Eye drop technique and patient-reported problems in a real-world population of eye drop users.

OBJECTIVE: To assess eye drop technique and patient-reported problems with eye drop instillation in a primary care sample of eye drop users. METHODS: Cross-sectional observational study in 136 community pharmacies in Belgium. Patient inclusion criteria were being age ≥ 18 years and using eye drops for ≥ 1 month (to ensure that patients were already familiar with eye drop instillation). Participants demonstrated their eye drop technique and completed a self-administered questionnaire. RESULTS: Participants (n = 678) had a mean age of 68.9 ± 12.4 years. During the demonstration, almost everyone (98.0%) successfully instilled at least one drop in the eye, although 14% required multiple attempts to achieve this. Only 3% of the sample exhibited perfect drop technique, meaning that they performed correctly all the steps. Most common deviations were touching the bottle to the eye or eyelid (40.7% of patients), and failing to close the eye (67.8%) and perform nasolacrimal occlusion for at least 1 min (94.7%) after drop instillation. Importantly, we found that 20% of ophthalmic suspensions were not shaken before use. Forty percent of patients reported ≥ 1 problem with eye drop instillation. Most common problems were difficulties with getting a drop in the eye (18.3% of patients), too many drops coming out of the bottle (14.6%), and difficulty squeezing the bottle (12.2%). About half of the sample recalled having had education in eye drop instillation technique. CONCLUSION: This study showed suboptimal eye drop technique in real-world clinical practice. A proactive role of community pharmacists in detecting and resolving these problems could be helpful.

Self-Medication With Over-the-Counter Analgesics: A Survey of Patient Characteristics and Concerns About Pain Medication.

Pain is a common reason for self-medication with over-the-counter (OTC) analgesics. However, this self-treating population has remained largely uncharacterized. This cross-sectional observational study investigated individuals who self-medicate their pain with OTC analgesics to elucidate their pain characteristics and medication use. In addition, presence of and risk factors for concerns about pain medication were examined. The clinical profile of the participants (n = 1,889) was worse than expected with long-standing pain complaints (median pain duration of 9 years), pain located at multiple body sites (median of 4, and 13% with ≥10 painful body areas), about one-third suffering from daily pain and about 40% experiencing substantial pain-related disability. Head (58.6% of sample), low back (43.6%), and neck (30.7%) were the most common pain locations. About 73% had a physician diagnosis, mainly migraine and osteoarthritis. Paracetamol (used by 68.6% of patients) and nonsteroidal anti-inflammatory drugs (46.8%) were the most frequently used pain medications. About 40% of our sample showed substantial concern about the perceived need for pain medication and the perceived potential for harmful effects (eg, fear for addiction). These findings highlight the importance for health professionals to systematically probe pain patients about their self-medication practices and explore attitudes about pain medication. Perspective: This study found that the clinical picture of people who self-medicate their pain with OTC analgesics looked worse than expected. We also identified substantial concerns about pain medication. Therefore, we recommend that health professionals systematically probe pain patients about their self-medication practices and explore concerns about pain medication.

A multivariate raw material property database to facilitate drug product development and enable in-silico design of pharmaceutical dry powder processes.

In current study a holistic material characterization approach was proposed and an extensive raw material property database was developed including a wide variety of APIs and excipients with different functionalities. In total 55 different materials were characterized and described by over 100 raw material descriptors related to particle size and shape distribution, specific surface area, bulk, tapped and true density, compressibility, electrostatic charge, moisture content, hygroscopicity, permeability, flowability and wall friction. Principal component analysis (PCA) was applied to reveal similarities and dissimilarities between materials and to identify overarching properties. The developed PCA model allows to rationalize the number of critical characterization techniques in routine characterization and to identify surrogates for use during early drug product development stages when limited amounts of active pharmaceutical ingredients are available. Additionally, the developed database will be the basis to build predictive models for in silico process and formulation development based on (a selection of) property descriptors.

Cranberry extract inhibits in vitro adhesion of F4 and F18+Escherichia coli to pig intestinal epithelium and reduces in vivo excretion of pigs orally challenged with F18+ verotoxigenic E. coli.

F4+E. coli and F18+E. coli infections are an important threat for pig industry worldwide. Antibiotics are commonly used to treat infected piglets, but the emerging development of resistance against antibiotics raises major concerns. Hence, alternative therapies to prevent pigs from F4+E. coli and F18+E. coli infections need to be developed. Since cranberry previously showed anti-adhesive activity against uropathogenic E. coli, we aimed to investigate whether cranberry extract could also inhibit binding of F4+E. coli and F18+E. coli to pig intestinal epithelium. Using the in vitro villus adhesion assay, we found that low concentrations of cranberry extract (20µg or 100µg/ml) have strong inhibitory activity on F4+E. coli (75.3%, S.D.=9.31 or 95.8%, S.D.=2.56, respectively) and F18+E. coli adherence (100% inhibition). This effect was not due to antimicrobial activity. Moreover, cranberry extract (10mg or 100mg) could also abolish in vivo binding of F4 and F18 fimbriae to the pig intestinal epithelium in ligated loop experiments. Finally, two challenge experiments with F18+E. coli were performed to address the efficacy of in-feed or water supplemented cranberry extract. No effect could be observed in piglets that received cranberry extract only in feed (1g/kg or 10g/kg). However, supplementation of feed (10g/kg) and drinking water (1g/L) significantly decreased excretion and diarrhea. The decreased infection resulted in a decreased serum antibody response indicating reduced exposure to F18+E. coli.

Effects of lactoferrin treatment on Escherichia coli O157:H7 rectal colonization in cattle.

The terminal rectal mucosa has been identified as the predominant colonization site of Escherichia coli O157:H7 in cattle, thus a possible intervention approach should directly target this colonization site. To determine the effect of lactoferrin on E. coli O157:H7 mucosal colonization at the rectum, five 6-month-old Holstein-Friesian calves were experimentally infected with E. coli O157:H7 and received daily rectal treatment with bovine lactoferrin. Three calves that did not receive the lactoferrin served as control group. The treatment decreased faecal shedding of E. coli O157:H7 and completely eliminated the infection in all animals (n=5) after 19 days administration. The rectal mucosa of all animals (n=5) was cleared from E. coli O157:H7 within 13 days of lactoferrin treatment. To evaluate the local immune responses, three calves treated previously with lactoferrin and three calves of the control group were re-infected when E. coli O157:H7 excretion was no longer detected. The rectal administration of lactoferrin resulted in an EspA- and EspB-specific IgA responses at the rectal mucosa. These mucosal antibodies were not detected in the animals which did not receive the lactoferrin powder. Interestingly, no serum IgA antibodies could be found in animals of the group that received the lactoferrin. These findings emphasize the ability of bovine lactoferrin to clear E. coli O157:H7 colonization in cattle, where lactoferrin may influence the local immune processes against E. coli O157:H7 infection. Thus, bovine lactoferrin treatment could be used in the field to eliminate high-level faecal excretion of E. coli O157:H7 in cattle.

Elucidation and visualization of solid-state transformation and mixing in a pharmaceutical mini hot melt extrusion process using in-line Raman spectroscopy.

Mixing of raw materials (drug+polymer) in the investigated mini pharma melt extruder is achieved by using co-rotating conical twin screws and an internal recirculation channel. In-line Raman spectroscopy was implemented in the barrels, allowing monitoring of the melt during processing. The aim of this study was twofold: to investigate (I) the influence of key process parameters (screw speed - barrel temperature) upon the product solid-state transformation during processing of a sustained release formulation in recirculation mode; (II) the influence of process parameters (screw speed - barrel temperature - recirculation time) upon mixing of a crystalline drug (tracer) in an amorphous polymer carrier by means of residence time distribution (RTD) measurements. The results indicated a faster mixing endpoint with increasing screw speed. Processing a high drug load formulation above the drug melting temperature resulted in the production of amorphous drug whereas processing below the drug melting point produced solid dispersions with partially amorphous/crystalline drug. Furthermore, increasing the screw speed resulted in lower drug crystallinity of the solid dispersion. RTD measurements elucidated the improved mixing capacity when using the recirculation channel. In-line Raman spectroscopy has shown to be an adequate PAT-tool for product solid-state monitoring and elucidation of the mixing behavior during processing in a mini extruder.

Pharmacokinetic analysis of modified-release metoprolol formulations: An interspecies comparison.

In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID® (reservoir) and Slow-Lopresor® (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic ß1-receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM® where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure. In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only. In both species, the reservoir formulation ZOK-ZID® was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels.

Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test.

This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation. The aim of the current study was to investigate the in-line blending capacity of this twin screw granulator, equipped with conveying elements only. The feasibility of in-line NIR (SentroPAT, Sentronic GmbH, Dresden, Germany) spectroscopy for evaluating the blend uniformity of powders after the granulator was tested. Anhydrous theophylline was used as a tracer molecule and was blended with lactose monohydrate. Theophylline and lactose were both fed from a different feeder into the twin screw granulator barrel. Both homogeneous mixtures and mixing experiments with induced errors were investigated. The in-line spectroscopic analyses showed that the twin screw granulator is a useful tool for in-line blending in different conditions. The blend homogeneity was evaluated by means of a novel statistical method being the moving F-test method in which the variance between two blocks of collected NIR spectra is evaluated. The α- and ß-error of the moving F-test are controlled by using the appropriate block size of spectra. The moving F-test method showed to be an appropriate calibration and maintenance free method for blend homogeneity evaluation during continuous mixing.

Continuous melt granulation: Influence of process and formulation parameters upon granule and tablet properties.

The pharmaceutical industry has a growing interest in alternative manufacturing models allowing automation and continuous production in order to improve process efficiency and reduce costs. Implementing a switch from batch to continuous processing requires fundamental process understanding and the implementation of quality-by-design (QbD) principles. The aim of this study was to examine the relationship between formulation-parameters (type binder, binder concentration, drug-binder miscibility), process-parameters (screw speed, powder feed rate and granulation temperature), granule properties (size, size distribution, shape, friability, true density, flowability) and tablet properties (tensile strength, friability, dissolution rate) of four different drug-binder formulations using Design of experiments (DOE). Two binders (polyethylene glycol (PEG) and Soluplus®) with a different solid state, semi-crystalline vs amorphous respectively, were combined with two model-drugs, metoprolol tartrate (MPT) and caffeine anhydrous (CAF), both having a contrasting miscibility with the binders. This research revealed that the granule properties of miscible drug-binder systems depended on the powder feed rate and barrel filling degree of the granulator whereas the granule properties of immiscible systems were mainly influenced by binder concentration. Using an amorphous binder, the tablet tensile strength depended on the granule size. In contrast, granule friability was more important for tablet quality using a brittle binder. However, this was not the case for caffeine-containing blends, since these phenomena were dominated by the enhanced compression properties of caffeine Form I, which was formed during granulation. Hence, it is important to gain knowledge about formulation behavior during processing since this influences the effect of process parameters onto the granule and tablet properties.

Stearic acid and high molecular weight PEO as matrix for the highly water soluble metoprolol tartrate in continuous twin-screw melt granulation.

Granules with release-sustaining properties were developed by twin screw hot melt granulation (HMG) using a combination of stearic acid (SA) and high molecular weight polyethylene oxide (PEO) as matrix for a highly water soluble model drug, metoprolol tartrate (MPT). Earlier studies demonstrated that mixing molten SA and PEO resulted in hydrogen bond formation between hydroxyl groups of fatty acid molecules and ether groups in PEO chains. These molecular interactions might be beneficial in order to elevate the sustained release effect of drugs from a SA/PEO matrix. This study aims to investigate the continuous twin screw melt granulation technique to study the impact of a SA/PEO matrix on the dissolution rate of a highly water soluble drug (MPT). Decreasing the SA/PEO ratio improved the release-sustaining properties of the matrix. The solid state of the granules was characterized using differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared (FTIR) and near infrared chemical imaging (NIR-CI) in order to understand the dissolution behavior. The results revealed a preferential interaction of the MPT molecules with stearic acid impeding the PEO to form hydrogen bonds with the stearic acid chains. However, this allowed the PEO chains to recrystallize inside the stearic acid matrix after granulation, hence, elevating the release-sustaining characteristics of the formulation.

The use of rheology to elucidate the granulation mechanisms of a miscible and immiscible system during continuous twin-screw melt granulation.

Twin-screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to granulate temperature and moisture sensitive drugs in a continuous way. Recently, the material behavior of an immiscible drug-binder blend during TS HMG was unraveled by using a rheometer and differential scanning calorimetry (DSC). Additionally, vibrational spectroscopic techniques proved the link between TS HMG and rheology since equal interactions at molecular level did occur in both processes. This allowed to use a rheometer to gain knowledge of the material behavior during hot melt processing of an immiscible drug-binder blend. However, miscibility of a drug-binder formulation and drug-binder interactions appear to influence the rheological properties and, hence conceivably also the granulation mechanism. The aim of this research was to examine if the TS HMG process of a miscible formulation system is comparable with the mechanism of an immiscible system and to evaluate whether rheology still serves as a useful tool to understand and optimize the hot melt granulation (HMG) process. The executed research (thermal analysis, rheological parameters and spectroscopic data) demonstrated the occurrence of a high and broad tan(δ) curve without a loss peak during the rheological temperature ramp which implies a higher material deformability without movement of the softened single polymer chains. Spectroscopic analysis revealed drug-polymer interactions which constrain the polymer to flow independently. As a result, the binder distribution step, which generally follows the immersion step, was hindered. This insight assisted the understanding of the granule properties. Inhomogeneous granules were produced due to large initial nuclei or adhesion of multiple smaller nuclei. Consequently, a higher granulation temperature was required in order to get the binder more homogeneously distributed within the granules.

Lubricant sensitivity in function of paddle movement in the forced feeder of a high-speed tablet press.

CONTEXT: The negative impact of magnesium stearate (MgSt) on the hardness of tablets is a well-known phenomenon, but the influence of paddle movement in the forced feeder on the lubricant effect during tablet compression is often neglected. OBJECTIVE: The purpose of this research was to investigate the influence of paddle speed in the forced feeder on tablet tensile strength (TS). MATERIALS AND METHODS: Mixtures of microcrystalline cellulose (MCC) and MgSt (0.5%) were blended using different methods (low & high shear). After blending, the formulations were compressed into tablets. All parameters of the tableting cycle were kept constant except the speed of the paddles in the forced feeder. RESULTS AND DISCUSSION: The blending technique affected the sensitivity of the formulation to the paddle speed. The TS of pure MCC tablets did not change in function of paddle speed, while tablets prepared by low shear mixing became softer at higher paddle speed. The TS of tablets manufactured using the high-shear mixed blend was low and did not vary in function of paddle speed, suggesting that overlubrication already occurred during the initial blending step. Furthermore, analysis of the machine parameters allowed evaluation of the influence of the paddles on the flowability, initial packing, and compactability of the powder mixtures. CONCLUSION: The results elucidated that during manufacturing of tablets using MgSt-containing blends care should not only be taken during the blending step prior to tableting, but also during the tableting process itself, as paddle speed can affect tablet TS, a critical quality attribute.

The use of Rheology Combined with Differential Scanning Calorimetry to Elucidate the Granulation Mechanism of an Immiscible Formulation During Continuous Twin-Screw Melt Granulation.

PURPOSE: Twin screw hot melt granulation (TS HMG) is a valuable, but still unexplored alternative to continuous granulation of moisture sensitive drugs. However, knowledge of the material behavior during TS HMG is crucial to optimize the formulation, process and resulting granule properties. The aim of this study was to evaluate the agglomeration mechanism during TS HMG using a rheometer in combination with differential scanning calorimetry (DSC). METHODS: An immiscible drug-binder formulation (caffeine-Soluplus(®)) was granulated via TS HMG in combination with thermal and rheological analysis (conventional and Rheoscope), granule characterization and Near Infrared chemical imaging (NIR-CI). RESULTS: A thin binder layer with restricted mobility was formed on the surface of the drug particles during granulation and is covered by a second layer with improved mobility when the Soluplus(®) concentration exceeded 15% (w/w). The formation of this second layer was facilitated at elevated granulation temperatures and resulted in smaller and more spherical granules. CONCLUSION: The combination of thermal and rheological analysis and NIR-CI images was advantageous to develop in-depth understanding of the agglomeration mechanism during continuous TS HMG and provided insight in the granule properties as function of process temperature and binder concentration.

Genipin-crosslinked gelatin microspheres as a strategy to prevent postsurgical peritoneal adhesions: In vitro and in vivo characterization.

BACKGROUND: Peritoneal adhesions are a common complication after abdominal surgery. They cause small bowel obstruction, female infertility and chronic abdominal pain. Peritoneal adhesions also hamper uniform drug distribution in the peritoneal cavity, thereby reducing the efficacy of intraperitoneal chemotherapy after cytoreductive surgery. AIM: The goal of this study was to develop a formulation that prevents peritoneal adhesions, evenly distributes in the abdominal cavity, and simultaneously extends residence time and improves local drug concentration. This report describes the formulation and characterization of genipin-crosslinked gelatin microspheres (GP-MS). METHODS AND RESULTS: Spheroid gelatin microspheres were prepared by an emulsification solvent extraction method. A higher degree of crosslinking was obtained by increasing genipin concentration and crosslinking time. The degree of crosslinking allowed to tailor the degradation rate of GP-MS, hence their residence time. GP-MS did not affect cell viability. In vivo experiments showed excellent GP-MS biocompatibility and degradation characteristics. GP-MS were distributed evenly throughout the abdominal cavity. Adhesions were induced in Balb/c mice by application of an abraded peritoneal wall-cecum model. GP-MS-treated mice developed significantly less postsurgical adhesions compared to saline and Hyalobarrier(®) group. Histopathological examination showed a decrease of peritoneal inflammation over time in GP-MS-treated mice with complete recovery of peritoneal wounds post-operative day 14. CONCLUSION: GP-MS are a promising strategy to prevent postoperative peritoneal adhesions and improve efficacy of postoperative intraperitoneal chemotherapy.

Vibrational spectroscopy to support the link between rheology and continuous twin-screw melt granulation on molecular level: A case study.

Twin screw hot melt granulation (TSHMG) is an innovative and continuous drug formulation process allowing granulation of moisture sensitive drugs. However, due to the lack of experience and in-depth process understanding, this technique is not yet widely used. During the TSHMG process, the microstructure of the granules is generated and modified and strongly depends on the flow behavior of the material. Hence, rheology might be a suitable tool to simulate and examine this process. However, chemical interactions of the material are influencing the physical properties leading to the microstructure. In this research project it is spectroscopically investigated whether the heat applied in a rheometer induces the same molecular effects as these occurring during TSHMG of the model formulation caffeine anhydrous/Soluplus®. Hence, it is evaluated whether rheology can be used as a simulation tool to improve the understanding of the material behavior at molecular level during continuous melt granulation. Therefore, in-line Raman spectroscopy is executed during TSHMG and in situ Fourier Transform Infra-red (FTIR) during oscillatory rheological experiments. The results from the in-line Raman monitoring revealed polymorph transition of caffeine anhydrous during twin screw melt granulation with Soluplus® which is stimulated depending on the binder concentration and/or granulation temperature. A correlation was seen between the FTIR spectra obtained during the rheological temperature ramp and the in-line collected Raman spectra during the melt granulation runs. The polymorphic conversion of caffeine anhydrous could be detected in the same temperature range with both techniques, proving the comparability of plate-plate rheometry and hot melt granulation (HMG) for this case with the used parameter settings. Process simulation using rheology combined with in situ FTIR seems a promising approach to increase process understanding and to facilitate binder and parameter selection for TSHMG.

Analysis of drug use in institutionalized individuals with intellectual disability and tube feeding.

OBJECTIVES: Little is known about the medication used by people with intellectual disabilities (ID) and enteral feeding tube (EFT). However, in light of the complexity associated with drug administration through EFT, data on medication use in this population may be helpful in the development of practical guidelines and staff training initiatives. METHODS: A cross-sectional, observational study was conducted in six Belgian residential care facilities (RCFs) for individuals with ID. Anonymized medication records of all residents receiving chronic medication through EFT were collected (n = 156). All chronic drugs were categorized according to the ATC classification, and medication records were checked for potential major drug-drug interactions (DDI). RESULTS: The 156 residents used a total of 1029 chronic drugs via EFT, with a median of six drugs per resident (range 1-14). A total of 148 different drug molecules were identified, belonging to 38 main ATC therapeutic groups (ATC level 2). Antiepileptics, drugs for constipation and drugs for acid-related disorders were the most frequently used groups. Seventy-four of the 156 screened medication records (47%) contained at least one potential DDI; in total, 116 potential interactions were identified, which represent 38 different interacting drug pairs. CONCLUSION: This study describes medication use through EFT among people with ID in Belgian RCFs, with antiepileptics being the most frequently used group. Our study also demonstrated that a high number of drugs is administered through EFT, and that the number of potential DDIs is high. These observations warrant an increased attention for drug administration through the EFT in individuals with ID.

Rationale and Safety Assessment of a Novel Intravaginal Drug-Delivery System with Sustained DL-Lactic Acid Release, Intended for Long-Term Protection of the Vaginal Microbiome.

Bacterial vaginosis is a prevalent state of dysbiosis of the vaginal microbiota with wide-ranging impact on human reproductive health. Based on recent insights in community ecology of the vaginal microbiome, we hypothesize that sustained vaginal DL-lactic acid enrichment will enhance the recruitment of lactobacilli, while counteracting bacterial vaginosis-associated bacteria. We therefore aimed to develop an intravaginal device that would be easy to insert and remove, while providing sustained DL-lactic acid release into the vaginal lumen. The final prototype selected is a vaginal ring matrix system consisting of a mixture of ethylene vinyl acetate and methacrylic acid-methyl methacrylate copolymer loaded with 150 mg DL-lactic acid with an L/D-lactic acid ratio of 1:1. Preclinical safety assessment was performed by use of the Slug Mucosal Irritation test, a non-vertebrate assay to evaluate vaginal mucosal irritation, which revealed no irritation. Clinical safety was evaluated in a phase I trial with six healthy nulliparous premenopausal volunteering women, with the investigational drug left in place for 7 days. Colposcopic monitoring according to the WHO/CONRAD guidelines for the evaluation of vaginal products, revealed no visible cervicovaginal mucosal changes. No adverse events related to the investigational product occurred. Total release from the intravaginal ring over 7 days was estimated through high performance liquid chromatography at 37.1 (standard deviation 0.9) mg DL-lactic acid. Semisolid lactic acid formulations have been studied to a limited extent in the past and typically consist of a large volume of excipients and very high doses of lactic acid, which is of major concern to mucosal safety. We have documented the feasability of enriching the vaginal environment with pure DL-lactic acid with a prototype intravaginal ring. Though the efficacy of this platform remains to be established possibly requiring further development, this approach may offer a novel avenue to modulate and protect the vaginal microbiota.

Spectroscopic evaluation of a freeze-dried vaccine during an accelerated stability study.

This research evaluates a freeze-dried live, attenuated virus vaccine during an accelerated stability study using Near Infrared (NIR) and Fourier Transform Infrared (FTIR) spectroscopy in addition to the traditional quality tests (i.e., potency assay and residual moisture analysis) and Modulated Differential Scanning Calorimetry (MDSC). Therefore, freeze-dried live, attenuated virus vaccines were stored during four weeks at 4°C (i.e., recommended storage condition) and at 37°C (i.e., accelerated storage condition) and weekly analyzed using these techniques. The potency assay showed that the virus titer decreased in two phases when the samples were stored at 37°C. The highest titer loss occurred during the first week storage at 37°C after which the degradation rate decreased. Both the residual moisture content and the relaxation enthalpy also increased according to this two-phase pattern during storage at 37°C. In order to evaluate the virus and its interaction with the amorphous stabilizer in the formulation (trehalose), the NIR spectra were analyzed via principal component analysis (PCA) using the amide A/II band (5029-4690cm(-1)). The FTIR spectra were also analyzed via PCA using the amide III spectral range (1350-1200cm(-1)). Analysis of the amide A/II band in the NIR spectra revealed that the titer decrease during storage was probably linked to a change of the hydrogen bonds (i.e., interaction) between the virus proteins and the amorphous trehalose. Analyzing the amide III band (FTIR spectra) showed that the virus destabilization was coupled to a decrease of the coated proteins ß turn and an increase of α helix. During storage at 4°C, the titer remained constant, no enthalpic relaxation was observed and neither the Amide A/II band (NIR spectra) nor the Amide III band (FTIR spectra) varied.

The heterogeneity of headache patients who self-medicate: a cluster analysis approach.

Patients with headache often self-treat their condition with over-the-counter analgesics. However, overuse of analgesics can cause medication-overuse headache. The present study aimed to identify subgroups of individuals with headache who self-medicate, as this could be helpful to tailor intervention strategies for prevention of medication-overuse headache. Patients (n = 1021) were recruited from 202 community pharmacies and completed a self-administered questionnaire. A hierarchical cluster analysis was used to group patients as a function of sociodemographics, pain, disability, and medication use for pain. Three patient clusters were identified. Cluster 1 (n = 498, 48.8%) consisted of relatively young individuals, and most of them suffered from migraine. They reported the least number of other pain complaints and the lowest prevalence of medication overuse (MO; 16%). Cluster 2 (n = 301, 29.5%) included older persons with mainly non-migraine headache, a low disability, and on average pain in 2 other locations. Prevalence of MO was 40%. Cluster 3 (n = 222, 21.7%) mostly consisted of patients with migraine who also report pain in many other locations. These patients reported a high disability and a severe limitation of activities. They also showed the highest rates of MO (73%).

Dressings Loaded with Cyclodextrin-Hamamelitannin Complexes Increase Staphylococcus aureus Susceptibility Toward Antibiotics Both in Single as well as in Mixed Biofilm Communities.

Bacteria reside within biofilms at the infection site, making them extremely difficult to eradicate with conventional wound care products. Bacteria use quorum sensing (QS) systems to regulate biofilm formation, and QS inhibitors (QSIs) have been proposed as promising antibiofilm agents. Despite this, few antimicrobial therapies that interfere with QS exist. Nontoxic hydroxypropyl-ß-cyclodextrin-functionalized cellulose gauzes releasing a burst of the antibiotic vancomycin and the QSI hamamelitannin are developed, followed by a sustained release of both. The gauzes affect QS and biofilm formation of Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of chronic wound infection and can be considered as candidates to be used to prevent wound infection as well as treat infected wounds.