Fast onset of thrombolytic effect of efficiently inhalable spray-dried rivaroxaban powder formulations.

Pulmonary embolism is a critical medical condition and can lead to cardiovascular arrest or death if left untreated. Pulmonary delivery of an anti-coagulant therapeutic could provide a locally limited and efficient therapy, moreover combined with a potentially fast onset of the therapeutic effect that is demanded in emergency situations. Rivaroxaban (riva) was formulated as an inhalable dry powder that can be administered directly to the lungs in order to reach high local drug doses.

Imaging-Based Drug Penetration Profiling in an Excised Sheep Cornea Model.

Formulations designed to address ocular conditions and diseases are predominantly administered topically. While in vitro test systems have been developed to assess corneal permeation under extended contact conditions, methods focusing on determining the penetration depth and kinetics of a substance within the cornea itself rather than through it, are scarce. This study introduces a method for time-dependent penetration depth analysis (10 and 60 min) by means of a semiquantitative imaging method in comparison with a quantitative corneal depth-cut technique, employing fluorescein sodium at concentrations of 0.

Enhanced browning of adipose tissue by mirabegron-microspheres.

Thermogenic brown adipose tissue (BAT) has emerged as an attractive target for combating obesity. However, pharmacological activation of energy expenditure by BAT and/or induction of browning of white adipose tissue (WAT) has been hampered by cardiovascular side effects. To address these concerns, we developed polylactide-co-glycolide acid (PLGA) microspheres loaded with mirabegron (MIR), a selective beta-3 adrenergic receptor (ADRB3) agonist, to achieve sustained local induction and activation of thermogenic adipocytes.

Membrane-Fusing Vehicles for Re-Sensitizing Transporter-Mediated Multiple-Drug Resistance in Cancer.

Reversing the multiple drug resistance (MDR) arising from the overexpression of the efflux transporters often fails mainly due to the high toxicity or the poor water solubility of the inhibitors of these transporters. Here, we demonstrate the delivery of an inhibitor targeting three ABC transporters (ABCB1, ABCC1 and ABCG2) directly to the cell membrane using membrane-fusing vehicles (MFVs). Three different transfected MDCK II cell lines, along with parental cells, were used to investigate the inhibitory effect of cyclosporine A (CsA) in solution versus direct delivery to the cell membrane.

Active nanoparticle targeting of MUC5AC ameliorates therapeutic outcome in experimental colitis.

Inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract and are characterized by chronic recurrent ulceration of the bowels. Colon-targeted drug delivery systems (DDS) have received significant attention for their potential to treat IBD by improving the inflamed tissue selectivity. Herein, antiMUC5AC-decorated drug loaded nanoparticles (NP) are suggested for active epithelial targeting and selective adhesion to the inflamed tissue in experimental colitis.

Focused ion beam-scanning electron microscopy provides novel insights of drug delivery phenomena.

Scanning electron microscopy (SEM) has long been a standard tool for morphological analyses, providing sub micrometer resolution of pharmaceutical formulations. However, analysis of internal morphologies of such formulations can often be biased due to the introduction of artifacts that originate from sample preparation. A recent advancement in SEM, is the focused ion beam scanning electron microscopy (FIB-SEM).

Recent progress in drug delivery systems for tyrosine kinase inhibitors in the treatment of lung cancer.

Lung cancer ranks as the second most commonly diagnosed cancer in both men and women worldwide. Despite the availability of diverse diagnostic and treatment strategies, it remains the leading cause of cancer-related deaths globally. The current treatment approaches for lung cancer involve the utilization of first generation (e.

Local perfusion of capillaries reveals disrupted beta-amyloid homeostasis at the blood-brain barrier in Tg2576 murine Alzheimer's model.

Background: Parenchymal accumulation of beta-amyloid (Aβ) characterizes Alzheimer's disease (AD). Aβ homeostasis is maintained by two ATP-binding cassette (ABC) transporters (ABCC1 and ABCB1) mediating efflux, and the receptor for advanced glycation end products (RAGE) mediating influx across the blood-brain barrier (BBB). Altered transporter levels and disruption of tight junctions (TJ) were linked to AD.

Polymeric Nanoparticles' Accumulation in Atopic Dermatitis: Clinical Comparison between Healthy, Non-Lesional, and Lesional Skin.

A major limitation in the current topical treatment strategies for inflammatory skin disorders is the inability to selectively target the inflamed site with minimal exposure of healthy skin. Atopic dermatitis is one of the most prevalent types of dermatitis. The use of polymeric nanoparticles for targeting inflamed skin has been recently proposed, and therefore the aim of this proof-of-concept clinical study was to investigate the skin penetration and deposition of polymeric biodegradable nanoparticles in the atopic dermatitis lesions and compare the data obtained to the deposition of the particles into the healthy skin or lesion-free skin of the atopic dermatitis patients.

Subcellular analysis of blood-brain barrier function by micro-impalement of vessels in acute brain slices.

The blood-brain barrier (BBB) is a tightly and actively regulated vascular barrier. Answering fundamental biological and translational questions about the BBB with currently available approaches is hampered by a trade-off between accessibility and biological validity. We report an approach combining micropipette-based local perfusion of capillaries in acute brain slices with multiphoton microscopy.

Enhancement of mitochondrial function using NO releasing nanoparticles; a potential approach for therapy of Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia. Increasing evidence is showing the important role of mitochondrial dysfunction in AD. Mitochondria based oxidative stress, decrease in respiratory chain activity and ATP production are all associated with AD, hence indicating that the enhancement of mitochondrial function and biogenesis present a promising therapeutic approach for AD.

Alternative Excipients for Protein Stabilization in Protein Therapeutics: Overcoming the Limitations of Polysorbates.

Given their safety and efficiency in protecting protein integrity, polysorbates (PSs) have been the most widely used excipients for the stabilization of protein therapeutics for years. In recent decades, however, there have been numerous reports about visible or sub-visible particles in PS-containing biotherapeutic products, which is a major quality concern for parenteral drugs. Alternative excipients that are safe for parenteral administration, efficient in protecting different protein drugs against various stress conditions, effective in protein stabilization in high-concentrated liquid formulations, stable under the storage conditions for the duration of the product's shelf-life, and compatible with other formulation components and the primary packaging are highly sought after.

Immune Modifying Effect of Drug Free Biodegradable Nanoparticles on Disease Course of Experimental Autoimmune Neuritis.

Guillain-Barre syndrome (GBS) is an autoimmune disease of demyelination and inflammation of peripheral nerves. Current treatments are limited to plasma exchange and intravenous immunoglobulins. Cargo-free nanoparticles (NPs) have been evaluated here for their therapeutic benefit on the disease course of experimental autoimmune neuritis (EAN), mimicking the human GBS.

Effect of Texture and Surface Chemistry on Deagglomeration and Powder Retention in Capsule-Based Dry Powder Inhaler.

Pulmonary delivery systems should administer a high dose of the required formulation with the designated dry powder inhaler (DPI) to achieve therapeutic success. While the effects of device geometry and individual components used on powder dispersion are described in literature, potential effects of DPI surface properties on powder retention within the device and deagglomeration have not been adequately studied, but could impact inhalation therapy by modifying the available dose. For this, inner parts of a model DPI were modified by plasma treatment using various processes.

Rivaroxaban lyospheres prepared by a dimethyl sulfoxide-based spray-freeze-drying process.

Spray-freeze-drying (SFD) processes are usually using aqueous solvent systems, which however, exclude the use of SFD for poorly water-soluble drugs/excipients. Here, we evaluated dimethyl sulfoxide for its suitability in formulating SFD particles (lyospheres®). Rivaroxaban was spray-freeze-dried from DMSO solutions containing polyvinyl pyrrolidone (PVP; Kollidon® 25), vinylpyrrolidone-vinyl acetate copolymer (PVP-VA; Kollidon® VA64) or polyvinyl alcohol 4-88 (PVA) forming porous lyospheres® (median particle size 250 to 350 µm).

State of the Art in Capsule-Based Dry Powder Inhalers: Deagglomeration Techniques and the Consequences for Formulation Aerosolization.

Commercially available dry powder inhalers (DPIs) are usually devices in a fixed combination with the intended formulation, and a change in medication by the physician often forces the patient to use a different device, requiring the patient to relearn how to use it, resulting in lower adherence and inadequate therapy. To investigate whether DPIs can achieve successful outcomes regardless of the formulation and flow rate used, a novel DPI and two commercially available devices were compared in vitro for their deagglomeration behavior for different binary blends and a spray-dried particle formulation. The results demonstrate that the novel device achieved the highest fine particle fraction (FPF) regardless of the formulations tested.

Assessment of joint pharmacokinetics and consequences for the intraarticular delivery of biologics.

Intraarticular (IA) injections provide the opportunity to deliver biologics directly to their site of action for a local and efficient treatment of osteoarthritis. However, the synovial joint is a challenging site of administration since the drug is rapidly eliminated across the synovial membrane and has limited distribution into cartilage, resulting in unsatisfactory therapeutic efficacy. In order to rationally develop appropriate drug delivery systems, it is essential to thoroughly understand the unique biopharmaceutical environments and kinetics in the joint to adequately simulate them in relevant experimental models.

Designing highly porous amorphous celecoxib particles by spray freeze drying leads to accelerated drug absorption in-vivo.

Poorly water-soluble drugs are still a major challenge to overcome in order to achieve sufficiently high oral bioavailability. Spray freeze drying (SFD) is proposed here as an alternative for the preparation of amorphous, free-flowing porous celecoxib spheres for enhanced drug dissolution. Tertiary butyl alcohol solutions of celecoxib + excipient (povidone, hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and Soluplus®) at variable ratios were sprayed into a cooled spray tower, followed by vacuum freeze drying.

Improving Transungual Permeation Study Design by Increased Bovine Hoof Membrane Thickness and Subsequent Infection.

Ungual formulations are regularly tested using human nails or animal surrogates in Franz diffusion cell experiments. Membranes sometimes less than 100 µm thick are used, disregarding the higher physiological thickness of human nails and possible fungal infection. In this study, bovine hoof membranes, healthy or infected with , underwent different imaging techniques highlighting that continuous pores traversed the entire membrane and infection resulted in fungal growth, both superficial, as well as in the membrane's matrix.

Cyclodextrin Complex Formation with Water-Soluble Drugs: Conclusions from Isothermal Titration Calorimetry and Molecular Modeling.

Cyclodextrin (CD) complexes are frequently used for enhancing the solubility or absorption of poorly water-soluble drugs. On the contrary, little is known about their complex formation with water-soluble drugs. Here, we have studied the interaction between 2-hydroxypropyl β-CD (HPβCD) and three water-soluble drugs, namely naloxone (NX), oxycodone (OC), and tramadol (TR), by isothermal titration calorimetry (ITC) combined with molecular modeling in view of the potential impact on drug release.

Blood-brain barrier models: Rationale for selection.

Brain delivery is a broad research area, the outcomes of which are far hindered by the limited permeability of the blood-brain barrier (BBB). Over the last century, research has been revealing the BBB complexity and the crosstalk between its cellular and molecular components. Pathologically, BBB alterations may precede as well as be concomitant or lead to brain diseases.