The spanish influenza pandemic: a lesson from history 100 years after 1918

In Europe in 1918, influenza spread through Spain, France, Great Britain and Italy, causing havoc with military operations during the First World War. The influenza pandemic of 1918 killed more than 50 million people worldwide. In addition, its socioeconomic consequences were huge. "Spanish flu", as the infection was dubbed, hit different agegroups, displaying a so-called "W-trend", typically with two spikes in children and the elderly. However, healthy young adults were also affected. In order to avoid alarming the public, several local health authorities refused to reveal the numbers of people affected and deaths. Consequently, it was very difficult to assess the impact of the disease at the time. Although official communications issued by health authorities worldwide expressed certainty about the etiology of the infection, in laboratories it was not always possible to isolate the famous Pfeiffer's bacillus, which was, at that time, deemed to be the cause of influenza. The first official preventive actions were implemented in August 1918; these included the obligatory notification of suspected cases and the surveillance of communities such as day-schools, boarding schools and barracks. Identifying suspected cases through surveillance, and voluntary and/or mandatory quarantine or isolation, enabled the spread of Spanish flu to be curbed. At that time, these public health measures were the only effective weapons against the disease, as no vaccines or antivirals were available. Virological and bacteriological analysis of preserved samples from infected soldiers and other young people who died during the pandemic period is a major step toward a better understanding of this pandemic and of how to prepare for future pandemics

Gastroresistant capsular device prepared by injection molding

In the present work, the possibility of manufacturing by injection molding (IM) a gastro-resistant capsular device based on hydroxypropyl methyl cellulose acetate succinate (HPMCAS) was investigated. By performing as an enteric soluble container, such a device may provide a basis for the development of advantageous alternatives to coated dosage forms. Preliminarily, the processability of the selected thermoplastic polymer was evaluated, and the need for a plasticizer (polyethylene glycol 1500) in order to counterbalance the glassy nature of the molded items was assessed. However, some critical issues related to the physical/mechanical stability (shrinkage and warpage) and opening time of the device after the pH change were highlighted. Accordingly, an in-depth formulation study was carried out taking into account differing release modifiers potentially useful for enhancing the dissolution/disintegration rate of the capsular device at intestinal pH values. Capsule prototypes with thickness of 600 and 900 \u3bcm containing Kollicoat\uae IR and/or Explotab\uae CLV could be manufactured, and a promising performance was achieved with appropriate gastric resistance in pH 1.2 medium and break-up in pH 6.8 within 1 h. These results would support the design of a dedicated mold for the development of a scalable manufacturing process

Erodible drug delivery systems for time-controlled release into the gastrointestinal tract

In oral delivery, lag phases of programmable duration that precede drug release may be advantageous in a number of instances, e.g. to meet chronotherapeutic needs or pursue colonic delivery. Systems that give rise to characteristic lag phases in their release profiles, i.e. intended for time-controlled release, are generally composed of a drug-containing core and a functional polymeric barrier. According to the nature of the polymer, the latter may delay the onset of drug release by acting as a rupturable, permeable or erodible boundary layer. Erodible systems are mostly based on water swellable polymers, such as hydrophilic cellulose ethers, and the release of the incorporated drug is deferred through the progressive hydration and erosion of the polymeric barrier upon contact with aqueous fluids. The extent of delay depends on the employed polymer, particularly on its viscosity grade, and on the thickness of the layer applied. The manufacturing technique may also have an impact on the performance of such systems. Double-compression and spray-coating have mainly been used, resulting in differing technical issues and release outcomes. In this article, an update on delivery systems based on erodible polymer barriers (coatings, shells) for time-controlled release is presented

The history of tuberculosis: The social role of sanatoria for the treatment of tuberculosis in Italy between the end of the 19th century and the middle of the 20th

Since ancient times, the most frequently prescribed remedy for the treatment of tuberculosis was a stay in a temperate climate. From the middle of the 19th century to the middle of the 20th, Europe saw the development of sanatoria, where patients were able to benefit from outdoor walks, physical exercise and a balanced diet. Moreover, the institutionalisation and isolation of patients deemed to be contagious remains one of the most efficacious measures for the control of this type of infection. The first sanatorium opened in Germany in 1854, while in Italy the earliest experiments were conducted at the beginning of the 20th century. At that time, it was widely believed in Italy that pulmonary tuberculosis could improve in a marine climate. By contrast, the scholar Biagio Castaldi described the salubrious effects of mountain air and documented a lower incidence of tuberculosis among mountain populations, which supported the hypothesis of a hereditary predisposition to the disease. In 1898, several local committees (Siena, Pisa, Padua) were founded to fight tuberculosis. The following year, these gave rise to the Lega Italiana (Italian League) under the patronage of the King of Italy, which helped to promote state intervention in the building of sanatoria. The pioneer of the institution of dedicated facilities for the treatment of tuberculosis was Edoardo Maragliano in Genoa in 1896. A few years later, in 1900, the first specialised hospital, with a capacity of 100 beds, was built in Budrio in a non-mountainous area, the aim being to treat patients within their habitual climatic environment. In the following years, institutes were built in Bologna, Livorno, Rome, Turin and Venice. A large sanatorium for the treatment of working-class patients was constructed in Valtellina by the fascist government at the beginning of the century, in the wake of studies by Eugenio Morelli on the climatic conditions of the pine woods in Sortenna di Sondalo, which he deemed to be ideal. In December 1916, the Italian Red Cross inaugurated the first military sanatorium in the \u201cLuigi Merello\u201d maritime hospice in Bergeggi (SV) to treat soldiers affected by curable tuberculosis. In 1919, a specific law mandated a 10-fold increase in funding for the construction of dispensaries and sanatoria. As a result, the Provincial Anti-tuberculosis Committees were transformed into Consortiums of municipal and provincial authorities and anti-TB associations, with the aim of coordinating the action to be undertaken. In 1927, the constitution of an Anti-tuberculosis Consortium in every province became a legal obligation. Despite this growth in social and healthcare measures, tuberculosis in Italy continued to constitute a major public health problem until the advent of antibiotics in the 1950s. Until that time, the sanatorium played a leading role in the treatment of tuberculosis in Italy, as in the rest of Europe

Erodible time-dependent colon delivery systems with improved efficiency in delaying the onset of drug release

To prepare swellable/erodible time-dependent colon delivery systems with improved efficiency in delaying drug release, the application of an outer Eudragit\uae NE film, which contained the superdisintegrant Explotab\uae V17 as a pore former, was attempted. Tablet cores were successively spray-coated with a hydroxypropyl methylcellulose (HPMC) solution and diluted Eudragit\uae NE 30 D, wherein fixed amounts of Explotab\uae V17 were present. The resulting two-layer systems yielded lag phases of extended duration as compared with formulations provided with the HPMC layer only. By raising the thickness of the outer film, longer lag times were generally observed, whereas the effectiveness in deferring the drug liberation was reduced by increasing the pore former content, which, however, also resulted in a lower data variability. The films containing 20% of Explotab\uae V17 effectively and consistently prolonged the in vitro lag phase imparted by HPMC as a function of their thickness. Stored for 3 years under ambient conditions, a two-layer system with this outer film composition pointed out unmodified release patterns. The same system proved to meet gastroresistance criteria when enteric coated. The results obtained indicated that the proposed strategy would enable the preparation of erodible delivery systems with reduced size, possibly suitable as multiple-unit dosage forms

Non-uniform drug distribution matrix system (NUDDMat) for zero-order release of drugs with different solubility

A decrease in the drug release rate over time typically affects the performance of hydrophilic matrices for oral prolonged release. To address such an issue, a Non-Uniform Drug Distribution Matrix (NUDDMat) based on hypromellose was proposed and demonstrated to yield zero-order release. The system consisted of 5 overlaid layers, applied by powder layering, having drug concentration decreasing from the inside towards the outside of the matrix according to a descending staircase function. In the present study, manufacturing and performance of the described delivery platform were evaluated using drug tracers having different water solubility. Lansoprazole, acetaminophen and losartan potassium were selected as slightly (SST), moderately (MST) and highly (HST) soluble tracers. By halving the thickness of the external layer, which contained no drug, linear release of HST and MST was obtained. The release behavior of the NUDDMat system loaded with a drug having pH-independent solubility was shown to be consistent in pH 1.2, 4.5 and 6.8 media. Based on these results, feasibility of the NUDDMat platform by powder layering was demonstrated using drugs having different physico-technological characteristics. Moreover, its ability to generate zero-order release was proved in the case of drugs with water solubility in a relatively wide range

3D printed multi-compartment capsular devices for two-pulse oral drug delivery

In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer. In this respect, a previously proposed capsular device able to control the release performance based on its design and composition, which could extemporaneously be filled, was improved to include multiple separate compartments so that differing active ingredients or formulations may be conveyed. The compartments, which may differ in thickness and composition, resulted from assembly of two hollow halves through a joint also acting as a partition. The systems were manufactured by fused deposition modeling (FDM) 3D printing, which holds special potential for product personalization, and injection molding (IM) that would enable production on a larger scale. Through combination of compartments having wall thickness of 600 or 1200\u3bcm, composed of promptly soluble, swellable/erodible or enteric soluble polymers, devices showing two-pulse release patterns, consistent with the nature of the starting materials, were obtained. Systems fabricated using the two techniques exhibited comparable performance, thus proving the prototyping ability of FDM versus IM

Novel hydrophilic matrix system with non-uniform drug distribution for zero-order release kinetics

A decrease in the release rate over time is typically encountered when dealing with hydrophilic matrix systems for oral prolonged release due to progressive increase of the distance the drug molecules have to cover to diffuse outwards and reduction of the area of the glassy matrix at the swelling front. In order to solve this issue, a novel formulation approach based on non-uniform distribution of the active ingredient throughout the swellable polymer matrix was proposed and evaluated. Various physical mixtures of polymer (high-viscosity hypromellose) and drug tracer (acetaminophen), having decreasing concentrations of the latter, were applied by powder-layering onto inert core seeds. The resulting gradient matrices showed to possess satisfactory physico-technological characteristics, with spherical shape and consistent thickness of the layers sequentially applied. The non-uniform matrix composition pursued was confirmed by Raman mapping analysis. As compared with a system having uniform distribution of the drug tracer, the multi-layer formulations were proved to enhance linearity of release. The simple design concept, advantageous technique, which involves no solvents nor high-impact drying operations, and the polymeric material of established use make the delivery platform hereby proposed a valuable strategy to improve the performance of hydrophilic matrix systems

Evaluation of Hot-Melt Extrusion and Injection Molding for Continuous Manufacturing of Immediate-Release Tablets

The exploitation of hot-melt extrusion and injection molding for the manufacturing of immediate-release (IR) tablets was preliminarily investigated in view of their special suitability for continuous manufacturing, which represents a current goal of pharmaceutical production because of its possible advantages in terms of improved sustainability. Tablet-forming agents were initially screened based on processability by single-screw extruder and micromolding machine as well as disintegration/dissolution behavior of extruded/molded prototypes. Various polymers, such as low-viscosity hydroxypropylcellulose, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, various sodium starch glycolate grades (e.g., Explotab\uae CLV) that could be processed with no need for technological aids, except for a plasticizer, were identified. Furthermore, the feasibility of both extruded and molded IR tablets from low-viscosity hydroxypropylcellulose or Explotab\uae CLV was assessed. Explotab\uae CLV, in particular, showed thermoplastic properties and a very good aptitude as a tablet-forming agent, starting from which disintegrating tablets were successfully obtained by either techniques. Prototypes containing a poorly soluble model drug (furosemide), based on both a simple formulation (Explotab\uae CLV and water/glycerol as plasticizers) and formulations including dissolution/disintegration adjuvants (soluble and effervescent excipients) were shown to fulfill the USP 37 dissolution requirements for furosemide tablets