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Striking the Optimal Solubility−Permeability Balance in Oral Formulation Development for Lipophilic Drugs: Maximizing Carbamazepine Blood Levels Avital Beig,§ Jonathan M. Miller,‡ David Lindley,‡ and Arik Dahan*,§ §

Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel ‡ AbbVie Incorporation, 1 North Waukegan Road, North Chicago, Illinois 60064, United States ABSTRACT: The purpose of this research was to investigate the performance of cosolvent based solubility-enabling formulations in oral delivery of lipophilic drugs, accounting for the gastrointestinal tract (GIT) luminal solubilization processes, the solubility−permeability interplay, and the overall in vivo systemic absorption. The poorly soluble antiepileptic agent carbamazepine was formulated in three cosolvent-based formulations: 20%, 60%, and 100% PEG-400, and the apparent solubility and rat permeability of the drug in these formulations were evaluated. The performance of the formulations in the dynamic GIT environment was assessed utilizing the biorelevant pH-dilution method. Then, the overall in vivo drug exposure was investigated following oral administration to rats. The three formulations showed dramatic solubility and permeability differences; the 100% PEG-400 provided the highest solubility enhancement and the 20% the poorest, while the exact opposite was evident from the permeability point of view. The dissolution results indicated that the 20% PEG-400 formulation crashes quickly following oral administration, but both the 60% and the 100% PEG-400 formulations allowed full solubilization of the dose throughout the entire GIT-like journey. The best in vivo performing formulation was the 60% PEG-400 (Fsys > 90%), followed by the 100% PEG-400 (Fsys = 76%), and the 20% PEG-400 formulation (Fsys ≈ 60%). In conclusion, this work demonstrates the in vivo solubility−permeability trade-off in oral delivery of lipophilic drugs; when a solubility-enabling formulation is developed, minimal threshold solubility should be targeted, that is just enough to allow solubilization of the drug dose throughout the GIT, while excess solubilizer should be avoided. KEYWORDS: BCS class II compounds, drug absorption, intestinal permeability, low solubility, oral drug delivery, solubility-enabling formulations, solubility−permeability interplay

1. INTRODUCTION Low aqueous solubility is a major challenge in today’s biopharmaceutics. Solubility-enabling formulations are frequently applied to tackle this problem, utilizing a variety of techniques. While the apparent solubility of the drug may be significantly enhanced by these formulations, we have recently discovered that this advantage comes with a price tag: a concomitant apparent permeability decrease may accompany the solubility increase.1 This solubility−permeability trade-off was evident for cyclodextrin-,2−4 surfactant-,5−7 and cosolventbased formulations.8,9 Since the solubility and the permeability are the two key factors dictating together oral drug absorption,10−13 increasing one on the expense of the other may not always be beneficial, and it is the balance between them that should be accounted for. This may explain why sometimes solubility-enabling formulations fail to improve the overall absorption of the drug despite a significant solubility increase. © XXXX American Chemical Society

In addition to the solubility−permeability trade-off, solubility-enabling formulations may fail to improve the overall absorption in cases where they do not perform well in the dynamic gastrointestinal tract (GIT) environment. The physiologically relevant pH-changes along the GIT, the relevant in vivo fluid volumes/dilution and composition, the residence times that the dosage form experiences throughout the GIT transit; in such a dynamic environment, a successful formulation will encourage solution mediated phase transformation, which results in supersaturation, but the nonsoluble drug formulated in a solubility-enabling formulation may also undergo an undesired precipitation that will lead to a failure.14−17 Biorelevant in vitro dissolution methods have Received: Revised: Accepted: Published: A

October 26, 2016 November 29, 2016 December 8, 2016 December 8, 2016 DOI: 10.1021/acs.molpharmaceut.6b00967 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Molecular Pharmaceutics

Figure 1. Illustration of the in vitro pH-dilution model, designed to mimic the dissolution of the tested drug/formulation throughout the GIT transit.

been pursued in recent years, showing some success.18−22 Gu et al. proposed a dissolution system that includes a “gastric” compartment, an “intestinal” compartment, and an “absorption” compartment, to mimic the GIT.23,24 Carino et al. successfully utilized the artificial stomach-duodenum model to simulate fasted state dog GIT.25−28 For lipid-based formulations, the dynamic lipolysis model has been shown to be useful in predicting in vivo performance.29−32 The purpose of this research was to investigate the performance of cosolvent based solubility-enabling formulations, accounting for the luminal solubilization processes throughout the GIT, the solubility−permeability interplay, and the overall in vivo systemic absorption. We have formulated the poorly soluble antiepileptic drug carbamazepine in three cosolvent-based formulations: 20%, 60%, and 100% PEG-400, evaluated the apparent solubility and permeability from these formulations, utilized the biorelevant pH-dilution method to assess the performance of the formulations in the dynamic GIT environment,33 and investigated the overall in vivo drug exposure allowed by these formulations following oral administration to rats. This unique setup allowed us to assess the performance of the different formulations in every individual step of the absorption cascade, and to estimate their relative contribution to the overall bioavailability.

Supernatant was carefully withdrawn and immediately assayed for drug content by UPLC. 2.3. Permeability Experiments. Carbamazepine in vivo effective permeability from different PEG-400 formulations (0− 30% w/w) was assessed in the single-pass intestinal perfusion (SPIP) model. A correlation describing the relationship between the PEG-400 level in the formulation and the effective rat permeability was developed,8 and this model was then used to estimate the intestinal permeability from higher PEG-400 content formulations (up to 100%) since running the experiment under high PEG-400 content may alter the intestinal tissue fluidity and integrity. SPIP studies were conducted using protocol approved by the Ben-Gurion University of the Negev Animal Use and Care Committee (Protocol IL-08-01-2015). Male Wistar rats weighing ∼300 g (Harlan, Israel) were housed and handled according to the BenGurion University of the Negev Unit for Laboratory Animal Medicine Guidelines. The experimental method followed previous reports.35,36 Briefly, anesthetized animals were placed on a 37 °C surface (Harvard Apparatus, Holliston, MA), a 10 cm jejunal segment was carefully cannulated on two ends and was flushed with blank 10 mM MES buffer (pH 6.5) to clean out any intestinal content. Then, the jejunal segment was perfused (12-channel Watson-Marlow 205S, Wilmington, MA) at a flow rate of 0.2 mL/min for 2 h with the different carbamazepine formulations.37,38 Outlet samples were collected every 10 min, and immediately assayed for drug content by UPLC. The effective permeability (Peff) through the rat jejunum in the single-pass intestinal perfusion studies was determined by the following equation:

2. MATERIALS AND METHODS 2.1. Materials. Carbamazepine, polyethylene glycol 400 (PEG-400), phenol red, MES buffer, and trifluoroacetic acid (TFA) were purchased from Sigma Chemical Co. (St. Louis, MO). KCl and NaCl were obtained from Fisher Scientific Inc. (Pittsburgh, PA). Acetonitrile and water (Merck KGaA, Darmstadt, Germany) were UPLC grade. All other chemicals were of analytical reagent grade. 2.2. Solubility Studies. Carbamazepine solubility in the three solubility-enabling formulations (20%, 60%, and 100% w/ w PEG-400/MES buffer) was measured at 37 °C, using a previously described method.34 PEG-400 solutions were added to glass vials containing excess amounts of carbamazepine. The vials were tightly closed and placed in a shaking water bath at 37 °C and 100 rpm. Establishment of equilibrium was assured by comparison of samples after 24 and 48 h. Before sampling, the vials were centrifuged at 10,000 rpm for 10 min.

Peff =

′ /C in′ ) −Q ln(Cout 2πRL

where Q is the perfusion flow rate (0.2 mL/min), C′out/C′in is the ratio of carbamazepine outlet vs inlet concentrations after water flux adjustment using the gravimetric method,39 R is the jejunal radius (set at 0.2 cm), and L is the exact length of the perfused jejunal segment as was accurately measured at the end-point of the experiment. 2.4. In Vitro pH-Dilution Experiments. To assess the performance of the formulations in the dynamic GIT environment, the biorelevant pH-dilution method was used,33 B

DOI: 10.1021/acs.molpharmaceut.6b00967 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Figure 2. Apparent solubility of carbamazepine as a function of PEG-400 level at 37 °C. n = 4 in each experimental group.

Carbamazepine dose (25 mg/kg) was dissolved in the different PEG-400 based formulations (2 mL) for the oral PK study. The formulations were freshly prepared 30 min prior to the PK experiment. Blood samples (400 μL) were collected via the jugular vein cannula at 0, 30, 60, 90, 120, 150, 180, 240, 360, and 480 min postdosing. Blood samples were immediately centrifuged and plasma was collected and stored at −70 °C until UPLC analysis. Plasma concentrations versus time curves for carbamazepine in individual rats were analyzed using WinNonlin Professional software (Certara, St. Louis, MO) by means of the noncompartmental analysis model. The systemic bioavailability of carbamazepine was calculated from the ratio of the AUCs normalized by dose after oral and intravenous administration. 2.6. Ultra-Performance Liquid Chromatography (UPLC). Carbamazepine content in the different samples was analyzed on a Waters (Milford, MA) Acquity UPLC H-Class system equipped with PDA detector and controlled by Empower software, using a method we have previously reported.43 Briefly, separation was achieved on a Waters (Milford, MA) Acquity UPLC BEH C18 1.7 μm 2.1 × 100 mm column, with a gradient mobile phase consisting of 60:40 going to 40:60 (v/v) water−acetonitrile at a flow rate of 0.5 mL/min. The total run time was 6 min. 2.7. Statistical Analysis. Solubility and pH-dilution studies were n = 4, in vivo permeability (SPIP) studies were n = 5, and in vivo bioavailability experiments in rats were n = 6. Values are expressed as means ± standard deviation (SD). To determine statistically significant differences among the experimental groups, the nonparametric Kruskal−Wallis test was used for multiple comparisons and the two-tailed nonparametric Mann−Whitney U-test for two-group comparison when appropriate; p < 0.05 was termed significant.

which investigates the drug dissolution from a given formulation while traveling along the GIT. The drug dose in the different formulations (150 μL) was first diluted into 1 × 10−4 M HCl (pH 4.0 solution) at a dilution factor of 1:0.5. The sample vial was agitated (100 rpm) using orbital shaker at 37 °C for 0.25 h. The vial was then further diluted with FaSSIF at a dilution factor of 1:0.9 and continued to be agitated for another 0.2 h. Further FaSSIF dilutions were carried out to mimic the small-intestinal environment, first with a dilution factor of 1:4.8 (agitation time: 2 h), and then 1:1.9 for 4.5 h (Figure 1). Throughout the experiment 50 μL samples were taken, ultracentrifuged at ∼150 000g, diluted with UPLC diluent, and injected into UPLC for determination of drug concentration. Comparison of solubilized drug and total drug content provides the insight into the solubilization performance of the formulations in the GIT. 2.5. In Vivo Bioavailability Studies in Rats. The pharmacokinetics of carbamazepine following single oral dose of the different formulations was studied in rats using protocol approved by the Ben-Gurion University of the Negev Animal Use and Care Committee (Protocol IL-07-01-2015). Male Wistar rats weighing ∼300 g (Harlan, Israel) were housed and handled according to the Ben-Gurion University of the Negev Unit for Laboratory Animal Medicine Guidelines. Prior to each experiment, the rats were fasted overnight (12 h) with free access to water. One day before to the PK study, a cannula was placed in the right jugular vein of the rats for easy blood withdrawal. The animals were anesthetized for the period of surgery by i.m. injection of 1 mL/kg of ketamine−xylazine solution (9%/1%, respectively) and placed on a 37 °C surface (Harvard Apparatus Inc., Holliston, MA). An indwelling cannula was placed in the right jugular vein of each animal for systemic blood sampling, by a previously described method.29,40−42 The cannula was tunneled underneath the skin and exteriorized at the back of the neck. After the surgery, animals were housed in metabolic cages to recover overnight (12 h). During this recovery period and throughout the experiment, food, but not water, was deprived.

3. RESULTS 3.1. Solubility. The apparent solubility of carbamazepine as a function of PEG-400 level is presented in Figure 2. It can be seen that PEG-400 significantly increases carbamazepine solubility in a concentration-dependent manner; increasing C


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Figure 3. In vivo rat intestinal permeability of carbamazepine from solutions consisting of increasing amounts of PEG-400. Black circles, experimental data (n = 5); open circles, predicted values.

Figure 4. Illustration of the solubility−permeability interplay that exists when using the cosolvent PEG-400 in solubility-enabling drug delivery systems.

amounts of PEG-400 resulted in continuing intense increase in carbamazepine apparent solubility, from 280 μg/mL without cosolvent up to more than 40 mg/mL (∼160-fold) in 100% PEG-400. 3.2. Permeability. The in vivo rat intestinal permeability of carbamazepine from solutions consisting of increasing amounts of PEG-400 is presented in Figure 3. It can be seen that the drug’s apparent permeability profoundly decrease as a function of PEG-400 level, with >10-fold decrease between the permeability in the absence of cosolvent to the permeability in the presence of 30% PEG-400. The theoretical dashed line in Figure 3 describes the relationship between PEG-400 level and the apparent permeability of carbamazepine, allowing to

estimate the drug’s permeability in PEG-400 levels beyond those investigated experimentally (white circles). 3.3. Solubility−Permeability Interplay. Figure 4 illustrates the solubility−permeability interplay that exists when using the cosolvent PEG-400. While significant solubility increase can certainly be achieved using cosolvent-based formulation, a concomitant permeability decrease accompanies the solubility increase resulting in the illustrated solubility− permeability trade-off (Figure 4). Specifically for the three PEG-400-based formulation investigated in this work, the solubility (left panel) vs the permeability (right panel) of carbamazepine from 20%, 60%, and 100% PEG-400 formulation is presented in Figure 5. The dramatic difference D


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Figure 5. Solubility (left panel; n = 4) vs the permeability (right panel; n = 5) of carbamazepine from the three PEG-400-based formulations (20%, 60%, and 100%) investigated in this work.

Figure 6. Ability of the three PEG-400 formulations to achieve and maintain complete dissolution of the carbamazepine dose in the dynamic GIT environment, using the pH-dilution method illustrated in Figure 1. Red circles, total drug concentration; black circles, solubilized drug concentration; n = 4.

400 formulations allowed full solubilization of the carbamazepine dose throughout the entire GIT-like journey. 3.5. Bioavailability Studies. The carbamazepine concentration−time plasma profiles following oral administration of the three PEG-400 based formulations are presented in Figure 7, and the resulted pharmacokinetic parameters are summarized in Table 1. The three PEG-400 based formulations resulted in significantly different systemic bioavailability of carbamazepine; the 20% PEG-400 formulation allowed good initial drug concentration followed by decreasing plasma levels (tmax = 30 min), while the other two formulations, the 100% and the 60% PEG-400, were able to deliver continuing blood drug concentrations, with tmax = 90 min and tmax = 120 min, respectively. Overall, the best performing formulation was the 60% PEG-400 formulation (Fsys > 90%), followed by the 100% PEG-400 (Fsys = 76%), and the lowest absorption (Fsys ∼ 60%) was delivered by the 20% PEG-400 formulation.

between these three solubility-enabling formulations, which is the reason we chose to study them, can be easily seen; while the 100% PEG-400 provides the highest solubility enhancement and the 20% the poorest, the exact opposite is evident from the permeability point of view. The immediate question that Figure 5 brings to mind is which of these three formulations will deliver the highest in vivo drug exposure following oral administration? 3.4. Biorelevant Dissolution. Ultimately, a successful solubility-enabling formulation should allow dissolution of the drug dose throughout its travel along the gastrointestinal tract (GIT). Hence, we have studied the ability of the three PEG-400 formulations to achieve and maintain complete dissolution of the carbamazepine dose in the dynamic GIT environment, using the pH-dilution method illustrated in Figure 1. The results of these studies are presented in Figure 6; while the 20% PEG-400 formulation crashed very quickly following exposure to media mimicking the GIT as evident from the rapid gap between the drug in solution vs the total drug load (left panel), both the 60% (middle panel) and the 100% (right panel) PEGE


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Figure 7. Carbamazepine concentration−time plasma profiles following oral administration of the three PEG-400 based formulations to rats. Average ± SD; n = 6.

trins,44 surfactants,6 hydrotropy,45 and cosolvents.46 This tradeoff is illustrated in Figure 4 that connects the increased carbamazepine apparent solubility (as the PEG-400 level increases) to the decreased intestinal permeability of the drug. We explain this interplay via the mathematical definition of drug permeation (P): P = DK/h, in which the drugs’ permeability is equal to its diffusivity through the membrane (D) times its membrane/aqueous partition coefficient (K) divided by the membrane thickness (h). The drugs’ partition coefficient (K) is governed by the equilibrium aqueous solubility of the drug, and since these solubilization techniques modify the drugs’ equilibrium solubility, they concomitantly decrease its partitioning and permeation. Naturally, solubilityenabling formulations are used for low-solubility, BCS class II/ IV compounds. When the starting (intrinsic) permeability of the drug is very high, as common for BCS class II compounds, it may be advisable to “sacrifice” some permeability in order to gain solubility. However, care must be taken not to lose excess of permeability by incorporating unnecessary amounts of solubilizer into the formulation; focusing merely on the solubility may lead to the wrong conclusion that the 100% PEG-400 formulation will be the best performing one. However, focusing merely on the permeability may lead to the opposite wrong conclusion, that the 20% PEG-400 formulation will deliver the highest bioavailability. It is evident that the balance between the solubility and the permeability may reflect the correct perspective; the 20% PEG-400 formulation hardly “sacrifices” any permeation, but does not allow enough solubilization in the dynamic GIT environment (as evident by the dissolution study presented in Figure 6), and hence fail to deliver as high bioavailability as the other formulations. In contrast, both the 60% and the 100% PEG-400 formulations fully solubilized the drug dose throughout its GIT travel (Figure 6); however, the 60% PEG-400 “sacrificed” less permeation than the 100% (Figure 5), resulting in the >90%

Table 1. Main Pharmacokinetic Parameters of Carbamazepine Following Oral Administration of the Three PEG-400 Based Formulations to Rats (25 mg/kg)a PK parameter

20% PEG

60% PEG

100% PEG

T1/2 (min) Tmax (min) Cmax (μg/mL) AUC0‑t (μg/mL·min) Fsys (%)

142 (49) 30 2.2 (0.2) 599 (66) 63 (7)

159 (53) 120 2.5 (0.2) 863 (116) 91 (8)

143 (37) 90 1.9 (0.4) 722 (99) 76 (8)

a

Data are presented as average (SD); n = 6. AUC following i.v. administration of 5 mg/kg carbamazepine to three rats was 942 (6) μg/mL·min.

4. DISCUSSION Since drug solubilization is a prerequisite for absorption, a successful solubility-enabling formulation will first allow the solubilization of the drug throughout the dynamic GIT environment. Then, after the drug is solubilized and adjacent to the intestinal membrane, partitioning into and permeation through the gut wall may occur. These two sequential processes are highlighted in the BCS, which pinpoints the solubility and the permeability as the two key parameters affecting oral drug absorption. The results presented in this article show that these two parameters are closely related and exhibit important interplay between them; while both the 100% and the 60% PEG-400 based formulations were able to fully solubilize the carbamazepine dose throughout the GIT (Figure 6), the apparent permeability afforded by the 60% PEG-400 formulation was significantly higher (Figure 5), resulting in the overall better systemic bioavailability following oral intake of the latter. We have previously described the solubility−permeability interplay when using various solubility-enabling techniques, showing the solubility−permeability trade-off for cyclodexF



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systemic bioavailability. When a solubility-enabling formulation is developed, minimal threshold solubility should be targeted, that is just enough to allow solubilization of the drug dose throughout the GIT, while excess solubilizer should be avoided. Indeed, the 100% PEG-400 formulation also completely solubilized the carbamazepine dose in the GIT, but with cosolvent amounts considerably higher than the necessary threshold, hampering the overall bioavailability (Fsys = 76%). It should be noted that solubility-enabling formulations that do not modify the drugs’ equilibrium solubility, e.g., supersaturation via amorphous solid dispersions, allow overcoming this solubility-permeability trade-off.47−49 In this case, higher solubility may be directly translated into higher flux/absorption, as the apparent permeability remains constant since the drugs’ equilibrium solubility and membrane/aqueous partitioning is not hampered. In this work, the biorelevant pH-dilution method was used,33 which investigates the drug dissolution from a given formulation while traveling along the GIT. Oftentimes, dissolution studies give little consideration to the dynamic changes in intestinal luminal environments and apparent drug concentration that may occur throughout the GIT transit. As a result, many in vitro dissolution tests fail to measure biorelevant drug solubility/dissolution and to be biorepresentative and biopredictive. Several attempts have been made aiming to increase the biorelevance and biopredictive power of the in vitro dissolution methodology.14,22,29,30,50−52 The method used in this work is based on serial dilutions of the formulation, first with simulated gastric fluid, followed by simulated intestinal fluid (Figure 1), mimicking the physiologically relevant pH, dilution volumes, and residence times throughout the GIT transit. This relatively easy to use methodology was previously shown to more closely capture the kinetic aspects of the actual in vivo drug dissolution process.33

REFERENCES

(1) Dahan, A.; Miller, J. The solubility−permeability interplay and its implications in formulation design and development for poorly soluble drugs. AAPS J. 2012, 14 (2), 244−251. (2) Beig, A.; Miller, J. M.; Dahan, A. The interaction of nifedipine with selected cyclodextrins and the subsequent solubility−permeability trade-off. Eur. J. Pharm. Biopharm. 2013, 85 (3), 1293−1299. (3) Miller, J. M.; Dahan, A. Predicting the solubility−permeability interplay when using cyclodextrins in solubility-enabling formulations: Model validation. Int. J. Pharm. 2012, 430 (1−2), 388−391. (4) Beig, A.; Agbaria, R.; Dahan, A. The use of captisol (SBE7-β-CD) in oral solubility-enabling formulations: Comparison to HPβCD and the solubility−permeability interplay. Eur. J. Pharm. Sci. 2015, 77, 73− 78. (5) Bermejo, M. V.; Pérez-Varona, A. T.; Segura-Bono, M. J.; MartínVillodre, A.; Plá-Delfina, J. M.; Garrigues, T. M. Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption I. Studies with polysorbate and taurocholate in rat colon. Int. J. Pharm. 1991, 69 (3), 221−231. (6) Miller, J. M.; Beig, A.; Krieg, B. J.; Carr, R. A.; Borchardt, T. B.; Amidon, G. E.; Amidon, G. L.; Dahan, A. The solubility−permeability interplay: Mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation. Mol. Pharmaceutics 2011, 8 (5), 1848−1856. (7) Amidon, G. E.; Higuchi, W. I.; Ho, N. F. H. Theoretical and experimental studies of transport of micelle-solubilized solutes. J. Pharm. Sci. 1982, 71 (1), 77−84. (8) Beig, A.; Miller, J. M.; Dahan, A. Accounting for the solubility− permeability interplay in oral formulation development for poor water solubility drugs: The effect of PEG-400 on carbamazepine absorption. Eur. J. Pharm. Biopharm. 2012, 81, 386. (9) Miller, J. M.; Beig, A.; Carr, R. A.; Webster, G. K.; Dahan, A. The solubility−permeability interplay when using cosolvents for solubilization: Revising the way we use solubility-enabling formulations. Mol. Pharmaceutics 2012, 9 (3), 581−590. (10) Amidon, G. L.; Lennernäs, H.; Shah, V. P.; Crison, J. R. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 12 (3), 413−420. (11) Dahan, A.; Miller, J.; Amidon, G. Prediction of solubility and permeability class membership: Provisional BCS classification of the world’s top oral drugs. AAPS J. 2009, 11 (4), 740−746. (12) Lennernäs, H.; Abrahamsson, B. The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension. J. Pharm. Pharmacol. 2005, 57 (3), 273− 285. (13) Dahan, A.; Miller, J. M.; Hilfinger, J. M.; Yamashita, S.; Yu, L. X.; Lennernäs, H.; Amidon, G. L. High-permeability criterion for BCS classification: Segmental/pH dependent Permeability considerations. Mol. Pharmaceutics 2010, 7 (5), 1827−1834. (14) Dahan, A.; Hoffman, A. Rationalizing the selection of oral lipid based drug delivery systems by an in vitro dynamic lipolysis model for improved oral bioavailability of poorly water soluble drugs. J. Controlled Release 2008, 129 (1), 1−10. (15) Gao, P.; Rush, B. D.; Pfund, W. P.; Huang, T.; Bauer, J. M.; Morozowich, W.; Kuo, M.-S.; Hageman, M. J. Development of a supersaturable SEDDS (S-SEDDS) formulation of paclitaxel with improved oral bioavailability. J. Pharm. Sci. 2003, 92 (12), 2386−2398. (16) Kostewicz, E. S.; Wunderlich, M.; Brauns, U.; Becker, R.; Bock, T.; Dressman, J. B. Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J. Pharm. Pharmacol. 2004, 56 (1), 43−51. (17) Murphy, D.; Rodríguez-Cintrón, F.; Langevin, B.; Kelly, R. C.; Rodríguez-Hornedo, N. Solution-mediated phase transformation of anhydrous to dihydrate carbamazepine and the effect of lattice disorder. Int. J. Pharm. 2002, 246 (1−2), 121−134. (18) Fagerberg, J. H.; Tsinman, O.; Sun, N.; Tsinman, K.; Avdeef, A.; Bergström, C. A. S. Dissolution rate and apparent solubility of poorly

5. CONCLUSIONS In conclusion, we demonstrate the in vivo solubility− permeability trade-off phenomenon in oral delivery of lipophilic drugs; we reveal that when a solubility-enabling formulation is developed, minimal threshold solubility should be targeted, that is just enough to allow solubilization of the drug dose throughout the GIT, while excess solubilizer should be avoided. This work can greatly impact the field of oral delivery of lipophilic drugs.

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AUTHOR INFORMATION

Corresponding Author

*Address: Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva 84105, Israel. Tel: +972-8-6479483. Fax: +972-8-6479303. E-mail: [email protected]. il. ORCID

Arik Dahan: 0000-0002-3498-3514 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is a part of Avital Beig’s Ph.D. Thesis. The work was supported by a research grant from AbbVie incorporation. G


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