Cocrystal Solubility Advantage and Dose/Solubility Ratio Diagrams: A Mechanistic Approach To Selecting Additives and Controlling Dissolution-Supersaturation-Precipitation Behavior.

Two of the main questions regarding cocrystal selection and formulation development are whether the will be stable and how fast can it dissolve the drug dose. Dissolving the drug dose may require cocrystals with a high solubility advantage over drug (SA = SCC/SD), but these may have limited potential to sustain drug supersaturation. Thus, we propose a twofold approach to mitigate the risk of drug precipitation by optimizing thermodynamic (SA) and kinetic factors (nucleation inhibitors). This risk can be evaluated by considering the cocrystal SA and drug dose/solubility ratio (D0D = Cdose/SD), which in tandem represent the maximum theoretical supersaturation that a cocrystal may generate, the driving force for drug precipitation, and the potential for dose-/solubility-limited absorption. cocrystals with SA and D0D values above critical supersaturation are prone to rapid precipitation, often negating their utility as a solubility enhancement tool. This work presents a mechanistic approach to controlling the dissolution-supersaturation-precipitation behavior of cocrystal systems, whereby relationships between SA, D0D, and the drug-solubilizing power of surfactants (SPD = SD,T/SD,aq) are used to fine-tune cocrystal-inherent supersaturation by rational additive selection. Experimental results with danazol-vanillin cocrystal demonstrate how SA, D0D, and SPD are key thermodynamic parameters to understanding the kinetic cocrystal behavior and how the risks of cocrystal development may be mitigated through the mechanistic formulation design.

Lipolysis-Permeation Setup for Simultaneous Study of Digestion and Absorption in Vitro.

Lipid-based formulations (LBFs) are a delivery strategy to enhance intestinal absorption of poorly water-soluble drugs. LBF performance is typically evaluated by in vitro lipolysis studies, but these do not accurately predict the in vivo performance. One possible reason is the absence of an absorptive membrane driving sink conditions in the serosal compartment. To explore the impact of absorption under sink conditions on the performance evaluation, we developed a lipolysis-permeation setup that allows simultaneous investigation of intestinal digestion of an LBF and drug absorption. The setup consists of two chambers, an upper one for digestion (luminal), and a lower, receiving one (serosal), separated by a Caco-2 monolayer. Digestions were performed with immobilized lipase, instead of the pancreatic extract typically used during lipolysis, since the latter has proven incompatible with Caco-2 cells. Danazol-loaded LBFs were used to develop the setup, and fenofibrate-loaded LBFs were used to establish an in vitro in vivo correlation. As in regular lipolysis studies, our setup allows for the evaluation of (i) the extent of digestion and (ii) drug distribution in different phases present during lipolysis of drug-loaded LBFs (i.e., oil, aqueous, and solid phase). In addition, our setup can determine drug permeation across Caco-2 monolayers and hence, the absorptive flux of the compound. The presence of the absorptive monolayer and sink conditions tended to reduce aqueous drug concentrations and supersaturation in the digestion chamber. The drug transfer across the Caco-2 membrane accurately reflected in vivo drug exposure upon administration of three different LBFs loaded with fenofibrate, where the traditional lipolysis setup failed to predict in vivo performance. As the new setup reflects the dynamic processes occurring in the gastrointestinal tract, it is a valuable tool that can be used in the development of LBFs prior to in vivo studies.

Effect of Surfactant-Bile Interactions on the Solubility of Hydrophobic Drugs in Biorelevant Dissolution Media.

Biorelevant dissolution media (BDM) methods are commonly employed to investigate the oral absorption of poorly water-soluble drugs. Despite the significant progress in this area, the effect of commonly employed pharmaceutical excipients, such as surfactants, on the solubility of drugs in BDM has not been characterized in detail. The aim of this study is to clarify the impact of surfactant-bile interactions on drug solubility by using a set of 12 surfactants, 3 model hydrophobic drugs (fenofibrate, danazol, and progesterone) and two types of BDM (porcine bile extract and sodium taurodeoxycholate). Drug precipitation and sharp nonlinear decrease in the solubility of all studied drugs is observed when drug-loaded ionic surfactant micelles are introduced in solutions of both BDM, whereas the drugs remain solubilized in the mixtures of nonionic polysorbate surfactants + BDM. One-dimensional and diffusion-ordered 1H NMR spectroscopy show that mixed bile salt + surfactant micelles with low drug solubilization capacity are formed for the ionic surfactants. On the other hand, separate surfactant-rich and bile salt-rich micelles coexist in the nonionic polysorbate surfactant + bile salt mixtures, explaining the better drug solubility in these systems. The nonionic alcohol ethoxylate surfactants show intermediate behavior. The large dependence of the drug solubility on surfactant-bile interactions (in which the drug molecules do not play a major role per se) highlights how the complex interplay between excipients and bile salts can significantly change one of the key parameters which governs the oral absorption of poorly water-soluble drugs, viz. the drug solubility in the intestinal fluids.

Micellar solubilization of poorly water-soluble drugs: effect of surfactant and solubilizate molecular structure.

OBJECTIVE: This study aims to clarify the role of surfactant and drug molecular structures on drug solubility in micellar surfactant solutions. SIGNIFICANCE: (1) Rationale for surfactant selection is provided; (2) the large data set can be used for validation of the drug solubility parameters used in oral absorption models. METHODS: Equilibrium solubility of two hydrophobic drugs and one model hydrophobic steroid in micellar solutions of 19 surfactants was measured by HPLC. The drug solubilization locus in the micelles was assessed by UV spectrometry. RESULTS: Danazol is solubilized much more efficiently than fenofibrate by ionic surfactants due to ion-dipole interactions between the charged surfactant head groups and the polar steroid backbone. Drug solubilization increases linearly with the increase of hydrophobic chain length for all studied surfactant types. Addition of 1-3 ethylene oxide (EO) units in the head group of dodecyl sulfate surfactants reduces significantly the solubilization of both studied drugs and decreases linearly the solubilization locus polarity of fenofibrate. The locus of fenofibrate solubilization is in the hydrophobic core of nonionic surfactant micelles and in the palisade layer of ionic surfactant micelles. CONCLUSIONS: Highest drug solubility can be obtained by using surfactants molecules with long chain length coupled with hydrophilic head group that provides additional drug-surfactant interactions (i.e. ion-dipole) in the micelles.

Heme Modification Contributes to the Mechanism-Based Inactivation of Human Cytochrome P450 2J2 by Two Terminal Acetylenic Compounds.

The mechanism-based inactivation of human CYP2J2 by three terminal acetylenic compounds: N-(methylsulfonyl)-6-(2-propargyloxyphenyl)hexanamide (MS), 17-octadecynoic acid (OD), and danazol (DZ) was investigated. The loss of hydroxyebastine (OHEB) carboxylation activity in a reconstituted system was time- and concentration-dependent and required NADPH for MS and OD, but not DZ. The kinetic constants for the mechanism-based inactivation of OHEB carboxylation activity were: KI of 6.1 µM and kinact of 0.22 min-1 for MS and KI of 2.5 µM and kinact of 0.05 min-1 for OD. The partition ratios for MS and OD were ∼10 and ∼20, respectively. Inactivation of CYP2J2 by MS or OD resulted in a loss of the native heme spectrum and a similar decrease in the reduced CO difference spectrum. A heme adduct was observed in the MS-inactivated CYP2J2. The possible reactive metabolite which covalently modified the prosthetic heme was characterized by analysis of the glutathione conjugates formed by MS or OD following oxygenation of the ethynyl moiety. Liquid chromatography-mass spectrometry showed that inactivation by MS or OD did not lead to modification of apoprotein. Interaction of CYP2J2 with DZ produced a type II binding spectrum with a Ks of 2.8 µM and the IC50 for loss of OHEB carboxylation activity was 0.18 µM. In conclusion, heme modification by MS and OD was responsible for the mechanism-based inactivation of CYP2J2. The results suggest that the ethynyl moiety of MS and OD faces the heme iron, whereas the isoxazole ring of DZ is preferentially oriented toward the heme iron of CYP2J2.

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-ß-cyclodextrin (HPßCD), 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. HPßCD 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 HPßCD, formulations containing 8.5% HPßCD 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 % HPßCD. Overall, this work assessed the contribution of each individual step of the absorption cascade to the success/failure of HPßCD-based formulation, allowing a more mechanistic development process of better solubility-enabling formulations.

Computational Models of the Gastrointestinal Environment. 2. Phase Behavior and Drug Solubilization Capacity of a Type I Lipid-Based Drug Formulation after Digestion.

Lipid-based drug formulations can greatly enhance the bioavailability of poorly water-soluble drugs. Following the oral administration of formulations containing tri- or diglycerides, the digestive processes occurring within the gastrointestinal (GI) tract hydrolyze the glycerides to mixtures of free fatty acids and monoglycerides that are, in turn, solubilized by bile. The behavior of drugs within the resulting colloidal mixtures is currently not well characterized. This work presents matched in vitro experimental and molecular dynamics (MD) theoretical models of the GI microenvironment containing a digested triglyceride-based (Type I) drug formulation. Both the experimental and theoretical models consist of molecular species representing bile (glycodeoxycholic acid), digested triglyceride (1:2 glyceryl-1-monooleate and oleic acid), and water. We have characterized the phase behavior of the physical system using nephelometry, dynamic light scattering, and polarizing light microscopy and compared these measurements to phase behavior observed in multiple MD simulations. Using this model microenvironment, we have investigated the dissolution of the poorly water-soluble drug danazol experimentally using LC-MS and theoretically by MD simulation. The results show how the formulation lipids alter the environment of the GI tract and improve the solubility of danazol. The MD simulations successfully reproduce the experimental results showing the utility of MD in modeling the fate of drugs after digestion of lipid-based formulations within the intestinal lumen.

Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type.

Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization.

Characterization of Supersaturated Danazol Solutions - Impact of Polymers on Solution Properties and Phase Transitions.

PURPOSE: Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated. METHODS: A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior. RESULTS: Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 µg/mL, with the maximum effectiveness being reached at 10 µg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase. CONCLUSIONS: The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.

Formulation and performance of danazol nano-crystalline suspensions and spray dried powders.

PURPOSE: This study focuses on the formulation optimization, in vitro and in vivo performance of differently sized nano-crystalline liquid suspensions and spray-dried powders of a poorly soluble BCS class II compound i.e. Danazol. METHODS: A DoE approach was utilized to optimize stabilizer concentration and formulate danazol (BCS class II) nano-crystalline suspensions and dry powders via wet milling followed by spray drying. Solubility studies were performed to select best stabilizers. Particle size, PXRD, contact angle measurement and in vitro dissolution were utilized in characterization of the liquid and spray-dried powder formulations. RESULTS: The liquid nano-crystalline suspensions followed particle size-dependent dissolution rates i.e. faster dissolution for smaller crystals. The spray-dried nano-crystal powders did not show fast dissolution profiles compared to the liquid nano-crystalline suspension. The poor dissolution of the spray-dried powder correlated to its high LogP value (i.e. LogP 4.53) and poor wetting (or polar surface-area). In vivo bioavailability studies showed superior performance of the liquid nano-crystalline suspensions compared to other milled and un-milled formulations. CONCLUSION: Wet-milling and spray-drying optimization for danazol nano-crystalline suspension was performed. This study indicates that drug candidates with high LogP values and low polar surface area may not be suitable for formulation as dry nano-crystals.

Impact of polymers on the precipitation behavior of highly supersaturated aqueous danazol solutions.

The phase behavior of supersaturated solutions of a relatively hydrophobic drug, danazol, was studied in the absence and presence of polymeric additives. To differentiate between phase separation to a noncrystalline phase and phase separation to a crystalline phase, an environmentally sensitive fluorescent probe was employed. Induction times for crystallization in the presence and absence of polymeric additives were studied using a combination of ultraviolet and fluorescence spectroscopy. It was found that, when danazol was added to aqueous media at concentrations above the amorphous solubility, liquid-liquid phase separation was briefly observed prior to crystallization, resulting in a short-lived, drug-rich noncrystalline danazol phase with an initial size of around 500 nm. The addition of polymers was found to greatly extend the lifetime of the supersaturated two phase system, delaying the onset of crystallization from a few minutes to a few hours. Below a certain threshold danazol concentration, found to represent the amorphous solubility, only crystallization was observed. Thus, although the addition of polymers was unable to prevent danazol from precipitating once a threshold concentration was exceeded, they did inhibit crystallization, leading to a solution with prolonged supersaturation. This observation highlights the need to determine the structure of the precipitating phase, since it is linked to the resultant solution concentration time profile.

The potential for drug supersaturation during intestinal processing of lipid-based formulations may be enhanced for basic drugs.

Co-administration of poorly water-soluble drugs (PWSD) with dietary or formulation lipids stimulates the formation of lipid colloidal phases such as vesicular and micellar species, and significantly expands the drug solubilization capacity of the small intestine. The mechanism of drug absorption from the solubilizing phases, however, has not been fully elucidated. Recently, we observed that drug supersaturation may be triggered during endogenous processing of lipid colloidal phases containing medium-chain lipid digestion products and that this may represent a mechanism to reverse the reduction in thermodynamic activity inherent in drug solubilization and thereby enhance absorption. The current studies expand these preliminary findings and explore the supersaturation tendency of five model PWSD during endogenous processing of intestinal colloidal phases containing long-chain lipid digestion products. Bile-lipid concentration ratios progressively increase during colloid transit through the gastrointestinal tract due to biliary dispersion of lipid digestion products and lipid absorption. The supersaturation potential was therefore evaluated under conditions of increasing bile and decreasing lipid concentrations and was found to be greater for the basic drugs cinnarizine (CIN) and halofantrine (HF), than the neutral drugs fenofibrate (FF) and danazol (DAN), and acidic drug meclofenamic acid (MFA). Assessment of intestinal absorptive flux using rat jejunal perfusion experiments subsequently showed that the absorption enhancement afforded by bile dilution of lipid colloidal phases was greater for CIN than DAN. The results confirm that bile plays a significantly greater role in the absorption of CIN (a weak base) from long-chain intestinal colloids when compared to DAN (an uncharged molecule) and that the difference reflects a greater propensity for supersaturation as intestinal colloids are dispersed and diluted by bile. The data suggest that coadministered digestible lipids may be particularly suited to enhance the absorption of poorly water-soluble weak bases.

Identifying a selective substrate and inhibitor pair for the evaluation of CYP2J2 activity.

CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess the role of CYP2J2 in drug metabolism, a selective substrate and potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as a specific CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled the determination of liver relative activity factor and intersystem extrapolation factor for CYP2J2. Amiodarone 4-hydroxylation correlated with astemizole O-demethylation but not with CYP2J2 protein content in a sample of human liver microsomes. To identify a specific CYP2J2 inhibitor, 138 drugs were screened using terfenadine and astemizole as probe substrates with recombinant CYP2J2. Forty-two drugs inhibited CYP2J2 activity by ≥50% at 30 µM, but inhibition was substrate-dependent. Of these, danazol was a potent inhibitor of both hydroxylation of terfenadine (IC(50) = 77 nM) and O-demethylation of astemizole (K(i) = 20 nM), and inhibition was mostly competitive. Danazol inhibited CYP2C9, CYP2C8, and CYP2D6 with IC(50) values of 1.44, 1.95, and 2.74 µM, respectively. Amiodarone or astemizole were included in a seven-probe cocktail for cytochrome P450 (P450) drug-interaction screening potential, and astemizole demonstrated a better profile because it did not appreciably interact with other P450 probes. Thus, danazol, amiodarone, and astemizole will facilitate the ability to determine the metabolic role of CYP2J2 in hepatic and extrahepatic tissues.

Luminal lipid phases after administration of a triglyceride solution of danazol in the fed state and their contribution to the flux of danazol across Caco-2 cell monolayers.

The first aim of this study was to characterize the luminal contents and their micellar phase after the administration of a heterogeneous liquid meal to healthy adults. The second aim was to evaluate the impact of micellar lipids and coarse lipid particles on danazol flux through intestinal monolayers. A third aim was to compare the micellar composition in the upper small intestine with the composition of fed state simulating intestinal fluid (FeSSIF-V2), a medium that has been proposed for investigating dissolution of poorly soluble drugs in the fed state. Danazol (150 mg), predissolved in the olive oil portion of the meal, was administered via the gastric port of a two-lumen tube to the antrum of eight adults. Aspirates from the ligament of Treitz [collected up to 4 h postdosing (~15 mL every 30 min)] were characterized physicochemically. Comparison of these characteristics with FeSSIF-V2 indicates that FeSSIF-V2 is an appropriate medium for evaluating drug solubilization in the luminal micellar phase in the fed state. Individual aspirates and their corresponding micellar phases were also diluted with aqueous transport medium and subjected to Caco-2 cell permeation experiments. Permeability coefficients for danazol in the diluted aspirates were smaller than those for the diluted micellar phases, which in turn were similar to those for aqueous transport medium. The high danazol concentrations overcompensated the reduced permeability coefficient values in the diluted aspirates in terms of total drug flux. We conclude that drug dissolved in the coarse lipid particles formed after administration of a triglyceride solution can directly contribute to the flux of lipophilic drugs across the intestinal mucosa.

Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance.

Incomplete desorption of liquid excipients reduces the in vitro and in vivo performance of self-emulsifying drug delivery systems solidified by adsorption onto an inorganic mesoporous carrier.

The purpose of the current study was to provide a mechanistic basis for in vitro and in vivo performance differences between lipid-based formulations solidified by adsorption onto a high surface area material and their respective liquid (i.e., nonadsorbed) counterparts. Two self-emulsifying formulations (based on either medium-chain or long-chain lipids) of the poorly water-soluble drug danazol were solidified by adsorption onto Neusilin US2. Liquid and adsorbed lipid-based formulations were subjected to in vitro dispersion-digestion tests, and additional in vitro experiments were performed to elucidate the cause of performance differences. The bioavailability of danazol after oral administration to rats was also assessed. The percentage of the dose solubilized in the aqueous phase during in vitro dispersion-digesting was ∼35% lower for the adsorbed formulations when compared to their liquid counterparts. This trend was also reflected in vivo, where the bioavailability of danazol after administration of the adsorbed formulations was ∼50% lower than that obtained after administration of the equivalent liquid formulation. Incomplete desorption of the microemulsion preconcentrate from the carrier on dispersion-digestion was identified as the main contributor to the reduced pharmaceutical performance of the adsorbed formulations. The results of the current study indicate that solidification of lipid-based formulations through adsorption onto a high surface area carrier may limit formulation (and drug) release in vivo and thereby reduce oral bioavailability.

Lipid digestion as a trigger for supersaturation: evaluation of the impact of supersaturation stabilization on the in vitro and in vivo performance of self-emulsifying drug delivery systems.

The generation of supersaturation in the gastrointestinal (GI) tract is an increasingly popular means of promoting oral absorption for poorly water-soluble drugs. The current study examined the impact of changes to the quantities of medium-chain (MC) lipid (Captex 300:Capmul MCM), surfactant (Cremophor EL) and cosolvent (EtOH), and the addition of polymeric precipitation inhibitors (PPI), on supersaturation during the dispersion and digestion of MC self-emulsifying drug delivery systems (SEDDS) containing danazol. The data suggest that digestion acts as a "trigger" for enhanced supersaturation and that solubilization/precipitation behavior is correlated with the degree of supersaturation on dispersion (S(M)DISP) or digestion (S(M)DIGEST). The ability of the formulation to maintain solubilization in vitro decreased as the S(M) of the formulation increased. PPI significantly increased supersaturation stabilization and precipitation was inhibited where S(M)DISP < 3.5 and S(M)DIGEST < 4. In the presence of polymer, some degree of supersaturation was maintained up to S(M)DIGEST ∼ 8. Differentiation in the ability of SEDDS to maintain drug solubilization stems from the ability to stabilize supersaturation and for MC SEDDS, utilization of lower drug loads, higher surfactant levels (balanced against increases in S(M)DISP), lower cosolvent and the addition of PPI enhanced formulation performance. In vivo studies confirmed the ability of PPI to promote drug exposure at moderate drug loads (40% of saturated solubility in the formulation). At higher drug loads (80% saturation) and in lipid-free SEDDS, this effect was lost, suggesting that the ability of PPIs to stabilize supersaturation in vitro may, under some circumstances, overestimate utility in vivo.

Application of dissolution/permeation system for evaluation of formulation effect on oral absorption of poorly water-soluble drugs in drug development.

PURPOSE: The aim of the present study is to evaluate the formulation effect on the oral absorption of poorly water-soluble drugs using a dissolution/permeation system (D/P system). METHODS: This D/P system, consisting of apical and basal chambers and a Caco-2 cell monolayer mounted between chambers, can be used to perform simultaneous analysis of drug dissolution and permeation process of drugs applied as various dosage forms. Oral administration study with rats was also performed for both drugs as the same dosage forms. RESULTS: When danazol, a low-soluble and high-permeable drug, was applied to the D/P system as various formulations, dissolved and permeated amounts were significantly high compared with those from a suspension form. On the other hand, whereas the dissolved amount of pranlukast, a low-soluble and low-permeable drug, was significantly increased by formulations, there were no significant changes observed in the permeated amount between suspension and formulation. The oral availability of danazol was significantly increased by formulations but not pranlukast, which corresponded well to in vitro evaluations. CONCLUSION: These results indicated that the D/P system might be applicable for selection of formulation on the basis of physicochemical drug properties.

A comparative evaluation of mono-, di- and triglyceride of medium chain fatty acids by lipid/surfactant/water phase diagram, solubility determination and dispersion testing for application in pharmaceutical dosage form development.

PURPOSE: To compare physiochemical properties of mono-, di- and triglycerides of medium chain fatty acids for development of oral pharmaceutical dosage forms of poorly water-soluble drugs using phase diagrams, drug solubility, and drug dispersion experiments. METHODS: Phase diagrams were prepared using a monoglyceride (glycerol monocaprylocaprate: Capmul MCM® EP), a diglyceride (glycerol dicaprylate) and two triglycerides (glycerol tricaprylate: Captex 8000®; caprylic/capric triglycerides: Captex 355 EP/NF®) in combination with a common surfactant (PEG-35 castor oil: Cremophor EL®) and water. Psuedoternary phase diagrams using mixtures of monoglyceride with either diglyceride or triglyceride were constructed to determine any potential advantage of using lipid mixtures. RESULT: The monoglyceride gave microemulsion (clear or translucent liquid) and emulsion phases, whereas di- and triglycerides exhibited an additional gel phase. Among individual mono-, di- and triglycerides, the oil-in-water microemulsion region was the largest for the diglyceride. Gel phase region within diglyceride and triglyceride phase diagrams could be practically eliminated and microemulsion regions expanded by mixing monoglyceride with di- or tri-glycerides (1:1). Addition of a model drug, danazol, had no effect on particle sizes of microemulsions formed. Dispersion of drug in aqueous media from mixtures of mono- and diglyceride or mono- and triglyceride was superior to individual lipids. CONCLUSION: Systematic study on comparison of mono-, di- and triglyceride of medium chain fatty acids will help formulators select components for optimal lipid-based formulation.

Excipient-mediated supersaturation stabilization in human intestinal fluids.

It was the purpose of this study to investigate excipient-mediated precipitation inhibition upon induction of supersaturation of poorly water-soluble drugs in aspirated human intestinal fluids (HIF) representing both the fasted and fed state. Etravirine, ritonavir, loviride, danazol and fenofibrate were selected as model compounds. For comparative purposes, precipitation inhibition was also evaluated in simple aqueous buffer, and in intestinal simulation media representative for the fasted and fed state (FaSSIF and FeSSIF, respectively). Supersaturation was induced in the test media containing predissolved excipient (HPMC-AS, HPMC-E5, HPMC-E50, HPMC-E4M, HPMC-P and PVP) at a defined degree of supersaturation (DS = 20) using the solvent shift method. The results illustrate that cellulosic polymers can reduce the precipitation rate and stabilize supersaturation in HIF. The extent of stabilization was compound and excipient dependent but independent of the nutritional state. Whenever excipient effects were observed, the predictive value of simple buffer or FaSSIF/FeSSIF was rather limited. In general, excipient-mediated precipitation inhibition was less pronounced in HIF compared to simple aqueous buffer or FaSSIF/FeSSIF. However, excipients showing no effect in simple aqueous buffer or FaSSIF/FeSSIF also proved to be ineffective in HIF, indicating the value of these simulation media in the elimination of excipients during formulation development.