Deformable Nanovesicles Synthesized through an Adaptable Microfluidic Platform for Enhanced Localized Transdermal Drug Delivery

Abstract

Phospholipid-based deformable nanovesicles (DNVs) that have flexibility in shape offer an adaptable and facile method to encapsulate diverse classes of therapeutics and facilitate localized transdermal delivery while minimizing systemic exposure. Here we report the use of a microfluidic reactor for the synthesis of DNVs and show that alteration of input parameters such as flow speeds as well as molar and flow rate ratios increases entrapment efficiency of drugs and allows fine-tuning of DNV size, elasticity, and surface charge. To determine the ability of DNV-encapsulated drug to be delivered transdermally to a local site, we synthesized, characterized, and tested DNVs carrying the fluorescently labeled hydrophilic bisphosphonate drug AF-647 zoledronate (AF647-Zol). AF647-Zol DNVs were lyophilized, resuspended, and applied topically as a paste to the calvarial skin of mice. High-resolution fluorescent imaging and confocal microscopy revealed significant increase of encapsulated payload delivery to the target tissue—cranial bone—by DNVs as compared to nondeformable nanovesicles (NVs) or aqueous drug solutions. Interestingly, NV delivery was not superior to aqueous drug solution. Our studies show that microfluidic reactor-synthesized DNVs can be produced in good yield, with high encapsulation efficiency, reproducibility, and stability after storage, and represent a useful vehicle for localized transdermal drug delivery.

<p>Preparation and in vitro and in vivo Study of Asiaticoside-Loaded Nanoemulsions and Nanoemulsions-Based Gels for Transdermal Delivery</p>

“…As a route of drug application, TDDS has many advantages including good drug compliance, ease of application, continuous drug release, no hepatic first-pass effect, and lower organ toxicity for some drugs used chronically. 12 However, the transdermal process is mainly limited by the barrier properties of the skin's outer stratum corneum (SC), 13 and researches have shown that permeation enhancers, 14 microneedle, 15 therapeutic 1 MHz frequency sonophoresis, 16 nanocarriers, 17 iontophoresis 18 could contribute to overcome SC of the skin. Nanocarriers including transferosomes, liposomes, lipid nanoparticles, vesicles, polymer micelles and nanoemulsions (NEs) are widely used in TDDS.…”

Mechanism of bisphosphonate-related osteonecrosis of the jaw (BRONJ) revealed by targeted removal of legacy bisphosphonate from jawbone using equilibrium competing inert hydroxymethylene diphosphonate

“…Deformable nano-scale vesicles (DNV) comprise a modified liposome drug carrier (Fig. 2A) synthesized by a controlled microfluidics system, which due to nanovesicle deformability allows penetration through the keratinized epithelial layer of skin (47).…”

“…1D), which are reported to play important roles in liposome drug delivery behavior (49,50). The optimal size for this purpose has been shown to be between 100 to 200 nm (47). After passing through the gingival and oral mucosa epithelial layers, DNV is expected to deliver HMDP to the bone mineral surface, which is negatively charged in isotonic solution (51).…”

“…Fabrication of the DNV formulation containing BP compounds followed the published method (47). Briefly, cationic DOTAP lipid with DPPC and CH were dissolved in a 10 mM chloroform solution at a 5:3:2 volume ratio and the mixture was allowed to dryness.…”

Effect of Ultrasound-Enhanced Transdermal Drug Delivery Efficiency of Nanoparticles and Brucine

“…However, due to the skin of the stratum corneum on the absorption of drugs has a certain blocking effect, transdermal drug absorption efficiency is often not satisfactory [ 11 ]. Therefore, the study of transdermal absorption of drugs is committed to the development of efficient and safe penetration technology which attracts lots of research, including iontophoresis, electroporation, micro-needle, ultrasonic penetration [ 12 , 13 ]. Ion introduction is a very effective method of transdermal administration, but the drug must be ionized before transdermal and the application is inconvenient [ 14 , 15 ].…”