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The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design.
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RESUMEN El ibuprofeno es uno de los fármacos más utilizados e indicado para terapias antiinflamatorias, dolor, entre otras patologías. Sin embargo, este fármaco presenta una baja y errática biodisponibilidad, debido a la pobre solubilidad acuosa intrínseca del mismo, por lo cual esta categorizado como clase II en el sistema de clasificación biofarmacéutica. El objetivo de este trabajo fue desarrollar, diseñar y evaluar un sistema de entrega de fármaco autoemulsificable (SEDDS) para mejorar la solubilidad y velocidad de disolución de ibuprofeno. Aceites, cosolventes, tensioactivos y portadores porosos fueron evaluados por su capacidad de mejorar la solubilidad del ibuprofeno, habilidad de autoemulsificación, robustez en diferentes pH y capacidad de adsorción. El aceite de coco, Tween 80 y propilenglicol lograron un aumento significativo de la solubilidad acuosa del ibuprofeno en un tiempo de autoemulsificación menor a 2 minutos. Neusilin US2® fue seleccionado como portador, dando como resultado un pequeño granulo de excelente fluidez, que permitió obtener comprimidos que cumplieron satisfactoriamente las pruebas de control de acuerdo con las especificaciones establecidas. Los SEDDS líquidos y sólidos son una alternativa de formulación ventajosa y prometedora para mejorar la solubilidad de fármacos pobremente solubles de acuerdo al sistema de clasificación biofarmacéutica, a través de sus propiedades de solubilización.
SUMMARY Ibuprofen is one of the most used drugs and it's indicated for anti-inflammatory therapies and pain, among other pathologies. However, this drug has a low and erratic bioavailability, due to its poor aqueous intrinsic solubility, which is categorized as class II in the Biopharmaceutical Classification System. The objective of this work was to develop, design and evaluate a self-emulsifying drug delivery system (SEDDS) to improve the solubility and dissolution rate of ibuprofen. Oils, co-solvents, surfactants and carriers were evaluated for their ability to improve the solubility of ibuprofen, self-emulsification ability, robustness at different pH levels and adsorption capacity. Coconut oil, Tween 80 and propylene glycol achieved a significant increase in the aqueous solubility of ibuprofen in a self-emulsification time of less than 2 minutes. Neusilin US2® was selected as carrier, resulting in a small granule of excellent fluidity, which allowed to obtain tablets that satisfactorily fulfilled the control tests according to the established specifications. The liquid and solid SEDDS are an advantageous and promising formulation alternative to improve the solubility of poorly soluble drugs according to the biopharmaceutical classification system, through their solubilization properties.
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Objective: To optimize a self-emulsifying drug delivery system (SEDDS) formulation for psoralen and isopsoralen (PSO and IPSO) isolated from Psoraleae Fructus. Methods: A D-optimal design was used to investigate the influence of oil percentage, surfactant percentage and cosurfactant percentage on several properties of SEDDS including particle size, polydispersity, equilibrium solubility, in situ intestine absorption rate and intestinal permeability. Furthermore, the desirability function approach was applied to obtain the optimal formulation for the system. Results: The oil percentage, surfactant percentage and cosurfactant percentage were optimized to be 53.6%, 35.7% and 10.7%, respectively, which means the model is available. Conclusions: The D-optimal design is valuable to optimize the SEDDS formulation and understand formulation compositions’ functions on SEDDS properties.
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Objective: To optimize the formulation of the self-emulsifying drug delivery system of total saponins of Sanguisorba officinalis and evaluate its characteristics. Methods: The formulation and its proportion of the self-emulsifying drug delivery system of total saponins of S. officinalis were optimized based on the solubility tests, formula compatibility, microemulsion area in the ternary phase diagram and D-optimal mixing experiment design. The dosage of oil phase, surfactant and co-surfactant were investigated by drug loading, particle size, and polydispersity index. The appearance, particle size, polydispersity index, Zeta potential, and in vitro release of preparation were finally evaluated. Results: The ratio of oil phase, surfactant, and co-surfactant was 0.25: 0.45:0.30. The drug loading was 23.93 mg/g, the average particle size was (207.92 ± 2.13) nm and the zeta potential was (38.84 ± 0.18) mV. The release of SEDDS was superior to the bulk drug apparently. Conclusion: The self-emulsifying drug delivery system of total saponins of S. officinalis was established. The technology was feasible and the quality was stable.
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Objective To prepare oxymatrine (OMT) phospholipid complex (PC) self-emulsifying drug delivery system (OMT-PC- SEDDS), and evaluate its quality and release in vitro. Methods The emulsifiers, co-emulsifiers and ratio of emulsifier to co-emulsifier (Km) were selected through the pseudo-ternary phase diagram method, using emulsified area as selection index, investigation of oil phase by solubility was determined to optimize the prescription. The appearance, average particle diameter, self-emulsification time, in vitro release characteristics, and stability of OMT-PC-SEDDS were evaluated. Results The optimum prescription of OMT-PC-SEDDS was emulsifier Kolliphor HS 15 and co-emulsifier ethanol mass ratio of 2:1, the mass ratio of medium chain triglyceride (MCT) to the total mass of Kolliphor HS 15 and ethanol was 2:8. The appearance of OMTPC-SEDDS was translucent clear liquid with good stability. OMT-PC-SEDDS diluted with water to form milky and pale blue emulsion. The emulsion was observed to be spherical by transmission electron microscopy and distributed evenly with average particle size of (355.00 ± 19.50) nm and Zeta potential of (-12.80 ± 0.66) mV. In pH 6.8 phosphate buffer, the in vitro release, the in vitro release of OMT, OMT-PC, and OMT-PC-SEDDS respectively reached 93.84%, 88.39%, and 88.61% at 4 h. Conclusion The prepared OMT-PC-SEDDS by optimum formulation of this study has a good particle size and good stability.
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Objective: To explore the intestinal absorption characteristics of tanshinone components self emulsifying drug delivery system (SEDDS). Methods: In situ single-pass perfusion method was used to investigate the absorption characteristics of cryptonshinone, tanshinone I, and tanshinone IIA in rats. The absorption parameters (Ka, Papp) of cryptotanshinone, tanshinone I, and tanshinone IIA were used as indicators to study their optimum absorption site among duodenum, jejunum, ileum, and colon. The effects of verapamil hydrochloride (P-glycoprotein inhibitor, P-gp inhibitor), probenecid (multi-drug resistant protein MRP2), and 2, 4-dinitrophenol (energy inhibitor) on the absorption of cryptonshinone, tanshinone I, and tanshinone IIA were also studied, as well as the effects of their different concentration. Results: Cryptonshinone, tanshinone I, and tanshinone IIA could be absorbed at all four intestinal segments, and the optimum absorption site was the upper segment of small intestine. The absorption of cryptotanshinone and tanshinone I were concentration-dependent at experimental concentration levels (1.05-4.19 mg/L and 1.22-5.56 mg/L), while tanshinone IIA was not affected obviously by its concentrations (2.43-11.12 mg/L). Verapamil hydrochloride had no significant influence on the absorption of cryptotanshinone or tanshinone I, while the absorption of tanshinone IIA was improved remarkably. Probenecid increased the absorption of cryptonshinone and tanshinone I apparently, while had no obvious effect on that of tanshinone IIA. 2,4-Dinitrophenol could decrease the absorption of cryptonshinone, tanshinone I, and tanshinone IIA apparently. Conclusion: Cryptonshinone and tanshinone I are supposed to be the substrate of MRP2 instead of P-gp. Tanshinone IIA is supposed to be the substrate of P-gp, instead of MRP2. The energy participated in the absorption of cryptonshinone, tanshinone I, and tanshinone IIA. Active absorption maybe also involved in the absorption of cryptonshinone, tanshinone I, and tanshinone IIA.
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Objective To optimize the formulation of essential oil of Alpiniae zerumbet self-emulsifying drug delivery system (EOFAZ-SEDDS) and evaluate its pharmacological properties. Methods The emulsifiers, co-emulsifiers and ratio of emulsifier to co-emulsifier (Km) were selected through the pseudo-ternary phase diagram method, using emulsified area as selection index, and determine the optimal prescription. The appearance, particle diameter, self-emulsification efficiency, and stability were evaluated. Results The optimal SEDDS was composed of volatile oil (60%), Kolliphor HS 15 (20%), and anhydrous ethanol (20%). The appearance of EOFAZ-SEDDS was translucent diluted-yellow solution. EOFAZ-SEDDS diluted with water to form milky and pale blue emulsion with a particle size of (171.67 ± 7.64) nm and Zeta potential of (-11.51 ± 1.22) mV. The emulsion was observed to be spherical by transmission electron microscopy and distributed evenly. The self-emulsifying time of EOFAZ-SEDDS in hydrochloric acid (0.1 mol/L) was short. With the increase of the volume of medium, the self-emulsifying time was prolonged. The precipitation and delamination of EOFAZ-SEDDS were not observed within 24 h after self-emulsifying, and no stratification was observed after 30 min centrifugation. Conclusion The EOFAZ-SEDDS prepared by optimum formulationthe of this study has a good particle size and good stability.
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Objective:To prepare total ginkgo flavonoid self-emulsifying drug delivery system(TGF-SMDDS)and estimate its char-acteristics in vitro. Methods:The formula of TGF-SMDDS was optimized based on the solubility tests,formula compatibility and microe-mulsion area in the pseudo ternary phase diagram. The appearance,morphology,particle size,zeta potential and in vitro dissolution of TGF-SMDDS were investigated. Results:The formula was composed of oleoyl macrogolglycerides as the oil phase,Tween-80 as the sur-factant and XCF as the co-surfactant. The ratio of oil phase,surfactant and co-surfactant was 10 ∶ 6 ∶ 4. The drug loading was 10. 0 mg· g -1 . After mixed with water,TGF-SMDDS was formed a clear and transparent microemulsion with homogeneous small spheres as seen un-der a transmission electron microscope. The particle size and zeta potential of TGF-SMDDS was(87. 4 ±26. 7)nm and( -13. 1 ±1. 5) mV,respectively. The accumulative dissolution of TGF-SMDDS in pH1. 2 hydrochloric acid solution was(96. 1 ±4. 8)% in 45 min. Con-clusion:The TGF-SMDDS can significantly enhance the dissolution of TGF in vitro,which may be a potential effective preparation for TGF.
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Objective:To develop an HPLC method for determining the total ginkgo flavonoid in self-emulsifying drug delivery sys-tem. Methods:Effective chromatographic separation was achieved using a phenomenex C18 column (250 mm × 4. 6 mm, 5 μm) with a mobile phase composed of methanol and water (0.4% phosphoric acid) with the ratio of 50 ∶50 (v/v). The mobile phase was pumped using an isocratic HPLC system at a flow rate of 1. 0 ml·min-1 , the detection wavelength was 360 nm and the column temper-ature was 30 ℃. Results:The three components in the total ginkgo flavonoid were well separated by the proposed method. The linear relationship between the peak area and the concentration was promising within the range of 2. 0-40. 0 μg·ml-1 for quercetin, 3. 0-60. 0 μg·ml-1 for kaempferide and 2. 0-40. 0 μg·ml-1 for isorhamnetin. The mean recovery of quercetin, kaempferide and isorham-netin was 98. 4%, 99. 7% and 100. 5% with RSD of 0. 92%,0. 62% and 1. 24% (n=9), respectively. Conclusion:The method is specific and stable in the determination of total ginkgo flavonoid in self-emulsifying drug delivery system.
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About 40% of the drug candidates have poor water solubility due to their low bioavailability. Self-emulsifying drug delivery systems (SEDDs) are mixtures of oils, surfactants and co-surfactants, which efficiently improve dissolution and bioavalabilty of sparingly soluble drugs by rapid self-emulsification. SEDDs belongs to lipid formulations, and size ranges from 100nm (SEDDs) to less than 50nm (SMEDDs). Lipophilic drugs can be dissolved in such systems, enabling them to be administered as a unit dosage form for per-oral administration. When such system is released in the lumen of the gastrointestinal tract, it disperses to form a micro/nano emulsion with the aid of GI fluid. These leads to solubilisation of drug that can subsequently be absorbed by lymphatic pathways, by passing the hepatic first pass effect.
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Objective To design and optimize the self-emulsifying drug delivery system ( SEDDS) of dihydromyricetin, and evaluate its quality in vitro. Methods The solubility of dihydromyricetin was measured in different oil phases,emulsifier and co-emulsifier solution. The best prescription was selected by comprehensively evaluating emulsification speed,particle size and drug loading via using the ternary phase diagram and orthogonal design test. Results The optimized formula of the self-emulsifying drug delivery system was oleic acidTween-80span-80N-butanol =1514714. Conclusion The optimized dihydromyricetin self-emulsifying drug delivery system significantly improves the solubility of dihydromyricetin, increases the physical and chemical properties of the formulation,and raises the dissolution of dihydromyricetin in artificial gastric fluid.
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Objective: To explore the feasibility of self-emulsifying drug delivery system (SEDDS) for multicomponents simuitaneous solubilization. Methods: The curcumin (Cur) components were used as model drug, D-optimal mixture design was used to optimize SEDDS prescription, and the contents of bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC), and Cur, SEDDS particle size, and emulsifying time were made as indicators to select and evaluate SEDDS, so as to explore the feasibility of SEDDS for the multicomponents simuitaneous solubilization. Results: The optimal SEDDS prescription was Obleique CC497-Tween 20-Transcutol P (0.21:0.50:0.29), SEDDS particle size was (248.8 ± 3.4) nm, and emulsifying time was (70 ± 1) s. At 37°C, the maximum loading capacities of SEDDS for BDMC, DMC, and Cur were 2.998, 12.220, and 52.561 mg/g, respectively, and the solubilities in water were 0.107, 0.661, and 1.648 mg/mL. Conclusion: SEDDS can realize the solubilization of multicomponent simultaneously.
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Aim of the present work was to develop and evaluate a solid self-emulsifying drug delivery system (SEDDS) for oral poorly water-soluble drug lornoxicam. The liquid (SEDDS) consisted of capmul MCM as oil phase, tween 20 as surfactant and PEG 400 as co-surfactant. Oil, surfactant and co-surfactant were selected on the basis of solubilisation capacity of drug and emulsification ability of surfactant and co-surfactants. The formulations were optimized by constructing the pseudo-ternary phase diagram. The liquid formulation was solidified by laboratory scale spray dryer, using Aerosil 200 as solid carrier. The solid SEDDS shows greater drug release thus, solid SEDDS improves the oral bioavailability and may provide the useful solid dosage form for oral poorly water soluble drugs.
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In this study, a solubility enhancing technique, Self-emulsifying drug delivery system (SEDDS), was considered to be developed for Ibuprofen, a poorly soluble drug. Capmul PG 8 was used as a co-solvent. As surfactant, hydrophilic surfactant Cremophor EL was considered. A fixed amount of Ibuprofen was added with fixed amount of excipients. Capmul PG8 showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Cremophor EL also showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Ibuprofen is a poorly soluble drug which was used as experimental drug and pH 7.2 phosphate buffer was used as dissolution medium. The amount of drug was measured form the absorbance of UV spectrophotometer at 221 nm. A 3-level factorial design was carried out to optimize the formulation using design expert software trial version 8.0.3.1. Capmul PG8 and Cremophor EL were used as independent variables where percent drug release at 5, 15 and 45 minutes. The optimized formula contains 24.10 mg Capmul PG8 and 71.02 mg Cremophor EL which releases 27.78%, 44.6% and 74.24% ibuprofen at the mentioned time interval. The present study shows that the Capmul PG8 and Cremophor EL have effect the release profile of capsule Ibuprofen. It is found that it is possible to increase the release of Ibuprofen by using Capmul PG8 and Cremophor EL.
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In this study, a solubility enhancing technique, Self-emulsifying drug delivery system (SEDDS), was considered to be developed for Ibuprofen, a poorly soluble drug. Capmul PG 8 was used as a co-solvent. As surfactant, hydrophilic surfactant Cremophor EL was considered. A fixed amount of Ibuprofen was added with fixed amount of excipients. Capmul PG8 showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Cremophor EL also showed a good solubilizing capacity which dissolved 300 mg/ml of Ibuprofen. Ibuprofen is a poorly soluble drug which was used as experimental drug and pH 7.2 phosphate buffer was used as dissolution medium. The amount of drug was measured form the absorbance of UV spectrophotometer at 221 nm. A 3-level factorial design was carried out to optimize the formulation using design expert software trial version 8.0.3.1. Capmul PG8 and Cremophor EL were used as independent variables where percent drug release at 5, 15 and 45 minutes. The optimized formula contains 24.10 mg Capmul PG8 and 71.02 mg Cremophor EL which releases 27.78%, 44.6% and 74.24% ibuprofen at the mentioned time interval. The present study shows that the Capmul PG8 and Cremophor EL have effect the release profile of capsule Ibuprofen. It is found that it is possible to increase the release of Ibuprofen by using Capmul PG8 and Cremophor EL
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Objective To establish the HPLC method for determination of self-emulsifying drug delivery system in Curcumin. Method Kromasil ODS C18 (150 mm?4.6 mm, 5 ?m) was used. The mobile phase was methanol-water (0.5% acetic acid glacial):(70∶30). The detection wavelength was set at 428 nm. The flow rate was 0.9 mL/min, with temperature of 32 ℃. Result The linear range of Curcumin was 4.5～112.5 ?g/mL, r=0.999 9. Conclusion This method was simple and accurate. It can be used for the determination of self-emulsifying drug delivery system in Curcumin.
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AIM: To evaluate the correlation between in vitro release and in vivo absorption of aniracetam in conventional tablets and self-emulsifying drug delivery system (SEDDS), to investigate pharmacokinetics of aniracetam self-emulsifying drug delivery system and conventional tablets of aniracetam after oral administration to rats. METHODS: Dissolution behavior of these formulations was evaluated in vitro to assess the properties of dosage forms. And a new RP-HPLC method was developed for the in vivo quantitative determination of 4-p-anisamidobutyric acid (PABA), the active metabolite of aniracetam. To approach the in vitro-in vivo correlation, fraction absorbed in vivo (f) was calculated by Wagner-Nelson method, and then compared with in vitro released drug percentages (Q%). RESULTS: Aniracetam was released rapidly from SEDDS with 80%±4% of accumulation dissolution rate compared to that from conventional tablets at 15 min. The recovery of active metabolite of aniracetam was about 90%, and the intra-days and inter-day precision were within 4% and 6%, respectively. The AUC0-∞ value of aniracetam SEDDS was (11 168±2 395) ng·mL-1·h, which was about 3 folds greater than conventional tablets. The parameter MRT0-∞ of aniracetam SEDDS and conventional tablets were (2.7±0.6) h and (1.7±0.6) h, respectively, and the difference was statistically significant(P<0.05). The linear equation of in vitro-in vivo correlation for conventional tablets was obtained by regression as well. Whereas nonlinear correlation was obtained for aniracetam SEDDS, which fitted the quadric model very well and the correlation coefficient was 0.972. CONCLUSION: Aniracetam can be released faster from SEDDS than that from conventional tablets, and SEDDS improved the bioavailability of aniracetam significantly. The SEDDS composed by oil and compound surfactants which could enhance the absorption showed the expressing rate of dissolution, and those formed the o/w microemulsion with gastrointestinal liquid could absorb through lymphatic transport route.
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OBJECTIVE: To prepare solid supersaturatable self-emulsifying drug delivery system of vinpocetine(VIN-S-sSEDDS) and to study its characteristics in vitro and in vivo.METHODS: VIN-S-sSEDDS was prepared by spray drying using hydroxypropyl methyl cellulose(HPMC) as supersaturation promoter and dextran-40 as solid carrier.VIN-S-sSEDDS was compared with conventional self-emulsifying drug delivery system containing vinpocetine(VIN-SEDDS) in respects of particle size,in vitro dissolution and bioavailability in rats(ig.).RESULTS: The particle size of VIN-S-sSEDDS(58.78 nm) was smaller than that of VIN-SEDDS(65.12 nm).The accumulative dissolution of VIN-S-sSEDDS within 2 h(88.7%) was higher than that of VIN-SEDDS(58.2%).The bioavailability of VIN-S-sSEDDS in rats(2.30) was higher than that of VIN-SEDDS(1.63).CONCLUSION: Prepared VIN-S-sSEDDS could apparently improve the dissolution and bioavailability of VIN,and it is superior to conventional self-emulsifying preparation.
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Objective To prepare the supersaturation self-emulsifying drug delivery system(S-SEDDS) containing silymarin and to evaluate its basic properties.Methods With the time of self-emulsifying,the consequence of color visual examination and particle size as parameters,the optimum formulations of silymarin SSEDDS were screened by solubility test,compatibility tests and pseudo ternary phase diagrams.The silymarin concentration was determined by HPLC.The in vitro dissolution characteristics of silymarin S-SEDDS were investigated with silymarin SEDDS as control.Results The optimum silymarin S-SEDDS was composed of medium chain triglycerides(MCT) 40%,Cremophor RH40(ethoxylated hydrogenatedcastor oil) 48%,Labrasol 12%.The time of self-emulsifying was less than 3 min,the average particle diameter was 49.6 nm,the adding amount of hydroxypropyl methylcellulose(HPMC) was 50 mg/g,and the average content of silymarin was 39.3 mg/g.The in vitro dissolution test of silymarin S-SEDDS showed that the presence of a small amount of cellulosic polymer effectively sustained a metastable supersaturated state by retarding precipitation kinetics.Conclusion The designed formulation of silymarin S-SEDDS is reasonable and provides a strong foundation for further development of new preparations.
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Objective To screen the formulation for tanshinone self-emulsifying drug delivery system (SEDDS) and evaluate its stability.Methods The optimal tanshinone SEDDS formulation was established through solubility experiment,emulsion examination,fully emulsified time,droplet size determination,and pseudo-ternary diagram drawing.The content and stability were evaluated by HPLC assay under the condition of illumination,high and low temperature.Results The oil phase,surfactant and co-surfactant in the optimal tanshinone SEDDS formulation were ethyl oleate,TX10,Tween 80,and isopropyl alcohol (60∶84∶21∶35).Conclusion The acquired formulation of tanshinone SEDDS is stable in the dark and room temperature.