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Coupled time-resolved synchrotron X-ray diffraction and differential scanning calorimetry combined with infrared spectroscopy are used to study the physical and thermal properties of polyoxyethylene glycol glycerides. Possible interdigitation of fatty acid chains is discussed.

Abstract: Lipid excipients are usually used for the development of sustained-release formulations. When used in relatively high quantities, Precirol® ATO 5 imparts sustained-release properties to solid oral dosage forms, by forming a lipid matrix. To control or adjust the drug release kinetics from such lipid matrix however, one must often resort to complementary ingredients or techniques. This study investigates the influence of poloxamers (Lutrol®) included in lipid matrices composed of glyceryl palmitostearate (Precirol® ATO 5) on their dissolution performance and their stability. The addition of these hydrophilic polymers in the lipid matrix increased the amount of theophylline released thanks to the swelling of the hydrophilic polymer and the creation of a porous network into the inert lipid matrix. The grade and the quantity of Lutrol® could modulate the extent of drug release. Theophylline was released mainly by the matrix erosion but also by diffusion through the pores as suggested by the Peppas’ model. Moreover, the addition of Lutrol® enhanced the stability during storage. The theophylline release was quite steady after 6 months in different conditions (temperature and humidity). Thus, the mixture of glyceryl palmitostearate and poloxamers is an approach with many advantages for the development of controlled-release formulations by capsule molding. [Copyright &y& Elsevier]

Compritol® 888 ATO is used as a lubricant in oral solid dosage formulations. It can also be used as a hot melt coating agent sprayed onto a powder. In this study, we compare the lubricant performance of Compritol® 888 ATO either used by classical blending or by hot melt coating onto Lactopress by compression tests. In physical mix, the Compritol concentration does not affect the compressibility. The same compressibility is obtained with lactose coated by 0.5 or 1% of Compritol, but a higher compressibility can be observed with 2 and 3%. Cohesiveness of lactose depends on the process: hot melt coating induces a decrease of tablet tensile strength. In terms of forces transmission during compression phase and axial ejection pressures, Compritol used by hot melt coating allows for a concentration of 0.5% to directly obtain the lubricant performance of 3% of Compritol used by blending. These results suggest that the hot melt coating process induces an homogenous repartition of the lubricant on the lactose surface, contrary to classical blending procedure. Thus, lubrication by hot melt coating seems to be a very efficient procedure. It could be used specifically for large surface area particulate systems producing a lot of friction. [Copyright &y& Elsevier]

The aim of this paper is to study the lubricant capacity of Compritol HD5 ATO, a glyceryl and polyethylene glycol dibehenate, obtained by atomization. This material is compared to Compritol 888 ATO, constituted only by glyceryl dibehenate. First, this study verifies that Compritol HD5 ATO and Compritol 888 ATO present the same granular characteristics and that their mixes with Lactopress present no structural differences. Secondly, in term of compressibility and cohesiveness, the use of Compritol 888 ATO or Compritol HD5 ATO with Lactopress does not involve any significant modification. Finally, the minor difference of lubricant capacity between Compritol HD5 ATO and Compritol 888 ATO has no consequence in compression practice. The presence of polyethylene glycol behenate does not decrease the glyceryl dibehenate compression functionality. This study concludes that Compritol HD5 ATO could be a very interesting excipient because it associates the glyceryl dibehenate lubricant capacity with the polyethylene glycol behenate-specific capacity in terms of dissolution enhancement. [Copyright &y& Elsevier]

Labrasol® and Gelucire® 44/14 are lipid-based excipients used for the oral drug delivery of poorly water-soluble drugs. These macrogolglycerides are composed of acylglycerols and PEG esters, potential substrates of digestive lipases. We developed an in vitro method to simulate the gastrointestinal lipolysis of these excipients and to evaluate the impact of lipolysis in vivo. At the end of the gastric phase, the composition of both excipients was significantly modified underlining the importance of gastric lipolysis in vivo. We also studied the influence of excipients’ lipolysis on the solubilization of a poorly water-soluble drug, cinnarizine, in aqueous phase. Gastrointestinal lipolysis of Labrasol® was a prerequisite to maintain cinnarizine in aqueous solution, whereas the lipolysis of Gelucire® 44/14 did not affect the cinnarizine solubilization.

Gelucire® 44/14, a lauroyl polyoxylglycerides obtained by polyglycolysis of hydrogenated coconut oil with PEG-32, is used to increase the oral bioavailability of poorly-water soluble drugs. It is a solid dispersion composed of a PEG ester fraction under a lamellar phase of 120 Å with a helical conformation and an acylglycerol fraction under a hexagonal packing. This excipient spontaneously evolves to its most stable phase of 120 Å after storage at 25 °C for 21 hours leading to physically stable formulations. Gelucire® 44/14 is a hydrophilic system that hydrates and swells in contact with water and forms cubic mesophases before complete erosion/emulsification. It is also lipolyzed by various enzymes such as gastric lipase or carboxyl ester hydrolase. After an in vitro gastrointestinal lipolysis simulation, the main components remaining are mono and diesters of PEG-32. These amphiphilic metabolites can explain the beneficial role of Gelucire® 44/14 on the solubility of poorly-water soluble drugs such as cinnarizine even after partial lipolysis of the lipid-based system. Finally that excipient can also increase the bioavailability of active substances by interacting with enterocyte-based proteins like P-glycoprotein or cytochromes P450.

An emerging concern globally, particularly in developed countries, is the rising prevalence of Inflammatory Bowel Disease (IBD), such as Crohn's disease. Oral delivery technologies that can release the active therapeutic cargo specifically at selected sites of inflammation offer great promise to maximise treatment outcomes and minimise off-target effects. Therapeutic strategies for IBD have expanded in recent years, with an increasing focus on biologic and nucleic acid-based therapies. Reliable site-specific delivery in the gastrointestinal (GI) tract is particularly crucial for these therapeutics to ensure sufficient concentrations in the targeted cells. Ingestible smart capsules hold great potential for precise drug delivery. Despite previous unsuccessful endeavours to commercialise drug delivery smart capsules, the current rise in demand and recent advancements in component development, manufacturing, and miniaturisation have reignited interest in ingestible devices. Consequently, this review analyses the advancements in various mechanical and electrical components associated with ingestible smart drug delivery capsules. These components include modules for device localisation, actuation and retention within the GI tract, signal transmission, drug release, power supply, and payload storage. Challenges and constraints associated with previous capsule design functionality are presented, followed by a critical outlook on future design considerations to ensure efficient and reliable site-specific delivery for the local treatment of GI disorders., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brendan T. Griffin and Joseph P. O'Shea report financial support was provided by University College Cork. Sophia V. Hoffmann, Brendan T. Griffin, Joseph P. O'Shea, and Vincent Jannin report financial support was provided under the GENEGUT project funded by the European Commission as a Horizon Europe Research and Innovation Action (RIA). Paul Galvin was supported by grants from Science Foundation Ireland (SFI/12/RC/2289-P2) and the European Commission (Grant agreement No. 101057525). Vincent Jannin reports a relationship with Capsugel Colmar that includes: employment. Paul Galvin reports a relationship with Tyndall National Institute that includes: employment. Brendan T. Griffin and Joseph P. O'Shea report a relationship with University College Cork that includes: employment. There are no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Ready-to-fill enteric hard capsule shells are an evolving field of oral drug and nutraceutical products. Lonza Capsugel ® Enprotect ® capsules were recently proven to provide reliable release in the small intestine after fasted intake, but robustness against postprandial intake needed to be proven. In this study, the capsules were administered to 16 healthy young subjects after intake of a light meal. The Enprotect ® capsules were labelled with 5 mg black iron oxide and 25 mg 13 C 3 -caffeine. Magnetic Resonance Imaging was used to identify the localization and visual dispersion of the capsule filling. The salivary appearance of caffeine was considered a second independent and sensitive marker for the initial release. Whereas the fasted gastric residence time of the capsules amounted to 43 ± 32 min, it was increased to 158 ± 36 min after postprandial intake. Therefore, the mean dispersion time according to MRI and the mean caffeine appearance time were increased to 196 ± 37 min and 189 ± 37 min, respectively. But, similar to fasted administration, no capsule disintegration or leakage was observed in the stomach and 38% of the capsules disintegrated in the jejunum and 62% in the ileum. The mean dispersion time after gastric emptying and the mean caffeine appearance time after gastric emptying amounted to 38 ± 21 min and 31 ± 17 min, respectively. Both did not relevantly change compared to the fasted intake. Only the absolute dispersion time and caffeine appearance were prolonged due to the increased gastric residence and no relevant influence of the light meal was observed on the disintegration or release behavior of Enprotect ® capsules after gastric emptying. The capsules also showed robust enteric properties after postprandial administration.

The dissolution characteristics of five capsules (Next Generation Enteric [NGE], Vcaps® Enteric [VCE], VCE DUOCAP® [VCE/VCE] system, Hard Gelatin Capsule [HGC] as negative control, and Creon® 10,000 U as market reference) were evaluated using an in vitro simulation of the stomach and upper intestinal tract with an acidic duodenal incubation (pH 4.5 for the first 10 min, pH 6 for the remaining 17 min) to simulate exocrine pancreatic insufficiency. Caffeine was a marker of capsule dissolution, and tributyrin to butyrate conversion measured pancrelipase activity. All capsules were filled with pancrelipase; the NGE, VCE, VCE/VCE, and HGC capsules also contained 50 mg caffeine. Caffeine was released first from the HGC capsule, followed by the VCE, NGE, and VCE/VCE capsules. Pancrelipase activity followed this trend and demonstrated a similar activity level over time for the NGE, VCE/VCE, and Creon® capsules. The HGC formulation confirmed gastric degradation of unprotected pancrelipase. NGE capsules provided similar protection to the simple fill formulation as observed for the complex formulation of the Creon® capsule in a setting with increased pepsin activity and may hasten the time needed to go from formula development to first-in-human studies for pH sensitive drugs or those requiring small intestine targeting., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: At the time of the study, Vanessa Gonzalez, Marine Agisson, Nicolas Madit, and Vincent Jannin were employees of Capsugel France SAS, a company from Lonza Capsules & Health Ingredients Division, manufacturing and selling capsules used in this study., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Many orally dosed APIs are bioavailable only when formulated as an enteric dosage form to protect them from the harsh environment of the stomach. However, an enteric formulation is often accompanied with a higher development effort in the first place and the potential degradation of fragile APIs during the coating process. Ready-to-use enteric hard capsules would be an easily available alternative to test and develop APIs in enteric formulations, while decreasing the time and cost of process development. In this regard, Lonza Capsugel ® Next Generation Enteric capsules offer a promising approach as functional capsules. The in vivo performance of these capsules was observed with two independent techniques (MRI and caffeine in saliva) in eight human volunteers. No disintegration or content release in the stomach was observed, even after highly variable individual gastric residence times (range 7.5 to 82.5 min), indicating the reliable enteric properties of these capsules. Seven capsules disintegrated in the distal part of the small intestine; one capsule showed an uncommonly fast intestinal transit (15 min) and disintegrated in the colon. The results for this latter capsule by MRI and caffeine appearance differed dramatically, whereas for all other capsules disintegrating in the small intestine, the results were very comparable, which highlights the necessity for reliable and complementary measurement methods. No correlation could be found between the gastric residence time and disintegration after gastric emptying, which confirms the robust enteric formulation of those capsules.

Type III lipid-based formulations (LBFs) combine poorly water-soluble drugs with oils, surfactants, and cosolvents to deliver the drugs into the systemic circulation. However, the solubility of the drug can be influenced by the colloidal phases formed in the gastrointestinal tract as the formulation is dispersed and makes contact with bile and other materials present within the GI tract. Thus, an understanding of the phase behavior of LBFs in the gut is critical for designing efficient LBFs. Molecular dynamics (MD) simulation is a powerful tool for the study of colloidal systems. In this study, we modeled the internal structures of five type III LBFs of loratadine containing poly(ethylene oxide) nonionic surfactants polysorbate 80 and polyoxyl hydrogenated castor oil (Kolliphor RH40) using long-timescale MD simulations (0.4-1.7 μs). We also conducted experimental investigations (dilution of formulations with water) including commercial Claritin liquid softgel capsules. The simulations show that LBFs form continuous phase, water-swollen reverse micelles, and bicontinuous and phase-separated systems at different dilutions, which correlate with the experimental observations. This study supports the use of MD simulation as a predictive tool to determine the fate of LBFs composed of medium-chain lipids, polyethylene oxide surfactants, and polymers.

Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps ® HPMC capsules, Vcaps ® Plus HPMC capsules, gelatin and DRcaps ® designed release capsules were used. The three HPMC-based capsules (Vcaps ® , Vcaps ® Plus and DRcaps ® capsules) were tested as single capsules; furthermore, seven DUOCAP ® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13 C 3 ) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP ® capsule-in-capsule configuration using a DRcaps ® designed release capsule within a DRcaps ® designed release outer capsule. In this combination, the inner DRcaps ® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps ® Plus HPMC capsules showed the fastest and most consistent disintegration.

Oral administration of active pharmaceutical ingredients, nutraceuticals, enzymes or probiotics requires an appropriate delivery system for optimal bioactivity and absorption. The harsh conditions during the gastrointestinal transit can degrade the administered products, hampering their efficacy. Enteric or delayed-release pharmaceutical formulations may help overcome these issues. In a Simulator of Human Intestinal Microbial Ecosystem model (SHIME) and using caffeine as a marker for release kinetics and L. acidophilus survivability as an indicator for protection, we compared the performance of ten capsule configurations, single or DUOCAP® combinations. The function of L. acidophilus and its impact on the gut microbiota was further tested in three selected capsule types, combinations of DRcaps® capsule in DRcaps® capsule (DR-in-DR) and DRcaps® capsule in Vcaps® capsule (DR-in-VC) and single Vcaps® Plus capsule under colonic conditions. We found that under stomach and small intestine conditions, DR-in-DR and DR-in-VC led to the best performance both under fed and fasted conditions based on the slow caffeine release and the highest L. acidophilus survivability. The Vcaps® Plus capsule however, led to the quickest caffeine and probiotic release. When DR-in-DR, DR-in-VC and single Vcaps® Plus capsules were tested through the whole gastrointestinal tract, including under colonic conditions, caffeine release was found to be slower in capsules containing DRcaps® capsules compared to the single Vcaps® capsules. In addition, colonic survival of L. acidophilus was significantly increased under fasted conditions in DR-in-DR or DR-in-VC formulation compared to Vcaps® Plus capsule. To assess the impact of these formulations on the microbial function, acetate, butyrate and propionate as well as ammonia were measured. L. acidophilus released from DR-in-DR or DR-in-VC induced a significant increase in butyrate and a decrease in ammonia, suggesting a proliferation of butyrate-producing bacteria and reduction in ammonia-producing bacteria. These data suggest that L. acidophilus included in DR-in-DR or DR-in-VC reaching the colon is viable and functional, potentially contributing to changes in colonic microbiota composition and diversity., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble drugs within such formulations. In order to validate the ability of MD to effectively model the properties of LBFs, this work investigates the well-known cyclosporine A formulations, Sandimmune® and Neoral®. Sandimmune® exhibits poor dispersibility and its absorption from the gastrointestinal tract is enhanced when administered after food, whereas Neoral® disperses comparatively well and shows no food effect., Methods: MD simulations were performed of both LBFs to investigate the differences observed in fasted and fed conditions. These conditions were also tested using an in vitro experimental model of dispersion and digestion., Results: These MD simulations were able to show that the food effect observed for Sandimmune® can be explained by large changes in drug solubilization on addition of bile. In contrast, Neoral® is well dispersed in water or in simulated fasted conditions, and this dispersion is relatively unchanged on moving to fed conditions. These differences were confirmed using dispersion and digestion in vitro experimental model., Conclusions: The current data suggests that MD simulations are a potential method to model the fate of LBFs in the gastrointestinal tract, predict their dispersion and digestion, investigate behaviour of APIs within the formulations, and provide insights into the clinical performance of LBFs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF., Methods: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS 2 ), and compared to the commercial acetate salt (OCT.OAc 2 ) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS 2 and OCT.OAc 2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats., Results: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS 2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS 2 . However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS 2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS 2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures., Conclusion: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible in vitro tended to display higher bioavailability of nilotinib in vivo . The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the in vivo bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.

Peptides are therapeutic molecules with high potential to treat a wide variety of diseases. They are large hydrophilic compounds for which absorption is limited by the intestinal epithelial border covered by mucus. This study aimed to evaluate the potential of Hydrophobic Ion Pairing combined with Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) to improve peptide transport across the intestinal border using Caco-2 cell monolayers (enterocyte-like model) and Caco-2/HT29-MTX co-cultured monolayers (mucin-secreting model). A Hydrophobic Ion Pair (HIP) was formed between Leuprolide (LEU), a model peptide, and sodium docusate. The marked increase in peptide lipophilicity enabled high encapsulation efficiencies in both NLC (84%) and SLN (85%). After co-incubation with the nanoparticles, confocal microscopy images of the cell monolayers demonstrated particles internalization and ability to cross mucus. Flow cytometry measurements confirmed that 82% of incubated SLN and 99% of NLC were internalized by Caco-2 cells. However, LEU transport across cell monolayers was not improved by the nanocarriers. Indeed, combination of particles platelet-shape and HIP low stability in the transport medium led to LEU burst release in this environment. Improvement of peptide lipidization should maintain encapsulation and enable benefit from nanocarriers enhanced intestinal transport., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Labrasol® ALF (Labrasol®), is a non-ionic surfactant excipient primarily used as a solubilising agent. It was investigated here as an intestinal permeation enhancer in isolated rat colonic mucosae in Ussing chamber and in rat in situ intestinal instillations. Labrasol® comprises mono-, di- and triglycerides and mono- and di- fatty acid esters of polyethylene glycol (PEG)-8 and free PEG-8, with caprylic (C 8 )- and capric acid (C 10 ) as the main fatty acids. Source components of Labrasol® as well as Labrasol® modified with either C 8 or C 10 as the sole fatty acid components were also tested to determine which element of Labrasol® was responsible for its permeability-enhancing properties. Labrasol® (4, 8 mg/mL) enhanced the transport of the paracellular markers, [ 14 C] mannitol, FITC-dextran 4000, and FITC-insulin across colonic mucosae. The enhancement was non-damaging, transient, and molecular weight-dependent. The PEG ester fraction of Labrasol® also had enhancing properties. When insulin was administered with Labrasol® in instillations, it had a relative bioavailability of 7% in jejunum and 12% in colon. C 8 - and C 10 versions of Labrasol® and the PEG ester fraction also induced similar bioavailability values in jejunal instillations: 6, 5 and 7% respectively. Inhibition of lipases in instillations did not reduce the efficacy of Labrasol®, suggesting that its mechanism as a PE is not simply due to liberated medium chain fatty acids. Labrasol® acts as an efficacious intestinal permeation enhancer and has potential for use in oral formulations of macromolecules and BCS Class III molecules., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Peptides are rarely orally administrated due to rapid degradation in the gastrointestinal tract and low absorption at the epithelial border. The objective of this study was to encapsulate a model water-soluble peptide in biodegradable and biocompatible solid lipid-based nanoparticles, i.e. Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) in order to protect it from metabolic degradation. Leuprolide (LEU) and a LEU-docusate Hydrophobic Ion Pair (HIP) were encapsulated in SLN and NLC by High Pressure Homogenization. The particles were characterized regarding their Encapsulation Efficiency (EE), size, morphology, peptide release in FaSSIF-V2, and protective effect towards proteases. Nanoparticles of 120 nm with platelet structures were obtained. Formation of HIP led to a significant increase in LEU EE. Particle size was moderately affected by the presence of simulated fluids. Nonetheless, an important burst release was observed upon dispersion in FaSSIF-V2. NLC were able to improve LEU-HIP resistance to enzymatic degradation induced by trypsin but presented no advantages in presence of α-chymotrypsin. SLN provided no protection regarding both proteases. Despite an increased amount of encapsulated peptide in solid lipid-based nanoparticles following HIP formation, the important specific surface area linked to their platelet structures resulted in an important peptide release upon dispersion in FaSSIF-V2 and limited protection towards enzymatic degradation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The use of three-dimensional printing (3DP) in the development of pharmaceutical dosage forms is growing rapidly. However, the research is almost exclusively focussed on polymer-based systems with very little reported on 3D printing of lipid-based formulations. Thus, the aim of the work was to explore the feasibility of 3DP technology to prepare solid lipid-based formulations. Here, 3DP was applied for the preparation of solid self-microemulsifying drug delivery systems (S-SMEDDS) with defined surface area to volume (SA/V) ratios., Methods: The S-SMEDDS formulations, comprised of Gelucire® 44/14, Gelucire® 48/16 and Kolliphor® P 188 were loaded with fenofibrate or cinnarizine as model drugs. The formulations were printed into four geometrical shapes - cylindrical, prism, cube and torus, and compared to a control cube manually prepared from bulk formulation., Results: The printing process was not significantly affected by the presence of the model drugs. The as-printed S-SMEDDS formulations were characterised using differential scanning calorimetry and wide-angle X-ray scattering. The kinetics of dispersion depended on the SA/V ratio values. The digestion process was affected by the initial geometry of the dosage form by virtue of the kinetics of dispersion of the dosage forms into the digestion medium., Conclusions: This proof of concept study has demonstrated the potential of 3DP for the development of customised S-SMEDDS formulations without the need for an additional carrier or additive and with optimisation could elaborate a new class of dosage forms based on 3D printed lipids. Graphical abstract Lipid based formulations were 3D printed in various shapes to control the surface are to volume ratio and consequently the kinetics of dispersion.

Gene therapy with RNA and pDNA-based drugs is limited by poor enzymatic stability and poor cellular permeation. The delivery of nucleic acids, in particular by the oral route, remains a major hurdle. This review will focus on the barriers to the oral delivery of nucleic acids and the strategies, in particular formulation strategies, which have been developed to overcome these barriers. Due to their very low oral bioavailability, the most obvious and most investigated biomedical applications for their oral delivery are related to the local treatment of inflammatory bowel diseases and colorectal cancers. Preclinical data but not yet clinical studies support the potential use of the oral route for the local delivery of formulated nucleic acid-based drugs., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Therapeutic peptides are facing an increasing interest as drugs for the treatment of many diseases. The challenge in the administration of such drugs, due to inherent properties of these peptides, is to make them bioavailable. Self-emulsifying drug delivery systems (SEDDS) are considered a suitable and promising strategy to deliver the peptides and increase their bioavailability. However, to enter into the SEDDS nanodroplets, the peptides must be made hydrophobic by complexation with surfactants (formation of hydrophobic ion pair, HIP). The aim of this work is to assess the possibility to quantify the amount of released peptides and of the remaining docusate/peptide HIP in the nanodroplets by Taylor Dispersion Analysis (TDA) on two therapeutic peptides (leuprorelin and desmopressin). It also clearly demonstrates that the logP value of the peptide has a strong influence on the extent of HIP inside of the SEDDS nanodroplets. For instance leuprorelin-docusate complex (logP = 3) was 100% inside of the nanodroplets at low ionic strength, while for desmopressin-docusate complex (logP = 0.5) only 30% were able to enter the nanodroplets. It was also shown that an increase in the ionic strength of the release media allowed to increase the amount of released peptide up to 80% for leuprorelin and 100% for desmopressin, at physiological ionic strength. TDA experiments allowed to determine the partitioning coefficient, logD value, of the peptide between the SEDDS and continuous aqueous phases. In conclusion, this work demonstrates that TDA is a rapid, straightforward and useful technique for developing SEDDS formulations., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route. They play various roles ranging from support vehicles to release rate modifiers, stabilizers, solubilizers, permeation enhancers and transfection agents. Focusing on selected applications, which were discussed at the Annual Scientific Meeting of the Gattefossé Foundation 2018, this manuscript recapitulates the fundamental roles of these two important classes of excipients, either employed alone or in combination, and provides insight on their functional properties in various types of drug formulations. Emphasis is placed on oral formulations for the administration of active pharmaceutical ingredients with low aqueous solubilities or poor permeation properties. Additionally, this review article covers the use of lipids and polymers in the design of colloidal injectable delivery systems, and as substrates in additive manufacturing technologies for the production of tailor-made dosage forms., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Self-dispersing lipid-based formulations, particularly self-microemulsifying drug delivery systems (SMEDDS) have gained an increased interest in recent times as a means to enhance the oral bioavailability of poorly water-soluble lipophilic drugs. Upon dilution, SMEDDS self-emulsify in an aqueous fluid and usually form a kinetically stable oil-in-water emulsion or in some rare cases a true thermodynamically stable microemulsion. The digestion of the formulation leads to the production of amphiphilic digestion products that interact with endogenous amphiphilic components and form self-assembled colloidal phases in the aqueous environment of the intestine. The formed colloidal phases play a pivotal role in maintaining the lipophilic drug in the solubilised state during gastrointestinal transit prior to absorption. Thus, this review describes the structural characterisation techniques employed for SMEDDS and the recent literature studies that elucidated the colloidal aspects during dispersion and digestion of SMEDDS and solid SMEDDS. Possible future studies are proposed to gain better understanding on the colloidal aspects of SMEDDS and solid SMEDDS., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: Three-dimensional printing (3DP) is a rapidly growing additive manufacturing process and it is predicted that the technology will transform the production of goods across numerous fields. In the pharmaceutical sector, 3DP has been used to develop complex dosage forms of different sizes and structures, dose variations, dose combinations and release characteristics, not possible to produce using traditional manufacturing methods. However, the technology has mainly been focused on polymer-based systems and currently, limited information is available about the potential opportunities for the 3DP of soft materials such as lipids., Methods: This review paper emphasises the most commonly used 3DP technologies for soft materials such as inkjet printing, binder jetting, selective laser sintering (SLS), stereolithography (SLA), fused deposition modeling (FDM) and semi-solid extrusion, with the current status of these technologies for soft materials in biological, food and pharmaceutical applications., Result: The advantages of 3DP, particularly in the pharmaceutical field, are highlighted and an insight is provided about the current studies for lipid-based drug delivery systems evaluating the potential of 3DP to fabricate innovative products. Additionally, the challenges of the 3DP technologies associated with technical processing, regulatory and material issues of lipids are discussed in detail., Conclusion: The future utility of 3DP for printing soft materials, particularly for lipid-based drug delivery systems, offers great advantages and the technology will potentially support patient compliance and drug effectiveness via a personalised medicine approach.

Lipid based-formulations can enhance the bioavailability of poorly water-soluble lipophilic drugs through enhanced solubilisation of drugs in the gastrointestinal (GI) tract during digestion. This study investigates the solubilisation behaviour of poorly water-soluble drugs upon digestion of solid self-microemulsifying drug delivery system (S-SMEDDS). The S-SMEDDS were prepared using two different core lipids, Gelucire® 44/14 (GEL) or glyceryl monooleate (GMO), and were loaded with two model drugs, fenofibrate (FEN) and cinnarizine (CINN). S-SMEDDS formulations were characterized using wide-angle X-ray scattering (WAXS) and Raman spectroscopy, and their structural behaviour and drug solubilisation behaviour were monitored using drug-related diffraction peaks during digestion under fasted and fed simulated intestinal conditions using time-resolved small and wide-angle X-ray scattering (SAXS/WAXS). The concentrations of FEN and CINN released into the aqueous phase (AP) during digestion were quantified using high-performance liquid chromatography (HPLC). Both model drugs, FEN and CINN, had greater solubility in the GMO-based S-SMEDDS formulations and were partially solubilised into lipid matrix and uniformly distributed in solid formulations. The extent of digestion was greater for the GEL-based systems (92-94%) than GMO-based systems (65-75%) as was the rate of digestion. GEL-based S-SMEDDS formulations formed a lamellar phase during digestion in the fasted state and formed mixed micelles in the fed state. In contrast, the GMO-based system formed the mixed micelles in both intestinal conditions. The time-resolved SAXS profiles revealed solubilisation of crystalline drugs into the lipolysis products. Synchrotron SAXS results were in correlation with the HPLC measurements, confirming the ability of the SAXS technique to monitor drug behaviour and showing that the digestion of S-SMEDDS can enhance drug solubilisation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Peptides are therapeutic molecules that can treat selectively and efficiently a wide range of pathologies. However, their intrinsic properties cause their rapid degradation in the human gastrointestinal (GI) tract resulting in poor bioavailability after oral administration. Yet, their encapsulation in nanocarriers offers them protection from this harsh environment and increases their permeability across the epithelium border. In particular, Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) have proven to improve peptide oral bioavailability. This article details different techniques used to produce SLN and NLC with potential or effective peptide encapsulation. Basic principles of covalent and non-covalent lipidization are described and discussed as a prerequisite to improve hydrophilic peptide encapsulation in lipid-based nanosuspensions. The last part of this review provides the key evaluation techniques to assay SLN and NLC for peptide oral bioavailability enhancement. Methods to assess the protective effects of the carriers are described as well as the techniques to evaluate peptide release upon lipid digestion by lipases. Furthermore, this review suggests different techniques to measure permeability improvements and describes the main in vitro cell models associated., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: It was the aim of this study to evaluate the mucus permeating properties of self-emulsifying drug delivery systems (SEDDS) exhibiting different size and zeta potential., Methods: Various SEDDS were prepared and characterized regarding droplet size, zeta potential and stability. Desmopressin was incorporated as model peptide drug and log P (SEDDS/water) was determined. Thereafter, mucus permeation studies with freshly isolated porcine mucus via Transwell method were performed. Moreover, the impact of water movement on mucus permeation of SEDDS was investigated. Different types of nanocarriers including nanoparticles and liposomes served as references., Results: SEDDS exhibited an initial droplet size of 25.0 ± 2.2, 49.5 ± 4.6, 123.5 ± 12.1, 226.2 ± 93.4 and 502.9 ± 93.7 nm and a zeta potential of +24.4 ± 4.6, +10.6 ± 2.0, 0.2 ± 3.8, -8.2 ± 3.4 and -35.1 ± 2.7 mV. Log P was in the range of 1.29-2.09 and mucus permeation studies with these SEDDS revealed a clear correlation between droplet size and permeation rate. The smaller SEDDS were, the higher their mucus permeating properties were. Negatively charged SEDDS demonstrated a higher permeation rate than positively charged SEDDS. In comparison to liposomes and solid nanocarriers SEDDS exhibited up to 5-fold higher mucus permeating properties., Conclusion: Small droplet size and negative zeta potential of SEDDS could be identified as key parameters for their mucus permeating properties., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Self-emulsifying drug delivery systems based on lipids have gained in interest in recent years due to their capacity to enhance the bioavailability of poorly water soluble drugs. Their oral intake suggests that they will be in contact with gastric and pancreatic enzymes during their passage through the gastrointestinal tract. The study of the evolution of such systems in the presence of enzymes is thus essential to develop better drug delivery vehicles. In this work, the lipolysis of two lipid based self-emulsifying drug delivery systems, Labrasol ® and Gelucire ® 44/14 by pancreatic enzymes and under conditions mimicking the gastrointestinal tract are presented. The following of the digestion is realized by Taylor dispersion analysis using fluorescent detection. A hydrophobic marker was used to tag the microdroplets. Results have shown that, Labrasol ® droplets decrease exponentially in size with lipolysis time, from 11.8 nm to 3.5 nm in 20 min. On the contrary, Gelucire ® 44/14 droplets increased sigmoïdally in size from 5.6 to 24.7 nm. Even after 120 min lipolysis, both systems maintained a solubilizing capacity of the hydrophobic marker., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate the digestibility of Solid Lipid Nanoparticles (SLN) of glyceryl dibehenate prepared either with surfactants by ultrasonication or without surfactant by spray-flash evaporation., Methods: SLN of glyceryl dibehenate (Compritol® 888 ATO) were produced by two processes: (i) high-shear homogenization with a solution of water-soluble surfactants followed by ultrasonication (ii) and Spray-Flash Evaporation (SFE) of the pure lipid. The digestibility of these nanoparticles was then tested by in vitro lipolysis using a pH-stat apparatus and the assay of glycerides by gel phase chromatography., Results: SLN of glyceryl dibehenate prepared by ultrasonication exhibited a mean particle size of 180nm and showed a limited digestion of the lipid excipient. SLN comprising only glyceryl dibehenate produced by SFE have a mean particle size between 235 and 411nm depending on process parameters. These nanoparticles were not digested by lipases. The presence of surfactant at the lipid/water interface of the SLN seems to be mandatory to allow the adsorption of the lipase and degradation of glyceryl behenate., Conclusions: Glyceryl dibehenate as a solid particle - even as a SLN - is not digested by pancreatin during in vitro lipolysis test., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: The aim of this study was to evaluate the protective effect of self-emulsifying drug delivery systems (SEDDS) for therapeutic peptides towards intestinal proteases and reduced glutathione (GSH)., Methods: Sodium docusate was applied as anionic surfactant for hydrophobic ion pairing with leuprorelin (LEU), insulin (INS) and desmopressin (DES). The complexes were loaded into SEDDS that were characterized regarding droplet size distribution and zeta potential. The release profile of the peptides was examined by dialysis membrane method. Enzymatic digestion studies were performed by applying α-chymotrypsin, trypsin and elastase. Furthermore, the protective effect of SEDDS towards degradation through thiol-disulfide exchange reactions was examined by addition of GSH., Results: SEDDS showed a mean droplet size of 0.27-3.9μm and a zeta potential of -25 to -33mV. All formulations provided a sustained release of the peptides over 6h. Degradation of the model peptides by intestinal proteases and GSH could only be observed in the release medium. In the oily phase of SEDDS neither any of the proteases nor GSH was soluble (≤0.1%). Furthermore, no degradation of the model peptides by proteases and GSH took place in the oily phase of SEDDS., Conclusion: SEDDS can provide a 100% protective effect towards protease degradation and deactivation by GSH. According to this, SEDDS might be promising tools for oral delivery of peptide drugs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Solid self-microemulsifying drug delivery systems (SMEDDS) have received considerable attention in recent times attempting to overcome the drawbacks of liquid SMEDDS. Earlier literature reports on solid SMEDDS have focussed on formulation development; however, the digestibility and propensity for self-assembly of the digested components with endogenous bile salts and phospholipids are unknown. Therefore, as a starting point, previously reported solid SMEDDS containing Gelucire® 44/14 (GEL) and the non-digestible surfactants, Vitamin E TPGS (TPGS) and Lutrol® F 127 (F 127), were prepared, and their dispersion and digestion behaviours were studied using an in vitro lipolysis model, coupled with small-angle X-ray scattering (SAXS) to determine the formed colloidal structures during digestion in real time. GEL alone was digested (89%) and formed a lamellar phase (Lα). When surfactants were added at a 40:60% w/w lipid to surfactants ratio, digestion was inhibited with a significant lag time being evident. However, increasing the fraction of GEL to 50% w/w enabled digestion with reduced lag time. The substitution of the non-digestible surfactants with digestible surfactants, sucrose esters S-1670 (S-1670) and Span® 60 (S-60), eliminated the digestion lag time, and the formation of colloidal structures was more similar to that of GEL alone.

Aim: The aim of this study was the formation and characterization of various ion pairs of therapeutic peptides with different surfactants in order to reach a high payload in self-emulsifying drug delivering systems (SEDDS)., Methods: Hydrophobic ion pairs (HIP) were formed between the anionic surfactants sodium docusate, dodecylsulfate and oleate and the peptides leuprorelin (LEU), insulin (INS) and desmopressin (DES). The efficiency of HIP formation was evaluated by quantifying the amount of formed complexes, log P value determination in n-octanol/water via HPLC and zeta potential measurements. Solvents and surfactants were screened regarding their complex solubilizing properties. Subsequently, peptide complexes were incorporated into SEDDS followed by payload and stability determination., Results: Independent from the type of peptide, docusate showed the most efficient HIP properties followed by dodecylsulfate and oleate. Ratios of 2:1 for LEU, 6:1 for INS and 1.5:1 for DES led to the highest quantity of formed complexes with docusate and log P increased at least by 3 units. The more docusate was added to each peptide, the more negative became the zeta potential of the resulting complex. Incorporating these optimized complexes into novel SEDDS containing Capryol 90, Labrafil M 2125 CS, Labrasol ALF, Peceol, propylene glycol, tetraglycol, Transcutol HP and Tween 20 allowed payloads of the LEU, DES and INS complexes above 10%. Moreover, SEDDS exhibited high stability and constant negative zeta potential over a 4h incubation time., Conclusion: Following the procedure described herein payloads >10% can be achieved for peptide drugs in SEDDS., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this present study, the secretory transport of P-gp substrates, rhodamine 123 and digoxin, was evaluated using a Caco-2/HT29-MTX co-culture characterized by an efflux mechanism and a paracellular permeability closer to the human intestinal barrier compared to the Caco-2 monolayer gold standard. The influence of simulated intestinal fluids termed FeSSIF and FaSSIF on the intestinal absorption was also assessed in comparison with a conventional saline buffer. Labrasol ® ALF and Gelucire ® 44/14 in saline buffer significantly decreased to 83% and 62%, the P-gp-mediated transport of rhodamine 123 across the co-culture, respectively. The effects of Gelucire ® 44/14 were much more exacerbated with the Caco-2 monolayer model with a reduced permeability to 34% but they were partially reversed in the co-culture with FeSSIF. The modulation by the lipid excipients of digoxin secretory transport across the Caco-2 monolayer and the co-culture was reduced compared with the rhodamine 123. This work also emphasizes the numerous parameters that have to be considered for predicting accurately the effects of potential P-gp inhibitors including the in-vitro model, the incubation media and the intrinsic properties of P-gp substrates., (Copyright © 2016 Elsevier B.V. All rights reserved.)