Non-Effective Improvement of Absorption for Some Nanoparticle Formulations Explained by Permeability under Non-Sink Conditions.

We evaluated the in vitro permeability of nanoparticle formulations of high and low lipophilic compounds under non-sink conditions, wherein compounds are not completely dissolved. The permeability of the highly lipophilic compound, griseofulvin, was improved by about 30% due to nanonization under non-sink conditions. Moreover, this permeability was about 50% higher than that under sink conditions. On the other hand, for the low lipophilic compound, hydrocortisone, there was no difference in permeability between micro-and nano-sized compounds under non-sink conditions. The nanonization of highly lipophilic compounds improves the permeability of the unstirred water layer (UWL), which in turn improves overall permeability. On the other hand, because the rate-limiting step in permeation for the low lipophilic compounds is the diffusion of the compounds in the membrane, the improvement of UWL permeability by nanonization does not improve the overall permeability. Based on this mechanism, nanoparticle formulations are not effective for low lipophilic compounds. To accurately predict the absorption of nanoparticle formulations, it is necessary to consider their permeability under non-sink conditions which reflect in vivo conditions.

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.

Tofogliflozin Salt Cocrystals with Sodium Acetate and Potassium Acetate.

We investigated the salt cocrystals formed by tofogliflozin with sodium acetate and potassium acetate by determining the crystal structures of the salt cocrystals and characterizing the solid states. The salt cocrystal screening using the slurry method and the liquid-assisted grinding method resulted in the formation of tofogliflozin-sodium acetate 1 : 1 and tofogliflozin-potassium acetate 1 : 1 salt cocrystals. Single-crystal X-ray diffraction revealed that, although each salt cocrystal belongs to a different space group, both of the salt cocrystals have almost similar structural features, including the conformation of tofogliflozin molecules, the coordination to Na+/K+ ions, and hydrogen bonds. The salt cocrystals exhibited extreme hygroscopicity with deliquescence, which is also a property of sodium acetate and potassium acetate. In addition, tofogliflozin-potassium acetate salt cocrystal had two polymorphs, which were enantiotropically related.

Characterization and Quality Control of Pharmaceutical Cocrystals.

Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

Characterizing the dissolution profiles of supersaturable salts, cocrystals, and solvates to enhance in vivo oral absorption.

The purposes of this study were to elucidate the type-specific characteristics of salt, cocrystal, and solvate formulations upon dissolution and precipitation, and to clarify their effect on enhancing oral absorption. Several types of solid formulations (dantrolene sodium salt [DAN-NA], pioglitazone hydrochloride salt [PIO-HCL], megestrol acetate saccharin cocrystal [MEG-SA], and an in-house compound ZR ethanolate [ZR-ETH]) that induce supersaturation of BCS class II drugs were compared to their crystalline free forms. An in vitro miniscale dissolution test in biorelevant media was used to characterize their dissolution profiles and residue forms. Both salts (DAN-NA and PIO-HCL) rapidly reached the maximum concentration within 5min, whereas the cocrystal (MEG-SA) did so slowly. After the maximum concentration had been reached, the dissolved concentrations of DAN-NA, PIO-HCL, and MEG-SA decreased, but that of ZR-ETH did not. Time-dependent XRPD analysis revealed that the initial solid state of each salt dissolved within 5min, whereas the cocrystal remained for more than 10min, and the solvate remained for 4h. It also revealed that PIO-HCL and MEG-SA precipitated to the stable free form, while DAN-NA precipitated to the metastable form, which maintains a higher concentration than the stable free form continuously. In vivo absorption in beagle dogs was also examined. The plasma AUC of DAN-NA, MEG-SA, and ZR-ETH was respectively 1.5-, 2.1-, and 11-fold more than each free form. On the other hand, the absorption of PIO-HCL was not enhanced compared with its free form. The results in the present study clarified that not only the precipitation rate and the form of precipitation but also the retention of the initial solid state in the absorption process contribute to enhancing the in vivo absorption of Class II drugs from solid formulations such as salts, solvates, and cocrystals.

Design and synthesis of an androgen receptor pure antagonist (CH5137291) for the treatment of castration-resistant prostate cancer.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.

Quantitative analysis of the effect of supersaturation on in vivo drug absorption.

The purpose of this study is to clarify the effects of intestinal drug supersaturation on solubility-limited nonlinear absorption. Oral absorption of a novel farnesyltransferase inhibitor (FTI-2600) from its crystalline free base and its HCl salt was determined in dogs. To clarify the contribution of supersaturation on improving drug absorption, in vivo intraluminal concentration of FTI-2600 after oral administration was estimated from the pharmacokinetics data using a physiologically based model. Dissolution and precipitation characteristics of FTI-2600 in a biorelevant media were investigated in vitro using a miniscale dissolution test and powder X-ray diffraction analysis. In the in vitro study, the HCl salt immediately dissolved but precipitated rapidly. The metastable amorphous free base precipitant, which did not convert into the stable crystalline free base in the simulated intestinal fluids for several hours, generated a 5-fold increase in dissolved concentration compared to the equilibrium solubility of the crystalline free base. By computer simulation, the intraluminal drug concentration after administration of the free base was estimated to reach the saturated solubility, indicating solubility-limited absorption. On the other hand, administration of the HCl salt resulted in an increased intraluminal concentration and the plasma concentration was 400% greater than that after administration of the free base. This in vivo/in vitro correlation of the increased drug concentrations in the small intestine provide clear evidence that not only the increase in the dissolution rate, but also the supersaturation phenomenon, improved the solubility-limited absorption of FTI-2600. These results indicate that formulation technologies that can induce supersaturation may be of great assistance to the successful development of poorly water-soluble drugs.

A theoretical-empirical analysis on the initial dissolution rate of drugs from polydispersed particles.

The purpose of this work is to clarify the relationship of mean particle size to the dissolution rate of polydispersed particles for Biopharmaceutical Classification System (BCS) Class II drugs. An equation for the initial dissolution rate of polydispersed particles relative to mean particle diameter was theoretically derived from the Noyes-Whitney equation assuming spherical particles and sink conditions. To verify the relationship of dissolution to the mean particle diameters, the dissolution rates of 6 types of hypothetically-generated log-normal polydispersed particles and 3 different sized particles of aprepitant, a designated BCS class II drug, were compared with known mean diameters calculated according to surface area-weighted mean diameter (D(3,2), commonly referred to as the Sauter mean diameter), length-weighted mean diameter (D(3,1)) and number-weighted mean diameter (D(3,0)). The results confirmed that the initial dissolution rates of polydispersed particles reflect the mean diameter and correlated best with the reciprocal of D(3,2) at the start of dissolution, in accord with our theoretical conclusions. The particle size required for sufficient dissolution of aprepitant was also investigated by examining the relationship between D(3,2) and oral absorption predicted using a physiological-based model.

Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds.

PURPOSE: To demonstrate improvement in the dissolution of exemestane and megestrol acetate from cocrystallization using various particle sizes and to investigate the mechanism of the improved dissolution. METHODS: Cocrystal screening was performed by slurry crystallization. The cocrystals were identified and characterized by powder X-ray diffraction, thermal analysis, and single crystal X-ray diffraction. Different particle sizes of each cocrystal were prepared from organic solutions. Solubility and dissolution rates were evaluated using dissolution tests. Transformation behavior of the cocrystals in suspension was analyzed by PXRD and polarization microscopy. RESULTS: Two novel cocrystals were obtained: exemestane (EX)/maleic acid (MAL) (cocrystal 1) and megestrol acetate (MA)/saccharin (SA) (cocrystal 2). Cocrystal 1 showed a high dissolution rate even with large particles. Cocrystal 2 showed supersaturation with fine particles. The transformation from cocrystal 1 to EX was observed within 1 min in suspension. Cocrystal 2 was transformed to MA within 2-4 h. CONCLUSIONS: Cocrystallizations of EX and MA improved initial dissolution rates compared to the respective original crystals. The mechanism of dissolution enhancement varied. With cocrystal 1, fine particle formation resulted in enhancement, whereas with cocrystal 2, enhancement was due to the maintenance of the cocrystal form and rapid dissolution before transformation to the original crystal.

Rate-limiting steps of oral absorption for poorly water-soluble drugs in dogs; prediction from a miniscale dissolution test and a physiologically-based computer simulation.

PURPOSE: Nonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption. METHODS: Oral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption. RESULTS: The rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption. CONCLUSION: The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.

Correction of permeability with pore radius of tight junctions in Caco-2 monolayers improves the prediction of the dose fraction of hydrophilic drugs absorbed by humans.

PURPOSE: To improve predictions of fraction dose absorbed (Fa) for hydrophilic drugs, a correction of paracellular permeability using the pore radius of tight junctions (TJs) in Caco-2 monolayers was performed. METHODS: The apparent permeability coefficient (P9app)) of drugs was measured using the Caco-2 assay and the parallel artificial membrane permeation assay (PAMPA), and values were corrected with the pore radius of TJs. RESULTS: An equation for calculating the pore radius of TJs from the P(app) of lucifer yellow was obtained. The optimal pore radius of TJs in Caco-2 monolayers for predicting human Fa was calculated to be 7 A. The correlation between the actual and predicted Fa was improved by using the P(app) corrected with the pore radius of TJs. Permeability in the PAMPA, which was corrected using the pore radius and membrane potential, was well correlated with that in the Caco-2 assay. Most of the hydrophilic drugs tested in this study were absorbed mainly through the paracellular pathway. CONCLUSIONS: The results suggest the necessity of optimizing paracellular permeation for the prediction of Fa, and also the importance of the paracellular pathway to the absorption of hydrophilic drugs. This method might contribute to the setting of appropriate dosages and the development of hydrophilic drugs.

Prediction of passive intestinal absorption using bio-mimetic artificial membrane permeation assay and the paracellular pathway model.

The purpose of this study was to construct and examine the prediction model for total passive permeation through the intestinal membrane. The paracellular pathway prediction model based on Renkin function (PP-RF) was combined with a bio-mimetic artificial membrane permeation assay (BAMPA), which is an in vitro method to predict transcellular pathway permeation, to construct the prediction model (BAMPA-PP-RF model). The parameters of the BAMPA-PP-RF model, e.g. apparent pore radius and potential drop of the paracellular pathway, were calculated from BAMPA permeability, the dissociation constant, the molecular radius and the fraction of a dose absorbed in humans consisting of 80 structurally diverse compounds. The apparent pore radius and the apparent potential drop obtained in this study were 5.61-5.65 A and 75-86 mV, respectively, and these were in accordance with the previously reported values. The mean square root error of the BAMPA-PP-RF model was 13-14%. The BAMPA-PP-RF model was shown to be able to predict the total passive permeability more adequately than BAMPA alone.