Hollow silicon microneedles, fabricated using combined wet and dry etching techniques, for transdermal delivery and diagnostics.

Microneedle-based technologies are the subject of intense research and commercial interest for applications in transdermal delivery and diagnostics, primarily because of their minimally invasive and painless nature, which in turn could lead to increased patient compliance and self-administration. In this paper, a process for the fabrication of arrays of hollow silicon microneedles is described. This method uses just two bulk silicon etches - a front-side wet etch to define the 500 µm tall octagonal needle structure itself, and a rear-side dry etch to create a 50 µm diameter bore through the needle. This reduces the number of etches and process complexity over the approaches described elsewhere. Ex-vivo human skin and a customised applicator were used to demonstrate biomechanical reliability and the feasibility of using these microneedles for both transdermal delivery and diagnostics. Microneedle arrays show no damage even when applied to skin up to 40 times, are capable of delivering several mL of fluid at flowrates of 30 µL/min, and of withdrawing 1 µL of interstitial fluid using capillary action.

Design and Analysis of Bio-Inspired Micro-Needle for Drug Delivery Applications.

Years of research show that the Trans-dermal drug delivery (TDD) route showed promising results due to good immunogenic responses. In this paper, we have proposed a bio-inspired micro-needle suggested by a snake belonging to the family of Elapids, since they inject venom with high pressures during the bite. The proposed micro-needle is strong enough to puncture the skin and withstand different kinds of loads during the insertion. The proposed micro-needle is of [Formula: see text] length, and the maximum compressive, buckling, bending, load it can handle are 0.27N, 0.16N, 0.024N respectively. The proposed micro-needle (MN) has an inner channel diameter of 44 [Formula: see text] and it gives a flow rate of [Formula: see text]/s. In our work, we have modeled a substrate of epidermis and dermis as a porous medium with porosity and permeability as 0.74, [Formula: see text] respectively. The porosity and permeability are calculated using an SEM image of the human dermis consisting of only collagen fibers and empty pores. We have applied Darcy's law to the modeled substrate and obtained the velocity field of the drug administrated. The diffusion study of Doxorubicin ( 87 µ mol/l) is carried out using Darcy velocity field and concentration gradient.

Assessment of drug delivery devices working at microflow rates.

Almost every medical department in hospitals around the world uses infusion devices to administer fluids, nutrition, and medications to patients to treat many different diseases and ailments. There have been several reports on adverse incidents caused by medication errors associated with infusion equipment. Such errors can result from malfunction or improper use, or even inaccuracy of the equipment, and can cause harm to patients' health. Depending on the intended use of the equipment, e.g. if it is used for anaesthesia of adults or for medical treatment of premature infants, the accuracy of the equipment may be more or less important. A well-defined metrological infrastructure can help to ensure that infusion devices function properly and are as accurate as needed for their use. However, establishing a metrological infrastructure requires adequate knowledge of the performance of infusion devices in use. This paper presents the results of various tests conducted with two types of devices.

Utilizing 4D Printing to Design Smart Gastroretentive, Esophageal, and Intravesical Drug Delivery Systems.

The breakthrough of 3D printing in biomedical research has paved the way for the next evolutionary step referred to as four dimensional (4D) printing. This new concept utilizes the time as the fourth dimension in addition to the x, y, and z axes with the idea to change the configuration of a printed construct with time usually in response to an external stimulus. This can be attained through the incorporation of smart materials or through a preset smart design. The 4D printed constructs may be designed to exhibit expandability, flexibility, self-folding, self-repair or deformability. This review focuses on 4D printed devices for gastroretentive, esophageal, and intravesical delivery. The currently unmet needs and challenges for these application sites are tried to be defined and reported on published solution concepts involving 4D printing. In addition, other promising application sites that may similarly benefit from 4D printing approaches such as tracheal and intrauterine drug delivery are proposed.

Recent Advances of Microneedles and Their Application in Disease Treatment.

For decades, scientists have been doing a lot of research and exploration to find effective long-term analgesic and/or disease-modifying treatments. Microneedles (MNs) are a simple, effective, and painless transdermal drug delivery technology that has emerged in recent years, and exhibits great promise for realizing intelligent drug delivery. With the development of materials science and fabrication technology, the MN transdermal drug delivery technology has been applied and popularized in more and more fields, including chronic illnesses such as arthritis or diabetes, cancer, dermatocosmetology, family planning, and epidemic disease prevention, and has made fruitful achievements. This paper mainly reviews the latest research status of MNs and their fabrication methodology, and summarizes the application of MNs in the treatment of various diseases, as well as the potential to use nanotechnology to develop more intelligent MNs-based drug delivery systems.

Hard polymeric porous microneedles on stretchable substrate for transdermal drug delivery.

Microneedles offer a convenient transdermal delivery route with potential for long term sustained release of drugs. However current microneedle technologies may not have the mechanical properties for reliable and stable penetration (e.g. hydrogel microneedles). Moreover, it is also challenging to realize microneedle arrays with large size and high flexibility. There is also an inherent upper limit to the amount and kind of drugs that can be loaded in the microneedles. In this paper, we present a new class of polymeric porous microneedles made from biocompatible and photo-curable resin that address these challenges. The microneedles are unique in their ability to load solid drug formulation in concentrated form. We demonstrate the loading and release of solid formulation of anesthetic and non-steroidal anti-inflammatory drugs, namely Lidocaine and Ibuprofen. Paper also demonstrates realization of large area (6 × 20 cm2) flexible and stretchable microneedle patches capable of drug delivery on any body part. Penetration studies were performed in an ex vivo porcine model supplemented through rigorous compression tests to ensure the robustness and rigidity of the microneedles. Detailed release profiles of the microneedle patches were shown in an in vitro skin model. Results show promise for large area transdermal delivery of solid drug formulations using these porous microneedles.

Floating Ricobendazole Delivery Systems: A 3D Printing Method by Co-Extrusion of Sodium Alginate and Calcium Chloride.

At present, the use of benzimidazole drugs in veterinary medicine is strongly limited by both pharmacokinetics and formulative issues. In this research, the possibility of applying an innovative semi-solid extrusion 3D printing process in a co-axial configuration was speculated, with the aim of producing a new gastro-retentive dosage form loaded with ricobendazole. To obtain the drug delivery system (DDS), the ionotropic gelation of alginate in combination with a divalent cation during the extrusion was exploited. Two feeds were optimized in accordance with the printing requirements and the drug chemical properties: the crosslinking ink, i.e., a water ethanol mixture containing CaCl2 at two different ratios 0.05 M and 0.1 M, hydroxyethyl cellulose 2% w/v, Tween 85 0.1% v/v and Ricobendazole 5% w/v; and alginate ink, i.e., a sodium alginate solution at 6% w/v. The characterization of the dried DDS obtained from the extrusion of gels containing different amounts of calcium chloride showed a limited effect on the ink extrudability of the crosslinking agent, which on the contrary strongly influenced the final properties of the DDS, with a difference in the polymeric matrix toughness and resulting effects on floating time and drug release.

Implantable Immunosuppressant Delivery to Prevent Rejection in Transplantation.

An innovative immunosuppressant with a minimally invasive delivery system has emerged in the biomedical field. The application of biodegradable and biocompatible polymer forms, such as hydrogels, scaffolds, microspheres, and nanoparticles, in transplant recipients to control the release of immunosuppressants can minimize the risk of developing unfavorable conditions. In this review, we summarized several studies that have used implantable immunosuppressant delivery to release therapeutic agents to prolong allograft survival. We also compared their applications, efficacy, efficiency, and safety/side effects with conventional therapeutic-agent administration. Finally, challenges and the future prospective were discussed. Collectively, this review will help relevant readers understand the different approaches to prevent transplant rejection in a new era of therapeutic agent delivery.

Design and simulation of the liposomal model by using a coarse-grained molecular dynamics approach towards drug delivery goals.

The simulated liposome models provide events in molecular biological science and cellular biology. These models may help to understand the cell membrane mechanisms, biological cell interactions, and drug delivery systems. In addition, the liposomes model may resolve specific issues such as membrane transports, ion channels, drug penetration in the membrane, vesicle formation, membrane fusion, and membrane protein function mechanism. One of the approaches to investigate the lipid membranes and the mechanism of their formation is by molecular dynamics (MD) simulations. In this study, we used the coarse-grained MD simulation approach and designed a liposome model system. To simulate the liposome model, we used phospholipids that are present in the structure of natural cell membranes (1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)). Simulation conditions such as temperature, ions, water, lipid concentration were performed based on experimental conditions. Our results showed a liposome model (ellipse vesicle structure) during the 2100 ns was formed. Moreover, the analysis confirmed that the stretched and ellipse structure is the best structure that could be formed. The eukaryotic and even the bacterial cells have elliptical and flexible structures. Usually, an elliptical structure is more stable than other assembled structures. The results indicated the assembly of the lipids is directed through short-range interactions (electrostatic interactions and, van der Waals interactions). Total energy (Van der Waals and electrostatic interaction energy) confirmed the designed elliptical liposome structure has suitable stability at the end of the simulation process. Our findings confirmed that phospholipids DOPC and DOPE have a good tendency to form bilayer membranes (liposomal structure) based on their geometric shapes and chemical-physical properties. Finally, we expected the simulated liposomal structure as a simple model to be useful in understanding the function and structure of biological cell membranes. Furthermore, it is useful to design optimal, suitable, and biocompatible liposomes as potential drug carriers.

Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse.

BACKGROUND: The blood-cerebrospinal fluid (CSF) barrier (BCSFB) is critically important to the pathophysiology of the central nervous system (CNS). However, this barrier prevents the safe transmission of beneficial drugs from the blood to the CSF and thus the spinal cord and brain, limiting their effectiveness in treating a variety of CNS diseases. METHODS: This study demonstrates a method on SD rats for reversible and site-specific opening of the BCSFB via a noninvasive, low-energy focused shockwave (FSW) pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg), posing a low risk of injury. RESULTS: By opening the BCSFB, the concentrations of certain CNS-impermeable indicators (70 kDa Evans blue and 500 kDa FITC-dextran) and drugs (penicillin G, doxorubicin, and bevacizumab) could be significantly elevated in the CSF around both the brain and the spinal cord. Moreover, glioblastoma model rats treated by doxorubicin with this FSW-induced BCSFB (FSW-BCSFB) opening technique also survived significantly longer than untreated controls. CONCLUSION: This is the first study to demonstrate and validate a method for noninvasively and selectively opening the BCSFB to enhance drug delivery into CSF circulation. Potential applications may include treatments for neurodegenerative diseases, CNS infections, brain tumors, and leptomeningeal carcinomatosis.

Jet injectors: Perspectives for small volume delivery with lasers.

Needle-free jet injectors have been proposed as an alternative to injections with hypodermic needles. Currently, a handful of commercial needle-free jet injectors already exist. However, these injectors are designed for specific injections, typically limited to large injection volumes into the deeper layers beneath the skin. There is growing evidence of advantages when delivering small volumes into the superficial skin layers, namely the epidermis and dermis. Injections such as vaccines and insulin would benefit from delivery into these superficial layers. Furthermore, the same technology for small volume needle-free injections can serve (medical) tattooing as well as other personalized medicine treatments. The research dedicated to needle-free jet injectors actuated by laser energy has increased in the last decade. In this case, the absorption of the optical energy by the liquid results in an explosively growing bubble. This bubble displaces the rest of the liquid, resulting in a fast microfluidic jet which can penetrate the skin. This technique allows for precise control over volumes (pL to µL) and penetration depths (µm to mm). Furthermore, these injections can be tuned without changing the device, by varying parameters such as laser power, beam diameter and filling level of the liquid container. Despite the published research on the working principles and capabilities of individual laser-actuated jet injectors, a thorough overview encompassing all of them is lacking. In this perspective, we will discuss the current status of laser-based jet injectors and contrast their advantages and limitations, as well as their potential and challenges.

Evaluation of Device-Based Cutaneous Channels Using Optical Coherence Tomography: Impact for Topical Drug Delivery.

BACKGROUND: Topical medications play a large role in the management of cutaneous diseases, but penetration is limited. Device-assisted drug delivery using mechanical destruction, lasers, and other energy-based modalities can increase penetration and absorption through creation of transcutaneous channels. OBJECTIVE: To examine real-time, in vivo cutaneous changes in response to various devices used to improve topical drug delivery through optical coherence tomography (OCT) imaging. METHODS AND MATERIALS: Treatment was performed with 8 medical devices, including mechanical destruction, lasers, and other energy-based modalities. Optical coherence tomography was used for real-time, noninvasive, in vivo imaging. RESULTS: Using OCT, microneedling and radiofrequency microneedling demonstrated no cutaneous channels. Both low-energy, low-density, fractional nonablative lasers produced transient channels, which closed within hours. The fractional nonablative 1,927-nm thulium fiber and 1,550-nm erbium fiber lasers created channels with epidermal debris within, which were still closing at 24 hours. The fractional thermomechanical ablative device and the fractional ablative CO2 laser produced channels that were still open at 24 hours. CO2 laser channels had thick rims of coagulated tissue and remained open for longer. CONCLUSION: Demonstrable differences among the devices were seen, and only some can produce observable channels, the characteristics of which vary with each technology.

Aerosol release, distribution, and prevention during aerosol therapy: a simulated model for infection control.

Aerosol therapy is used to deliver medical therapeutics directly to the airways to treat respiratory conditions. A potential consequence of this form of treatment is the release of fugitive aerosols, both patient derived and medical, into the environment and the subsequent exposure of caregivers and bystanders to potential viral infections. This study examined the release of these fugitive aerosols during a standard aerosol therapy to a simulated adult patient. An aerosol holding chamber and mouthpiece were connected to a representative head model and breathing simulator. A combination of laser and Schlieren imaging was used to non-invasively visualize the release and dispersion of fugitive aerosol particles. Time-varying aerosol particle number concentrations and size distributions were measured with optical particle sizers at clinically relevant positions to the simulated patient. The influence of breathing pattern, normal and distressed, supplemental air flow, at 0.2 and 6 LPM, and the addition of a bacterial filter to the exhalation port of the mouthpiece were assessed. Images showed large quantities of fugitive aerosols emitted from the unfiltered mouthpiece. The images and particle counter data show that the addition of a bacterial filter limited the release of these fugitive aerosols, with the peak fugitive aerosol concentrations decreasing by 47.3-83.3%, depending on distance from the simulated patient. The addition of a bacterial filter to the mouthpiece significantly reduces the levels of fugitive aerosols emitted during a simulated aerosol therapy, p≤ .05, and would greatly aid in reducing healthcare worker and bystander exposure to potentially harmful fugitive aerosols.

Electrosprayed chitosan-coated alginate-pectin beads as potential system for colon-targeted delivery of ellagic acid.

BACKGROUND: Ellagic acid (EA), a potent dietary antioxidant, has limited bioavailability owing to its rapid absorption in the stomach and small intestine, and EA is transformed to more bioavailable compounds - urolithins - in the colon. An encapsulation system that sustains the release of EA in the gastrointestinal system and delivers more EA into the colon could improve the oral bioavailability of EA. Electrosprayed EA-loaded alginate-pectin beads were produced and coated with low- (LC) and high-molecular-weight chitosan (HC). The EA release from uncoated and coated beads under simulated gastrointestinal conditions was evaluated. The samples were characterized by particle size, gel strength, scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) analysis. RESULTS: The encapsulation efficiency (EE%) of EA ranged from 49.53% to 69.85% for uncoated beads, which was elevated up to 86.50% by coating, and LC coating provided higher EE%. Pectin addition to alginate and chitosan coating reduced the gel strength and changed the size depending on the molecular weight of chitosan. SEM images of pectin-added beads showed fewer cracks but more wrinkles, and chitosan coating presented more aggregated surfaces. The ionic interaction of alginate-pectin-chitosan and the entrapment of EA were confirmed by FTIR. In the gastric medium, EA release was very low from uncoated beads (15.2-19.8%), and totally restricted by chitosan coating. In the intestinal stage, EA release from LC-coated alginate-pectin beads was only 18%, and it was between 55% and 65% for uncoated or HC-coated counterparts. CONCLUSION: The LC-coated alginate-pectin beads could be further explored as a potential system for colon-targeted delivery of EA. © 2021 Society of Chemical Industry.

Biopolymer nanoparticles: a strategy to enhance stability, bioavailability, and biological effects of phenolic compounds as functional ingredients.

Phenolic compounds are abundant in nature and have multiple beneficial effects on human health due to their antioxidant, anti-inflammatory, antithrombotic, antiallergenic, anticancer, and antiatherosclerotic properties. For this reason, phenolics are becoming relevant functional ingredients for several industries, mainly the food industry, derived from food consumer exigencies and regulations. However, the use of their beneficial properties still presents some limitations, such as chemical instability under environmental and processing conditions, which leads to structural changes and compromises their biological activities. They also present poor water solubility and sensitivity to pH changes, decreasing their bioavailability in the organism. The technologies for extraction and stabilization of these compounds have evolved rapidly in the development of different delivery systems to encapsulate sensitive active molecules. Biopolymeric nanoparticles are biodegradable polymer-based colloidal systems with sizes ranging from 1 to 1000 nm, and different techniques can be carried out to develop them. These systems have emerged as a green and effective alternative to improve stability, bioavailability, and biological effects of phenolic compounds. This comprehensive review aims to present an overview of recent advances in encapsulation processes of phenolic compounds within biopolymer nanoparticles as delivery systems and the impact on their physicochemical properties and biological effects after encapsulation. © 2021 Society of Chemical Industry.

Developing inhaled drugs for respiratory diseases: A medicinal chemistry perspective.

Despite the devastating impact of many lung diseases on human health, there is still a significant unmet medical need in respiratory diseases, for which inhaled delivery represents a crucial strategy. More guidance on how to design and carry out multidisciplinary inhaled projects is needed. When designing inhaled drugs, the medicinal chemist must carefully balance the physicochemical properties of the molecule to achieve optimal target engagement in the lung. Although the medicinal chemistry strategy is unique for each project, and will change depending on multiple factors, such as the disease, target, systemic risk, delivery device, and formulation, general guidelines aiding inhaled drug design can be applied and are summarised in this review.

Influence of additives on swelling and mucoadhesion properties of glyceryl monooleate liquid crystals

Abstract Liquid crystalline systems of glyceryl monooleate/water are used as drug delivery systems due to their complex structure that controls drug diffusion. Mucoadhesive properties of glyceryl monooleate suggest it can be used for buccal delivery. Using additives is a strategy to modify physical and chemical properties of liquid crystalline systems and optimize their performance as a drug delivery system. However, the presence of additives can significantly alter properties such as phase behavior, swelling and mucoadhesion. Our aim is to investigate the influence of additives on swelling and mucoadhesion of glyceryl monooleate-based liquid crystals, intending them to be used as buccal drug delivery systems. The systems were characterized regarding their mesophases, swelling rate, and mucoadhesion. All the systems studied were able to absorb water and presented mucoadhesion, which is interesting for the development of buccal drug delivery systems. Additives induced phase transitions and affected the swelling performance, while mucoadhesive properties were poorly affected. Propylene glycol increased water uptake, while oleic acid induced the phase transition to the hexagonal phase and reduced the swelling rate. The association of oleic acid (5%) and propylene glycol (10%) resulted in a cubic phase system with strong mucoadhesive properties that can be a potential drug carrier for buccal delivery.

Profiling the physicochemical and solid state properties of edible Tetracarpidium conophorum oil and its admixtures for drug delivery

Abstract The study is aimed at investigating the functional physicochemical and solid state characteristics of food-grade Tetracarpidium conophorum (T. conophorum) oil for possible application in the pharmaceutical industry for drug delivery. The oil was obtained by cold hexane extraction and its physicochemical properties including viscosity, pH, peroxide, acid, and thiobarbituric acid values, nutrient content, and fatty acid profile were determined. Admixtures of the oil with Softisan®154, a hydrogenated solid lipid from palm oil, were prepared to obtain matrices which were evaluated by differential scanning calorimetry, fourier-transform infrared spectroscopy, and x-ray diffractometry. Data from the study showed that T. conophorum oil had Newtonian flow behaviour, acidic pH, insignificant presence of hyperperoxides and malondialdehyde, contains minerals including calcium, magnesium, zinc, copper, manganese, iron, selenium, and potassium, vitamins including niacin (B3), thiamine (B1), cyanocobalamine (B12), ascorbic acid (C), and tocopherol (E), and long-chain saturated and unsaturated fatty acids including n-hexadecanoic acid, 9(Z)-octadecenoic acid, and cis-13-octadecenoic acid. The lipid matrices had low crystallinity and enthalpy values with increased amorphicity, and showed no destructive intermolecular interaction or incompatibility between T. conophorum oil and Softisan® 154. In conclusion, the results have shown that, in addition to T. conophorum oil being useful as food, it will also be an important excipient for the development of novel, safe, and effective lipid-based drug delivery systems.