Drug Delivery Profile Research Articles

BioMOF@cellulose Glycerogel Scaffold with Multifold Bioactivity: Perspective in Bone Tissue Repair.

The development of new biomaterials for musculoskeletal tissue repair is currently an important branch in biomedicine research. The approach presented here is centered around the development of a prototypic synthetic glycerogel scaffold for bone regeneration, which simultaneously features therapeutic activity. The main novelty of this work lies in the combination of an open meso and macroporous nanocrystalline cellulose (NCC)-based glycerogel with a fully biocompatible microporous bioMOF system (CaSyr-1) composed of calcium ions and syringic acid. The bioMOF framework is further impregnated with a third bioactive component, i.e., ibuprofen (ibu), to generate a multifold bioactive system. The integrated CaSyr-1(ibu) serves as a reservoir for bioactive compounds delivery, while the NCC scaffold is the proposed matrix for cell ingrowth, proliferation and differentiation. The measured drug delivery profiles, studied in a phosphate-buffered saline solution at 310 K, indicate that the bioactive components are released concurrently with bioMOF dissolution after ca. 30 min following a pseudo-first-order kinetic model. Furthermore, according to the semi-empirical Korsmeyer-Peppas kinetic model, this release is governed by a case-II mechanism, suggesting that the molecular transport is influenced by the relaxation of the NCC matrix. Preliminary in vitro results denote that the initial high concentration of glycerol in the NCC scaffold can be toxic in direct contact with human osteoblasts (HObs). However, when the excess of glycerol is diluted in the system (after the second day of the experiment), the direct and indirect assays confirm full biocompatibility and suitability for HOb proliferation.

Research Strategies for Precise Manipulation of Micro/Nanoparticle Drug Delivery Systems Using Microfluidic Technology: A Review

AbstractMicrofluidic technology facilitates precise control over fluid mixing and interactions between the components, including self-assembly and precipitation. It offers new options for accurately manufacturing particles and holds significant potential in advancing micro/nanoparticle drug delivery systems (DDSs). Various microchannel/microfluidic chips have been explored to construct micro/nanoparticle DDSs. The precise manipulation of particle size, morphology, structure, stiffness, surface characteristics, and elasticity through microfluidic technology relies on specific microchannel geometrical designs and the application of exogenous energy, adhering to the principles of fluid motion. Consequently, this enables reproducible control over critical quality attributes (CQAs), such as particle size and distribution, encapsulation efficiency, drug loading, in vitro and in vivo drug delivery profiles, Zeta potential, and targeting capabilities, for micro/nanoparticle DDSs. In this review, we categorize microfluidic techniques and explore recent research developments in novel microchannel structures spanning the past 5 years (2018–2023) and their applications in micro/nanoparticle DDSs. Additionally, we elucidate the latest manipulation strategies of microfluidic techniques that impact foundational structures related to the CQAs of micro/nanoparticle DDSs. Furthermore, we offer insights into the industrial applications and challenges microfluidic techniques face in the context of novel micro/nanoparticle DDSs.

Mini-review of the bi-component nanofibrous scaffolds and drug delivery applications

Drug delivery systems perform to improve the drug's efficacy and heal the affected region. Electrospun nanofibers are strong drug carriers as a scaffold due to their high specific surface area, easy processing, lightweight material. Fibrous scaffolds encapsulating functional bioactive agents are important for drug delivery applications, and they show higher encapsulation efficiency and higher drug loading capacity than various types of carrier materials such as hydrogels, micro/nanobeads, films, conventional fibers, and sponges. In comparison to conventional electrospinning, bi-component electrospinning where drug loading does not occur largely on the surface of the polymer matrix, core-shell nanofibers showed delayed release and a decrease in burst release because the drug was loaded into the core layer. The purpose of this mini-review is to investigate the production and applications of the drug-loaded bi-component nanofibers in structure core-shell, side-by-side, hollow nanofibers, and also emulsion nanofibers using co-axial nozzles. Further, the parameters which influence of these electrospinning process, such as working conditions and polymer properties, as well as drug delivery profile of the resulting nanofibers, have been outlined briefly. The limited clinical studies on the nanofibers have been discussed. Eventually, perspectives on the problems, possibilities, and new approaches for electrospinning advancements have been presented, as well.

Low fouling and pH-responsive poly(N-vinyl imidazole)/poly(ethylene glycol) methacrylate copolymer gels for colon targeted diclofenac sodium delivery

Protein and cell adhesion onto drug delivery matrices interferes with the predesigned drug delivery profile to the targeted site. Antifouling surfaces are needed to overcome this problem and improve the effectiveness and efficiency of drug delivery systems. Copolymers of N-vinyl imidazole (NVI) with poly(ethylene glycol methacrylate) (PEGMA) were synthesized via free radical polymerization under cryogenic conditions as potential pH-responsive drug delivery systems resistant to protein and cell adhesion. FTIR spectroscopy, elemental analysis, thermal analysis (DSC), mechanical tests, contact angle, surface energy, and SEM analysis provide the physicochemical properties of the samples. Static adsorption/adhesion experiments show that the copolymer cryogels resist BSA adhesion. Furthermore, the copolymer cryogels demonstrate anti-cell adhesion behavior against colon colorectal carcinoma (HCT-116) cells. They are non-cytotoxic toward HDFa fibroblasts. Diclofenac sodium (DS) - loaded copolymer cryogels show pH-dependent sustained drug delivery. The release studies show a limited release in stomach pH (2.0). On the other hand, enhanced release is observed in pH 5.0 and pH 7.4 within 15 h. The quantities of diclofenac sodium released from the copolymer cryogels are sufficient to show anti-inflammatory activity.

Silicon-Based Piezo Micropumps Enable Fully Flexible Drug Delivery Patterns

Drug release plays a crucial role in drug delivery. While current formulation approaches are capable of coarse-tuning the release profile, their precision and reproducibility are limited by the physicochemical properties of the excipients and active pharmaceutical ingredient (API). Innovative and advanced approaches are urgently needed, especially for site-specific targeting of drugs and to address their pharmacological requirements for optimal therapy. The 5 × 5 × 0.6 mm3 piezoelectric micropump developed by Fraunhofer EMFT was designed to enable precise drug delivery in a low volume format. In this study, we investigated the ability of the micropump to deliver solutions of highly soluble APIs using a wide range of customized pump profiles. Additionally, we examined the ability of the micropump to deliver suspensions containing various defined particle sizes. While results for suspensions indicate that pumping performance is highly dependent on the size and concentration of the suspended particles, results with API solutions demonstrate high precision and reproducibility of release, coupled with maximum flexibility in the release profile of the API. The piezoelectric micropump thus lays the cornerstone in the development of a wide range of innovative drug delivery profiles, enabling customized release profiles to be programmed and thus paving the way to fully personalized medicine.

Advances in Therapeutic Contact Lenses for the Management of Different Ocular Conditions.

In the advent of an increasingly aging population and due to the popularity of electronic devices, ocular conditions have become more prevalent. In the world of medicine, accomplishing eye medication administration has always been a difficult task. Despite the fact that there are many commercial eye drops, most of them have important limitations, due to quick clearance mechanisms and ocular barrers. One solution with tremendous potential is the contact lens used as a medication delivery vehicle to bypass this constraint. Therapeutic contact lenses for ocular medication delivery have attracted a lot of attention because they have the potential to improve ocular bioavailability and patient compliance, both with minimal side effects. However, it is essential not to compromise essential features such as water content, optical transparency, and modulus to attain positive in vitro and in vivo outcomes with respect to a sustained drug delivery profile from impregnated contact lenses. Aside from difficulties like drug stability and burst release, the changing of lens physico-chemical features caused by therapeutic or non-therapeutic components can limit the commercialization potential of pharmaceutical-loaded lenses. Research has progressed towards bioinspired techniques and smart materials, to improve the efficacy of drug-eluting contact lenses. The bioinspired method uses polymeric materials, and a specialized molecule-recognition technique called molecular imprinting or a stimuli-responsive system to improve biocompatibility and support the drug delivery efficacy of drug-eluting contact lenses. This review encompasses strategies of material design, lens manufacturing and drug impregnation under the current auspices of ophthalmic therapies and projects an outlook onto future opportunities in the field of eye condition management by means of an active principle-eluting contact lens.

A NIR-Activated and Mild-Temperature-Sensitive Nanoplatform with an HSP90 Inhibitor for Combinatory Chemotherapy and Mild Photothermal Therapy in Cancel Cells.

Mild photothermal therapy (PTT) shows great potential to treat cancers while avoiding unwanted damage to surrounding normal cells. However, the efficacy of mild PTT is normally moderate because of the low hyperthermia temperature and limited light penetration depth. Chemotherapy has unlimited penetration but often suffers from unsatisfactory efficacy in view of the occurrence of drug resistance, suboptimal drug delivery and release profile. As a result, the combinatory of chemotherapy and mild PTT would integrate their advantages and overcome the shortcomings. Herein, we synthesized an NIR-activatable and mild-temperature-sensitive nanoplatform (BDPII-gel@TSL) composed of temperature-sensitive liposomes (TSL), heat shock protein 90 (HSP90) inhibitor (geldanamycin) and photothermal agent (BDPII), for dual chemotherapy and mild PTT in cancer cells. BDPII, constructed with donor-acceptor moieties, acts as an excellent near-infrared (NIR) photothermal agent (PTA) with a high photothermal conversion efficiency (80.75%). BDPII-containing TSLs efficiently produce a mild hyperthermia effect (42 °C) under laser irradiation (808 nm, 0.5 W cm-2). Importantly, the phase transformation of TSL leads to burst release of geldanamycin from BDPII-gel@TSL, and this contributes to down-regulation of the overexpression of HSP90, ensuring efficient inhibition of cancer cell growth. This research provides a dual-sensitive synergistic therapeutic strategy for cancer cell treatment.

Cyclodextrins as Multi-Functional Ingredients in Dentistry.

Cyclodextrins are present in a variety of oral hygiene compositions. The present work describes the role of cyclodextrins in several toothpastes and mouthwashes that are already available in the market, as well as their prospective use in other applications as investigated in studies in the literature. Moreover, cyclodextrins are under study for the development of materials used in various techniques of dental repair, such as fillings, cements and binders therein. Their role in each of the innovative materials is presented. Finally, the prospect of the use of cyclodextrin-based delivery systems for the oral cavity is introduced, with a focus on new cyclodextrin molecules with dual action as bone-targeting agents and osteogenic drugs, and on new cross-linked cyclodextrin particles with a high drug loading and sustained drug delivery profile for the treatment of diseases that require prolonged action, such as periodontitis. In conclusion, cyclodextrins are herein demonstrated to act as versatile and multi-action ingredients with a broad range of applications in dentistry.

A standard 96-well based high throughput microfluidic perfusion biofilm reactor for in situ optical analysis.

Biofilm infections represent a major public health threat due to their high tolerance to antimicrobials and the lack of specific anti-biofilm drugs. To develop such drugs, it is crucial to have high-throughput biofilm growth systems that can emulate in vivo conditions without the cost and complexity of animal models. However, no current biofilm reactor can provide in vivo-like conditions in a high throughput standard microtiter format. This paper demonstrates a novel high-throughput (HT) microfluidic perfusion biofilm reactor (HT-μPBR) compatible with a standard 96-well microtiter plate for in situ optical analysis. A snap-on liquid-tight cover for standard microtiter plates was designed and fabricated with fluidic channels to provide closed-loop recirculating perfusion. Our system takes steps toward providing in vivo-like conditions with controlled shear stress and nutrient delivery. We describe the system fabrication and usage in optical analysis of biomass and viability of Escherichia coli (E. coli) biofilms. The HT-μPBR was set to perfuse at 1mL/min corresponding to an average shear rate of approximately [Formula: see text] on the bottom surface of a single well. Biofilms were detected on well plate bottoms and measured using a fluorescence microscope and plate reader to determine biomass and viability. Samples cultured in the HT-μPBR showed increased biomass while maintaining viability after 24h. The HT-μPBR can further be combined with HT antibiotic susceptibility testing and additional optical techniques such as time-lapse imaging to improve understanding of the drug reaction mechanism as well as the optimization of drug combinations and delivery profiles.

Drug delivery improvements to enable a flexible care setting for monoclonal antibody medications in oncology - Analogue-based decision framework

Introduction : The substantial acceleration in healthcare spending together with the expenditures to manage the COVID-19 pandemic demand drug delivery solutions that enable a flexible care setting for high-dose monoclonal antibodies (mAbs) in oncology. Areas covered : This expert opinion introduces an analogue-based framework applied to guide decision making for associated product improvements for mAb medications that are either already authorized or in late-stage clinical development. The four pillars of this framework comprise (1) the drug delivery profile of current and emerging treatments in the market, (2) the needs and preferences of people treated with mAbs, (3) existing healthcare infrastructures, and (4) country-dependent reimbursement and procurement models. The following product optimization examples for mAb-based treatments are evaluated based on original research and review articles in the field: subcutaneous formulations, an established drug delivery modality to reduce parenteral dosing complexity, fixed-dose combinations, an emerging concept to complement combination therapy, and (connected) on-body delivery systems, an identified future opportunity to support dosing outside of a controlled healthcare institutional environment. Expert opinion : Leveraging existing synergies and learnings from other disease areas is a measure to reduce associated development and commercialization costs and thus to provide sustainable product offerings already at initial launch of a medication.

Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery.

Nano-emulgel is an emerging drug delivery system intended to enhance the therapeutic profile of lipophilic drugs. Lipophilic formulations have a variety of limitations, which includes poor solubility, unpredictable absorption, and low oral bioavailability. Nano-emulgel, an amalgamated preparation of different systems aims to deal with these limitations. The novel system prepared by the incorporation of nano-emulsion into gel improves stability and enables drug delivery for both immediate and controlled release. The focus on nano-emulgel has also increased due to its ability to achieve targeted delivery, ease of application, absence of gastrointestinal degradation or the first pass metabolism, and safety profile. This review focuses on the formulation components of nano-emulgel for topical drug delivery, pharmacokinetics and safety profiles.

Natural Products as Outstanding Alternatives in Diabetes Mellitus: A Patent Review.

Diabetes mellitus (DM) is a metabolic syndrome that can be considered a growing health problem in the world. High blood glucose levels are one of the most notable clinical signs. Currently, new therapeutic alternatives have been tackled from clinicians' and scientists' points of view. Natural products are considered a promising source, due to the huge diversity of metabolites with pharmaceutical applications. Therefore, this review aimed to uncover the latest advances in this field as a potential alternative to the current therapeutic strategies for the treatment of DM. This purpose is achieved after a patent review, using the Espacenet database of the European Patent Office (EPO) (2016-2022). Final screening allowed us to investigate 19 patents, their components, and several technology strategies in DM. Plants, seaweeds, fungi, and minerals were used as raw materials in the patents. Additionally, metabolites such as tannins, organic acids, polyphenols, terpenes, and flavonoids were found to be related to the potential activity in DM. Moreover, the cellular transportation of active ingredients and solid forms with special drug delivery profiles is also considered a pharmaceutical technology strategy that can improve their safety and efficacy. From this perspective, natural products can be a promissory source to obtain new drugs for DM therapy.

One-Step Preparation of Carboxymethyl Cellulose-Phytic Acid Hydrogels with Potential for Biomedical Applications.

Hydrogels based on natural, biodegradable materials have gained considerable interest in the medical field due to their improved drug delivery profiles and tissue-mimicking architecture. In this regard, this study was devoted to the preparation and characterization of new physically crosslinked hydrogels based on carboxymethyl cellulose and an unconventional crosslinking agent, phytic acid. Phytic acid, in addition to its antioxidant and antibacterial effects, can improve the biological properties and stability of gels, without adding toxicity. Fourier transform infrared (FTIR) spectroscopy, rheological studies and thermal analysis confirmed the hydrogel formation. The influence of the ratio between the cellulose derivative and the crosslinker upon the morphological structure and water uptake was evidenced by scanning electron microscopy (SEM) and swelling measurements in simulated body fluids. Furthermore, procaine was entrapped within the hydrogels and used as a model drug for in vitro studies, which highlighted the dependence of the drug release on the phytic acid content of the matrix. The materials demonstrated antibacterial effects against Escherichia coli and Staphylococcus aureus bacteria. The biocompatibility was assessed on fibroblast cells, and according to our results, hydrogels can improve cell viability highlighting the potential of these systems as therapeutic scaffolds for skin tissue engineering.

Ultrasound Responsive Smart Implantable Hydrogels for Targeted Delivery of Drugs: Reviewing Current Practices.

Over the last two decades, the process of delivering therapeutic drugs to a patient with a controlled release profile has been a significant focus of drug delivery research. Scientists have given tremendous attention to ultrasound-responsive hydrogels for several decades. These smart nanosystems are more applicable than other stimuli-responsive drug delivery vehicles (ie UV-, pH- and thermal-, responsive materials) because they enable more efficient targeted treatment via relatively non-invasive means. Ultrasound (US) is capable of safely transporting energy through opaque and complex media with minimal loss of energy. It is capable of being localized to smaller regions and coupled to systems operating at various time scales. However, the properties enabling the US to propagate effectively in materials also make it very difficult to transform acoustic energy into other forms that may be used. Recent research from a variety of domains has attempted to deal with this issue, proving that ultrasonic effects can be used to control chemical and physical systems with remarkable specificity. By obviating the need for multiple intravenous injections, implantable US responsive hydrogel systems can enhance the quality of life for patients who undergo treatment with a varied dosage regimen. Ideally, the ease of self-dosing in these systems would lead to increased patient compliance with a particular therapy as well. However, excessive literature has been reported based on implanted US responsive hydrogel in various fields, but there is no comprehensive review article showing the strategies to control drug delivery profile. So, this review was aimed at discussing the current strategies for controlling and targeting drug delivery profiles using implantable hydrogel systems.

Optimization of Initial Drug Distribution in Spherical Capsules for Personalized Release.

Customization of the rate of drug delivered based on individual patient requirements is of paramount importance in the design of drug delivery devices. Advances in manufacturing may enable multilayer drug delivery devices with different initial drug distributions in each layer. However, a robust mathematical understanding of how to optimize such capabilities is critically needed. The objective of this work is to determine the initial drug distribution needed in a spherical drug delivery device such as a capsule in order to obtain a desired drug release profile. This optimization problem is posed as an inverse mass transfer problem, and optimization is carried out using the solution of the forward problem. Both non-erodible and erodible multilayer spheres are analyzed. Cases with polynomial forms of initial drug distribution are also analyzed. Optimization is also carried out for a case where an initial burst in drug release rate is desired, followed by a constant drug release rate. More than 60% reduction in root-mean-square deviation of the actual drug release rate from the ideal constant drug release rate is reported. Typically, the optimized initial drug distribution in these cases prevents or minimizes large drug release rate at early times, leading to a much more uniform drug release overall. Results demonstrate potential for obtaining a desired drug delivery profile over time by carefully engineering the drug distribution in the drug delivery device. These results may help engineer devices that offer customized drug delivery by combining advanced manufacturing with mathematical optimization.

Indirect Additive Manufacturing: A Valid Approach to Modulate Sorption/Release Profile of Molecules from Chitosan Hydrogels.

This work studied the influence of hydrogel’s physical properties (geometry and hierarchical roughness) on the in vitro sorption/release profiles of molecules. To achieve this goal, chitosan (CS) solutions were cast in 3D-printed (3DP) molds presenting intricate shapes (cubic and half-spherical with/without macro surface roughness) and further immersed in alkaline solutions of NaOH and NaCl. The resulting physically crosslinked hydrogels were mechanically stable in aqueous environments and successfully presented the shapes and geometries imparted by the 3DP molds. Sorption and release profiles were evaluated using methyl orange (MO) and paracetamol (PMOL) as model molecules, respectively. Results revealed that distinct MO sorption/PMOL release profiles were obtained according to the sample’s shape and presence/absence of hierarchical roughness. MO sorption capacity of CS samples presented both dependencies of hierarchical surface and geometry parameters. Hence, cubic samples without a hierarchical surface presented the highest (up to 1.2 × greater) dye removal capacity. Moreover, PMOL release measurements were more dependent on the surface area of hydrogels, where semi-spherical samples with hierarchical roughness presented the fastest (~1.13 × faster) drug delivery profiles. This work demonstrates that indirect 3DP (via fused filament fabrication (FFF) technology) could be a simple strategy to obtain hydrogels with distinct sorption/release profiles.

Abstract No. 351 Microneedle array platform with spatial control of heating and drug delivery profiles for experimental studies in small animals

Therapeutic strategies combining energy-based interventions and intratumoral immunotherapy are under investigation, however, the relationship between spatial energy-delivery profiles and bioeffects are not currently well understood. We are developing a microneedle array-based platform for experimental studies in small-animal tumor models investigating intratumoral immunotherapy in conjunction energy-based therapies. This abstract reports on the simulation-based characterization of spatially modulated thermal profiles achievable with the microneedle array.

Validation of Psychophysiological Measures for Caffeine Oral Films Characterization by Machine Learning Approaches.

(1) Background: The oral films are a new delivery system that can carry several molecules, such as neuromodulator molecules, including caffeine. These delivery systems have been developed and characterized by pharmacokinetics assays. However, new methodologies, such as psychophysiological measures, can complement their characterization. This study presents a new protocol with psychophysiological parameters to characterize the oral film delivery systems based on a caffeine model. (2) Methods: Thirteen volunteers (61.5% females and 38.5% males) consumed caffeine oral films and placebo oral films (in different moments and without knowing the product). Electrocardiogram (ECG), electrodermal (EDA), and respiratory frequency (RF) data were monitored for 45 min. For the data analysis, the MATLAB environment was used to develop the analysis program. The ECG, EDA, and RF signals were digitally filtered and processed, using a windowing process, for feature extraction and an energy mean value for 5 min segments. Then, the data were computed and presented to the entries of a set of Machine Learning algorithms. Finally, a data statistical analysis was carried out using SPSS. (3) Results: Compared with placebo, caffeine oral films led to a significant increase in power energy in the signal spectrum of heart rate, skin conductance, and respiratory activity. In addition, the ECG time-series power energy activity revealed a better capacity to detect caffeine activity over time than the other physiological modalities. There was no significant change for the female or male gender. (4) Conclusions: The protocol developed, and the psychophysiological methodology used to characterize the delivery system profile were efficient to characterize the drug delivery profile of the caffeine. This is a non-invasive, cheap, and easy method to apply, can be used to determine the neuromodulator drugs delivery profile, and can be implemented in the future.

Implantable Microfluidic Device: An Epoch of Technology.

Implantable microfluidic devices are milestones in developing devices that can measure parameters like ocular pressure and blood glucose level or deliver various components for therapeutic needs or behavioral modification. Researchers are currently focusing on the miniaturization of almost all its tools for a better healthcare platform. Implantable microfluidic devices are a combination of various systems including, but not limited to, microfluidic platforms, reservoirs, sensors, and actuators, implanted inside the body of a living entity (in vivo) with the purpose of directly or indirectly helping the entity. It is a multidisciplinary approach with immense potential in the area of the biomedical field. Significant resources are utilized for the research and development of these devices for various applications. The induction of an implantable microfluidic device into an animal would enable us to measure the responses without any repeated invasive procedures. Such data would help in the development of a better drug delivery profile. Implantable microfluidic devices with reservoirs deliver specific chemical or biological products to treat situations like cancers and diabetes. They can also deliver fluorophores for specific imaging inside the body. Implantable microfluidic devices help provide a microenvironment for various cell differentiation procedures. These devices know no boundaries, and this article reviews these devices based on their design and applications.

Electrospinning of stimuli‐responsive polymers for controlled drug delivery: pH‐ and temperature‐driven release

Stimuli-responsive polymers have attracted academic interest over the last 60 years due to their potential use in developing systems with a range of functionalities that can be activated by external artificial triggers. The diversity of responses and stimuli, which can be achieved through careful polymer selection and processing, opens up applications in nearly every sector. In particular, the use of responsive polymers for the controlled delivery of drugs and bioactive compounds has been heavily researched. This review provides an overview of the recent advancements in electrospinning of temperature- and pH-responsive polymers to create networks of nanofibres with controlled drug delivery profiles for biomedical applications.