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, 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.

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.

Improved Oral Bioavailability and Hypolipidemic Effect of Syringic Acid via a Self-microemulsifying Drug Delivery System.

This study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) to enhance the solubility, oral bioavailability, and hypolipidemic effects of syringic acid (SA), a bioactive and poorly-soluble polyphenol. Based on the response surface methodology-central composite design (RSM-CCD), an optimum formulation of SA-SMEDDS, consisting of ethyl oleate (oil, 12.30%), Cremophor-EL (surfactant, 66.25%), 1,2-propanediol (cosurfactant, 21.44%), and drug loading (50 mg/g), was obtained. The droplets of SA-SMEDDS were nanosized (16.38 ± 0.12 nm), spherically shaped, and homogeneously distributed (PDI = 0.058 ± 0.013) nanoparticles with high encapsulation efficiency (98.04 ± 1.39%) and stability. In vitro release study demonstrated a prolonged and controlled release of SA from SMEDDS. In vitro cell studies signified that SA-SMEDDS droplets substantially promoted cellular internalization. In comparison with the SA suspension, SA-SMEDDS showed significant prolonged Tmax, t1/2, and MRT after oral administration. Also, SA-SMEDDS exhibited a delayed in vivo elimination, increased bioavailability (2.1-fold), and enhanced liver accumulation. Furthermore, SA-SMEDDS demonstrated significant improvement in alleviating serum lipid profiles and hepatic steatosis in high-fat diet-induced hyperlipidemia in mice. Collectively, SMEDDS demonstrated potential as a nanosystem for the oral delivery of SA with enhanced bioavailability and hypolipidemic effects.

Novel Drug Delivery Approach via Self-Microemulsifying Drug Delivery System for Enhancing Oral Bioavailability of Asenapine Maleate: Optimization, Characterization, Cell Uptake, and In Vivo Pharmacokinetic Studies.

Asenapine maleate (AM)-loaded self-microemulsifying drug delivery system (AM-SMEDDS) was prepared to increase its oral bioavailability. AM-SMEDDS was developed using Capryol 90, Cremophor EL, and Transcutol HP as oil, surfactant, and cosurfactant, respectively, by spontaneous emulsification method. Pseudoternary diagram showed maximum region at 3:1 ratio of Cremophor EL/Transcutol HP. The AM-SMEDDS showed globule size and zeta potential of 21.1 ± 1.2 nm and - 19.3 ± 1.8 mV, respectively. Globules were found to be of spherical shape and uniformly distributed by transmission electron microscopy. In vitro drug release study showed 99.2 ± 3.3% of drug release at the end of 8 h in phosphate buffer pH 6.8. Ex vivo drug release study showed only 15% of drug diffusion through stomach and ~ 85% drug was diffused through intestinal membrane. Confocal and flow cytometry study showed that cellular uptake of coumarin-6 loaded SMEDDS was significantly enhanced by Caco-2 cells as that of coumarin-6 solution. The relative bioavailability of AM-SMEDDS was found to be 23.53 times greater than AM suspension. Intestinal lymphatic transport study using Cycloheximide (CHX) showed that the AUCtotal of AM-SMEDDS reduced about 35.67% compared with that without the treatment of CHX indicating involvement of lymphatic system in intestinal absorption of AM-loaded SMEDDS. These findings demonstrated the potential of SMEDDS for oral bioavailability improvement of AM via lymphatic uptake. Graphical Abstract.

Self-microemulsifying drug-delivery system for improved oral bioavailability of probucol: preparation and evaluation.

The objective of our investigation was to design a self-microemulsifying drug-delivery system (SMEDDS) to improve the bioavailability of probucol. SMEDDS was composed of probucol, olive oil, Lauroglycol FCC, Cremophor EL, Tween-80, and PEG-400. Droplet sizes were determined. In vitro release was investigated. Pharmacokinetics and bioavailability of probucol suspension, oil solution, and SMEDDS were evaluated and compared in rats. Plasma drug concentration was determined by high-performance liquid chromatography. After administration of probucol suspension, plasma drug concentration was very low. Relative bioavailability of SMEDDS was dramatically enhanced in an average of 2.15- and 10.22-fold that of oil solution and suspension, respectively. It was concluded that bioavailability of probucol was enhanced greatly by SMEDDS. Improved solubility and lymphatic transport may contribute to the enhancement of bioavailability.

Preparation and characterization of self-microemulsifying oral fast dissolving films of total ginkgo flavonoid / 中草药

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.

Preparation and evaluation of puerarin self-microemulsifying drug delivery system / 中草药

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.

Self-microemulsifying drug delivery system of Acanthopanax senticosus total saponin / 中草药

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.

Preparation and evaluation of self-microemulsifying drug delivery systems containing tanshinone Ⅱ_A / 中草药

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.

Formulation and characteristics of self-microemulsifying drug delivery system for breviscapine / 中草药

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.

Self-microemulsifying drug delivery system of flavonoids in hawthorn leaves / 中草药

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.

Preparation and evaluation of self-microemulsifying drug delivery systems with tanshinone Ⅱ_A / 中草药

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.