Assessment of subcutaneously administered insulins using in vitro release cartridge: Medium composition and albumin binding.

Biotherapeutics is the fastest growing class of drugs administered by subcutaneous injection. In vitro release testing mimicking physiological conditions at the injection site may guide formulation development and improve biopredictive capabilities. Here, anin vitrorelease cartridge (IVR cartridge) comprising a porous agarose matrix emulating subcutaneous tissue was explored.

Development of UV-Vis Imaging Compatible Chromatographic Matrix with Application for Injectable Formulation Characterization.

Transport within human tissue matrices, e.g., the subcutaneous tissue, exhibits some resemblance to chromatographic processes.

Generic benzalkonium chloride-preserved travoprost eye drops are not identical to the branded polyquarternium-1-preserved travoprost eye drop: Effect on cultured human conjunctival goblet cells and their physicochemical properties.

Purpose: To investigate the effect of polyquaternium-1 (PQ)-preserved and benzalkonium chloride (BAK)-preserved travoprost eye drops on viability of primary human conjunctival goblet cell (GC) cultures and on secretion of mucin and cytokines. Furthermore, to evaluate the physicochemical properties of the branded travoprost eye drop Travatan® and available generics.

Methods: The effect of travoprost eye drops was evaluated on GC cultures.

Methodological Considerations in Development of UV Imaging for Characterization of Intra-Tumoral Injectables Using cAMP as a Model Substance.

A UV imaging release-testing setup comprising an agarose gel as a model for tumorous tissue was developed. The setup was optimized with respect to agarose concentration (0.5% (/)), injection procedure, and temperature control.

Impact of benzalkonium chloride-preserved and preservative-free latanoprost eye drops on cultured human conjunctival goblet cells upon acute exposure and differences in physicochemical properties of the eye drops.

Objective: To investigate the short-term impact on human conjunctival goblet cell (GC) survival and mucin release of acute exposure to benzalkonium chloride (BAK) preserved and preservative-free (PF) 0.005% (w/v) latanoprost (LT) eye drops, and to compare the eye drops' physicochemical properties.

Methods And Analysis: Primary GC cultures were established from human conjunctival donor tissue.

Spatially and time-resolved SAXS for monitoring dynamic structural transitions during in situ generation of non-lamellar liquid crystalline phases in biologically relevant media.

Formation of high viscous inverse lyotropic liquid crystalline phases in situ upon exposure of low viscous drug-loaded lipid preformulations to synovial fluid provides a promising approach for design of depot formulations for intra-articular drug delivery. Rational formulation design relies on a fundamental understanding of the synovial fluid-mediated dynamic structural transitions occurring at the administration site. At conditions mimicking the in vivo situation, we investigated in real-time such transitions at multiple positions by synchrotron small-angle X-ray scattering (SAXS) combined with an injection-cell.

Establishing research priorities related to osteoarthritis care via stakeholder input from patients.

Introduction: Stakeholder involvement in research is emphasised to improve relevance. We aimed to identify, define and prioritise important research topics seen from the point of view of people with osteoarthritis (OA).

Methods: We invited 1,315 members of the user panel of the Danish Rheumatism Association to answer an electronic survey that included; 1) an open-ended question about important research topics (free-text response option), 2) 15 predefined research topics to be rated for importance and 3) predefined topics grouped into four categories in which the most important was prioritised.

Towards functional characterization of excipients for oral solid dosage forms using UV-vis imaging. Liberation, release and dissolution.

The purpose of this study was to investigate whole-dosage form UV-vis imaging as a potential tool for functional characterization of excipients used in solid oral dosage forms. To this end, tablets (average mass 260.0 mg, 224.

Initial Leuprolide Acetate Release from Poly(d,l-lactide--glycolide) Forming Implants as Studied by Ultraviolet-Visible Imaging.

The initial drug release from forming implants is affected by factors such as the physicochemical properties of the active pharmaceutical ingredient, the type of the excipients utilized, and the surrounding environment. The feasibility of UV-vis imaging for characterization of the initial behavior of poly(d,l-lactide--glycolide) (PLGA)/1-methyl-2-pyrrolidinone (NMP) forming implants was investigated. The release of leuprolide acetate (LA) and implant formation in real time were monitored using dual-wavelength imaging at 280 and 525 nm, respectively, in matrices based on agarose gel and hyaluronic acid (HA) solution emulating the subcutaneous matrix.

Towards in vitro in vivo correlation for modified release subcutaneously administered insulins.

Therapeutic proteins and peptides are mainly administrated by subcutaneous injection. In vitro release testing of subcutaneous injectables performed using methods that take the structure and environment of the subcutaneous tissue into account may improve predictability of the in vivo behavior and thereby facilitate establishment of in vitro in vivo correlations. The aim of the study was to develop a biopredictive flow-through in vitro release method with a gel-type matrix for subcutaneously administered formulations and to explore the possibility of establishing a level A in vitro in vivo correlation for selected insulin products.

Diclofenac Prodrugs for Intra-articular Depot Injectables: In Vitro Hydrolysis and Species Variation.

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of nonsteroidal anti-inflammatory drugs are promising for management of joint pain. As candidates for this delivery approach, 5 diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid.

Citrem-phosphatidylcholine nano-self-assemblies: solubilization of bupivacaine and its role in triggering a colloidal transition from vesicles to cubosomes and hexosomes.

Improvement of pain management strategies after arthroscopic surgery by multimodal analgesia may include the use of long-acting amide local anesthetics. Among these anesthetics, the low molecular weight local anesthetic agent bupivacaine (BUP) is attractive for use in postoperative pain management. However, it has a relatively short duration of action and imposes a higher risk of systemic toxicity at relatively large bolus doses.

Transport characteristics in a novel in vitro release model for testing the performance of intra-articular injectables.

There is a need for bio-predictive and well-characterized in vitro release models in the development of intra-articular depot formulations. Here, the commercially-available Scissor system, a membrane-based two-compartment release testing instrument, was applied to characterize the transport and release of the drug diclofenac employing conditions intended to mimic transport in the synovial joint. The fate of hyaluronic acid and human serum albumin, the main bio-relevant components incorporated in the system, was investigated.

UV-vis Imaging of Piroxicam Supersaturation, Precipitation, and Dissolution in a Flow-Through Setup.

Evaluation of drug precipitation is important in order to address challenges regarding low and variable bioavailability of poorly water-soluble drugs, to assess potential risk of patient safety with infusion therapy, and to explore injectable in situ suspension-forming drug delivery systems. Generally, drug precipitation is assessed in vitro through solution concentration analysis methods. Dual-wavelength UV-vis imaging is a novel imaging technique that may provide an opportunity for simultaneously monitoring changes in both solution and solid phases during precipitation.

Concomitant monitoring of implant formation and drug release of in situ forming poly (lactide-co-glycolide acid) implants in a hydrogel matrix mimicking the subcutis using UV-vis imaging.

For poly (lactide-co-glycolide acid) (PLGA)-based in situ forming implants, the rate of implant formation plays an important role in determining the overall drug release kinetics. Currently, in vitro techniques capable of characterizing the processes of drug release and implant formation at the same time are not available. A hydrogel-based in vitro experimental setup was recently developed requiring only microliter of formulation and forming a closed system potentially suitable for interfacing with various spectroscopic techniques.

Phase separation of in situ forming poly (lactide-co-glycolide acid) implants investigated using a hydrogel-based subcutaneous tissue surrogate and UV-vis imaging.

Phase separation of in situ forming poly (lactide-co-glycolide acid) (PLGA) implants with agarose hydrogels as the provider of nonsolvent (water) mimicking subcutaneous tissue was investigated using a novel UV-vis imaging-based analytical platform. In situ forming implants of PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin representing fast and slow phase separating systems, respectively, were evaluated using this platform. Upon contact with the agarose hydrogel, the phase separation of the systems was followed by the study of changes in light transmission and absorbance as a function of time and position.

Long-Acting Diclofenac Ester Prodrugs for Joint Injection: Kinetics, Mechanism of Degradation, and In Vitro Release From Prodrug Suspension.

A prodrug approach for local and sustained diclofenac action after injection into joints based on ester prodrugs having a pH-dependent solubility is presented. Inherent ester prodrug properties influencing the duration of action include their pH-dependent solubility and charge state, as well as susceptibility to undergo esterase facilitated hydrolysis. In this study, physicochemical properties and pH rate profiles of 3 diclofenac ester prodrugs differing with respect to the spacer carbon chain length between the drug and the imidazole-based promoiety were determined and a rate equation for prodrug degradation in aqueous solution in the pH range 1-10 was derived.

Role of Electrostatic Interactions on the Transport of Druglike Molecules in Hydrogel-Based Articular Cartilage Mimics: Implications for Drug Delivery.

In the field of drug delivery to the articular cartilage, it is advantageous to apply artificial tissue models as surrogates of cartilage for investigating drug transport and release properties. In this study, artificial cartilage models consisting of 0.5% (w/v) agarose gel containing 0.

A prodrug approach involving in situ depot formation to achieve localized and sustained action of diclofenac after joint injection.

Long-acting nonsteroidal anti-inflammatory drug formulations for intra-articular injection might be effective in the management of joint pain and inflammation associated sports injuries and osteoarthritis. In this study, a prodrug-based delivery system was evaluated. The synthesized diclofenac ester prodrug, a weak base (pKa 7.

Microenvironmental pH measurement during sodium naproxenate dissolution in acidic medium by UV/vis imaging.

Variable dissolution from sodium salts of drugs containing a carboxylic acid group after passing the acidic environment of the stomach may affect oral bioavailability. The aim of the present proof of concept study was to investigate pH effects in relation to the dissolution of sodium naproxenate in 0.01M hydrochloric acid.

Mechanism of action of lung damage caused by a nanofilm spray product.

Inhalation of waterproofing spray products has on several occasions caused lung damage, which in some cases was fatal. The present study aims to elucidate the mechanism of action of a nanofilm spray product, which has been shown to possess unusual toxic effects, including an extremely steep concentration-effect curve. The nanofilm product is intended for application on non-absorbing flooring materials and contains perfluorosiloxane as the active film-forming component.

PEGylation of phytantriol-based lyotropic liquid crystalline particles--the effect of lipid composition, PEG chain length, and temperature on the internal nanostructure.

Poly(ethylene glycol)-grafted 1,2-distearoyl-sn-glycero-3-phosphoethanolamines (DSPE-mPEGs) are a family of amphiphilic lipopolymers attractive in formulating injectable long-circulating nanoparticulate drug formulations. In addition to long circulating liposomes, there is an interest in developing injectable long-circulating drug nanocarriers based on cubosomes and hexosomes by shielding and coating the dispersed particles enveloping well-defined internal nonlamellar liquid crystalline nanostructures with hydrophilic PEG segments. The present study attempts to shed light on the possible PEGylation of these lipidic nonlamellar liquid crystalline particles by using DSPE-mPEGs with three different block lengths of the hydrophilic PEG segment.

SPECT/CT imaging of radiolabeled cubosomes and hexosomes for potential theranostic applications.

We have developed a highly efficient method for the radiolabeling of phytantriol (PHYT)/oleic acid (OA)-based hexosomes based on the surface chelation of technetium-99m ((99m)Tc) to preformed hexosomes using the polyamine 1, 12-diamino-3, 6, 9-triazododecane (SpmTrien) as chelating agent. We also report on the unsuccessful labeling of cubosomes using the well-known chelating agent hexamethylpropyleneamine oxime (HMPAO). The (99m)Tc-labeled SpmTrien-hexosomes ((99m)Tc-SpmTrien-hexosomes) were synthesized with good radiolabeling (84%) and high radiochemical purity (>90%).

Prolonged naproxen joint residence time after intra-articular injection of lipophilic solutions comprising a naproxen glycolamide ester prodrug in the rat.

Intra-articular injection of oil solutions of lipophilic prodrugs that rapidly degrade to their parent compound in synovial fluid may constitute a feasible approach to increase the joint residence time of non-steroidal anti-inflammatory drugs. In this in vivo study, oil solutions of the N,N-diethyl glycolamide ester prodrug of naproxen (16 mg/ml) were injected into the rat knee joint by dosing 6 μl formulation per 100g body weight. The sustained release properties were compared to those of intra-articularly injected aqueous and oil solutions of naproxen by monitoring the naproxen serum concentrations over time.