Randy Mellaerts

Increasing the oral bioavailability of the poorly water soluble drug itraconazole with ordered mesoporous silica.

This study aims to evaluate the in vivo performance of ordered mesoporous silica (OMS) as a carrier for poorly water soluble drugs. Itraconazole was selected as model compound. Physicochemical characterization was carried out by SEM, TEM, nitrogen adsorption, DSC, TGA and in vitro dissolution. After loading itraconazole into OMS, its oral bioavailability was compared with the crystalline drug and the marketed product Sporanox in rabbits and dogs. Plasma concentrations of itraconazole and OH-itraconazole were determined by HPLC-UV. After administration of crystalline itraconazole in dogs (20mg), no systemic itraconazole could be detected. Using OMS as a carrier, the AUC0-8 was boosted to 681+/-566 nM h. In rabbits, the AUC0-24 increased significantly from 521+/-159 nM h after oral administration of crystalline itraconazole (8 mg) to 1069+/-278 nM h when this dose was loaded into OMS. Tmax decreased from 9.8+/-1.8 to 4.2+/-1.8h. No significant differences (AUC, Cmax, and Tmax) could be determined when comparing OMS with Sporanox in both species. The oral bioavailability of itraconazole formulated with OMS as a carrier compares well with the marketed product Sporanox, in rabbits as well as in dogs. OMS can therefore be considered as a promising carrier to achieve enhanced oral bioavailability for drugs with extremely low water solubility.

Ordered mesoporous silica material SBA-15: a broad-spectrum formulation platform for poorly soluble drugs.

Encapsulating poorly soluble drugs in mesoporous silicates is an emerging strategy to improve drug dissolution. This study evaluates the applicability of the ordered mesoporous silicate SBA-15 as an excipient to enhance dissolution, for a test series of 10 poorly soluble compounds with a high degree of physicochemical diversity (carbamazepine, cinnarizine, danazol, diazepam, fenofibrate, griseofulvin, indomethacin, ketoconazole, nifedipine, and phenylbutazone). A generic solvent impregnation method was used to load all model compounds. The target drug content was 20%. The physical nature of the formulations was investigated using differential scanning calorimetry (DSC) and the pharmaceutical performance evaluated by means of in vitro dissolution. Aliquots of each formulation were stored at 25 degrees C/52% RH for 6 months, and again subjected to DSC and in vitro dissolution. The target drug content of 20% was attained in all cases. DSC data evidenced the noncrystalline state of the confined drugs. All SBA-15 formulations exhibited an enhanced dissolution as compared to their corresponding crystalline materials, and the high pharmaceutical performance of all formulations was retained during the 6 months storage period. The results of this study suggest that encapsulation in SBA-15 can be applied as a dissolution-enhancing formulation approach for a very wide variety of poorly soluble drugs.

Physical state of poorly water soluble therapeutic molecules loaded into SBA-15 ordered mesoporous silica carriers: A case study with itraconazole and ibuprofen

The ordered mesoporous silica material SBA-15 was loaded with the model drugs itraconazole and ibuprofen using three different procedures: (i) adsorption from solution, (ii) incipient wetness impregnation, and (iii) heating of a mixture of drug and SBA-15 powder. The location of the drug molecules in the SBA-15 particles and molecular interactions were investigated using nitrogen adsorption, TGA, DSC, DRS UV-vis, and XPS. The in vitro release of hydrophobic model drugs was evaluated in an aqueous environment simulating gastric fluid. The effectiveness of the loading method was found to be strongly compound dependent. Incipient wetness impregnation using a concentrated itraconazole solution in dichloromethane followed by solvent evaporation was most efficient for dispersing itraconazole in SBA-15. The itraconazole molecules were located on the mesopore walls and inside micropores of the mesopore walls. When SBA-15 was loaded by slurrying it in a diluted itraconazole solution from which the solvent was evaporated, the itraconazole molecules ended up in the mesopores that they plugged locally. At a loading of 30 wt %, itraconazole exhibited intermolecular interactions inside the mesopores revealed by UV spectroscopy and endothermic events traced with DSC. The physical mixing of itraconazole and SBA-15 powder followed by heating above the itraconazole melting temperature resulted in formulations in which glassy itraconazole particles were deposited externally on the SBA-15 particles. Loading with ibuprofen was successful with each of the three loading procedures. Ibuprofen preferably is positioned inside the micropores. In vitro release experiments showed fast release kinetics provided the drug molecules were evenly deposited over the mesoporous surface.

Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica

The aim of the present study was to evaluate the effect of release rate from ordered mesoporous silica materials on the rate and extent of absorption of the poorly soluble drug fenofibrate. Three ordered mesoporous silica materials with different pore diameter (7.3 nm, 4.4 nm and 2.7 nm) were synthesized and loaded with fenofibrate via impregnation. Release experiments were conducted under sink conditions and under supersaturating conditions in biorelevant media, simulating the fasted and the fed state. Subsequently, all silica-based formulations were evaluated in vivo (rat model). The release experiments under sink conditions indicated a clear increase in release rate with increasing pore size. However, under supersaturating conditions (FaSSIF), the, pharmaceutical performance (in terms of both the degree and duration of supersaturation), increased with decreasing pore size. The same trend was observed in vivo (fasted state): the area under the plasma concentration-time profile amounted to 102 ± 34 μMh, 86 ± 19 μMh and 20 ± 13 μMh for the materials with pore diameter of 2.7 nm, 4.4 nm and 7.3 nm, respectively. The results of this, study demonstrate that a decrease in drug release rate - and thus, a decrease of the rate at which supersaturation is created - is beneficial to the absorption of fenofibrate.

Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole

The release of poorly soluble drugs from mesoporous silicates is often associated with the generation of supersaturation, which implies the risk of drug precipitation and reduced availability for absorption. The aim of this study was to enhance the in vivo performance of an ordered mesoporous silicate (SBA-15) by combining it with the precipitation inhibitors hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS). The poorly soluble weak base itraconazole was used as a model compound. Formulations were prepared by physically blending itraconazole-loaded SBA-15 with the precipitation inhibitors. In vitro release experiments implementing a transfer from simulated gastric fluid to simulated intestinal fluid were used to evaluate the pharmaceutical performance. Subsequently, the formulations were evaluated in vivo in rats. When high enough amounts of HPMC were co-administered with itraconazole-loaded SBA-15 (itraconazole:SBA-15:HPMC 1:4:6), the extent of absorption was increased by more than 60% when compared to SBA-15 without precipitation inhibitors (AUC 14,937+/-1617 versus 8987+/-2726nMh). HPMCAS was found ineffective in enhancing the in vivo performance of SBA-15 due to its insolubility in the stomach. The results of this study demonstrate that the pharmaceutical performance of SBA-15 is enhanced through addition of an appropriate precipitation inhibitor.

Ordered mesoporous silica induces pH-independent supersaturation of the basic low solubility compound itraconazole resulting in enhanced transepithelial transport.

The majority of innovative drug candidates are poorly water soluble and exhibit basic properties. This makes them highly dependent on the in vivo encountered acid-neutral pH sequence to achieve a sufficient dissolution and thus absorption. In this study, we evaluated the pH-independent generation of intraluminally induced supersaturation of the model compound itraconazole and its beneficial effect on the extent of absorption in the Caco-2 system and the rat in situ perfusion system. Local supersaturation was obtained by means of a solvent shift method and a novel formulation strategy based on ordered mesoporous silica (OMS) as a carrier. In vitro results evidenced that both methods were capable of creating a supersaturated state of itraconazole in fasted state simulated intestinal fluid (FaSSIF) when no preceding acidic dissolution was simulated. The extent of supersaturation exceeded 21.9 and 9.6 during at least 4h for the solvent shift method and OMS as a carrier, respectively. As compared to saturation conditions (0.09+/-0.01 microg), supersaturation induced by the solvent shift method as well as by the use of OMS increased transport across a Caco-2 cell monolayer more than 16-fold, resulting in the basolateral appearance of 2.20+/-0.29 microg and 1.46+/-0.03 microg itraconazole after 90 min, respectively. In the absence of an acid-neutral pH sequence, the performance of the marketed product Sporanox was inferior with total transport amounting to 0.12+/-0.03 microg after 90 min. Enhanced absorption was confirmed in the in situ perfusion model where OMS was able to boost total transport of itraconazole after 60 min from 0.03+/-0.01 nmol cm(-1) to 0.70+/-0.09 nmol cm(-1) compared to saturated equilibrium conditions in FaSSIF. The solid dosage form Sporanox again failed to achieve a similar extent of absorption enhancement (0.29+/-0.01 nmol cm(-1)). These findings suggest that intraluminal supersaturation can be created by the use of OMS and that preceding dissolution of basic compounds in the acidic medium of the stomach is not required to allow for efficient intestinal absorption. The use of OMS appears to be a promising strategy for the delivery of especially basic low solubility compounds in patients suffering from hypochlorhydria; the pH independency may also result in a more reproducible systemic exposure.

Potential of amorphous microporous silica for ibuprofen controlled release

Amorphous microporous silica (AMS) xerogel materials were synthesized in an acid-catalyzed sol-gel process. The porosity of AMS was adapted by varying sol-gel synthesis parameters including the molar hydrolysis ratio (r-value), HCl:Si molar ratio, the type of silicon alkoxide source and the solvent. AMS particles of millimeter size were loaded with ibuprofen, by heat treatment and melt impregnation. In vitro release experiments were performed in simulated gastric and intestinal fluid. The release kinetics were critically depending on the AMS particle size distribution and the micropore diameter. The release was interpreted as configurational diffusion in the AMS micropores. The stability of unloaded and ibuprofen loaded AMS material upon storage was investigated using nitrogen physisorption, DSC analysis and in vitro release experiments. Ibuprofen loaded AMS formulations show remarkable stability, which can be attributed to the presence of ibuprofen molecules in the channels, functioning as scaffolds to support the pore structure.

Preventing release in the acidic environment of the stomach via occlusion in ordered mesoporous silica enhances the absorption of poorly soluble weakly acidic drugs

This study aimed to assess the pharmaceutical performance of formulations consisting of either indomethacin or glibenclamide and the ordered mesoporous silica material SBA-15. Both compounds were loaded on SBA-15 via solvent impregnation. Adsorption in the SBA-15 mesopores was confirmed using nitrogen physisorption. Differential scanning calorimetry results suggested that both compounds were dispersed monomolecularly onto the SBA-15 surface. In in vitro experiments simulating the gastric-to-intestinal transition, the release of both compounds from SBA-15 remained under 1% in simulated gastric fluid (SGF, pH 1.2), whereas both drugs were completely released within 10 min after transfer to fasted state simulated intestinal fluid (FaSSIF, pH 6.5). As both drugs exhibited very rapid precipitation from the supersaturated state in SGF, the preferential release in FaSSIF--where conditions are more favourable by virtue of either much higher solubility (indomethacin) or more stable supersaturation (glibenclamide)--was considered crucial towards achieving optimal absorption. This hypothesis was confirmed by an in vivo study, where the extent of absorption of a glibenclamide-SBA-15 formulation was found to be more than fourfold higher than that of the commercial glibenclamide product Daonil®.

Growth of Itraconazole Nanofibers in Supersaturated Simulated Intestinal Fluid

Many drug compounds have limited solubility in water. To enhance the oral bioavailability of such compounds, pharmaceutical formulations target the creation of a supersaturated solution. Release of the compound from ordered mesoporous silica carrier is such a means for reaching supersaturation. Little is known about the evolution of supersaturated intestinal media. The present study reveals the phase transitions of the poorly water-soluble drug itraconazole in simulated intestinal fluid under conditions corresponding to supersaturation. Electron spin resonance of n-doxylstearic acid spin probes evidenced that during supersaturation itraconazole is solubilized inside the hydrophobic core of mixed micelles composed of lecithin and bile salt. Cryogenic transmission electron microscopy revealed that the supersaturated state of itraconazole provokes the formation of nanofibers with a uniform diameter of 12 nm. The nanofiber length determined via dynamic light scattering increases from 220 to 1480 nm after 30 and 90 min, respectively. Nanofibers drastically reduced transepithelial transport of itraconazole across a Caco-2 cell monolayer mimicking the gastrointestinal absorption. Based on our study, we suggest the existence of an optimum intraluminal itraconazole supersaturation at which itraconazole absorption is enhanced but formation of itraconazole nanofibers prevented.

In situ FT-IR investigation of etravirine speciation in pores of SBA-15 ordered mesoporous silica material upon contact with water.

Ordered mesoporous silica (OMS) has been recognized as promising adsorbent material for drug molecules with low aqueous solubility. The release of drug molecules from OMS upon contact with aqueous environment enhances their oral bioavailability. The release is governed by a complex interplay of adsorption, diffusion, and intermolecular interaction inside OMS pores. The presence of water hampers in situ FT-IR investigation of the behavior of the drug molecules upon release. The poorly water-soluble etravirine molecule having two nitrile functions was selected for an in situ FT-IR spectroscopic investigation of the release process. The stretching vibration of the nitrile organic function (υ(CN)) is a spectral feature that is accessible to FT-IR even in the presence of water. Etravirine depending on the loading was found to be present in SBA-15 pores as isolated adsorbed molecules, solvated molecules, and aggregates with intermolecular interaction similar to the crystalline state, each with a different spectroscopic fingerprint. Etravirine evacuation from the SBA-15 pores was shown to proceed in the solvated state. Surprisingly, the etravirine clusters inside pores were converted more readily into solvated molecules compared to individually adsorbed molecules.