ABSTRACT
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 13C3-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.
ABSTRACT
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.
Subject(s)
Exocrine Pancreatic Insufficiency , Pancrelipase , Humans , Pancrelipase/therapeutic use , Capsules , Caffeine/therapeutic use , Gastrointestinal Agents , Exocrine Pancreatic Insufficiency/drug therapy , Duodenum , GelatinABSTRACT
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.
ABSTRACT
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 13C3) 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.
ABSTRACT
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.
Subject(s)
Lipids/chemistry , Loratadine/chemistry , Surface-Active Agents/chemistry , Drug Compounding , Excipients/chemistry , Molecular Dynamics Simulation , Polysorbates/chemistry , Water/chemistryABSTRACT
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.
Subject(s)
Cyclosporine/chemistry , Lipids/chemistry , Bile/chemistry , Chemistry, Pharmaceutical/methods , Digestion , Excipients/chemistry , Molecular Dynamics Simulation , Solubility/drug effects , Water/chemistryABSTRACT
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.
Subject(s)
Caffeine , Polymers , Capsules , Chemistry, Pharmaceutical , Ecosystem , HumansABSTRACT
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.DoS2), and compared to the commercial acetate salt (OCT.OAc2) 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.DoS2 and OCT.OAc2 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.DoS2 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.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 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.
Subject(s)
Drug Compounding/methods , Drug Delivery Systems/methods , Excipients/pharmacokinetics , Gastrointestinal Absorption/physiology , Gastrointestinal Agents/pharmacokinetics , Octreotide/pharmacokinetics , Administration, Oral , Animals , Caco-2 Cells , Excipients/administration & dosage , Excipients/chemical synthesis , Gastrointestinal Absorption/drug effects , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/chemical synthesis , Humans , Male , Octreotide/administration & dosage , Octreotide/chemical synthesis , Rats , Rats, Sprague-Dawley , SaltsABSTRACT
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.
Subject(s)
Gastrointestinal Tract/metabolism , Intestinal Absorption , Administration, Oral , Animals , Computer Simulation , Drug Compounding , Food-Drug Interactions , Humans , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolismABSTRACT
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.
Subject(s)
Drug Carriers/chemistry , Leuprolide/pharmacokinetics , Lipids/chemistry , Nanostructures , Caco-2 Cells , Coculture Techniques , Dioctyl Sulfosuccinic Acid/chemistry , HT29 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Intestinal Absorption , Intestinal Mucosa/metabolism , Leuprolide/administration & dosage , Leuprolide/chemistry , Mucus/metabolism , Nanoparticles , Peptides/administration & dosage , Peptides/chemistry , Peptides/pharmacokineticsABSTRACT
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.
Subject(s)
Digestion/drug effects , Pyrimidines/metabolism , Surface-Active Agents/metabolism , Administration, Oral , Animals , Biological Availability , Chemistry, Pharmaceutical/methods , Excipients/metabolism , Fatty Acids/metabolism , Hydrophobic and Hydrophilic Interactions , Lipolysis/drug effects , Male , Rats , Rats, Sprague-Dawley , Solubility/drug effects , Suspensions/metabolismABSTRACT
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 (C8)- and capric acid (C10) as the main fatty acids. Source components of Labrasol® as well as Labrasol® modified with either C8 or C10 as the sole fatty acid components were also tested to determine which element of Labrasol® was responsible for its permeability-enhancing properties. Labrasol® (4, 8â¯mg/mL) enhanced the transport of the paracellular markers, [14C] 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. C8- and C10 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.
Subject(s)
Colon/drug effects , Excipients/pharmacology , Glycerides/pharmacology , Intestinal Absorption/drug effects , Intestinal Mucosa/drug effects , Jejunum/drug effects , Animals , Colon/metabolism , Excipients/pharmacokinetics , Glycerides/pharmacokinetics , In Vitro Techniques , Intestinal Mucosa/metabolism , Jejunum/metabolism , Male , Rats , Rats, Wistar , Tight Junctions/drug effects , Tight Junctions/metabolismABSTRACT
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.
Subject(s)
Drug Delivery Systems , Pharmaceutical Preparations/administration & dosage , Administration, Oral , Animals , Humans , Pharmaceutical Preparations/chemistry , Solubility , Water/chemistryABSTRACT
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 120â¯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.
Subject(s)
Dioctyl Sulfosuccinic Acid/chemistry , Leuprolide/chemistry , Lipids/chemistry , Nanoparticles/chemistry , Surface-Active Agents/chemistry , Chymotrypsin/chemistry , Drug Liberation , Gastrointestinal Tract/chemistry , Hydrophobic and Hydrophilic Interactions , Particle Size , Trypsin/chemistryABSTRACT
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.
Subject(s)
Cinnarizine/pharmacology , Drug Carriers/chemistry , Fenofibrate/pharmacology , Lipids/chemistry , Printing, Three-Dimensional , Drug Delivery Systems/methods , Drug Liberation , Kinetics , Polyethylene Glycols/chemistry , Proof of Concept Study , Solubility , Surface-Active Agents/chemistry , WaterABSTRACT
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.
Subject(s)
Nucleic Acids/administration & dosage , Administration, Oral , Animals , Gastrointestinal Tract , Humans , Translational Research, BiomedicalABSTRACT
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 (logPâ¯=â¯3) was 100% inside of the nanodroplets at low ionic strength, while for desmopressin-docusate complex (logPâ¯=â¯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.
Subject(s)
Ions/chemistry , Peptides/chemistry , Biological Availability , Chemistry, Pharmaceutical/methods , Dioctyl Sulfosuccinic Acid/chemistry , Drug Delivery Systems/methods , Drug Liberation/drug effects , Emulsifying Agents/chemistry , Emulsions/chemistry , Hydrophobic and Hydrophilic Interactions , Leuprolide/chemistry , Solubility/drug effects , Surface-Active Agents/chemistryABSTRACT
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.
Subject(s)
Colloids/chemistry , Digestion , Drug Delivery Systems , Animals , Humans , Intestinal Absorption , Lipid Metabolism , Lipids/administration & dosage , Lipids/chemistry , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/chemistry , Solubility , Water/chemistryABSTRACT
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.
Subject(s)
Lipids/chemistry , Polymers/chemistry , Administration, Oral , Animals , Dosage Forms , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Excipients/chemistry , Humans , Lipids/administration & dosage , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Polymers/administration & dosage , Printing, Three-Dimensional , Technology, PharmaceuticalABSTRACT
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.