Solubility-permeability Interplay Research Articles

Investigating the effect of whey and casein proteins on drug solubility from a paediatric drug absorption perspective

Considering the predominantly milk-based diet of neonates and infants and their immature gastrointestinal digestion, milk proteins may affect drug behaviour and absorption in this population. Using in vitro models, this study investigated the impact of the representative milk proteins, whey and casein, on the solubility and permeation of the lipophilic model drugs spironolactone, clopidogrel and ritonavir. Drug solubility experiments revealed that the presence of milk proteins increased drug solubility. Next, permeation studies demonstrated that the same milk proteins reduced drug permeation across an artificial membrane. These results highlight the importance of the solubility-permeability interplay and indicate the effect of these proteins may be considered during (paediatric) drug development. Lastly, the findings underscore the importance of considering milk protein-drug interactions to optimize drug delivery strategies during (paediatric) drug development and especially for the youngest and most vulnerable part of this population.

Bridging the gap between in vitro and in vivo solubility-permeability interplay

Use of solubilization carriers for poorly soluble drugs may disturb transmembrane absorption by lowering the activity of drug molecules, which is known as the solubility-permeability interplay. However, although many in vitro studies have indicated the negative impacts of use of solubilization carriers for oral absorption, in vivo studies that showed the interplay effect are limited. This study provides systematic in vitro, in situ, and in vivo investigation of the interplay effect of cyclodextrin using dexamethasone as a model drug. The evaluation methods included permeation through polymeric, artificial lipid, cell, and intestinal closed-loop membranes. Then, the results were compared with oral administration studies in mice and dogs. Although the interplay effect was clearly observed in the in vitro studies, no obvious interplay was found in the in vivo studies, suggesting that the interplay effect is more prominent in the in vitro permeation studies. Absence of in vivo interplay was attributed to the dilution effect in the gastrointestinal tract, interaction of the drug with living components, and clearance of the drug after membrane permeation. Overall, this investigation clearly demonstrated the applicability and limitations of in vitro permeation studies for predicting the interplay effects of solubilizers after the oral administration.

Complex formation with modified cyclodextrins for improving biopharmaceutical properties of baricitinib, a novel immunomodulatory drug

Baricitinib is an orally active drug that has recently been approved by FDA and EMA for the treatment of rheumatoid arthritis, alopecia areata, COVID-19 and other inflammatory diseases. The application of baricitinib is limited by its poor aqueous solubility. In this context, this work aims to improve the pharmacologically important properties of baricitinib through inclusion complex formation with modified cyclodextrins. For the first time, the complexation of baricitinib with the modified cyclodextrins in aqueous solutions was studied using 1H NMR, capillary electrophoresis, and isothermal saturation method. Thermodynamic parameters of the complexation of the modified cyclodextrins with different ionized forms of baricitinib were obtained and analyzed. The impact of the nature of cyclodextrin substituents and the degree of ionization of baricitinib on the inclusion complex formation and solubilization is considered. The increase in baricitinib solubility in the presence of the modified cyclodextrins is accompanied by a decrease in the membrane permeability of the drug. It was shown that concentration dependences of the permeability coefficient can be used to predict the binding constants of baricitinib with cyclodextrins and the solubility-permeability interplay.

Solubility-permeability interplay of hydrotropic solubilization of piroxicam

Objectives In this research paper, an investigation has been made to assess the simultaneous effect of a solubility enhancement approach, i.e., hydrotropy on the solubility and apparent permeability of piroxicam. The solubility of piroxicam (PRX) a BCS (biopharmaceutics classification system) class II drug has been increased using a mixed hydrotropy approach. This study is based on identifying the pattern of solubility-permeability interplay and confirming whether every solubility gain results in a concomitant decrease in permeability or permeability remains unaffected. Method Solid dispersions of PRX were formulated using two hydrotropes, viz., sodium benzoate (SB) and piperazine (PP) by solvent evaporation method. A comprehensive 32factorial design was employed to study the effect of hydrotropes on the solubility and permeability of PRX. Subsequently, PRX tablets containing these solid dispersions were formulated and evaluated. Key findings SB and PP displayed a significant increase in the solubility of PRX ranging from 0.99 to 2.21 mg/mL for F1–F9 batches attributed to the synergistic effect of hydrotropes. However, there is a reduction in PRX permeability with increasing hydrotrope levels. The decline in permeability was notably less pronounced compared to the simultaneous rise in aqueous solubility of PRX. Conclusion An evident tradeoff between permeability and solubility emerged through the mixed hydrotropic solubilization for PRX. As PRX has generally higher intrinsic permeability, it has been assumed that this permeability loss will not affect the overall absorption of PRX. However, it may affect the absorption of drugs with limited permeability. Therefore, solubility permeability interplay should be investigated during solubility enhancement.

Ethanol-based solubility-enabling oral drug formulation development: Accounting for the solubility-permeability interplay

The aim of the current work was to investigate the key factors that govern the success/failure of an ethanol-based solubility-enabling oral drug formulation, including the effects of the ethanol on the solubility of the drug, the permeability across the intestinal membrane, the drug's dissolution in the aqueous milieu of the gastrointestinal tract (GIT), and the resulting solubility-permeability interplay. The concentration-dependent effects of ethanol-based vehicles on the solubility, the in-vitro Caco-2 permeability, the in-vivo rat permeability, and the biorelevant dissolution of the BCS class II antiepileptic drug carbamazepine were studied, and a predictive model describing the solubility-permeability relationship was developed. Significant concentration-dependent solubility increase of CBZ was obtained with increasing ethanol levels, that was accompanied by permeability decrease, both in Caco-2 and in rat perfusion studies, demonstrating a tradeoff between the increased solubility afforded by the ethanol and a concomitant permeability decrease. When ethanol absorption was accounted for, an excellent agreement was achieved between the predicted permeability and the experimental data. Biorelevant dissolution studies revealed that minimal ethanol levels of 30 % and 50 % were needed to fully dissolve 1 and 5 mg CBZ dose respectively, with no drug precipitation.In conclusion, key factors to be accounted for when developing ethanol-based formulation include the drug's solubility, permeability, the solubility-permeability interplay, and the drug dose intended to be delivered. Only the minimal amount of ethanol sufficient to solubilize the drug dose throughout the GIT should be used, and not more than that, to avoid unnecessarily permeability loss, and to maximize overall drug absorption.

Solubility-permeability interplay of a supersaturated lutein delivery system constructed by glycosylated stevioside and hydroxypropyl-methylcellulose

This study investigated the solubilizing capacity of glycosylated stevioside/hydroxypropyl-methylcellulose (stevia-G-HPMC) complexes with varying mass ratios on lutein. The impact on the steady-state flux and permeability coefficient of intracellular lutein was also explored through the construction of a Caco-2 cellular transport model. The results indicated that the equilibrium solubility of lutein linearly increased with an increase in stevia-G amount. The stability constants of the ternary system surpassed those of the binary system. Molecular dynamics simulation revealed a tight and stable structure in lutein supersaturated complexes. Meanwhile, lutein-stevia-G-HPMC complexes demonstrated superior cumulative penetrations, with the peak Papp (AP → BL) value being (3.24 ± 0.89) × 10−5 cm·s−1. There was a slight decrease in Papp (BL → AP), which improved the forward transport of lutein. Highly soluble lutein in aqueous environments saturated the extracellular transport proteins on the AP side of cell membranes, thereby maintaining the high permeability transport. Notably, the permeability trend of lutein in Caco-2 cells negatively correlated with the equilibrium solubility and matched the single exponential growth model. When the mass ratio of lutein, stevia-G and HPMC was 1:21:5, the solubility-permeability trade-off of lutein was effectively maintained.

Solubility-Permeability Interplay in Facilitating the Prediction of Drug Disposition Routes, Extent of Absorption, Food Effects, Brain Penetration and Drug Induced Liver Injury Potential

Here I detail the use of measures of permeability rate and solubility in predicting drug disposition characteristics through the utilization of the Biopharmaceutics Drug Disposition Classification System (BDDCS) and the Extended Clearance Classification System (ECCS) as well as the accuracy of the systems in predicting the major route of elimination and the extent of oral absorption of a new small molecule therapeutics. I compare the BDDCS and ECCS with the FDA Biopharmaceutics Classification System (BCS). I also detail the use of the BCS in predicting food effects and the BDDCS in predicting brain disposition of small molecule therapeutics and in validating DILI predictive metrics. This review provides an update of the current status of these classification systems and their uses in the drug development process.

On the use of linear model-based optimization to obtain optimum solubility permeability balance (OSPB) in cinnarizine-hydrotropic blends

The objectives of this work are (1) To scrutinize the various hydrotropes for acting as cinnarizine solubility augmenting excipient, (2) To show the existence of solubility-permeability interplay phenomenon on cinnarizine-hydrotrope blend through anin vitroexperimental set up and (3) To apply linear model-based optimization (by using Design Expert®software) for finding out optimum solubility permeability balance on cinnarizine-hydrotrope blend. Among the tested six-different hydrotropic molecules such as nicotinamide, sodium acetate, sodium benzoate, sodium citrate, sodium salicylate and urea, the cinnarizine solubility values were found to increase from 2.39 ± 0.00 to 57.98 ± 0.02 and 150.42 ± 0.02 µg/ml, respectively, for sodium benzoate and sodium salicylate at 40 % w/v concentration levels. However, the solubility enhancement effect produced by these two hydrotropic molecules was occurred at the expense of cinnarizine permeability value (from 44.00 × 10−5 to 35.00 ± 12.00 (×10−5) cm/sec) indicating the presence of solubility-permeability interplay/tradeoff phenomenon. Indeed, the Box-Behnken design yielded the optimized formula for preparing cinnarizine-hydrotrope blends possessing the maximum drug solubility value without significant reduction of drug permeability value. Hence, the quality by design approach plays a crucial role in optimizing the cinnarizine-hydrotropic formulations.

Improvement in Solubility-Permeability Interplay of Psoralens from Brosimum gaudichaudii Plant Extract upon Complexation with Hydroxypropyl-β-cyclodextrin.

Psoralen (PSO) and 5-methoxypsoralen (5-MOP) are widely used drugs in oral photochemotherapy against vitiligo and major bioactive components of root bark extract of Brosimum gaudichaudii Trécul (EBGT), previously standardized by LC-MS. However, the exceptionally low water solubility of these psoralens can cause incomplete and variable bioavailability limiting their applications and patient adherence to treatment. Therefore, the purpose of this work was to investigate the effects of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex on the solubility and jejunal permeability of PSO and 5-MOP from EBGT. Characterization of inclusion complexes were evaluated by current methods in nuclear magnetic resonance studies on aqueous solution, Fourier transform infrared spectroscopy, thermal analysis, and scanning electron microscopy in solid state. Ex vivo rat jejunal permeability was also investigated and compared for both pure psoralens and plant extract formulation over a wide HP-β-CD concentration range (2.5 to 70 mM). Phase solubility studies of the PSO- and 5-MOP-HP-β-CD inclusion complex showed 1:1 inclusion complex formation with small stability constants (Kc < 500 M−1). PSO and 5-MOP permeability rate decreased after adding HP-β-CD by 6- and 4-fold for pure standards and EBGT markers, respectively. Nevertheless, the complexation with HP-β-CD significantly improved solubility of PSO (until 10-fold) and 5-MOP (until 31-fold). As a result, the permeability drop could be overcome by solubility augmentation, implying that the HP-β-CD inclusion complexes with PSO, 5-MOP, or EBGT can be a valuable tool for designing and developing novel oral drug product formulation containing these psoralens for the treatment of vitiligo.

Flux-Based Formulation Development\u2014A Proof of Concept Study

The work aimed to develop the Absorption Driven Drug Formulation (ADDF) concept, which is a new approach in formulation development to ensure that the drug product meets the expected absorption rate. The concept is built on the solubility-permeability interplay and the rate of supersaturation as the driving force of absorption. This paper presents the first case study using the ADDF concept where not only dissolution and solubility but also permeation of the drug is considered in every step of the formulation development. For that reason, parallel artificial membrane permeability assay (PAMPA) was used for excipient selection, small volume dissolution-permeation apparatus was used for testing amorphous solid dispersions (ASDs), and large volume dissolution-permeation tests were carried out to characterize the final dosage forms. The API-excipient interaction studies on PAMPA indicated differences when different fillers or surfactants were studied. These differences were then confirmed with small volume dissolution-permeation assays where the addition of Tween 80 to the ASDs decreased the flux dramatically. Also, the early indication of sorbitol’s advantage over mannitol by PAMPA has been confirmed in the investigation of the final dosage forms by large-scale dissolution-permeation tests. This difference between the fillers was observed in vivo as well. The presented case study demonstrated that the ADDF concept opens a new perspective in generic formulation development using fast and cost-effective flux-based screening methods in order to meet the bioequivalence criteria.Graphical

Dose-Dependent Solubility-Permeability Interplay for Poorly Soluble Drugs under Non-Sink Conditions.

We investigated the solubility–permeability interplay using a solubilizer additive under non-sink conditions. Sodium lauryl sulfate (SLS) was used as a solubilizer additive. The solubility and permeability of two poorly soluble drugs at various doses, with or without SLS, were evaluated by flux measurements. The total permeated amount of griseofulvin, which has high permeability, increased by the addition of SLS. On the other hand, triamcinolone, which has low permeability, showed an almost constant rate of permeation regardless of the SLS addition. The total permeated amount of griseofulvin increased by about 20–30% when the dose amount exceeded its solubility, whereas its concentration in the donor chamber remained almost constant. However, the total permeated amount of triamcinolone was almost constant regardless of dose amount. These results suggest that the permeability of the unstirred water layer (UWL) may be affected by SLS and solid drugs for high-permeable drugs. The effect of solid drugs could be explained by a reduction in the apparent UWL thickness. For the appropriate evaluation of absorption, it would be essential to consider these effects.

Orally Administered Drug Solubility-Enhancing Formulations: Lesson Learnt from Optimum Solubility-Permeability Balance.

Although oral drug delivery is considered as most acceptable route for administering the active pharmaceutical ingredients to patients of all age-groups with the exceptions of bed-ridden patients and infants, the extent and rate of drug reaching the systemic circulation (in other word, drug bioavailability) always depends on many factors such as drug solubility in gastrointestinal fluids and drug permeation into intraluminal epithelial membrane structure, absence (fasting state) and presence (fed state) of food materials in the gastrointestinal tract, and individual variations in gastric emptying time. Taking the most influential factors like drug solubility and its permeability into consideration, these two factors play a pivotal role and even act as the litmus test for the formulation scientists who involve in oral dosage form development. It is very clear that there should be an optimum solubility and permeability balance to be reachable for getting the desired drug bioavailability to exert the intended therapeutic activity. The objectives of current review are (1) to provide an overview of two-different categories of poorly water soluble API molecules, (2) to describe briefly three-different case studies taken from drug solubility-enhancing formulations dealing with interplay between solubility and permeability, and (3) to showcase selected examples of solubility-permeability interplay phenomena arising out from the various orally administrable dosage forms. The lessons learnt from the past and current literatures are certainly encouraging to go ahead for oral dosage form development but with the prior knowledge about the possible existence of solubility-permeability interplay/tradeoff phenomenon.

Adequate formulation approach for oral chemotherapy: Etoposide solubility, permeability, and overall bioavailability from cosolvent- vs. vitamin E TPGS-based delivery systems

Injectable-to-oral conversions for anticancer drugs represent an important trend. The goal of this research was to investigate the suitability of formulation approaches for anticancer oral drug delivery, aiming to reveal mechanistic insights that may guide oral chemotherapy development. TPGS vs. PEG-400 were studied as oral formulations for the anticancer drug etoposide, accounting for drug solubility, biorelevant dissolution, permeability, solubility-permeability interplay, and overall bioavailability. Increased etoposide solubility was demonstrated with both excipients. Biorelevant dissolution revealed that TPGS or PEG-400, but not aqueous suspension, allowed complete dissolution of the entire drug dose. Both TPGS and PEG-400 resulted in decreased in-vitro etoposide permeability across artificial membrane, i.e. solubility-permeability tradeoff. While PEG-400 resulted in the same solubility-permeability tradeoff also in-vivo, TPGS showed the opposite trend: the in-vivo permeability of etoposide was markedly increased in the presence of TPGS. This increased permeability was similar to the drug permeability under P-gp inhibition. Rat PK study demonstrated significantly higher etoposide bioavailability from TPGS vs. PEG-400 or suspension (AUC of 72, 41, and 26 µg·min/mL, respectively). All in all, TPGS-based delivery system allows overcoming the solubility-permeability tradeoff, increasing systemic etoposide exposure. Since poor solubility and strong efflux are common to many anticancer agents, this work can aid in the development of better oral delivery approach for chemotherapeutic drugs.

Active intestinal drug absorption and the solubility-permeability interplay

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug’s apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients’ nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs.

The Solubility-Permeability Trade-Off of Progesterone With Cyclodextrins Under Physiological Conditions: Experimental Observations and Computer Simulations

This study intended to evaluate the effect of cyclodextrins on the apparent solubility and permeability of lipophilic drugs under physiological conditions and establish in silico model to choose the optimal amount of cyclodextrins for cyclodextrin-containing oral formulations. In order to study the effect of cyclodextrins under physiological conditions, bile salts and lecithin were added into the rat intestinal perfusion solution to simulate the fasted intestinal fluid. In addition, the in vivo oral absorption performances of cyclodextrin-containing formulations were simulated by gastrointestinal simulation technology based on the advanced compartmental absorption and transit model. The permeability of progesterone was not significantly different between 0.1 mM and 1 mM of 2-hydroxypropyl-β-cyclodextrins (HP-β-CD) under physiological conditions. When the concentration of HP-β-CD was 1 mM, the permeability of progesterone under physiological conditions was significantly higher than that in vitro. The in silico model established in this study was validated by in vivo studies of 4 formulations containing different dosage of cyclodextrin, proving that it was accurate and reliable. In conclusion, this work that demonstrates the permeability of lipophilic drugs could not decrease quickly among a certain range of dosage of HP-β-CD in vivo. Studying the solubility-permeability interplay under physiological conditions would be more meaningful.

Influence of hydrophilic polymers addition into cinnarizine–β-cyclodextrin complexes on drug solubility, drug liberation behaviour and drug permeability

The aims of this study were (1) to prepare cinnarizine (CNZ)–β-cyclodextrin (β-CD) complexes by the kneading, co-precipitation and co-evaporation methods with (ternary system) or without (binary system) the addition of two different hydrophilic polymers [hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP)] in their two different grades (HPMC E5-LV or K4M and PVP K-25 or K-30) and (2) to determine the polymers influence on enhancing the CNZ solubility and the in vitro CNZ liberation behaviour or drug permeation characteristics via artificial membrane from the prepared CNZ–β-CD binary and ternary complexes in 0.1 N HCl (pH 1.2). The presence of hydrophilic polymers in ternary complex system did produce irregular-shaped but smooth-surfaced particles while binary complex system (with no polymer addition) did not. The ternary complexes prepared with HPMC K4M, β-CD and CNZ showed higher solubility efficiency value compared to other tested hydrophilic polymers to make ternary complex systems. Consequently, irrespective of the three preparation methods, the ternary complex systems exhibited higher drug libration behaviour in comparison to the binary complex system, physical mixtures and CNZ powder. But because of the possible presence of a solubility and permeability interplay or tradeoff particularly in the binary and ternary complex systems, the CNZ permeation amount in 0.1 N HCl (pH 1.2) via artificial membrane was established to a minimum compared to the CNZ powder. Therefore, the CNZ–β-CD complexes with or without the HPMC and PVP should unequivocally be used with great care by considering the solubility–permeability interplay or tradeoff into account.

Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide

Vitamin E TPGS (TPGS) has both surfactant and P-glycoprotein (P-gp) inhibitory effects. While surfactants were previously found to cause solubility-permeability tradeoff, TPGS P-gp inhibitory effects may change this unfavorable interplay. The purpose of this research was to investigate the solubility-permeability interplay when using TPGS vs. amorphous solid dispersions (ASD) as oral drug delivery systems for the anticancer, P-gp substrate, lipophilic drug etoposide. The concentration-dependent effects of TPGS (0–100mg/mL) vs. ASD on the solubility of etoposide, as well as the in-vitro (PAMPA) vs. in-vivo (intestinal rat perfusion) permeability of the drug were studied, and the resulting solubility-permeability interplay was analyzed. TPGS above CMC (0.3mg/mL) increased etoposide solubility linearly, and ASD allowed significant supersaturation. Etoposide in-vitro PAMPA permeability decreased markedly with increasing TPGS levels, similarly to the solubility-permeability tradeoff previously defined for surfactants. In contrast, the presence of TPGS significantly increased etoposide in-vivo rat permeability, attributable to P-gp inhibition, similarly to the effect of the potent P-gp inhibitor GF120918 (10µg/mL). High supersaturation achieved via ASD increased the drug's in-vivo permeability to the level obtained by TPGS or GF120918, supporting P-gp saturation. In conclusion, unique pattern of solubility-permeability interplay was found, involving concomitant increase of both the solubility and the permeability, as opposed to the previously reported tradeoff for solubilization methods and the unchanged permeability for supersaturation; P-gp inhibition/saturation by TPGS or by supersaturation allows simultaneous increase of both solubility and permeability, representing a significant advantage of such drug delivery approaches when suitable.

Toward Successful Cyclodextrin Based Solubility-Enabling Formulations for Oral Delivery of Lipophilic Drugs: Solubility-Permeability Trade-Off, Biorelevant Dissolution, and the Unstirred Water Layer.

The purpose of this work was to investigate key factors dictating the success/failure of cyclodextrin-based solubility-enabling formulations for oral delivery of low-solubility drugs. We have studied the solubility, the permeability, and the solubility-permeability interplay, of the highly lipophilic drug danazol, formulated with different levels (8.5, 10, 20, and 30%) of the commonly used hydroxypropyl-β-cyclodextrin (HPβCD), accounting for the biorelevant solubilization of the drug along the gastrointestinal tract (GIT), the unstirred water layer (UWL) adjacent to the GI membrane, and the overall absorption. HPβCD significantly increased danazol solubility, and decreased the drugs' permeability, in a concentration-dependent manner. These Peff results were in good correlation (R2 = 0.977) to literature rat AUC data of the same formulations. Unlike vehicle without HPβCD, formulations containing 8.5% HPβCD and above were shown to successfully dissolve the drug dose during the entire biorelevant dissolution experiment. We conclude that CD-based solubility-enabling formulations should contain the minimal amount of CD sufficient to dissolve the drug dose throughout the GIT, and not more than that; excess CD does not provide solubility gain but causes further permeability loss, and the overall absorption is then impaired. Moreover, a significant UWL effect was revealed in danazol intestinal permeability, and accounting for this effect allowed an excellent prediction of the solubility-permeability trade-off vs % HPβCD. Overall, this work assessed the contribution of each individual step of the absorption cascade to the success/failure of HPβCD-based formulation, allowing a more mechanistic development process of better solubility-enabling formulations.

Gastrointestinal behavior of itraconazole in humans – Part 2: The effect of intraluminal dilution on the performance of a cyclodextrin-based solution

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is known to enable absorption of the lipophilic drug itraconazole. Since the interaction between HP-β-CD and itraconazole is characterized by a non-lineair, AP-type phase-solubility diagram, the present study aimed to investigate the influence of intraluminal dilution (water intake) on the behavior and performance of an orally administered cyclodextrin-based solution of itraconazole. Subsequently, the in vivo behavior was simulated by combining in vitro dilution with permeation assessment. After the administration of a Sporanox® solution to healthy volunteers with or without a glass of water, gastrointestinal and systemic concentrations of itraconazole were simultaneously monitored. Independently of the intake of water, no gastric precipitation of itraconazole was observed. After transfer to the duodenum, precipitation occurred and was more pronounced in the condition with water, resulting in a 7.6-fold reduction in duodenal AUC0-3h compared to the condition without water. Nevertheless, plasma concentration-time profiles did not demonstrate any significant differences in AUC0-8h, Cmax and tmax. Application of freshly aspirated intestinal fluids on Caco-2 cells clearly confirmed that higher intestinal itraconazole concentrations after intake of Sporanox® without water do not generate a substantially increased itraconazole uptake. A two-stage in vitro dilution test was combined with a permeation compartment to capture this solubility-permeability interplay. In conclusion, this work demonstrates that variations in intraluminal dilution may have a drastic impact on the gastrointestinal behavior of lipophilic drugs in the presence of cyclodextrins. In the case of an AP-type interaction with cyclodextrins, the trade-off between solubility and permeability may be affected.

Advantageous Solubility-Permeability Interplay When Using Amorphous Solid Dispersion (ASD) Formulation for the BCS Class IV P-gp Substrate Rifaximin: Simultaneous Increase of Both the Solubility and the Permeability.

Rifaximin is a BCS class IV (low-solubility, low-permeability) drug and also a P-gp substrate. The aims of this work were to assess the efficiency of different rifaximin amorphous solid dispersion (ASDs) formulations in achieving and maintaining supersaturation and to investigate the consequent solubility-permeability interplay. Spray-dried rifaximin ASDs were prepared with different hydrophilic polymers and their ability to achieve and maintain supersaturation was assessed. Then, rifaximin's apparent intestinal permeability was investigated as a function of increasing supersaturation both in vitro using the parallel artificial membrane permeability assay (PAMPA) and in vivo using the single-pass rat intestinal perfusion (SPIP) model. The efficiency of the different ASDs to achieve and maintain supersaturation of rifaximin was found to be highly polymer dependent, and the copovidone/HPC-SL formulation was found to be superior to the other two, allowing supersaturation of 200× that of the crystalline solubility for 20h. In vitro, rifaximin flux was increased and the apparent permeability was constant as a function of increasing supersaturation level. In vivo, on the other hand, absorption rate coefficient (k a) was first constant as a function of increasing supersaturation, but at 250×, the crystalline solubility k a was doubled, similar to the k a in the presence of the strong P-gp inhibitor GF120918. In conclusion, a new and favorable nature of solubility-permeability interplay was revealed in this work: delivering high supersaturation level of the BCS class IV drug rifaximin via ASD, thereby saturating the drugs' P-gp-mediated efflux transport, led to the favorable unique win-win situation, where both the solubility and the permeability increased simultaneously.