Exploring novel type of lipid-bases drug delivery systems that contain one lipid and one water-soluble surfactant only.

None of transitional lipid-based drug delivery systems (LBDDS) includes compositions containing one lipid and one water-soluble surfactant that form stable microemulsions. The conversion of liquid LBDDS to solid LBDDS has been limited by low drug loading. Previously, we have developed drug solid microemulsions containing one lipid and TPGS (a water-soluble surfactant) that achieved high drug loading and remarkably increased oral bioavailability. This study aimed to test if binary lipid systems (BLS), composed of one lipid and one water-soluble surfactant that form stable self-emulsifying microemulsions, is not an exclusive but widely applicable type of LBDDS for other lipids and surfactants and evaluate the influences of chemical structures of lipids and surfactants on microemulsions and solid microemulsions. We systemically identified new BLS by using a library of lipids and surfactants. Propylene glycol diesters and glycerol triesters were favorable for forming stable microemulsions with Tween 80, Cremophor EL, or TPGS. To the best of our knowledge, this is the first report exploring and confirming that the BLS is a new addition to traditional LBDDS, provides a promising option for researchers, and has the potential to increase drug loading to facilitate the development of solid microemulsions.

Lipid-Based Nanoparticles as Oral Drug Delivery Systems: Overcoming Poor Gastrointestinal Absorption and Enhancing Bioavailability of Peptide and Protein Therapeutics.

Delivery and formulation of oral peptide and protein therapeutics have always been a challenge for the pharmaceutical industry. The oral bioavailability of peptide and protein therapeutics mainly relies on their gastrointestinal solubility and permeability which are affected by their poor membrane penetration, high molecular weight and proteolytic (chemical and enzymatic) degradation resulting in limited delivery and therapeutic efficacy. The present review article highlights the challenges and limitations of oral delivery of peptide and protein therapeutics focusing on the application, potential and importance of solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) as lipid-based drug delivery systems (LBDDSs) and their advantages and drawbacks. LBDDSs, due to their lipid-based matrix can encapsulate both lipophilic and hydrophilic drugs, and by reducing the first-pass effect and avoiding proteolytic degradation offer improved drug stability, dissolution rate, absorption, bioavailability and controlled drug release. Furthermore, their small size, high surface area and surface modification increase their mucosal adhesion, tissue-targeted distribution, physiological function and half-life. Properties such as simple preparation, high-scale manufacturing, biodegradability, biocompatibility, prolonged half-life, lower toxicity, lower adverse effects, lipid-based structure, higher drug encapsulation rate and various drug release profile compared to other similar carrier systems makes LBDDSs a promising drug delivery system (DDS). Nevertheless, undesired physicochemical features of peptide and protein drug development and discovery such as plasma stability, membrane permeability and circulation half-life remain a serious challenge which should be addressed in future.

Absorption of cinnarizine from type II lipid-based formulations: Impact of lipid chain length, supersaturation, digestion, and precipitation inhibition.

Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0-24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0-24 h (1.5 - 3.2-fold) and Cmax (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0-24 h reduced to 47 - 67%, Cmax to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC0-24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.

Solubility of Poorly Soluble Drugs in Phosphatidylcholine-Based Drug Delivery Systems: Comparison of the Loading Capacity in the Bulk Formulation and Its Dispersed State.

The aim of this study was to determine the drug loading capacity of phosphatidylcholine-based formulations for four poorly water-soluble drug substances (clofazimine, fenofibrate, artemether, cannabidiol). Two self-dispersing lipid formulations were investigated, which consisted of soybean phospholipids, medium-chain triglycerides and ethanol with a different phospholipid-oil ratio. The direct loading of the bulk formulation was conducted with dual centrifugation, which proved to be a suitable method for screening experiments with the highly viscous formulations. To estimate possible precipitation after dispersion in the gastrointestinal fluids, the solubility of the drugs was investigated in the dispersed formulations. For this purpose, nanodispersions were prepared from the bulk formulations via high pressure homogenization and subsequently subjected to passive loading. A newly developed HPLC method with Charged Aerosol Detection allowed a simultaneous evaluation of the content of soybean lecithin and medium-chain triglycerides in the nanodispersions. When comparing the two phosphatidylcholine-based formulations, a high content of oil was advantageous with regard to a high loading capacity. Drug substances with melting points below 150 °C exhibited a high solubility in the phospholipid-based formulations. A surprisingly high solubility was observed for artemether and cannabidiol with up to 13.0% and 33.3% drug loaded to the formulations, respectively. In the dispersions, a similar solubility as in the bulk formulations was obtained for fenofibrate and cannabidiol. Clofazimine yielded a higher loading result in the nanodispersions than in the bulk formulation.

Digestion is a critical element for absorption of cinnarizine from supersaturated lipid-based type I formulations.

Enabling formulations, such as lipid-based formulations (LBFs), are means to deliver challenging-to-formulate, poorly soluble drugs. LBFs may be composed of lipids, surfactants and/or cosolvents and can be classified depending on the proportions of the components and the hydrophilicity of the surfactant according to the Lipid Formulations Classification System, ranging from type I (very lipophilic) to type IV (hydrophilic). In cases where drug solubility in LBFs does not suffice, e.g. for preclinical toxicity studies, supersaturated LBFs can be used in order to increase the drug load. However, the effect of digestion on drug absorption from supersaturated type I formulations (consisting exclusively of lipids) still remains relatively unexplored and unclear. In the present study, the impact of lipid digestion on absorption of cinnarizine-loaded supersaturated lipid-based formulations of type I was investigated in rats by pre-dosing of the lipase inhibitor orlistat. The lipid chain length and the drug dose were varied by testing medium-chain triglycerides (MCT) and long-chain triglycerides (LCT), both supersaturated and non-supersaturated. Due to the physical instability of supersaturated formulations of cinnarizine, i.e. a potential of precipitation of cinnarizine, the impact of the addition of the amphiphilic polymer Soluplus®, as a potential precipitation inhibitor, was also investigated. The supersaturated systems resulted in a 2.3 - 3.3-fold higher Area Under the Curve (AUC0-24 h, not dose-normalized) and 1.4 - 2.2-fold higher maximum plasma concentration (Cmax, not dose-normalized) than non-supersaturated formulations (statistically significant with p = 0.05), whereas the addition of Soluplus® did not reveal any benefit. Results indicated that lipase inhibition affected the in vivo performance of LBFs: Co-administration of the lipase inhibitor significantly reduced Cmax and AUC0-24 h (both to 33-39 %, not dose-normalized) for the LCT formulations and, though not significant, a similar trend was observed for the AUC0-24 h of the MCT formulations (to 53-87 %), suggesting a higher dependency on lipolysis for LCT. Also, tmax tended to decrease to 20-60 % when compared to the animals not dosed with orlistat but lacking statistical significance. Without lipase inhibition, the LCT in general lead to better absorption of cinnarizine as compared to MCT, with 1.2-1.7-fold higher AUC0-24 h and 1.4-1.8-fold higher Cmax, but without showing statistical significance. Overall, the study revealed that lipolysis plays a major role in drug absorption from supersaturated lipid-based formulations type I.

Harnessing the multifunctionality of lipid-based drug delivery systems for the local treatment of osteoarthritis.

Osteoarthritis (OA) is a widespread joint condition affecting millions globally, presenting a growing socioeconomic burden thus making the development of more effective therapeutic strategies crucial. This review emphasizes recent advancements in lipid-based drug delivery systems (DDSs) for intra-articular administration of OA therapeutics, encompassing non-steroidal anti-inflammatory drugs, corticosteroids, small molecule disease-modifying OA drugs, and RNA therapeutics. Liposomes, lipid nanoparticles, lipidic mesophases, extracellular vesicles and composite systems exhibit enhanced stability, targeted delivery, and extended joint retention, which contribute to improved therapeutic outcomes and minimized systemic drug exposure. Although active targeting strategies hold promise, further research is needed to assess their targeting efficiency in physiologically relevant conditions. Simultaneously, multifunctional DDSs capable of delivering combinations of distinct therapeutic classes offer synergistic effects and superior OA treatment outcomes. The development of such long-acting systems that resist rapid clearance from the joint space is crucial, where particle size and targeting capabilities emerge as vital factors. Additionally, combining cartilage lubrication properties with sustained drug delivery has demonstrated potential in animal models, meriting further investigation in human clinical trials. This review highlights the crucial need for direct, head-to-head comparisons of novel DDSs with standard treatments, particularly within the same drug class. These comparisons are essential in accurately evaluating their effectiveness, safety, and clinical applicability, and are set to significantly shape the future of OA therapy.

Self-emulsifying drug delivery systems (SEDDS) disrupt the gut microbiota and trigger an intestinal inflammatory response in rats.

Self-emulsifying drug delivery systems (i.e. SEDDS, SMEDDS and SNEDDS) are widely employed as solubility and bioavailability enhancing formulation strategies for poorly water-soluble drugs. Despite the capacity for SEDDS to effectively facilitate oral drug absorption, tolerability concerns exist due to the capacity for high concentrations of surfactants (typically present within SEDDS) to induce gastrointestinal toxicity and mucosal irritation. With new knowledge surrounding the role of the gut microbiota in modulating intestinal inflammation and mucosal injury, there is a clear need to determine the impact of SEDDS on the gut microbiota. The current study is the first of its kind to demonstrate the detrimental impact of SEDDS on the gut microbiota of Sprague-Dawley rats, following daily oral administration (100 mg/kg) for 21 days. SEDDS comprising a lipid phase (i.e. Type I, II and III formulations according to the Lipid Formulation Classification Scheme) induced significant changes to the composition and diversity of the gut microbiota, evidenced through a reduction in operational taxonomic units (OTUs) and alpha diversity (Shannon's index), along with statistically significant shifts in beta diversity (according to PERMANOVA of multi-dimensional Bray-Curtis plots). Key signatures of gut microbiota dysbiosis correlated with the increased expression of pro-inflammatory cytokines within the jejunum, while mucosal injury was characterised by significant reductions in plasma citrulline levels, a validated biomarker of enterocyte mass and mucosal barrier integrity. These findings have potential clinical ramifications for chronically administered drugs that are formulated with SEDDS and stresses the need for further studies that investigate dose-dependent effects of SEDDS on the gastrointestinal microenvironment in a clinical setting.

Thiolation of non-ionic surfactants for the development of lipid-based mucoadhesive drug delivery systems.

The aim of this study was to develop thiolated self-emulsifying drug delivery systems (SEDDS) and nanostructured lipid carriers (NLCs) with improved mucoadhesive properties. Two non-ionic surfactants bearing a short and long PEG chain, namely polyoxyethylene (10) stearyl ether (PSE10) and polyoxyethylene (100) stearyl ether (PSE100), were thiolated for the first time by substituting the terminal hydroxyl group with a thiol group. The synthesis was confirmed by FT-IR, NMR and Ellman's test. SEDDS and NLCs containing these thiolated compounds were investigated for size, polydispersity index (PDI) and ζ potential. Subsequently, mucus diffusion studies, rheological evaluations after mixing the nanocarriers with mucus and mucoadhesion studies on porcine intestinal mucosa were performed. All nanocarriers had a size less than 250 nm, a maximum PDI of 0.3 and a ζ potential < -9.0 mV. Mucus diffusion studies resulted in the rank order of increasing diffusivity: PSE10-SH < PSE100-SH < PSE10-OH < PSE100-OH for NLCs and PSE10-OH < PSE100-OH < PSE100-SH < PSE10-SH for SEDDS. The mucoadhesive properties and increase in viscosity of SEDDS and NLCs ranked: PSE100-OH < PSE10-OH < PSE100-SH < PSE10-SH. In addition, the short chain PSE10-SH showed higher mucus interactions than the long chain PSE100-SH for both SEDDS and NLCs. The thiolated PSE surfactants appeared to be promising excipients for the design of highly mucoadhesive drug delivery systems.

Lipid-based solubilization technology via hot melt extrusion: promises and challenges.

INTRODUCTION: Self-emulsifying drug delivery systems (SEDDS) are a promising strategy to improve the oral bioavailability of poorly water-soluble drugs (PWSD). However, poor drug loading capacity and formulation instability are the main setbacks of traditional SEDDS. The use of polymeric precipitation inhibitors was shown to create supersaturable SEDDS with increased drug loads, and their solidification can help to overcome the instability challenge. As an alternative to several existing SEDDS solidification technologies, hot melt extrusion (HME) has the potential for lean and continuous manufacturing of supersaturable solid-SEDDS. Despite being ubiquitously applied in solid lipid and polymeric processing, HME has not yet been widely considered for the preparation of SEDDS. AREAS COVERED: The review begins why SEDDS as the preferred lipid-based delivery systems (LBDS) is suitable for the oral delivery of PWSD and discusses the common barriers to oral administration. The potential of LBDS to surmount them is discussed. SEDDS as the flagship of LBDS for PWSD is proposed with a special emphasis on solid-SEDDS. Finally, the opportunities and challenges of HME from the lipid-based excipient (LBE) processing and product performance standpoint are highlighted. EXPERT OPINION: HME is a continuous, solvent-free, cost-effective, and scalable technology for manufacturing solid supersaturable SEDDS. Several critical formulations and process parameters for successfully preparing SEDDS via HME are identified.

Controlling drug release by introducing lipase inhibitor within a lipid formulation.

Drug overdose connected to marketed pharmaceutical products, particularly opioids, occurs at an alarming rate. Novel strategies through innovative formulation approaches that reduce the likelihood of overdose while allowing safe therapeutic outcomes are urgently required. The current study provides a proof-of-concept for a new formulation approach by co-formulating drug with a lipase inhibitor within a solid lipid formulation in order to prevent or reduce the harmful effects of taking multiple doses of an oral solid dose form. Lipase inhibitor controlled-release (LICR) formulations were created using a simple hot melt method to co-formulate the inhibitor (orlistat) and ibuprofen, as the model drug, within the lipid matrix. The digestion and drug release kinetics were determined using an in vitro lipolysis model. Above a threshold level of orlistat there was decreased digestibility of multiple doses of the LICR formulations, leading to reduced drug release. Upon administration of the formulations in capsules to rats, the LICR formulation displayed the lowest exposure of ibuprofen during the pharmacokinetic studies. This novel formulation approach shows promise in preventing accidental drug overdose after oral administration of multiple doses of formulation.

Relative bioavailability enhancement of simvastatin via dry emulsion systems: Comparison of spray drying and fluid bed layering technology.

Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3% vs 71.5%), encapsulation efficiency (80.0% vs 68.4%), relative one month product stability (93.8% vs 85.5%), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115% relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms.

The Potential of Macroporous Silica-Nanocrystalline Cellulose Combination for Formulating Dry Emulsion Systems with Improved Flow Properties: A DoE Study.

The objective of this study was to explore the possible use of a new combination of two excipients, i.e., nanocrystalline cellulose (NCC) and macroporous silica (MS), as matrix materials for the compounding of dry emulsion systems and the effects these two excipients have on the characteristics of dry emulsion powders produced by the spray drying process. A previously developed liquid O/W nanoemulsion, comprised of simvastatin, 1-oleoyl-rac-glycerol, Miglyol 812 and Tween 20, was employed. In order to comprehend the effects that these two matrix formers have on the spray drying process and on dry emulsion powder characteristics, alone and in combination, a DoE (Design of Experiment) approach was used. The physicochemical properties of dry emulsion samples were characterised by atomic force microscopy, scanning electron microscopy, mercury intrusion porosimetry, energy-dispersive X-ray spectroscopy and laser diffraction analysis. Additionally, total release and dissolution experiments were performed to assess drug release from multiple formulations. It was found that the macroporous silica matrix drastically improved flow properties of dry emulsion powders; however, it partially trapped the oil-drug mixture inside the pores and hindered complete release. NCC showed its potential to reduce oil entrapment in MS, but because of its rod-shaped particles deposited on the MS surface, powder flowability was deteriorated.

In vitro lipolysis and physicochemical characterization of unconventional star anise oil towards the development of new lipid-based drug delivery systems.

Lipid-based drug delivery systems are widely used for enhancing the bioavailability of poorly water-soluble drugs. However, following oral intake, lipid excipients often undergo gastrointestinal lipolysis, which drastically affects drugs solubility and bioavailability. That's why developing new lipid excipients which are resistant to digestion would be of great interest. We studied here the potential role of the unconventional Chinese star anise whole seedpod oil (CSAO) as an alternative multifunctional lipid excipient. Pancreatic lipase-mediated digestion of the extracted crude oil emulsion was assessed in vitro. Pancreatic lipase, being a strict sn-1,3-regioselective lipase, showed a high (16-fold) olive oil to CSAO activity ratio, which could be attributed to fatty acids composition and triglycerides intramolecular structure. For the sake of comparison, the non-regioselective lipase Novozyme® 435 exhibited higher activity than pancreatic lipase on CSAO emulsion, perhaps due to its ability to release fatty acids from the internal sn-2 position of TAGs. Apart counteracting lipolysis, CSAO oil also showed additional biopharmaceutical benefits including moderate antioxidant and antihypertensive activities. Altogether, these findings highlight for the first time the potential use of star anise unconventional whole seedpod oil as a multifunctional lipid excipient for the development of new lipid formulations.

Charge reversal self-emulsifying drug delivery systems: A comparative study among various phosphorylated surfactants.

HYPOTHESIS: Phosphorylated surfactants having ethoxylate spacer arms are promising excipients for charge reversal self-emulsifying drug delivery systems (SEDDS). EXPERIMENTS: 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid disodium salt (PA), 2-((2,3-bis(oleoyloxy)propyl)dimethylammonio)ethyl hydrogen phosphate (DOCP), nonylphenol monophosphate ester (PNPP), C12-15 alcohol 3 ethoxylate phosphate ester (PME) and polyoxyethylene (9) dioctanoyl glycerol pyrophosphate (DGPP) loaded SEDDS were developed and characterized. Zeta potential of SEDDS was measured before and after incubation with intestinal alkaline phosphatase (IAP). Phosphate release was monitored by incubation of SEDDS with isolated as well as cell-associated IAP. Primary amine content on the surface of SEDDS was determined in parallel. Cytotoxicity was evaluated on Caco-2 cells and in vitro hemolysis test was performed. Cellular uptake studies were performed by confocal scanning microscopy. FINDINGS: SEDDS formulations exhibited a size in the range of 17 and 193 nm and a polydispersity index (PDI) ≤ 0.5. Charge reversal from negative to positive values could be achieved in case of PNPP and PME loaded SEDDS with a zeta potential changing from -13 mV to +9 mV and from -7 to +2 mV, respectively, within 6 h. Significant amounts of phosphate were released from PNPP and PME loaded SEDDS incubated with isolated IAP and from all formulations incubated with cell-associated IAP in accordance with an increase in primary amines on the surface of oily droplets. SEDDS exhibited a concentration and time-dependent cytotoxicity. PNPP and PME SEDDS displayed an increased cellular uptake.

Predicting the API partitioning between lipid-based drug delivery systems and water.

Partitioning tests in water are early-stage standard experiments during the development of pharmaceutical formulations, e.g. of lipid-based drug delivery system (LBDDS). The partitioning behavior of the active pharmaceutical ingredient (API) between the fatty phase and the aqueous phase is a key property, which is supposed to be determined by those tests. In this work, we investigated the API partitioning between LBDDS and water by in-silico predictions applying the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and validated these predictions experimentally. The API partitioning was investigated for LBDDS comprising up to four components (cinnarizine or ibuprofen with tricaprylin, caprylic acid, and ethanol). The influence of LBDDS/water mixing ratios from 1/1 up to 1/200 (w/w) as well as the influence of excipients on the API partitioning was studied. Moreover, possible API crystallization upon mixing the LBDDS with water was predicted. This work showed that PC-SAFT is a strong tool for predicting the API partitioning behavior during in-vitro tests. Thus, it allows rapidly assessing whether or not a specific LBDDS might be a promising candidate for further in-vitro tests and identifying the API load up to which API crystallization can be avoided.

Solidification of self-emulsifying drug delivery systems (SEDDS): Impact on storage stability of a therapeutic protein.

Four solidification methods for self-emulsifying drug delivery systems (SEDDS) were compared to evaluate the impact of solidification on storage stability of an incorporated protein. Papain was loaded in SEDDS via hydrophobic ion pairing (HIP). Liquid SEDDS (l-SEDDS) were either solidified by adsorption to solid excipients such as magnesium-aluminometasilicate via wet granulation (ssilica-SEDDS) and carbohydrates via lyophilisation (scarbo-SEDDS) or by incorporation of high-melting PEG-surfactants (sPEG-SEDDS) and triglycerides (soil-SEDDS) in SEDDS preconcentrates. L- and s-SEDDS were compared regarding intrinsic emulsion properties, solid-state form of papain, enzyme stability and activity during storage. HIP with deoxycholate showed a precipitation efficiency of 82% and papain maintained 90% of its initial activity. Incorporated papain was present in an amorphous state, confirming a molecular dispersion in all preconcentrates. In comparison to l-SEDDS each solidification method investigated improved the storage stability of incorporated papain. Neither precipitation nor phase separation was observed for s-SEDDS. sPEG-SEDDS demonstrated with 87.8% the highest enzymatic activity and displayed according to the following rank order: sPEG-SEDDS > soil-SEDDS > ssilica-SEDDS > scarbo-SEDDS > l-SEDDS the highest remaining papain activity after 30 days of storage. This work clearly demonstrates that solidified SEDDS can provide a significantly improved storage stability for therapeutic proteins compared to corresponding liquid formulations.

Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems.

Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.

Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients.

OBJECTIVE: This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. SIGNIFICANCE: While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. METHODS AND RESULTS: Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. CONCLUSIONS: The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs.

Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across PermeapadⓇ membrane and in vivo absorption.

Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic PermeapadⓇ membrane to establish a potential in vivo - in vitro correlation. A secondary objective was to investigate the influence of lipid composition on in vitro and in vivo performance of lipid systems. Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems. Long chain systems displayed higher celecoxib bioavailability than equivalent medium chain systems, both at supersaturated and non-supersaturated drug loads. In vitro passive permeation of celecoxib was studied using both steady-state and dynamic conditions and correlated well with in vivo pharmacokinetic results with respect to compositional effects. In contrast, permeation studies indicated that flux and percentage permeated of supersaturated systems, either at steady-state or under dynamic conditions, decreased or were unchanged relative to non-supersaturated systems. This study has shown that by using two cell-free PermeapadⓇ permeation models coupled with rat-adapted gastro-intestinal conditions, bio-predictive in vitro tools can be developed to be reflective of in vivo scenarios. With further optimization, such models could be successfully used in pharmaceutical industry settings to rapidly screen various prototype formulations prior to animal studies.

Solubility of Pharmaceutical Ingredients in Natural Edible Oils.

Natural edible oils (NEOs) are common excipients for lipid-based formulations. Many of them are complex mixtures comprising hundreds of different triglycerides (TGs). One major challenge in developing lipid-based formulations is the variety in NEO compositions affecting the solubility of active pharmaceutical ingredients. In this work, solubilities of indomethacin (IND), ibuprofen (IBU), and fenofibrate (FFB) in soybean oil and in coconut oil were measured via differential scanning calorimetry, high-performance liquid chromatography, and Raman spectroscopy. Furthermore, this work proposes an approach that mimics NEOs using one key TG and models the API solubilities in these NEOs based on perturbed-chain statistical associating fluid theory (PC-SAFT). Key TGs were determined using the 1,2,3-random hypothesis, and PC-SAFT parameters were estimated via a group-contribution method. Using the proposed approach, the solubility of IBU and FFB was modeled in soybean oil and coconut oil. Furthermore, the solubilities of five more APIs (IND, cinnarizine, naproxen, griseofulvin, and felodipine) were modeled in soybean oil. All modeling results were found in very good agreement with the experimental data. The influence of different NEO kinds on API solubility was examined by comparing FFB and IBU solubilities in soybean oil and refined coconut oil. PC-SAFT was thus found to allow assessing the batch-to-batch consistency of NEO batches in silico.