Enable Drug Delivery Research Articles

In Situ Salification in Polar Solvents: a Paradigm for Enabling Drug Delivery of Weakly Ionic Drugs as Amorphous Solid Dispersion.

Solubility challenge for a poorly water-soluble drug gets further intensified when it is weakly ionic because the most common solubility enhancement technique, salt formation, becomes less feasible. Salt screening for such drugs often concludes with either a difficult to crystalize salt or an unstable salt, leading the scientists to explore other solubility enhancement technique like amorphous solid dispersions which is comparatively costlier, time-consuming and may require use of hazardous organic solvents. Present study evaluated in situ salification in polar protic solvents for dissolving poorly water-soluble drug Itraconazole which is weakly ionic and not very amenable to formation of stable inorganic salts. Through systematic selection of solvents, counterions and polymers, an amorphous solid dispersion of drug salt was obtained. In vitro characterizations with polarized light microscopy (PLM), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR) and X-ray powder diffraction (XRD) confirmed the physical and chemical stability of the amorphous solid dispersion. In vivo pharmacokinetic study showed that the drug salt amorphous solid dispersion achieved 45 times higher plasma exposure compared to crystalline drug. This study provides one of the first data sets for the hypothesis that in situ drug salts can be utilized for manufacturing amorphous solid dispersions of weakly ionic drugs and leverages the solubility advantage of salts and amorphous state.

The effect of nanoparticle size on the ability to cross the blood-brain barrier: an in vivo study.

Our goal was to develop an efficient nanoparticle-based system that can overcome the restrictive mechanism of the blood-brain barrier (BBB) by targeting insulin receptors and would thus enable drug delivery to the brain. Insulin-coated gold nanoparticles (INS-GNPs) were synthesized to serve as a BBB transport system. The effect of nanoparticle size (20, 50 and 70 nm) on their ability to cross the BBB was quantitatively investigated in Balb/C mice. The most widespread biodistribution and highest accumulation within the brain were observed using 20 nm INS-GNPs, 2 h post injection. In vivo CT imaging revealed that particles migrated to specific brain regions, which are involved in neurodegenerative and neuropsychiatric disorders. These findings promote the optimization of nanovehicles for transport of drugs through the BBB. The insulin coating of the particles enabled targeting of specific brain regions, suggesting the potential use of INS-GNPs for delivery of various treatments for brain-related disorders.

Advanced Analgesic Drug Delivery and Nanobiotechnology.

Transdermal administration of analgesic medications offers several benefits over alternative routes of administration, including a decreased systemic drug load with fewer side effects, and avoidance of drug degradation by the gastrointestinal tract. Transdermal administration also offers a convenient mode of drug administration over an extended period of time, particularly desirable in pain medicine. A transdermal administration route may also offer increased safety for drugs with a narrow therapeutic window. The primary barrier to transdermal drug absorption is the skin itself. Transdermal nanotechnology offers a novel method of achieving enhanced dermal penetration with an extended delivery profile for analgesic drugs, due to their small size and relatively large surface area. Several materials have been used to enhance drug duration and transdermal penetration. The application of nanotechnology in transdermal delivery of analgesics has raised new questions regarding safety and ethical issues. The small molecular size of nanoparticles enables drug delivery to previously inaccessible body sites. To ensure safety, the interaction of nanoparticles with the human body requires further investigation on an individual drug basis, since different formulations have unique properties and side effects.

Dodecyl Amino Glucoside Enhances Transdermal and Topical Drug Delivery via Reversible Interaction with Skin Barrier Lipids.

Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic. Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

Patent Profiling for Nano Enabled Drug Delivery

Nano Enabled Drug Delivery (NEDD) is widely researched and developed to improve the administration and efficacy of pharmaceutical compounds and molecules. To understand the research situation of NEDD from macro perspectives, we used the patent data to analyze from three aspects and got some interesting results: NEDD was developing steadily, but “safety problems” were becoming big challenges in recent years. NEDD was a highly interdisciplinary emerging field, whose more attractive subsystems were “vector” and “cargo”. One superpower, US, and several strong countries formed the global research pattern. Such “tech mining” offers a systematic perspective on the emerging science or technology under study that is not readily achievable within the individual knowledge of particular researchers.

Triboelectric liquid volume sensor for self-powered lab-on-chip applications

Technology for enabling drug delivery with precise control is strongly demanded by patients with diabetes or other chronic diseases. More intelligent functions such as drug loading and delivery in controllable manner without requiring electrical power will make low-cost drug delivery patches come true. One of the promising candidates is triboelectric technology which has been deployed as nanogenerators and self-powered glucose sensors recently. In this paper, the drug delivery is triggered by finger-pressing on a polymer based micropump. Considering that the finger-pressing should be an action of very low frequency, e.g., 1 to 2Hz, triboelectric energy harvester (TEH) based on contact-separation mode between patterned biocompatible polymer layer and Aluminum (Al) film is integrated with microneedles on a flexible skin patch. Leveraging triboelectric materials and compatible fabrication technology, we successfully develop a self-powered flexible skin patch for transdermal insulin delivery with novel liquid volume sensor to monitor delivered drug volume and flexible energy harvester using the same triboelectric mechanism. With 3stacked polymer layers, the TEH of 2×2cm2 area generates 33μW by gentle finger tapping at 2Hz. Such energy could be harvested even during drug delivery via finger pressing. In future we can further store harvested energy in a battery to provide required operation power for other active components or glucose sensors integrated in this skin patch. The developed flexible skin patch for transdermal drug delivery is further validated by in vivo experiments in rats.

Persistence, distribution, and impact of distinctly segmented microparticles on cochlear health following in vivo infusion.

Delivery of pharmaceuticals to the cochleae of patients with auditory dysfunction could potentially have many benefits from enhancing auditory nerve survival to protecting remaining sensory cells and their neuronal connections. Treatment would require platforms to enable drug delivery directly to the cochlea and increase the potential efficacy of intervention. Cochlear implant recipients are a specific patient subset that could benefit from local drug delivery as more candidates have residual hearing; and since residual hearing directly contributes to post-implantation hearing outcomes, it requires protection from implant insertion-induced trauma. This study assessed the feasibility of utilizing microparticles for drug delivery into cochlear fluids, testing persistence, distribution, biocompatibility, and drug release characteristics. To allow for delivery of multiple therapeutics, particles were composed of two distinct compartments; one containing polylactide-co-glycolide (PLGA), and one composed of acetal-modified dextran and PLGA. Following in vivo infusion, image analysis revealed microparticle persistence in the cochlea for at least 7 days post-infusion, primarily in the first and second turns. The majority of subjects maintained or had only slight elevation in auditory brainstem response thresholds at 7 days post-infusion compared to pre-infusion baselines. There was only minor to limited loss of cochlear hair cells and negligible immune response based on CD45+ immunolabling. When Piribedil-loaded microparticles were infused, Piribedil was detectable within the cochlear fluids at 7 days post-infusion. These results indicate that segmented microparticles are relatively inert, can persist, release their contents, and be functionally and biologically compatible with cochlear function and therefore are promising vehicles for cochlear drug delivery. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1510-1522, 2016.

Novel delivery systems with nonsteroidal anti-inflammatory drugs

Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of serious gastrointestinal side effects. Therefore, recent trends in the development of NSAIDs aim to reduce the incidence of side effects, and improve patient compliance. One of the strategies to improve efficacy and safety of oral NSAIDs is the development of combination products that contain gastroprotective agents. Several products containing NSAID in combination with proton pump inhibitors (ketoprofen/omeprazole, naproxen/esomeprazole), H2-receptor antagonists (ibuprofen/famotidine), and prostaglandin analogues (diclofenac/misoprostol) are currently available on the market. Another approach refer to the special formulation design to allow dose reduction while preserving drug therapeutic efficacy. An example is SoluMatrix® technology, a manufacturing process that produce submicron-sized drug particles with enhanced dissolution and absorption properties. Patented SoluMatrix® technology has been successfully employed to develop low-dose diclofenac, meloxicam, indomethacin and naproxen products. Topical NSAID formulations enable drug delivery to target tissues, while reducing systemic exposure and concomitant side effects associated with oral NSAIDs. Dermal/transdermal NSAID delivery systems are subject of intensive investigation. So far, several 'advanced' drug delivery systems with diclofenac, ibuprofen and ketoprofen have been designed.

Novel Nanostructured Polymeric Carriers to Enable Drug Delivery for Cardiovascular Diseases.

Applications of polymeric nanotechnologies for enabling therapies for cardiovascular diseases have shown recent success. Both intravenous and oral administration have been investigated and achieved different degrees of development. While circulating polymeric nanostructured carriers are subjected to a number of interactions, smart nanoparticle design has enabled the formulation of active molecules to be delivered to specific targets for cardiovascular effects. This review aims at outlining the multiple factors that can affect the fate of polymeric nanostructured carriers in systemic circulation. With an understanding of these factors, the literature on the various polymeric nanostructured carriers is reviewed. Finally, the emerging uses of nanotechnology to formulate orally administered drugs for cardiovascular diseases are depicted.

MEMS: Enabled Drug Delivery Systems.

Drug delivery systems play a crucial role in the treatment and management of medical conditions. Microelectromechanical systems (MEMS) technologies have allowed the development of advanced miniaturized devices for medical and biological applications. This Review presents the use of MEMS technologies to produce drug delivery devices detailing the delivery mechanisms, device formats employed, and various biomedical applications. The integration of dosing control systems, examples of commercially available microtechnology-enabled drug delivery devices, remaining challenges, and future outlook are also discussed.

Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: Demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI)

Mucus barriers lining mucosal epithelia reduce the effectiveness of nanocarrier-based mucosal drug delivery and imaging (“theranostics”). Here, we describe liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, e.g., the diaCEST MRI contrast agent barbituric acid (BA). We observed that polyethylene glycol (PEG)-coated liposomes containing ≥7mol% PEG diffused only ~10-fold slower in human cervicovaginal mucus (CVM) compared to their theoretical speeds in water. 7mol%-PEG liposomes contained sufficient BA loading for diaCEST contrast, and provided improved vaginal distribution compared to 0 and 3mol%-PEG liposomes. However, increasing PEG content to ~12mol% compromised BA loading and vaginal distribution, suggesting that PEG content must be optimized to maintain drug loading and stability. Non-invasive diaCEST MRI illustrated uniform vaginal coverage and longer retention of BA-loaded 7mol%-PEG liposomes compared to unencapsulated BA. Liposomal MPP with optimized PEG content hold promise for drug delivery and imaging at mucosal surfaces. From the Clinical EditorThis team of authors characterized liposome-based mucus-penetrating particles (MPP) capable of loading hydrophilic agents, such as barbituric acid (a diaCEST MRI contrast agent) and concluded that liposomal MPP with optimized PEG coating enables drug delivery and imaging at mucosal surfaces.

Nanoparticle enabled drug delivery across the blood brain barrier: in vivo and in vitro models, opportunities and challenges.

The blood brain barrier (BBB) maintains homeostasis by regulating the transport of chemicals at the brain interface. However, it is also one of the largest obstacles for drug delivery to the central nervous system (CNS). The utilization of nanoparticles as drug delivery vehicles is one potential solution to overcome this barrier. This review highlights the characteristics of the BBB that inhibit the passage of drugs to the brain, evaluates the efficiency of current in vitro models to mimic the BBB, and discusses the use of nanoparticles in both in vivo and in vitro models to enhance drug permeability across the barrier. In addition, this review describes factors that influence the passage of nanoparticles (type of polymers and surfactant coating, nanoparticle size) across the barrier. Protein opsonization and phagocytic activity of the reticuloendothelial system limits the amount of drug delivered to the brain, and this article summarizes methods to circumvent these issues. This paper also reviews literature covering opportunities and challenges provided with current applications of nanoparticle drug delivery systems for diseases of the brain, including cancer, HIV, and Alzheimer's disease.

Expanding the Therapeutic Potential of Statins by Means of Nanotechnology Enabled Drug Delivery Systems

Statins are effective lipid lowering agents traditionally used for the primary and secondary prevention of cardiovascular disease. Statins also exert a range of pleiotropic effects that make them attractive candidates for use in a wide range of disorders, in particular inflammatory and immune mediated conditions. However, the exploitation of such pleiotropic effects has been greatly hindered by poor bioavailability and adverse effects on muscles and the liver at higher doses. Nanotechnology is often suggested as the solution to this problem, as it enables an increased bioavailability of statins. Moreover, colloidal carriers can offer targeted drug delivery approaches that enable localised biological effects of statins, further reducing their potential for unwanted toxicity and adverse effects. This article reviews the available evidences for the increased potential of statin therapy when administered in nano-formulations such as nanocrystals, nanoparticles, liposomes, micelles and various nano-enabled devices.

Nanotechnologies in Drug Delivery - An Industrial Perspective

The design and manufacture of objects in the 10-1000 nm range, referred to as nanotechnologies, has opened access to new drug delivery tools embracing a variety of applications. While some of these applications are simply based on the high level of dispersion (i.e. high surface/volume ratio) of the nano-objects, others involve constructs bearing multiple functionalities (encapsulation, long circulation, targeting), taking advantage of the compatibility of the nanoparticles size with the design of the drug delivery at the cellular and sub-cellular levels. This article is an attempt to analyze the current knowledge and impact of nanotechnologies in drug delivery, from an industrial perspective. Various aspects such as the routes of administration, raw materials, expected biopharmaceutical perfomances are considered, together with the different levels of differentiation of nanotechnologies, as compared to standard formulations. The needed degree of refinement of the understanding of the physico-chemistry and the biopharmacy of the nano-objects, together with the existence of methodological gaps to manage their quality, are discussed considering the specific context of the drug delivery challenge (colloidal dispersion versus targeting). Even though nanotechnologies were primarily envisaged for life cycle management, to avoid the combination of the risks associated to a new drug delivery system to the risks associated to a new drug, the scope of nanotechnologies is currently broadening with their development as enabling drug delivery technologies for biomolecules, and their use in translational sciences. The added value of nanotechnologies is also discussed in these contexts.

NanoCluster budesonide formulations enable efficient drug delivery driven by mechanical ventilation

Agglomerates of budesonide nanoparticles (also known as 'NanoClusters') are fine dry powder aerosols that were hypothesized to enable drug delivery through ventilator circuits. These engineered powders were delivered via a Monodose inhaler or a novel device, entrained through commercial endotracheal tubes, and analyzed by cascade impaction. Inspiration flow rates and other parameters such as inspiration patterns and inspiration volumes were controlled by a ventilator. NanoCluster budesonide (NC-Bud) formulations had a higher efficiency of aerosol delivery compared to micronized budesonide with NC-Bud showing a much higher percent emitted fraction (%EF). Different inspiration patterns (sine, square, and ramp) did not affect the powder performance of NC-Bud when applied through a 5.0 mm endotracheal tube. The aerosolization of NC-Bud also did not change with the inspiration volume (1.5-2.5 L) nor with the inspiration flow rate (20-40 L/min) suggesting fast emptying times for budesonide capsules. The %EF of NC-Bud was higher at 51% relative humidity compared to 82% RH. The novel device and the Monodose showed the same efficiency of drug delivery but the novel device fit directly to a ventilator and endotracheal tubing connections. The new device combined with NanoCluster formulation technology allowed convenient and efficient drug delivery through endotracheal tubes.

Transferrin receptor antibody-modified α-cobrotoxin-loaded nanoparticles enable drug delivery across the blood–brain barrier by intranasal administration

A novel drug carrier for brain delivery, maleimide–poly(ethyleneglycol)–poly(lactide) (maleimide–PEG–PLA) nanoparticles (NPs) conjugated with mouse–anti-rat monoclonal antibody OX26 (OX26–NPs), was developed and its brain delivery property was evaluated. The diblock copolymers of maleimide–PEG–PLA were synthesized and applied to α-cobrotoxin (αCT)-loaded NPs which were characterized by transmission electron micrograph imaging, Fourier-transform IR, and X-ray diffraction. The NPs encapsulating αCT had a round and vesicle-like shape with a mean diameter around 100 nm, and the OX26 had covalently conjugated to the surface of NPs. MTT studies in brain microvascular endothelial cells (BMEC) revealed a moderate decrease in the cell viability of αCT, when incorporated in OX26–NPs compared to free αCT in solution. A higher affinity of the OX26–αCT–NPs to the BMEC was shown in comparison to αCT–NPs. Then, OX26–αCT–NPs were intranasally (i.n.) administered to rats, and αCT in the periaqueductal gray was monitored for up to 480 min using microdialysis technique in free-moving rats, with i.n. αCT–NPs, i.n. OX26–αCT–NPs, intramuscular injection (i.m.) αCT–NPs, and i.m. OX26–αCT–NPs. The brain transport results showed that the corresponding absolute bioavailability (F abs) of i.n. OX26–αCT–NPs were about 125 and 155 % with i.n. αCT–NPs and i.m. OX26–αCT–NPs, respectively, and it was found that both the C max and AUC of the four groups were as follows: i.n. OX26–αCT–NPs > i.n. αCT–NPs > i.m. OX26–αCT–NPs > i.m. αCT–NPs, while αCT solution, as control groups, could hardly enter the brain. These results indicated that OX26–NPs are promising carriers for peptide brain delivery.

Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles

Arsenic trioxide (As2O3) is a promising anticancer agent for solid tumors. However, the high toxicity to normal tissues resulting from the lack of tumor specificity remains a huge challenge in its systemic application. Targeted vectors enabling drug delivery to specific cancer cells bring about great potential for better therapeutic efficacy whereas low side effects in cancer treatments. Our previous work has demonstrated that the anti-CD44v6 single chain variable fragment (scFvCD44v6) screened out from the human phage-displayed scFv library possesses high specificity and affinity to membrane antigen CD44v6 over-expressing in a subset of epithelium-derived cancers, such as pancreatic, hepatocellular, colorectal and gastric cancers. Herein, a maleimide-functionalized amphiphilic diblock copolymer of poly (ethylene glycol) and poly (d, l-lactide) (mal-PEG-PDLLA) was synthesized and assembled to vesicles with arsenite ion (As) encapsulated in their cores (As-NPs). Conjugation of scFvCD44v6 with mal-PEG-PDLLA (scFv-As-NPs) enabled more efficient delivery of As and exhibited higher cytotoxic activity than non-targeted ones (As-NPs) in human pancreatic cancer cells PANC-1. Furthermore, the targeted delivery of As induced more significant gene suppression in terms of the expression of anti-apoptotic Bcl-2 protein. Consequently, the expression level of cleaved caspase-3 which is a molecular indicator of cell apoptosis was remarkably elevated. In animal tests, scFv-As-NPs were found to greatly increase accumulation of drug in tumor site and potentiate the efficacy of As in inhibiting tumor growth owing to the enhanced cell apoptosis. These results imply that our tumor specific nanocarriers provide a highly efficient and safe platform for pancreatic cancer therapy.

Selective delivery of an anticancer drug with aptamer-functionalized liposomes to breast cancer cells in vitro and in vivo

Selective targeting of cancer cells is a critical step in cancer diagnosis and therapy. To address this need, DNA aptamers have attracted significant attention as possible targeting ligands. However, while their use in targeting cancer cells in vitro has been reported, their effectiveness has rarely been established in vivo. Here we report the development of a liposomal drug delivery system for targeted anticancer chemotherapy. Liposomes were prepared containing doxorubicin as a payload, and functionalized with AS1411, a DNA aptamer with strong binding affinity for nucleolin. AS1411 aptamer-functionalized liposomes increased cellular internalization and cytotoxicity to MCF-7 breast cancer cells as compared to non-targeting liposomes. Furthermore, targeted liposomal doxorubicin improved antitumor efficacy against xenograft MCF-7 breast tumors in athymic nude mice, attributable to their enhanced tumor tissue penetration. This study suggests that AS1411 aptamer-functionalized liposomes can recognize nucleolin overexpressed on MCF-7 cell surface, and therefore enable drug delivery with high specificity and selectivity.

Use of High Resolution Mass Spectrometry for Analysis of Polymeric Excipients in Drug Delivery Formulations

Two polymeric excipients, typically used in enabling drug delivery approaches, are Gelucire 44/14 (a product of Gattefosse s.a, St Priest, France) and polysorbate 80; these are known to improve solubility of poorly water-soluble drugs and, hence, increase their effective bioavailability. In addition to the use of Gelucire 44/14 and polysorbate 80 as excipients in drugs, they are also widely used as cosmetic and food additives. In general, complex structures and compositions of drug excipients impact performance of the formulation in vivo and consequently affect drug absorption. Therefore, a comparison between excipients from different suppliers and batches to batch would provide an indication of the impact on drug product performance and also the study of the effectiveness of the system and any problems associated with the formulation. In this study, high resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) is used to compare two different batches of Gelucire 44/14 and polysorbate 80. With the high resolving power of FTICR MS, it was possible to differentiate between batches of excipients from differences in the identified components. The improved resolution offered by FTICR MS allowed assignment of four polymeric series differences in the two batches of polysorbate 80 and the presence of one compound and three polymeric series differences in the two batches of Gelucire 44/14. The increase in the number of components assigned in the excipients batch using FTICR-MS, compared to the numbers previously assigned by lower resolution TOF MS, underlines the importance of high resolution techniques in analysis of highly complex mixtures.

A Human Vascular Model Based on Microdialysis for the Assessment of the Vasoconstrictive Dose–Response Effects of Norepinephrine and Vasopressin in Skin

Microdialysis enables drug delivery in the skin and simultaneous measurement of their effects. The present study aimed to evaluate dose-dependent changes in blood flow and metabolism during microdialysis of norepinephrine and vasopressin. We investigated whether increasing concentrations of norepinephrine (NE, 1.8-59 μmol/L) and vasopressin (VP, 1-100 nmol/L), delivered sequentially in one catheter or simultaneously through four catheters, yield dose-dependent changes in blood flow (as measured using urea clearance) and metabolism (glucose and lactate). We found a significant dose-dependent vasoconstriction with both drugs. Responses were characterized by a sigmoid dose response model. Urea in the dialysate increased from a baseline of 7.9 ± 1.7 to 10.9 ± 0.9 mmol/L for the highest concentration of NE (p < 0.001) and from 8.1 ± 1.4 to 10.0 ± 1.7 mmol/L for the highest concentration of VP (p = 0.037). Glucose decreased from 2.3 ± 0.7 to 0.41 ± 0.18 mmol/L for NE (p = 0.001) and from 2.7 ± 0.6 to 1.3 ± 0.5 mmol/L for VP (p < 0.001). Lactate increased from 1.1 ± 0.4 to 2.6 ± 0.5 mmol/L for NE (p = 0.005) and from 1.1 ± 0.4 to 2.6 ± 0.5 mmol/L for VP (p = 0.008). There were no significant differences between responses from a single catheter and from those obtained simultaneously using multiple catheters. Microdialysis in the skin, either with a single catheter or using multiple catheters, offers a useful tool for studying dose response effects of vasoactive drugs on local blood flow and metabolism without inducing any systemic effects.