Wheat germ agglutinin modified mixed micelles overcome the dual barrier of mucus/enterocytes for effective oral absorption of shikonin and gefitinib.

The combination of shikonin (SKN) and gefitinib (GFB) can reverse the drug resistance of lung cancer cells by affecting energy metabolism. However, the poor solubility of SKN and GFB limits their clinical application because of low bioavailability. Wheat germ agglutinin (WGA) can selectively bind to sialic acid and N-acetylglucosamine on the surfaces of microfold cells and enterocytes, and is a targeted biocompatible material. Therefore, we created a co-delivery micelle system called SKN/GFB@WGA-micelles with the intestinal targeting functions to enhance the oral absorption of SKN and GFB by promoting mucus penetration for nanoparticles via oral administration. In this study, Caco-2/HT29-MTX-E12 co-cultured cells were used to simulate a mucus/enterocyte dual-barrier environment, and HCC827/GR cells were used as a model of drug-resistant lung cancer. We aimed to evaluate the oral bioavailability and anti-tumor effect of SKN and GFB using the SKN/GFB@WGA-micelles system. In vitro and in vivo experimental results showed that WGA promoted the mucus penetration ability of micelles, significantly enhanced the uptake efficiency of enterocytes, improved the oral bioavailability of SKN and GFB, and exhibited good anti-tumor effects by reversing drug resistance. The SKN/GFB@WGA-micelles were stable in the gastrointestinal tract and provided a novel safe and effective drug delivery strategy.

Synergistic treatment of androgenetic alopecia with follicular co-delivery of minoxidil and cedrol in metal-organic frameworks stabilized by covalently cross-linked cyclodextrins.

Androgenetic alopecia seriously affects the physical and mental health of patients. The main clinical therapeutic agent, minoxidil tincture, is challenged by solvent irritation and dose-dependent side effects. Our recent work has identified a biosafety natural product, cedrol, that is synergistic in combination with minoxidil, thereby improving medication safety by substantially reducing the clinical dose of minoxidil. In addition, ccross-linked CD-MOF were designed as carriers for hair follicle delivery, and γ-CD in the carriers was cross-linked by diphenyl carbonate with covalent bonds to protect the CD-MOF from rapid disintegration in an aqueous environment. This improved nanocarrier has a drug loading of 25%, whereas nanocarriers increased drug delivery to the hair follicles through ratchet effect, and increased human dermal papilla cells uptake of drugs via endocytosis pathways mainly mediated by lattice proteins, energy-dependent active transport, and lipid raft-dependent, thus improved cell viability, proliferation, and migration, followed by significantly enhancing the anti-androgenetic alopecia effect, with cedrol focusing on inhibiting 5α-reductase and activating Shh/Gli pathway, and minoxidil, which up-regulated VEGF, down-regulated TGF-ß, and activated ERK/AKT pathway. This drug combination provides a new therapeutic strategy for androgenetic alopecia, while the newly developed cross-linked CD-MOF has been shown to serve as a promising follicular delivery vehicle.

Cardamonin-loaded liposomal formulation for improving percutaneous penetration and follicular delivery for androgenetic alopecia.

Androgenic alopecia (AGA) has a considerable impact on the physical and mental health of patients. Nano preparations have apparent advantages and high feasibility in the treatment of AGA. Cardamonin (CAR) has a wide range of pharmacological activities, but it has the problems of poor solubility in water and low bioavailability. There are few, if any, researches on the use of nano-loaded CAR to improve topical skin delivery of AGA. In this study, a CAR-loaded liposomal formulation (CAR@Lip and CAR@Lip Gel) was developed and characterized. The prepared CAR@Lip exhibited a uniform and rounded vesicle in size. CAR@Lip and CAR@Lip Gel can significantly improve the cumulative release of CAR. Additionally, CAR@Lip can obviously promote the proliferation and migration of human dermal papilla cells (hDPCs). Cell uptake revealed that the uptake of CAR@Lip significantly increased compared with the free drug. Furthermore, both CAR@Lip and CAR@Lip Gel groups could markedly improve the transdermal performance of CAR, and increase the topical content of the drug in the hair follicle compared with CAR. The ratchet effect of hair follicles could improve the skin penetration depth of nanoformulations. Notably, Anti-AGA tests in the mice showed that CAR@Lip and CAR@Lip Gel groups could promote hair growth, and accelerate the transition of hair follicles to the growth stage. The anti-androgen effect was revealed by regulating the expression of IGF-1, VEGF, KGF, and TGF-ß, participating in SHH/Gli and Wnt/ß-catenin pathways. Importantly, the nanoformulations had no obvious skin irritation. Thus, our study showed that CAR-loaded liposomal formulation has potential application in the treatment of AGA.

TPGS-mediated Transethosomes Enhance Transdermal Administration of Curcumin via Effects on Deformability and Stability.

BACKGROUND: Adding a suitable surfactant can enhance the transdermal permeability of transethosomes while also leveraging its functionality as a functional material. In this study, transethosomes were prepared using D-α-tocopherol acid polyethylene glycol succinate (TPGS) as edge activators for transdermal delivery of curcumin (Cur). METHODS: The TPGS-mediated curcumin-loaded transethosomes (Cur@TES) were prepared and formulated optimally, and the optimized formulations were characterized for their morphology, particle size, entrapment efficiency (EE) and drug loading (DL). The stability and deformability of Cur@TES were investigated, while the transdermal delivery of Cur@TES was investigated through in vitro transdermal assays and fluorescence imaging. A mouse ear swelling model was performed to determine the anti-inflammatory effect of Cur@TES. RESULTS: Cur@TES appeared round or elliptical in shape. The particle size, EE and DL for the optimized formulation were observed as 131.2 ± 7.2 nm, 97.68 ± 2.26%, and 6.58 ± 0.62%, respectively. X-ray diffraction analysis confirmed the formation of disordered structures in the inner core of the vesicles. Moreover, Cur@TES system demonstrated better stability and deformability compared to the curcumin-loaded ethosomes (Cur@ES). In-vitro transdermal experiments demonstrated that Cur@TES significantly increased the amount of drug retained in the skin (P＜0.05). Fluorescence imaging confirmed that the skin distribution were distinctly enhanced with the delivery by TPGS mediated transethosomes. In addition, Cur@TES showed a significant inhibitory effect on Inflammatory swelling in the mouse ear-swelling model. CONCLUSION: TPGS-mediated transethosomes exhibit significant transdermal advantages and enhanced anti-inflammatory effects, providing a new perspective for the transdermal delivery of curcumin.

Superhydrophobic Surface-Assisted Preparation of Microspheres and Supraparticles and Their Applications.

Superhydrophobic surface (SHS) has been well developed, as SHS renders the property of minimizing the water/solid contact interface. Water droplets deposited onto SHS with contact angles exceeding 150°, allow them to retain spherical shapes, and the low adhesion of SHS facilitates easy droplet collection when tilting the substrate. These characteristics make SHS suitable for a wide range of applications. One particularly promising application is the fabrication of microsphere and supraparticle materials. SHS offers a distinct advantage as a universal platform capable of providing customized services for a variety of microspheres and supraparticles. In this review, an overview of the strategies for fabricating microspheres and supraparticles with the aid of SHS, including cross-linking process, polymer melting, and droplet template evaporation methods, is first presented. Then, the applications of microspheres and supraparticles formed onto SHS are discussed in detail, for example, fabricating photonic devices with controllable structures and tunable structural colors, acting as catalysts with emerging or synergetic properties, being integrated into the biomedical field to construct the devices with different medicinal purposes, being utilized for inducing protein crystallization and detecting trace amounts of analytes. Finally, the perspective on future developments involved with this research field is given, along with some obstacles and opportunities.

A Compound Essential Oil Alters Stratum Corneum Structure, Potentially Promoting the Transdermal Permeation of Hydrophobic and Hydrophilic Ingredients.

BACKGROUND: The stratum corneum (SC) is the main barrier of the skin, and cosmeceuticals are different from ordinary cosmetics in that they need to deliver active ingredients targeting specific skin problems through the SC into the deeper layers of the skin. Thus, we designed a compound essential oil (CEO) extracted from Salvia miltiorrhiza Bge and Cinnamomum cassia Presl, supplemented with borneol to deliver active ingredients through the SC. METHODS: The CEO was prepared by flash extraction combined with the microwave method. Moreover, the main components of the CEO were determined using gas chromatography-mass spectrometry (GCMS). Visualization techniques, such as scanning electron microscopy (SEM), haematoxylin-eosin (HE) staining, and confocal laser scanning microscopy (CLSM), were used to study the permeationpromoting mechanism of the CEO on the skin. Furthermore, the permeation-promoting effects of the CEO on both hydrophobic and hydrophilic ingredients were tested via in vitro skin penetration experiments and in vivo microdialysis experiments. RESULTS: The results indicated the ability of the CEO to alter the structure of the SC, leading to enhanced transdermal permeation of hydrophobic and hydrophilic ingredients. The 1.5% CEO group demonstrated the best permeation-promoting effect compared to the other CEO groups and blank groups (P<0.05). Furthermore, the CEO displayed an expedited permeability-promoting effect on hydrophobic ingredients compared to hydrophilic ingredients. CONCLUSION: It is concluded that the prepared CEO can promote the transdermal permeation of hydrophobic and hydrophilic ingredients. This study will provide a reference for the application of the prepared CEO in the development of cosmeceuticals with natural efficacy.

Evaluating the Effect of Microcrystalline Cellulose Variations on Tablet Quality of Natural Plant Product Using a Design of Experiment Approach.

Microcrystalline cellulose (MCC) of different grades from different manufacturers differ in particulate and powder properties significantly. The choice of MCC is important to the development of a tablet formulation with satisfactory quality. In this study, the effects of five different MCCs (KG 802, Pharmacel 102, MC 302, M 200, and PH 112) that had different compactibility and tablet disintegration on the tablet quality of two different natural plant products (NPPs) were evaluated systematically, including Crataegi Folium ethanol extract (CF-E) and Sarcandrae Herba water extract (SH-W). The result of D-optimal mixture designs demonstrated that KG 802 showed the best ability to improve compression properties and tensile strength, followed by Pharmacel 102, MC 302, and M 200. PH 112 did the weakest. However, MCCs of different grades had no different influence on the disintegration of NPP tablets. Similar results were found in the experiments of the two different NPP powders, suggesting the generalization of the finding. Moreover, KG 802-containing CF-E formulations showed the largest optimum region size, that is, the lowest production risk. The design space sizes of SH-W were hardly sensitive to the change of MCCs, due to the better tabletability. In conclusion, the properties of MCCs could transfer to the high NPP loading (70%) formulations, leading to the variations on the compression properties and tablet quality. The poorer the tabletability of NPP, the more obvious the variation. The result is promising for the use of MCC and the manufacturing of high drug-loading NPP tablets by direct compression.

[Improvement in compatibility of hot melt pressure-sensitive adhesive with cinnamon volatile oil and in vitro transdermal property by physical blending].

Hot melt pressure-sensitive adhesive(HMPSA) has broad application potential in the field of traditional Chinese medicine(TCM) plasters due to its high drug loading, weak skin irritation, satisfactory adhesion, etc. compared with rubber plasters.However, the structure of HMPSA is prone to suffer from the damage caused by volatile oils in TCM plasters. In view of this, a kind of HMPSA with a stable structure was prepared by physical blending of DINCH, polypropylene wax and liquid rubber(LIR) in the present study, which is denoted as DPL. The dosage of cinnamon volatile oil(CVO), the model drug, was selected with viscosity, softening point and cohesion as evaluation indexes. The interaction between DPL and HMPSA was investigated by Fourier transform infrared spectroscopy(FT-IR) and differential scanning calorimetry(DSC). The compatibility of HMPSA with CVO and its transdermal ability were studied by in vitro transdermal test, adhesion, scanning electron microscopy( SEM) and rheological evaluation. The results showed that 5% CVO began to damage the structure of HMPSA. The initial adhesion and holding adhesion of DPL-modified HMPSA(DPL-HMPSA) were not significantly changed compared with those of HMPSA, whereas the 180° peel strength was decreased. FI-IR unraveled that DPL formed the n-π conjugated system with styrene-isoprene-styrene block copolymer(SIS), and there was no significant difference in the glass transition temperature according to DSC results, which indicated the good compatibility of DPL with HMPSA. With 5% CVO loaded, the drug content of DPL-HMPSA was 1. 14 times higher than that of HMPSA, and the decrease rate of drug content in DPL-HMPSA was 16% lower than that in HMPSA after 3 months. SEM demonstrated that CVO did not cause obvious structural damage to DPL-HMPSA. Rheological evaluation revealed that the storage modulus and loss factor of DPL-HMPSA were higher than those of HMPSA, and the cohesion was also stronger. The percutaneous penetration rate of cinnamaldehyde in DPL-HMPSA was 2. 25 times that of HMPSA. In conclusion, DPL-HMPSA had more stable structure, better compatibility with CVO, and higher in vitro transdermal efficiency of cinnamaldehyde than before the modification. This study can provide reference for the mitigation of the matrix structure damage caused by volatile oil components in TCM plasters and the enhancement of the content and in vitro transdermal rate of drug.

O/W microemulsion droplets diffuse through hydrogel network to achieve enhanced transdermal drug delivery.

To overcome the poor water solubility of total flavones of Arisaematis rhizoma, microemulsions (MEs) can be used as a carrier for transdermal administration to promote their solubilization and skin permeability. Here, we investigated the physical compatibility of MEs in hydrogels and their skin permeation-enhancing effects. Transparency of microemulsion-based hydrogels (MBGs) was analyzed to evaluate ME compatibility with different hydrogel matrices. Transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy were used to explore the microstructures of MBGs and ME-hydrogel combinations. Uniform and transparent MBG was obtained by adding 1% sodium hyaluronate (SH) to the optimized ME. MBG prepared with SH as a matrix expressed pseudoplastic-fluid and shear-thinning characteristics, making it easy to apply in clinical settings. No new FTIR peak occurred in the MBG compared with ME and hydrogel matrix, indicating a physical combination of ME and the polymer network gel. Nanoscale droplets of ME migrated in the gel network, and the migration capacity and in vitro transdermal permeation flux negatively correlated with SH concentration in the gel system. In conclusion, in MBGs, ME can keep nanoscale droplets migrating in the hydrogel network, thereby enhancing transdermal drug delivery.