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

AbstractThis 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

Pharmaceutical and biopharmaceutical evaluation of ordered mesoporous silicates as dissolution-enhancing excipients

Estimates are that around 70% of contemporary drug candidates exhibit insufficient aqueous solubility to allow for their adequate and reproducible absorption from the gastrointestinal tract following oral administration. A variety of formulation techniques can be utilised to improve the systemic exposure of orally administered poorly soluble drugs, and it is increasingly apparent that adsorption on ordered mesoporous silicates presents a valuablemeans to do so. The large regular repeating mesoporous structures of ordered mesoporous silicates offer the possibility of adsorbing large amounts of drug. Adsorption of drugs onto the silica surface not only increases the surface area available for contact with the dissolution medium, but also increases apparent solubility by virtue of a loss of drug crystallinity. Typically, exposure to aqueous media of these drug-silica systems is associated with a rapid displacement of drug molecules from the silica surface, resulting in a drug release rate that is faster than the dissolution rate of the corresponding crystalline from.Whilst the first published results on this newly introduced technology are promising, truly compelling evidence for the potential of OMSs is essentially lacking, most notably because current knowledge on the pharmaceutical performance of these materials has been established on a very limited database of in vitro and to a much lesser extent in vivo experiments in animal models. Furthermore, many of the published data sets are heavily biased towards studies with ibuprofen and/or studies in which in vitro release experiments are conducted under conditions that are not reflective of the conditions that prevail in the human gastrointestinal tract. The main objective of this dissertation research was to gain more insight into the pharmaceutical performance of OMSs, with a strong focus on evaluating in vivo performance (using the rat as preclinical model). The experiments were divided into four studies of which the aim was to:1. To evaluate the applicability (in terms of loading, release and physical stability) of the OMS material SBA-15 to a series of ten physicochemically diverse poorly soluble drugs.2. Assess the usefulness of co-administering precipitation inhibitors with SBA-15 in order to enhance absorption. Itraconazole (a weak base) was used a model drug in this study.3. Investigate whether the extent of precipitation following release could be reduced and thus: the extent absorption increased by decelerating the release rate from OMSs. Fenofibrate (a neutral drug) was used a model compound in this study.4. Explore the utility of targeting the release of weakly acidic drugs from OMSs to the small intestine. Glibenclamide (in vitro and in vivo) and indomethacin (in vitro) were used in this study.In view of the very limited number of compounds that had been formulated successfully with OMSs, we set up a first study in which we explored the loading, release and physical stability of ten physicochemically diverse compoundsformulated with the OMS material SBA-15. The main conclusions from this study were that (i) we could use a generic impregnation procedure (using methylene chloride as a solvent) to load all model compounds on SBA-15 to obtain a drug payload of 20%; (ii) all of these formulations were non-crystalline (as observed using DSC); (iii) for all model compounds the release rate from SBA-15 was faster than the dissolution rate of the corresponding crystalline material and that (iv) no recrystallisation wasobserved upon storage at 25 °C/52% RH for at least six months such that the pharmaceuticalperformance of the formulations was fully retained after storage. These findings suggest that the formulate-ability with OMSs (i.e. the ability to yield non-crystalline, physically stable, dissolution-enhancing formulations with a realistic drug payload) is relatively independent of the physicochemical profile of the drug compound. This is an interesting outcome, in that successful formulation with all of today s solubility/dissolution-enhancing approaches depends, at least to some extent, on the physicochemical properties of the active compound. In addition, in view of the fact that the widespread use of amorphous drug forms has predominantly been limited by physical stability issues, the ability of SBA-15 to retain a wide variety of drugs in a non-crystalline state for extended periods of time seems to offer enormous possibilities.Whilst the observation that formulation with OMSs resulted in adissolution-enhancing effect for a large range of compounds, enhancing dissolution is a necessary but not sufficient step to increase absorption. Release from OMSs in vivo is likely to be associated with the creation of supersaturation, which may well increase the flux of drug across the gastrointestinal epithelium but also holds the risk of drug precipitation. Therefore, in a subsequent series of experiments, we aimed to assess the pharmaceutical performance of OMS-based formulations under biorelevant conditions, that is, by using biorelevant media such as FaSSIF and FeSSIF and by taking the phenomenon of supersaturation and the associated likelihood of precipitation into account. For these experiments, we selected a weak base (itraconazole), a neutral drug (fenofibrate) and a weak acid (glibenclamide dataset supported by invitro data collected with indomethacin) as model compounds. The data obtained from these biorelevant release experiments were tied with the data from subsequent in vivo studies anapproach that enabled us to gain insights into the in vivo behaviour of OMS-based formulations.In a first in vivo study, we used itraconazole as a model compound. Earlier work by our group had demonstrated that this compound is readily released in SGF to generate a stable supersaturated solution. However, supersaturated itraconazole precipitates rapidly in simulated intestinal media. We therefore assumed that we could enhance the performance of OMSs by co-administration of an excipient that is capable of inhibiting precipitation upon the gastric-to-intestinal transition. Based on a series of cosolvent-induced supersaturation experiments and in vitro release experiments simulating the gastric-to-intestinal transition, the polymer hydroxypropylmethylcellulose 2910 (HPMC) was identified as the most suitable inhibitor of itraconazole precipitation. Co-administration of HPMC in vivo resulted in a more than 60% increase in the extent of absorption as compared to SBA-15 without precipitation inhibitors.Whilst co-administration of a precipitation inhibitor is likely to enhance the performance of OMSs, it may not be useful to all compounds. For instance, unpublished results by our group had demonstrated that the precipitation kinetics of fenofibrate could not be effectively inhibited by excipients. This made us think of another option to minimise precipitation following release, viz. decreasing drug release from the silica material. It was our hypothesis that decreasing drug release would attenuate the degree of supersaturation in vivo, thereby reducing the risk of precipitation. In order to test this hypothesis, we synthesised three different OMS materials with different pore diameter which were then loaded with fenofibrate. Whilst sink conditions indicated a clear increase in release rate with increasing pore size, under supersaturating conditions (FaSSIF) this trend was inversed in that a slower release rate was associated with a state of supersaturation that was maintained for a longer period of time, such that a smaller pore diameter resulted in a higher area under the concentration-time curve. The enhanced supersaturation profile observed in FaSSIF was also reflected in vivo, in that the area under the plasma concentration-time profile increased with decreasing pore diameter.A last in vivo study was set up to gain more insight into the behaviour of weakly acidic drugs formulated with OMS. Prior to the start of our experiments, we assumed that precipitation following release of this class of compounds could be minimised by targeting release to the small intestine. The rationale for this assumption is that weakly acidic drugs, by their very nature, exhibit higher solubility at the pH-values prevailing in the small intestine as compared to those in the stomach. The lower solubility in the stomach, and the consequent higher driving force for precipitation, is likely to lead to more rapid precipitation of the released drug fraction. If significant precipitation takes place in the stomach, i.e. prior to reaching the small intestine (the major site of absorption), the dissolution-enhancing effect of OMSs may be totally abolished. Initially, we thought of enteric coating as a way to avoid release in the stomach. However, during the first experiments conducted within the framework of this study, it appeared that the weakly acidic model drug glibenclamide and indomethacin were released only to a negligibly low extent in SGF (less than 1% for both drugs), but rapidly and completely in FaSSIF. This preferential release in FaSSIF was considered crucial towards achieving adequate absorption, since solubility and supersaturation experiments had demonstrated that conditions for release were more favourable in FaSSIF as compared to SGF from both a thermodynamic (i.e. higher solubility mainly of relevance to indomethacin) as well as a kinetic (i.e.slower precipitation - mainly of relevance to glibenclamide) point of view. The preferential release under the conditions that typically prevail in the small intestine led to a high pharmaceutical performance, in that the extent of absorption of glibenclamide formulated with SBA-15 was found to be more than fourfold higher than that of the commercially available glibenclamide formulation Daonil®.In conclusion, this dissertation research has highlighted the potential of OMSs to improve the systemic exposure of orally administered poorly water soluble drugs. The exceptional ability of OMSs to physically stabilise non-crystalline drugs, as demonstrated in Chapter 3, seems to offer enormous possibilities. What appears to be the major concern associated with the technology is the likelihood of precipitation following release. As demonstrated in Chapters 4, 5 and 6, precipitation following release can be minimised through, respectively,co-administration of a precipitation inhibitor, tuning (i.e. decreasing) the mesopore diameter or targeting release to the small intestine. Whichever of these strategies is most successful depends, at least to some extent, on the physicochemical properties of the compound and the propensity of the compound to precipitate from the supersaturated state. Besides being insightful in the field of OMS-based drug delivery systems, the data described in this dissertation also illustrate a number of concepts that might usefully be incorporated informulation strategies for non-OMS-based supersaturating drug delivery systems.nrpages: 150status: publishe

Impregnation of Fenofibrate on mesoporous silica using supercritical carbon dioxide

International audienceLow 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

Impregnation of Fenofibrate on mesoporous silica using supercritical carbon dioxide

International audienceLow 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

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.status: publishe

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 DaonilRstatus: publishe

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 (SGFsp) 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.status: publishe

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, 4.4nm 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±34Mh, 86±19Mh and 20±13Mh for the materials with pore diameter of 2.7 nm, 4.4nm 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.status: publishe

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.Whenhigh 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 ± 2726 nM h). 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.status: publishe

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.status: publishe