Nanocrystals self-stabilized Pickering emulsion loaded with active components of Tongmai prescription: preparation, characterization and evaluation by Caco-2 cell model / 药学学报

It is of great significance to apply the nanocrystals self-stabilized Pickering emulsion (NSSPE) to traditional Chinese medicine (TCM) compounds, and to study the effect of NSSPE on the oral absorption of various components with different solubility and permeability. In the study, NSSPE of Tongmai prescription was prepared by the high pressure homogenization method with nanocrystals of main active components (puerarin, ferulic acid, salvianolic acid B and tanshinone IIA) of Tongmai prescription as solid particle stabilizers and a mixture of Ligusticum chuanxiong essential oil and Labrafil M 1944 CS as oil phase. The NSSPE had better physical stability than nanocrystals suspension and blank emulsion. The adsorption of nanocrystals on the surface of oil droplets was confirmed by scanning electron microscopy and fluorescence microscopy. The surface adsorption rates of puerarin, ferulic acid, salvianolic acid B and tanshinone ⅡA in NSSPE were 15.40% ± 3.19%, 15.39% ± 5.07%, 10.97% ± 3.70% and 31.51% ± 1.60%, respectively. When solid active components were prepared into nanocrystals suspension, the cellular uptake and transport across Caco-2 cells were increased significantly for puerarin and tanshinone IIA. The uptake rates of ferulic acid, ligustilide and tanshinone IIA in NSSPE were further increased compared with the physical mixture of nanocrystals suspension and oil, and the transports of ligustilide and tanshinone IIA were also significantly improved. The main absorption mechanisms of NSSPE were passive diffusion and caveolin-mediated endocytosis, which were determined mainly by the microstructure of NSSPE. In conclusion, NSSPE could be applied to complicated TCM. The "micro" and "nano" synergistic microstructure with drug nanocrystals adsorbed on the surface of micron-sized oil droplets could not only improve the physical stability of NSSPE, but also promote the absorption of various components in NSSPE, which made NSSPE a promising oral drug delivery system for TCM.

Preparation and in vitro release of quercetin nanocrystals self-stabilized Pickering emulsion / 中国中药杂志

A new quercetin nanocrystals self-stabilized Pickering emulsion(QT-NSSPE) was prepared by high-pressure homogenization combined with probe ultrasonic method. The influences of oil fraction, quercetin(QT) concentration, and pH of water phase on the formation of QT-NSSPE were investigated. On this basis, the QT-NSSPE prepared under optimal conditions was evaluated in terms of microstructure, stability, and in vitro release and the droplet size and drug loading were 15.82 μm and 4.87 mg·mL~(-1), respectively. The shell structure formed by quercetin nanocrystals(QT-NC) on the emulsion droplet surface was observed under a scanning electron microscope(SEM). X-ray diffraction(XRD) showed that the crystallinity of adsorbed QT-NC decreased significantly as compared with the raw QT. There were not significant changes of QT-NSSPE properties after 30 days of storage at room temperature. The in vitro release experiment confirmed that QT-NSSPE has a higher accumulative release rate than the raw QT. All these results indicated that QT-NSSPE has a great stability and a satisfactory in vitro release behavior, which is a promising new oral delivery system for QT.

Study on oral absorption mechanisms of puerarin in nanocrystals self-stabilized pickering emulsion / 中国中药杂志

Nanocrystals self-stabilized Pickering emulsion(NSSPE) is a new kind of emulsion where only nanocrystals of poorly soluble drugs are used as stabilizers. Our previous study showed that NSSPE with Ligusticum chuanxiong oil as the main oil phase can significantly promote oral absorption of puerarin. The present study aimed to explore its absorption mechanism in oral administration. The in vitro dissolution test was carried out to study the effect of NSSPE on release of puerarin. The effects and mechanism of NSSPE on uptake and transport of puerarin across Caco-2 cell were investigated. The results showed that the drug release rate of NSSPE was similar to that of nanocrystals, with their cumulative dissolution of puerarin not affected by pH of releasing mediums, both significantly higher than that of crude material. The uptake of puerarin in NSSPE was concentration-dependent and significantly higher than that of solution or surfactant stabilized emulsion. Genistein and indomethacin, inhibitors of lipid rafts/caveolin, could significantly reduce the uptake of puerarin in NSSPE. Compared with solution, NSSPE and surfactants stabilized emulsion obviously increased transport rate K_a and apparent permeability coefficient P_(app) of puerarin in AP → BL direction, but there was no significant difference in BL → AP direction. It could be inferred that there were both passive and active transport mechanisms, as well as lipid raft/caveolin mediated endocytosis for absorption of NSSPE. The promoted oral absorption of puerarin in NSSPE was mainly related to the existing nanocrystal form which could promote dissolution, puerarin as well as Ligusticum chuanxiong oil which could promote drug transmembrane transport and inhibit drug efflux. It is the unique structure and composition of the compound NSSPE that promoted the oral absorption of puerarin.

Pickering emulsion technology and its application progress in volatile oil of Chinese materia medica / 中草药

Pickering emulsion, a kind of emulsion stabilized only by solid particles, has become a new research hotspot of chemistry, material science and medicine industry, because it can be used to prepare the emulsions with superior stability, low toxicity and biocompatibility, which are useful to improve the stability and bioavailability of Chinese materia medica (CMM) volatile oils. This review presented recent systematic studies, characteristics of Pickering emulsion and its applications in CMM volatile oils in recent years, in order to provide basis for the application of Pickering emulsification technology in CMM volatile oils.

Research progress of Pickering emulsion drug delivery systems / 药学学报

Pickering emulsion is a new type of emulsion which is stabilized by the adsorption of solid particles on the interface of emulsion droplets. In recent years, its applications in pharmacy have attracted more and more attention because of its higher resistance to coalescence and better safety than traditional surfactant emulsions. The Pickering emulsion was first used for topical administration to reduce skin irritation of surfactants and promote transdermal absorption of drugs. Recently, new oral and injectable Pickering emulsions have also been reported, which can promote oral absorption of insoluble drugs, improve stability of drugs, control drug release, targeted-delivery drugs, and serve as the carrier for novel immunological adjuvants. All these studies show Pickering emulsion a promising drug delivery system. However, its development in pharmacy is still in its infancy. There are many factors influencing the preparation of Pickering emulsions. But there is no systematic analysis of these factors up to now. In this review, we gave an overview of Pickering emulsions from their application in pharmaceutical field, preparation and evaluation, focusing on the effects of solid particles, oil phase, preparation technology and interaction of various factors on the fabrication of Pickering emulsions. The challenges and future directions of this exciting and rapidly expanding research area were further commented on, in order to provide reference for the in-depth study of Pickering emulsion drug delivery systems.

Three-dimensional structure of beads self-assembled by cyclodextrin using synchrotron radiation X-ray microcomputed tomography / 药学学报

Beads, a novel drug delivery system self-assembled by cyclodextrins (CDs) and oil, has potential applications in the solidification of oil drugs and improving the bioavailability of lipid-soluble drugs. However, very few researches were dedicated to the mechanism of beads formation. In this study, three-dimensional structures of beads were visualized and investigated using synchrotron radiation X-ray microcomputed tomography (SR-μCT). The structural changes of beads attributed by drying process were analyzed and confirmed via visualization results of SR-μCT. Productively, it was proposed that Pickering emulsion droplets obtained during beads formation process were spatially localized orderly. Moreover, the effects of loading lipid soluble drug, namely, vitamin K1, on the structural changes of beads were also analyzed. It is well known that the surface tension of oil phase could be changed by the addition of lipid soluble constituents. It was reasonable that the three-dimensional structure of beads might be altered during the drug loading of vitamin K1 into the beads. However, although the morphologies of beads were changed to some extent, the ordered Pickering emulsion droplets during the process of beads formation was successfully illustrated based on the SR-μCT results. Conclusively, according to the three-dimensional structural analysis of the beads, this study revealed the organized architecture for Pickering emulsion droplet assembly and beads formation in cyclodextrin semi-inclusion complex, which significantly complements the formation mechanism of beads, and provides a structural basis for the further study of beads.

Intestinal absorption of puerarin nanocrystalline self-stabilizing pickering emulsion in rats / 中国中药杂志

To study the intestinal absorption characteristics of drug's nanocrystalline self-stabilizing Pickering emulsion (NSSPE) in situ in rats. Rat single-pass intestinal perfusion model was established, and high performance liquid chromatography (HPLC) was used to detect the concentration of puerarin in rat intestinal perfusion solution, assay the absorption rate constant (Ka) and the intestinal apparent permeability coefficient (Papp) of NSSPE in duodenum, jejunum, ileum, and colon, which were compared with those of raw material, nanocrystal and normal emulsion, respectively. For NSSPE, the Ka and Papp values were in the following order: duodenum>jejunum>ileum (<0.05)>colon (<0.01). However, there was no obvious difference between jejunum and ileum. As compared with raw material, nanocrystal and normal emulsion, the Ka and Papp values of NSSPE in duodenum were significantly higher than those of other three preparations (<0.05); and the Ka and Papp values of NSSPE in jejunum and colon were significantly higher than those of raw material, nanocrystal and normal emulsion (<0.01); and the Ka and Papp of NSSPE in ileum were also higher than those of raw material and normal emulsion (<0.05), but had no obvious difference with nanocrystal. The results showed that NSSPE could significantly improve the absorption of puerarin in the intestine of rats.

Stability optimization of puerarin nanocrystalline self-stabilizied Pickering emulsion by response surface methodology / 中国中药杂志

A new Pickering emulsion, puerarin nanocrystalline self-stabilized Pickering emulsion (Pu-NSSPE) was developed. Box-Behnken design was used for optimizing the preparation formulation of Pu-NSSPE to improve its stability, and the effects of concentration of puerarin, volume ratio of water to oil, and pH value of water phase on the stratification index of emulsion, droplet size and drug concentration in emulsion were investigated. Results showed that the optimized Pu-NSSPE could be prepared with the concentration of puerarin of 0.5%, the volume ratio of water to oil of 9∶1 and the pH of water of 9. The size of emulsion droplet of optimized Pu-NSSPE was (12.70±1.17) μm and the drug content was (4.49±0.21) g•L⁻¹. The above indexes had no significant changes within the storage of 6 months at room temperature, indicating good stability. Microstructure characterizations by scanning electron micrograph, confocal laser scanning microscope and fluorescence microscope showed that the optimized Pu-NSSPE had a stable core-shell structure of emulsion droplet formed by the adsorption of puerarin nanocrystallines at the surface of oil droplets, which may be the microstructure reason for the long stability of Pu-NSSPE.

Study on feasibility of puerarin nanocrystalline self-stabilizied Pickering emulsion / 中草药

Objective: To investigate the feasibility of Pickering emulsion stabilized by puerarin nanocrystalline. Methods: The new puerarin nanocrystalline self-stabilized Pickering emulsion (Pu-NSSPE) has been developed using the high pressure homogenization method. The influences of drug addition sequence, property, and construction of oil phase, drug concentration, oil/water ratio, homogenization pressure, and pH value of water phase on the formation and stability of Pu-NSSPE were investigated to optimize the preparation technology of Pu-NSSPE. Results: The stability and structure of optimized Pu-NSSPE were studied. It was difficult to form stable Pu-NSSPE if puerarin was first added into water during preparation. The three-phase contact angle and pH value of water phase were key factors for the formation and stability of Pu-NSSPE. Pickering emulsion could be stabilized by puerarin nanocrystalline only when three-phase contact angle of puerarin approaches 90° and water phase was alkaline. When the drug concentration was between 1.0-5.0 mg/mL, stable Pu-NSSPE could be formed. The higher oil/water ratio was, the more oil creamed from Pu-NSSPE was. Low homogenization pressure (below 80 MPa) could not form stable Pu-NSSPE. The size of emulsion droplet of optimized Pu-NSSPE was (10.66 ± 4.81) μm, and drug content was 4.28 mg/mL. The appearance, morphology, and size of emulsion droplets, Zeta potential and drug content were not changed significantly after storage for six months at room temperature. The adsorption of puerarin at the surface of oil droplets was observed by fluorescence microscope. Conclusion: Nanocrystalline of puerarin could stabilize Pickering emulsions, which will provide a promising drug delivery system for puerarin.

Preparation of poorly soluble drug curcumin nanocrystalline self-stabilized Pickering emulsion / 中草药

Objective: To prepare curcumin nanocrystalline (Cur-NC) self-stabilized Pickering emulsion (Cur-NCSPE). Methods: Cur-NCSPE was prepared by high pressure homogenization. The influences of homogenization pressure on Cur-NC size and drug content on Cur-NCSPE formation were studied. The morphology and structure of emulsion droplets were observed by optical microscope and scanning electron microscope. Furthermore, the stability and in vitro release properties of Cur-NCSPE were evaluated. Results: The particle size of Cur-NC was slightly changed when homogeneous pressure was greater than 100 MPa. With the increase of Cur, the amount of Cur-NC on the surface of oil droplets increases, and the particle size decreases. When the amount of drug added can completely cover the surface of oil droplets, increasing the amount of drug had little effect on the particle size. Cur-NCSPE was more stable than Cur-NC and Cur, and the in vitro release rate of Cur-NCSPE was significantly higher than that of Cur-NC and Cur coarse power. Conclusion: The Cur-NCSPE is prepared successfully, which is expected to provide a novel oral administration technology platform for the poorly soluble drugs.

Preparation and evaluation of silybin nanocrystallines self-stabilizing Pickering emulsion / 药学学报

A new silybin nanocrystallines self-stabilizing Pickering emulsion (SN-SSPE) was developed using the high pressure homogenization method to improve the oral bioavailability of silybin. The influences of homogenization pressure from 50 to 120 MPa and drug content from 100 mg to 1000 mg on the formation of SN-SSPE were studied. The morphology, structure and size of emulsion droplet in SN-SSPE were characterized using scanning electron micrograph and confocal laser scanning microscope. SN-SSPE was evaluated, including stability, in vitro release and in vivo oral bioavailability. The particle size of silybin nanocrystallines (SN-NC) was decreased as the pressure increased until 100 MPa. When the drug content reached 300 mg or above, stable SN-SSPE was formed from sufficient SN-NC covering surfaces of oil droplets completely. The emulsion droplet of SN-SSPE with the size of 27.3±3.1 μm showed a core-shell structure consisting of oil droplet as core and SN-NC as shell. SN-SSPE showed a high stability over 40 days. In vitro release rate of SN-SSPE was faster than silybin coarse powder and similar to silybin nanocrystallines suspension (SN-NCS). After intragastric administration in rats, the peak concentration of SN-SSPE was increased by 2.5-fold and 2.3-fold compared with SN-NCS and silybin coarse powder, respectively. The AUC of SN-SSPE was increased by 1.4-fold and 3.8-fold compared with SN-NCS and silybin coarse powder, respectively. All these results showed that nanocrystallines of the poorly soluble drug could stabilize Pickering emulsions, which provides a promising application to the improvement of the oral bioavailability of poorly soluble drugs.

Formation mechanism of Pickering emulsions induced by self-assembly of medium chain triglycerides and α-cyclodextrin / 药学学报

In this study, the Pickering emulsions were prepared using medium chain triglycerides (MCT) and α-cyclodextrin (α-CD) and the formation mechanism was studied by means of several physicochemical techniques. The MCT/α-CD microparticles, which stabilized the emulsions, were characterized by the measurement of interfacial tension and the contact angle (θow), powder X ray diffraction (XRD), scanning electron microscope (SEM), high performance liquid chromatography (HPLC), differential interference microscope (DIM), Cryo-scanning electron microscopy (Cryo-SEM). The physical stability of emulsions with different α-CD content in the continuous aqueous phase was investigated by determination of the droplet size and sedimentation rate, combined with the observation of droplet morphologies by the inverted phase contrast microscope. As a result, it was observed that the amphiphilic supramolecule of MCT and α-CD were indeed formed. Furthermore, MCT/α-CD microparticles formed by the aggregation of MCT/α-CD supramolecule absorbed at the oil/water interface, and then forming a membrane structure to stabilize emulsion. In addition, the average θow for the MCT/α-CD microparticles was (46.1±3.4)° which stabilized O/W emulsion. When the content of α-CD was increased in the continuous phase, there were more microparticles formed at the oil/water interface and in the continuous aqueous phase, which resulted in smaller particle size of droplet and higher viscosity of the continuous phase. In summary, the study suggest that α-CD/MCT/water emulsions were of O/W Pickering emulsions and the physical stability was better for emulsions with higher content of α-CD in the continuous phase.

The application research progress of pickering emulsion in pharmaceutical field / 中国药学杂志

Pickering emulsions stabilized by solid microparticles, having the advantages of strong interfacial stability, non-toxicity and eco-friendliness compared with the traditional surfactant-stabilized emulsions, have been the focus of considerable researches in recent years. In this review, the application studies on Pickering emulsions were summarized from the following aspects:the stabilization theory about Pickering emulsions, solid microparticles used in Pickering emulsions, the applications of Pickering emulsions in pharmaceutical field and the new Pickering emulsion stabilized by drug nanocrystalline itself. These research progress would promote and expand the application of Pickering emulsions in pharmaceutical field.