Estimating the Oral Absorption from Self-Nanoemulsifying Drug Delivery Systems Using an In Vitro Lipolysis-Permeation Method.
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ABSTRACT:
SUBMITTER: Klitgaard M
PROVIDER: S-EPMC8065752 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Bioactive oils of natural origin have gained huge interests from health care professionals and patients. Objective: To design a bioactive self-nanoemulsifying drug delivery system (Bio-SNEDDS) comprising curcumin (CUR) and piperine (PP) by incorporating bioactive natural oils in the formulation. Methods: The self-emulsifying properties of apricot, avocado, black seed and Zanthoxylum rhetsa seed oils were screened within various SNEDDS formulations. Each liquid SNEDDS formulation was loaded with both CUR and PP. The optimal liquid SNEDDS were solidified using Aeroperl® and Neusilin® at 1:1 w/w ratio. Liquid and solid SNEDDS were characterized by droplet size analysis, equilibrium solubility, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. In-vitro dissolution studies were performed to evaluate the efficiency of CUR and PP release from solid Bio-SNEDDS. Results: The liquid SNEDDS comprised of black seed oil exhibited excellent self-emulsification performance, low droplet size along with transparent appearance. The inclusion of the cosolvent Transcutol P improved the solubilization capacity of both CUR and PP. The liquid SNEDDS were efficiently solidified using the two adsorbents and presented the drugs within amorphous state. In particular, SNEDDS comprised of black seed oil/Imwitor988/Transcutol P/Cremophor RH40 (20/20/10/50) and when solidified with Neusilin showed enhanced CUR and PP release (up to 60% and 77%, respectively). In addition, this formulation efficiently delivers the highly bioactive black seed oil to the patient. Conclusions: The optimized Bio-SNEDDS comprising black seed oil showed outstanding self-emulsification characteristics along with enhanced CUR/PP dissolution upon solidification.
| S-EPMC7181043 | biostudies-literature
Project description:Due to its extreme lipophilicity, the oral delivery of cinnarizine (CN) encounters several problems such as poor aqueous solubility and pH-dependent dissolution, which result in low and erratic bioavailability. The current study aims to design self-nanoemulsifying drug delivery systems (SNEDDS) of CN that circumvent such obstacles. Equilibrium solubility of CN was determined in a range of anhydrous and diluted lipid-based formulations. Dynamic dispersion tests were carried out to investigate the efficiency of drug release and magnitude of precipitation that could occur upon aqueous dilution. Droplet sizes of selected formulations, upon (1:1,000) aqueous dilution, were presented. The optimal formulations were enrolled in subsequent dissolution studies. The results showed that increasing lipid chain length and surfactant lipophilicity raised the formulation solvent capacity, while adding co-solvents provoked a negative influence. The inclusion of mixed glycerides and/or hydrophilic surfactants improved the drug release efficiency. Generally, no significant precipitation was observed upon aqueous dilution of the formulations. Five formulations were optimal in terms of their superior self-emulsifying efficiency, drug solubility, dispersion characteristics, and lower droplet size. Furthermore, the optimal formulations showed superior dissolution profile compared to the marketed (Stugeron®) tablet. Most importantly, they could resist the intensive precipitation observed with the marketed tablet upon shifting from acidic to alkaline media. However, SNEDDS containing medium-chain mixed glycerides showed the highest drug release rate and provide great potential to enhance the oral CN delivery. Accordingly, the lipid portion seems to be the most vital component in designing CN self-nanoemulsifying systems.
| S-EPMC3429665 | biostudies-literature
Project description:BackgroundRecently, we found that berberine (BBR) exerts anti-acute myeloid leukemia activity, particularly toward high-risk and relapsed/refractory acute myeloid leukemia MV4-11 cells in vitro. However, the poor water solubility and low bioavailability observed with oral BBR administration has limited its clinical use. Therefore, we design and develop a novel oil-in-water self-nanoemulsifying system for BBR (BBR SNE) to improve oral bioavailability and enhance BBR efficacy against acute myeloid leukemia by greatly improving its solubility.ResultsThis system (size 23.50?±?1.67 nm, zeta potential -?3.35?±?0.03 mV) was prepared with RH40 (surfactant), 1,2-propanediol (co-surfactant), squalene (oil) and BBR using low-energy emulsification methods. The system loaded BBR successfully according to thermal gravimetric, differential scanning calorimetry, and Fourier transform infrared spectroscopy analyses. The release profile results showed that BBR SNE released BBR more slowly than BBR solution. The relative oral bioavailability of this novel system in rabbits was significantly enhanced by 3.41-fold over that of BBR. Furthermore, Caco-2 cell monolayer transport studies showed that this system could help enhance permeation and prevent efflux of BBR. Importantly, mice with BBR SNE treatment had significantly longer survival time than BBR-treated mice (P?<?0.001) in an MV4-11 engrafted leukemia murine model.ConclusionsThese studies confirmed that BBR SNE is a promising therapy for acute myeloid leukemia.
| S-EPMC6172716 | biostudies-literature
Project description:Sesamin (SSM) is a water-insoluble compound that is easily eliminated by liver metabolism. To improve the solubility and bioavailability of SSM, this study developed and characterized a self-nanoemulsifying drug delivery system (SNEDDS) for the oral delivery of SSM and conducted pharmacokinetic assessments. Oil and surfactant materials suitable for SNEDDS preparation were selected on the basis of their saturation solubility at 37 ± 0.5 °C. The mixing ratios of excipients were determined on the basis of their dispersibility, transmittance (%), droplet sizes, and polydispersity index. An SNEDDS (F10) formulation comprising glyceryl trioctanoate, polyoxyethylene castor oil, and Tween 20 at a ratio of 10:10:80 (w/w/w) was the optimal formulation. This formulation maintained over 90% of its contents in different storage environments for 12 weeks. After the self-emulsification of SNEDDS, the SSM dispersed droplet size was 66.4 ± 31.4 nm, intestinal permeability increased by more than three-fold, relative bioavailability increased by approximately 12.9-fold, and absolute bioavailability increased from 0.3% to 4.4%. Accordingly, the developed SNEDDS formulation can preserve SSM's solubility, permeability, and bioavailability. Therefore, this SNEDDS formulation has great potential for the oral administration of SSM, which can enhance its pharmacological application value.
| S-EPMC7397308 | biostudies-literature
Project description:Self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising platform to improve oral absorption of drugs with poor solubility and low permeability. However, large polarity molecules with insufficient lipid solubility, such as paclitaxel (PTX), would suffer from inferior formulation of SNEDDS due to poor compatibility. Herein, phospholipid-drug complex (PLDC) and SNEDDS were integrated into one system to facilitate oral delivery of PTX. First, PTX was formulated into PLDC in response to its inferior physicochemical properties. Then, the prepared PLDC was further formulated into SNEDDS by integrating these two drug delivery technologies into one system (PLDC-SNEDDS). After PLDC-SNEDDS dispersed in aqueous medium, nanoemulsion was formed immediately with an average particle size of ?30?nm. Furthermore, the nanomulsion of PLDC-SNEDDS showed good colloidal stability in both HCl solution (0.1?mol/l, pH 1.0) and phosphate buffer solution (PBS, pH 6.8). In vivo, PTX-PLDC-SNEDDS showed distinct advantages in terms of oral absorption efficiency, with a 3.42-fold and 2.13-fold higher bioavailability than PTX-PLDC and PTX solution, respectively. Our results suggest that the integration of PLDC into SNEDDS could be utilized to facilitate the oral delivery of hydrophobic drugs with large polarity.
| S-EPMC7032203 | biostudies-literature
Project description:Lipid-based formulations (LBFs) are a delivery strategy to enhance intestinal absorption of poorly water-soluble drugs. LBF performance is typically evaluated by in vitro lipolysis studies, but these do not accurately predict the in vivo performance. One possible reason is the absence of an absorptive membrane driving sink conditions in the serosal compartment. To explore the impact of absorption under sink conditions on the performance evaluation, we developed a lipolysis-permeation setup that allows simultaneous investigation of intestinal digestion of an LBF and drug absorption. The setup consists of two chambers, an upper one for digestion (luminal), and a lower, receiving one (serosal), separated by a Caco-2 monolayer. Digestions were performed with immobilized lipase, instead of the pancreatic extract typically used during lipolysis, since the latter has proven incompatible with Caco-2 cells. Danazol-loaded LBFs were used to develop the setup, and fenofibrate-loaded LBFs were used to establish an in vitro in vivo correlation. As in regular lipolysis studies, our setup allows for the evaluation of (i) the extent of digestion and (ii) drug distribution in different phases present during lipolysis of drug-loaded LBFs (i.e., oil, aqueous, and solid phase). In addition, our setup can determine drug permeation across Caco-2 monolayers and hence, the absorptive flux of the compound. The presence of the absorptive monolayer and sink conditions tended to reduce aqueous drug concentrations and supersaturation in the digestion chamber. The drug transfer across the Caco-2 membrane accurately reflected in vivo drug exposure upon administration of three different LBFs loaded with fenofibrate, where the traditional lipolysis setup failed to predict in vivo performance. As the new setup reflects the dynamic processes occurring in the gastrointestinal tract, it is a valuable tool that can be used in the development of LBFs prior to in vivo studies.
| S-EPMC6437649 | biostudies-literature
Project description:The development of self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80 (LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides (40% to 75%), Kolliphor® RH40 (5% to 55%), LPC (0 to 40%) and ethanol (0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200?nm. The use of medium-chain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor® RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor® RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor® RH40 as a reference for formulation developers.
| S-EPMC7037638 | biostudies-literature
Project description:Reformulating poorly water-soluble drugs as supersaturated lipid-based formulations achieves higher drug loading and potentially improves solubilisation and bioavailability. However, for the weak base blonanserin, silica solidified supersaturated lipid-based formulations have demonstrated reduced in vitro solubilisation compared to their liquid-state counterparts. Therefore, this study aimed to understand the influence of supersaturated drug load on blonanserin solubilisation from liquid and silica solidified supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) during in vitro lipolysis. Stable liquid super-SNEDDS with varying drug loads (90-300% of the equilibrium solubility) were solidified by imbibition into porous silica microparticles (1:1 lipid: silica ratio). In vitro lipolysis revealed greater blonanserin solubilisation from liquid super-SNEDDS compared to solid at equivalent drug saturation levels, owing to strong silica-BLON/lipid interactions, evidenced by a significant decrease in blonanserin solubilisation upon addition of silica to a digesting liquid super-SNEDDS. An increase in solid super-SNEDDS drug loading led to increased solubilisation, owing to the increased drug:silica and drug:lipid ratios. Solidifying SNEDDS with silica enables the fabrication of powdered formulations with higher blonanserin loading and greater stability than liquid super-SNEDDS, however at the expense of drug solubilisation. These competing parameters need careful consideration in designing optimal super-SNEDDS for pre-clinical and clinical application.
| S-EPMC9864080 | biostudies-literature
Project description:PURPOSE:To evaluate the performance of artificial membranes in in vitro lipolysis-permeation assays useful for absorption studies of drugs loaded in lipid-based formulations (LBFs). METHODS:Polycarbonate as well as PVDF filters were treated with hexadecane, or lecithin in n-dodecane solution (LiDo) to form artificial membranes. They were thereafter used as absorption membranes separating two compartments mimicking the luminal and serosal side of the intestine in vitro. Membranes were subjected to dispersions of an LBF that had been digested by porcine pancreatin and spiked with the membrane integrity marker Lucifer Yellow (LY). Three fenofibrate-loaded LBFs were used to explore the in vivo relevance of the assay. RESULTS:Of the explored artificial membranes, only LiDo applied to PVDF was compatible with lipolysis by porcine pancreatin. Formulation ranking based on mass transfer in the LiDo model exposed was the same as drug release in single-compartment lipolysis. Ranking based on observed apparent permeability coefficients of fenofibrate with different LBFs were the same as those obtained in a cell-based model. CONCLUSIONS:The LiDo membrane was able to withstand lipolysis for a sufficient assay period. However, the assay with porcine pancreatin as digestive agent did not predict the in vivo ranking of the assayed formulations better than existing methods. Comparison with a Caco-2 based assay method nonetheless indicates that the in vitro in vivo relationship of this cell-free model could be improved with alternative digestive agents.
| S-EPMC7239831 | biostudies-literature
Project description:Heparins show great anticoagulant effect with few side effects, and are administered by subcutaneous or intravenous route in clinics. To improve patient compliance, oral administration is an alternative route. Nonetheless, oral administration of heparins still faces enormous challenges due to the multiple obstacles. This review briefly analyzes a series of barriers ranging from poorly physicochemical properties of heparins, to harsh biological barriers including gastrointestinal degradation and pre-systemic metabolism. Moreover, several approaches have been developed to overcome these obstacles, such as improving stability of heparins in the gastrointestinal tract, enhancing the intestinal epithelia permeability and facilitating lymphatic delivery of heparins. Overall, this review aims to provide insights concerning advanced delivery strategies facilitating oral absorption of heparins.
| S-EPMC7486512 | biostudies-literature