Xiaoqing Miao

Enhanced in vitro and in vivo uptake of a hydrophobic model drug coumarin-6 in the presence of cucurbit[7]uril

This report describes, for the first time, cucurbit[7]uril-assisted quantitative in vitro and in vivo uptake of a hydrophobic model drug, coumarin-6, by both an epithelial cell model and a zebrafish model. The transcellular delivery pathway study suggested multiple mechanisms involved, including macropinocytosis, clathrin and lipid raft-mediated endocytosis/exocytosis.

A strategy for the improvement of the bioavailability and antiosteoporosis activity of BCS IV flavonoid glycosides through the formulation of their lipophilic aglycone into nanocrystals.

Epimedium-derived flavonoid glycosides are widely used for the prevention of osteoporosis, but these compounds generally exhibit poor membrane permeability and oral absorption. To address these limitations, the bioactive lipophilic aglycone icaritin (ICT) was selected and successfully developed into nanocrystals (ICTN) through the antisolvent-precipitation method. After the parameters in the preparation of ICTN were optimized, the morphology, crystallinity, adsorption of the stabilizers on the ICT surface, and the dissolution of the resulting nanocrystals were characterized. The pharmacokinetics in rat and the in vitro antiosteoporosis activity of serum withdrawn after the oral administration of ICTN to rats on mouse osteoblastic cells were evaluated. Consistent with its good performance in stabilizing the ICT nanosuspension, atomic force microscopy showed that hydroxypropyl methylcellulose (HPMC) exhibits better adsorption on the ICT surface compared with other stabilizers. Needle-shaped crystals (∼ 220 nm in diameter) with a high drug loading (∼ 90%) were generated when 0.16 mL of the ICT acetone solution (10 mg/mL) was injected quickly into 2 mL of the HPMC solution (0.02%, w/w) under ultrasonication for 10 s at room temperature. The thermal analysis demonstrated that the majority of the particles are in their crystalline forms, similarly to the unformulated ICT. After oral administration, ICTN exhibited a faster dissolution rate and significantly faster absorption, as supported by the increased AUC0-36h and Cmax and the reduced Tmax of these nanocrystals compared with the raw suspension (p < 0.05). Compared with blank serum, enhanced proliferation and differentiation activities were observed when serum withdrawn after the oral administration of ICTN in rat was incubated with osteoblast MC3T3-E1 cells. The present delivery system could provide a new promising strategy for BCS IV glycoside of flavonoids or other natural products by formulation of their bioactive lipophilic aglycone forms to enhance oral absorption and in vivo bioactivity.

High-affinity host–guest complex of cucurbit[7]uril with a bis(thiazolium) salt

A biologically- and pharmaceutically-relevant bis(thiazolium) dication model compound, α,α′-bis(thiazolium)-p-xylene (BTX2+), forms a strong 1 : 1 host–guest inclusion complex with cucurbit[7]uril (CB[7]). The complexation stoichiometry, binding affinity and geometry were studied via 1H NMR and UV-visible titrations, ESI-MS, and molecular modeling (ab initio calculations). The hydrogen/deuterium exchange reactions of the C(2)-proton of BTX2+ were conducted in the absence and presence of CB[7] in D2O at 25 °C and at an ionic strength of 0.20 M. The inhibition of C(2)-H/D exchange of the guest bis(thiazolium) dication upon complexation with CB[7] exhibited a second-order rate constant that decreased by more than four-fold in the presence of CB[7]. The supramolecular-controlled stability of thiazolium cations through complexation with CB[7] host molecules is anticipated to have applications for stability enhancement of thiazolium based drugs and to potentially draw interest in the application of CB[n] host molecules with regard to the formulation and delivery of these drugs.

Transport Mechanism of Coumarin 6 Nanocrystals with Two Particle Sizes in MDCKII Monolayer and Larval Zebrafish

Nanocrystals (NCs) were utilized as oral formulations in commercial products to deliver lipophilic drug, but their transport mechanisms are not fully understood. This study aimed to explore the transport mechanism of NCs using in vitro Madin-Darby canine kidney II (MDCK II) cells and in vivo larval zebrafish models. Coumarin 6 (C6) was formulated into NCs with particle size of 67.5 ± 5.2 and 190 ± 9.2 nm. In vitro studies showed that 70 nm NCs accumulated in lysosome and endoplasmic reticulum (ER) as destinations. Lipid raft pathways mediated the endocytosis, while lipid raft, ER/Golgi, and Golgi/plasma membrane pathways were involved in exocytosis and transcytosis process. However, 200 nm NCs accumulated more in a lysosome, where lipid raft pathways were also involved in the endocytosis process. In vivo studies in larval zebrafish model further confirmed that the above network plays an important role in the absorption and distribution of C6-NCs.

Formulation of 20(S)-protopanaxadiol nanocrystals to improve oral bioavailability and brain delivery.

The aim of this study was to fabricate 20(S)-protopanaxadiol (PPD) nanocrystals to improve PPDs oral bioavailability and brain delivery. PPD nanocrystals were fabricated using an anti-solvent precipitation approach where d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was optimized as the stabilizer. The fabricated nanocrystals were nearly spherical with a particle size and drug loading of 90.44 ± 1.45 nm and 76.92%, respectively. They are in the crystalline state and stable at 4°C for at least 1 month. More than 90% of the PPD could be rapidly released from the nanocrystals, which was much faster than the physical mixture and PPD powder. PPD nanocrystals demonstrated comparable permeability to solution at 2.52 ± 0.44×10(-5)cm/s on MDCK monolayers. After oral administration of PPD nanocrystals to rats, PPD was absorbed quickly into the plasma and brain with significantly higher Cmax and AUC0-t compared to those of the physical mixture. However, no brain targeting was observed, as the ratios of the plasma AUC0-t to brain AUC0-t for the two groups were similar. In summary, PPD nanocrystals are a potential oral delivery system to improve PPDs poor bioavailability and its delivery into the brain for neurodegenerative disease and intracranial tumor therapies in the future.

Nanosuspension development of scutellarein as an active and rapid orally absorbed precursor of its BCS class IV glycoside scutellarin.

This work addressed solubility and membrane permeability problems of Biopharmaceutics Classification System (BCS) Class IV glycoside scutellarin (SG) by developing a nanosuspension of its aglycone scutellarein (S) as a precursor. An S nanosuspension containing poloxamer 188 was prepared using antisolvent precipitation where hydroxypropyl-β-cyclodextrin was utilized as a lyophilizing protectant. Particle size and polydispersity index after redispersion were 342.6 ± 18.2 and 0.32 ± 0.06 nm, respectively. The dissolution rate of the S nanosuspension was superior compared with the physical mixture. No free S, but SG and SGs isomer were detected in plasma following oral delivery of SG or S, S nanosuspension or physical mixture of S. The Cmax values of SG after dosing with the S nanosuspension were 12.0, 8.0, and 4.5-fold higher than the SG, S, or physical mixture, respectively. The Tmax and mean residence time (MRTlast ) of SG after dosing with the S nanosuspension were significantly shorter than S and SG. Treatments with SG, S, or S nanosuspensions reduced the hemorrhage rate in a zebrafish model, but the S nanosuspension exhibited the strongest rescue effect. This study highlights a new strategy to circumvent BCS Class IV flavonoid glycosides using a formulation of their aglycone as a precursor to accelerate oral absorption and improve bioactivity.

Effects of nanosuspension formulations on transport, pharmacokinetics, in vivo targeting and efficacy for poorly water-soluble drugs.

A surprisingly large proportion of new chemical entities (NCE) is emerging from the drug discovery pipeline, and many active components extracted from herbal medicines are water insoluble, which represents a great challenge for their development. Nanosuspensions, which are submicron colloidal dispersions of pure drug particles that are stabilised by a small percentage of the excipients, could dramatically enhance the saturated solubility, dissolution rate and adhesion of drug particles to cell membranes. Nanosuspensions are the most suitable for drugs that require high dosing or have limited administrative volume. After 20 years of development, several oral products and one injectable product are commercially available. The aim of this review is to fill the gap between rational formulation designs and the in vivo performance of poorly water-soluble drug nanosuspensions. Specifically, this review will correlate characteristics of nanosuspension formulations, including drug property, particle size, crystallinity, stabiliser and surface property, with their transport, pharmacokinetics, bioactivity and toxicity after delivery by different administration routes. The elucidation of the mechanisms of targeted drug delivery, cellular transport and internalisation of nanosuspensions are also reviewed to interpret the in vivo performance of these nanosuspensions. Moreover, the recent application of nanosuspensions for poorly water-soluble herbal medicines is highlighted.

Zebrafish: A promising in vivo model for assessing the delivery of natural products, fluorescence dyes and drugs across the blood-brain barrier

&NA; The blood brain barrier (BBB) is the network of capillaries that controls the passage of substances from the blood into the brain and other parts of the central nervous system (CNS). As this barrier is the major obstacle for drug delivery into CNS, a credible BBB model is very necessary to assess the BBB permeability of novel neuroactive compounds including thousands of bioactive compounds which have been extracted from medicinal plants and have the potential for the treatment of CNS diseases. Increasing reports indicated that zebrafish has emerged as a timely, reproducible model for BBB permeability assessment. In this review, the development and functions of the BBB in zebrafish, such as its anatomical morphology, tight junctions, drug transporters and enzyme expression, are compared with those in mammals. The studies outlined in this review describe the utilization of the zebrafish as a BBB model to investigate the permeability and distribution of fluorescent dyes and drugs. Particularly, this review focuses on the use of zebrafish to evaluate the delivery of natural products and nanosized drug delivery systems across the BBB. Due to the highly conserved nature of both the structure and function of the BBB between zebrafish and mammals, zebrafish has the potential to be developed as a model for assessing and predicting the permeability of BBB to novel compounds. Graphical abstract Figure. No caption available.

Chinese Medicine in Inhalation Therapy: A Review of Clinical Application and Formulation Development

Chinese medicine (CM) in inhalation therapy has a long history of applications since ancient China in the forms of smoke, steam vapor, medicated pillows and aromatic sachets. Over the years, thousands of clinical treatments involving the inhalation of CMs have been reported for the treatment of respiratory disease. Shuanghuanglian, Yuxingcao and Qingkailing are primarily applied in pneumonia and bronchitis. At present, metered dose inhalation (MDI), aromatic inhalation and nebulized inhalation are used extensively in practice. In particular, nebulized CM for the treatment of respiratory diseases has been applied as a noninvasive route with reduced serious adverse reactions and is equivalent to or more efficacious than its intravenous counterparts. Although nebulized CM is widely used in clinical practice, only three MDI and five aromatic inhalations of CM products have been approved by the China Food and Drug Administration (CFDA), and no products in the form of a dry powder inhaler (DPI) or in dosage forms intended for nebulization have been reported. The development of formulations for CM has focused on improving the aerodynamic performance of the particles prepared by spray drying, enhancing the bioavailability and local concentration in the respiratory tract, and increasing the mucoadhesion and sustained release of the CM upon the incorporation of novel excipients. New devices, including MDI and nebulizer devices, have been developed for the delivery of the above-mentioned particles to the pulmonary system. Although the development of CM inhalation products to meet the international quality standards is facing a number of challenges, the inhalation of CMs show great potential for further exploration, particularly as an alternative route to IV infusion for the treatment of respiratory diseases.