Hyaluronidase-powered microneedles for significantly enhanced transdermal delivery efficiency.

Microneedles (MNs) with enhanced delivery efficiency have revolutionized the transdermal drug delivery system for treating systemic illness. However, the bioavailability of MNs was still far from the clinical requirements by only overcoming the stratum corneum barrier. Herein, hyaluronidase (HAase)-powered MNs were developed as a top-down permeation-enhancement strategy to hijack the sequential transdermal barriers for improved bioavailability. HAase MNs with robust mechanical strength showed excellent skin penetration ability and significantly enhanced the transdermal delivery efficacy of macromolecular drugs as compared to that of HAase-absent MNs, resulting in considerable effect to subcutaneous injection in terms of biodistribution, bioavailability, and therapeutical efficacy. As evidenced from the distribution of trypan blue and fluorescence underlying skin, the positive effects exerted by HAase MNs could be ascribed to the depolymerization of HA that would loosen the subcutaneous space and destruct the extracellular matrix barrier to promote drug diffusion and permeation in larger area and greater depth. Notably, the transient interconversion of keratin from α-helix to ß-sheet that might assist the drug residues on the skin surface permeate across the stratum corneum during administration might be another reason not to be ignored. As a labor-saving strategy, HAase-powered MNs offers a promising and painless administration route for macromolecules.

Guanidinium-rich lipopeptide functionalized bacteria-absorbing sponge as an effective trap-and-kill system for the elimination of focal bacterial infection.

Focal bacterial infections are often difficult to treat due to the rapid emergence of antibiotic-resistant bacteria, high risk of relapse, and severe inflammation at local lesions. To address multidrug-resistant skin and soft tissue infections, a bacteria-absorbing sponge was prepared to involve a "trap-and-kill" mechanism. The system describes a guanidinium-rich lipopeptide functionalized lyotropic liquid-crystalline hydrogel with bicontinuous cubic networks. Amphiphilic lipopeptides can be spontaneously anchored to the lipid-water interface, exposing their bacterial targeting sequences to enhance antibacterial trapping/killing activity. Computational simulations supported our structural predictions, and the sponge was confirmed to successfully remove ∼98.8% of the bacteria in the medium. Release and degradation behavior studies indicated that the bacteria-absorbing sponge could degrade, mediate enzyme-responsive lipopeptide release, or generate ∼200 nm lipopeptide nanoparticles with environmental erosion. This implies that the sponge can effectively capture and isolate high concentrations of bacteria at the infected site and then sustainably release antimicrobial lipopeptides into deep tissues for the eradication of residual bacteria. In the animal experiment, we found that the antibacterial performance of the bacterial-absorbing sponge was significant, which demonstrated not only a long-term inhibition effect to disinfect and avoid bacterial rebound, but also a unique advantage to protect tissue from bacterial attack. STATEMENT OF SIGNIFICANCE: Host defense peptides/peptidomimetics (HDPs) have shown potential for the elimination of focal bacterial infections, but the application of their topical formulations suffers from time-consuming preparation processes, indistinctive toxicity reduction effects, and inefficient bacterial capture ability. To explore new avenues for the development of easily prepared, low-toxicity and high-efficiency topical antimicrobials, a guanidinium-rich lipopeptide was encapsulated in a lyotropic liquid-crystalline hydrogel (denoted as "bacteria-absorbing sponge") to achieve complementary superiorities. The superior characteristic of the bacteria-absorbing sponge involves a "trap-and-kill" mechanism, which undergoes not only a long-term inhibition effect to disinfect and avoid bacterial rebound, but also effective bacterial capture and isolating action to confine bacterial diffusion and protect tissues from bacterial attack.

Supersaturable organic-inorganic hybrid matrix based on well-ordered mesoporous silica to improve the bioavailability of water insoluble drugs.

Mesoporous silica with uniform 2-D hexagonal pores has been newly employed as facile reservoir to impove the dissolution rate of water insoluble drugs. However, rapid drug release from mesoporous silica is usually accompanied by the generation of supersaturated solution, which leads to the drug precipitation and compromised absorption. To address this issue, a supersaturated ternary hybrid system was constructed in this study by utilizing inorganic mesoporous silica and organic precipitation inhibitor. Vinylprrolidone-vinylacetate copolymer (PVP VA64) with similar solubility parameter to model drug fenofibrate (FNB) was expected to well inhibit the precipitation. Mesoporous silica Santa Barbara amorphous-15 (SBA-15) was synthesized in acidic media and hybrid matrix was produced by hot melt extrusion technique. The results of in vitro supersaturation dissolution test obviously revealed that the presence of PVP VA64 could effectively sustain a higher apparent concentration. PVP VA64 was suggested to simultaneously reduce the rate of nucleation and crystal growth and subsequently maintain a metastable supersaturated state. The absorption of FNB delivered by the organic-inorganic hybrid matrix was remarkably enhanced in beagle dogs, and its AUC value was 1.92-fold higher than that of FNB loaded mesoporous silica without PVP VA 64. In conclusion, the supersaturated organic-inorganic hybrid matrix can serve as a modular strategy to enhance the oral availability of water insoluble drugs.

Dissolving Microneedles with Spatiotemporally controlled pulsatile release Nanosystem for Synergistic Chemo-photothermal Therapy of Melanoma.

High aggressiveness and recurrence of melanoma tumors require multiple systemic drug administrations, causing discomfort and severe side effects to the patients. Topical treatment strategies that provide repetitively controllable and precise drug administrations will greatly improve treatment effects. Methods: In this study, a spatiotemporally controlled pulsatile release system, which combined dissolving microneedles (DMNs) and thermal-sensitive solid lipid nanoparticles (SLNs), was constructed to realize multiple doses of dual-modal chemo-photothermal therapy in a single administration. Paclitaxel (PTX) and photothermal agent IR-780 were encapsulated into SLNs and were concentrated in the tips of DMNs (PTX/IR-780 SLNs @DMNs). Equipped with several needles, the DMN patch could be directly inserted into the tumor site and provide a stable "Zone accumulation" to constrain the PTX/IR-780 SLNs at the tumor site with uniform distribution. Results:In vitro experiments showed that after irradiation with near-infrared light, the PTX/IR-780 SLNs gradually underwent phase transition, thereby accelerating the release of PTX. When irradiation was switched off, the PTX/IR-780 SLNs cooled to re-solidify with limited drug release. Compared with intravenous and intratumoral injections, very few SLNs from PTX/IR-780 SLNs @DMNs were distributed into other organs, resulting in enhanced bioavailability at the tumor site and good safety. In vivo analysis revealed that PTX/IR-780 SLNs @DMNs exhibited significant anti-tumor efficacy. In particular, the primary tumor was completely eradicated with a curable rate of 100% in 30 days and the highest survival rate of 66.67% after 100 days of treatment. Conclusion: Herein, we developed a DMN system with a unique spatiotemporally controlled pulsatile release feature that provides a user-friendly and low-toxicity treatment route for patients who need long-term and repeat treatments.

Data on the drug release profiles and powder characteristics of the ethyl cellulose based microparticles prepared by the ultra-fine particle processing system.

Ethyl cellulose (EC) based microparticles (MPs) could provide sustained release for Huperzine A. The drug release mechanism of MPs was exploited to achieve an ideal drug release profile. We previously found that the wettability of MPs greatly contributed to facilitating drug release, which was detailed in a research article entitled "Huperzine A loaded multiparticulate disintegrating tablet: Drug release mechanism of ethyl cellulose microparticles and pharmacokinetic study" (Peng et al., 2019) [1]. In this article, the influence of different polymers and drugs on the drug release behavior was investigated to broaden or compensate this finding. Besides, powder characterization of MPs was used to evaluate the further application of MPs for tablets.

Formation Mechanism, In vitro and In vivo Evaluation of Dimpled Exenatide Loaded PLGA Microparticles Prepared by Ultra-Fine Particle Processing System.

Spherical poly (D, L-lactic-co-glycolic acid) microparticles (PLGA-MPs) have long been investigated in order to achieve sustained delivery of proteins/peptides. However, the formation mechanism and release characteristics of the specific shape MPs were still unknown. This study aimed to develop a novel-dimpled exenatide-loaded PLGA-MPs (Exe-PLGA-MPs) using an ultra-fine particle processing system (UPPS) and investigate the formation mechanism and release characteristics. Exe-PLGA-MPs were prepared by UPPS and optimized based on their initial burst within the first 24 h and drug release profiles. Physicochemical properties of Exe-PLGA-MPs, including morphology, particle size, and structural integrity of Exe extracted from Exe-PLGA-MPs, were evaluated. Furthermore, pharmacokinetic studies of the optimal formulation were conducted in Sprague-Dawley (SD) rats to establish in vitro-in vivo correlations (IVIVC) of drug release. Exe-PLGA-MPs with dimpled shapes and uniform particle sizes achieved a high encapsulation efficiency (EE%, 91.50 ± 2.65%) and sustained drug release for 2 months in vitro with reduced initial burst (20.42 ± 1.64%). Moreover, the pharmacokinetic studies revealed that effective drug concentration could be maintained for 3 weeks following a single injection of dimpled Exe-PLGA-MPs with high IVIVC. Dimpled PLGA-MPs prepared using the UPPS technique could thus have great potential for sustained delivery of macromolecular proteins/peptides.

Polymer⁻Surfactant System Based Amorphous Solid Dispersion: Precipitation Inhibition and Bioavailability Enhancement of Itraconazole.

The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer⁻surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0⁻24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer⁻surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug.

A liquid crystalline precursor incorporating chlorhexidine acetate and silver nanoparticles for root canal disinfection.

Lyotropic liquid crystals (LLC) have received increasing attention as a drug delivery system. In this study, a novel intra-canal disinfectant based on the glycerol monooleate (GMO) LLC precursor incorporation with chlorhexidine (CHX) and silver nanoparticles (Ag-NPs) was designed and evaluated. The LLC precursor with excellent fluidity was able to penetrate deeply into the complex tiny collateral branch root canals. The transformation of cubic LLC in root canals upon coming into contact with water provided long-lasting disinfection against multidrug-resistant bacteria to avoid the endodontic reinfection and follow-up visits. The GMO-ethanol-water (48% : 12% : 40%, w/w) formulation containing 0.5% CHX and 0.02% Ag-NPs was selected for further studies. The low viscosity of the precursor presented excellent injectability and flowabilities. From the in vitro release test, the release behaviours were found to be influenced by CHX and Ag-NP contents, allowing the optimized precursor to obtain a 28-day release profile. The CHX-Ag-NP containing LLC precursor exhibited an excellent and sustained sterilization effect on Enterococcus faecalis for more than one month with a bacterial inactivation rate of ≥98.5%, which was far more than the minimum clinical requirement (7 days). Furthermore, no in vitro toxicity was observed in the cytotoxicity evaluation. The CHX-Ag-NP containing LLC precursor was proved to be a promising intra-canal disinfectant in our study.

Anhydrous reverse micelle lecithin nanoparticles/PLGA composite microspheres for long-term protein delivery with reduced initial burst.

To address the issue of initial burst release from poly (lactic-co-glycolic) acid (PLGA) microspheres prepared by water-in-oil-in-water (W/O/W) double emulsion technique, PLGA composite microspheres containing anhydrous reverse micelle (ARM) lecithin nanoparticles were developed by a modified solid-in-oil-in-water (S/O/W) technique. Bovine serum albumin (BSA) loaded ARM lecithin nanoparticles, which were obtained by initial self-assembly and subsequent lipid inversion of the lecithin vesicles, were then encapsulated into PLGA matrix by the S/O/W technique to form composite microspheres. In vitro release study indicated that BSA was slowly released from the PLGA composite microspheres over 60 days with a reduced initial burst (11.42 ±â€¯2.17% within 24 h). The potential mechanism of reduced initial burst and protein protection using this drug delivery system was analyzed through observing the degradation process of carriers and fitting drug release data with various kinetic models. The secondary structure of encapsulated BSA was well maintained through the steric barrier effect of ARM lecithin nanoparticles, which avoided exposure of proteins to the organic solvent during the preparation procedure. In addition, the PLGA composite microspheres exhibited superior biocompatibility without notable cytotoxicity. These results suggested that ARM lecithin nanoparticles/PLGA composite microspheres could be a promising platform for long-term protein delivery with a reduced initial burst.