9 research outputs found
Hybrid Dendrimer Hydrogel/PLGA Nanoparticle Platform Sustains Drug Delivery for One Week and Antiglaucoma Effects for Four Days Following One-Time Topical Administration
We report a novel hybrid polyamidoamine (PAMAM) dendrimer hydrogel/poly(lactic-co-glycolic acid) (PLGA) nanoparticle platform (HDNP) for codelivery of two antiglaucoma drugs, brimonidine and timolol maleate. This platform was not cytotoxic to human corneal epithelial cells. Cellular uptake of Nile red-encapsulating PLGA nanoparticles was significantly increased by dendrimer hydrogel. A prolonged residence time of nanoparticles was demonstrated through investigation of FluoSpheres loaded into dendrimer hydrogel. Both brimonidine and timolol maleate were slowly released in vitro over a period of 28-35 days. Following topical administration of one eye drop (30 µL of 0.7% w/v brimonidine and 3.5% w/v timolol maleate) in normotensive adult Dutch-belted male rabbits, the HDNP formulation resulted in a sustained and effective IOP reduction (18% or higher) for 4 days. Furthermore, the HDNP maintained significantly higher concentrations of brimonidine in aqueous humor and cornea as well as timolol maleate in the aqueous humor, cornea, and conjunctiva up to 7 days as compared to saline, DH, and PLGA nanoparticle dosage forms, without inducing ocular inflammation or discomfort. Histological analysis of the cornea and conjunctiva did not reveal any morphological or structural changes. Our work demonstrated that this new platform is capable of enhancing drug bioavailability and sustaining effective IOP reduction over an extended period of time. This newly developed platform can greatly reduce dosing frequency of topical formulations, thus, improving long-term patient compliance and reducing enormous societal and economic costs. Given its high structural adaptability, many other chronic ocular diseases would benefit from long-lasting drug delivery of this new platform
Polyamidoamine Dendrimer Hydrogel for Enhanced Delivery of Antiglaucoma Drugs
Dendrimer hydrogel (DH), made from ultraviolet-cured polyamidoamine dendrimer G3.0 tethered with three polyethylene glycol (PEG, 12,000 Da)-acrylate chains (8.1% w/v) in pH 7.4 phosphate buffered saline (PBS), was studied for the delivery of brimonidine (0.1% w/v) and timolol maleate (0.5% w/v), two antiglaucoma drugs. DH was found to be mucoadhesive to mucin particles and nontoxic to human corneal epithelial cells. DH increased the PBS solubility of brimonidine by 77.6% and sustained the in vitro release of both drugs over 56-72 hours. As compared to eye drop formulations (PBS-drug solutions), DH brought about substantially higher human corneal epithelial cells uptake and significantly increased bovine corneal transport for both drugs. DH increased timolol maleate uptake in bovine corneal epithelium, stroma, and endothelium by 0.4- to 4.6-fold. This work demonstrated that DH can enhance the delivery of antiglaucoma drugs in multiple aspects and represents a novel platform for ocular drug delivery. From the Clinical Editor: Dendrimer hydrogel was studied as agent for simultaneous delivery of two anti-glaucoma drugs, one hydrophobic and one hydrophilic. Superiority over standard PBS-based formulation was clearly demonstrated for both drugs. The work may be a novel platform for ocular drug delivery
Room-Temperature All-solid-state Rechargeable Sodium-ion Batteries with a Cl-doped Na3PS4 Superionic Conductor.
All-solid-state sodium-ion batteries are promising candidates for large-scale energy storage applications. The key enabler for an all-solid-state architecture is a sodium solid electrolyte that exhibits high Na(+) conductivity at ambient temperatures, as well as excellent phase and electrochemical stability. In this work, we present a first-principles-guided discovery and synthesis of a novel Cl-doped tetragonal Na3PS4 (t-Na3-xPS4-xClx) solid electrolyte with a room-temperature Na(+) conductivity exceeding 1 mS cm(-1). We demonstrate that an all-solid-state TiS2/t-Na3-xPS4-xClx/Na cell utilizing this solid electrolyte can be cycled at room-temperature at a rate of C/10 with a capacity of about 80 mAh g(-1) over 10 cycles. We provide evidence from density functional theory calculations that this excellent electrochemical performance is not only due to the high Na(+) conductivity of the solid electrolyte, but also due to the effect that "salting" Na3PS4 has on the formation of an electronically insulating, ionically conducting solid electrolyte interphase
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New Insights into the Interphase between the Na Metal Anode and Sulfide Solid-State Electrolytes: A Joint Experimental and Computational Study.
In this work, we investigated the interface between the sodium anode and the sulfide-based solid electrolytes Na3SbS4 (NAS), Na3PS4 (NPS), and Cl-doped NPS (NPSC) in all-solid-state-batteries (ASSBs). Even though these electrolytes have demonstrated high ionic conductivities in the range of 1 mS cm-1 at ambient temperatures, sulfide sold-state electrolytes (SSEs) are known to be unstable with Na metal, though the exact reaction mechanism and kinetics of the reaction remain unclear. We demonstrate that the primary cause of capacity fade and cell failure is a chemical reaction spurred on by electrochemical cycling that takes place at the interface between the Na anode and the SSEs. To investigate the properties of the Na-solid electrolyte interphase (SSEI) and its effect on cell performance, the SSEI was predicted computationally to be composed of Na2S and Na3Sb for NAS and identified experimentally via X-ray photoelectron spectroscopy (XPS). These two compounds give the SSEI mixed ionic- and electronic-conducting properties, which promotes continued SSEI growth, which increases the cell impedance at the expense of cell performance and cycle life. The SSEI for NPS was similarly found to be comprised of Na2S and Na3P, but XPS analysis of Cl-doped NPS (NPSC) showed the presence of an additional compound at the SSEI, NaCl, which was found to mitigate the decomposition of NPS. The methodologies presented in this work can be used to predict and optimize the electrochemical behavior of an all-solid-state cell. Such joint computational and experimental efforts can inform strategies for engineering a stable electrolyte and SSEI to avoid such reactions. Through this work, we call for more emphasis on SSE compatibility with both anodes and cathodes, essential for improving the electrochemical properties, longevity, and practicality of Na-based ASSBs
Preparation of budesonide and budesonide-PLA microparticles using supercritical fluid precipitation technology
The objective of this study was to prepare and characterize microparticles of budesonide alone and budesonide and polylactic acid (PLA) using supercritical fluid (SCF) technology. A precipitation with a compressed antisolvent (PCA) technique employing supercritical CO2 and a nozzle with 100-μm internal diameter was used to prepare microparticles of budesonide and budesonide-PLA. The effect of various operating variables (temperature and pressure of CO2 and flow rates of drug-polymer solution and/or CO2) and formulation variables (0.25%, 0.5%, and 1% budesonide in methylene chloride) on the morphology and size distribution of the microparticles was determined using scanning electron microscopy. In addition, budesonide-PLA particles were characterized for their surface charge and drug-polymer interactions using a zeta meter and differential scanning calorimetry (DSC), respectively. Furthermore, in vitro budesonide release from budesonide-PLA microparticles was determined at 37°C. Using the PCA process, budesonide and budesonide-PLA microparticles with mean diameters of 1 to 2 μm were prepared. An increase in budesonide concentration (0.25%–1% wt/vol) resulted in budesonide microparticles that were fairly spherical and less aggiomerated. In addition, the size of the microparticles increased with an increase in the drug-polymer solution flow rate (1.4–4.7 mL/min) or with a decrease in the CO2 flow rate (50–10 mL/min). Budesonide-PLA microparticles had a drug loading of 7.94%, equivalent to ∼80% encapsulation efficiency. Budesonide-PLA microparticles had a zeta potential of— 37±4 mV, and DSC studies indicated that SCF processing of budesonide-PLA microparticles resulted in the loss of budesonide crystallinity. Finally, in vitro drug release studies at 37°C indicated 50% budesonide release from the budesonide-PLA microparticles at the end of 28 days. Thus, the PCA process was successful in producing budesonide and budesonide-PLA microparticles. In addition, budesonide-PLA microparticles sustained budesonide release for 4 weeks
New Insights into the Interphase between the Na Metal Anode and Sulfide Solid-State Electrolytes: A Joint Experimental and Computational Study
In
this work, we investigated the interface between the sodium anode
and the sulfide-based solid electrolytes Na<sub>3</sub>SbS<sub>4</sub> (NAS), Na<sub>3</sub>PS<sub>4</sub> (NPS), and Cl-doped NPS (NPSC)
in all-solid-state-batteries (ASSBs). Even though these electrolytes
have demonstrated high ionic conductivities in the range of 1 mS cm<sup>–1</sup> at ambient temperatures, sulfide sold-state electrolytes
(SSEs) are known to be unstable with Na metal, though the exact reaction
mechanism and kinetics of the reaction remain unclear. We demonstrate
that the primary cause of capacity fade and cell failure is a chemical
reaction spurred on by electrochemical cycling that takes place at
the interface between the Na anode and the SSEs. To investigate the
properties of the Na-solid electrolyte interphase (SSEI) and its effect
on cell performance, the SSEI was predicted computationally to be
composed of Na<sub>2</sub>S and Na<sub>3</sub>Sb for NAS and identified
experimentally via X-ray photoelectron spectroscopy (XPS). These two
compounds give the SSEI mixed ionic- and electronic-conducting properties,
which promotes continued SSEI growth, which increases the cell impedance
at the expense of cell performance and cycle life. The SSEI for NPS
was similarly found to be comprised of Na<sub>2</sub>S and Na<sub>3</sub>P, but XPS analysis of Cl-doped NPS (NPSC) showed the presence
of an additional compound at the SSEI, NaCl, which was found to mitigate
the decomposition of NPS. The methodologies presented in this work
can be used to predict and optimize the electrochemical behavior of
an all-solid-state cell. Such joint computational and experimental
efforts can inform strategies for engineering a stable electrolyte
and SSEI to avoid such reactions. Through this work, we call for more
emphasis on SSE compatibility with both anodes and cathodes, essential
for improving the electrochemical properties, longevity, and practicality
of Na-based ASSBs
Dicarba α‑Conotoxin Vc1.1 Analogues with Differential Selectivity for Nicotinic Acetylcholine and GABA<sub>B</sub> Receptors
Conotoxins
have emerged as useful leads for the development of
novel therapeutic analgesics. These peptides, isolated from marine
molluscs of the genus <i>Conus</i>, have evolved exquisite
selectivity for receptors and ion channels of excitable tissue. One
such peptide, α-conotoxin Vc1.1, is a 16-mer possessing an interlocked
disulfide framework. Despite its emergence as a potent analgesic lead,
the molecular target and mechanism of action of Vc1.1 have not been
elucidated to date. In this paper we describe the regioselective synthesis
of dicarba analogues of Vc1.1 using olefin metathesis. The ability
of these peptides to inhibit acetylcholine-evoked current at rat α9α10
and α3β4 nicotinic acetylcholine receptors (nAChR) expressed
in <i>Xenopus</i> oocytes has been assessed in addition
to their ability to inhibit high voltage-activated (HVA) calcium channel
current in isolated rat DRG neurons. Their solution structures were
determined by NMR spectroscopy. Significantly, we have found that
regioselective replacement of the native cystine framework with a
dicarba bridge can be used to selectively tune the cyclic peptide’s
innate biological activity for one receptor over another. The 2,8-dicarba
Vc1.1 isomer retains activity at γ-aminobutyric acid (GABA<sub>B</sub>) G protein-coupled receptors, whereas the isomeric 3,16-dicarba
Vc1.1 peptide retains activity at the α9α10 nAChR subtype.
These singularly acting analogues will enable the elucidation of the
biological target responsible for the peptide’s potent analgesic
activity