Pharmaceutical drugs are an important part of the global healthcare system, with some estimates suggesting over 50% of the world's population takes at least one medication per day. Most drugs are ...delivered as immediate-release formulations that lead to a rapid increase in systemic drug concentration. Although these formulations have historically played an important role, they can be limited by poor patient compliance, adverse side effects, low bioavailability, or undesirable pharmacokinetics. Drug delivery systems featuring first-order release kinetics have been able to improve pharmacokinetics but are not ideal for drugs with short biological half-lives or small therapeutic windows. Zero-order drug delivery systems have the potential to overcome the issues facing immediate-release and first-order systems by releasing drug at a constant rate, thereby maintaining drug concentrations within the therapeutic window for an extended period of time. This release profile can be used to limit adverse side effects, reduce dosing frequency, and potentially improve patient compliance. This review covers strategies being employed to attain zero-order release or alter traditionally first-order release kinetics to achieve more consistent release before discussing opportunities for improving device performance based on emerging materials and fabrication methods.
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•A critical review of translational zero-order drug delivery systems.•Summary of the current state of common drug delivery devices.•Discussion of the techniques being employed to advance towards zero-order release.•Insight on the future of zero-order drug release.
Fungal biofilms cause a major clinical problem with a shrinking armamentarium for treatment. Here, the design and synthesis of voriconazole‐inbuilt zinc 2‐methylimidazolates frameworks (V‐ZIF) is ...reported. Voriconazole is built in through coordination‐binding between zinc and voriconazole. These metal–organic‐frameworks with inbuilt voriconazole, reduce inadvertent voriconazole‐leakage, yield a zero‐order release kinetics of voriconazole, aid antifungal penetration in Candida albicans biofilms, and prevent Candida aggregation yielding better dispersal. Once accumulated in an acidic C. albicans biofilm, voriconazole dissociates from the metal–organic framework to cause membrane‐damage and killing of inhabiting fungi. Moreover, in a murine model, the V‐ZIFs eradicate open‐wound infections caused by C. albicans better than voriconazole in solution, with negligible side effects to the healthy tissues of major organs. Thus, V‐ZIFs may provide a welcome addition to the antifungal armamentarium currently available for the treatment of fungal biofilms.
Voriconazole‐inbuilt zinc 2‐methylimidazolates frameworks are fabricated through coordination‐binding between zinc and voriconazole. These metal–organic frameworks (MOFs) with inbuilt voriconazole yield zero‐order release kinetics of voriconazole and aid antifungal penetration in C. albicans biofilms. Once accumulated in an acidic C. albicans biofilm, voriconazole dissociates from the MOF to cause membrane‐damage and killing of inhabiting fungi.
Microparticles are successfully engineered through controlled interfacial self‐assembly of polymers to harmonize ultrahigh drug loading with zero‐order release of protein payloads. To address their ...poor miscibility with carrier materials, protein molecules are transformed into nanoparticles, whose surfaces are covered with polymer molecules. This polymer layer hinders the transfer of cargo nanoparticles from oil to water, achieving superior encapsulation efficiency (up to 99.9%). To control payload release, the polymer density at the oil–water interface is enhanced, forming a compact shell for microparticles. The resultant microparticles can harvest up to 49.9% mass fraction of proteins with zero‐order release kinetics in vivo, enabling an efficient glycemic control in type 1 diabetes. Moreover, the precise control of engineering process offered through continuous flow results in high batch‐to‐batch reproducibility and, ultimately, excellent scale‐up feasibility.
A controlled interfacial polymer self‐assembly enables the engineering of a microparticle that simultaneously features efficient protein and peptide encapsulation (up to 99.9%), ultrahigh mass fraction of therapeutics (up to 49.9%), and zero‐order release of payloads. The developed strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performances of water‐soluble therapeutics.
One of the main objectives of Material Flow Control (MFC) is to ensure delivery performance. Traditional MFC realizes this through independent decisions at two levels: order release and production ...authorization on the shop floor. This hierarchical decision-making can be improved by integration because these decisions are interconnected. This study introduces a new reinforcement learning method that combines, and jointly optimizes various MFC decisions. It enhances the delivery performance of an agent by enabling it to interact with the environment and to learn the parameters of the decision model. Results from a make-to-order pure job shop simulation model demonstrate that the new approach outperforms exiting MFC methods in most cases. This extends existing literature on MFC, which remains entrenched in traditional decision methods, and existing literature on reinforcement learning in the context of production planning and control, which remains largely focused on production scheduling. It has important implications for the future design of production planning and control systems and practice, specifically in contexts where data is readily available or a digital shadow can be obtained.
•Transcends hierarchical material flow control.•Integrates release, authorization and dispatching decision.•Outlines a new material flow control mechanism that uses reinforcement learning.•Demonstrates that the new mechanism can outperform the state-of-the-art.
Poly(lactic-
-glycolic acid) (PLGA) is the most prevalent polymer drug delivery vehicle in use today. There are about 20 commercialized drug products in which PLGA is used as an excipient. In more ...than half of these formulations, PLGA is used in the form of microparticles (with sizes in the range between 60 nm and 100 μm). The primary role of PLGA is to control the kinetics of drug release toward achieving sustained release of the drug. Unfortunately, most drug-loaded PLGA microparticles exhibit a common drawback: an initial uncontrolled burst of the drug. After 30 years of utilization of PLGA in controlled drug delivery systems, this initial burst drug release still remains an unresolved challenge. In this Review, we present a summary of the proposed mechanisms responsible for this phenomenon and the known factors affecting the burst release process. Also, we discuss examples of recent efforts made to reduce the initial burst release of the drug from PLGA particles.
Programmable engineered DNA origami provides infinite possibilities for customizing nanostructures with controllable precision and configurable functionality. Here, a strategy for fabricating an ...amphiphilic triangular DNA origami with a central nanopore that integrates phase‐stabilizing, porous‐gated, and affinity‐delivering effects is presented. By introducing the DNA origami as a single‐component surfactant, the water‐in‐oil‐in‐water (W/O/W) emulsion is effectively stabilized with decreased interfacial tension. Microscopic observation validates the attachment of the DNA origami onto the water‐in‐oil and oil‐in‐water interfaces. Furthermore, fluorescence studies and molecular docking simulations indicate the binding interactions of DNA origami with arbutin and coumaric acid at docking sites within central nanopores. These central nanopores are functionalized as molecular gates and affinity‐based scaffold for the zero‐order release of arbutin and coumaric acid at a constant rate regardless of concentration gradient throughout the whole releasing period. In vivo zebrafish results illustrate the advantages of this zero‐order release for anti‐melanogenesis therapy over direct exposure or Fickian diffusion. The DNA origami‐based W/O/W emulsion presents anti‐melanogenic effects against UV‐B exposure without cardiotoxicity or motor toxicity. These results demonstrate that this non‐toxic amphiphilic triangular DNA origami is capable of solely stabilizing the W/O/W emulsion as well as serving as nanopore gates and affinity‐based scaffold for constant release.
Customized amphiphilic triangular DNA origami with a central nanopore successfully attaches onto the water‐in‐oil and oil‐in‐water interfaces as a single‐component surfactant to solely stabilize the water‐in‐oil‐in‐water emulsion. The nanopores with specific binding interactions are functionalized as nano‐porous gated materials for the zero‐order release of arbutin and coumaric acid for anti‐melanogenesis therapy.
This work designed a pH-sensitive sodium alginate hydrogel for combating bacterial infection caused by tissue damage. The antibacterial hydrogels were prepared using sodium alginate, citric acid, and ...vancomycin by one-step in situ method. Vancomycin (Van) was loaded into hydrogels via reversible imine bonds for controlled drug delivery. The morphology, swelling properties, and antibacterial activity of hydrogel were characterized. The hydrogel shown strong water absorbent behavior and pH-dependent performance. The result under weak acid conditions, the drug release rate of van-loaded gel was faster than neutral and alkaline conditions and followed zero-order kinetic release model, and the cumulative release amount could reach 86.7 % over 320 min. The van-loaded gel had highly effective antibacterial activity in a weak acid environment, the combination of citric acid and vancomycin had a synergistic therapeutic effect for acute infection. The drug-loaded hydrogel shows good biocompatibility. Compared with gauze, the drug-loaded hydrogel exhibited good coagulation properties, high platelet adhesion, high fluid absorption capacity, and proper balance of fluid on the wound bed. This work proposed this simple alginate-based drug delivery system has potential applications in the field of clinical treatment of infections.
•SA-CA-Van hydrogels were prepared by a simple physical cross-linking.•SA-CA-Van hydrogels showed high fluid absorption properties and pH-dependent performance.•The cumulative release of SA-CA-Van gel can reach 86.7% in acidic conditions, following zero-order release kinetics.•SA-CA-Van hydrogel have efficient synergistic antibacterial effect for acute bacterial infection.•The SA-CA-Van dressing exhibited good biocompatibility, coagulation properties, and high platelet adhesion.
DNA Origami‐Based Emulsion
An amphiphilic triangular DNA origami successfully attaches onto the water‐in‐oil and oil‐in‐water interfaces to solely stabilize the W/O/W emulsion. The DNA origami‐based ...emulsion is functionalized as a material platform for a bind‐and‐release of specific cargos. More information can be found in article 2104831 by Xingyu Lin, Zisheng Luo, and co‐workers.
3D printing has been recently employed in the design and fabrication of medicine, aiming to improve their properties and release behavior. In the current work an oral solid dosage form was created by ...Fused Deposition Modeling (FDM), using a custom built filament comprised of a water soluble polymer polyvinyl alcohol (PVA), mannitol and hydrochlorothiazide (HCTZ) as model drug and further co-formulated via Hot-Melt Extrusion (HME). This composition was printed as the inner part of a three-compartment hollow cylinder dosage form using a dual extrusion 3D FDM printer, whereas the outer parts of the formulation consisted of water-insoluble polylactic acid (PLA). The produced formulations were characterized by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Release studies were performed in pH 1.2 and 6.8 whereas time-lapsed X-ray microfocus Computed Tomography (4D-CT), was employed to visualize volumetric and morphological changes of the formulations during the dissolution procedure. The results showed that HCTZ was incorporated in the amorphous state. Dissolution studies demonstrated that HCTZ exhibited zero-order kinetics whereas 4D-CT revealed a bi-directional smooth and homogenous reduction of PVA further corroborating the dissolution studies. The results showed that FDM printing might be used to ‘fine tune’ the release of drug molecules.
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Poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide) (PLA) polymers were used successfully in the preparation of polymer shell microcapsules with mononuclear aqueous cores by ...the internal phase separation method. These microcapsules were prepared with varying amounts of polymer and water and loaded with fluorescein sodium as a model water soluble drug. Evaluation of drug loading and encapsulation efficiency reveals an optimum polymer to water ratio of around 1:3. Prepared PLGA and PLA microcapsules exhibit sustained drug release over 7 and 49 days, respectively. Drug release from both microcapsule types follow zero order kinetics over the first 90% release. Further tuning of release rate is found possible by preparing microcapsules with mixtures of PLGA and PLA polymers at varying ratios. These results suggest that aqueous core-PLGA and PLA microcapsules would be promising platforms for a wide range of sustained drug delivery systems for many hydrophilic drugs.
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