an important area of modern drug delivery technology, given that a large number of highly active potential drug candidates are relatively hydrophobic in nature.1,2 Additionally, oral administration routes are highly preferred as a result of increased patient compliance3 as well as the avoidance of needles/pain and sterile conditions during formulation. Numerous types of oral formulations have been proposed in order to overcome the obstacles related to poor bioavailability of hydrophobic APIs, which include making use of (i) micelles,4 (ii) micro/nanoemulsions,2 (iii) liposomes,5 (iv) dendrimers,6 (v) biodegradable polymer and mesoporous silica nanoparticles,3,7,8 and (vi) water-soluble excipients, such © 2017 American Chemical Society
Received: Revised: Accepted: Published: 1831
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4, 2017 23, 2017 29, 2017 29, 2017 DOI: 10.1021/acs.molpharmaceut.7b00168 Mol. Pharmaceutics 2017, 14, 1831−1839
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Figure 1. (a) Space-filled representation of the solid-state extended structure of CD-MOF-1 (C gray, O red, K purple). (b) (γ-CD)6 cubic unit constructed by coordination of K+ cations (purple spheres) to the primary face of γ-CD with a central pore diameter of approx 1.7 nm. Coordination of K+ cations to the secondary face of the γ-CD tori making up the cubic units results in the formation of the extended porous structure. (c) Structural formula of CD-MOF-1 revealing the coordination of potassium ions on a single γ-CD macrocycle. (d) Structural formula of ibuprofen.
any bitter tastes,11 (ii) increase the drug “shelf life” by protecting the API from various degradation processes,12 (iii) can be used to develop sublingual and orally fast-dispersing/ disintegratable dosing forms,13,14 and (iv) enable liquid and oily APIs to be formulated as a powered product.15 As a result of their many facets, CDs are found in at least 35 pharmaceutical formulations with β-CD used in the majority of these products,16 and furthermore, natural cyclodextrins have been classified as “Generally Recognized as Safe” by the U.S. Food and Drug Administration.17 An alternative formulation strategy for APIs that is currently being pursued takes advantage of the porous nature of metal− organic frameworks (MOFs) and the ease with which the porosity of these materials can be modified. Although MOFs traditionally contained components that may be toxic, newer generations of MOFs have been prepared with biocompatible metals and organic linkers,18−21 wherein the pore size can be tuned to accommodate a wide variety of drug molecules, the metal can be used as an imaging contrast agent22 and the organic linker itself can be transformed20 to the API. Encapsulation within MOFs is not limited to drug delivery applications, with the encapsulation of catalysts23−25 and photosensitizers26 within MOFs to promote specific reactions in confined spaces, and recently, the inclusion27,28 of molecular switches within MOFs, in order to increase the robustness of these systems, also being areas of intense research. Recently, we reported29,30 the syntheses and structures of “green” porous materials produced from γ-CD and alkali metal cations, namely, CD-MOFs (Figure 1a−c). These materials are easily prepared in the laboratory on a large scale from food-grade reagents. This porous structure is based upon six γ-CD tori that are coordinated to alkali metal cations on the primary face in an alternating manner, forming (γ-CD)6 cubes. These cubes are
linked together in three dimensions by coordination of alkali metal cations on the secondary faces of the γ-CD tori, leading to an extended porous superstructure. Previous investigations of this material have shown that CD-MOF (i) is very effective in the sequestration of CO2 as a result of both chemisorption and physisorption processes,31−33 (ii) can incorporate photocatalysts and metal nanoparticles within the framework,34−36 (iii) is amenable to postsynthetic functionalization, leading to the synthesis of gel-like materials,37 and (iv) can be used as a separation medium for the purification of a wide variety of petrochemicals, including benzene, toluene, ethylbenzene, the regioisomers of xylene, and haloaromatic and alicyclic compounds, as well as for the resolution of enantiomers.38,39 CD-MOFs are water-soluble, and given the fact that they are constructed from γ-CD, they may also possess some of the properties that are favorable for the development of oral drug formulations that have been realized with both the naturally occurring and chemically modified cyclodextrins. Additionally, γ-CD can be hydrolyzed by salivary α-amylase,17 whereas αand β-CD are essentially stable to this enzyme but are instead digested by intestinal microflora,9 leading to the possibility that drug formulations based on CD-MOFs could result in rapid dispersal dosing. To probe CD-MOF as a potential candidate for formulation technologies, a recent Monte Carlo simulation study40 of the loading of CD-MOF-1 with the ubiquitous nonsteroidal antiflammatory drug (NSAID) ibuprofen showed that it is possible to incorporate a maximum of 27 wt % of this drug within this porous framework. Ibuprofen (Figure 1d) is a widely available and moderately potent NSAID that has a low systemic toxicity, and, unlike some other NSAIDs, such as aspirin, indomethacin, and piroxicam, it has a relatively low risk of side-effects caused by gastric damage.41 The mode of action of ibuprofen is believed 1832
DOI: 10.1021/acs.molpharmaceut.7b00168 Mol. Pharmaceutics 2017, 14, 1831−1839
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Figure 2. 1H NMR spectrum (500 MHz, D2O, 298 K) of CD-MOF-1 crystallized in the presence of the potassium salt of ibuprofen. Integration of the signals corresponding to the anomeric protons of γ-CD and the protons of ibuprofen reveal the presence of a 2:1 ratio of ibuprofen: γ-CD. Signals at 1.19 and 2.23 ppm correspond to residual EtOH and Me2CO, respectively.
pharmacokinetics, against control samples containing the potassium salt of ibuprofen, by measuring the concentration of ibuprofen found in blood plasma samples over time. It was found that oral administration of the CD-MOF-1-based cocrystal results in the same rapid uptake of ibuprofen that is typically found for ibuprofen salts; yet the CD-MOF-1-based cocrystal results in a statistically significant increase (over 2fold) of the half-life of ibuprofen in blood plasma. These results suggest that the CD-MOF-1/ibuprofen cocrystal may be suitable for dosings that require both rapid and sustained pain relief. In addition, the preparation of the CD-MOF-1based pharmaceutical cocrystals by absorption of the free-acid of ibuprofen into the framework is less intensive than production of pure ibuprofen salts. Also, the CD-MOF-1based cocrystal does not appear to be as susceptible to atmospheric moisture as the potassium salt of ibuprofen, which is one of the reasons why this ibuprofen derivative has yet to be used in commercial formulations in the form of a tablet, yet it is available in the form of a liquid-filled gelatin capsule. The potassium salt of ibuprofen, unlike the free-acid form, is soluble in water, and the enhanced solubility of this salt and others, such as the lysinate and sodium salts, is known to increase the rate of uptake of ibuprofen compared to the free-acid, which generally reaches peak blood plasma concentration after 1.5−2 h.54
to be through inhibition of the cyclo-oxygenase (COX) enzymes, particularly the COX-2 enzyme,41 which is localized mainly in inflammatory cells and tissues. Ibuprofen has not only been considered for acute pain relief, but it has also been used to treat chronic inflammatory and degenerative diseases42 and is also under consideration for treating a variety of cancers.43,44 It has even been shown to extend the lifespans of yeast, worms, and flies.45 This API has also been entrapped in a variety of MOFs, including UiO-66 that had been modified with a variety of functional groups resulting46 in loading ranges from 13 to 36 wt %, MIL-101(Cr) and 10% NH2-MIL-101(Cr) with loadings47 of 46 and 47 wt %, respectively, MIL-53(Cr) and MIL-53(Fe) that show48 loading capacities of around 20 wt %, and MIL-100 and MIL-101 with ibuprofen loadings19 of 26 and 58 wt %, respectively. Very few investigations, however, have considered the use22,49−53 of MOFs in vivo, as a consequence of the toxic nature of the transition metal ions and/or the organic linkers. The investigations that have probed in vivo activity have focused mainly on intravenous, rather than oral, dosing as a result of the poor water solubility of the MOFs that were used. Herein, we discuss the loading of ibuprofen within CDMOF-1 using two protocols, cocrystallization and absorption, and show that it is experimentally possible to achieve loadings that match the theoretically calculated capacity. Additionally, we performed IC50 cell viability studies on CD-MOF and ibuprofen and found these materials to be nontoxic up to a concentration of 100 μM. The pharmaceutical cocrystal was tested on mice in order to assess the oral bioavailability and 1833
DOI: 10.1021/acs.molpharmaceut.7b00168 Mol. Pharmaceutics 2017, 14, 1831−1839
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Figure 3. (a) Powder X-ray diffraction of freshly prepared CD-MOF-1 formulations of ibuprofen prepared by cocrystallization from the potassium salt of ibuprofen and absorption of the free-acid form of ibuprofen within preexisting CD-MOF-1, compared to the predicted R32 and I432 diffraction patterns of CD-MOF-1. The pattern of ibuprofen is shown to confirm that no free ibuprofen exists within any of the pharmaceutical cocrystals. (b) PXRD patterns of CD-MOF-1/ibuprofen formulations after storage in ambient conditions for three months revealing that these samples retain their crystallinity over time.
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RESULTS AND DISCUSSION Ibuprofen can be incorporated into CD-MOF-1 using two methods. They are (i) crystallization of the CD-MOF-1 with the potassium salt of ibuprofen as the source of alkali metal cations required to form the framework, with charge balance achieved by the incorporation of ibuprofen anions and (ii) absorption of the free-acid form of ibuprofen into CD-MOF-1. The first method is identical in principle to the synthesis of edible CD-MOF-1 using potassium benzoate and making use of EtOH vapor diffusion into the aqueous solution in order to generate appropriate conditions for crystallization. In this case, two ibuprofen anions are expected to be present per γ-CD ring: this molar ratio is confirmed to be the case by using 1H NMR (Figure 2) and comparing the integration of the signals corresponding to the anomeric proton of γ-CD to the signals arising from ibuprofen. This loading level equates to 23 wt % of ibuprofen within CD-MOF-1. Furthermore, powder X-ray diffraction (PXRD, Figure 3) confirmed that the sample crystallized by diffusion of EtOH vapor into an aqueous solution of γ-CD and the potassium salt of ibuprofen is indeed CD-MOF-1. It is important to note that this sample crystallizes in the I432 space group, a situation that is usually observed for samples prepared from alkali metal hydroxides, rather than the R32 space group that is observed when potassium benzoate is used29,30 as the alkali metal source with EtOH vapor diffusion. Although large single crystals suitable for analysis by singlecrystal X-ray diffraction were readily obtained, the ibuprofen anions could not be located within the porous framework as a result of a large amount of disorder within the porous structure, which has previously been observed in the case of CD-MOFs grown with guest organic anions within the framework.30
The second approach relies on the crystallization of CDMOF-1 using potassium hydroxide as the alkali metal source. For the purposes of preparing a pharmaceutical cocrystal, EtOH, rather than MeOH, was used to generate the conditions required for crystallization. After washing the prepared CDMOF crystals with EtOH and drying them under high vacuum at room temperature overnight, the crystals were suspended in a range of different solvents containing ibuprofen in the free acid form, and this solution was left to equilibrate for 5 days. The loading of ibuprofen within CD-MOF-1 was determined by dissolution of the crystals in a 50% v/v H2O/EtOH solution followed by analysis using UV−vis absorption spectroscopy. It was found that the solvent used during the absorption process is critical in controlling the amount of ibuprofen that is taken up by CD-MOF-1. When relatively nonpolar solvents are used, the uptake of ibuprofen within CD-MOF-1 is low, approximately 5 wt % ibuprofen is loaded within the MOF using hexanes and CH2Cl2. When EtOH is used as the solvent during absorption, however, the loading of ibuprofen within CDMOF-1 increases substantially to 26 wt %, very close to what is predicted40 by Monte Carlo simulations to be the maximum loading capacity of ibuprofen within the MOF. Given that maximum loading of ibuprofen within CD-MOF-1 is achieved in the presence of more polar solvents, it is highly likely that the mechanism of loading is associated with an anion exchange process, wherein the free acid of ibuprofen is deprotonated by the hydroxyl anions present in CD-MOF-1, and this newly formed anion now acts to balance the positive charge of the framework. Further evidence of this loading process is seen when loading is attempted on CD-MOF-1 that has undergone prior anion exchange with HCl, or CD-MOF-1 that has been 1834
DOI: 10.1021/acs.molpharmaceut.7b00168 Mol. Pharmaceutics 2017, 14, 1831−1839
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Figure 4. IC50 studies of ibuprofen and CD-MOF-1 on the viability of (a) MCF-10A and (b) MDA-MB-231 cell lines. For both samples tested, no IC50 value could be determined up to a concentration of 100 μM.
that the framework preferentially absorbs the (R)-(−)-enantiomer in an enantiomeric excess of ∼58%. Although this framework does not preferentially absorb the pharmaceutically active enantiomer, this result indicates that the MOF could be used to readily separate enantiomers, not only of ibuprofen, but of other drugs where it is critical that only one enantiomer is administered to a patient, i.e., naproxen. It can also be inferred that the anion exchange process is not enantioselective, and the nature of the counteranion within CD-MOF is an important factor when considering applications of this framework. Viability studies (Figure 4) of both CD-MOF-1 and ibuprofen were carried out in vitro on two cell lines: MCF10A (human mammary epithelial cells) and MDA-MB-231 (human breast adenocarcinoma). In the case of both cell lines, no IC50 value could be obtained for CD-MOF-1 and ibuprofen up to concentrations of 100 μM. Therefore, we can conclude that CD-MOF-1 does not appear to be toxic, and formulations including CD-MOF-1 should be safe for use in animal studies. Animal studies were conducted on 25 g female CD-1 IGS mice (Crl:CD1(ICR)), and the pharmaceutical mixtures and cocrystals were administered at a dose of 75 mg/kg ibuprofen by oral gavage using a suspension in vegetable oil. Three mice per time point for each mixture or cocrystal were euthanized, and blood samples were collected after 10, 20, 30, 45, 60, 90, 120, and 240 min, which were then centrifuged at 1500 rpm for 10 min at 4 °C to obtain plasma. Blood plasma samples were stored at −80 °C for transport for analysis by LC/MS. Three mixtures or cocrystals of ibuprofen were tested: the potassium salt of ibuprofen and a physical mixture of 23 wt % ibuprofen, potassium salt with γ-CD (which is analogous to a stoichiometric loading of ibuprofen within CD-MOF-1 created by cocrystallization) were used as control samples, and the third sample consisted of bulk CD-MOF-1 loaded with 26 wt % ibuprofen by the absorption protocol. The potassium salt of ibuprofen was considered to be the most appropriate control for ibuprofen in this study, as the results of the solventdependent absorption loading of ibuprofen suggest that an anion exchange process is occurring within CD-MOF-1, i.e., deprotonation of the free-acid form of ibuprofen, which is facilitated by water-miscible polar solvents. In fact, this method of generating the potassium salt of ibuprofen is very simple and
grown from KCl (see Supporting Information, Figure S2), which reveals less than one percent by weight loading of ibuprofen in EtOH. When loading of ibuprofen into CD-MOF1, where Cl− is the counteranion for the framework (henceforth referred to as CD-MOF-1-Cl), is undertaken in hexane, rather than EtOH, a loading of 11−15 wt % is achieved. When the framework is dissolved in H2O, a fine white precipitate is observed, indicative of the presence of the free acid of ibuprofen; however, exposure of the framework to a 50% mixture of EtOH and H2O results in complete dissolution of both CD-MOF-1 and ibuprofen. In both of the loading scenarios that were tested, a racemic mixture of ibuprofen was used. Although the (S)-(+)-enantiomer of ibuprofen is the pharmaceutically active isomer, the (R)-(−)-enantiomer is not toxic, unlike other NSAIDs, such as naproxen, and, moreover, it can be metabolized in such a manner that it undergoes unidirectional chiral inversion to the (S)-(+)-enantiomer.55 Since we have previously shown39 that CD-MOF has the ability to resolve enantiomers using HPLC techniques, it was our hope that it might be possible to crystallize or absorb the pharmaceutically active enantiomer selectively within CD-MOF-1. Enantioselective absorption has also been simulated56 to take place within the chiral framework HMOF-1. Circular dichroism experiments, however, show no enantioselectivity upon uptake of a racemic mixture of ibuprofen within CD-MOF-1 using the loading conditions described previously in EtOH where the ibuprofen anion is formed. It is possible, however, to crystallize and absorb the pure enantiomers into the CD-MOF, which gives similar loading results as the racemic mixture of ibuprofen. The use of the (S)-(+)-enantiomer for commercial formulations has not been seen to be necessary as (i) a result of the low toxicity of the (R)-(−)-enantiomer, (ii) the inversion of the (R)(−)-enantiomer to the pharmaceutically active enantiomer, and (iii) the additional cost associated with the resolution of enantiomers, either by separation or enantioselective synthesis. Enantioselective uptake of ibuprofen is observed within CDMOF-1-Cl where the loading experiments were performed in hexane. Circular dichroism studies (see Supporting Information, Figure S3) on the mixtures created upon dissolution of CD-MOF-1-Cl/ibuprofen cocrystals in 50% H2O/EtOH reveal 1835
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a statistically significant difference in the maximum concentration of ibuprofen. This observation would tend to suggest that γ-CD, or the byproducts of γ-CD hydrolysis, acts as an excipient for the absorption of ibuprofen, most likely by enhancing the solubility of ibuprofen after protonation in the digestive tract to the free-acid form. A large standard deviation for ibuprofen concentration in blood plasma is observed for this particular control sample, suggesting that preparation of this mixture may play a large role on its performance. The plasma concentration data from the CD-MOF-1-based cocrystal has less variance, indicating that this sample may be a more reliable means of delivery of ibuprofen. The half-lives of the mixtures or cocrystals containing γ-CD, as either the free molecule or as part of CD-MOF-1, are statistically significantly longer than the potassium salt of ibuprofen alone. This difference leads to the interesting prospect of the development of a rapid acting formulation of ibuprofen that is also effective for long periods of time. Although the AUC0‑t and AUC0‑∞ values for the samples containing γ-CD are higher than those for the pure potassium salt of ibuprofen, which would indicate greater bioavailability of ibuprofen in the formulations containing γ-CD (either as a free molecule or CD-MOF-1), they are not statistically significant (P = 0.05) in this study. Salts of ibuprofen are used in commercially available formulations, including the lysinate, arginate, and sodium salts. These derivatives are typically more expensive than the free-acid form of ibuprofen, particularly the amino acid derivatives, but these derivatives all show faster rates of uptake than the free-acid form. The potassium salt is only used in liquid-filled gelatin capsules as a solution to the very hygroscopic nature of the potassium salt. Incorporation of the ibuprofen anion within CD-MOF-1 provides an alternative method for preparing rapidly bioavailable versions of ibuprofen, and given that it uses renewable and inexpensive ingredients, it may be more cost-effective than the currently available means of delivery. Additionally, CD-MOF-1 could be used as a fastdispersing pharmaceutical cocrystal since γ-CD can be hydrolyzed by salivary α-amylase, which is another potential advantage over current liquid filled capsules. Apart from the need for further pharmacological testing, particularly comparisons to commercially available formulations, other considerations regarding the use of CD-MOF-1/ibuprofen cocrystals for oral dosages include the compactability of the formulation in order to be able to produce suitable tablets as well as the presence of potassium ions, which could lead to hyperkalemia. Conversely, very high doses of ibuprofen can lead to hypokalemia,58 in which case the presence of potassium ions may be beneficial. Previous work has suggested that it is possible to prepare CD-MOFs from sodium salts,30 particularly sodium carbonate, which upon crystallization with γ-CD and MeOH produces crystals with similar unit cell dimensions in the I432 space group. On-going development of CD-MOF as a formulation technology, created using either sodium or
results in a cocrystal that is stable under atmospheric conditions, unlike the potassium salt of ibuprofen alone, which is very hygroscopic, inhibiting tabletability. It is used, however, in rapid release gelatin capsules. After storage under ambient conditions for several months, the CD-MOF-1 cocrystal shows no signs of hygroscopicity, and the crystallinity of the porous extended framework is maintained; however, the intensities of the X-ray signals are rather different. Although the pharmaceutical cocrystals show no visible signs of degradation from ambient humidity, it is possible that the change in X-ray intensities observed in the PXRD data are a result of interaction of the CD-MOF with water vapor.
Figure 5. Pharmacokinetic data (n = 3) for the three ibuprofen formulations tested in mice (25 g, 75 mg/kg) administered by oral gavage of a suspension of the formulation in vegetable oil (200 μL).
Pharmacokinetic data are shown in Figure 5 and Table 1. The Microsoft Excel Add-in, PKSolver,57 was used to determine the pharmacokinetic parameters Cmax, Tmax, AUC0‑t, AUC0‑∞ (area under the curve until the last time point and infinity, respectively), and the half-life (t1/2), and results are reported as mean ± standard deviation. One-way analysis of variance was carried out to evaluate the difference of the pharmacokinetic parameters between different samples, followed by a Tukey’s multiple comparison test in order to determine which means are statistically significantly different (P = 0.05). The maximum concentration of ibuprofen in plasma samples for all three samples is reached rapidly, between 10−20 min, which is ideal for analgesic drugs as this time interval corresponds to a rapid onset of pain/inflammation relief. Unexpectedly, the control sample, consisting of a physical mixture of 23 wt % ibuprofen, potassium salt with γ-CD, shows
Table 1. Pharmacokinetic Data for Ibuprofen Formulations Following Oral Administration to Mice formulation
Cmax (μg/mL)
tmax (h)
AUC0−4h (μg·h/mL)
AUC0−∞ (μg·h/mL)
t1/2 (h)
IBU K salt IBU K salt (23 wt %)/γ-CD CD-MOF/IBU (26 wt %)
108.3 ± 4.6 224.2 ± 45.7a 93.6 ± 12.5
0.28 ± 0.19 0.17 0.28 ± 0.19
144.0 ± 28.2 273.6 ± 71.1 193.4 ± 27.5
158.8 ± 37.1 335.7 ± 122.5 290.7 ± 76.3
1.07 ± 0.29 1.46 ± 0.48b 2.35 ± 0.68b
a
Statistically significant difference (P = 0.05) in Cmax from other two formulations. bStatistically significant difference (P = 0.05) in t1/2 from formulation of pure ibuprofen, potassium salt. 1836
DOI: 10.1021/acs.molpharmaceut.7b00168 Mol. Pharmaceutics 2017, 14, 1831−1839
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Notes
CONCLUSIONS We have shown that the NSAID ibuprofen can be incorporated within the porous architecture of CD-MOF-1 in pharmaceutically relevant quantities. Although MOFs have been frequently discussed as potential drug-delivery vehicles, very few instances of in vivo studies involving MOFs have been reported to date. In this instance, CD-MOF-1 is a nontoxic, biocompatible MOF, and as a result of its assembly employing well-tolerated alkali cations, as opposed to transition metals, it is able to incorporate pharmaceutically active anions readily within its extended structure. Pharmacokinetic data reveal that, following oral administration, CD-MOF-1 cocrystals of the potassium salt of ibuprofen exhibit similar bioavailability and rapid uptake in blood plasma as the pure potassium salt of ibuprofen. The samples that include the presence of γ-CD, however, show a statistically significant increase in the half-life of ibuprofen when compared to the ibuprofen salt alone. These results suggests that CD-MOF-1 is effective as a delivery vehicle for NSAIDs that could result in quick pain relief and extended duration of the analgesic effect. Furthermore, the ease of creating this CDMOF-1-based cocrystal, by absorption of the free-acid of ibuprofen directly within the framework, resulting in a stable powder of the potassium salt, could be advantageous for creating salts of other acid forms of NSAIDs such as naproxen, as well as other drug molecules that are prone to limited salt form tabletability. Given that CD-MOF-1 is assembled from γCD, it is expected that drug formulations based on CD-MOF-1 will (i) exhibit the same advantages that have been reported when using free cyclodextrins, as well as (ii) enhancing the bioavailability of a wide range of poorly water-soluble drugs and (iii) may even be used to generated solid formulations of liquid and oily APIs. The metabolism and pharmacokinetics of ibuprofen across different species are known59 to differ. It is clear that, given the promising results obtained for CD-MOF-1based ibuprofen pharmaceutical cocrystals in mice, further studies focused on a broader range of CD-MOF and API combinations using significantly larger data sets and different species, eventually including humans, appear to be warranted.
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The authors declare the following competing financial interest(s): Y.Y.B. and J.F.S. have a financial interest in the start-up company PanaceaNano, which is seeking to commercialize CD-MOF.
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ACKNOWLEDGMENTS This research is part of the Joint Center of Excellence in Integrated Nano-Systems (JCIN) at King Abdulaziz City for Science and Technology (KACST) and Northwestern University (NU). The authors would like to thank both KACST and NU for their continued support of this research. This work was supported by the services of the Developmental Therapeutics Core (DTC) of NU. DTC is supported by Cancer Center Support Grant P30 CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the Northwestern University Keck Biophysics Facility.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.7b00168. Materials and general methods, preparation of pharmaceutical cocrystals, cell studies, pharmacokinetic studies, optical micrographs, PXRD patterns, and circular dichroism studies (PDF) CD-MOF-1 (CIF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
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[email protected]. ORCID
Karel J. Hartlieb: 0000-0003-0160-0561 J. Fraser Stoddart: 0000-0003-3161-3697 1837
DOI: 10.1021/acs.molpharmaceut.7b00168 Mol. Pharmaceutics 2017, 14, 1831−1839
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