In Vitro and In Vivo Performance of Pickering Emulsion-Based Powders of Omega-3 Polyunsaturated Fatty Acids.

Omega-3 polyunsaturated fatty acids (n-3 PUFA) are essential nutrients for human health and have been linked to a variety of health benefits, including reducing the risk of cardiovascular diseases. In this paper, a spray-dried powder formulation based on Pickering emulsions stabilized with cellulose nanocrystals (CNC) and hydroxypropyl methylcellulose (HPMC) has been developed. The formulation was compared in vitro and in vivo to reference emulsions (conventional Self-Emulsifying Drug Delivery System, SEDDS) to formulate n-3 PUFA pharmaceutical products, specifically in free fatty acid form. The results of in vivo studies performed in fasted dogs showed that Pickering emulsions reconstituted from powders are freely available (fast absorption) with a similar level of bioavailability as reference emulsions. In the studies performed with dogs in the fed state, the higher bioavailability combined with slower absorption observed for the Pickering emulsion, compared to the reference, was proposed to be the result of the protection of the n-3 PUFAs (in free fatty acid form) against oxidation in the stomach by the solid particles stabilizing the emulsion. This observation was supported by promising results from short-term studies of chemical stability of powders with n-3 PUFA loads as high as 0.8 g oil/g powder that easily regain the original emulsion drop sizes upon reconstitution. The present work has shown that Pickering emulsions may offer a promising strategy for improving the bioavailability and stability as well as providing an opportunity to produce environmentally friendly (surfactant free) and patient-acceptable solid oral dosage forms of n-3 PUFA in the free fatty acid form.

Bioavailability enhancement of coenzyme Q10: An update of novel approaches.

Coenzyme Q10 (CoQ10) is an essential, lipid-soluble vitamin involved in electron transport in the oxidoreductive reactions of the mitochondrial respiratory chain. Structurally, the quinone ring is connected to an isoprenoid moiety, which has a high molecular weight. Over the years, coenzyme Q10 has become relevant in the treatment of several diseases, like neurodegenerative disorders, coronary diseases, diabetes, hypercholesterolemia, cancer, and others. According to studies, CoQ10 supplementation might be beneficial in the treatment of CoQ10 deficiencies and disorders associated with oxidative stress. However, the water-insoluble nature of CoQ10 is a major hindrance to successful supplementation. So far, many advancements in CoQ10 bioavailability enhancement have been developed using novel drug carriers such as solid dispersion, liposomes, micelles, nanoparticles, nanoemulsions, self-emulsifying drug systems, or various innovative approaches (CoQ10 complexation with proteins). This article aims to provide an update on methods to improve CoQ10 solubility and bioavailability.

Improvement of dissolution profile of eplerenone with solidified self-emulsifying drug delivery systems (S-SEDDS).

CONTEXT: Eplerenone is a member of antihypertensives used individually or in combination with other medicines. Eplerenone exhibits poor solubility and is considered a class II drug. OBJECTIVE: Increasing the solubility of eplerenone by using both liquid and solid self-emulsifying drug delivery systems as an alternative to its marketed tablet product. METHODS: Solubility studies of eplerenone were done with different oils, surfactants, and co-surfactants to determine which one has the highest solubility for eplerenone and determine the preference in the formulations of liquid self-emulsifying drug delivery system. The solidification process was carried out with the adsorption to solid carrier method. Optimal ratios of components were specified with the pseudo-ternary phase diagram technique. Self-emulsifying drug delivery system formulations were characterized in terms of chemical interaction, droplet size/distribution, crystallization behaviors, and rheological evaluation. In vitro drug release studies were conducted and compared to pure drugs and marketed products. RESULTS: The solubility screening results showed high solubility of EPL in triacetin (11.99 mg/mL) as oil, Kolliphor®EL (≈ 2.65 mg/mL), and Tween80 (≈ 1.91 mg/mL) as surfactant and polyethylene glycol 200 (PEG200) (≈ 8.50 mg/mL), dimethyl sulfoxide (≈ 7.57 mg/mL), TranscutolP (≈ 6.03 mg/mL) as co-surfactant, respectively. Rheology studies revealed that liquid self-emulsifying drug delivery formulations exhibited non-Newtonian pseudoplastic flow. CONCLUSION: Solid self-emulsifying drug delivery systems prepared with Aerosil and Neusilin have shown tremendous improvement in terms of eplerenone dissolution by releasing the entire dose with boosted effect within 5 and 30 min respectively compared to the marketed product and pure eplerenone (p < 0.05).

Preparation and characterisation of self-emulsifying drug delivery system (SEDDS) for enhancing oral bioavailability of metformin hydrochloride using hydrophobic ion pairing complexation.

AIM: The aim of this study was preparation of a self-emulsifying drug delivery system (SEEDS) containing metformin hydrochloride. METHODS: Hydrophobic ion paired complexes were prepared by electrostatic interaction between metformin and sodium lauryl sulphate (SLS). The nanodroplets were optimised using two-level full factorial methodology and their morphology were examined. In vitro release of metformin from SEDDS was evaluated in simulated gastric and intestinal fluids. Finally, the ex-vivo efficacy of the optimised formulation in enhancing the intestinal permeability of metformin was evaluated using non-everted intestinal sac. RESULTS: The data revealed that in weight ratio 1:4(metformin: SLS), the highest recovery was achieved. The physico-chemical properties of the optimised nano-droplets including size, polydispersity index (PdI), zeta potential, and loading efficiency (%) were 192.33 ± 9.9 nm, 0.275 ± 0.051; -1.52 mV, and 93.75 ± 0.77% (w/w), respectively. CONCLUSIONS: The data obtained from the intestinal transport study demonstrated that SEDDS can significantly enhance the oral permeability of the compound.

Enhanced Intestinal Permeability of Cefixime by Self-Emulsifying Drug Delivery System: In-Vitro and Ex-Vivo Characterization.

BACKGROUND: Cefixime (CFX) belongs to a group of third-generation cephalosporin antibiotics with low water solubility and low intestinal permeability, which ultimately leads to significantly low bioavailability. AIM: This study aimed to increase solubility, improve drug release, and intestinal permeability of CFX by loading into SEDDS. METHODS: Suitable excipients were selected based on drug solubility, percent transmittance, and emulsification efficiency. Pseudo-ternary phase diagram was fabricated for the identification of effective self-emulsification region. The best probably optimized formulations were further assessed for encumbered drug contents, emulsification time, cloud point measurement, robustness to dilution, mean droplet size, zeta potential, polydispersity index (PDI), and thermodynamic and chemical stability. Moreover, in vitro drug release studies and ex vivo permeation studies were carried out and apparent drug permeability Papp of different formulations was compared with the marketed brands of CFX. RESULTS: Amongst the four tested SEDDS formulations, F-2 formulation exhibited the highest drug loading of 96.32%, emulsification time of 40.37 ± 3 s, mean droplet size of 19.01 ± 1.12 nm, and demonstrated improved long-term thermodynamic and chemical stability when stored at 4 °C. Release studies revealed a drug release of 97.32 ± 4.82% within 60 min in simulated gastric fluid. Similarly, 97.12 ± 5.02% release of CFX was observed in simulated intestinal fluid within 120 min; however, 85.13 ± 3.23% release of CFX was observed from the marketed product. Ex vivo permeation studies displayed a 2.7-fold increase apparent permeability compared to the marketed product in 5 h. CONCLUSION: Owing to the significantly improved drug solubility, in vitro release and better antibacterial activity, it can be assumed that CFX-loaded SEDDS might lead to an increased bioavailability and antibacterial activity, possibly leading to improved therapeutic effectiveness.

Development of SEDDS formulation containing caffeine for dermal delivery.

OBJECTIVE: The objective of this work was to develop a self-emulsifying drug delivery system (SEDDS) containing caffeine for the treatment of cellulite. METHODS: SEDDS were prepared using the solution method. 0.5% (w/v) caffeine was added to the previously selected excipients. The system was characterized by droplet size, zeta potential, emulsification time and long-term stability. In vitro release and skin permeation were investigated using Franz-type diffusion cells. The cytotoxicity was evaluated on normal human keratinocytes. RESULTS: Caffeine SEDDS were thermodynamically stable, with a zeta potential less than - 22 mV and droplet size around 30 nm, and were long-term stable. The permeation study showed that the formulation promoted caffeine accumulation in the skin layers, suggesting an increase in local circulation. Cytotoxicity studies on HaCaT cells were not conclusive as the surfactant used indicated false-positive results due to its high molar mass. CONCLUSION: It was possible to obtain a stable SEDDS that could cause an increase in blood flow in the applied area, resulting in cellulite reduction.

OBJECTIF: L'objectif de ce travail était de développer un système d'administration de médicaments auto-émulsifiants (SEDDS) contenant de la caféine pour le traitement de la cellulite. MÉTHODES: Les SEDDS ont été préparés par la méthode en solution. 0,5 % (p/v) de caféine a été ajouté aux excipients préalablement sélectionnés. Le système a été caractérisé par la taille des gouttelettes, le potentiel zêta, le temps d'émulsification et la stabilité à long terme. La libération in vitro et la perméation cutanée ont été étudiées dans des cellules de diffusion de type Franz. La cytotoxicité était évaluée sur des kératinocytes humains normaux. RÉSULTATS: Les SEDDS de caféine étaient thermodynamiquement stables, avec un potentiel Zeta inférieur à -22 mV et une taille de gouttelettes d'environ 30 nm, et stables à long terme. L'étude de perméation a montré que les formulations favorisent l'accumulation de caféine dans les couches de la peau, suggérant une augmentation de la circulation locale. Les études de cytotoxicité sur les cellules HaCaT n'ont pas été concluantes car le surfactant utilisé indique des résultats faussement positifs dus à une masse molaire élevée. CONCLUSION: Il a été possible d'obtenir un SEDDS stable qui peut provoquer une augmentation du flux sanguin dans la zone appliquée, entraînant une réduction de la cellulite.

Oil-water partition coefficient preparation and detection in the dihydroartemisinin self-emulsifying drug delivery system.

BACKGROUND: The aim of the present study is to increase the solubility of dihydroartemisinin (DHA) using the self-emulsifying drug delivery system (SEDDS). METHODS: We first conducted solubility test and ternary phase diagram, then, in order to optimize the formulation of the DHA self-emulsifying agent, the design mixture method was selected in the design expert software. Next, optimal prescription validation and preliminary formulation evaluation were conducted. By comparing the oil-water partition coefficient in vitro, the improvement of the in vivo osmotic absorption of DHA via self-emulsification was evaluated. RESULTS: The optimal prescription ratio of oleic acid polyethylene glycol glyceride, polyoxyethylene hydrogenated castor oil, and diethylene glycol monoethyl ether in the DHA self-emulsifying preparation = 0.511:0.2:0.289 (w/w/w), with a drug-loading capacity of 26.3634 mg/g, solubility of 2.5448 mg/ml, and self-emulsification time of 230 s. The solubility self-emulsification was approximately 20.52 × higher in DHA than in the crude drug. The self-emulsification could improve DHA permeability and promoting in vivo DHA absorption. CONCLUSION: The DHA SEDDS could significantly improve DHA solubility and in vivo absorption.

Preparation and evaluation of a lipid-based drug delivery system to improve valsartan oral bioavailability: pharmacokinetic and pharmacodynamic analysis.

Antihypertensive treatment reduces the risk of cardiovascular complications in patients with high mortality with hypertension. Valsartan is highly selective antihypertensive that is rapidly absorbed after oral administration, but its oral bioavailability is only 25%. It is absorbed from the upper part of the gastrointestinal tract but is less soluble in this acidic environment. We aimed to develop a lipid-based formulation to produce a self-emulsifying drug delivery system (SEDDS) for valsartan. Solubility studies were performed to identify the components of the SEDDS that provided the best dissolution of valsartan. Ternary phase diagrams were drawn using the titration method with oil, surfactants and co-surfactants in which valsartan was highly soluble, and microemulsion formulations with the highest area were determined. Characterization and in vitro release studies were performed to optimize the formulation. In vitro release profiles of commercial and SEDDS formulations showed the F2 formulation release rate increased at pH 1.2 fasted state simulated gastric fluid. After oral administration, plasma drug concentrations in rats indicate that the F2 formulation provided a 4.2-fold greater AUC for valsartan than the commercial formulaiton, resulting in an 8.5-fold greater Cmax. These findings suggest the F2 formulation increases valsartan solubility, resulting in an improved oral pharmacokinetic profile. According to the pharmacodynamic study, the F2 formulation is more effective than the commercial formulation in restoring systolic and diastolic blood pressure within a few hours.

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening.

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects. Among the synthesized compounds, the 4-phenylderivative 12 and the 6-phenylderivative 25 exerted a promising F508del CFTR rescue ability. On these compounds, preliminary in vivo pharmacokinetic (PK) studies were carried out, evidencing a favorable PK profile per se or after incorporation into lipid formulations. Therefore, the selected compounds are good candidates for future extensive investigation to evaluate and develop novel CFTR correctors based on the angelicin structure.

Formulation, Characterization and Permeability Studies of Fenugreek (Trigonella foenum-graecum) Containing Self-Emulsifying Drug Delivery System (SEDDS).

Fenugreek is used as a spice and a traditional herbal medicine for a variety of purposes, given its antidiabetic and antioxidant effects. Self-emulsifying drug delivery systems (SEDDS) of herbal drugs are targets of extensive research aiming to increase bioavailability and stability. The study's objective was to formulate SEDDS containing Trigonella foenum-graecum extract to improve the stability of herbal extract and to increase their permeability through a Caco-2 monolayer. A characterized fenugreek dry extract was used for the formulations, while the SEDDS properties were examined by particle size analysis and zeta potential measurements. Permeability assays were carried out on Caco-2 cell monolayers, the integrity of which was monitored by follow-up trans-epithelial electric resistance measurements (TEER). Cytocompatibility was tested by the MTT method, and an indirect dissolution test was performed, using DPPH antioxidant reagent. Two different SEDDS compositions were formulated from a standardized fenugreek dry extract at either the micro- or the nanoemulsion scale with sufficient stability, enhanced bioavailability of the compounds, and sustained release from HPMC capsules. Based on our results, a modern, non-toxic, cytocompatible fenugreek SEDDS formulation with high antioxidant capacity was developed in order to improve the permeability and bioavailability of all components.

Development of Self-Emulsifying Drug Delivery Systems (SEDDSs) Displaying Enhanced Permeation of the Intestinal Mucus Following Sustained Release of Prototype Thiol-Based Mucolytic Agent Load.

In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from −17.31 mV to −7.72 mV. On Caco-2 cells, SEDDSs at 1−3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100−NAC and RS 100−NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.

Enhanced Oral Bioavailability of ß-Caryophyllene in Healthy Subjects Using the VESIsorb® Formulation Technology, a Novel Self-Emulsifying Drug Delivery System (SEDDS).

ß-Caryophyllene (BCP), a common constituent of many spice and food plants, is gaining increased attention due to recent research identifying numerous potential health benefits. Due to limited oral bioavailability observed in preclinical models, the described benefits of BCP may be maximized by using a suitable delivery system. Additionally, human pharmacokinetics (PK) remain unknown. This study evaluates the relative oral bioavailability of BCP formulated in a self-emulsifying drug delivery system (SEDDS) based on VESIsorb® formulation technology (BCP-SEDDS) compared to BCP neat oil. Hence, a randomized, double-blind, cross-over design, single oral dose study (100 mg BCP) in 24 healthy subjects (12 men/12 women) was performed under fasting conditions. Pharmacokinetic parameters were analyzed from individual concentration-time curves. The data show that BCP-SEDDS resulted in a 2.2/2.0-fold increase in AUC0-12h/AUC0-24h and a 3.6-fold increase in Cmax compared to BCP neat oil. Moreover, BCP was absorbed faster from BCP-SEDDS (Tmax: 1.43 h) compared to BCP neat oil (Tmax: 3.07 h). Gender analysis revealed that there is no significant difference between men and women for both the investigated formulations and all investigated PK endpoints. In conclusion, BCP-SEDDS offers a well-tolerated and effective oral delivery system to significantly enhance the oral bioavailability of BCP in humans.

In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax.

The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.

Metabolic profile of curcumin self-emulsifying drug delivery system in rats determined by ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

Curcumin (Cur) is a natural anticancer pigment, but its poor absorption and extensive metabolism limit its clinical applications. In this study, an ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry method was employed to investigate the metabolic profiles of a Cur self-emulsifying drug delivery system (C-SEDDS) in rat plasma, urine, bile and feces after oral administration at 100 mg/kg. Protein precipitation, solid-phase and ultrasonic extractions were used to prepare different biosamples. A total of 34 metabolites were identified using available reference standards, or tentatively identified based on the mass spectrometric fragmentation patterns and the chromatographic elution order. Nine metabolites of Cur were found for the first time in vivo. Glucuronidation, sulfation, reduction, dehydroxylation, demethylation, demethoxylation and methylation were its possible metabolic reactions. Moreover, the differences were compared in terms of plasma metabolites found in C-SEDDS-treated, Cur suspension-treated and rats treated with a commercial curcuminoid phospholipid complex administered at the same oral dose. Dihydrocurcumin (DHC), DHC glucuronide and methylated DHC were found only in the metabolic profile of C-SEDDS-treated rat plasma, suggesting that different drug delivery systems may cause a change in Cur metabolic pathways. This study provides a sensitive and rapid method for the identification of Cur metabolites in biosamples.

Impact of bile salts and a medium chain fatty acid on the physical properties of self-emulsifying drug delivery systems.

The aim of this study was the evaluation of the influence of bile salts and fatty acids, important components of intestinal fluids, on physical characteristics of self-emulsifying drug delivery systems (SEDDS) such as size, polydispersity (PDI), zeta potential (Zp), turbidity (T%), cloud point temperature (CPT) and drug release. At this purpose, nonionic (ni-SEDDS) and cationic (c-SEDDS) were emulsified in aqueous media containing increasing concentrations of bile salts (BS) and decanoate (Dec). Zp of ni-SEDDS and c-SEDDS became highly negative at 15 mM BS and Dec. Size of ni-SEDDS decreased of 112 nm and of 76 nm at 15 mM BS and Dec, respectively. Size of c-SEDDS decreased of 53 nm at 15 mM BS, but it was not affected by 15 mM Dec. PDI and T% of ni- and c-SEDDS were lowered as well. CPT of ni-SEDDS increased from 70 °C to 97 °C and 84 °C at 15 mM BS and Dec. CPT of c-SEDDS decreased from above 100 °C to 80 °C and to 85 °C at 1.5 mM BS and at 5 mM Dec, respectively. Generally, BS had a more pronounced effect on SEDDS Zp, size, PDI, T %, and CPT than Dec. The release of the model drug quinine was accelerated by BS and Dec. As BS and fatty acids affect the physical characteristics and drug release behavior of SEDDS, their impact should be addressed during the development process.

Sustained release of curcumin self-emulsifying drug delivery system (SEDDS) from solvent-cast Soluplus® films.

The objective of the present study was to investigate the feasibility of formulating and loading Curcumin SEDDS (Self-Emulsified Drug Delivery Systems) into films made from Soluplus® as the film-forming polymer. Films with up to 30% of Curcumin SEDDS were prepared by the solvent casting technique and analyzed for their mechanical and dissolution properties. A nine-run, two-factor, three-level factorial design was utilized to investigate the effect of SEDDS load (10, 20, and 30% w/w) and film thickness (10, 25, and 40 mils) on the tensile strength, elongation, and adhesiveness of the films. The dissolution profile of the films was also investigated by a USP Type 1 method. SEDDS loading was found to plasticize Soluplus® and to yield transparent films of good mechanical properties. Increasing SEDDS load, however, was found to reduce the tensile strength of the films, while increasing their adhesiveness and elongation. On the other hand, while an increase in film thickness was found to increase the tensile strength of the films, it reduced the elongation capacity of the films. Loading SEDDS into Soluplus® films was also found to sustain their release over 6 h, where a significant delay in release was found at lower SEDDS loads. This study demonstrated that Soluplus® can be used not only to formulate SEDDS into polymeric films but also to sustain their release over an extended time.

Cosolvents in Self-Emulsifying Drug Delivery Systems (SEDDS): Do They Really Solve Our Solubility Problems?

The aim of this study was to investigate the fate and the impact of cosolvents in self-emulsifying drug delivery systems (SEDDS). Three different SEDDS comprising the cosolvents DMSO (FD), ethanol (FE), and benzyl alcohol (FBA) as well as the corresponding formulations without these cosolvents (FD0, FE0, and FBA0) were developed. Mean droplet size, polydispersity index (PDI), ζ potential, stability, and emulsification time were determined. Cosolvent release studies were performed via the dialysis membrane method and Taylor dispersion analysis (TDA). Furthermore, the impact of cosolvent utilization on payloads in SEDDS was examined using quinine as a model drug. SEDDS with and without a cosolvent showed no significant differences in droplet size, PDI, and ζ potential. The emulsification time was 3-fold (FD0), 80-fold (FE0), and 7-fold (FBA0) longer due to the absence of the cosolvents. Release studies in demineralized water provided evidence for an immediate and complete release of DMSO, ethanol, and benzyl alcohol. TDA confirmed this result. Moreover, a 1.4-fold (FD), 2.91-fold (FE), and 2.17-fold (FBA) improved payload of the model drug quinine in the selected SEDDS preconcentrates was observed that dropped after emulsification within 1-5 h due to drug precipitation. In parallel, the quinine concentrations decreased until reaching the same levels of the corresponding SEDDS without cosolvents. Due to the addition of hydrophilic cosolvents, the emulsifying properties of SEDDS are strongly improved. As hydrophilic cosolvents are immediately released from SEDDS during the emulsification process, however, their drug solubilizing properties in the resulting oily droplets are very limited.

Development and In Vitro Evaluation of Stearic Acid Phosphotyrosine Amide as New Excipient for Zeta Potential Changing Self-Emulsifying Drug Delivery Systems.

PURPOSE: Development of zeta potential changing SEDDS containing newly synthesized derivative stearic acid phosphotyrosine amide. METHODS: Stearoyl chloride was conjugated with phosphotyrosine, which is substrate for the brush border enzyme intestinal alkaline phosphate. The synthesized derivative was implemented in different SEDDS formulations and the zeta potential changing properties and the concluding mucus diffusion abilities were evaluated. RESULTS: Stearic acid phosphotyrosine amide was successfully synthesized and incorporated into SEDDS. A SEDDS formulation containing the new derivative showed a zeta potential of -14 mV before, and + 2 mV after enzymatic cleavage by intestinal alkaline phosphatase. Experiments on a Caco-2 monolayer demonstrated that the phosphate cannot only be cleaved by isolated enzyme, but also by enzyme, which was expressed by cells. The mucus diffusion abilities of the untreated, negatively charged SEDDS were significantly higher compared to the enzymatically cleaved, positively charged SEDDS. CONCLUSION: The developed stearic acid phosphotyrosine represents a promising excipient for zeta potential changing SEDDS. Graphical Abstract.

Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems.

To improve the solubility and oral bioavailability of a novel antimalarial agent ELQ-331(a prodrug of ELQ-300), spray-dried dispersions (SDD) and a self-emulsifying drug delivery system (SEDDS) were developed. SDD were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) polymer carrier and Aeroperl® 300 Pharma and characterized by differential scanning calorimetry, powder X-ray diffraction. For SEDDS, solubility in oils, surfactants, and co-surfactants was determined and ternary phase diagram was constructed to show self-emulsifying area. SEDDS were characterized for spontaneous emulsification and droplet size distribution. The amorphous ELQ-331 SDD improved the solubility to 10× in fast-state simulated intestinal fluid and addition of sodium lauryl sulphate externally to SDDs further improved the solubility to ∼28.5× versus non-formulated drug. SEDDS had good self-emulsifying characteristics with small emulsion droplet sizes and narrow particle distribution. Oral pharmacokinetic studies for SDD and SEDDS formulations were performed in rats. The ELQ-331 rapidly converted to ELQ-300 soon after oral administration in rats. Exposure levels of ELQ-300 were about 1.4-fold higher (based on AUC) in SEDDS than SDD formulations. Poorly soluble drugs like ELQ-331 can be formulated using SDD or SEDDS to improve solubility and oral bioavailability.

Paclitaxel-Loaded Colloidal Silica and TPGS-Based Solid Self-Emulsifying System Interferes Akt/mTOR Pathway in MDA-MB-231 and Demonstrates Anti-tumor Effect in Syngeneic Mammary Tumors.

A solid self-emulsifying drug delivery system (SEDDS) of paclitaxel (PTX) was developed that could enhance its oral bioavailability and neutralize other niggles associated with conventional delivery systems of PTX. TPGS-centered SEDDS containing PTX was optimized by Box-Behnken experimental design and then formulated as fumed colloidal silica-based solid SEDDS microparticles (Si-PTX-S-SEDDS). AFM analysis exhibited round-shaped microparticles of approximately 2-3 µM diameter, whereas after reconstitution, particle size measurement showed nanoemulsion droplets of 30.00 ± 2.00 nm with a zeta potential of 17.38 ± 2.88 mV. Si-PTX-S-SEDDS displayed improved efficacy proven by reduced IC50 of 0.19 ± 0.03 µM against MDA-MB-231 cells and a 45.83-fold higher cellular uptake in comparison to free PTX. Molecular mechanistic studies showed mitochondria-mediated intrinsic pathway of apoptosis following Akt/mTOR pathway, which is accompanied by survivin downregulation. Rhodamine 123 assay and chylomicron flow blocking studies revealed P-gp inhibition potential and lymphatic uptake of Si-PTX-S-SEDDS, responsible for over 4-fold increment in oral bioavailability compared to PTX administered as Taxol. In vivo anti-tumor studies in syngeneic mammary tumor model in SD rats revealed higher efficacy of Si-PTX-S-SEDDS as evident from significant reduction in tumor burden. In total, the developed Si-PTX-S-SEDDS formulation was found as an appropriate option for oral delivery of PTX.