Enhanced Dissolution of Amphotericin B through Development of Amorphous Solid Dispersions Containing Polymer and Surfactants.

Amphotericin B (AmB) is the gold standard for antifungal therapy; however, its poor solubility limits its administration via intravenous infusion. A promising formulation strategy to achieve an oral formulation is the development of amorphous solid dispersions (ASDs) via spray-drying. Inclusion of surfactants into ASDs is a newer concept, yet it offers increased dissolution opportunities when combined with a polymer (HPMCAS 912). We developed both binary ASDs (AmB:HPMCAS 912 or AmB:surfactant) and ternary ASDs (AmB:HPMCAS 912:surfactant) using a variety of surfactants to determine the optimal surfactant carbon chain length and functional group for achieving maximal AmB concentration during in vitro dissolution. The ternary ASDs containing surfactants with a carbon chain length of 14 ± 2 carbons and a sulfate functional group increased the dissolution of AmB by 90-fold compared to crystalline AmB. These same surfactants, when added to a binary ASD, however, were only able to achieve up to a 40-fold increase, alluding to a potential interaction occurring between excipients or excipient and drug. This potential interaction was supported by dynamic light scattering data, in which the ternary formulation produced a single peak at 895.2 dnm. The absence of more than one peak insinuates that all three components are interacting in some way to form a single structure, which may be preventing AmB self-aggregation, thus improving the dissolution concentration of AmB.

Biorelevant Dissolution Method Considerations for the Appropriate Evaluation of Amorphous Solid Dispersions: are Two Stages Necessary?

Biorelevant dissolution testing has been widely used to better understand a drug or formulation's behavior in the human gastrointestinal (GI) tract. The successful evaluation of biorelevant dissolution behavior requires recognizing the importance of utilizing suitable biorelevant media in conjunction with an appropriate dissolution method, especially for supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs). However, most conventional biorelevant dissolution testing methods are not able to accurately reflect the dissolution, supersaturation, and precipitation tendencies of a drug or formulation, which could misinform ASD formulation screening and optimization. In this study, we developed a single compartment 2-stage pH-shift dissolution testing method to simulate the changes in pH, media composition, and transit time in the GI tract, and results were compared against the conventional single compartment 1-stage dissolution method. Nine model drugs were selected based on their ionization properties (i.e. acid, base or neutral) and precipitation tendency (i.e. moderate or slow crystallizer). The dissolution results confirmed that 2-stage pH-shift dissolution is the preferred biorelevant dissolution method to assess non-ionized weak base (nifedipine) and neutral (griseofulvin) compounds exhibiting a moderate precipitation rate from solution when formulated as ASDs. Finally, we designed a flowchart guidance for the appropriate biorelevant dissolution performance characterization of different categories of ASD formulations.

Do Macrocyclic Peptide Drugs Interact with Bile Salts under Simulated Gastrointestinal Conditions?

Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.

Enhancing Intestinal Absorption of a Model Macromolecule via the Paracellular Pathway using E-Cadherin Peptides.

Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro, were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C10). Cyclic HAVN1 and ADTC5 peptides increased FD4 bioavailability by 7.2- and 4.4-fold compared to control, respectively (not statistically significant). In contrast, C10 provided a statistically significant 10.7-fold relative bioavailability enhancement for FD4. Importantly, this study represents the first report of cyclic E-cadherin peptides as intestinal membrane permeation enhancers. The findings described herein demonstrate the potential of enzymatically stabilized cyclic E-cadherin peptides for increasing poorly permeable drug absorption via the oral route.

In Vitro Performance and Chemical Stability of Lipid-Based Formulations Encapsulated in a Mesoporous Magnesium Carbonate Carrier.

Lipid-based formulations can circumvent the low aqueous solubility of problematic drug compounds and increase their oral absorption. As these formulations are often physically unstable and costly to manufacture, solidification has been suggested as a way to minimize these issues. This study evaluated the physicochemical stability and in vitro performance of lipid-loaded mesoporous magnesium carbonate (MMC) particles with an average pore size of 20 nm. A medium chain lipid was loaded onto the MMC carrier via physical adsorption. A modified in vitro lipolysis setup was then used to study lipid release and digestion with 1H nuclear magnetic resonance spectroscopy. The lipid loading efficiency with different solidification techniques was also evaluated. The MMC, unlike more commonly used porous silicate carriers, dissolved during the lipolysis assay, providing a rapid release of encapsulated lipids into solution. The digestion of the dispersed lipid-loaded MMC therefore resembled that of a coarse dispersion of the lipid. The stability data demonstrated minor degradation of the lipid within the pores of the MMC particles, but storage for three months did not reveal extensive degradation. To conclude, lipids can be adsorbed onto MMC, creating a solid powder from which the lipid is readily released into the solution during in vitro digestion. The chemical stability of the formulation does however merit further attention.

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.

Application of an adsorption isotherm to explain incomplete drug release from ordered mesoporous silica materials under supersaturating conditions.

Ordered mesoporous silica (OMS) materials have received significant attention in recent years for use as effective supersaturating oral delivery systems for poorly water-soluble drugs. Whilst OMS materials are indeed capable of generating drug supersaturation, previous research has demonstrated incomplete drug release to always be a feature of OMS formulations. A dynamic adsorption equilibrium between drug adsorbed to OMS and free drug in solution has been hypothesized as the underlying cause of incomplete release. Therefore, the aim of this study was to characterize the adsorption of hydrophobic ritonavir (as a model poorly water-soluble drug) to OMS from supersaturated solutions. Importantly, this study represents the first report of drug adsorption by mesoporous materials under supersaturating conditions. Extensive adsorption of ritonavir from solution by mesoporous SBA-15 silica was observed for the concentration range spanning below the crystalline solubility to slightly above the amorphous solubility of ritonavir, with the extent of drug adsorption increasing with the extent of supersaturation. The Brunauer-Emmett-Teller (BET) isotherm equation (adapted for solution phase adsorption) provided the best fit to the adsorption data (R2 = 0.94) and afforded important mechanistic insights. Hydrogen bonding between ritonavir and SBA-15 surface silanols drives adsorption from subsaturated/saturated solutions, whereas the increased thermodynamic activity of the drug drives adsorption from supersaturated solutions. These observations account for the incomplete release of drug molecules from OMS materials under both dilute and supersaturating conditions. In summary, the high surface free energy of OMS materials and high reactivity of surface silanol moieties leads to incomplete drug release under a wide range of dissolution conditions. The findings described herein have significant implications for the application of OMS materials for oral drug delivery, especially for poorly water-soluble drugs which rely on supersaturation for adequate exposure in vivo.

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.

Improving Correlations Between Drug Solubilization and In Vitro Lipolysis by Monitoring the Phase Partitioning of Lipolytic Species for Lipid-Based Formulations.

Solution proton nuclear magnetic resonance analysis was used in conjunction with in vitro lipolysis to elucidate the time-dependent speciation and release of lipolytic products during the digestion of lipid-loaded inorganic particles, allowing correlations to be made between the phase partitioning of lipolytic products and an encapsulated poorly soluble drug. Silicon dioxide, montmorillonite, and laponite were used to encapsulate medium chain triglycerides into solid-state lipid-based formulations (LBFs), and coumarin 102 was selected as a model poorly soluble compound. The specific inorganic carrier material used to encapsulate medium chain triglycerides significantly impacted the release and partitioning of the solubilizing lipolytic products, that is, diglycerides, monoglycerides, and fatty acids. A strong linear correlation was obtained between drug solubilization and fatty acid release to the aqueous phase (R2 = 0.996), indicating fatty acids to be the most important lipid species for enabling solubilization and potential drug absorption in vivo. This method was developed to improve upon the use of pH-stat titration for characterizing LBF digestion during in vitro lipolysis studies and is demonstrated herein to provide useful insights into how the selected inorganic carrier material impacts LBF performance when solid-state LBF powders are fabricated via adsorption.

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.

Spray Dried Smectite Clay Particles as a Novel Treatment against Obesity.

PURPOSE: To explore the feasibility of spray dried smectite clay particles fabricated from montmorillonite or laponite materials for adsorbing dietary lipids and reducing rodent weight gain in vivo. METHODS: Spray dried montmorillonite (SD-MMT) and spray dried laponite (SD-LAP) particles were prepared via spray drying. Particle morphology, surface area and redispersion/aggregation properties in aqueous media were characterized. The ability of SD-MMT and SD-LAP particles to inhibit lipid digestion kinetics and adsorb lipid species from solution was assessed during in vitro lipolysis using proton nuclear magnetic resonance analysis. SD-MMT and SD-LAP particles were dosed to rodents fed a high-fat diet and their effect on body weight gain was evaluated. RESULTS: Both SD-MMT and SD-LAP particles adsorbed significant quantities of medium chain triglycerides and lipolytic products from solution during in vitro lipolysis. At a concentration of 50% w/w relative to lipid content, SD-MMT and SD-LAP particles adsorbed 42% and 94% of all lipid species, respectively. SD-MMT and SD-LAP particles also reduced the extent of rodent weight gain relative to the negative control treatment group and performed similarly to orlistat via an alternate mechanism of action. CONCLUSIONS: Spray dried smectite clay particles (SD-MMT and SD-LAP) with significant adsorptive capacities for dietary lipids and digestion products were successfully fabricated. These particles may be developed as novel anti-obesity treatments with fewer adverse effects than currently marketed treatment options.

Inorganic surface chemistry and nanostructure controls lipolytic product speciation and partitioning during the digestion of inorganic-lipid hybrid particles.

HYPOTHESIS: Solid-state lipid formulations, whereby liquid lipids are encapsulated in inorganic particle matrices, have attracted significant interest for drug/nutrient delivery in recent years. We hypothesized that the surface chemistry of the inorganic material used to encapsulate lipids impacts the lipase-mediated digestion and partitioning of lipolytic species between the solubilized aqueous and insoluble pellet phases. EXPERIMENTS: Medium chain triglycerides were spray dried with silica nanoparticles, montmorillonite or laponite platelets to form inorganic-lipid hybrid particles. In vitro lipolysis studies were conducted under gastric (pH 1.6) and intestinal (pH 7.5) conditions, and the speciation and partitioning of lipolytic products between the aqueous and pellet phases was characterized using solution-state proton nuclear magnetic resonance and fourier transform infrared spectroscopy. FINDINGS: Under gastric conditions, greater than 80% of all lipid species remained adsorbed within each lipolysis pellet after 60 min. Approximately 40%, 50-60% and 80-90% of all lipid species were adsorbed from solution by silica-, montmorillonite- and laponite-based particle matrices during intestinal lipolysis. Monoglycerides were preferentially adsorbed by silica, whereas triglycerides and fatty acids were adsorbed by montmorillonite and laponite. Adsorption of lipolytic products from solution is expected to impact significantly on drug/nutrient solubilization and absorption in vivo. To the best of our knowledge, this is the first report characterizing the speciation and phase behavior of lipolytic products released from solid-state lipid formulations during in vitro lipolysis studies.

Montmorillonite and Laponite Clay Materials for the Solidification of Lipid-Based Formulations for the Basic Drug Blonanserin: In Vitro and in Vivo Investigations.

Solid-state lipid-based formulations offer great potential for the improved oral delivery of poorly water-soluble drugs. This study investigates the use of the high-surface-area clay materials, montmorillonite and laponite, as solid carriers for lipid-based formulations. The unique cation-exchange properties of clay platelets were exploited to preload the ionizable hydrophobic compound, blonanserin, prior to encapsulating a drug-loaded lipid solution. Thus, solid-state lipid-based formulations with dual-loading capabilities were developed and studied. These formulations were compared with simple clay-based lipid formulations, where blonanserin was loaded in the lipid phase only. The drug release behavior of all clay-based formulations was assessed during in vitro dissolution studies under simulated gastric conditions and in vitro fasting intestinal lipolysis studies. Montmorillonite- and laponite-based lipid formulations significantly reduced blonanserin solubilization relative to a control lipid solution and silica-lipid hybrid particles, owing to incomplete drug release from the clay cation-exchange sites. This phenomenon was replicated during in vivo pharmacokinetic studies, whereby the bioavailability of simple clay-based lipid formulations was decreased relative to controls. Importantly, the solid-state dual-loaded montmorillonite-based lipid formulation provided an optimal pharmacokinetic performance, achieving the same degree of bioavailability enhancement as the control lipid solution. These findings indicate the potential of solid-state dual-loaded clay-based lipid formulations for increasing drug loading levels and enhancing the oral absorption of poorly soluble weak base compounds.

Supersaturation Potential of Ordered Mesoporous Silica Delivery Systems. Part 1: Dissolution Performance and Drug Membrane Transport Rates.

Ordered mesoporous silica materials have shown great potential as oral drug delivery systems for poorly soluble drugs. However, the ability of these delivery systems to generate drug supersaturation has not been widely investigated, and the recently noted phenomenon of incomplete drug release is not well understood. Therefore, the aim of this study was to comprehensively evaluate the release of hydrophobic drug molecules into solution from ordered mesoporous silica, focusing on the extent and duration of drug supersaturation. The dissolution and supersaturation behavior of ritonavir, following loading into mesoporous SBA-15 silica particles, was investigated by undertaking simple in vitro dissolution studies in phosphate buffer pH 6.8 and fasted state simulated intestinal fluid, as well as membrane flux studies using a side-by-side diffusion cell apparatus. It was found that supersaturated ritonavir solutions were generated from ritonavir-loaded mesoporous SBA-15 particles; however, drug release was always incomplete, even under sink conditions. In addition, the percentage drug release was observed to decrease significantly as the theoretical supersaturation ratio and dose of ritonavir-loaded SBA-15 formulation increased. The data obtained suggest an equilibrium exists between drug adsorbed to the SBA-15 silica surface and free drug present in solution. The findings described herein are highly significant in aiding our understanding of ordered mesoporous silica as a supersaturating drug delivery system for bioavailability enhancement.

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.

Montmorillonite-lipid hybrid carriers for ionizable and neutral poorly water-soluble drugs: Formulation, characterization and in vitro lipolysis studies.

Lipid-based formulations (LBFs) are a popular strategy for enhancing the gastrointestinal solubilization and absorption of poorly water-soluble drugs. In light of this, montmorillonite-lipid hybrid (MLH) particles, composed of medium-chain triglycerides, lecithin and montmorillonite clay platelets, have been developed as a novel solid-state LBF. Owing to the unique charge properties of montmorillonite, whereby the clay platelet surfaces carry a permanent negative charge and the platelet edges carry a pH-dependent charge, three model poorly water-soluble drugs with different charge properties; blonanserin (weak base, pKa 7.7), ibuprofen (weak acid, pKa 4.5) and fenofibrate (neutral), were formulated as MLH particles and their performance during biorelevant in vitro lipolysis at pH 7.5 was investigated. For blonanserin, drug solubilization during in vitro lipolysis was significantly reduced 3.4-fold and 3.2-fold for MLH particles in comparison to a control lipid solution and silica-lipid hybrid (SLH) particles, respectively. It was hypothesized that strong electrostatic interactions between the anionic montmorillonite platelet surfaces and cationic blonanserin molecules were responsible for the inferior performance of MLH particles. In contrast, no significant influence on drug solubilization was observed for ibuprofen- and fenofibrate-loaded MLH particles. The results of the current study indicate that whilst MLH particles are a promising novel formulation strategy for poorly water-soluble drugs, drug ionization tendency and the potential for drug-clay interactions must be taken into consideration to ensure an appropriate performance.

Nanostructured Montmorillonite Clay for Controlling the Lipase-Mediated Digestion of Medium Chain Triglycerides.

Biocompatible lipid hybrid particles composed of montmorillonite and medium chain triglycerides were engineered for the first time by spray drying oil-in-water emulsions stabilized by montmorillonite platelets to form montmorillonite-lipid hybrid (MLH) microparticles containing up to 75% w/w lipid. In vitro lipolysis studies under simulated intestinal conditions indicated that the specific porous nanoarchitecture and surface chemistry of MLH particles significantly increased the rate (>10-fold) and extent of lipase-mediated digestion compared to that of coarse and homogenized submicrometer triglyceride emulsions. Proton nuclear magnetic resonance studies verified the rapid and enhanced production of fatty acids for MLH particles; these are electrostatically repelled by the negatively charged montmorillonite platelet faces and avoid the "interfacial poisoning" caused by incomplete digestion that retards lipid droplet digestion. MLH particles are a novel biomaterial and encapsulation system that optimize lipase enzyme efficiency and have excellent potential as a smart delivery system for lipophilic biomolecules owing to their exceptional physicochemical and biologically active properties. These particles can be readily fabricated with varying lipid loads and thus may be tailored to optimize the solubilization of specific bioactive molecules requiring reformulation.

Silica encapsulated lipid-based drug delivery systems for reducing the fed/fasted variations of ziprasidone in vitro.

Ziprasidone is a poorly water-soluble antipsychotic drug that demonstrates low fasted state oral bioavailability and a clinically significant two-fold increase in absorption when dosed postprandially. Owing to significant compliance challenges faced by schizophrenic patients, a novel oral formulation of ziprasidone that demonstrates improved fasted state absorption and a reduced food effect is of major interest, and is therefore the aim of this research. Three lipid-based drug delivery systems (LBDDS) were developed and investigated: (a) a self-nanoemulsifying drug delivery system (SNEDDS), (b) a solid SNEDDS formulation, and (c) silica-lipid hybrid (SLH) microparticles. SNEDDS was developed using Capmul MCM® and Tween 80®, and solid SNEDDS was fabricated by spray-drying SNEDDS with Aerosil 380® silica nanoparticles as the solid carrier. SLH microparticles were prepared in a similar manner to solid SNEDDS using a precursor lipid emulsion composed of Capmul MCM® and soybean lecithin. The performance of the developed formulations was evaluated under simulated digesting conditions using an in vitro lipolysis model, and pure (unformulated) ziprasidone was used as a control. While pure ziprasidone exhibited the lowest rate and extent of drug solubilization under fasting conditions and a significant 2.4-fold increase in drug solubilization under fed conditions, all three LBDDS significantly enhanced the extent of drug solubilization under fasting conditions between 18- and 43-folds in comparison to pure drug. No significant difference in drug solubilization for the fed and fasted states was observed for the three LBDDS systems. To highlight the potential of LBDDS, mechanism(s) of action and various performance characteristics are discussed. Importantly, LBDDS are identified as an appropriate formulation strategy to explore further for the improved oral delivery of ziprasidone.

Oral nanomedicine approaches for the treatment of psychiatric illnesses.

Psychiatric illnesses are a leading cause of disability and morbidity globally. However, the preferred orally dosed pharmacological treatment options available for depression, anxiety and schizophrenia are often limited by factors such as low drug aqueous solubility, food effects, high hepatic first-pass metabolism effects and short half-lives. Furthermore, the discovery and development of more effective psychotropic agents has stalled in recent times, with the majority of new drugs reaching the market offering similar efficacy, but suffering from the same oral delivery concerns. As such, the application of nanomedicine formulation approaches to currently available drugs is a viable option for optimizing oral drug delivery and maximizing treatment efficacy. This review focuses on the various delivery challenges encountered by psychotropic drugs, and the ability of nanomedicine formulation strategies to overcome these. Specifically, we critically review proof of concept in vitro and in vivo studies of nanoemulsions/microemulsions, solid lipid nanoparticles, dendrimers, polymeric micelles, nanoparticles of biodegradable polymers and nanosuspensions, and provide new insight into the various mechanisms for improved drug performance. The advantages and limitations of current oral nanomedicine approaches for psychotropic drugs are discussed, which will provide guidance for future research directions and assist in fostering the translation of such delivery systems to the clinical setting. Accordingly, emphasis has been placed on correlating the in vitro/in vivo performance of these nanomedicine approaches with their potential clinical outcomes and benefits for patients.

Novel Nanostructured Solid Materials for Modulating Oral Drug Delivery from Solid-State Lipid-Based Drug Delivery Systems.

Lipid-based drug delivery systems (LBDDS) have gained significant attention in recent times, owing to their ability to overcome the challenges limiting the oral delivery of poorly water-soluble drugs. Despite the successful commercialization of several LBDDS products over the years, a large discrepancy exists between the number of poorly water-soluble drugs displaying suboptimal in vivo performances and the application of LBDDS to mitigate their various delivery challenges. Conventional LBDDS, including lipid solutions and suspensions, emulsions, and self-emulsifying formulations, suffer from various drawbacks limiting their widespread use and commercialization. Accordingly, solid-state LBDDS, fabricated by adsorbing LBDDS onto a chemically inert solid carrier material, have attracted substantial interest as a viable means of stabilizing LBDDS whilst eliminating some of the various limitations. This review describes the impact of solid carrier choice on LBDDS performance and highlights the importance of appropriate solid carrier material selection when designing hybrid solid-state LBDDS. Specifically, emphasis is placed on discussing the ability of the specific solid carrier to modulate drug release, control lipase action and lipid digestion, and enhance biopharmaceutical performance above the original liquid-state LBDDS. To encourage the interested reader to consider their solid carrier choice on a higher level, various novel materials with the potential for future use as solid carriers for LBDDS are described. This review is highly significant in guiding future research directions in the solid-state LBDDS field and fostering the translation of these delivery systems to the pharmaceutical marketplace.