Controlled Drug Delivery Devices Research Articles

Injectable and 3D Extrusion Printable Hydrophilic Silicone-Based Hydrogels for Controlled Ocular Delivery of Ophthalmic Drugs.

While silicone elastomers have found widespread use in the biomedical industry, 3D printing them has proven to be difficult due to the material's slow drying time, low viscosity, and hydrophobicity. Herein, we arrested the hydrophilic silicone (HS) macrochains into a semi-interpenetrating polymer network (semi-IPN) via an in situ photogelation-assisted 3D microextrusion printing technique. The flow behavior of the pregel solutions and the mechanical properties of the printed HS hydrogels were tested, showing a high elastic modulus (approximately 15 kPa), a low tan δ, high elasticity, and delayed network rupturing. The uniaxial compression tests demonstrated a nearly negligible permanent deformation, suggesting that the printed hybrid hydrogel maintained its elastic properties. Drug loading and diffusion in the microporous hydrogel are shown via the non-Fickian anomalous transport mechanism, leading to highly tunable loading/releasing profiles (approximately 20% cumulative release) depending on the HS concentration. The drug encapsulation exhibits exceptional stability, remaining intact without any degradation even after a storage period of 1 month. As far as we know, this is the first soft biomaterial based on HS that functions as an exceptional controlled drug delivery device.

Nanoliter Liquid Packaging in a Bioresorbable Microsystem by Additive Manufacturing and its Application as a Controlled Drug Delivery Device

AbstractPrecise packaging of nanoliter amounts of liquid in a microsystem is important for many biomedical applications. However, existing liquid encapsulation technologies have limitations in terms of liquid waste, evaporation, trapped bubbles, and liquid degradation. In this study, multiple additive manufacturing techniques for nanoliter liquid packaging in bioresorbable microsystems is used. Two‐photon photolithography is used for bioresorbable reservoir fabrication, while inkjet printing (IJP) is used for precise nanoliter liquid packaging. Dual IJP allows for micro‐reservoirs to be filled with precise amounts of drug solution and subsequently and rapidly sealed with a layer of lipids mixed with Fe3O4 nanoparticles. Combining these two printing techniques can overcome the previous limitations of liquid encapsulation technologies. To demonstrate the relevance of this technique, a wirelessly activated, bioresorbable multi‐reservoir microcapsule that can be used for controlled drug delivery is presented. The microcapsules and their content are shown to be stable during fabrication, storage, and operation. Multiple cargo release events are triggered independently by the local melting of the sealing layer, resulting from magnetically induced Fe3O4 nanoparticle heating. The operation of the capsule is demonstrated in tissue phantoms and in vitro cell cultures.

Controlled Drug Delivery Device for Cornea Treatment and Novel Method for Its Testing.

A new solution for local anesthetic and antibiotic delivery after eye surgery is presented. A contact lens-shaped collagen drug carrier was created and loaded by Levofloxacin and Tetracaine with a riboflavin crosslinked surface layer, thus impeding diffusion. The crosslinking was confirmed by Raman spectroscopy, whereas the drug release was investigated using UV-Vis spectrometry. Due to the surface barrier, the drug gradually releases into the corneal tissue. To test the function of the carrier, a 3D printed device and a new test method for a controlled drug release, which mimics the geometry and physiological lacrimation rate of the human eye, were developed. The experimental setup with simple geometry revealed that the prepared drug delivery device can provide the prolonged release profile of the pseudo-first-order for up to 72 h. The efficiency of the drug delivery was further demonstrated using a dead porcine cornea as a drug recipient, without the need to use live animals for testing. Our drug delivery system significantly surpasses the efficiency of antibiotic and anesthetic eyedrops that would have to be applied approximately 30 times per hour to achieve the same dose as that delivered continuously by our device.

Development and Evaluation of Etodolac Osmotic Capsule

controlled release formulations have been developed based on their significant advantages over conventional immediate release dosage forms, such as the decrease of dosing frequency, the increase of patient compliance, better dosing patterns, the reduction of side effects, or the maintenance of the drug concentration within a desired range, i.e., an overall improved therapeutic benefit. However, oral controlled release formulations are exposed to changing environment during transit through the GI-tract which may affect their performances e.g. physiological factors such as patient age or food-intake. Reported as releasing drug independently of these factors, oral osmotically-driven systems (OODS) have taken an integral place in the pharmaceutical field. The dissolution profile of orally delivered drugs can be controlled through the use of osmotically controlled drug delivery devices. The most commonly used device is the osmotic tablet/Capsule, which is essentially a tablet/Capsule core that is coated with a rate-limiting semipermiable membrane. Using osmotic pressure as driving force, various OCODDS design and compositions have been developed. Numerous products are launched based on these systems. In present investigation attempts are taken to formulate, optimize and develop an economic osmotically controlled Capsule containing drugs belonging to non steroidal anti-inflammatory category to release the drug in controlled manner. Such formulations are most beneficial for the patients shifted on long term pain management therapy(e.g. in arthritis) in view to reduce the associated side effects of these drugs.

Poly(1-vinylpyrrolidone-co-vinyl-acetate)-based electrospun dissolvable nanofibrous film for quercetin administration

This study used electrospinning to produce a water-soluble polymeric nanofibrous film incorporated with quercetin. Scanning Electron Microscopy showed that the diameter of the nanofibers decreased from (670 ± 200) nm to (390 ± 90) nm as the amount of quercetin increased from 0% to 15%. The FTIR confirmed the presence of quercetin in the films and suggested the formation of physical interactions between the drug and the polymer. The XRD results confirmed the amorphous character of the nanofibers, and the loss of crystallinity by quercetin, due to the electrospinning process itself and the physical interactions with the polymer. The dissolution assays confirmed that the nanofibers and quercetin completely dissolved in the medium. This dissolution process reached equilibrium within 3 min. Although the material would not be effective as a controlled drug delivery device, it would be effective as a dissolvable film. The quick dissolution of both the drug and the matrix is attractive for the administration of quercetin because it would increase the bioavailability of the drug in the body, overcoming the limited dissolution of crystalline quercetin.

Soft iontronic delivery devices based on an intrinsically stretchable ion selective membrane

Implantable electronically controlled drug delivery devices can provide precision therapeutic treatments by highly spatiotemporally controlled delivery. Iontronic delivery devices rely on the movement of ions rather than liquid, and can therefore achieve electronically controlled precision delivery in a compact setting without disturbing the microenvironment within the tissue with fluid flow. For maximum precision, the delivery device needs to be closely integrated into the tissue, which is challenging due to the mechanical mismatch between the soft tissue and the harder devices. Here we address this challenge by developing a soft and stretchable iontronic delivery device. By formulating an ink based on an in-house synthesized hyperbranched polyelectrolyte, water dispersed polyurethane, and a thickening agent, a viscous ink is developed for stencil patterning of soft ion exchange membranes (IEMs). We use this ink for developing soft and stretchable delivery devices, which are characterized both in the relaxed and stretched state. We find that their functionality is preserved up to 100% strain, with small variations in resistance due to the strain. Finally, we develop a skin patch to demonstrate the outstanding conformability of the developed device. The presented technology is attractive for future soft implantable delivery devices, and the stretchable IEMs may also find applications within wearable energy devices.

Preparation of biocompatible chitosan nanoparticles loaded with Aloe vera extract for use as a novel drug delivery mechanism to improve the antibacterial characteristics of cellulose-based fabrics

The primary goal of this study was to develop nanotechnology-based controlled drug delivery devices. As a nano carrier for Aloe vera extract, chitosan nanoparticles (CSNPs) were used. The ionic gelation method was used to make CSNPs from chitosan solution using tripolyphosphate (TPP). The generated high-performance CSNPs were then loaded with Aloe vera extract to create Aloe vera-laden chitosan nanoparticle nanocomposites. The nanocomposite is then employed as a superb antibacterial material with the least amount of toxicity. To impart antibacterial activity without cytotoxicity, cotton (100%) and viscose (100%) samples were treated with varied doses of this compound. The treated fabrics with chitosan nanoparticles and their nanocomposite with various concentrations prevented the growth of both Gram-positive and Gram-negative bacteria, according to the findings. The embedding of chitosan nanoparticles into fabrics and their bioactive material loaded were revealed using Fourier Transform Infrared spectroscopy (FTIR) and Scanning Electron Microscope (SEM) research. Finally, the cytotoxicity of CSNPs and Aloe vera extract loaded CSNPs nanocomposite was assessed using a cell viability assay, confirming that the produced nanocomposite is non-toxic and tissue compatible, just like CS.

Formulation and Evaluation of Enteric Coated Elementary Osmotic Tablets of Aceclofenac

This study aimed to develop a controlled drug delivery device for aceclofenac, a non-steroidal anti-inflammatory drug. Therefore, the agent was projected to develop an osmotic pump with enteric coating. The strength of the semipermeable membrane was improved by optimizing the formulation of the device, which can control the drug release over a prolonged period of time. The formulations were designed and optimized by using the statistical design of experiment followed by 32 factorial design to discover the best formulation. Several evaluation tests were performed to assess the physical parameters of the formulations. The percentage drug release of the formulations was observed for up to 9 h. The model 3D graph analysis indicated that as an osmogen, a higher percentage of potassium chloride was utilized more effectively than mannitol for the rapid dissolution of osmotic tablets. The optimized formulation can release 88.60±0.02% up to 9 h. The accelerated stability study confirmed that the optimized formulation was stable. The formulated osmotic tablets of aceclofenac were therapeutically safe and effective and did not release any drug content in the simulated gastric medium for a predetermined time.

Design and Operation of Hybrid Microfluidic Iontronic Probes for Regulated Drug Delivery

AbstractHighly controlled drug delivery devices play an increasingly important role in the development of new neuroengineering tools. Stringent—and sometimes contradicting—demands are placed on such devices, ranging from robustness in freestanding devices, to overall device miniaturization, while maintaining precise spatiotemporal control of delivery with high chemical specificity and high on/off ratio. Here, design principles of a hybrid microfluidic iontronic probe that uses flow for long‐range pressure‐driven transport in combination with an iontronic tip that provides electronically fine‐tuned pressure‐free delivery are explored. Employing a computational model, the effects of decoupling the drug reservoir by exchanging a large passive reservoir with a smaller microfluidic system are reported. The transition at the microfluidic‐iontronic interface is found to require an expanded ion exchange membrane inlet in combination with a constant fluidic flow, to allow a broad range of device operation, including low source concentrations and high delivery currents. Complementary to these findings, the free‐standing hybrid probe monitored in real time by an external sensor is demonstrated. From these computational and experimental results, key design principles for iontronic devices are outlined that seek to use the efficient transport enabled by microfluidics, and further, key observations of hybrid microfluidic iontronic probes are explained.

An overview of polymeric nano-biocomposites as targeted and controlled-release devices.

In recent years, controlled drug delivery has become an important area of research. Nano-biocomposites can fulfil the necessary requirements of a targeted drug delivery device. This review describes use of polymeric nano-biocomposites in controlled drug delivery devices. Selection of suitable biopolymer and methods of preparation are discussed.

In vitro Evaluations of Biodegradable Polyacrylamide Grafted Moringa Bark Gum Graft Copolymer (MOG-g- PAAM) as Biomedical and Controlled Drug Delivery Device Synthesized by Microwave Accelerated free Radical Synthesis

In vitro Evaluations of Biodegradable Polyacrylamide Grafted Moringa Bark Gum Graft Copolymer (MOG-g- PAAM) as Biomedical and Controlled Drug Delivery Device Synthesized by Microwave Accelerated free Radical Synthesis

Radio frequency controlled wireless drug delivery devices

Drug delivery devices have revolutionized the course of therapeutic treatment in the recent past. These devices provide a firm foundation for diverse strategies to overcome the limitations of systemic administration that cannot provide a high drug potency at the specific disease infected body tissues. The ongoing developments in the pharmaceutical industry have focused on exploring the reliable actuating mechanisms that can provide therapy and dispense drugs precisely to control therapeutic effects with minimum toxicity. The wireless actuation of drug delivery devices has been considered as an intervening noninvasive approach to release encapsulated drug compounds. This review paper highlights implantable and transdermal drug delivery devices that are based on wirelessly controlled microchips, micropumps, microvalves, and magnetic robots. Their key features, such as working principle, dimensions, materials, operating frequency, and wireless actuation through radio frequency for drug delivery are explained. The interaction of radio waves with electrically conductive and magnetic nanoparticles is also discussed for drug delivery. Furthermore, the radio frequency assisted data telemetry and wireless power transfer techniques are elucidated for drug delivery devices. The opportunities to enhance the patients' control on therapeutic indexes and release mechanisms are still possible by incorporating advanced wireless sensors for concocting future innovations in the wirelessly controlled drug delivery devices.

Nanoparticle- and Nanoporous-Membrane-Mediated Delivery of Therapeutics.

Pharmaceutical particulates and membranes possess promising prospects for delivering drugs and bioactive molecules with the potential to improve drug delivery strategies like sustained and controlled release. For example, inorganic-based nanoparticles such as silica-, titanium-, zirconia-, calcium-, and carbon-based nanomaterials with dimensions smaller than 100 nm have been extensively developed for biomedical applications. Furthermore, inorganic nanoparticles possess magnetic, optical, and electrical properties, which make them suitable for various therapeutic applications including targeting, diagnosis, and drug delivery. Their properties may also be tuned by controlling different parameters, e.g., particle size, shape, surface functionalization, and interactions among them. In a similar fashion, membranes have several functions which are useful in sensing, sorting, imaging, separating, and releasing bioactive or drug molecules. Engineered membranes have been developed for their usage in controlled drug delivery devices. The latest advancement in the technology is therefore made possible to regulate the physico-chemical properties of the membrane pores, which enables the control of drug delivery. The current review aims to highlight the role of both pharmaceutical particulates and membranes over the last fifteen years based on their preparation method, size, shape, surface functionalization, and drug delivery potential.

From Microscale to Macroscale: Nine Orders of Magnitude for a Comprehensive Modeling of Hydrogels for Controlled Drug Delivery.

Because of their inherent biocompatibility and tailorable network design, hydrogels meet an increasing interest as biomaterials for the fabrication of controlled drug delivery devices. In this regard, mathematical modeling can highlight release mechanisms and governing phenomena, thus gaining a key role as complementary tool for experimental activity. Starting from the seminal contribution given by Flory–Rehner equation back in 1943 for the determination of matrix structural properties, over more than 70 years, hydrogel modeling has not only taken advantage of new theories and the increasing computational power, but also of the methods offered by computational chemistry, which provide details at the fundamental molecular level. Simulation techniques such as molecular dynamics act as a “computational microscope” and allow for obtaining a new and deeper understanding of the specific interactions between the solute and the polymer, opening new exciting possibilities for an in silico network design at the molecular scale. Moreover, system modeling constitutes an essential step within the “safety by design” paradigm that is becoming one of the new regulatory standard requirements also in the field-controlled release devices. This review aims at providing a summary of the most frequently used modeling approaches (molecular dynamics, coarse-grained models, Brownian dynamics, dissipative particle dynamics, Monte Carlo simulations, and mass conservation equations), which are here classified according to the characteristic length scale. The outcomes and the opportunities of each approach are compared and discussed with selected examples from literature.

Design of diffusion-controlled drug delivery devices for controlled release of Paclitaxel.

Controlled drug delivery devices were predicted in a reverse engineering framework for the controlled release of Paclitaxel, an anti-cancer drug, widely used in the treatment of solid tumors. Using quantitative structure-property relationship models for mutual diffusion coefficients of the drug in biocompatible and biodegradable polymers and partition coefficients of the drug between polymers and blood, a framework was developed to predict optimal drug delivery devices for desired dosage regimens. The validation of the predicted mutual diffusion and partition coefficients using experimental data was reported in previous studies. Optimal design parameters along with selection of most appropriate polymers suitable for different dosage regimens, selected based on current clinical practice, were predicted for maximum bioavailability of the drug while maintaining the released drug concentration in blood within the therapeutic range. Reservoir and monolithic type of diffusion-controlled drug delivery devices of different shapes and sizes were predicted with different initial drug loadings and bioavailability for different dosage regimens. The effects of the released Paclitaxel from these devices on the tumor growth were also modeled using a previously reported mathematical pharmacokinetic-pharmacodynamic model. The proposed approach can easily be used to design other diffusion-controlled drug delivery devices.

Controlled release of antibiotics from photopolymerized hydrogels: Kinetics and microbiological studies

The development of convenient synthetic methods and improved materials for the production of high load-capacity and biocompatible drug delivery systems is a challenging task with important implications in health sciences. In this work, acrylamide/2-hydroxyethylmethacrylate and N-isopropylacrylamide/2-hydroxyethylmethacrylate hydrogels were synthesized by photopolymerization using energy-efficient green-LEDs. A functionalized silsesquioxane was used as both crosslinker and co-initiator for the photopolymerization. The hybrid organic-inorganic nature of the silsesquioxane improved the resulting hydrogels' properties increasing their swelling capacity and biocompatibility. Additionally, the mild conditions used during the photopolymerization allowed the synthesis of hydrogels in the presence of antibiotics yielding high load-capacity materials in which the drug preserves its molecular structure and antimicrobial activity (as confirmed by HPLC and microbiological assays).The materials were characterized by FTIR, DSC and SEM. Additionally, the kinetics of gels´ swelling and drug release were studied under physiological conditions (pH 7.4 and 37 °C). The results demonstrate how hydrogel composition affects the antibiotics-release kinetics. The final drug release percentage increased with increasing molar fraction of acrylamide or N-isopropylacrylamide and in most cases exceeded 85%. Finally, the antibacterial effect of loaded gels was characterized using a number of assays against Gram negative and Gram positive bacteria. The observed antibacterial effect correlated well with swelling and drug release results. Furthermore, gels are not toxic for isolated erythrocytes as demonstrated by haemolytic tests. Overall, our results indicate that the produced hydrogels are promising materials to develop controlled drug-delivery devices such as capsules, dermatological patches and others.

Remotely controlled nanofluidic implantable platform for tunable drug delivery

Chronic diseases such as hypertension and rheumatoid arthritis are persistent ailments that require personalized lifelong therapeutic management. However, the difficulty of adherence to strict dosing schedule compromises therapeutic efficacy and safety. Moreover, the conventional one-size-fits-all treatment approach is increasingly challenged due to the intricacies of inter- and intra-individual variabilities. While accelerated technological advances have led to sophisticated implantable drug delivery devices, flexibility in dosage and timing modulation to tailor precise treatment to individual needs remains an elusive goal. Here we describe the development of a subcutaneously implantable remote-controlled nanofluidic device capable of sustained drug release with adjustable dosing and timing. By leveraging a low intensity electric field to modify the concentration driven diffusion across a nanofluidic membrane, the rate of drug administration can be increased, decreased or stopped via Bluetooth remote command. We demonstrate in vitro the release modulation of enalapril and methotrexate, first-line therapeutics for treatment of hypertension and rheumatoid arthritis, respectively. Further, we show reliable remote communication and device biocompatibility via in vivo studies. Unlike a pulsatile release regimen typical of some conventional controlled delivery systems, our implant offers a continuous drug administration that avoids abrupt fluctuations, which could affect response and tolerability. Our system could set the foundation for an on-demand delivery platform technology for long term management of chronic diseases.

Flexible wireless powered drug delivery system for targeted administration on cerebral cortex

The controlled drug delivery devices helps timely drug administrations and maintenance of effective dose to maximize curing effects with minimal side effects. Application of this technology to various body parts has been limited, especially in organs with curved surface, such as the brain and the eye. Herein, we report a flexible drug delivery microdevice (f-DDM) for controlled administration on the curved organ surface. The unique structure of the f-DDM consists of freestanding gold membranes over the multireservoir array was implemented by reversing the typical fabrication order of the reservoir and sealing membrane. We optimized the design of the f-DDM by a finite element analysis to prevent thermal damage during the laser transfer and the applying current density for reliable drug release through an electrochemical analysis. The wireless power transfer system was applied to f-DDM, which shows stable wirelessly powered operation. The f-DDM was flexible enough to be implantable on the curved cerebral cortex and successfully adopted for delivery of two different chemicals or prevention of seizure activity using an anti-epileptic drug. Our study opens a new avenue for the controlled, region-specific, and combinatorial application of drugs, the key factors for precision medicine.

Modeling of non‐Fickian diffusion and dissolution from a thin polymeric coating: An application to drug‐eluting stents

SummaryIn this paper, we present a general model for non‐Fickian diffusion and drug dissolution from a controlled drug delivery device coated with a thin polymeric layer. First, we study the stability and deduce an analytic solution to the problem. Then, we consider this solution and provide suitable boundary conditions to replace the problem of mass transport in the coating of a coronary drug‐eluting stent. With this approach, we reduced the computational cost of performing numerical simulations in complex 3‐dimensional geometries. The model for mass transport by a coronary drug‐eluting stent is coupled with a non‐Newtonian blood model flow. In order to show the effectiveness of the method, numerical experiments and a model validation with experimental data are also included. In particular, we investigate the influence of the non‐Newtonian flow regime on the drug deposition in the arterial wall.

Application of Chitosan and its Derivatives in Nanocarrier Based Pulmonary Drug Delivery Systems.

The respiratory tract as a non-invasive route of drug administration is gaining increasing attention in the present time on achieving both local and the systemic therapeutic effects. Success in achieving pulmonary delivery, requires overcoming barriers including mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time and rate to target sites. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically. We searched and reviewed the literature focusing on chitosan and chitosan derivative based nanocarrier systems used in pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for this purpose. Chitosan, a natural linear bio-polyaminosaccharide is central in the development of novel drug delivery systems (NDDS) including nanoparticles for use in the treatment of various respiratory diseases. It achieves this through its unique properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation across membranes. It also achieves sustained and targeted effects, primary requirements for an effective pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, employed in the management of respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis. This review will be of interest to both the biological and formulation scientists as it provides a summary on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available for pulmonary drug delivery and so this area has enormous potential in the field of respiratory science.