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

Introduction: 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). Methods: 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. Results: 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. Conclusion: 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.

Development and Optimization of Andrographis paniculata Extract-Loaded Self-Microemulsifying Drug Delivery System Using Experimental Design Model.

The objectives of this study were to develop an optimized formulation for an Andrographis paniculata extract (AGPE)-loaded self-microemulsifying drug delivery system (SMEDDS) using an experimental design and evaluate the characteristics of the developed SMEDDS. The solubility of andrographolide (AGP) in various solvents was investigated. The pseudo-ternary phase was constructed to provide an optimal range for each component to form microemulsions (MEs). The formulation was optimized using an I-optimal design mixture type, where the physical stability, droplet size, polydispersity index, and zeta potential were examined. Soft capsules of the optimized AGPE-loaded SMEDDS were manufactured. The dissolution and ex vivo membrane permeation were studied. Oleic acid, Tween® 80, and PEG 400 were the best solubilizers for AGP. The promising surfactant to co-surfactant ratio to generate ME was 3:1. The optimized SMEDDS contained 68.998% Tween® 80, with 13.257% oleic acid and 17.745% PEG 400. The assayed content of AGP, uniformity of dosage unit, and stability complied with the expected specifications. The dissolution and membrane permeability of AGPE-loaded SMEDDS was significantly improved from the A. paniculata extract (p < 0.05). All in all, the developed optimized AGPE-loaded SMEDDS was proven to contain optimal composition and AGP content where a stable ME could spontaneously be formed with enhanced delivery efficacy.

Fabrication of controlled-release polymeric microneedles containing progesterone-loaded self-microemulsions for transdermal delivery.

Progesterone (PG) has been approved for hormone replacement therapy to mitigate the risk of endometrial carcinoma. However, there has been a lack of success in oral PG due to its rapid degradation. Transdermal PG has advantages but lacks efficacy due to its poor solubility (Log p = 3.9). Therefore, this study aimed to evaluate how combining self-microemulsifying drug delivery systems (SMEDDS) and polymeric microneedles (MNs) could improve the transdermal delivery of PG in a controlled-release manner. Among PG-SMEDDS, PG-SME5 was selected for its desirable properties and stability. The two-layer polymeric MNs formulation incorporating PG-SME5 (PG-SMEDDS-tMNs) was formulated from aqueous blends of polymers as a first layer and 20% PCL as a second layer. It successfully penetrated neonatal porcine skin with the dissolution of the first layer observed within 15 min after application. In vitro skin permeation revealed that the percentage of PG which permeated the skin over 82 h using PG-SMEDDS-tMNs was higher than a PG-suspension and PG-SMEDDS. The Higuchi kinetic showed controlled release over 15 days of PG from PG-SMEDDS-tMNs. These studies suggested that incorporating PG-SMEDDS into controlled-release two-layer polymeric MNs could be a promising approach for improving the transdermal delivery of PG.

Comparative pharmacokinetics of 11 major bioactive components between two dosage forms of Qixue Shuangbu Prescription in rats by ultra-high-performance liquid chromatography-tandem mass spectrometry.

Although Qixue Shuangbu Prescription (QSP) is a classic Chinese medicine prescription for treating chronic heart failure. Low bioavailability due to the insolubility and poor biofilm permeability of the main bioactive ingredients of QSP is still a key factor limiting its efficacy. In this study, a novel self-microemulsifying drug delivery system was proposed to effectively improve the bioavailability of QSP. The qualified ultra-high-performance liquid chromatography-tandem mass spectrometry methodology was established to investigate the pharmacokinetics characteristics of the QSP self-microemulsifying drug delivery system. Our results showed that 11 components in the self-microemulsifying drug delivery system group had prolonged T1/2 and MRT0-t values compared with QSP extract. The Cmax of calycosin-7-glucoside (CG), vanillic acid and paeoniflorin increased 2.5 times, 2.4 times and 2.3 times, respectively. The relative bioavailability values of CG, paeoniflorin and ononin were most significantly affected, increasing by 383.2%, 336.5% and 307.1%, respectively. This study promoted the development of new dosage forms of QSP and provided a useful reference for improving dosage forms to solve the problem of low bioavailability of traditional Chinese medicine.

Improved Therapeutic Efficacy of MT102, a New Anti-Inflammatory Agent, via a Self-Microemulsifying Drug Delivery System, in Ulcerative Colitis Mice.

MT-102 is a new anti-inflammatory agent derived from Juglans mandshurica and Isatis indigotica. Its therapeutic potential is hindered by low aqueous solubility, impacting its in vivo efficacy. Therefore, this study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) for MT-102 to enhance its oral efficacy in treating ulcerative colitis. Solubility assessment in different oils, surfactants, and cosurfactants led to a SMEDDS formulation of MT-102 using Capmul MCM, Tween 80, and propylene glycol. Based on a pseudoternary phase diagram, the optimal SMEDDS composition was selected, which consisted of 15% Capmul MCM, 42.5% Tween 80, and 42.5% propylene glycol. The resulting optimized SMEDDS (SMEDDS-F1) exhibited a narrow size distribution (177.5 ± 2.80 nm) and high indirubin content (275 ± 5.58 µg/g, a biomarker). Across an acidic to neutral pH range, SMEDDS-F1 showed rapid and extensive indirubin release, with dissolution rates approximately 15-fold higher than pure MT-102. Furthermore, oral administration of SMEDDS-F1 effectively mitigated inflammatory progression and symptoms in a mouse model of ulcerative colitis, whereas pure MT-102 was ineffective. SMEDDS-F1 minimized body weight loss (less than 5%) without any significant change in colon length and the morphology of colonic tissues, compared to those of the healthy control group. In addition, oral administration of SMEDDS-F1 significantly inhibited the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α. In conclusion, the SMEDDS-F1 formulation employing Capmul MCM, Tween 80, and propylene glycol (15:42.5:42.5, w/w) enhances the solubility and therapeutic efficacy of MT-102.

A comparative study on the preparation and evaluation of solubilizing systems for silymarin.

Silymarin (SM) exhibits clinical efficacy in treating liver injuries, cirrhosis, and chronic hepatitis. However, its limited water solubility and low bioavailability hinder its therapeutic potential. The primary objective of this study was to compare the in vitro and in vivo characteristics of the four distinct SM solubilization systems, namely SM solid dispersion (SM-SD), SM phospholipid complex (SM-PC), SM sulfobutyl ether-ß-cyclodextrin inclusion complex (SM-SBE-ß-CDIC) and SM self-microemulsifying drug delivery system (SM-SMEDDS) to provide further insights into their potential for enhancing the solubility and bioavailability of SM. The formation of SM-SD, SM-PC, and SM-SBE-ß-CDIC was thoroughly characterized using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and powder X-ray diffractometry (PXRD) techniques to analyze the changes in their microscopic structure, molecular structure, and crystalline state. The particle size and polydispersity index (PDI) of SM-SMEDDS were 71.6 ± 1.57 nm, and 0.13 ± 0.03, respectively. The self-emulsifying time of SM-SMEDDS was 3.0 ± 0.3 min. SM-SMEDDS exhibited an improved in vitro dissolution rate and demonstrated the highest relative bioavailability compared to pure SM, SM-SD, SM-PC, SM-SBE-ß-CDIC, and Legalon®. Consequently, SMEDDS shows promise as a drug delivery system for orally administered SM, offering enhanced solubility and bioavailability.

Cinnamon oil solid self-microemulsion mediates chronic mild stress-induced depression in mice by modulating monoamine neurotransmitters, corticosterone, inflammation cytokines, and intestinal flora.

Cinnamon oil (CO) is a classic Chinese medicine with excellent soothing effects on exhaustion, weakness and depression. Cinnamaldehyde is the main active ingredient of cinnamic oil. Although CO have antidepression-like effects, limited information is available. Furthermore, the disadvantages of CO, such as low oral availability and difficult portability, limit its development. In this study, a Cinnamon Oil Solid Self-Microemulsifying Drug Delivery System (CO-S-SME) was designed, prepared. In addition, we explored the effects and mechanisms of CO-S-SME on chronic unpredictable mild stress (CUMS)-induced depression-like behavior, monoamine neurotransmitters, inflammatory factors, intestinal flora in mice. Mice were subjected CUMS to establish the depression model. The antidepressant effect of CO-S-SME was evaluated by behavioral tests. In addition, the expression levels of neurotransmitters, corticosterone (CORT) and inflammatory factors in CUMS mice were analyzed by enzyme-linked immunosorbent assay. In addition, we explored the effects of CO-S-SME on the diversity and richness of intestinal flora of mice in each group. Behavioral tests showed that CO-S-SME could effectively improve depression-like behaviors in CUMS mice. Specifically, CO-S-SME treatment effectively increased neurotransmitter levels and reduced the expressions of corticosterone and inflammatory factors in CUMS mice. CO-S-SME also changed the intestinal flora composition, decreased the ratio of Firmicutes to Bacteroidetes, reduced relative abundances of Lactobacillus, modulated Alpha diversity and beta diversity. These results suggest that CO-S-SME an act as a good antidepressant, exhibiting effects via monoamine neurotransmitters, CORT, inflammation cytokines, and intestinal flora.

Application of Design of Experiments in the Development of Self-Microemulsifying Drug Delivery Systems.

Oral delivery has become the route of choice among all other types of drug administrations. However, typical chronic disease drugs are often poorly water-soluble, have low dissolution rates, and undergo first-pass metabolism, ultimately leading to low bioavailability and lack of efficacy. The lipid-based formulation offers tremendous benefits of using versatile excipients and has great compatibility with all types of dosage forms. Self-microemulsifying drug delivery system (SMEDDS) promotes drug self-emulsification in a combination of oil, surfactant, and co-surfactant, thereby facilitating better drug solubility and absorption. The feasible preparation of SMEDDS creates a promising strategy to improve the drawbacks of lipophilic drugs administered orally. Selecting a decent mixing among these components is, therefore, of importance for successful SMEDDS. Quality by Design (QbD) brings a systematic approach to drug development, and it offers promise to significantly improve the manufacturing quality performance of SMEDDS. Furthermore, it could be benefited efficiently by conducting pre-formulation studies integrated with the statistical design of experiment (DoE). In this review, we highlight the recent findings for the development of microemulsions and SMEDDS by using DoE methods to optimize the formulations for drugs in different excipients with controllable ratios. A brief overview of DoE concepts is discussed, along with its technical benefits in improving SMEDDS formulations.

Development and Evaluation of Self-Microemulsifying Drug Delivery System for Improving Oral Absorption of Poorly Water-Soluble Olaparib.

The purpose of this study is to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) to improve the oral absorption of poorly water-soluble olaparib. Through the solubility test of olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. The various physicochemical properties of microemulsion incorporating olaparib were confirmed by investigating the morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and absorption of olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul® MCM 10%, Labrasol® 80% and PEG 400 10%. The fabricated microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that they were maintained well without any problems of physical or chemical stability. The dissolution profiles of olaparib were significantly improved compared to the value of powder. Associated with the high dissolutions of olaparib, the pharmacokinetic parameters were also greatly improved. Taken together with the results mentioned above, the microemulsion could be an effective tool as a formulation for olaparib and other similar drugs.

Incorporating a Lipophilic Disulfide-Bridged Linoleic Prodrug into a Self-Microemulsifying Drug Delivery System to Facilitate Oral Absorption of Paclitaxel.

The oral absorption of paclitaxel (PTX) is restricted by poor solubility in the gastrointestinal tract (GIT), low permeability, and high first-pass metabolism. Lipid carriers, such as a self-microemulsifying drug delivery system (SMEDDS), have been deemed as promising vehicles for promoting oral delivery of PTX. Herein, a lipophilic disulfide-bridged linoleic prodrug (PTX-S-S-LA) was synthesized and efficiently incorporated into SMEDDS to facilitate the oral absorption of PTX. This study mainly aims to evaluate the usefulness of the disulfide-bridged linoleic prodrug incorporated with SMEDDS and provides a new strategy for efficient oral delivery of PTX. The prodrug SMEDDS showed a markedly higher drug loading efficiency (3-fold) compared to that of parent PTX. PTX-S-S-LA SMEDDS significantly increased the drug partition (about 1.9-fold) in the intestinal micellar aqueous phase compared to PTX in the in vitro lipolysis study. Additionally, the gastrointestinal (GI) biodistribution study demonstrated that SMEDDS could enhance the GI biological adhesion and go through the lymphatic system to transport. Moreover, it was found that the reduction-sensitive prodrug (PTX-S-S-LA) has good stability in the GIT, leading to an improved antitumor efficiency without significant GI toxicity. Overall, the PTX-linoleic prodrug (PTX-S-S-LA) in combination with SMEDDS provides a promising way to enable effective oral delivery of PTX.

Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus.

To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.

Development, characterisation, and in vitro anti-tumor effect of self-microemulsifying drug delivery system containing polyphyllin I.

Polyphyllin I (PPI), an effective active ingredient in Paris polyphylla, has a diverse set of pharmacological properties. However, due to its poor solubility and oral absorption, its application and development are limited. In the study, we were committed to improving the solubility of PPI by developing a self-microemulsifying drug delivery system of PPI (PPI-SMEDDS), screening the best preparation process, and evaluating the quality and the in vivo pharmacokinetics of PPI, and PPI-SMEDDS following oral administration to rats were also studied. In addition, the pharmacological activities against human lung adenocarcinoma cell A549 in vitro were assessed. The best formulation had 15.89% ethyl oleate, 47.38% Cremophor RH40, and 36.73% 1,2 propylene glycol. The produced PPI-SMEDDS was clear and transparent, with an average particle size of 24.51 nm and a zeta potential of -17.54 ± 0.51 mV. In vitro, the cumulative release rate of PPI-SMEDDS was nearly 80% within 2 h. PPI-SMEDDS had a substantially greater area under the curve than PPI following oral treatment in rats, and the relative bioavailability of PPI in rats was 278.99%. More importantly, the anti-tumor effect of PPI-SMEDDS in vitro was significantly greater than that of PPI. These findings suggested that PPI-SMEDDS has the potential to improve the solubility, oral bioavailability of PPI, and anti-tumor effect, laying the groundwork for future research on the new PPI dosage form.

Enhanced oral absorption of insulin: hydrophobic ion pairing and a self-microemulsifying drug delivery system using a D-optimal mixture design.

The lipophilicity of a peptide drug can be considerably increased by hydrophobic ion pairing with amphiphilic counterions for successful incorporation into lipid-based formulations. Herein, to enhance the oral absorption of insulin (INS), a self-microemulsifying drug delivery system (SMEDDS) formulation was developed. Prior to optimization, INS was complexed with sodium n-octadecyl sulfate (SOS) to increase the loading into the SMEDDS. The INS-SOS complex was characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and its dissociation behavior. The SMEDDS was optimized using a D-optimal mixture design with three independent variables including Capmul MCM (X1, 9.31%), Labrasol (X2, 49.77%), and Tetraglycol (X3, 40.92%) and three response variables including droplet size (Y1, 115.2 nm), INS stability (Y2, 46.75%), and INS leakage (Y3, 17.67%). The desirability function was 0.766, indicating excellent agreement between the predicted and experimental values. The stability of INS-SOS against gastrointestinal enzymes was noticeably improved in the SMEDDS, and the majority of INS remained in oil droplets during release. Following oral administration in diabetic rats, the optimized SMEDDS resulted in pharmacological availabilities of 3.23% (50 IU/kg) and 2.13% (100 IU/kg). Thus, the optimized SMEDDS is a good candidate for the practical development of oral delivery of peptide drugs such as INS.

Design, Characterization, and Evaluation of Diosmetin-Loaded Solid Self-microemulsifying Drug Delivery System Prepared by Electrospray for Improved Bioavailability.

Diosmetin (DIOS) is a functional compound with poor water solubility, bad permeability, and crystal form. Self-microemulsifying drug delivery system (SMEDDS) was an effective formulation to overcome these shortcomings. In this study, liquid SMEDDS was prepared using Capmul® MCM C8 EP/NF, Cremophor EL, and PEG 400 (2:5.6:2.4, w/w/w) as excipients. Then, the novel technology of electrospray solidified liquid SMEDDS and prepared solid SMEDDS for inhibiting crystallization. Polyvinyl pyrrolidone (PVP) was used as carrier to construct DIOS-loaded solid SMEDDS, with polyethylene oxide (PEO) contributing to the formation of regular sphere in the process of spinning. The particle size of solid SMEDDS (194 ± 5 nm) was much bigger than of liquid SMEDDS (25 ± 1 nm), while DIOS-loaded solid SMEDDS showed greater dissolution rates in pH 1.2 and pH 6.8 media through in vitro drug release study. The solid nanoparticles were smooth and uniform from the graph of a scanning electron microscope (SEM). The graph of a transmission electron microscope (TEM) showed that small droplets were loaded in the matrix. Furthermore, DIOS was encapsulated by matrix in amorphous state via differential scanning calorimetry (DSC) and attenuated total reflection Fourier transform infrared (ATR-FTIR). The crystalline of DIOS was not formed in solid SMEDDS due to the characteristic peaks of DIOS disappeared in X-ray diffraction (XRD) pattern. Therefore, the oral bioavailability of DIOS improved significantly compared with liquid SMEDDS (4.27-fold). Hence, solid SMEDDS could improve the solubility and bioavailability of DIOS, through transfer of the state of crystalline to amorphous by electrospray technology.

Development and Optimization of Vitamin D3 Solid Self-Microemulsifying Drug Delivery System: Investigation of Flowability and Shelf Life.

We report herein the design of a solid self-microemulsifying drug delivery system (SMEDDS) of vitamin D3 for augmentation of its solubility and dissolution. The studies employed a 32 full factorial design by employing JMP 13.2.1, software for preparation of liquid SMEDDS. Further, the prediction profiler was utilized to optimized liquid SMEDDS-Vit.D3 (OF) formulation. The solidification of liquid SMEDDS-Vit.D3 formulation was carried out by physical adsorption over Neusilin US2 and Aerosil 200 carriers. Solid-state evaluation of SMEDDS-Vit.D3 suggested the transformation of crystalline to amorphous form of Vit.D3 which is responsible for imparting more aqueous solubility and thus enhancement in dissolution behaviour. The investigation of flow behaviours viz. flow function (FF) and effective angle of wall friction (EAWF) of solid SMEDDS-Vit.D3 was performed using powder flow tester. Solid SMEDDS-Vit.D3 prepared using Neusilin US2 showed good flow behaviour and hence was developed into tablets. The tablets showed good quality control parameters as per pharmacopeial standards. The in vitro dissolution studies demonstrated more dissolution of Vit.D3 in SMEDDS (liquid, solid, and tablet) when compared to the unprocessed drug. The shelf life (T90) of tablets was reported to be 28.12 months suggesting excellent stability of Vit.D3 in solid SMEDDS. In nutshell, our research works explore the utilization of SMEDDS for the oral delivery of Vit.D3 to gain maximum health-related benefits.

Strategies to Improve Insulin Delivery through Oral Route: A Review.

Diabetes mellitus is found to be among the most suffered and lethal diseases for mankind. Diabetes mellitus type-1 is caused by the demolition of pancreatic islets responsible for the secretion of insulin. Insulin is the peptide hormone (anabolic) that regulates the metabolism of carbohydrates, fats, and proteins. Upon the breakdown of the natural process of metabolism, the condition leads to hyperglycemia (increased blood glucose levels). Hyperglycemia demands outsourcing of insulin. The subcutaneous route was found to be the most stable route of insulin administration but faces patient compliance problems. Oral Insulin delivery systems are the patient-centered and innovative novel drug delivery system, eliminating the pain caused by the subcutaneous route of administration. Insulin comes in contact across various barriers in the gastrointestinal tract, which has been discussed in detail in this review. The review describes about the different bioengineered formulations, including microcarriers, nanocarriers, Self-Microemulsifying Drug Delivery Systems (SMEDDs), Self-Nanoemulsifying drug delivery systems (SNEDDs), polymeric micelles, cochleates, etc. Surface modification of the carriers is also possible by developing ligand anchored bioconjugates. A study on evaluation has shown that the carrier systems facilitate drug encapsulation without tampering the properties of insulin. Carrier-mediated transport by the use of natural, semi-synthetic, and synthetic polymers have shown efficient results in drug delivery by protecting insulin from harmful environment. This makes the formulation readily acceptable for a variety of populations. The present review focuses on the properties, barriers present in the GI tract, overcome the barriers, strategies to formulate oral insulin formulation by enhancing the stability and bioavailability of insulin.

Preparation，characterization and gastric mucosal permeability of evodiamine phospholipid complex self- microemulsifying drug delivery system / 中国药房

OBJE CTIVE To prepare and characterize evodiamine phospholipid complex self-microemulsifying drug delivery system（EVO-PC-SMEDDS），and to investigate its gastric mucosal permeability. METHODS EVO-PC-SMEDDS was prepared ， and particle size ，polydispersity（PDI）and Zeta potential were tested ，and microscopic observation was carried out. The stability of EVO-PC-SMEDDS in simulated gastric liquid with different pH （1.2，2.0，4.0，7.0）was investigated. The entrapment efficiency and drug-loading amount of the preparation were determined ，and the in vitro release was investigated. The gastric mucosal permeability of EVO-PC-SMEDDS was studied by combining rat gastric mucosal tissue and Ussing Chamber technology. RESULTS The particle size of EVO-PC-SMEDDS was （53.63±1.51）nm，PDI and Zeta potential were 0.217±0.017 and （－12.20±0.15）mV，entrapment efficiency was （95.25±0.97）％ and drug-loading amount was （19.30±1.21）mg/g. EVO-PC- SMEDDS exhibited a uniformly dispersed round spherical shape under transmission electron microscope. Stability experiments showed that EVO-PC-SMEDDS exhibited no significant change in particle size ，PDI and Zeta potential under the simulated gastric fluid with different pH and showed excellent stability. Results of in vitro release test showed that compared with evodiamine （EVO），in vitro accumulative release of EVO-PC-SMEDDS were enhanced 6.83-fold，which was in line with the first-order kinetic release model. Results of gastric mucosal permeability showed that gastric mucosal permeation transport ，permeation rate ， permeation flux and area under curve of cumulative permeability of EVO-PC-SMEDDS were higher than those of EVO ， respectively. CONCLUSIONS EVO-PC-SMEDDS is prepared N successfully and shows good stability. It could significantly improve the release behavior and gastric mucosal permeability of EVO.

Development of Self-Microemulsifying Drug Delivery System to Improve Nisoldipine Bioavailability: Cell Line and In Vivo Evaluations : Development of Self-Microemulsifying Drug Delivery System.

The authors attempted to fabricate a novel lipid-based formulation of a lipophilic drug, nisoldipine (NISO). As NISO belongs to BCS class 2 drug, it suffers from low bioavailability (5%). Hence, the research was intended to ameliorate oral bioavailability of NISO via intestinal lymphatic transport. The NISO loaded self microemulsifying drug delivery system (SMEDDS) (NISO SMEDDS) was prepared using Peceol, Cremophor EL, and Transcutol HP. The Cremophor EL and Transcutol HP at 1:1 ratio showed maximum microemulsifying area, and average globule size was 16.78 ± 0.97 nm with PDI 0.121 ± 0.024. Cellular uptake studies (confocal microscopy and flow cytometry) using Caco-2 cells depicted higher fluorescence with coumarin-6 loaded SMEDDS as that of coumarin-6 solution which indicated deeper penetration. Mean fluorescence intensity (MFI) of coumarin-6 loaded SMEDDS was significantly improved (9.92-fold) in contrast to coumarin-6 solution. The NISO SMEDDS showed enhanced permeability (5.02 times) across Caco-2 cells compared to NISO suspension. The bioavailability improvement with NISO SMEEDS was 2.14 times relative to suspension, and lymphatic uptake was involved in oral absorption of NISO SMEDDS.

Preparation and in vitro/in vivo evaluation of a self-microemulsifying drug delivery system containing chrysin.

OBJECTIVE: To prepare a self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of chrysin. METHODS: The preparation conditions were determined using factor analysis method. Preliminarily screening was conducted using compatibility tests and pseudo-ternary phase diagram studies. The central composite design-response surface methodology was used to determine the maximum drug loading and optimize SMEDDS formation, as characterized by surface morphology, pH, diameter, polydispersity index (PDI), zeta potential, and phase type. In vitro release of chrysin-suspension and chrysin-SMEDDS was investigated using the bulk-equilibrium reverse dialysis bag technique. Short-term stability of chrysin-SMEDDS at high and low temperatures was assessed. Pharmacokinetic behaviors were evaluated after intragastric and intravenous administration to rats. RESULTS: The final optimal formulation was medium chain triglyceride:oleic acid:Cremophor RH40: Transcutol HP (w/w) (12%:12%:32%:44%), with a drug loading capacity of 5 mg/g. Diluted chrysin-SMEDDS was characterized as an oil-in-water type and spherical, with a diameter, pH, PDI, and zeta potential of 28.26 ± 0.83 nm, 5.60 ± 0.84, 0.18 ± 0.01, and -23.13 ± 0.95 mV, respectively. The release speed of chrysin-SMEDDS was significantly higher than that of chrysin-suspension, and the release process was not affected by the media pH. In vivo pharmacokinetic data revealed that the oral bioavailability of chrysin-SMEDDS was 2.7-fold higher than that of chrysin suspension, compared with the chrysin microemulsion. CONCLUSION: The optimal SMEDDS formulation increased the dissolution and oral bioavailability of chrysin and may be useful for investigating chrysin efficacy in animal disease models and toxicokinetic studies.

In vitro and in vivo correlation for lipid-based formulations: Current status and future perspectives.

Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.