Analytical and Non-Analytical Variation May Lead to Inappropriate Antimicrobial Dosing in Neonates: An In Silico Study.

BACKGROUND: Therapeutic drug monitoring (TDM) of aminoglycosides and vancomycin is used to prevent oto- and nephrotoxicity in neonates. Analytical and nonanalytical factors potentially influence dosing recommendations. This study aimed to determine the impact of analytical variation (imprecision and bias) and nonanalytical factors (accuracy of drug administration time, use of non-trough concentrations, biological variation, and dosing errors) on neonatal antimicrobial dosing recommendations. METHODS: Published population pharmacokinetic models and the Australasian Neonatal Medicines Formulary were used to simulate antimicrobial concentration-time profiles in a virtual neonate population. Laboratory quality assurance data were used to quantify analytical variation in antimicrobial measurement methods used in clinical practice. Guideline-informed dosing recommendations based on drug concentrations were applied to compare the impact of analytical variation and nonanalytical factors on antimicrobial dosing. RESULTS: Analytical variation caused differences in subsequent guideline-informed dosing recommendations in 9.3-12.1% (amikacin), 16.2-19.0% (tobramycin), 12.2-45.8% (gentamicin), and 9.6-19.5% (vancomycin) of neonates. For vancomycin, inaccuracies in drug administration time (45.6%), use of non-trough concentrations (44.7%), within-subject biological variation (38.2%), and dosing errors (27.5%) were predicted to result in more dosing discrepancies than analytical variation (12.5%). Using current analytical performance specifications, tolerated dosing discrepancies would be up to 14.8% (aminoglycosides) and 23.7% (vancomycin). CONCLUSIONS: Although analytical variation can influence neonatal antimicrobial dosing recommendations, nonanalytical factors are more influential. These result in substantial variation in subsequent dosing of antimicrobials, risking inadvertent under- or overexposure. Harmonization of measurement methods and improved patient management systems may reduce the impact of analytical and nonanalytical factors on neonatal antimicrobial dosing.

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.

Population Pharmacokinetics of Oral-Based Administration of Cannabidiol in Healthy Adults: Implications for Drug Development.

Background and Objectives: Cannabidiol (CBD) is increasingly being studied as a therapeutic option for a range of health conditions; however, the pharmacokinetics of CBD is not well understood. This study characterized CBD pharmacokinetics in healthy adults using a population pharmacokinetic approach, informing drug development of oral-based dose forms of CBD. Materials and Methods: CBD concentration-time data were obtained from a phase I, randomized, open-label, four-way crossover study (n=12) and modeled using Phoenix NLME. Monte Carlo simulations were conducted to estimate CBD exposure with chronic dosing as intended for clinical use (50 mg b.i.d.). Results: A three-compartment pharmacokinetic model with a chain of absorption transit compartments and first-order elimination most adequately described CBD pharmacokinetics. Substantial variability in population pharmacokinetic parameters was identified (up to 60%CV), which could not be accounted for by any covariates. Simulations indicated a 3.6-fold difference in drug exposure at steady state with multiple dosing (AUCτ 95% prediction interval: 65.5-138 ng·h/mL), and variability in the time to reach steady state, which was predicted to be up to ∼3 weeks in some individuals (95% prediction interval: 18.6-297 h). Conclusions: The findings of this study have important implications for drug development. The lack of a clear dose-response relationship, due to large pharmacokinetic variability, indicates that a one-size-fits-all approach to CBD dosing may not be feasible, at least with current dosing approaches. Furthermore, an extended time to reach steady state means that the full effect of a selected dose level is not truly observed for some time and requires careful consideration in trial design.

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.

Role of Silica Intrawall Microporosity on Abiraterone Acetate Solubilization and In Vivo Oral Absorption.

SBA-15 mesoporous silica (MPS) has been widely used in oral drug delivery; however, it has not been utilized for solidifying lipid-based formulations, and the impact of their characteristic intrawall microporosity remains largely unexplored. Here, we derive the impact of the MPS microporosity on the in vitro solubilization and in vivo oral pharmacokinetics of the prostate cancer drug abiraterone acetate (AbA) when coencapsulated along with medium chain lipids into the pores. AbA in lipid (at 80% equilibrium solubility) was imbibed within a range of MPS particles (with comparable morphology and mesoporous structure but contrasting microporosity ranging from 0-247 m2/g), and their solid-state properties were characterized. Drug solubilization studies during in vitro lipolysis revealed that microporosity was the key factor in facilitating AbA solubilization by increasing the surface area available for drug-lipid diffusion. Interestingly, microporosity hindered hydrolysis of AbA to its active metabolite, abiraterone (Ab), under simulated intestinal conditions. This unique relationship between microporosity and AbA/Ab aqueous solubilization behavior was hypothesized to have significant implications on the subsequent bioavailability of the active metabolite. In vivo oral pharmacokinetics studies in male Sprague-Dawley rats revealed that MPS with moderate microporosity attained the highest relative bioavailability, while poor in vitro-in vivo correlations (IVIVC) existed between in vitro drug solubilization during lipolysis and in vivo AUC. Despite this, a reasonable IVIVC was established between the in vitro solubilization and in vivoCmax, providing evidence for an association between silica microporosity and oral drug absorption.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Coadministered Ruxolitinib and Artemether-Lumefantrine in Healthy Adults.

Despite repeated malaria infection, individuals living in areas where malaria is endemic remain vulnerable to reinfection. The Janus kinase (JAK1/2) inhibitor ruxolitinib could potentially disrupt the parasite-induced dysfunctional immune response when administered with antimalarial therapy. This randomized, single-blind, placebo-controlled, single-center phase 1 trial investigated the safety, tolerability, and pharmacokinetic and pharmacodynamic profile of ruxolitinib and the approved antimalarial artemether-lumefantrine in combination. Ruxolitinib pharmacodynamics were assessed by inhibition of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3). Eight healthy male and female participants ages 18 to 55 years were randomized to either ruxolitinib (20 mg) (n = 6) or placebo (n = 2) administered 2 h after artemether-lumefantrine (80/480 mg) twice daily for 3 days. Mild adverse events occurred in six participants (four ruxolitinib; two placebo). The combination of artemether-lumefantrine and ruxolitinib was well tolerated, with adverse events and pharmacokinetics consistent with the known profiles of both drugs. The incidence of adverse events and artemether, dihydroartemisinin (the major active metabolite of artemether), and lumefantrine exposure were not affected by ruxolitinib coadministration. Ruxolitinib coadministration resulted in a 3-fold-greater pSTAT3 inhibition compared to placebo (geometric mean ratio = 3.01 [90% confidence interval = 2.14 to 4.24]), with a direct and predictable relationship between ruxolitinib plasma concentrations and %pSTAT3 inhibition. This study supports the investigation of the combination of artemether-lumefantrine and ruxolitinib in healthy volunteers infected with Plasmodium falciparum malaria. (This study has been registered at ClinicalTrials.gov under registration no. NCT04456634.).

Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines.

BACKGROUND: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets. METHODS: Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (Cmin), maximum serum concentration and area under the concentration-time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold. RESULTS: In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758-0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%). CONCLUSIONS: The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with Cmin of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target.

The effect of high-dose, short-term caffeine intake on the renal clearance of calcium, sodium and creatinine in healthy adults.

The consumption of caffeine has been linked to osteoporosis, believed to be due to enhanced bone resorption as a result of increased calcium excretion in the urine. However, the amount of calcium in the urine may not necessarily reflect the true effect of caffeine on calcium clearance. This study therefore examined the impact of high-dose, short-term caffeine intake on renal clearance of calcium, sodium and creatinine in healthy adults. In a double-blind clinical study, participants chewed caffeine (n = 12) or placebo (n = 12) gum for 5 minutes at 2-hour intervals over a 6-hour treatment period (800 mg total caffeine). Caffeine increased renal calcium clearance by 77%. Furthermore, the effect was positively correlated with sodium clearance and urine volume, suggesting that caffeine may act through inhibition of sodium reabsorption in the proximal convoluted tubule. This study confirmed that caffeine does increase renal calcium clearance and fosters further investigation into safe consumption of caffeine.

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.

Porous Nanostructure, Lipid Composition, and Degree of Drug Supersaturation Modulate In Vitro Fenofibrate Solubilization in Silica-Lipid Hybrids.

The unique nanostructured matrix obtained by silica-lipid hybrids (SLHs) is well known to improve the dissolution, absorption, and bioavailability of poorly water-soluble drugs (PWSDs). The aim of this study was to investigate the impact of: (i) drug load: 3-22.7% w/w, (ii) lipid type: medium-chain triglyceride (Captex 300) and mono and diester of caprylic acid (Capmul PG8), and (iii) silica nanostructure: spray dried fumed silica (FS) and mesoporous silica (MPS), on the in vitro dissolution, solubilization, and solid-state stability of the model drug fenofibrate (FEN). Greater FEN crystallinity was detected at higher drug loads and within the MPS formulations. Furthermore, an increased rate and extent of dissolution was achieved by FS formulations when compared to crystalline FEN (5-10-fold), a commercial product; APO-fenofibrate (2.4-4-fold) and corresponding MPS formulations (2-4-fold). Precipitation of FEN during in vitro lipolysis restricted data interpretation, however a synergistic effect between MPS and Captex 300 in enhancing FEN aqueous solubilization was attained. It was concluded that a balance between in vitro performance and drug loading is key, and the optimum drug load was determined to be between 7-16% w/w, which corresponds to (200-400% equilibrium solubility in lipid Seq). This study provides valuable insight into the impact of key characteristics of SLHs, in constructing optimized solid-state lipid-based formulations for the oral delivery of PWSDs.

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.

Enhancement of abiraterone acetate oral bioavailability by supersaturated-silica lipid hybrids.

Abiraterone acetate (AbA) has an oral bioavailability of <10% due to its poor water solubility. Here we investigate the performance of silica-lipid hybrids (SLH) and supersaturated SLH (super-SLH) in improving oral bioavailability of AbA. Specifically, we investigate the influence of lipid type and AbA saturation level of the equilibrium solubility in the lipid (Seq), and explore in vitro-in vivo correlation (IVIVC). An oral pharmacokinetic study was conducted in fasted Sprague-Dawley rats. Suspensions of the formulations were administered via oral gavage at an AbA dose of 25 mg/kg. Plasma samples were collected and analyzed for drug content. SLH with a saturation level of 90% Seq enhanced the oral bioavailability of unformulated AbA by 31-fold, and super-SLH with saturation levels of 150, 200 and 250% Seq, enhanced the bioavailability by 11, 10 and 7-fold, respectively. In comparison with the commercial product Zytiga, SLH (90% Seq) increased the oral bioavailability 1.43-fold whereas super-SLH showed no improvement. A reasonable IVIVC existed between the performance of unformulated AbA, SLH and super-SLH, in the in vitro lipolysis and in vivo oral pharmacokinetic studies. SLH and super-SLH significantly enhanced the oral bioavailability of AbA. Additionally, supersaturation of SLH improved drug loading but did not correlate with enhanced AbA bioavailability.

Supersaturated-Silica Lipid Hybrids Improve in Vitro Solubilization of Abiraterone Acetate.

PURPOSE: Abiraterone acetate (AbA) is a poorly water-soluble drug with an oral bioavailability of <10% and a significant pharmaceutical food effect. We aimed to develop a more efficient oral solid-state lipid-based formulation for AbA using a supersaturated silica-lipid hybrid (super-SLH) approach to achieve high drug loading, improve in vitro solubilization and mitigate the food effect, while gaining a mechanistic insight into how super-SLH are digested and release drug. METHODS: The influence of super-SLH saturation level and lipid type on the physicochemical properties and in vitro solubilization during lipolysis of the formulations was investigated and compared to the commercial product, Zytiga. RESULTS: Super-SLH achieved significantly greater levels of AbA solubilization compared to Zytiga. Solubilization was influenced by the AbA saturation level, which determined the solid state of AbA and the relative amount of lipid, and the lipid utilized, which determined its degree of digestion and the affinity of the lipid and digestion products to the silica. A fine balance existed between achieving high drug loads using supersaturation and improving performance using the lipid-based formulation approach. The non-supersaturated SLH prepared with Capmul PG8 mitigated the 3-fold in vitro food effect. CONCLUSION: SLH and super-SLH improve in vitro solubilization of AbA, remove the food effect and demonstrate potential to improve oral bioavailability in vivo. Graphical Abstract Abiraterone acetate was formulated as silica-lipid hybrids and demonstrated enhanced in vitro solubilization in comparison to pure abiraterone acetate and commercial product, Zytiga.

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.

Stimulus-Responsive Antibiotic Releasing Systems for the Treatment of Wound Infections.

There remains an unmet need for innovative treatments for chronic wound infections as they continue to be a financial and social burden on society. Because of the dynamic nature of wounds, this study investigated the utilization of stimulus-responsive plasma polymers for the development of pH- and thermoresponsive antibiotic delivery systems for the treatment of wound infections. Porous silicon films were loaded with the antibiotic levofloxacin (LVX) and subsequently coated with plasma polymer layers: first, poly(1,7-octadiene) (pOCT) for stability, followed by either the temperature-responsive polymer poly N,N-diethylacrylamide (pDEA) or the pH- responsive polymer poly 2-(diethylamino)ethyl methacrylate (pDEAEMA), to fabricate two delivery systems. The delivery systems were thoroughly characterized chemically and physically and tested in vitro through drug release and bacterial zone of inhibition studies. After a 16 h time point, the system containing pDEA achieved 3.2-fold greater release at 45 °C compared to 22 °C, whereas the system containing pDEAEMA achieved a 2.2-fold greater release when exposed to pH 8.5 media compared to pH 6.2 media. Furthermore, both systems retained their antimicrobial activity and demonstrated stimulus-responsive release to form zones of inhibition on relevant wound pathogens, Pseudomonas aeruginosa, Staphylococcus epidermidis and Staphylococcus aureus. Therefore, this proof-of-principle study confirms that stimulus-responsive porous silicon films can be utilized to deliver antibiotic when exposed to physiologically relevant stimuli such as pH and temperature with the potential to be applied to other pharmaceutics.

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.

Supersaturated Silica-Lipid Hybrid Oral Drug Delivery Systems: Balancing Drug Loading and In Vivo Performance.

Supersaturated silica-lipid hybrid (super-SLH) drug carriers are a recent strategy to improve the drug loading of oral solid lipid based formulations, however they are yet to be studied in vivo. This study investigated the in vivo pharmacokinetics (PK) of super-SLH containing ibuprofen (IBU), as a model Biopharmaceutics Classification Scheme (BCS) class II drug, analyzing the influence of supersaturated drug loading on oral bioavailability and assessing in vitro-in vivo correlation (IVIVC). In addition, super-SLH was directly compared with spray-dried SLH and Nurofen to explore its potential advantages over the well-established and commercial formulations. Fasted male Sprague-Dawley rats were administered formulation suspensions (10 mg/kg IBU) via oral gavage, and blood samples were acquired and plasma was analyzed for IBU concentrations over 24 hours. In vivo, super-SLH with drug loads of 9.5 (99.5% saturated) and 19.3% w/w (227% saturated) achieved bioavailabilities equal to spray-dried SLH and 2.2-fold greater than Nurofen. This effect diminished for super-SLH with a drug load of 29.1% w/w (389% saturated), which exhibited a bioavailability of less than Nurofen due to its greater extent of supersaturation and larger content of crystalline IBU. The super-SLH containing 19.3% w/w IBU provided the greatest PK performance, achieving the same degree of bioavailability enhancement as spray-dried SLH and requiring 63% less formulation. A significant positive IVIVC was observed between the performances of the formulations. These findings indicate the potential of super-SLH as an improved oral solid lipid based formulation strategy for enhancing oral bioavailability of other BCS class II drugs.

Supersaturated silica-lipid hybrids (super-SLH): An improved solid-state lipid-based oral drug delivery system with enhanced drug loading.

The method of supersaturation for achieving high drug loads in lipid-based formulations is under exploited and relatively unexplored, especially in the case of solid-state lipid-based formulations. Silica-lipid hybrids are solid-state lipid-based formulations designed for improving the oral delivery of poorly water-soluble drugs. However, their application to compounds of low potency and requiring large doses is limited by their low drug loading capacity. Here, an innovative technique to fabricate supersaturated silica-lipid hybrid formulations (super-SLH) has been established and the relationship between drug load and performance investigated. Using the model poorly water-soluble drug, ibuprofen, super-SLH was fabricated possessing drug loads ranging from 8 to 44% w/w, i.e. greater than the previously developed standard ibuprofen silica-lipid hybrids (5.6% w/w). Drug crystallinity of the encapsulated ibuprofen ranged from non-crystalline to part-crystalline with an increase in drug load. Super-SLH achieved improved rates and extents of dissolution when compared to pure ibuprofen, regardless of the drug load. The percentage increase in dissolution extent at 60 min varied from 200 to 600%. The results of the current study indicate that supersaturation greatly improves drug loading and that 16-25% w/w is the optimum loading level which retains optimal dissolution behaviour for the oral delivery of ibuprofen, which has the potential to be translated to other poorly water-soluble drugs.