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Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the
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The objective of this study was to determine specific combination of pharmaceutical excipients that lead to formulation of efficient nebivolol hydrochloride SMEDDS and its subsequent formulation into IR-SET (Immediate release- Self emulsifying tablet) which will enhance its solubility and dissolution. Solubility and Pseudo-ternary phase studies were carried out to identify the excipients showing highest solubility and to identify the zone of microemulsion with selected ingredients. Liquid-SMEDDS (L-SMEDDS) were optimized for Concentration of oil(X1) and Smix(X2) and formulated using a combination of Kollisolv GTA as oil, Tween 80 as surfactant and propylene glycol as co-surfactant which gave smaller droplet size(Y1) 55.98nm , Emulsification time (Y2) 16±1.5 s,% transmittance (Y3) 99.94±0.47%. Neusilin US2 was used as solid carrier for solidification of L-SMEDDS in to Solid-SMEDDS (S-SMEDDS) by adsorption technique. IR-SET of nebivolol were formulated with S-SMEDDS and optimized for the concentration of binder (X1) (PVP K30) and superdisintegrant (X2) (KOLLIDON CL) which showed low Disintegration time (Y1) (92±0.5s) and low Friability(Y2)(0.424±0.03%). Also the DSC and XRD data revealed the molecular state of the drug in S-SMEDDS. The extent of in-vivo drug release and ex-vivo diffusion values from L-SMEDDS and IR-SET was much higher than pure drug and marketed tablet. In conclusion, the results showed potential of SMEDDS to improve solubility and thus the bioavailability.
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Objective To evaluate the effects of different solubilizing techniques on the in vitro dissolution and in vivo pharmacokinetics of Sirolimus (SRL). Methods Solid dispersions (SD), inclusion complex (IC), self-micro emulsifying drug delivery system (SMEDDS) and nano-structured lipid carrier (NLC) were selected as the solubilization technology for SRL. SRL-SMEDDS and SRL-NLC have obtained the optimal prescription in the previous studies. Additionally, the formulation process of SRL-SD and SRL-IC was screened by using inclusion rate and dissolution profiles as indicators. 0.4% SDS, water and buffer solutions with pH 1.2, 4.5, 6.8, 7.4 were used as dissolution media. The dissolution profile of the commercially available formulation Rapamune® and the lab-made solubilized preparations were investigated. The in vivo absorption of the above preparations was examined using a pharmacokinetic test in Beagle dogs. Results In 0.4% SDS, the dissolution of each preparation exceeded 80% in 2 h. In the medium of pH 1.2, the dissolution of SRL-SD could not be measured while the dissolution of IC, SMEDDS and NLC increased first and then decreased. In other media, the dissolution of the SRL was reduced. The SRL-IC showed the best dissolution without a significant decrease. The relative bioavailability of APIs, SRL-SD, SRL-IC, SRL-NLC and SRL-SMEDDS were 9.1%, 18.7%, 33.2%, 78.0%, and 97.6% respectively in vivo pharmacokinetic tests. Conclusion SD, SMEDDS, NLC, and IC can improve the in vitro dissolution and in vivo absorption of SRL. Among them, SMEDDS has the most significant improvement in the bioavailability of SRL.
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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 (<0.01). The absorption rate constant () and the apparent permeability coefficient () for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values ofandof 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 () of the blocking model were significantly lower than those of the control model (<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.
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Objective: To establish and validate a LC-MS/MS method for quantitative analysis of a new anti-stroke compound TID-101 in rat plasma and to study the pharmacokinetics and bioavailability of TID-101 self-(micro)emulsified drug delivery system(SMEDDS). Methods: The plasma samples were treated with methanol for precipitating protein. The chromatographic separation was achieved with a acetonitrile-water mobile phase. Detection of TID-101 and the internal standard (IS) dexamethasone acetate was achieved by electrospray ionization (ESI) source in the negative ion mode at m/z 353.4→323.2 and m/z 433.4→353.4. The method was applied for pharmacokinetics study of TID-101 between SMEDDS in rats. Results: The method was linear over TID-101 concentration range from 10-95 000 ng/ml with the correlation coefficients (r) of 0.9998. The intra-run and inter-run relative standard deviations(RSD) were less than 15% and the average absolute recovery values were 83.4-87.0%. The validated method was applied to a pharmacokinetic study in rats after intravenous administration of TID-101 fat emulsion injection and oral administration of TID-101 suspension and SMEDDS. The bioavailability of TID-101 API and SMEDDS was 2.8% and 14.9%, respectively. Conclusion: The analysis method is simple, accurate, and sensitive for assaying the in vivo pharmacokinetic study of TID-101 in rats. SMEDDS could effectively enhance the oral bioavailability of TID-101.
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Objective To establish and validate a LC-MS/MS method for quantitative analysis of a new anti-stroke compound TID-101 in rat plasma and to study the pharmacokinetics and bioavailability of TID-101 self-(micro)emulsified drug delivery system (SMEDDS). Methods The plasma samples were treated with methanol for precipitating protein. The chromatographic separation was achieved with a acetonitrile-water mobile phase. Detection of TID-101 and the internal standard (IS) dexamethasone acetate was achieved by electrospray ionization(ESI)source in the negative ion mode at m/z 353.4→323.2 and m/z 433.4→353.4. The method was applied for pharmacokinetics study of TID-101 between SMEDDS in rats. Results The method was linear over TID-101 concen?tration range from 10-95 000 ng/ml with the correlation coefficients(r)of 0.9998. The intra-run and inter-run relative standard devia?tions(RSD)were less than 15%and the average absolute recovery values were 83.4-87.0%. The validated method was applied to a pharmacokinetic study in rats after intravenous administration of TID-101 fat emulsion injection and oral administration of TID-101 suspension and SMEDDS. The bioavailability of TID-101 API and SMEDDS was 2.8% and 14.9%,respectively. Conclusion The analysis method is simple,accurate,and sensitive for assaying the in vivo pharmacokinetic study of TID-101 in rats. SMEDDS could effectively enhance the oral bioavailability of TID-101.
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The field of SMEDDS is designed to enhance bioavailability of poorly-water soluble compounds. Yet, these systems have the capacity to solubilize aqueous-based materials within its lipid matrix as L2 phase (W/O microemulsion). This characteristic is utilized in this investigation to incorporate aqueous flavors within oil vehicle as an approach to mask bitter taste of drugs. Miscibility profiles and self-micro-emulsifying regions for various lipid composites were screened by constructing ternary phase diagrams using different types of oil, cosurfactant and surfactant. Solubility of bitter taste model drug was measured in various optimized vehicles. Dynamic equilibrium phase studies were performed and phase boundaries were determined for the lipid-aqueous flavors-water systems. Self-micro-emulsifying system comprising Crodamol GTCC/ Glycerox 767HC /Croduret 40 ss at ratios of {0/80/20}, {6/54/40} or {10/40/50} have shown capacity to solubilize, aqueous-based materials including; strawberry flavor, sucrose and citric acid as L2 phase. Phase behavior study has revealed that clear dispersions can be obtained at all dilutions with water. Potential flavored self-microemulsifying lipid formulations representing type III lipid class system were developed. Aqueous flavors loaded into these vehicles can be used to mask bitter tastes in oral pharmaceuticals.
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Objective To review the newly developed solid self-microemulsifying drug delivery system (S-SMEDDS).Meth-ods Relevant literatures at home and abroad in recent years were consulted and summarized .Results Solid self-microemulsions car-rier, solidification technology and controlled release formulations were discussed , in order to provide relevant references for improving the bioavailability of water-insoluble drugs and the SMEDDS technology for drug release characteristics .Conclusion The utilization of the solid self-emulsifying drug delivery system could significantly enhance the oral bioavailability of water -insoluble drugs .As a new formulation, S-SMEDDS presented huge potential .
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The aim of this study was to develop a formulation to improve the oral absorption of baicalin (BA) by combining a phospholipid complex (PC) and self-emulsifying microemulsion drug delivery system (SMEDDS), termed BA-PC-SMEDDS. BA-PC was prepared by a solvent evaporation method and evaluated by complexation percentage (CP). The physicochemical properties of BA-PC were determined. The synergistic effect of PC and SMEDDS on permeation of BA was studied in vitro with Caco-2 cells and in situ with a single pass intestinal perfusion model. The improved bioavailability of BA in BA-PC-SMEDDS was confirmed in an in vivo rat model. The CP of BA-PC reached 100% when the molar ratio of drug to phospholipid (PP) was ≥1:1. The solubility of BA-PC increased in both water and octanol, and the log P o/w of BA-PC was increased significantly. BA-PC-SMEDDS could be dispersed more evenly in water, compared to BA and BA-PC. Both the Caco-2 cell uptake and single-pass intestinal perfusion models illustrated that transport of BA in BA-PC was lower than that of free BA, while improved significantly in BA-PC-SMEDDS. The relative bioavailability of BA-PC(1:2)-SMEDDS was 220.37%. The combination system of PC and SMEDDS had a synergistic effect on improving the oral absorption of BA.
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Improvement of bio-availability of poorly water soluble drugs presents one of the furthermost challenge in drug formulations. One of the most admired and commercially viable formulation approach for this challenge is solid self micro emulsifying drug delivery system (S-SMEDDS). There are many techniques to convert liquid SMEDDS to solid, but an adsorption technique is simple and economic. Hence aim of present study was to develop S-SMEDDS of poorly water soluble drug Telmisartan (TEL) using Aerosil 200 as solid carrier. Liquid SMEDDS was prepared using Acrysol EL 135, Tween 80 and PEG 400 as oil, surfactant and co-surfactant and was converted to S-SMEDDS by adsorbing it on Aerosil 200. Prepared S-SMEDDS was evaluated for flow properties, drug content, reconstitution properties, DSC, SEM, in-vitro drug release and ex-vivo intestinal permeability study. Results showed that prepared S-SMEDDS have good flow property with 99.45 ± 0.02% drug content. Dilution study by visual observation showed that there was spontaneous micro emulsification and no sign of phase separation. Droplet size was found to be 0.34 μm with polydispersity index of 0.25. DSC thermogram showed that crystallization of TEL was inhibited. SEM photograph showed smooth surface of S-SMEDDS with less aggregation. Drug releases from S- SMEDDS were found to be significantly higher as compared with that of plain TEL. Ex-vivo intestinal permeability study revealed that diffusion of drug was significantly higher from S-SMEDDS than that of suspension of plain TEL. Study concluded that S-SMEDDS can effectively formulated by adsorption technique with enhanced dissolution rate and concomitantly bioavailability.
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Improvement of bio-availability of poorly water soluble drugs presents one of the furthermost challenge in drug formulations. One of the most admired and commercially viable formulation approach for this challenge is solid self micro emulsifying drug delivery system (S-SMEDDS). There are many techniques to convert liquid SMEDDS to solid, but an adsorption technique is simple and economic. Hence aim of present study was to develop S-SMEDDS of poorly water soluble drug Telmisartan (TEL) using Aerosil 200 as solid carrier. Liquid SMEDDS was prepared using Acrysol EL 135, Tween 80 and PEG 400 as oil, surfactant and co-surfactant and was converted to S-SMEDDS by adsorbing it on Aerosil 200. Prepared S-SMEDDS was evaluated for flow properties, drug content, reconstitution properties, DSC, SEM, in-vitro drug release and ex-vivo intestinal permeability study. Results showed that prepared S-SMEDDS have good flow property with 99.45 ± 0.02% drug content. Dilution study by visual observation showed that there was spontaneous micro emulsification and no sign of phase separation. Droplet size was found to be 0.34 μm with polydispersity index of 0.25. DSC thermogram showed that crystallization of TEL was inhibited. SEM photograph showed smooth surface of S-SMEDDS with less aggregation. Drug releases from S- SMEDDS were found to be significantly higher as compared with that of plain TEL. Ex-vivo intestinal permeability study revealed that diffusion of drug was significantly higher from S-SMEDDS than that of suspension of plain TEL. Study concluded that S-SMEDDS can effectively formulated by adsorption technique with enhanced dissolution rate and concomitant-ly bioavailability.
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Objective: To prepare the total ginkgo flavonoid (TGF) self- microemulsifying oral fast dissolving films (SMEOFDF) and evaluate its in vitro properties. Methods: The formulation of TGF self-microemulsifying drug delivery system (SMEDDS) was optimized based on the solubility method and the pseudo-ternary phase diagram, and then the influence of formulation on disintegration time and film forming property were observed by single factor test. Microemulsified performance, disintegration time, content uniformity, and release profiles in vitro were investigated. The surface feature of TGF SMEOFDF was detected by scanning electron microscope and the crystal form of drug was characterized by differential scanning calorimetry. Results: The average particle size was (48.1 ± 5.45) nm with non-difference from SMEDDS. The average time to disintegrating was (9.94 ± 0.26) s and the releasing drug at 5 min of TGF SMEOFDF was (70.98 ± 0.31)% in vitro. Conclusion: SMEOFDF which has both advantages of SMEDDS and fast dissolving oral films is a new dosage form with profound application prospect.
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Objective: To study the formulation of puerarin (PUE) self-microemulsifying drug delivery system (SMEDDS). Methods: The optimum formulation of PUE SMEDDS was screened by test of solubility, compatibility of oil and surfactant, and pseudo-ternary phase diagram, and the prescription of PUE SMEDDS was optimized by particle size, self-microemulsifying time, and drug loading; The physicochemical characteristics and stability were also determined. Results: The optimum SMEDDS composed of Miglyol 812N (19.0%), oleic acid (19.0%), polysorbate 80 (19.0%), EL-35 (19.0%), 1, 2-propanediol (19.0%), and puerarin (5.0%). The particle size was (17.28 ± 0.24) nm, and self- microemulsifying time was less than 120 s; The appearance, content of PUE, particle size, and self-microemulsifying time had no obvious changes under room temperature storage for six months. Conclusion: The acquired PUE SMEDDS is stable with small particle size, which meets the needs of good SMEDDS formulation.
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Objective: To study in vivo pharmacokinetic characteristic of supersaturable self microemulsion drug delivery system (S-SMEDDS) of silybin in rats. Methods: According to the random design, 12 male rats were divided into one control group and one experimental group by six each. SMEDDS of silybin was given to the control group and S-SMEDDS of silybin to the experimental group by both ig administration at dosage of 533 mg/kg, respectively. Blood sampling was conducted by means of an automated blood sampling device (Accusampler) at different time points. After ig administration of S-SMEDDS of silybin to rats, the silybin concentrations in plasma were determined by HPLC and the pharmacokinetic parameters were calculated by non-compartment model of statistical moment analysis. Results: The main pharmacokinetic parameters of the control and experimental groups were as follows: tmax is (1.00 ± 0.40) and (1.50 ± 0.84) h, Cmax is (5.68 ± 0.52) and (16.10 ± 4.06) μg/mL, AUC0→1 is (27.30 ± 3.29) and (82.64 ± 12.36) μg·h·mL-1, respectively. Conclusion: This assessment demonstrates that the oral absorption bioavailability could be substantially improved via the approach: by S-SMEDDS of silybin.
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Objective To optimize the formulation of self-microemulsifying drug delivery systems containing tanshinone ⅡA(tanshinone ⅡA-SMEDDS) and assess the quality of tanshinone ⅡA-SMEDDS. Methods Pseudoternary phase diagrams were used to choose the oil,emulsifier,co-emulsifier,and their proportion in the formulation on the basis of the ability to form emulsions and regions. Then the self-emulsifying time,droplet and morphology,size distribution,?-potential,stability,and other aspects of the quality were evaluated. Results The formulation of tanshinone ⅡA-SMEDDS was as follows:ethyl oleate-Labrasol-PEG 400=10%:45%:45%,drug loading ratio was 2.25 mg/g. The self-microemulsifying time of tanshinone ⅡA-SMEDDS in 0.1 mol/L hydrochloric acid solution was less than 1 min,the emulsion drops were spherical shape with average particle size of (84.9?2.1) nm and the average ?-potential (-24.0?1.15) mV (n=3). So tanshinone ⅡA-SMEDDS was stable. Conclusion In this paper,the tanshinone ⅡA-SMEDDS has a good self-emulsifying performance. It is expected to further stabilize the preparation of tanshinone ⅡA self-microemulsifying agents.
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Objective To study formulation and characteristics of self-microemulsifying drug delivery system for breviscapine(BRV-SMEDDS).Methods The optimum formulations of BRV-SMEDDS were screened by solubility tests,formula compatibility,and pseudo-ternary phase diagrams.And the physicochemical characters,dissolution in vitro and in situ rat's intestine absorption of BRV-SMEDDS were also observed.Results The optimum formulation of SMEDDS was composed of Maisine 35-1-Cremophor RH40-PEG400-TEA=25∶40∶35∶7.The particle diameter was 88.6 nm.The percent of accumulated dissolution of BRV in SMEDDS in vitro was up to 97.8% at 1h,which was 8.0 times as much as that of BRV powder,and 5.1 times as BRV tablets.In the tests of in situ rat's intestine absorption,the permeability coefficient of BRV-SMEDDS was increased by 3.4 times as much as BRV powder,and 3.3 times as BRV tablets.Conclusion The dissolution and absorption of BRV is improved by formulation of SMEDDS.It could provide reference for the new dosage form of BRV.
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Objective To develop the formulation of self-microemulsifying drug delivery system for hawthorn leaves flavonoids (HAW-SMEDDS). Methods The optimum formulations of oil phase, surfactant, and assistant surfactant for HAW-SMEDDS were screened by solubility test, compatibility test, and pseudo-ternary phase diagrams, with the time of formulating microemulsion, the consequence of visual examination, and particle size as indexes. The dissolution of HAW-SMEDDS was measured, taking the commercial tablet Yixintong Tablet as reference. Results The optimum self-microemulsifying drug delivery system was composed of Labrasol (35%), Transcutol P (10%). The particle diameter was (39.5?5.4) nm, the time of self-microemulsifying was less than 1 min. The percent of accumulated dissolution of hawthorn leaves flavonoids in SMEDDS in distilled water was up to 70% at 10 min, while that in the Yixintong Tablet was less than 50% at 60 min. Conclusion The formulation of HAW-SMEDDS preparation could meet the request of the design. It could provide the reference for the new dosage form.
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Objective The self-microemulsifying drug delivery system(SMEDDS) with tanshinone ⅡA was prepared in order to develop its new dosage forms.Methods Pseudo ternary phase diagrams were used to evaluate the self-microemulsification existence area under emulsifier,coemulsifer,and oil phase.The HPLC analysis in vitro was set up.Solubility in various vehicles was determined.The self-microemulsification efficiency was assessed,such as stability,particle size,and Zeta potential.Results The solubi-lity of tanshinone ⅡA in SMEDDS was about 2.5 mg/g,droplet size was within 20 nm,and the absolute value of Zeta potential was over 60 mV.The stability of SMEDDS with tanshinone ⅡA was better in centrifugal condition with high temperature but not good enough to the light.Conclusion The SMEDDS can make tanshinone ⅡA solublized in water,and is an optimum vehicle in new dosage forms of tanshinone ⅡA.
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Objective To develop self-microemulsifying drug delivery system(SMEDDS) of Acanthopanax senticosus total saponins(ASTS) and the determination method.Methods The equilibrium solubility of ASTS in different compositions of oils,emulsifier and assistant emulsifier was investigated.The self-microemulsion formula was optimized by constructing the pseudo-ternary phase diagrams of blank SMEDDS and the studying the self-microemulsifying efficiency and the stability of drug-loaded SMEDDS.Taking isofraxidin,an effective component of A.senticosus,as the content determination index,the content was determined by HPLC.Results The optimal self-microemulsion formula was composed of Caf,propanediol,and ethyl linolenate.The ratio of them was 16∶4∶5.The average particle size was 40 nm.The average content of isofraxidin was 92.6 ?g/mL.Conclusion The acquired microemulsion with small particle size is stable.The content determination method of taking isofraxidin as the quality control index is accurate and reliable.