Nutraceutically-enhanced oral delivery of vitamin D3 via Bio-SNEDDS: Demonstrating in vivo superiority over pediatric formulations.

BACKGROUND: Vitamin D3 (VD3) deficiency among children in Saudi Arabia remains a pressing concern due to its poor bioavailability and the limitations of current pediatric formulations. To address this challenge, we developed a groundbreaking pediatric self-nanoemulsifying drug delivery system (Bio-SNEDDS) for VD3, fortified with black seed oil and moringa seed oil for dual therapeutic benefits. Through meticulous formulation optimization using ternary phase diagrams and comprehensive testing, our Bio-SNEDDS demonstrated exceptional performance. METHODS: Bio-SNEDDS were manufactured by incorporating Black seed oil and moringa seed oil as bioactive nutraceutical excipients along with various cosurfactant and surfactants. Bio-SNEDDS were systematically optimized through ternary phase diagrams, visual tests, droplet size analysis, drug solubilization studies, dispersion assessments, and pharmacokinetic testing in rats compared to Vi-De 3®. RESULTS: Pseudoternary phase diagrams identified oil blends producing large nanoemulsion regions optimal for SNEDDS formation. The optimized F1 Bio-SNEDDS showed a mean droplet diameter of 33.7 nm, solubilized 154.46 mg/g VD3 with no metabolite formation, and maintained >88% VD3 in solution during 24 h dispersion testing. Notably, in vivo pharmacokinetic evaluation at a high VD3 dose demonstrated an approximately two-fold greater relative bioavailability over Vi-De 3®, validating the superb oral delivery performance of Bio-SNEDDS even under challenging high-dose conditions. CONCLUSIONS: The Bio-SNEDDS provides an effective VD3 delivery strategy with established in vivo superiority over marketed products, along with offering additional health benefits from the natural oils.

A Quality by Design Approach for Developing SNEDDS Loaded with Vemurafenib for Enhanced Oral Bioavailability.

Vemurafenib (VMF) is a practically insoluble (< 0.1 µg/mL) and least bioavailable (1%) drug. To enhance its oral bioavailability and solubility, we formulated a reliable self-nano emulsifying drug delivery system (SNEDDS). A Quality by Design (QbD) approach was used to optimize the ratio of Capryol 90, Tween 80, and Transcutol HP. VMF-loaded SNEDDS was characterized for its size, polydispersity index (PDI), zeta potential, drug content, and transmittance. The in vitro release profile of the drug loaded in SNEDDS was compared to the free drug in two media, pH 6.8 and 1.2, and the data obtained were analyzed with different mathematical models. A reverse-phase ultra-pressure liquid chromatography (UPLC) technique with high sensitivity and selectivity was developed and validated for the quantification of VMF in analytical and bioanalytical samples. Dissolution efficiency for SNEDDS was estimated using different models, which proved that the developed novel SNEDDS formulation had a better in vitro dissolution profile than the free drug. A 2.13-fold enhanced oral bioavailability of VMF-loaded SNEDDS compared to the free drug demonstrates the superiority of the developed formulation. This work thus presents an overview of VMF-loaded SNEDDS as a promising alternative to improve the oral bioavailability of the drug.

Drug permeation enhancement, efficacy, and safety assessment of azelaic acid loaded SNEDDS hydrogel to overcome the treatment barriers of atopic dermatitis.

Atopic dermatitis is one of the most widespread chronic inflammatory skin conditions that can occur at any age, though the prevalence is highest in children. The purpose of the current study was to prepare and optimize the azelaic acid (AzA) loaded SNEDDS using Pseudo ternary phase diagram, which was subsequently incorporated into the Carbopol 940 hydrogel for the treatment of atopic dermatitis. The composition was evaluated for size, entrapment efficiency, in vitro, ex vivo, and in vivo studies. The polydispersity index of the optimized preparation was found to be less than 0.5, and the size of the distributed globules was found to be 151.20 ± 3.67 nm. The SNEDDS hydrogel was characterized for pH, viscosity, spreadability, and texture analysis. When compared to the marketed formulation, SNEDDS hydrogel was found to have a higher rate of permeation through the rat skin. In addition, a skin irritation test carried out on experimental animals showed that the SNEDDS formulation did not exhibit any erythematous symptoms after a 24-h exposure. In conclusion, the topical delivery of AzA through the skin using SNEDDS hydrogel could prove to be an effective approach for the treatment of atopic dermatitis.

Augmented experimental design for bioavailability enhancement: a robust formulation of abiraterone acetate.

Abiraterone acetate (ABRTA) is clinically beneficial in management of metastatic castration-resistant prostate cancer (PC-3). With highlighted low solubility and permeability, orally hampered treatment of ABRTA necessitate high dose to achieve therapeutic efficacy. To triumph these challenges, we aimed to develop intestinal lymphatic transport facilitating lipid-based delivery to enhance bioavailability. ABRTA-containing self-nano emulsified drug delivery (ABRTA-SNEDDS) was statistically optimized by D-optimal design using design expert. Optimized formulation was characterized for particle size, thermodynamic stability, in vitro release, in vivo bioavailability, intestinal lymphatic transport, in vitro cytotoxic effect, anti-metastatic activity, and apoptosis study. Moreover, hemolysis and histopathology studies have been performed to assess pre-clinical safety. Nano-sized particles and successful saturated drug loading were obtained for optimized formulation. In vitro release upto 98.61 ± 3.20% reveal effective release of formulation at intestinal pH 6.8. ABRTA-SNEDDS formulation shows enhanced in vivo exposure of Abiraterone (2.5-fold) than ABRTA suspension in Sprague-Dawley rats. In vitro efficacy in PC-3 cell line indicates 3.69-fold higher therapeutic potential of nano drug delivery system. Hemolysis and histopathology study indicates no significant toxicities to red blood cells and tissues, respectively. Apparently, an opportunistic strategy to increasing bioavailability of ABRTA via intestinal lymphatic transport will create a viable platform in rapidly evolving chemotherapy. Enhanced translational utility of delivery was also supported through in vitro therapeutic efficacy and safety assessments. HighlightsAbiraterone acetate is a prostate cancer drug, impeded with low bioavailability.ABRTA loaded in self nano emulsifying drug delivery enhanced its bioavailability.Intestinal lymphatic transport played role in enhanced bioavailability of ABRTA.ABRTA-SNEDDS enhanced in vitro cytotoxic activity of ABRTA.ABRTA-SNEDDS found safe in preclinical safety evaluations.

Oral Bioactive Self-Nanoemulsifying Drug Delivery Systems of Remdesivir and Baricitinib: A Paradigmatic Case of Drug Repositioning for Cancer Management.

Oral anticancer therapy mostly faces the challenges of low aqueous solubility, poor and irregular absorption from the gastrointestinal tract, food-influenced absorption, high first-pass metabolism, non-targeted delivery, and severe systemic and local adverse effects. Interest has been growing in bioactive self-nanoemulsifying drug delivery systems (bio-SNEDDSs) using lipid-based excipients within nanomedicine. This study aimed to develop novel bio-SNEDDS to deliver antiviral remdesivir and baricitinib for the treatment of breast and lung cancers. Pure natural oils used in bio-SNEDDS were analyzed using GC-MS to examine bioactive constituents. The initial evaluation of bio-SNEDDSs were performed based on self-emulsification assessment, particle size analysis, zeta potential, viscosity measurement, and transmission electron microscopy (TEM). The single and combined anticancer effects of remdesivir and baricitinib in different bio-SNEDDS formulations were investigated in MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. The results from the GC-MS analysis of bioactive oils BSO and FSO showed pharmacologically active constituents, such as thymoquinone, isoborneol, paeonol and p-cymenene, and squalene, respectively. The representative F5 bio-SNEDDSs showed relatively uniform, nanosized (247 nm) droplet along with acceptable zeta potential values (+29 mV). The viscosity of the F5 bio-SNEDDS was recorded within 0.69 Cp. The TEM suggested uniform spherical droplets upon aqueous dispersions. Drug-free, remdesivir and baricitinib-loaded bio-SNEDDSs (combined) showed superior anticancer effects with IC50 value that ranged from 1.9-4.2 µg/mL (for breast cancer), 2.4-5.8 µg/mL (for lung cancer), and 3.05-5.44 µg/mL (human fibroblasts cell line). In conclusion, the representative F5 bio-SNEDDS could be a promising candidate for improving the anticancer effect of remdesivir and baricitinib along with their existing antiviral performance in combined dosage form.

Development of miconazole nitrate nanoparticles loaded in nanoemulgel to improve its antifungal activity.

Miconazole is a synthetic derivative of imidazole, a medication with a broad-spectrum antifungal agent that is used to treat localized vaginal, skin, and nail infections. The aim of the study was to develop an innovative technique to improve the permeability and efficacy of topical miconazole nitrate. A nanoemulgel of miconazole nitrate was formulated by the incorporation of a nanoemulsion and a hydrogel. The nanoemulsion was first optimized using a self-emulsifying technique, and the drug was then loaded into the optimum formulation and evaluated prior to mixing with the hydrogel. Miconazole nitrate nanoemulgel formulations were evaluated for their physical characteristics and antifungal activity. Based on the results, the formulation with 0.4 % Carbopol showed the highest release profile (41.8 mg/ml after 2 h); thus, it was chosen as the optimum formulation. A cell diffusion test was performed to examine the ability of the Miconazole nitrate nanoemulgel to penetrate the skin and reach the bloodstream. Percentage cumulative drug releases of 29.67 % and 23.79 % after 6 h were achieved for the MNZ nanoemulgel and the commercial cream, Daktazol, respectively. The antifungal activity of the novel MNZ nanoemulgel formulation was tested against Candida albicans and compared to Daktazol cream and almond oil; the results were: 40.9 ± 2.3 mm, 25.4 ± 2.7 mm and 18 ± 1.9 mm, respectively. In conclusion, a novel MNZ nanoemulgel showing superior antifungal activity compared to that of the commercial product has been developed. This nanotechnology technique is a step toward making pharmaceutical dosage forms that has a lot of promise.

Cinnamaldehyde-Based Self-Nanoemulsion (CA-SNEDDS) Accelerates Wound Healing and Exerts Antimicrobial, Antioxidant, and Anti-Inflammatory Effects in Rats' Skin Burn Model.

Cinnamaldehyde, the main phytoconstituent of the cinnamon oil, has been reported for its potential wound healing activity, associated to its antimicrobial and anti-inflammatory effects. In this study, we are reporting on the cinnamaldehyde-based self-nanoemulsifying drug delivery system (CA-SNEDDS), which was prepared and evaluated for its antimicrobial, antioxidant, anti-inflammatory, and wound healing potential using the rat third-degree skin injury model. The parameters, i.e., skin healing, proinflammatory, and oxidative/antioxidant markers, were evaluated after 3 weeks of treatment regimens with CA-SNEDDS. Twenty rats were divided randomly into negative control (untreated), SNEDDS control, silver sulfadiazine cream positive control (SS), and CA-SNEDDS groups. An aluminum cylinder (120 °C, 10-s duration) was used to induce 3rd-degree skin burns (1-inch square diameter each) on the rat's dorsum. At the end of the experiment, skin biopsies were collected for biochemical analysis. The significantly reduced wound size in CA-SNEDDS compared to the negative group was observed. CA-SNEDDS-treated and SS-treated groups demonstrated significantly increased antioxidant biomarkers, i.e., superoxide dismutase (SOD) and catalase (CAT), and a significant reduction in the inflammatory marker, i.e., NAP-3, compared to the negative group. Compared to SNEDDS, CA-SNEDDS exhibited a substantial antimicrobial activity against all the tested organisms at the given dosage of 20 µL/disc. Among all the tested microorganisms, MRSA and S. typhimurium were the most susceptible bacteria, with an inhibition zone diameter (IZD) of 17.0 ± 0.3 mm and 19.0 ± 0.9 mm, respectively. CA-SNEDDS also exhibited strong antifungal activity against C. albicans and A. niger, with IZD of 35.0 ± 0.5 mm and 34.0 ± 0.5 mm, respectively. MIC and MBC of CA-SNEDDS for the tested bacteria ranged from 3.125 to 6.25 µL/mL and 6.25 to 12.5 µL/mL, respectively, while the MIC and MBC for C. albicans and A. niger were 1.56 µL/mL and 3.125 µL/mL, respectively. The MBIC and MBEC of CA-SNEDDS were also very significant for the tested bacteria and ranged from 6.25 to 12.5 µL/mL and 12.5 to 25.0 µL/mL, respectively, while the MBIC and MBEC for C. albicans and A. niger were 3.125 µL/mL and 6.25 µL/mL, respectively. Thus, the results indicated that CA-SNEDDS exhibited significant wound healing properties, which appeared to be attributed to the formulation's antimicrobial, antioxidant, and anti-inflammatory effects.

Self-Nanoemulsifying Drug Delivery System (SNEDDS) of Apremilast: In Vitro Evaluation and Pharmacokinetics Studies.

Psoriatic arthritis is an autoimmune disease of the joints that can lead to persistent inflammation, irreversible joint damage and disability. The current treatments are of limited efficacy and inconvenient. Apremilast (APR) immediate release tablets Otezla® have 20-33% bioavailability compared to the APR absolute bioavailability of 73%. As a result, self-nanoemulsifying drug delivery systems (SNEDDS) of APR were formulated to enhance APR's solubility, dissolution, and oral bioavailability. The drug assay was carried out using a developed and validated HPLC method. Various thermodynamic tests were carried out on APR-SNEDDS. Stable SNEDDS were characterized then subjected to in vitro drug release studies via dialysis membrane. The optimum formulation was F9, which showed the maximum in vitro drug release (94.9%) over 24 h, and this was further investigated in in vivo studies. F9 was composed of 15% oil, 60% Smix, and 25% water and had the lowest droplet size (17.505 ± 0.247 nm), low PDI (0.147 ± 0.014), low ZP (-13.35 mV), highest %T (99.15 ± 0.131) and optimum increases in the relative bioavailability (703.66%) compared to APR suspension (100%) over 24 h. These findings showed that APR-SNEDDS is a possible alternative delivery system for APR. Further studies are warranted to evaluate the major factors that influence the encapsulation efficiency and stability of APR-containing SNEDDS.

Enhanced oral bioavailability and anti-hyperuricemic activity of liquiritin via a self-nanoemulsifying drug delivery system.

BACKGROUND: This study focused on the development of a self-nanoemulsifying drug delivery system (SNEDDS) to improve, potentially, the solubility and oral bioavailability of liquiritin (LQ). METHODS: The solubility of LQ in different types of excipient, namely oils (OLs), emulsifiers (EMs), and co-emulsifiers (CO-EMs), was evaluated, and a pseudo-ternary phase diagram (PTPD) and the formulation optimization were established. The prepared self-nanoemulsifying drug delivery system of liquiritin (LQ-SNEDDS) was assessed using droplet size (DS), zeta potential (ZP), polydispersity index (PDI), droplet morphology, drug release in vitro, and oral bioavailability. RESULTS: After the dilution of the LQ-SNEDDS, a transparent nanoemulsion was obtained with an acceptable DS (24.70 ± 0.73 nm), ZP (-18.69 ± 1.44 mV), and PDI (0.122 ± 0.006). The LQ-SNEDDS that was developed had a better release rate in vitro than the free LQ suspension. Pharmacokinetic evaluation showed that the relative oral bioavailability of LQ-SNEDDS was increased by 5.53 times, and LQ-SNEDDS exhibited a delayed half life and longer retention time in comparison with those of free LQ. Similarly, LQ-SNEDDS had a better urate lowering effect and provided better organ protection than free LQ at the same dose (P < 0.05). CONCLUSIONS: The incorporation of LQ into SNEDDS could serve as a promising approach to improve the solubility, oral bioavailability, and anti-hyperuricemic effect of LQ. © 2021 Society of Chemical Industry.

Comparative Bioavailability Study of Solid Self-Nanoemulsifying Drug Delivery System of Fenofibric Acid in Healthy Male Subjects.

OBJECTIVE: This study aimed to evaluate the effect of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formation on the bioavailability of fenofibric acid. SUBJECT AND METHODS: Three formulations of fenofibric acid, namely, S-SNEDDS containing medium-chain triglyceride (FS1), S-SNEDDS containing long-chain triglyceride (FS2), and FSt as tablet of innovator product, were used in this study. Bioavailability study was conducted in 12 Indonesian healthy male subjects after a single-dose administration of each formulation with three-way crossover design. Blood samples were collected from 0 to 72 h after drug administration and then analyzed using the high-performance liquid chromatography method. Data were statistically analyzed using the ANOVA and the Wilcoxon signed-rank test using a p value of 0.05. Dissolution test was carried out with USP dissolution apparatus using three medium (pH 1.2, 4.5 and 6.8). RESULTS: The rates of absorption of fenofibric acid from S-SNEDDS FS1 and FS2 were significantly increased about 1.78 and 2.40 times, respectively, relative to FSt. Tmax values of FS1 and FS2 were shorter than FSt, namely, 0.96 ± 0.438 h (FS1), 0.71 ± 0.445 h (FS2), and 1.71 ± 0.840 h (FSt), respectively. Meanwhile, the Cmax and AUC values of FS1, FS2, and FSt were found to be not significantly different with a p value of >0.05. S-SNEDDS formation increased the dissolution rate in acid medium. CONCLUSIONS: S-SNEDDS increased the dissolution rate in acid medium and absorption rate of fenofibric acid but did not increase the extent of fenofibric acid absorption.

Development and Characterization of Celecoxib Solid Self-nanoemulsifying Drug Delivery Systems (S-SNEDDS) Prepared Using Novel Cellulose-Based Microparticles as Adsorptive Carriers.

Self-nanoemulsifying drug delivery systems (SNEDDS) represent an interesting platform for improving the oral bioavailability of poorly soluble lipophilic drugs. While Liquid-SNEDDS (L-SNEDDS) effectively solubilize the drug in vivo, they have several drawbacks, including poor storage stability. Solid-SNEDDS (S-SNEDDS) combine the advantages of L-SNEDDS with those of solid dosage forms, particularly stability. The aim of the present study was to convert celecoxib L-SNEDDS into S-SNEDDS without altering their release behavior. Various commercially available adsorptive carrier materials were investigated, as well as novel cellulose-based microparticles prepared by spray drying from an aqueous dispersion containing Diacel® 10 and methyl cellulose or gum arabic as a binder prior to their use. Particle size and morphology of the carrier materials were screened by scanning electron microscopy and their effects on the loading capacity for L-SNEDDS were investigated, and comparative in vitro dissolution studies of celecoxib L-SNEDDS and the different S-SNEDDS were performed immediately after preparation and after 3 months of storage. Among the adsorptive carrier materials, the novel cellulose-based microparticles were found to be the most suitable for the preparation of celecoxib S-SNEDDS from L-SNEDDS, enabling the preparation of a solid, stable formulation while preserving the in vitro release performance of the L-SNEDDS formulation.

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.

Lipid Based Formulations in Hard Gelatin and HPMC Capsules: a Physical Compatibility Study.

PURPOSE: To investigate the compatibility between hard gelatin and HPMC capsules with a range of different isotropic lipid based formulations containing multiple excipients. METHODS: The miscibility was investigated for 350 systems applying five different oils (Labrafac ™ lipophile WL1349, Maisine® CC, Captex 300 EP/NF, olive oil, and Capmul MCM EP/NF), five different surfactans (Labrasol ® ALF, Labrafil M 2125 CS, Kolliphor ® ELP, Kolliphor ® HS 15, Tween 80) and three different cosolvents (propylene glycol, polyethylene glycol 400, and Transcutol ® HP). For the isotropic systems capsule compatibility was investigated in both gelatin and HPMC capsules at 25°C at 40% and 60% relative humidity by examining physical damages to the capsules and weight changes after storage. RESULTS: The miscibility of lipid based vehicles was best when the formulation contained monoglycerides and surfactants with a hydrophilic-lipophilic balance value <12. Gelatin capsules in general resulted in a better compatibility when compared to HPMC capsules for the evaluated formulations. Addition of water to the formulation improved the capsule compatibility for both capsule types. The expected capsule mass change could partly be predicted in binary systems using the provided data of the single excipients weighted for its formulation proportion. CONCLUSIONS: The capsule compatibility was driven by the components incorporated into the formulations, where more was compatible with gelatin than HPMC capsules. Prediction of the mass change from individual excipient contributions can provide a good first estimate if a vehicle is compatible with a capsule, however, this needs to be proved experimentally.

Hydrophobic ion pairing with cationic derivatives of α-, ß-, and γ-cyclodextrin as a novel approach for development of a self-nano-emulsifying drug delivery system (SNEDDS) for oral delivery of heparin.

To enhance the oral bioavailability of heparin, a self-nano-emulsifying drug delivery system (SNEDDS) was developed using hydrophobic ion-pairing with cationic polymers of α-, ß-, and γ-cyclodextrins (CPCDs). Hydrophobic ion paired complexes were formed, and the recovery of heparin was determined in n-hexane and isopropyl myristate (IPM). The SNEDDSs were prepared and were optimized using D-optimal response surface methodology (RSM). The determination of the recovery of complexes in IPM revealed that in cationic α-cyclodextrin, the highest recovery was achieved at the heparin: CPCD weight ratio of 1:0.5. However, in cationic ß-cyclodextrin the highest recovery was obtained at the weight ratio of 1:4. Similar to CPßCD, for ealed that in c the highest recovery was obtained at 1:4 weight ratio. The size of optimized nano-droplets was found to be 127.00 ± 4.1, 184.00 ± 6.43, and 216.00 ± 5.43 nm; polydispersity index (PdI) values were reported as 0.372 ± 0.005, 0.163 ± 0.008, 0.236 ± 0.003; and calculated loading efficiency (LE%) were 84.60 ± 3.62, 91.06 ± 2.49, and 92.81 ± 0.70% for SNEDDS preparations incorporating cationic derivatives of α-, ß-, and γ-cyclodextrin, respectively. The in vitro release study revealed that SNEDDS preparations containing cationic γ-cyclodextrin posed the slowest release rate. Data achieved from cellular uptake study showed that the SNEDDS containing α-cyclodextrin had the highest cumulative uptake percentage after 6 h post-exposure; same results were obtained in the intestinal transport study demonstrating SNEDDS containing α-cyclodextrin posed the highest transport efficiency with Papp of 24.85 × 10-r ± 1.06 × 10-± cm.s-m.

Hepatoprotective Effects of Bioflavonoid Luteolin Using Self-Nanoemulsifying Drug Delivery System.

Luteolin (LUT) is a natural pharmaceutical compound that is weakly water soluble and has low bioavailability when taken orally. As a result, the goal of this research was to create self-nanoemulsifying drug delivery systems (SNEDDS) for LUT in an attempt to improve its in vitro dissolution and hepatoprotective effects, resulting in increased oral bioavailability. Using the aqueous phase titration approach and the creation of pseudo-ternary phase diagrams with Capryol-PGMC (oil phase), Tween-80 (surfactant), and Transcutol-HP (co-emulsifier), various SNEDDS of LUT were generated. SNEDDS were assessed for droplet size, polydispersity index (PDI), zeta potential (ZP), refractive index (RI), and percent of transmittance (percent T) after undergoing several thermodynamic stability and self-nanoemulsification experiments. When compared to LUT suspension, the developed SNEDDS revealed considerable LUT release from all SNEDDS. Droplet size was 40 nm, PDI was <0.3, ZP was -30.58 mV, RI was 1.40, percent T was >98 percent, and drug release profile was >96 percent in optimized SNEDDS of LUT. For in vivo hepatoprotective testing in rats, optimized SNEDDS was chosen. When compared to LUT suspension, hepatoprotective tests showed that optimized LUT SNEDDS had a substantial hepatoprotective impact. The findings of this investigation suggested that SNEDDS could improve bioflavonoid LUT dissolution rate and therapeutic efficacy.

Rp-HPLC Determination of Quercetin in a Novel D-α-Tocopherol Polyethylene Glycol 1000 Succinate Based SNEDDS Formulation: Pharmacokinetics in Rat Plasma.

Despite its proven efficacy in diverse metabolic disorders, quercetin (QU) for clinical use is still limited because of its low bioavailability. D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) is approved as a safe pharmaceutical adjuvant with marked antioxidant and anti-inflammatory activities. In the current study, several QU-loaded self-nanoemulsifying drug delivery systems (SNEDDS) were investigated to improve QU bioavailability. A reversed phase high performance liquid chromatography (RP-HPLC) method was developed, for the first time, as a simple and sensitive technique for pharmacokinetic studies of QU in the presence of TPGS SNEDDS formula in rat plasma. The analyses were performed on a Xterra C18 column (4.6 × 100 mm, 5 µm) and UV detection at 280 nm. The analytes were separated by a gradient system of methanol and phosphate buffer of pH 3. The developed RP-HPLC method showed low limit of detection (LODs) of 7.65 and 22.09 ng/mL and LOQs of 23.19 and 66.96 ng/mL for QU and TPGS, respectively, which allowed their determination in real rat plasma samples. The method was linear over a wide range, (30-10,000) and (100-10,000) ng/mL for QU and TPGS, respectively. The selected SNEDDS formula, containing 50% w/w TPGS, 30% polyethylene glycol 200 (PEG 200), and 20% w/w pumpkin seed oil (PSO), showed a globule size of 320 nm and -28.6 mV zeta potential. Results of the pharmacokinetic studies showed 149.8% improvement in bioavailability of QU in SNEDDS relative to its suspension. The developed HPLC method proved to be simple and sensitive for QU and TPGS simultaneous determination in rat plasma after oral administration of the new SNEDDS formula.

Design and characterization of propolis extract loaded self-nano emulsifying drug delivery system as immunostimulant.

This current study aims to optimize, characterize, and observe the stability of the self-nano emulsifying drug delivery system (SNEDDS) of propolis extract (PE) for improving the immune response. Optimization of the selected composition of SNEDDS was conducted using a D-optimal mixture design. SNEDDS was prepared by loading 150 mg/mL of PE in oil, surfactant, and cosurfactant phases. The thermodynamic stability test was carried out with phase separation parameters followed by the robustness to dilution and accelerated stability test. The immunostimulant activity was examined in vitro and in vivo by determining the phagocytic activity, cell proliferation, production of nitrite oxide levels of RAW 264.7 cells, phagocytic activity of macrophages, and the number of leukocytes, neutrophils, and lymphocytes. The formula optimization showed that the formula containing Capryol-90, Cremophor RH40, and PEG 400 at a ratio of 30: 34: 36 was optimum. The verification response of the optimum formula with drug loading showed that the transmittance, droplet size, and zeta potential were 96.90 ± 0.00%, 28.7 ± 1.20 nm, and -56.5 ± 2.05 mV, respectively. The thermodynamic stability test and robustness to dilution did not find any separation phase. The accelerated stability test results were classified as stable. The in vitro and in vivo immunostimulant activity test showed that PE-loaded SNEDDS exhibited a higher immunostimulant effect than PE. In conclusion, the optimum and stable composition of PE loaded SNEDDS was found with a simple and accurate method using the D-Optimal mixture design and demonstrated an immunostimulant activity.

Impact of solidification on micromeritic properties and dissolution rate of self-nanoemulsifying delivery system loaded with docosahexaenoic acid.

Development of self-nanoemulsifying drug delivery systems (SNEDDS) of docosahexaenoic acid (DHA) is reported with the aim to achieve enhanced dissolution rate. The optimized composition of liquid SNEDDS (L-SNEDDS) formulation was Labrafil M1944 CS, 47% v/v Tween 80, 27% v/v Transcutol P, and 0.1% v/v DHA. L-SNEDDS were solidified using Syloid XDP 3150 as solid porous carrier. The droplet size, polydispersity index, zeta potential, percentage drug loading, and cloud point for L-SNEDDS were found to be 43.51 ± 1.36 nm, 0.186 ± 0.053, -19.20 ± 1.21 mV, 93.23 ± 1.71, and 88.60 ± 2.54 °C, respectively. Similarly, for solid SNEDDS (S-SNEDDS) the above parameters were found to be 57.32 ± 1.87 nm, 0.261 ± 0.043, -16.60 ± 2.18 mV, 91.23 ± 1.88, and 89.50 ± 1.18 °C, respectively. The formulations (L-SNEDDS, S-SNEDDS powder, and S-SNEDDS tablet) showed significant (p<.05) improvement in dissolution rate of drug in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) as compared to unprocessed DHA. In both the dissolution media, the dissolution rate was found more that 85% in 90 min. Absence of drug precipitation, phase separation, and turbidity during thermodynamic stability studies indicated that the developed SNEDDS were stable. Hence, it was concluded that SNEDDS have offered sufficient stability as well as dissolution rate of DHA.

Bioactive Self-Nanoemulsifying Drug Delivery Systems (Bio-SNEDDS) for Combined Oral Delivery of Curcumin and Piperine.

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.

Enhancement of the intestinal absorption of bortezomib by self-nanoemulsifying drug delivery system.

Purpose: Intestinal drug absorption is one of the main factors that govern the fraction of oral dose absorbed (Fa) of drugs. It is reported that oral absorption of bortezomib (BTZ) can be restricted by its low intestinal permeability. In this study, we aimed to evaluate the impact of self-nanoemulsifying drug delivery systems (SNEDDS) on the intestinal absorption and Fa of BTZ.Methods: Intestinal permeability studies were conducted using in situ single-pass intestinal perfusion (SPIP) technique in rats. Human intestinal absorption (Peff (Human)) and Fa values of BTZ and BTZ-SNEDDS were predicted based on SPIP data.Results: Based on the obtained data, Peff (rat) values of (3.36 ± 0.5) × 10-5 and (8.9 ± 3) × 10-5 cm/s (mean ± SEM) were calculated for BTZ and BTZ-SNEDDS, respectively. Meanwhile, Peff (human) values of (7 × 10-5) and (68 × 10-5) cm/sec were predicted for BTZ and BTZ-SNEDDS, respectively. Besides, Fa (human) values of 72.5 and 97% were estimated for BTZ and BTZ-SNEDDS, respectively.Conclusions: According to the obtained data, it is concluded that SNEDDS can be considered as a promising drug delivery system to improve the intestinal absorption and Fa values of BTZ.