Self-microemulsifying Drug Delivery System Research Articles

Self Emulsifying Delivery System of Cissus quadrangularis: Evidence of Enhanced Efficacy and Promising Pharmacokinetic Profile in the Management of Osteoporosis.

Treatment therapies used to manage osteoporosis are associated with severe side effects. So worldwide herbs are widely studied to develop alternative safe & effective treatments. Cissus quadrangularis (CQ) has a significant role in bone health and fracture healing. It is documented that its extracts increase osteoblastic differentiation & mineralization. Currently, Cissus quadrangularis is available in the form of tablets in the market for oral delivery. But these conventional forms are associated with poor bioavailability. There is a need for a novel drug delivery system with improving oral bioavailability. Therefore, a Cissus quadrangularis-loaded self-emulsifying drug delivery system (CQ-SEDDS) was developed which disperses rapidly in the gastrointestinal fluids, yielding nano-emulsions containing a solubilized drug. This solubilized form of the drug can be easily absorbed through lymphatic pathways and bypass the hepatic first-pass effect. The emulsification efficiency, zeta potential, globule size, in-vitro dissolution, ex-vivo, in-vivo and bone marker studies were performed to assess the absorption and permeation potential of CQ incorporated in SEDDS. CQ-SEDDS with excipients Tween 80, Cremophor RH40, Transcutol HP & α-Tocopherol acetate had shown about 76% enhancement in the bioavailability of active constituents of CQ. This study provided the pre-clinical data of CQ-SEDDS using osteoporotic rat model studies.

Self-emulsifying drug delivery systems containing sulfate-based surfactants: Are they responsive to alkaline phosphatase?

This study aimed to develop self-emulsifying drug delivery systems (SEDDS) containing sulfate-based surfactants, namely, sodium dodecyl sulfate (SDS), sodium octyl sulfate (SOS) and sodium cetearyl sulfate (SCS), and to evaluate intestinal alkaline phosphatase (IAP)-triggered sulfate release from these SEDDS.Results showed a time-dependent release of para-nitrophenol from para-nitrophenyl phosphate (p-NPP) and para-nitrophenyl sulfate (p-NPS) when incubated with isolated IAP indicating that the enzyme can also cleave sulfate groups. Moreover, sulfate release from p-NPS and sulfate-based surfactants was observed. SEDDS containing sulfate-based surfactants exhibited a narrow droplet size distribution and polydispersity index (PDI). A droplet size of 35.31 ± 0.41 nm to 41.15 ± 0.98 nm, PDI of 0.17 ± 0.02 to 0.26 ± 0.02 and zeta potential of 9.59 ± 0.85 mV to −18.53 ± 2.75 mV were recorded. Droplet size and PDI showed a minor increase upon contact with isolated IAP. Incubation with isolated IAP caused a rapid sulfate release from sulfate-based surfactant-containing SEDDS (SDS-SEDDS, SOS-SEDDS and SCS-SEDDS). Furthermore, resulting SEDDS exhibited a non-toxic profile. According to these results, SEDDS containing sulfate-based surfactants can be considered as valid alternative to IAP-responsive drug delivery systems containing phosphorylated auxiliary agents.

Solid Self-Nanoemulsifying Drug Delivery Systems of Furosemide: In Vivo Proof of Concept for Enhanced Predictable Therapeutic Response.

Liquid self-nano emulsifying drug delivery systems (SNEDDS) of furosemide (FSM) have been explored as a potential solution for enhancing solubility and permeability but are associated with rapid emulsification, spontaneous drug release, and poor in vivo correlation. To overcome the shortcoming, this study aimed to develop liquid and solid self-emulsifying drug delivery systems for FSM, compare formulation dynamics, continue in vivo therapeutic efficacy, and investigate the advantages of solidification. For this purpose, liquid SNEDDS (L-SEDDS-FSM) were formed using oleic acid as an oil, chremophore EL, Tween 80, Tween 20 as a surfactant, and PEG 400 as a co-surfactant containing 53 mg/mL FSM. At the same time, solid SNEDDS (S-SEDDS-FSM) was developed by adsorbing liquid SNEDDS onto microcrystalline cellulose in a 1:1 ratio. Both formulations were evaluated for size, zeta potential, lipase degradation, and drug release. Moreover, in vivo diuretic studies regarding urine volume were carried out in mice to investigate the therapeutic responses of liquid and solid SNEDDS formulations. After dilution, L-SEDDS-FSM showed a mean droplet size of 115 ± 4.5 nm, while S-SEDDS-FSM depicted 116 ± 2.6 nm and zeta potentials of -5.4 ± 0.55 and -6.22 ± 1.2, respectively. S-SEDDS-FSM showed 1.8-fold reduced degradation by lipase enzymes in comparison to L-SEDDS-FSM. S-SEDDS-FSM demonstrated a sustained drug release pattern, releasing 63% of the drug over 180 min, in contrast to L-SEDDS-FSM, exhibiting 90% spontaneous drug release within 30 min. L-SEDDS-FSM exhibited a rapid upsurge in urine output (1550 ± 56 μL) compared to S-SEDDS-FSM, showing gradual urine output (969 ± 29 μL) till the 4th h of the study, providing sustained urine output yet a predictable therapeutic response. The solidification of SNEDDS effectively addresses challenges associated with spontaneous drug release and precipitation observed in liquid SNEDDS, highlighting the potential benefits of solid SNEDDS in improving the therapeutic response of furosemide.

Combination of the Topical Photodynamic Therapy of Chloroaluminum Phthalocyanine Liposomes with Fexinidazole Oral Self-Emulsifying System as a New Strategy for Cutaneous Leishmaniasis Treatment.

Cutaneous leishmaniasis (CL) is a neglected tropical disease. The treatment is restricted to drugs, such as meglumine antimoniate and amphotericin B, that exhibit toxic effects, high cost, long-term treatment, and limited efficacy. The development of new alternative therapies, including the identification of effective drugs for the topical and oral treatment of CL, is of great interest. In this sense, a combination of topical photodynamic therapy (PDT) with chloroaluminum phthalocyanine liposomes (Lip-ClAlPc) and the oral administration of a self-emulsifying drug delivery system containing fexinidazole (SEDDS-FEX) emerges as a new strategy. The aim of the present study was to prepare, characterize, and evaluate the efficacy of combined therapy with Lip-ClAlPc and SEDDS-FEX in the experimental treatment of Leishmania (Leishmania) major. Lip-ClAlPc and SEDDS-FEX were prepared, and the antileishmanial efficacy study was conducted with the following groups: 1. Lip-ClAlPc (0.05 mL); 2. SEDDS-FEX (50 mg/kg/day); 3. Lip-ClAlPc (0.05 mL)+SEDDS-FEX (50 mg/kg/day) combination; 4. FEX suspension (50 mg/kg/day); and 5. control (untreated). BALB/c mice received 10 sessions of topical Lip-ClAlPc on alternate days and 20 consecutive days of SEDDS-FEX or FEX oral suspension. Therapeutical efficacy was evaluated via the parasite burden (limiting-dilution assay), lesion size (mm), healing of the lesion, and histological analyses. Lip-ClAlPc and SEDDS-FEX presented physicochemical characteristics that are compatible with the administration routes used in the treatments. Lip-ClAlPc+SEDDS-FEX led to a significant reduction in the parasitic burden in the lesion and spleen when compared to the control group (p < 0.05) and the complete healing of the lesion in 43% of animals. The Lip-ClAlPc+SEDDS-FEX combination may be promising for the treatment of CL caused by L. major.

In-vitro Lipolysis, Stability and Pharmacodynamic Study of Cilnidipine Loaded Self-emulsifying Drug Delivery System

Aim: The aim of this research work was to investigate the potential ability of cilnidipineloaded- Self-Emulsifying Drug Delivery System (SEDDS) to improve the solubility and oral bioavailability of cilnidipine. background: The limited oral bioavailability of BCS class II drugs restricts the clinical utility of drugs. Self-emulsifying drug delivery systems (SEDDS) are widely used for poorly water-soluble drugs to enhance their solubility and oral bioavailability. Background: The therapeutic value of drugs is constrained by the low oral bioavailability of BCS class II drugs. In order to improve the solubility and oral bioavailability of poorly water-soluble drugs, SEDDS are frequently utilised. Methods: To develop the cilnidipine-loaded-SEDDS formulation, Canola oil as the oil phase, tween 80 as the surfactant, and PEG 300 as the co-surfactant were used. The SEDDS formulation was evaluated based on stability study per ICH guidelines, drug precipitation during in-vitro lipolysis study under fasted and fed state, and in vivo pharmacodynamic study in Wistar rats. The content of the drug was determined by assay of SEDDS formulation using the official method of cilnidipine. Result: The pharmacodynamic study demonstrated that cilnidipine-loaded SEDDS formulation significantly produced a rapid antihypertensive effect (within 2 h) that lasted for 24 h in comparison to drug suspension. During the in vitro lipolysis study, the concentration of the drug recovered from the aqueous phase under both fasted and fed state was more than 90% after 10 minutes, with a minute amount of drug involved in precipitation. At stability conditions of 30±2 °C/65±5%RH for a duration of six months, the SEDDS formulation was found to be stable. The content of cilnidipine in the SEDDS formulation was found to be 98.4%. Conclusion: A BCS class-II drug's oral bioavailability and dissolution might be improved using the self-emulsifying drug delivery method.

LIQUID AND SOLID SELF-EMULSIFYING DRUG DELIVERY SYSTEMS (SEDDS) CONTAINING VALSARTAN: STABILITY ASSESSMENT AND PERMEABILITY STUDIES

Objective: Valsartan (VST) is a Biopharmaceutical classification system (BSC) class II active ingredient with a bioavailability of approximately 25% and is utilized to treat high blood pressure (hypertension). This study aimed was to showcase the stability and increase the permeability of VST by developing self-emulsifying drug delivery systems (SEDDS) and solidified SEDDS (S-SEDDS) formulations. Material and Method: The ratios of the components were determined by the pseudo-ternary phase diagram, and the characterization studies were conducted in the previous study. Stability was performed in long-term (25±2˚C, 60±5% relative humidity) and accelerated (40±2˚C, 75±5% relative humidity) conditions. The intestinal permeability of SEDDS formulations was evaluated by Caco-2 cells. Result and Discussion: Formulations for 12 month, droplet sizes were found to be 67.52 ± 5.26 nm and 176.93 ± 17.34 nm for SEDDS of VST (VST-SEDDS) and S-SEDDS of VST (VST-S-SEDDS), respectively. During this period, polydispersity indexes were: VST-SEDDS, 0.56±0.1; VST-S-SEDDS, 0.58±0.05. Both formulations increased VST permeability across Caco-2 cells: VST-SEDDS by 2.32x (powder) and 2.18x (commercial); VST-S-SEDDS by 1.38x (powder) and 1.30x (commercial). The formulation components did not have cytotoxic effects. These results demonstrated that newly developed VST-SEDDS and VST-S-SEDDS formulations with high permeability may be a desirable approach for antihypertensive therapy.

Formulation, Optimization and Evaluation of Solid SMEDDS of Pioglitazone

This investigation assessed 32 formulations of liquid self-microemulsifying drug delivery system (L-SMEDDS) for pioglitazone (PGZ). The optimal PLS12 formulation comprises 40% capmul MC8 (oil), 40% cremophore RH40 (surfactant), and 20% PEG (co-surfactant). PLS12 exhibited approximately 75 nm droplet size, below 200 nm, and a PDI of 0.47, indicating nanosized droplets with uniform distribution. The formulation demonstrated stability, and achieved supreme drug loading capacity. The enhanced L-SMEDDS was solidified into solidified SMEDDS utilizing Sylloid 244 FP, subsequently in a free-flowing powder without drug interactions. Tablets were successfully formulated by incorporating S-SMEDDS with diverse tableting excipients. The selected tablet batch passed quality control and stability tests. The tablet exhibited a rapid and pH-independent release profile. The combined impact of SMEDDS and tablets collectively enhanced the solubility and dissolution of PGZ hydrochloride

African Breadfruit Seed Oil as Lipid Phase of Self-Emulsifying Drug Delivery System for Improved Gastrointestinal Fluid Solubility of Ibuprofen: Design and Evaluation

Introduction: Rain forest vegetations all over the world produce large quantity of economically important seed oils which, in most developing countries are utilized only as food condiments but hardly employed in pharmaceutical formulations.&#x0D; Objectives: The purpose of this work was to formulate ibuprofen-loaded self-emulsifying drug delivery system for the enhancement of the gastrointestinal fluid solubility of this poorly water soluble drug.&#x0D; Methods: The breadfruit seed oil was extracted by the soxhlet extraction technique and characterized for various physicochemical properties including acid, iodine, peroxide, saponification values and organoleptic properties.  The super saturation solubility process, water titration studies and pseudo ternary phase diagrams were used to select and quantify the components of the emulsion systems. The liquid self-emulsifying drug delivery systems were converted to solid forms by adsorption onto a blend of miceocrystalline cellulose and Aerosil-200 powders. The resulting wet mass was dried and processed for encapsulation.&#x0D; Results: The percentage yield of the oil from the extraction process was 20.68 % while the acid, iodine, and saponification values were, 4.12 ± 1.24, 21.91 ± 0.88, and 302.45 ± 1.22 respectively. The ibuprofen exhibited higher solubility in the hydrolysed oil than in the crude form. Fourier transform infrared analysis did not reveal existence of component incompatibility. The optimized liquid and solid emulsions exhibited standard characteristics that were compatible to previous literature reports. The formulations also exhibited superior drug release properties over two control samples.&#x0D; Conclusion: It was concluded that Breadfruit seed oil has the potential to function as the lipid component of ibuprofen-loaded self-emulsifying drug delivery system formulated to enhance the aqueous solubility of the drug.

Development of a self-microemulsifying drug delivery system to deliver delamanid via a pressurized metered dose inhaler for treatment of multi-drug resistant pulmonary tuberculosis

Tuberculosis (TB) is a serious health issue that contributes to millions of deaths throughout the world and increases the threat of serious pulmonary infections in patients with respiratory illness. Delamanid is a novel drug approved in 2014 to deal with multi-drug resistant TB (MDR-TB). Despite its high efficiency in TB treatment, delamanid poses delivery challenges due to poor water solubility leading to inadequate absorption upon oral administration. This study involves the development of novel formulation-based pressurized metered dose inhalers (pMDIs) containing self-microemulsifying mixtures of delamanid for efficient delivery to the lungs. To identify the appropriate self-microemulsifying formulations, ternary diagrams were plotted using different combinations of surfactant to co-surfactant ratios (1:1, 2:1, and 3:1). The combinations used Cremophor RH40, Poly Ethylene Glycol 400 (PEG 400), and peppermint oil, and those that showed the maximum microemulsion region and rapid and stable emulsification were selected for further characterization. The diluted self-microemulsifying mixtures underwent evaluation of dose uniformity, droplet size, zeta potential, and transmission electron microscopy. The selected formulations exhibited uniform delivery of the dose throughout the canister life, along with droplet sizes and zeta potentials that ranged from 24.74 to 88.99 nm and − 19.27 to − 10.00 mV, respectively. The aerosol performance of each self-microemulsifying drug delivery system (SMEDDS)-pMDI was assessed using the Next Generation Impactor, which indicated their capability to deliver the drug to the deeper areas of the lungs. In vitro cytotoxicity testing on A549 and NCI-H358 cells revealed no significant signs of toxicity up to a concentration of 1.56 µg/mL. The antimycobacterial activity of the formulations was evaluated against Mycobacterium bovis using flow cytometry analysis, which showed complete inhibition by day 5 with a minimum bactericidal concentration of 0.313 µg/mL. Moreover, the cellular uptake studies showed efficient delivery of the formulations inside macrophage cells, which indicated the potential for intracellular antimycobacterial activity. These findings demonstrated the potential of the Delamanid-SMEDDS-pMDI for efficient pulmonary delivery of delamanid to improve its effectiveness in the treatment of multi-drug resistant pulmonary TB.

Self-emulsifying drug delivery systems (SEDDS) containing Cymbopogon citratus essential oil: Enhancing the stability and acaricide efficacy against Rhipicephalus (Boophilus) microplus

The objectives of this study were to develop a self-emulsifying drug delivery system (SEDDS) to enhance the stability and efficacy of Cymbopogon citratus essential oil or lemongrass oil (LEO) against cattle tick larvae and engorged females. The system with the highest oil loading in SEDDS was composed of LEO (23.33%w/w), Tween 80: SGKH 4000 in a 2:1 ratio as surfactant (66.67%w/w), and propylene glycol as co-surfactant (10%w/w). The selected SEDDS-LEO has a particle size of 18.78 nm with a narrow size distribution (polydispersity index of 0.27). Notably, the stability of SEDDS was superior to that of the original oil, both during long-term storage and under accelerated conditions. SEDDS-LEO at oil concentrations ranging from 1.458% to 5.833% w/v showed a significantly higher percentage of egg-laying reduction against adult ticks compared with the original oil at the same concentrations (p < 0.05). Furthermore, SEDDS-LEO demonstrated greater larvicidal efficacy than the original oil, with lower LC50 and LC90 values of 0.91 mg/mL and 1.20 mg/mL, respectively, whereas the original oil's LC50 and LC90 values were 1.17 mg/mL and 1.74 mg/mL, respectively. Our findings indicate that SEDDS-LEO is a promising candidate for use as an acaricide in the control of tick populations in dairy cattle.

Enhancing oral bioavailability of an antifungal thiazolylhydrazone derivative: Development and characterization of a self-emulsifying drug delivery system

RN104 (2-[2-(cyclohexylmethylene)hydrazinyl)]-4-phenylthiazole) is a thiazolylhydrazone derivative with prominent antifungal activity. This work aimed to develop a self-emulsifying drug delivery system (SEDDS) loaded with RN104 to improve its biopharmaceutical properties and enhance its oral bioavailability. Medium chain triglycerides, sorbitan monooleate, and polysorbate 80 were selected as components for the SEDDS formulation based on solubility determination and a pseudo-ternary phase diagram. The formulation was optimized using the central composite design in response surface methodology. The optimized condition consisted of medium chain triglycerides, sorbitan monooleate, and polysorbate 80 in a mass ratio of 65.5:23.0:11.5, achieving maximum drug loading (10 mg/mL) and minimum particle size (118.4 ± 0.7 nm). The developed RN104-SEDDS was fully characterized using dynamic light scattering, in vitro release studies, stability assessments, polarized light microscopy, and transmission electron microscopy. In vivo pharmacokinetic studies in mice demonstrated that RN104-SEDDS significantly improved oral bioavailability compared to free RN104 (the relative bioavailability was 2133 %). These results clearly indicated the successful application of SEDDS to improve the pharmacokinetic profile and to enhance the oral bioavailability of RN104, substantiating its potential as a promising antifungal drug candidate.

Development of a self-microemulsifying drug delivery system using a Dunnione to enhance bioavailability

Development of a self-microemulsifying drug delivery system using a Dunnione to enhance bioavailability

Lactoferrin Reduces Surfactant Content in the Self-Emulsifying Drug Delivery System.

Self-emulsifying drug delivery systems (SEDDSs) can effectively be employed to formulate drugs with poor oral bioavailability due to low aqueous solubility and high first-pass metabolism. High surfactant content is an existing challenge toward the successful application of SEDDS. A SEDDS is developed with lactoferrin, a natural emulsifier to reduce the Tween content of a fenofibrate (FEN) formulation. FEN SEDDS (SEDDS without lactoferrin) and FEN Lf-SEDDS (SEDDS with lactoferrin) were developed with 30% and 21% Tween content, respectively. Both formulations containing Crodamol GTCC as a lipid component were thermodynamically stable. No significant difference was observed in zeta potential (-9.25 to -12.63 mV), drug content (>85%), and percentage transmittance (>99%) between the two formulations. FEN Lf-SEDDS resulted in higher viscosity and larger particle size than FEN SEDDS. Solidified SEDDS with Aerosil 200 significantly improved in vitro drug release from both formulations than pure FEN. However, FEN SEDDS and FEN Lf-SEDDS did not show a significant difference in cumulative percent release or dissolution efficiency at 120 min. It can be concluded that lactoferrin containing SEDDS with 27% lesser synthetic surfactants (Tween 80 and Span 80) can result in similar physicochemical characteristics. Oral pharmacokinetic study of FEN Lf-SEDDS in a rat model resulted in 1.3 and 5.5 times higher relative bioavailability than marketed product and pure drug, respectively. The addition of lactoferrin could substitute synthetic surfactants in self-emulsifying drug delivery systems significantly.

APPROACH TO OPTIMIZE THE SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEM FOR AZILSARTAN MEDOXOMIL USING BOX BEHNKEN DESIGN AND DESIRABILITY FUNCTION

Objective: Develop and optimize a novel self-micro emulsifying drug delivery system (SMEDDS) for enhancing the water solubility of Azilsartan (AZL) by employing the Box-Behnken design and the desirability function. Methods: The formulation of AZL-SMEDDS consists of clove oil (oil component), Tween 20 (surfactant), propylene glycol (co-surfactant) as the independent variables and the active drug. Using a 3-level Design, the impact of independent variables on the formulation was examined. These variables' specified ranges are 20-40 mg, 50-80 mg, and 5-30 mg for X1, X2 and X3 respectively. Particle size (Y1), PDI (Y2), and dissolution % (Y3) were the response variables investigated in this study. Results: The results indicated that the optimal values for Clove oil (X1), Tween 20 (X2), and Propylene glycol (X3) were determined to be 28.69, 76.45, and 24.93 (mg), respectively. Based on these optimized conditions, the predicted data points for the response variables Particle Size (Y1), Polydispersity (Y2), and dissolution % (Y3) were determined to be 59.85 nm, 0.729 and 55.406%, respectively. Conclusion: The empirical results obtained from the optimized formulation exhibited a strong correlation with the predicted values. The optimized AZL-SMEDDS formulation demonstrated a rapid rate of drug solubility and greater bioavailability than AZL powder.

Formulation and Characterization of Self-Microemulsifying Drug Delivery System (SMEDDS) of Sertraline Hydrochloride.

Sertraline hydrochloride is the most widely used selective serotonin reuptake inhibitor (SSRI) for the treatment of several depressive disorders. Its applicability is limited due to extensive metabolism and poor oral bioavailability of 44 %. The current research focused on improving the solubility and oral bioavailability of Sertraline by using microemulsions developed by a self-micro emulsifying drug delivery system (SMEDDS) for significant antidepressant action. SMEDDS were developed by selecting appropriate proportions of oil, surfactant, and co-solvents and out of them isopropyl myristate, tween 80 and propylene glycol were identified as best. The emulsification zone was demonstrated by a ternary phase diagram, and compatibility was confirmed with Fourier-transformed infrared spectroscopy (FT-IR). The formulated SMEDDS were characterized for robustness to dilution, globule size (GS), polydispersity index (PDI), viscosity, in-vitro dissolution and diffusion study, and drug release kinetics study. All the batches (A1-A9) passes the test and A3 was selected as an optimized batch that doesn't show phase separation, precipitation with globule size (101 nm), PDI (0.319), drug content (99.14±0.35 %), viscosity (10.71±0.02 mPa), self-emulsification time (46 sec), in-vitro drug release (98.25±0.22 %) within 8 h, release kinetics (Higuchi) and effective antidepressant in in-vitro diffusion studies. An optimized batch A3 observed circular in shape estimated by Transmission electron microscopy (TEM) and passes all the thermodynamic stability testing with loss of 0.271 mg of the drug after 90 days and showed marked antidepressant action with higher stability.

Lipid-Based Self-Microemulsion of Niclosamide Achieved Enhanced Oral Delivery and Anti-Tumor Efficacy in Orthotopic Patient-Derived Xenograft of Hepatocellular Carcinoma in Mice.

We previously identified niclosamide as a promising repurposed drug candidate for hepatocellular carcinoma (HCC) treatment. However, it is poorly water soluble, limiting its tissue bioavailability and clinical application. To overcome these challenges, we developed an orally bioavailable self-microemulsifying drug delivery system encapsulating niclosamide (Nic-SMEDDS). Nic-SMEDDS was synthesized and characterized for its physicochemical properties, in vivo pharmacokinetics and absorption mechanisms, and in vivo therapeutic efficacy in an orthotopic patient-derived xenograft (PDX)-HCC mouse model. Niclosamide ethanolamine salt (NEN), with superior water solubility, was used as a positive control. Nic-SMEDDS (5.6% drug load) displayed favorable physicochemical properties and drug release profiles in vitro. In vivo, Nic-SMEDDS displayed prolonged retention time and plasma release profile compared to niclosamide or NEN. Oral administration of Nic-SMEDDS to non-tumor bearing mice improved niclosamide bioavailability and Cmax by 4.1- and 1.8-fold, respectively, compared to oral niclosamide. Cycloheximide pre-treatment blocked niclosamide absorption from orally administered Nic-SMEDDS, suggesting that its absorption was facilitated through the chylomicron pathway. Nic-SMEDDS (100 mg/kg, bid) showed greater anti-tumor efficacy compared to NEN (200 mg/kg, qd); this correlated with higher levels (p < 0.01) of niclosamide, increased caspase-3, and decreased Ki-67 in the harvested PDX tissues when Nic-SMEDDS was given. Biochemical analysis at the treatment end-point indicated that Nic-SMEDDS elevated lipid levels in treated mice. We successfully developed an orally bioavailable formulation of niclosamide, which significantly enhanced oral bioavailability and anti-tumor efficacy in an HCC PDX mouse model. Our data support its clinical translation for the treatment of solid tumors.

Effects of excipients on the interactions of self-emulsifying drug delivery systems with human blood plasma and plasma membranes.

Due to its versatility in formulation and manufacturing, self-emulsifying drug delivery systems (SEDDS) can be used to design parenteral formulations. Therefore, it is necessary to understand the effects of excipients on the behavior of SEDDS formulations upon parenteral administration, particularly their interactions with blood plasma and cell membranes. In this study, we prepared three neutrally charged SEDDS formulations composed of medium-chain triglycerides as the oil phase, polyoxyl-35 castor oil (EL35) and polyethylene glycol (15)-hydroxystearate (HS15) as the nonionic surfactants, medium-chain mono- and diglycerides as the co-surfactant, and propylene glycol as the co-solvent. The cationic surfactant, didodecyldimethylammonium bromide (DDA), and the anionic surfactant, sodium deoxycholate (DEO), were added to the neutral SEDDS preconcentrates to obtain cationic and anionic SEDDS, respectively. SEDDS were incubated with human blood plasma and recovered by size exclusion chromatography. Data showed that SEDDS emulsion droplets can bind plasma protein to different extents depending on their surface charge and surfactant used. At pH 7.4, the least protein binding was observed with anionic SEDDS. Positive charges increased protein binding. SEDDS stabilized by HS15 can adsorb more plasma protein and induce more plasma membrane disruption activity than SEDDS stabilized by EL35. These effects were more pronounced with the HS15 + DDA combination. The addition of DDA and DEO to SEDDS increased plasma membrane disruption (PMD) activities, and DDA (1% w/w) was more active than DEO (2% w/w). PMD activities of SEDDS were concentration-dependent and vanished at appropriate dilution ratios.

Development of lipid-based SEDDS using digestion products of long-chain triglyceride for high drug solubility: Formulation and dispersion testing

A self-emulsifying drug delivery system (SEDDS) containing long chain lipid digestion products (LDP) and surfactants was developed to increase solubility of two model weakly basic drugs, cinnarizine and ritonavir, in the formulation. A 1:1.2 w/w mixture of glyceryl monooleate (Capmul GMO-50; Abitec) and oleic acid was used as the digestion product, and a 1:1 w/w mixture of Tween 80 and Cremophor EL was the surfactant used. The ratio between LDP and surfactant was 1:1 w/w. Since the commercially available Capmul GMO-50 is not pure monoglyceride and contained di-and-triglycerides, the digestion product used would provide 1:2 stoichiometric molar ratio of monoglyceride and fatty acid after complete digestion in gastrointestinal fluid. Both cinnarizine and ritonavir had much higher solubility in oleic acid (536 and 72 mg/g, respectively) than that in glyceryl monooleate and glyceryl trioleate. Therefore, by incorporating oleic acid in place of glyceryl trioleate in the formulation, the solubility of cinnarizine and ritonavir could be increased by 5-fold and 3.5-fold, respectively, as compared to a formulation without the fatty acid. The formulation dispersed readily in aqueous media, and adding 3 mM sodium taurocholate, which is generally present in GI fluid, remarkably improved the dispersibility of SEDDS and reduced particle size of dispersions. Thus, the use of digestion products of long-chain triglycerides as components of SEDDS can enhance the drug loading of weakly basic compounds and increase dispersibility in GI fluids.

Preparation and Evaluation of a Self-Emulsifying Drug Delivery System for Improving the Solubility and Permeability of Ticagrelor.

Ticagrelor (TCG) is a BCS class IV antiplatelet drug used to prevent platelet aggregation in patients with acute coronary syndrome, having poor solubility and permeability. The goal of this study was to develop a self-nanoemulsifying drug delivery system (SNEDDS) of TCG to improve its solubility and permeability. The excipients were selected based on the maximum solubility of TCG and observed by UV spectrophotometer. Different combinations of oil, surfactant, and co-surfactant (1:1, 2:1, and 3:1) were used to prepare TCG-SNEDDS formulations, and pseudo-ternary phase diagrams were plotted. The nanoemulsion region was observed. Clove oil (10-20%), Tween-80 (45-70%), and PEG-400 (20-45%) were used as an oil, surfactant, and co-surfactant, respectively. The selected formulations (F1, F2, F3, F4, F5, and F6) were analyzed for ζ potential, polydispersity index (PDI), ζ size, self-emulsification test, cloud point determination, thermodynamic studies, entrapment efficiency, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), in vitro dissolution, ex vivo permeation, and pharmacodynamic study. The TCG-SNEDDS formulations exhibited ζ potential from -9.92 to -6.23 mV, a ζ average of 11.85-260.4 nm, and good PDI. The in vitro drug release in phosphate buffer pH 6.8 from selected TCG-SNEDDS F4 was about 98.45%, and F6 was about 97.86%, displaying improved dissolution of TCG in 0.1 N HCl and phosphate buffer pH 6.8, in comparison to 28.05% of pure TCG suspension after 12 h. While the in vitro drug release in 0.1 N HCl from F4 was about 62.03%, F6 was about 73.57%, which is higher than 10.35% of the pure TCG suspension. In ex vivo permeability studies, F4 also exhibited an improved apparent permeability of 2.7 × 10-6versus 0.6708 × 10-6 cm2/s of pure drug suspension. The pharmacodynamic study in rabbits demonstrated enhanced antiplatelet activity from TCG-SNEDDS F4 compared to that from pure TCG suspension. These outcomes imply that the TCG-SNEDDS may serve as an effective means of enhancing TCG's antiplatelet activity by improving the solubility and permeability of TCG.

Novel solid self-emulsifying drug delivery system to enhance oral bioavailability of cabazitaxel

In this study, a novel cabazitaxel solid self-emulsifying drug delivery system (CTX S-SEDDS) was developed by solvent evaporation and liquid–solid compression technology, which overcame the limitations of the traditional SEDDS and improved the oral bioavailability. From the results of solubility, pseudo-ternary phase diagram, and single-factor analysis, Tween 80 (surfactant), Tricaprylin (oil), and Glyceryl monooleate (oil) with the ratio of 30:55:15 showed optimized particle size (140.87 nm), short emulsification and high cabazitaxel (CTX) loading capacity (50 mg·g−1). Based on the liquid–solid compression mathematical model, Syloid XDP3050 was determined as carrier material and Syloid 244FP as coating material. The prepared CTX S-SEDDS showed excellent flowability, tabletability, and reconstitution property. In vivo pharmacokinetics in rats demonstrated the absolute bioavailability of CTX S-SEDDS (17.27 %) was significantly enhanced compared with CTX solution (1.69 %), which was close to that of CTX-SEDSS (20.48 %). Lymphatic absorption was verified by in vitro imaging to be an important absorption route for self-emulsifying preparations. These results suggested that CTX S-SEDDS could enhance oral bioavailability of poorly water-soluble drug cabazitaxel while avoiding SEDDS limitations and harnessing the dual advantages of solid and liquid preparations.