The effects of Atractylodes macrocephala extract BZEP self-microemulsion based on gut-liver axis HDL/LPS signaling pathway to ameliorate metabolic dysfunction-associated fatty liver disease in rats.

OBJECTIVES: To elucidate the therapeutic effects and mechanisms of Atractylodes macrocephala extract crystallize (BZEP) and BZEP self-microemulsion (BZEPWR) on metabolic dysfunction-associated fatty liver disease (MAFLD) induced by "high sugar, high fat, and excessive alcohol consumption" based on the gut-liver axis HDL/LPS signaling pathway. METHODS: In this study, BZEP and BZEPWR were obtained via isolation, purification, and microemulsification. Furthermore, an anthropomorphic MAFLD rat model of "high sugar, high fat, and excessive alcohol consumption" was established. The therapeutic effects of BZEPWR and BZEP on the model rats were evaluated in terms of liver function, lipid metabolism (especially HDL-C), serum antioxidant indexes, and liver and intestinal pathophysiology. To determine the lipoproteins in the serum sample, the amplitudes of a plurality of NMR spectra were derived via deconvolution of the composite methyl signal envelope to yield HDL-C subclass concentrations. The changes in intestinal flora were detected via 16 S rRNA gene sequencing. In addition, the gut-liver axis HDL/LPS signaling pathway was validated using immunohistochemistry, immunofluorescence, and western blot. RESULTS: The findings established that BZEPWR and BZEP improved animal signs, serum levels of liver enzymes (ALT and AST), lipid metabolism (TC, TG, HDL-C, and LDL-C), and antioxidant indexes (GSH, SOD, and ROS). In addition, pathological damage to the liver, colon, and ileum was ameliorated, and the intestinal barrier function of the model rats was restored. At the genus level, BZEPWR and BZEP exerted positive effects on beneficial bacteria, such as Lactobacillus and norank_f__Muribaculaceae, and inhibitory effects on harmful bacteria, such as unclassified_f__Lachnospiraceae and Blautia. Twenty HDL-C subspecies were detected, and their levels were differentially increased in both BZEPWR and BZEP groups, with BZEPWR exhibiting a stronger elevating effect on specific HDL-C subspecies. Also, the gut-liver axis HDL/LPS signaling pathway was studied, which indicated that BZEPWR and BZEP significantly increased the expressions of ABCA1, LXR, occludin, and claudin-1 proteins in the gut and serum levels of HDL-C. Concomitantly, the levels of LPS in the serum and TLR4, Myd88, and NF-κB proteins in the liver were decreased. CONCLUSION: BZEPWR and BZEP exert restorative and reversal effects on the pathophysiological damage to the gut-liver axis in MAFLD rats, and the therapeutic mechanism may be related to the regulation of the intestinal flora and the HDL/LPS signaling pathway.

Preparation of Self-microemulsion Solids of Kaempferia galanga (L.) Volatile Oil and Its Effect on Rats with Gastric Ulcer.

Kaempferia galanga volatile oil (KVO), the main effective component of the medicinal plant Kaempferia galanga L., possesses a variety of pharmacological activities such as anti-inflammatory, antioxidant, and anti-angiogenic activities and has therapeutic potential for gastric ulcer (GU). However, poor solubility as well as instability limits the clinical application of KVO. In this study, K. galanga volatile oil self-microemulsion solids (KVO-SSMEDDS) were prepared to improve its bioavailability and stability, and the therapeutic effects were evaluated in a rat model with GU. The ratio of oil phase, emulsifier, and co-emulsifier in the KVO-SMEDDS prescription were optimized by plotting the pseudo-ternary phase diagram with the star point design-response surface method. Based on the optimal prescription, self-microemulsifying drug delivery system (SMEDDS) was prepared as solid particles (S-SMEDDS). The prepared KVO-SSMEDDS had a rounded and non-adhesive appearance, formed an O/W emulsion after dissolution in water, and had a uniform particle size distribution with good stability and solubility. It was administered to GU model animals, and the results showed that a certain dose of KVO-SSMEDDS solution could increase the content of gastric mucosal protective factors PGE2, TGF-α, and EGF in gastric tissues and serum, and the expression of inflammatory factors IL-8 and TNF-α was downregulated. Meanwhile, the expression of the NF-κB/COX-2 pathway proteins was inhibited. In conclusion, the prepared KVO-SSMEDDS has good dispersion, solubility, and stability and has a therapeutic effect on rats with GU.

Sustained release gel (polymer-free) of itraconazole-loaded microemulsion for oral candidiasis treatment: time-kill kinetics and cellular uptake.

Itraconazole (ICZ) was prepared in a self-microemulsifying (SM) gel. This gel was intended for use in the oral mucosa, where low volume and flow of saliva result in limited solubility and absorption of drugs that are poorly water-soluble. The drug-loaded gel formulation (ICZ-SM) was selected as a clear solution in the ternary phase diagram to improve the solubility of ICZ. Seven ratios (S1-S7) were prepared by mixing polyoxyl 35 castor oils (P35), a medium chain with a blend of mono-, di-, and triglycerides (MCT), and water. Phase separation of large-sized emulsions by countering with artificial saliva were observed in dilution tests for the formulation contained MCT, P35, and water at the ratios of 70:20:10 (S1), 10:80:10 (S3), and 20:60:20 (S4). Formulations in the ratios of 15:50:35 (S5) and 19:43:38 (S6) produced strong ICZ-SM gels, as shown by rheology tests, whereas the formulations at the ratios of 30:60:10 (S2) and 10:43:47 (S7) exhibited no elasticity. A model of zero-order kinetic (S5) and first-order kinetic (S6) were found to best fit the release kinetics of ICZ from the gels. Time-killing assays revealed that S5 and S6 required less time compared with S2 and the ICZ solution. Furthermore, S5 exhibited the highest increase in cell uptake compared with S2, S6, and the ICZ solution. These findings suggest that the ICZ-SM gel was a free polymer capable of delivering an ICZ for the treatment of oral candidiasis, and that ICZ-SM gels applied locally exhibit enhanced absorption into cells.

A designed self-microemulsion delivery system for dihydromyricetin and its dietary intervention effect on high-fat-diet fed mice.

The present study aims to design a self-microemulsion delivery system (d-α-tocopheryl polyethylene glycol 1000 succinate - quillaja saponin) to enhance the absorptivity of dihydromyricetin (DMY-S), and to investigate its dietary intervention effect on high-fat-diet (HFD) fed mice. We find DMY-S can inhibit the increase of body weight and fat mass, preventing non-alcoholic fatty liver disease. Compared to the model group, the abundance of mice intestinal flora is mainly changed in certain bacterial genera of Firmicutes and Bacteroides, including norank_f_Muribaculaceae and Blautia. The result of metabolism analysis indicated that the expression levels of cincassiol B, creatine, pantothenic acid and aminobutyric acid in the liver tissues of mice treated with DMY-S showed a down-regulation. The DMY-S prevented hyperlipidemia in HFD mice mainly by affecting different pathways including glycerophospholipid metabolism, sphingolipid metabolism and pantothenate and CoA biosynthesis.

Extra virgin olive oil-based phospholipid complex/self-microemulsion enhances oral absorption of salvianolic acid B through inhibition of catechol-O-methyltransferase-mediated metabolism.

The oral bioavailability of many phenolic acid drugs is severely limited due to the high hydrophilicity and extensive first-pass effect induced by catechol-O-methyltransferase (COMT) metabolism. The present study investigated the inhibitory activity of the pharmaceutical excipients of extra virgin olive oil (EVOO) against COMT and evaluated the potential of a self-microemulsion loaded with a phospholipid complex containing EVOO for oral absorption enhancement of salvianolic acid B (SAB), a model phenolic acid. In vitro COMT assay showed that EVOO could effectively inhibit enzyme activity in the rat liver cytosol. Next, the SAB phospholipid complex/self-microemulsion containing EVOO (named SP-SME1) was prepared and characterized (particle size, 243.60 ± 6.96 nm and zeta potential, -23.67 ± -1.36 mV). The phospholipid complex/self-microemulsion containing ethyl oleate (EO) (named SP-SME2) was taken as the control group. Compared with free SAB, the apparent permeability coefficient (Papp value) of the two SP-SMEs significantly increased (12.0-fold and 10.90-fold). Pharmacokinetic study demonstrated that the AUC0-∞ value of SAB for the SP-SME1 group significantly increased by 4.72 and 2.82 times compared to those for free SAB (p < 0.001) and SP-SME2 (p < 0.01), respectively. Moreover, the AUC0-∞ value of monomethyl-SAB (metabolite of SAB, MMS) for the SP-SME1 group decreased by 0.83 times compared to that for SP-SME2. In conclusion, the EVOO-based phospholipid complex/self-microemulsion greatly enhanced the oral absorption of SAB, which was mainly attributed to the inhibition of COMT activity induced by EVOO.

Pharmacokinetics study of a supersaturatable self-microemulsifying drug delivery system for ellagic acid by UHPLC-Q-TOF-MS.

To evaluate the bioavailability of ellagic acid loaded super-saturatable self-microemulsifying drug delivery system (S-SMEDDS), its pharmacokinetic properties were studied in rats with an ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry. The plasma samples were treated by solid-phase extraction method, and gallic acid was used as the internal standard when determining the concentration of ellagic acid. Results showed that the established analytical method was sensitive and accurate, which is applicable to the pharmacokinetic study of ellagic acid. The drug was found to be absorbed rapidly in vivo, and the plasma concentration-time curve showed double peaks, indicating that ellagic acid were reabsorbed by entero-hepatic circulation after oral administration. Compared with ellagic acid suspension, the apparent clearance of ellagic acid-loaded S-SMEDDS and SMEDDS reduced significantly, and the AUC 0~t of them were 4.7 and 5.8-fold increase, respectively. Therefore, the bioavailability of ellagic acid-loaded S-SMEDDS was higher than that of the suspension and SMEDDS.

Enhanced Stability of the Pharmacologically Active Lactone Form of 10-Hydroxycamptothecin by Self-Microemulsifying Drug Delivery Systems.

10-Hydroxycamptothecin (HCPT) is a DNA inhibitor of topoisomerase I and exerts antitumor activities against various types of cancer. However, reversible conversion from a pharmacologically active lactone form to an inactive carboxylate form of HCPT and poor water solubility hamper its clinical applications. To overcome these shortcomings, we designed a fine self-microemulsifying drug delivery system (SMEDDS) for HCPT to effectively protect HCPT in its active lactone form as well as improving dissolution rates. A formulation of HCPT-SMEDDS that contained ethyl oleate, D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and polyethylene glycol 400 (PEG400) was optimized by using the central composite design and response surface methodology. Following 1:100 aqueous dilution of the optimized HCPT-SMEDDS, the droplet size of resulting microemulsions was 25.6 ± 0.7 nm, and the zeta potential was - 15.2 ± 0.4 mV. The optimized HCPT-SMEDDS appeared to stabilize the lactone moiety of HCPT with 73.6% being present in the pharmacologically active lactone forms in simulated intestinal fluid, but only 45.7% for free HCPT. Furthermore, the physically stable formulation showed the active lactone form predominated in HCPT-SMEDDS (> 95%) for 6 months under the accelerated storage condition. Meanwhile, the optimized SMEDDS formulation also significantly improved dissolution rates and membrane permeability of the lactone form of HCPT. Therefore, HCPT-SMEDDS involved designing for the ease of manufacture, and provided a potent oral dosage form for preserving its active lactone form as well as enhancing the dissolution rate.

Enhancing in vivo oral bioavailability of cajaninstilbene acid using UDP-glucuronosyl transferase inhibitory excipient containing self-microemulsion.

Cajaninstilbene acid (CSA) exerts wide pharmacological activities, such as anti-inflammation, hypoglycaemic activity, analgesic effect and cognition improvement. However, it underwent severe phase II metabolism mediated by UDP-glucuronosyltransferase (UGT) in the gastrointestinal (GI) tract after oral administration, affecting its oral bioavailability. In the present study, we utilize UGT inhibitory excipient containing self-microemulsion (SME) delivery system to reduce the production of glucuronide metabolites and increase its oral bioavailability. The present results showed that although similar properties in physiochemical, cytotoxicity, cellular uptake, absorption and transport across rat everted gut sacs between SME-1 (inhibitory excipient containing SME) and SME-2 (control SME, without inhibitory excipient), an improved absolute bioavailability of 57.3 % was conferred by SME-1, significantly higher than the value of 35.4 % by SME-2 and 34.0 % by free CSA. Noticeably, the significantly lower AUC value of CSA glucuronide was determined in rats treated with SME-1 than those either treated with SME-2 or free CSA. Thus, the ability of SME-1 to enhance oral bioavailability of CSA is mainly attributed to the inhibition of phase II metabolism in the GI tract.

[Preparation and in vitro quality evaluation of self-microemulsion co-loaded with tenuifolin and ß-asarone].

To prepare and optimize the self-microemulsion co-loaded with tenuifolin and ß-asarone(TF/ASA-SMEDDS) and evaluate its quality. The prescription compositions of TF/ASA-SMEDDS were screened by solubility test, single factor test and pseudo-tern-ary phase diagram, and the prescriptions were further optimized by Box-Behnken response surface method, with the drug loading and particle size as the evaluation indexes. Then the optimized TF/ASA-SMEDDS was evaluated for emulsified appearance, particle size, morphology and drug release in vitro. The optimized prescription for TF/ASA-SMEDDS was as follows: caprylic citrate triglyceride polyoxyethylene castor oil-glycerol(10.8∶39.2∶50), drug loading of(5.563±0.065) mg·g~(-1) for tenuifolin and(5.526±0.022) mg·g~(-1) for ß-asarone; uniform and transparent pan-blue nanoemulsion can be formed after emulsification, with particle size of(28.84±0.44) nm. TEM showed that TF/ASA-SMEDDS can form spherical droplets with a uniform particle size after emulsification; In vitro release test results showed that the drug release rate and cumulative release of tenuifolin and ß-asarone were significantly improved. The preparation process of TF/ASA-SMEDDS was simple and can effectively improve in vitro release of tenuifolin and ß-asarone.

Improving The Oral Absorption Of Nintedanib By A Self-Microemulsion Drug Delivery System: Preparation And In Vitro/In Vivo Evaluation.

OBJECTIVE: Nintedanib (NDNB) is a triple receptor tyrosine kinase inhibitor with poor solubility in neutral conditions and low bioavailability. A self-microemulsifying drug delivery system (SMEDDS) of NDNB was developed to improve drug solubility in physical conditions and absorption in vivo. METHODS: The NDNB-SMEDDS formulation was optimized via pseudo-ternary phase diagrams. The physicochemical properties of NDNB-SMEDDS, viz., morphological observation, droplet size, stability, compatibility and in vitro release were investigated. The permeability of NDNB-SMEDDS was detected using both a Caco-2 cell monolayer in vitro and an intestinal perfusion study in vivo. Furthermore, the pharmacokinetic characteristics of NDNB-SMEDDS were evaluated. RESULTS: The optimal formulation was composed of MCT as an oil phase, RH 40 as a surfactant and ethylene glycol as a co-surfactant. The average droplet size of the microemulsion was about 23 nm with good stability within 30 days. The formulation did not exhibit any obvious cytotoxic effect on Caco-2 cells. Permeability of nintedanib in a Caco-2 cell monolayer was enhanced by 2.8-fold upon incorporation in SMEDDS compared with the drug solution. The intestinal perfusion study demonstrated that the P app of NDNB-SMEDDS increased by 3.0-fold in the entire intestine and 3.2-fold in the colon in comparison with the drug solution. The pharmacokinetics study showed that the AUC of the NDNB-SMEDDS increased significantly. CONCLUSION: This study showed that the self-microemulsion formulations could improve the absorption of nintedanib, and can thus serve as a promising carrier for the oral delivery of nintedanib.

Effect of ß-sitosterol self-microemulsion and ß-sitosterol ester with linoleic acid on lipid-lowering in hyperlipidemic mice.

BACKGROUND: The hypolipidemic effect of phytosterols has been wildely recognized, but its application is limited due to its insolubility in water and low solubility in oil. In this study, ß-sitosterol ester with linoleic acids and ß-sitosterol self-microemulsions were prepared and their hypolipidemic effects on hyperlipidemia mice were studied. METHODS: Firstly, the mice were randomly divided into normal group and model group,they were fed with basic diet and high-fat diet for 70 days respectively. After high-fat model mice was successfully established, the model group was further divided into eight groups: HFD (high-fat diet feeding), SELA-TSO(8 ml/kg, SELA:700 mg/kg), TSO (8 ml/kg), SSSM (8 ml/kg,SS:700 mg/kg), NLSM (8 ml/kg), SSHT-TSO (8 ml/kg, SS: 700 mg/kg) and SS-TSO (8 ml/kg, SS: 700 mg/kg) groups, and treated with ß-sitosterol ester with linoleic acid, ß-sitosterol self-microemulsion, commercial ß-sitosterol health tablets and ß-sitosterol powder for 35 days, respectively, and blank control groups were established. At the end of the treatment period, the blood lipid level, tissues, cholesterol and lipids in feces of mice in each group were investigated. Statistical and analytical data with SPSS 17.0 Software,statistical significance was set at p* < 0.05 and p** < 0.01 levels . RESULTS: The order of lowering blood lipid effect is listed as: SSSM> SELA-TSO > SSHT-TSO > SS-TSO, which shows that ß-sitosterolself-microemulsion have the highest treatment effect among the experimental groups. CONCLUSIONS: In this study, a new formulation of ß-sitosterol was developed, and its hypolipidemic effect was investigated. The results showed that ß-sitosterol self-microemulsion has a good blood lipid lowering effect.

Formulation Development of Albendazole-Loaded Self-Microemulsifying Chewable Tablets to Enhance Dissolution and Bioavailability.

Albendazole is an anthelmintic agent with poor solubility and absorption. We developed a chewable tablet (200 mg drug equivalent), containing a self-microemulsifying drug delivery system (SMEDDS), with oral disintegrating properties. The emulsion was developed using sesame and soybean oils along with surfactant/co-surfactants, and the tablets were prepared by wet granulation using superdisintegrants and adsorbents. Infra-red (IR) spectral studies revealed no interaction between the drug and excipients, and all physical and chemical parameters were within acceptable limits. Stability studies for the formulation indicated no significant change over time. An in vitro release study indicated 100% drug release within 30 min, and in vivo plasma concentrations indicated that the area under the curve (AUC) of albendazole in rats administered SMEDDS chewable tablets was significantly higher than in those administered commercial tablets or powder (p-value < 0.05). The systemic bioavailability of albendazole achieved through the SMEDDS tablets was 1.3 times higher than that achieved by the administration of comparable quantities of albendazole commercial tablets. This was due to the higher dissolution of albendazole SMEDDS in the chewable tablets. We conclude that the SMEDDS chewable formulation can be used to improve the dissolution and systemic availability of poorly water-soluble drugs.

Preparation and Pharmacokinetics Evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of Osthole.

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the Tmax and mean residence time (MRT(0-t)) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

Improving oral bioavailability of resveratrol by a UDP-glucuronosyltransferase inhibitory excipient-based self-microemulsion.

Self-microemulsifying (SME) drug delivery system has been developed to increase oral bioavailabilities, and inhibitory excipients are capable of improving oral bioavailability by inhibiting enzyme mediated intestinal metabolism. However, the potential of enzyme inhibitory excipients containing SME in boosting resveratrol bioavailability remains largely uninvestigated. In this study, we set out to prepare SME-1 with UGT inhibitory excipients (excipients without inhibitory activities named SME-2 as control) to increase the bioavailability of RES by inhibiting intestinal metabolism. Results demonstrated that similar physicochemical properties such as size, polydistribution index and in vitro release, cellular uptake and permeability in Caco-2 cells as well as in vivo lymphatic distribution between inhibitory SME-1 and non-inhibitory SME-2 were observed. In vivo study demonstrated that the molar ratios of RES-G/RES were 7.25±0.48 and 5.06±2.42 for free drug and SME-2, respectively, and the molar ratio decreased to 0.36±0.10 in SME-1 group. Pharmacokinetic study confirmed that the inhibitory excipients containing SME demonstrated potential in increasing bioavailability of RES from 6.5% for the free RES and 12.9% for SME-2 to 76.1% in SME-1 through modulating the glucuronidation by UGT inhibitory excipients.

Preparation and evaluation of self-microemulsions for improved bioavailability of ginsenoside-Rh1 and Rh2.

Due to intestinal cytochrome P450 (CYP450)-mediated metabolism and P-glycoprotein (P-gp) efflux, poor oral bioavailability hinders ginsenoside-Rh1 (Rh1) and ginsenoside-Rh2 (Rh2) from clinical application. In this study, Rh1 and Rh2 were incorporated into two self-microemulsions (SME-1 and SME-2) to improve oral bioavailability. SME-1 contained both CYP450 and P-gp inhibitory excipients while SME-2 only consisted of P-gp inhibitory excipients. Results for release, cellular uptake, transport, and lymph node distribution demonstrated no significant difference between either self-microemulsions in vivo, but were elevated significantly in comparison to the free drug. The pharmaceutical profiles in vivo showed that the bioavailability of Rh1 in SME-1 (33.25%) was significantly higher than that in either SME-2 (21.28%) or free drug (12.92%). There was no significant difference in bioavailability for Rh2 between SME-1 (48.69%) or SME-2 (41.73%), although they both had remarkable increase in comparison to free drug (15.02%). We confirmed that SME containing CYP450 and P-gp inhibitory excipient could distinctively improve the oral availabilities of Rh1 compared to free drug or SME containing P-gp inhibitory excipient. No notable increase was observed between either SME for Rh2, suggesting that Rh2 undergoes P-gp-mediated efflux, but may not undergo distinct CYP450-mediated metabolism.

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake.

Huperzine A (Hup-A) is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS) was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP) technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration-time curve (AUC) of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01). The absorption rate constant (Ka) and the apparent permeability coefficient (Papp) for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of Ka and Papp of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (Cmax) of the blocking model were significantly lower than those of the control model (P<0.05). The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

Development and in vivo evaluation of self-microemulsion as delivery system for α-mangostin.

α-Mangostin (MG) is a versatile bioactive compound isolated from mangosteen and possesses significant pharmacokinetic shortages. To augment the potential clinical efficacy, MG-loaded self-microemulsion (MG-SME) was designed and prepared in this study, and its potential as a drug loading system was evaluated based on the pharmacokinetic performance and tissue distribution feature. The formula of MG-SME was optimized by an orthogonal test under the guidance of ternary phase diagram, and the prepared MG-SME was characterized by encapsulation efficiency, size distribution, and morphology. Optimized high performance liquid chromatography method was employed to determine concentrations of MG and characterize the pharmacokinetic and tissue distribution features of MG in rodents. It was found that diluted MG-SME was characterized as spherical particles with a mean diameter of 24.6 nm and an encapsulation efficiency of 87.26%. The delivery system enhanced the area under the curve of MG by 4.75 times and increased the distribution in lymphatic organs. These findings suggested that SME as a nano-sized delivery system efficiently promoted the digestive tract absorption of MG and modified its distribution in tissues. The targeting feature and high oral bioavailability of MG-SME promised a good clinical efficacy, especially for immune diseases.

[Effects of different preparation technologies on concentrations of puerarin and catalpol in plasma and brain of rats after oral administration].

To compare the effects of different preparation technologies on the concentrations of puerarin and catalpol in plasma and brain of rats after oral administration, in order to lay an experimental basis for developing new oral Zige preparations. The nanocrystal, self-microemulsions (tween-80 and Cremophor RH-40 as emulsifiers) and inclusion complex of HP-ß-CD containing puerarin and catalpol were prepared. The concentrations of puerarin and catalpol in plasma and brain of rats after oral administration were determined by HPLC-MS/MS method. The pharmacokinetic parameters and brain target index were compared. The results showed that preparation technologies had different influences on the concentrations of puerarin and catalpol in plasma and brain. The self-microemulsion (tween-80) could significantly increase the oral absorption of puerarin than other technologies(P<0.05), and inclusion complex could remarkably increase the oral absorption of catalpol than nanocrystal(P<0.01). For puerarin, the brain targeting index of inclusion complex was the highest (P<0.05); but for catalpol, the brain targeting index of inclusion complex and self-microemulsions were both higher than nanocrystal (P<0.05). The self-microemulsion(tween-80) had the highest AUCbrain of puerarin than other groups (P<0.01); the inclusion complex had the highest AUCbrain for catalpol, but there was no significant difference compared with self-microemulsions. In conclusion, the self-microemulsion (tween-80) technology could increase the amount of puerarin and catalpol in brain, and was expected to be used in new oral Zige preparations.

Bromocriptine tablet of self-microemulsifying system adsorbed onto porous carrier to stimulate lipoproteins secretion for brain cellular uptake.

Both low solubility and high hepatic metabolism cause low oral bioavailability of bromocriptine mesylate (BM) leading to very low drug amount in brain. Self-microemulsion (SME) tablets were developed to improve solubility, stimulate lipoprotein synthesis to promote lymphatic transport, avoid hepatic metabolism and target drug to brain. SME liquid containing castor oil, Tween(®) 80 and Cremophor(®) EL was prepared and then adsorbed onto solid carries, Aerosil(®)200, Aeroperl(®)300 or NeusilinUS2(®), yielding SME powders. The optimal ratios of SME liquid to carriers determined from flowability and scanning electron photomicrographs before tableting were 1.5:1, 2:1 and 2.5:1 for Aerosil(®)200, Aeroperl(®)300 and NeusilinUS2(®), respectively. Only Aeroperl(®)300 SME tablet had comparable dissolution to BM commercial tablet. From in vitro study in Caco-2 cells, fluorescein loaded SME tablet showed higher uptake than fluorescein loaded in either oil or surfactant. Although significantly lower amount of drug was permeated from SME tablet than from commercial tablet, higher drug uptake was obviously observed (P<0.05). In addition, higher lipoprotein synthesis expressing as content of apolipoprotein B (apo-B) found in secreted chylomicron resulted in higher drug uptake in co-culture of brain endothelial cells (bEnd.3) and astrocytes (CTX TNA2) from drug loaded SME tablet when compared to commercial tablet (P<0.05) due to binding of apo-B to LDL receptors expressed on the surface of endothelial cells. Therefore, tablet of SME adsorbed onto porous carrier potentially delivered BM to brain via lymphatic transport by increasing the lipoprotein synthesis.