Ordered mesoporous silica to enhance the bioavailability of poorly water-soluble drugs: Proof of concept in man.

Formulating poorly water soluble drugs using ordered mesoporous silica materials is an emerging approach to tackle solubility-related bioavailability problems. The current study was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96h post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75h) and extent of absorption (AUC0-24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. The results of this study serve as a proof of concept in man for this novel formulation approach.

Evaluation of Three Amorphous Drug Delivery Technologies to Improve the Oral Absorption of Flubendazole.

This study investigates 3 amorphous technologies to improve the dissolution rate and oral bioavailability of flubendazole (FLU). The selected approaches are (1) a standard spray-dried dispersion with hydroxypropylmethylcellulose (HPMC) E5 or polyvinylpyrrolidone-vinyl acetate 64, both with Vitamin E d-α-tocopheryl polyethylene glycol succinate; (2) a modified process spray-dried dispersion (MPSDD) with either HPMC E3 or hydroxypropylmethylcellulose acetate succinate (HPMCAS-M); and (3) confining FLU in ordered mesoporous silica (OMS). The physicochemical stability and in vitro release of optimized formulations were evaluated following 2 weeks of open conditions at 25°C/60% relative humidity (RH) and 40°C/75% RH. All formulations remained amorphous at 25°C/60% RH. Only the MPSDD formulation containing HPMCAS-M and 3/7 (wt./wt.) FLU/OMS did not crystallize following 40°C/75% RH exposure. The OMS and MPSDD formulations contained the lowest and highest amount of hydrolyzed degradant, respectively. All formulations were dosed to rats at 20 mg/kg in suspension. One FLU/OMS formulation was also dosed as a capsule blend. Plasma concentration profiles were determined following a single dose. In vivo findings show that the OMS capsule and suspension resulted in the overall highest area under the curve and Cmax values, respectively. These results cross-evaluate various amorphous formulations and provide a link to enhanced biopharmaceutical performance.

Impregnation of Fenofibrate on mesoporous silica using supercritical carbon dioxide.

Low oral bioavailability can be circumvented by the formulation of the poorly water soluble drug in ordered mesoporous silica (OMS-L-7). Fenofibrate is an orally administered, poorly water-soluble active pharmaceutical ingredient (API), used clinically to lower lipid levels. Fenofibrate was loaded into silica using two methods: incipient wetness and supercritical impregnation. This study investigates the impact of loading and the impact of varying supercritical carbon dioxide (scCO2) processing conditions. The objective is to enhance Fenofibrate loading into silica while reducing degree of the drug crystallinity, so as to increase the drug's dissolution rate and its bioavailability. The comparison of both impregnation processes was made in terms of impregnation yields and duration as well as physical characterization of the drug. While incipient wetness method led to a Fenofibrate loading up to 300 mgdrug/gsilica in 48 h of impregnation, the supercritical impregnation method yielded loading up to 485 mgdrug/gsilica in 120 min of impregnation duration, at 16 MPa and 308 K, with a low degree of crystallinity (about 1%) comparable to the crystallinity observed via the solvent method. In addition to the enhancement of impregnation efficiency, the supercritical route provides a solvent-free alternative for impregnation.

Lipid-based formulations solidified via adsorption onto the mesoporous carrier Neusilin® US2: effect of drug type and formulation composition on in vitro pharmaceutical performance.

The current study determined the extent to which the desorption of lipid-based formulations (LBFs) from a mesoporous magnesium aluminometasilicate (Neusilin®-US2) carrier is governed by drug properties, LBF composition, and LBF-to-adsorbent ratio. A secondary objective was to evaluate the impact of testing parameters (medium composition, pH, dilution, and agitation) on in vitro LBF performance. Two self-emulsifying LBFs, with high/low lipid-surfactant ratios were studied in detail using danazol, fenofibrate, cinnarizine, and mefenamic acid as model drugs. A wider range of 38 different danazol-containing LBF were also evaluated, where desorption was evaluated immediately after preparation and after 1 month of storage. The results revealed that incomplete desorption from Neusilin® was a feature of all drugs and LBFs tested. Desorption was insensitive to agitation but increased under conditions where ionizable drugs were charged. In addition, formulations containing a higher proportion (>30%) of hydrophilic surfactant consistently exhibited higher desorption, and were least susceptible to decreased desorption on storage. In summary, although Neusilin® is an effective vehicle for LBF solidification, its use is accompanied by a risk of incomplete desorption of the vehicle from the carrier, irrespective of the drug. Lipid Formulation Classification System (LFCS)Type IIIB LBFs comprising higher quantities of hydrophilic surfactants appear to desorb most from Neusilin®. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.

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.

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®.

The conflict between in vitro release studies in human biorelevant media and the in vivo exposure in rats of the lipophilic compound fenofibrate.

The performance of four different lipid-based (Tween 80-Captex 200P, Tween 80-Capmul MCM, Tween 80-Caprol 3GO and Tween 80-soybean oil) and one commercially available micronized formulation (Lipanthyl Micronized(®)) of the lipophilic compound fenofibrate was compared in vitro in various biorelevant media and in vivo in rats. In simulated gastric fluid without pepsin (SGF(sp)) and fasted state simulated intestinal fluid (FaSSIF), only Tween 80-Captex 200P system resulted in a stable fenofibrate concentration, but no supersaturation was obtained. The other three lipid based systems created fenofibrate supersaturation; however they did not maintain it. In fed state simulated intestinal fluid (FeSSIF), all lipid-based formulations resulted in complete dissolution of fenofibrate during the experiment, which represented a supersaturated state for Tween 80-Capmul MCM and Tween 80-Caprol 3GO systems. In both FaSSIF and FeSSIF, all lipid-based formulations yielded a higher fenofibrate concentration than the micronized formulation. Contrary to the in vitro results, no significant difference in the in vivo performance was observed among the four tested lipid-based formulations both in the fasted and the fed states. The in vivo performance of all lipid-based formulations was better than that of Lipanthyl Micronized(®), in the fasted as well as in the fed state. The fact that for the lipid based systems the in vitro differences in pharmaceutical performance were not translated into in vivo differences can be attributed to the continuous excretion of bile in the gastrointestinal tract of rats, causing enhanced solubilizing capacity for lipophilic drugs. This study clearly points to the conflicting situation that might arise during the preclinical phase of the development of lipid based formulations of lipophilic drugs as the performance of such systems is very often evaluated by both in vitro release studies in human biorelevant media as well as in vivo studies in rats. Care must be taken to select a relevant animal model.

Molecular organization of hydrophobic molecules and co-adsorbed water in SBA-15 ordered mesoporous silica material.

The purpose of this study was to improve our understanding of the molecular organization of hydrophobic guest molecules in the presence of co-adsorbed water inside SBA-15 ordered mesoporous silica material. Understanding this adsorption competition is essential in the development of applications of controlled adsorption and desorption. The poorly water soluble drug compound itraconazole and the fluorescent probe Nile red were selected for the study. The interaction between itraconazole and SBA-15 was investigated using FT-IR, (1)H MAS NMR and (29)Si MAS NMR spectroscopy, by determination of adsorption isotherms and release kinetics in simulated gastric fluid. The distribution and migration of the hydrophobic fluorescent probe Nile red was visualized in situ using confocal fluorescence microscopy. For both molecules, there was a pronounced influence of the co-adsorbed water on adsorption, hydrophobic aggregation and migration in SBA-15 pores. These insights contribute to the development of practical methods for loading ordered mesoporous silica materials with hydrophobic molecules.

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.

Comparison of the complexation between methylprednisolone and different cyclodextrins in solution by 1H-NMR and molecular modeling studies.

Complexation in solution between methylprednisolone and three different cyclodextrins [2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), gamma-cyclodextrin (gamma-CD), and 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD)] was studied using phase solubility analysis, one and two-dimensional (1)H-NMR and molecular modeling. Estimates of the complex formation constant (K(1:1)) show that the tendency of methylprednisolone to complex with CDs follows the order: gamma-CD > HP-gamma-CD > HP-beta-CD. The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (H-3', H-5', and H-6') coupled with minimal variation of shifts from protons located on the outer sphere of gamma-CD (H-1', H-2', and H-4') provided clear evidence of inclusion complexation. The molecular modeling study, indicated inclusion complexation between methylprednisolone and gamma-CD and HP-gamma-CD by entrance of the A and B rings of methylprednisolone into the CD cavity from its bigger rim. For the methylprednisolone: HP-beta-CD complex, the molecular modeling study could not be carried out; hence, two possibilities of complex formation are proposed: (1) methylprednisolone enters HP-beta-CD from the wider rim by its D and C ring, (2) the A and B ring of methylprednisolone enters deeper in to the CD cavity so that a part of the A ring of steroidal structure is outside of the cavity.

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.

Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS.

In order to gain a better understanding of the reasons of successful self-microemulsifying drug delivery systems (SMEDDS) formulation, ten poorly water-soluble drugs, exhibiting different physicochemical properties, were selected. The solubility of the compounds was determined in various oils (long and medium chain) and surfactants (HLB>12 and HLB<10). The best performing excipients were selected for SMEDDS formulation. The droplet size and zeta potential of SMEDDS were measured in the absence and the presence of drug. Media, time and the presence of drug showed little or no influence on droplet size of most systems. Some systems displayed a different zeta potential in the presence of drugs. In vitro pharmaceutical performance of the SMEDDS formulations was investigated using the dialysis bag method in reverse mode next to conventional in vitro release methodology. The results suggested that the measured concentration of the compounds inside the dialysis bag corresponded to solubility of the compound in the release medium, which suggested that the formation of micelles inside the dialysis bag was delayed or disturbed. Conventional in vitro release methodology with pH change from acidic to neutral appeared as a simple method which gives valuable information about the dispersion and the solubilization ability of the SMEDDS formulation at different pHs. In general, formulate-ability in SMEDDS was found to depend on the solubility of the drugs in the excipients and log P of the compounds (the optimal log P was found between 2 and 4).

Itraconazole/TPGS/Aerosil200 solid dispersions: characterization, physical stability and in vivo performance.

Solid dispersions were successfully prepared by co-spray-drying of TPGS-stabilized itraconazole nanosuspensions with Aerosil200, followed by heat treatment of the powders. The itraconazole/Aerosil200 weight ratios amounted to 50/50, 30/70, 40/60 and 20/80. The itraconazole content of the powders was close to the expected value, with relative errors between 0.3% and 7.8%. X-ray powder diffraction (XRPD), solid state NMR (SSNMR) and differential scanning calorimetry (DSC) evaluation on the powders revealed the formation of amorphous itraconazole and the absence of glassy itraconazole. Dissolution of the powders was enhanced compared to crystalline and glassy itraconazole (a 2-dimensional structured form of itraconazole). However, no clear trend could be observed between drug loading and dissolution performance of the solid dispersions. Upon storage, conversion to crystalline itraconazole was observed for the 50/50 powder based on XRPD, SSNMR and DSC measurements. Although the 40/60 powder remained X-ray amorphous upon storage, DSC did reveal that a small fraction (7.5+/-1.6% after 10 months of storage) of itraconazole crystallized upon storage. For the 30/70 and 20/80 dispersions, no crystallization could be seen. After 10 months of storage, important changes in the dissolution behavior of the powders were observed. A decrease in dissolution performance was seen for the 50/50 dispersion, which could be attributed to the crystallization of itraconazole. On the other hand, the 40/60, 30/70 and 20/80 dispersions showed an increase in dissolution rate (more than 60% after 10 min). Although not completely clear at this stage, adsorption of itraconazole onto the Aerosil200 surface during storage might be responsible for this behavior. Finally, in vivo experiments were performed in the rat. Oral bioavailability of the 30/70 dispersion was, although lower compared to the marketed Sporanox formulation, significantly enhanced compared to the crystalline drug.

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.

High-throughput study of phenytoin solid dispersions: formulation using an automated solvent casting method, dissolution testing, and scaling-up.

A high-throughput experimentation method for studying the dissolution of phenytoin, a poorly water soluble drug, was developed and validated. Solid dispersions with 12 excipients (7 polymers and 5 surfactants) were prepared and tested. Each excipient was screened with three drug loadings: 10, 20, and 40% (w/w). Each solid dispersion was prepared in triplicate, for a total of 108 samples. The drug dissolution was studied in simulated gastric fluid without pepsin plus 1% sodium laurylsulfate. This study led to the identification of three improved formulations, exhibiting an extent of dissolution higher than 90% after both 30 and 60 min. The HTE results could be reproduced at a larger scale using a conventional solvent evaporating method, proving the reliability of the HTE protocol.

Stable sugar-based protein formulations by supercritical fluid drying.

The aim of this work was to produce stable, sugar-containing protein formulations by supercritical fluid (SCF) drying. Lysozyme solutions with and without added sucrose or trehalose were dried by spraying them in an SCF composed of CO(2) and ethanol or CO(2) only. The protein-to-sugar ratio was varied between 1:0 and 1:10 (w/w). Dried formulations were stored at 4 degrees C for three months and analyzed by Karl Fischer titration, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy. Lysozyme stability after reconstitution was determined by an enzymatic activity assay, UV/Vis spectroscopy, and SDS-PAGE. Smooth, spherical particles of 1-25 microm size were obtained. All formulations were initially amorphous. Crystallization during storage only occurred with a protein-to-sugar ratio of 1:10 and could be avoided by performing SCF drying without ethanol. Absence of residual ethanol in dried trehalose formulations increased the glass transition temperature up to 120 degrees C. Lysozyme in dried formulations was structurally stable, with exception of the 1:0 and 1:1 protein-to-sugar ratios, where reversible protein aggregation occurred. The results show that by avoiding ethanol, which up to now has been considered mandatory for efficient drying of aqueous solutions, and by choosing the proper protein-to-sugar ratio, it is possible to obtain stable, sugar-based protein formulations through SCF drying.