The Therapeutic Benefits of Nanoencapsulation in Drug Delivery to the Anterior Segment of the Eye: A Systematic Review.

Background: Although numerous nanoparticle formulations have been developed for ocular administration, concerns are being raised about a possible mismatch between potential promises made by the field of nanoparticle research and demonstration of actual therapeutic benefit. Therefore, the primary focus of this present review was to critically assess to what extent nanoencapsulation of ocular drugs improved the therapeutic outcome when treating conditions in the anterior segment of the eye. Methods: A systematic search was conducted using Medline, PubMed, and Embase databases as well as Google Scholar for published peer-reviewed articles in English focusing on conventional nanoparticles used as drug delivery systems to the anterior segment of the eye in in vivo studies. The major therapeutic outcomes were intraocular pressure, tear secretion, number of polymorphonuclear leucocytes and pupil size. The outcome after encapsulation was compared to the non-encapsulated drug. Results: From the search, 250 results were retrieved. Thirty-eight studies met the inclusion criteria. Rabbits were used as study subjects in all but one study, and the number of animals ranged from 3 to 10. Coated and uncoated liposomes, lipid-based and polymeric nanoparticles, as well as micelles, were studied, varying in both particle size and surface charge, and encapsulating a total of 24 different drugs, including 6 salts. The majority of the in vivo studies demonstrated some improvement after nanoencapsulation, but the duration of the benefit varied from less than 1 h to more than 20 h. The most common in vitro methods performed in the studies were drug release, transcorneal permeation, and mucin interaction. Discussion: Nanoparticles that are small and mucoadhesive, often due to positive surface charge, appeared beneficial. Although in vitro assays can unravel more of the hidden and sophisticated interplay between the encapsulated drug and the nanoparticle structure, they suffered from a lack of in vitro-in vivo correlation. Therefore, more research should be focused towards developing predictive in vitro models, allowing rational design and systematic optimization of ocular nanoparticles with minimal animal experimentation.

Medication dose calculation errors and other numeracy mishaps in hospitals: Analysis of the nature and enablers of incident reports.

AIMS: To investigate medication dose calculation errors and other numeracy mishaps in hospitals and examine mechanisms and enablers which lead to such errors. DESIGN: A retrospective study using descriptive statistics and thematic analysis of the nature and enablers of reported incidents. METHODS: Medication dose calculation errors and other numeracy mishaps were identified from medication-related incidents reported to the Norwegian Incident Reporting System in 2016 and 2017. The main outcome measures were medications and medication classes involved, severity of harm, outcome, and error enablers. RESULTS: In total, we identified 100 numeracy errors, of which most involved intravenous administration route (n = 70). Analgesics were the most commonly reported drug class and morphine was the most common individual medication. Overall, 78 incidents described patient harm. Frequent mechanisms were 10- or 100-fold errors, mixing up units, and incorrect strength/rate entered into infusion pumps. The most frequent error enablers were: double check omitted or deviated (n = 40), lack of safety barriers to intercept prescribing errors (n = 25), and emergency/stress (n = 21). CONCLUSION: Numeracy errors due to lack of or improper safeguards occurred during all medication management stages. Dose miscalculation after dilution of intravenous solutions, infusion pump programming, and double-checking were identified as unsafe practices. We discuss measures to prevent future calculation and numeracy errors. IMPACT: Our analysis of medication dose calculation errors and other numeracy mishaps demonstrates the need for improving safety steps and increase standardization for medication management procedures. We discuss organizational, technological, and educational measures to prevent harm from numeracy errors.

Solid lipid nanoparticle-loaded mucoadhesive buccal films - Critical quality attributes and in vitro safety & efficacy.

The objective of this work was to develop and characterize solid lipid nanoparticle (SLN)-loaded mucoadhesive films to reveal their potential as successful drug formulations. SLNs based on lipid (Lipoid S100) and surfactant (polysorbate 80) were prepared using the solvent-injection method, and their properties examined using experimental designs. Further, the marker coumarin 6 (C6) was solubilized in the particles as a model for a lipophilic drug. Lipid and surfactant concentrations influenced the particle size, while C6 had minor impact. The particle size distribution was narrow and the storage stability satisfactory for 4 months (4 ℃). The incorporation of the nanoparticles into a film matrix consisting of HPMC and glycerol, increased film thickness and flexibility, and slightly decreased the mechanical strength. The mucin interaction and disintegration time of the films were unimpaired. Film uniformity was satisfactory. Solubilisation in SLNs reduced the rate and extent of permeation of C6 through a monolayer of mucus-producing HT29-MTX cells. When the particles were incorporated into the mucoadhesive film, this effect was compensated for. In conclusion, this project was a first step in the successful development of an SLN-loaded mucoadhesive film formulation and served its purpose in revealing the formulation's uniformity, mucoadhesiveness and biocompatibility.

Severe and fatal medication errors in hospitals: findings from the Norwegian Incident Reporting System.

BACKGROUND: Even with global efforts to prevent medication errors, they still occur and cause patient harm. Little systematic research has been done in Norway to address this issue. OBJECTIVES: To describe the frequency, stage and types of medication errors in Norwegian hospitals, with emphasis on the most severe and fatal medication errors. METHODS: Medication errors reported in 2016 and 2017 (n=3557) were obtained from the Norwegian Incident Reporting System, based on reports from 64 hospitals in 2016 and 55 in 2017. Reports contained categorical data (eg, patient age, incident date) and free text data describing the incident. The errors were classified by error type, stage in the medication process, therapeutic area and degree of harm, using a modified version of the WHO Conceptual Framework for the International Classification for Patient Safety. RESULTS: Overall, 3372 reports were included in the study. Most medication errors occurred during administration (68%) and prescribing (24%). The leading types of errors were dosing errors (38%), omissions (23%) and wrong drug (15%). The therapeutic areas most commonly involved were analgesics, antibacterials and antithrombotics. Over half of all errors were harmful (62%), of which 5.2% caused severe harm, and 0.8% were fatal. CONCLUSIONS: Medication errors most commonly occurred during medication administration. Dosing errors were the most common error type. The substantial number of severe and fatal errors causing preventable patient harm and death emphasises an urgent need for error-prevention strategies. Additional studies and interventions should further investigate the error-prone medication administration stage in hospitals and explore the dynamics of severe incidents.

Micellisation Mechanism and Behaviour of Soluplus®â»Furosemide Micelles: Preformulation Studies of an Oral Nanocarrier-Based System.

: In this study, self-assembling Soluplus® micelles were examined for inherent properties. Through calorimetric analysis, the critical micelle concentration (CMC) could be determined at 25 and 37 °C, and the influence of three media (Milli-Q water, phosphate-buffered saline (PBS) with a pH of 7.4 and 0.1 M HCl) on the lower critical solution temperature (LCST) was detected. Furthermore, the solubilisation of a poorly soluble drug, furosemide, into the Soluplus® micelles was studied. The concentration-dependent properties of the micellar system were assessed through an examination of the micellar size, polydispersity, morphology, viscosity and solubilising properties, which were all found to be affected by the concentration, but temperature, pH and the composition of the test medium were also found to have an effect. Homogeneity in the estimated micellar size and morphology was shown for monophasic micelle dispersions in lower concentrations and with a shift towards more complex structures or aggregates in higher concentrations. The micelles were further investigated in terms of drug release and biocompatibility with mucus-producing HT29-MTX cells, where no biocompatibility issues were found. In this research, the implications for oral drug delivery are discussed and valuable preformulation information is provided on the micellar properties of a Soluplus® drug system in a liquid or semi-solid form.

Development of a bioadhesive nanoformulation with Glycyrrhiza glabra L. extract against Candida albicans.

Glycyrrhiza glabra L. is considered an important source of bioactive compounds. This study aimed at the development of an efficient solution for the treatment of oral candidiasis. Several extracts of Glycyrrhiza glabra L. were prepared using different solvents and their potential in vitro antifungal activity was assessed. Ethanolic extracts showed the most promising results against C. albicans. This extract was incorporated into mucoadhesive nanoparticles (PLA, PLGA and alginate), which were further included in an oral gel, an oral film and a toothpaste, respectively. The results showed that nanoparticles were successfully produced, presenting a mean size among 100-900 nm with high encapsulation efficiency. In vitro studies showed that the most bioadhesive formulation was the oral film with extract-loaded PLGA nanoparticles, followed by the toothpaste with extract-loaded alginate nanoparticles and the oral gel with extract-loaded PLA nanoparticles.

An in vitro study of mucoadhesion and biocompatibility of polymer coated liposomes on HT29-MTX mucus-producing cells.

Drug delivery to the oral cavity poses a significant challenge due to the short residence time of the formulations at the site of action. From this point of view, nanoparticulate drug delivery systems with ability to adhere to the oral mucosa are advantageous as they could increase the effectiveness of the therapy. Positively, negatively and neutrally charged liposomes were coated with four different types of polymers: alginate, low-ester pectin, chitosan and hydrophobically modified ethyl hydroxyethyl cellulose. The mucoadhesion was studied using a novel in vitro method allowing the liposomes to interact with a mucus-producing confluent HT29-MTX cell-line without applying any external force. MTT viability and paracellular permeability tests were conducted on the same cell-line. The alginate-coated liposomes achieved a high specific (genuine) mucin interaction, with a low potential of cell-irritation. The positively charged uncoated liposomes achieved the highest initial mucoadhesion, but also displayed a higher probability of cell-irritation. The chitosan-coated liposomes displayed the highest potential for long lasting mucoadhesion, but with the drawback of a higher general adhesion (tack) and a higher potential for irritating the cells.

Mucus can change the permeation rank order of drug candidates.

The aim of the study was to test the effect of mucus on the permeability of newly developed structurally related free fatty acid receptor 1-agonists TUG-488, TUG-499 and TUG-424, which were compared to the more hydrophilic ketoprofen and the more hydrophobic testosterone as reference drugs. The model membrane was cell monolayers consisting of methotrexate treated HT29 cells grown for approximately one, two or three weeks, and thereby differing in the amount of goblet cells and hence mucus. The results show that the permeation of all compounds was high and that mucus in most cases only had a minor influence. However, for one of the drug candidates, TUG-499, mucus had a clear impact, and this could not be explicitly related to the hydrophobicity of this compound. Secreted mucus thus changed the obtained rank order of permeation. This was especially apparent when the experiments were carried out at a lower agitation. These results indicate that an experimental system without mucus can give a faulty rank order of permeation compared to mucous membranes when structurally related drug candidates are tested.

Discovery of a potent and selective free fatty acid receptor 1 agonist with low lipophilicity and high oral bioavailability.

The free fatty acid receptor 1 (FFA1, also known as GPR40) mediates enhancement of glucose-stimulated insulin secretion and is emerging as a new target for the treatment of type 2 diabetes. Several FFA1 agonists are known, but the majority of these suffer from high lipophilicity. We have previously reported the FFA1 agonist 3 (TUG-424). We here describe the continued structure-activity exploration and optimization of this compound series, leading to the discovery of the more potent agonist 40, a compound with low lipophilicity, excellent in vitro metabolic stability and permeability, complete oral bioavailability, and appreciable efficacy on glucose tolerance in mice.

Identification of a potent and selective free fatty acid receptor 1 (FFA1/GPR40) agonist with favorable physicochemical and in vitro ADME properties.

The free fatty acid receptor 1 (FFA1, also known as GPR40) enhances glucose-stimulated insulin secretion from pancreatic ß-cells and is recognized as an interesting new target for treatment of type 2 diabetes. Several series of selective FFA1 agonists are already known. Most of these are derived from free fatty acids (FFAs) or glitazones and are relatively lipophilic. Aiming for the development of potent, selective, and less lipophilic FFA1 agonists, the terminal phenyl of a known compound series was replaced by nitrogen containing heterocycles. This resulted in the identification of 37, a selective FFA1 agonist with potent activity on recombinant human FFA1 receptors and on the rat insulinoma cell line INS-1E, optimal lipophilicity, and excellent in vitro permeability and metabolic stability.

In-vitro permeability of poorly water soluble drugs in the phospholipid vesicle-based permeation assay: the influence of nonionic surfactants.

OBJECTIVES: The aim of this study was to determine the influence of nonionic surfactants on drug permeability using the phospholipid vesicle-based permeation assay (PVPA), which excludes other than trans-membrane diffusion pathways. METHODS: Barrier integrity was monitored both by electrical resistance and permeability measurement of the hydrophilic marker calcein. Permeability of the model drugs ketoprofen and nadolol across the PVPA-barrier was measured by HPLC-UV. Micelle association of the model drugs was determined using ultrafiltration, whereby micelle-bound drug and molecular drug were separated. KEY FINDINGS: The nonionic surfactant poloxamer 188 was demonstrated not to affect barrier integrity. Drug permeability was found depressed in the presence of poloxamer 188 in a concentration-dependent manner. Both drugs were found to associate with poloxamer 188 micelles. The extent of the decrease in permeability correlated mostly, but not in all cases, with the fraction of micelle-bound drug. CONCLUSIONS: Micelle association was one important but not the only factor affecting drug permeability across the PVPA-barrier.

New insights into the mucoadhesion of pectins by AFM roughness parameters in combination with SPR.

The object of this study was to assess the mucoadhesion of the three main commercially available types of pectin by atomic force microscopy (AFM) and surface Plasmon resonance (SPR). Polyacrylic acid and polyvinyl pyrrolidone were used as positive and negative control, respectively. Image analysis of the AFM scans revealed a significant change of roughness parameters when low-ester pectin was introduced to mica supported bovine submaxillarymucin, indicating a high mucoadhesion for this type of pectin. Only minor changes were observed with high-ester and amidated pectin. The same ranking order of adhesion affinity was confirmed by SPR. In conclusion, a high specific mucin interaction of pectin with a high charge density was demonstrated directly on a molecular scale without interference from the viscoelastic properties or the intra-molecular interactions between the polymer chains themselves, using two independent methods.

Permeation modulating properties of natural polymers--effect of molecular weight and mucus.

The permeation modulating effects of 5 natural polymers; low-ester, amidated and high-ester pectin, as well as hyaluronic acid and chitosan were tested at two different molecular weights each. The model membrane was methotrexate treated HT29 cells grown for 2 or 3 weeks, respectively, thereby differing in the amount of goblet cells and hence mucus. The pectins decreased the permeation of the paracellular marker carboxyfluorescein. Free acid groups and a high molecular weight increased this membrane protective effect. Chitosan displayed pronounced and hyaluronic acid modest permeation enhancing properties. In this case, a low molecular weight accentuated the effect. In all cases, the permeation modulating properties were reduced by mucus.

Mucoadhesion and drug permeability of free mixed films of pectin and chitosan: an in vitro and ex vivo study.

The objective of this study was to identify the important factors for the drug permeability and mucoadhesion of casted free pectin/chitosan combination films. The factors varied were: the type of pectin (low and high methoxyl pectin) and the ratio pectin:chitosan (25:75, 50:50 and 75:25). The model drug used for measuring drug permeability was paracetamol. A texture analyzer was used for measuring mucoadhesion by using two different setups: (1) in vitro tensile tests measuring the detachment force of films versus a mucin dispersion and (2) ex vivo shear tests measuring the friction forces between pre-hydrated films and fresh porcine small intestine, with the system immersed in phosphate buffer, pH 6.8. The type of pectin used in the combination films did not have a significant effect on the drug permeability. The ex vivo mucoadhesion test revealed significant differences between low and high methoxyl pectin only for the 50:50 pectin:chitosan films. For that type of film, the peak and friction forces were highest for high methoxyl pectin. Both the mucoadhesion and drug permeability generally increased with decreasing amounts of pectin relative to chitosan in the films.

Effect of pectin type and plasticizer on in vitro mucoadhesion of free films.

The objective was to measure and compare the specific and general mucin interaction of plasticized and unplasticized pectin films. The pectin types differed in the type and degree of substitution. Mucoadhesive properties were measured by using a texture analyzer. Pectin with an intermediate degree of methoxylation (36%) displayed substantially higher general and specific mucin interaction than amidated, acetylated, and high methoxylated pectin. This was explained with extensive hydrogen bonding in addition to favorable wetting properties. When comparing all plasticized films to all unplasticized films, a consistent and statistically significant increase in the peak force was observed on adding an effective plasticizer.

Ex vivo mucoadhesion of different zinc-pectinate hydrogel beads.

The objective of this study was to investigate the mucoadhesive properties of pre-swelled hydrogel beads made of six types of pectin from three manufacturers. The types of pectin differed mainly in the degree of methoxylation and degree of amidation. Zinc ions were used as cross-linking agent. The mucoadhesive properties were tested on an inverted fresh porcine small intestine attached to a rotating cylinder. Beads made of pectin with a high degree of methoxylation (70%) showed superior mucoadhesive results compared to the other formulations, which could be correlated to the lower amount of zinc in this formulation, subsequently leading to a lower amount of cross-linking and higher mobility of the polymer chains of these beads. This study therefore also indicated the importance of doing mucoadhesive measurements on relevant formulations, and not basing the understanding solely on investigating polymer solutions. Samples from different manufacturers produced the same results.

In vitro measurements of mucoadhesive properties of six types of pectin.

The objective of this study was to measure and compare the specific- and general mucin interaction of six pectin types from three manufacturers, differing mainly in the degree of methoxylation and degree of amidation. Mucoadhesive properties were measured using a texture analyzer. It was found that an intermediate degree of methoxylation (35 and 36%) improved the specific mucin interaction. Amidation did not increase mucin interaction. Samples from different manufacturers did not alter these conclusions. This study indicates that the general classification of pectin as a poor mucoadhesive, without differentiating between the amount and type of substituents, probably is an oversimplification.