Impact of Food on the Oral Absorption of N-Acetyl-D-Mannosamine in Healthy Men and Women.

N-Acetyl-D-mannosamine (ManNAc) is an endogenous monosaccharide and precursor of N-acetylneuraminic acid (Neu5Ac), a critical sialic acid. ManNAc is currently under clinical development to treat GNE myopathy, a rare muscle-wasting disease. In this randomized, open-label, 2-sequence, crossover study, 16 healthy women and men were administered a single oral dose of ManNAc under fasting and fed conditions. Blood samples were collected for 48 hours after dosing for quantification of plasma ManNAc and Neu5Ac concentrations. Noncompartmental pharmacokinetic and deconvolution analyses were performed using baseline-corrected plasma concentration data. Administration of ManNAc in the fed state resulted in a 1.6-fold increase in ManNAc exposure, compared to fasting conditions. A concurrent increase in Neu5Ac exposure was observed in the presence of food. Deconvolution analysis indicated that the findings were attributed to prolonged absorption rather than an enhanced rate of absorption. The impact of food on ManNAc pharmacokinetics was greater in women than men (fed/fasted area under the concentration-time curve from time 0 to infinity mean ratio: 198% compared to 121%). It is hypothesized that the presence of food slows gastric emptying, allowing a gradual release of ManNAc into the small intestine, translating into improved ManNAc absorption. The results suggest that taking ManNAc with food may enhance its therapeutic activity and/or reduce the daily dosage requirement.

The Influence of Blonanserin Supersaturation in Liquid and Silica Stabilised Self-Nanoemulsifying Drug Delivery Systems on In Vitro Solubilisation.

Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90-300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application.

Bio-enabling strategies to mitigate the pharmaceutical food effect: A mini review.

The concomitant administration of oral drugs with food can result in significant changes in bioavailability, leading to variable pharmacokinetics and considerable clinical implications, such as over- or under-dosing. Consequently, there is increasing demand for bio-enabling formulation strategies to reduce variability in exposure between the fasted and fed state and/or mitigate the pharmaceutical food effect. The current review critically evaluates technologies that have been implemented to overcome the positive food effects of pharmaceutical drugs, including, lipid-based formulations, nanosized drug preparations, cyclodextrins, amorphisation and solid dispersions, prodrugs and salts. Additionally, improved insight into preclinical models for predicting the food effect is provided. Despite the wealth of research, this review demonstrates that application of optimal formulation strategies to mitigate the positive food effects and the evaluation in preclinical models is not a universal approach, and improved standardisation of models to predict the food effects would be desirable. Ultimately, the successful reformulation of specific drugs to eliminate the food effect provides a panoply of advantages for patients with regard to clinical efficacy and compliance.

Harnessing the potential of nanostructured formulations to mimic the food effect of lurasidone.

Lurasidone is an important antipsychotic drug indicated for the treatment of schizophrenia and bipolar disorder, with an oral bioavailability of 9-19% owing to its poor aqueous solubility. Additionally, lurasidone exhibits a 2-fold positive food effect, such that patients must administer their medication with a meal, leading to significant non-compliance. The aim of this research was to evaluate the in vitro and in vivo performance of lurasidone when engineered as nanostructured systems. Specifically, a nanosuspension, nano-emulsion and silica-lipid hybrid (SLH) microparticles were formulated and the influence of composition and nanostructure on the mechanism of solubilisation was compared. Formulations were shown to enhance fasted state solubilisation levels in vitro by up to 5.9-fold, compared to pure drug. Fed- and fasted-state solubilisation profiles revealed that in contrast to the nanosuspension and nano-emulsion, lurasidone SLH mitigated the positive pharmaceutical effect of lurasidone. In vivo pharmacokinetic evaluations revealed that the nanosuspension, nano-emulsion and SLH enhanced the bioavailability of lurasidone by 3-fold, 2.4-fold and 8.8-fold, respectively, compared to pure drug after oral administration. For lurasidone, the combination of lipid-based nanostructure and porous silica nanostructure (SLH) led to optimal fasted state bioavailability which can ultimately result in enhanced treatment efficacy, easier dosing regimens and improved patient outcomes.

The Influence of Solidification on the in vitro Solubilisation of Blonanserin Loaded Supersaturated Lipid-Based Oral Formulations.

Supersaturated silica-lipid hybrids have previously demonstrated improved in vitro solubilisation and in vivo oral bioavailability of poorly water-soluble drugs, however were only fabricated using a single lipid (LFCS type I formulations) and were not compared to their liquid precursors. This study investigated the influence of lipid formulation classification (type I vs. type II vs. type IIIA/SNEDDS) and physical state (liquid LBF vs. solidified with silica) on the in vitro solubilisation of the poorly soluble, weak base, anti-psychotic drug, blonanserin (BLON), from a supersaturated lipid-based formulation (LBF). Stable liquid supersaturated LBF were fabricated using BLON (loaded at 150% of its equilibrium solubility), and solidified through encapsulation within porous silica microparticles at a 1:1 ratio. Their physicochemical properties and in vitro solubilisation during lipolysis were compared. Supersaturated BLON was encapsulated in the non-crystalline form. All supersaturated LBF improved the solubilisation of pure BLON during lipolysis regardless of their lipid formulation type or their physical state (1.7- to 13.4-fold). SNEDDS achieved greater solubilisation than the type II formulations (1.4- to 1.7-fold). Furthermore, the liquid precursors achieved greater solubilisation than the silica solidified formulations (4.5- to 5.7-fold). Additionally, in an attempt to increase BLON solubilisation, a spray-dried SNEDDS and dual-loaded solidified super-SNEDDS solidified with silica pre-loaded with BLON was developed, however did not significantly improve solubilisation. Liquid SNEDDS were identified as the optimal oral supersaturated LBF strategy for BLON based on in vitro lipolysis studies. Solidification of LBF using silica is a viable strategy for improving stability, however for drugs such as BLON, solidification may impede in vitro release and solubilisation.

A safety, tolerability, and pharmacokinetic study of a novel simvastatin silica-lipid hybrid formulation in healthy male participants.

Simvastatin (SIM) is a commonly used cholesterol-lowering drug that can reduce the risk of major cardiovascular events. However, due to its poor intrinsic water solubility, the drug is poorly absorbed from the gastrointestinal tract and exhibits a low oral bioavailability of approximately 5%. The aim of this study was to fabricate and optimize SIM encapsulated silica-lipid hybrids (SLH) as a solid-state lipid-based formulation to enhance absorption and bioavailability during a human in vivo pharmacokinetic study. SLH formulations were formulated by spray drying a submicron emulsion with either Aerosil® 300 fumed silica nanoparticles (SLH-A) or Syloid® 244 amorphous micronized silica (SLH-B). A cross-over, double-blinded study design was implemented to evaluate the performance of SLH formulations compared with a commercially available formulation in 12 healthy male participants after oral administration under fasting conditions. SLH formulations enhanced the bioavailability of SIM up to 1.6-fold and more importantly the active simvastatin acid (SIMA), 3.5-fold when compared with an equivalent dose of commercial formulation. The results demonstrate that the porous nanostructure of SLH impact systemic SIM and SIMA concentrations and may serve as a novel approach to enhance the bioavailability of specifically the parent or metabolite. No significant difference was observed in exposure when SLH formulations were administered at 10 mg in comparison with 20 mg of the commercial formulation, suggesting the potential for dose reduction. The study indicated that SLH formulations were safe and well-tolerated when administered to healthy males, confirming the commercial potential of SLH to enhance the bioavailability of poorly water-soluble drugs. Graphical abstract.

Enhancing the oral bioavailability of simvastatin with silica-lipid hybrid particles: The effect of supersaturation and silica geometry.

Silica-lipid hybrid (SLH) microparticles are a solidified lipid-based drug delivery system under investigation for their aptitude to enhance the oral bioavailability of poorly water-soluble drugs. The cholesterol-lowering agent, simvastatin (SIM), is poorly water-soluble and undergoes extensive first pass metabolism, resulting in a low oral bioavailability of approximately 5%. Hence, the current pre-clinical studies investigated the application of SLH technology to SIM with a supersaturation approach, aiming to enhance bioavailability and drug loading capacity. Additionally, the effect of silica was explored by evaluating the performance of SLH fabricated with silica of different particle geometries. SLH microparticles with supersaturated SIM loading levels ranging from 100% to 400% above the equilibrium solubility were successfully fabricated using either Aerosil® 300 or Syloid® 244 silica. All SLH formulations existed as white free-flowing powders, consisting of spherical porous microparticles for Aerosil® 300, and aggregated irregular microparticles for Syloid® 244. During in vitro dissolution in pH 7.0 media, the SLH formulations performed up to 4.4-fold greater than pure SIM powder. Furthermore, in vivo oral pharmacokinetics in male Sprague-Dawley rats revealed that the SLH formulations enhanced the oral bioavailability of SIM up to 6.1-fold and 2.9-fold, in comparison to pure SIM powder and a commercially available formulation (Simvastatin Sandoz®), respectively. The greatest in vivo performance enhancement was observed for the SLH formulation manufactured with Syloid® 244 silica with a supersaturation level of 200%. SLH technology demonstrated to be a successful formulation strategy to significantly improve the oral bioavailability of SIM in rodents and therefore, has a strong potential to also improve the oral bioavailability of SIM in humans.

Oral formulation strategies to improve the bioavailability and mitigate the food effect of abiraterone acetate.

Abiraterone acetate, marketed as Zytiga®, is an antiandrogen medication used in the treatment of prostate cancer. Abiraterone acetate is a BCS Class IV compound associated with several oral delivery challenges. Its low solubility and high lipophilicity lead to poor oral bioavailability (<10%) and a dramatic positive food effect (5-10-fold). Hence, a large dose of abiraterone acetate (1000 mg per day) is prescribed to patients who must fast for at least 1 h before and 2 h after administration. The recent expiry of Zytiga®s' patent has led to the emergence of publications describing improved oral formulation strategies for abiraterone acetate. This review aims to discuss the characteristics of abiraterone acetate that lead to its unfavorable oral delivery, examine the oral formulation strategies that have been applied, and to describe potential alternative oral formulation strategies that have been used for other BCS Class IV drugs, to determine the most valuable strategies to develop novel and improved alternatives to the current commercial product. Specific emphasis of this review is placed on enabling oral formulation strategies that can improve solubilization and bioavailability, reduce the clinical dose and remove the pharmaceutical food effect to ultimately provide prostate cancer patients with a more efficient formulation with greater patient compliance.

The effect of drug ionization on lipid-based formulations for the oral delivery of anti-psychotics.

Lipid-based formulations (LBFs) are well-known to improve the oral bioavailability of poorly water-soluble drugs (PWSDs) by presenting the drug to the gastrointestinal environment in a molecularly dispersed state, thus avoiding the rate-limiting dissolution step. Risperidone and lurasidone are antipsychotics drugs which experience erratic and variable absorption, leading to a low oral bioavailability. The aim of this research was to develop and investigate the performance of risperidone and lurasidone when formulated as an emulsion and silica-lipid hybrid (SLH). Lurasidone and risperidone were dissolved in Capmul® MCM at 100% and 80% their equilibrium solubility, respectively, prior to forming a sub-micron emulsion. SLH microparticles were fabricated by spray-drying a silica stabilised sub-micron emulsion to form a solid powder. The performances of the formulations were evaluated in simulated intestinal media under digesting conditions, where the emulsion and SLH provided a 17-fold and 23-fold increase in LUR solubilisation, respectively. However, the performance of RIS was reduced by 2.2-fold when encapsulated within SLH compared to pure drug. Owing to its pKa, RIS adsorbed to the silica and thus, dissolution was significantly hindered. The results reveal that LBFs may not overcome the challenges of all PWSDs and physiochemical properties must be carefully considered when predicting drug performance.

Contrasting Anti-obesity Effects of Smectite Clays and Mesoporous Silica in Sprague-Dawley Rats.

Porous colloids have been shown to exert unique bioactivities for mediating lipid (fat) metabolism and thereby offer significant potential as anti-obesity therapies. In this study, we compare the capacity for two classes of colloids, that is, smectite clays (Laponite XLG, LAP; montmorillonite, MMT) and mesoporous silica (SBA-15 ordered silica; MPS), to impede intestinal lipid hydrolysis and provoke lipid and carbohydrate excretion through adsorption within their particle matrices. A two-stage in vitro gastrointestinal lipolysis model revealed the capacity for both smectite clays and MPS to inhibit the rate and extent of lipase-mediated digestion under simulated fed state conditions. Each system adsorbed more than its own weight of organic media (i.e., lipid and carbohydrates) after 60 min lipolysis, with MMT adsorbing >10% of all available organics through the indiscriminate adsorption of fatty acids and glycerides. When co-administered with a high-fat diet (HFD) to Sprague-Dawley rats, treatment with MMT and MPS significantly reduced normalized rodent weight gain compared to a negative control, validating their potential to restrict energy intake and serve as anti-obesity therapies. However, in vitro-in vivo correlations revealed poor associations between in vitro digestion parameters and normalized weight gain, indicating that additional/alternate anti-obesity mechanisms may exist in vivo, while also highlighting the need for improved in vitro assessment methodologies. Despite this, the current findings emphasize the potential for porous colloids to restrict weight gain and promote anti-obesity effects to subjects exposed to a HFD and should therefore drive the development of next-generation food-grade biomaterials for the treatment and prevention of obesity.

A self-emulsifying Omega-3 ethyl ester formulation (AquaCelle) significantly improves eicosapentaenoic and docosahexaenoic acid bioavailability in healthy adults.

PURPOSE: Application of intelligent formulation design has the ability to address the poor bioavailability and improve the fasted state bioavailability of fish oils. In this study we assessed the ability of a self-emulsifying drug delivery system (SEDDS), AquaCelle®, as an additive to enhance the oral absorption of Omega-3 ethyl esters (EE) in healthy subjects under low-fat diet conditions. METHODS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) EE were formulated with AquaCelle®. A single dose (680 mg dose of oil containing 272 mg of EPA EE and 204 mg of DHA EE), randomized, double-blind, study measured uptake of EPA and DHA over 24 h in healthy adults. Participants were randomized into two groups, receiving either the SEDDS AquaCelle® fish oil formulation or the unformulated fish oil EE as control. RESULTS: The AquaCelle® fish oil EE formulation demonstrated instant and complete emulsification on addition to water to produce an emulsion with an average diameter of 43 µm, compared to the oil alone which did not emulsify. The study revealed a significant difference in absorption (Cmax and AUC0-24h) between the AquaCelle® group and the control group. The AquaCelle® group was capable of increasing maximum plasma concentrations and absorption (AUC0-24h) of total Omega-3 (EPA + DHA) 3.7- and 7.1-fold, respectively, compared to the control. CONCLUSION: Formulating Omega-3 EE with a SEDSS concentrate (AquaCelle®) demonstrated a significant improvement in the oral absorption of Omega-3 fatty acids without requiring a high-fat meal.

Nanostructured clay particles supplement orlistat action in inhibiting lipid digestion: An in vitro evaluation for the treatment of obesity.

Obesity is a rapidly growing epidemic, with over one-third of the global population classified as overweight or obese. Consequently, an urgent need exists to develop innovative approaches and technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions technologies that regulate energy uptake, to curb the rising trend in obesity statistics. In this study, nanostructured clay (NSC) particles, fabricated by spray drying delaminated dispersions of commercial clay platelets (Veegum® HS and LAPONITE® XLG), were delivered as complimentary, bioactive excipients with the potent lipase inhibitor, orlistat, for the inhibition of fat (lipid) hydrolysis. Simulated intestinal lipolysis studies were performed by observing changes in free fatty acid concentration and revealed that a combinatorial effect existed when NSC particles were co-administered with orlistat, as evidenced by a 1.2- to 1.6-fold greater inhibitory response over 60 min, compared to dosing orlistat alone. Subsequently, it was determined that a multifaceted approach to lipolysis inhibition was presented, whereby NSC particles adsorbed high degrees of lipid (up to 80% of all lipid species present in lipolysis media) and thus physically shielded the lipid-in-water interface from lipase access, while orlistat covalently attached and blocked the lipase enzyme active site. Thus, the ability for NSC particles to enhance the biopharmaceutical performance and potency of orlistat is hypothesised to translate into promising in vivo pharmacodynamics, where this novel approach is predicted to lead to considerably greater weight reductions for obese patients, compared to dosing orlistat alone.

Solidification to improve the biopharmaceutical performance of SEDDS: Opportunities and challenges.

Self-emulsifying drug delivery systems (SEDDS) offer potential for overcoming the inherent slow dissolution and poor oral absorption of hydrophobic drugs by retaining them in a solubilised state during gastrointestinal transit. However, the promising biopharmaceutical benefits of liquid lipid formulations has not translated into widespread commercial success, due to their susceptibility to long term storage and in vivo precipitation issues. One strategy that has emerged to overcome such limitations, is to combine the solubilisation and dissolution enhancing properties of lipids with the stabilising effects of solid carrier materials. The development of intelligent hybrid drug formulations has presented new opportunities to harness the potential of emulsified lipids in optimising oral bioavailability for lipophilic therapeutics. Specific emphasis of this review is placed on the impact of solidification approaches and excipients on the biopharmaceutical performance of self-emulsifying lipids, with findings highlighting the key design considerations that should be implemented when developing hybrid lipid-based formulations.

Nanocrystal-silica-lipid hybrid particles for the improved oral delivery of ziprasidone in vitro.

The synergistic effect of nanosizing and lipid-based drug delivery systems (LBDDS) was explored to enhance formulation drug loading levels and improve drug solubilisation in the gastrointestinal environment. A novel formulation combining drug nanocrystals and silica-lipid hybrid (SLH) microparticles as a solid-state LBDDS was developed for the challenging poorly water-soluble drug, ziprasidone. A ziprasidone nanosuspension was fabricated via high-pressure homogenisation, achieving a mean particle size of 280 nm. In vitro dissolution studies revealed the nanosuspension to exhibit a significant 2.4-fold increase in the extent of drug dissolution, relative to pure drug. Novel ziprasidone nanocrystal-loaded SLH microparticles (ncSLH) were formulated by freeze-drying a precursor drug-loaded emulsion with drug nanocrystals and silica nanoparticles. Drug loading levels were increased at least 17-fold relative to conventional SLH microparticles, resulting in an increase in crystalline drug content and a change in surface atomic composition. The in vitro performance was evaluated by quantifying solubilisation levels during simulated intestinal lipolysis studies. Novel ncSLH significantly improved the in vitro fasted state solubilisation of ziprasidone (up to 4.7-fold), thus indicating the potential for such a formulation to overcome some of the various challenges faced by poorly water-soluble, brick-dust drug molecules.