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To realize the double-roll thin strip continuous casting process for the production of high-quality steels, it is necessary to seek a new type of refractory material tailored for delivery device employed in this process. Therefore, the present study aimed to design and prepare MgAl 2 O 4 –C refractories for this purpose as well as to study their physical and mechanical properties, thermal shock resistance, oxidation kinetics, and to perform molten steel experiments after pre-oxidation treatment. The results of the present study demonstrated that the specimens could maintain high mechanical and thermal shock properties even after pre-oxidation treatment. After pre-oxidation at 1100 °C/1 h, the cold compressive strength of the specimen reached 17.63 MPa, with a residual strength ratio (thermal shock resistance) of 77.99%. Analysis of oxidation kinetics based on the shrinking core model indicated an increase in the effective diffusion coefficient and complete oxidation time with higher pre-oxidation temperature. Pre-oxidation of MgAl 2 O 4 –C refractories has been shown to be effective in reducing carbon penetration into the molten steel from carbon-containing refractories, thus maintaining the stability of the molten steel composition. This effect was attributed to enhanced contact and wettability between the steel and refractories, an augmented thickness of the pre-oxidized decarburized layer, the formation of a dense magnesium oxide layer, and the emergence of the MgAl 1·9 Fe 1 O 4 phase. Consequently, an MgAl 2 O 4 –C refractories designed for the delivery device was proposed along with anticipated applicability in the double-roll continuous casting process. [ABSTRACT FROM AUTHOR]

The delivery device is one of the key components in ensuring uniform grain spacing and achieving high-speed precision seeding. In this paper, a new type of high-speed airflow-assisted delivery device for maize is presented. The gas–solid flow in the delivery device was numerically studied by the coupling method of CFD and DEM. The influence of the structural parameters of the delivery device on the movement of the seeds and the airflow field was analyzed in detail. The matching relationship between the inlet-airflow velocity and the operating speed of the seeder was explored. The results show that the position of the intake seed chamber mainly affects the negative pressure in the distribution area of the mixing chamber. The increase in the shrinkage angle results in the decrease in pressure loss and the decrease in airflow velocity in the delivery chamber. As the diffusion angle increases, the airflow forms a stable straight jet flow and the airflow velocity in the delivery chamber increases. As the ejection angle increases, the bouncing degree of the seed decreases, thereby ensuring the consistency of the seed-ejection direction. The research results show that, when the intake seed chamber is located in the middle, the shrinkage angle is 70°, the diffusion angle is 30°, and the exit angle is 60°, the air-assisted delivery device has better performance. With the increase in inlet wind speed, the seed-ejection speed can also be increased according to a certain proportion, which can meet the requirements of zero-speed seeding and ensure the uniformity of seed spacing, providing a new seed delivery scheme. In the future, if invasive damage to the seed shell is guaranteed to be minimized in high-speed airflow, the new delivery device can meet the requirements of precision seeding under high-speed conditions.

Neuroimmune interactions underlying the development of pain sensitization in models of neuropathic pain have been widely studied. In this study, we evaluated the development of allodynia and its reduction associated with peripheral antineuroinflammatory effects induced by a dexamethasone-loaded biodegradable implant. Chronic constriction injury (CCI) of the sciatic nerve was performed in Wistar rats. The electronic von Frey test was applied to assess mechanical allodynia. The dexamethasone-loaded implant was placed perineurally at the moment of CCI or 12 days after surgery. Dorsal root ganglia (DRG; L4-L5) were harvested and nuclear extracts were assayed by Western blot for detection of nuclear factor (NF)-κB p65/RelA translocation. Dexamethasone delivered from the implant delayed the development of allodynia for approximately three weeks in CCI rats when the implantation was performed at day 0, but allodynia was not reversed when the implantation was performed at day 12. NF-κB was activated in CCI rat DRG compared with naïve or sham animals (day 15), and dexamethasone implant inhibited p65/RelA translocation in CCI rats compared with control. This study demonstrated that the dexamethasone-loaded implant suppresses allodynia development and peripheral neuroinflammation. This device can reduce the potential side effects associated with oral anti-inflammatory drugs.

Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs.

Although insulin delivery devices are widely used by the patients, there is a paucity of published guidelines to help professionals manage their patients in insulin therapies. To provide simple and easily implementable guidelines to health care physicians on the choice of insulin delivery devices in routine clinical practice, experts in diabetes gathered together and discussed the recommendations at the National insulin Summit 2018. An ideal insulin delivery device should accurately deliver the prescribed dose of insulin and be easy to use. Recommendations are: (1) insulin should be initiated by using an insulin device if the patient seems to discontinue insulin therapy. (2) Pen devices offer accurate dosing than a syringe and vial and are associated with cost savings in the long term. (3) Switching over from syringes and vial to disposable pen devices improves adherence. (4) FlexPen® offers better accuracy, and it requires lower dose force and injection force than SoloStar® and KwikPen® (5). Durable delivery pens such as NovoPen® 4 maintain accuracy and low dose force compared with vials and syringes. (6) One pen should be used by only one patient. (7) Regular counseling on the proper use of the pen device is required regularly. This consensus-based recommendation is a useful reference tool for health care practitioners to initiate insulin therapy in patients with diabetes by using the appropriate insulin pen device. [ABSTRACT FROM AUTHOR]

Intraperitoneal insulin delivery has higher benefits than subcutaneous insulin administration but has limitations, including obstruction of the catheter used in delivery devices. To overcome these limitations this study assessed safety and efficacy of an alternative approach involving a new delivery device, named ExOlin®, allowing diffuse release of insulin in the extraperitoneal site. The aim of this study is to validate both safety and efficacy of insulin delivery in extraperitoneal using ExOlin® device. Safety of the ExOlin® device implantation in the extraperitoneal site was investigated over a 3-month period in Wistar rat and landrace swine models before comparing efficacy pharmacokinetics and hepatic first-pass metabolism of insulin after focal delivery using a catheter or diffuse release via ExOlin® device in extraperitoneal. Implantation in rat and swine models demonstrated good integration of the device, validating the safety of the extraperitoneal site. In diabetic rats, direct insulin administration at the extraperitoneal showed an efficacy comparable to intraperitoneal and statistically significantly higher than subcutaneous route as shown by 23% lower AUC calculated from glycaemia profile. Diffuse extraperitoneal delivery of insulin via ExOlin® device in diabetic rats exhibited better efficacy than the subcutaneous route with up to six-fold lower peripheral insulin and higher hepatic first-pass than with intraperitoneal injection. Similar results were confirmed in the swine model after injecting insulin lispro via the device at the extraperitoneal site. In conclusion, diffuse administration of insulin at the extraperitoneal site via ExOlin® device is a new promising approach to physiologically treating type 1 diabetes. It can therefore be considered as a promising alternative to intraperitoneal route. Unlabelled Image • Despites its efficacy, i.p. insulin faces issues including catheter obstruction. • Extraperitoneal is safe for implantation of ExOlin®, a new delivery device. • Extraperitoneal insulin delivery via ExOlin® shows high efficacy in diabetic rats. • This approach provides, in rat and swine, portal levels comparable to i.p. insulin. • ExOlin® in extraperitoneal may replace i.p. devices for physiological delivery. [ABSTRACT FROM AUTHOR]

Bacteriophage lambda has a double-stranded DNA genome and a long, flexible, non-contractile tail encoded by a contiguous block of 11 genes downstream of the head genes. The tail allows host recognition and delivery of viral DNA from the head shell to the cytoplasm of the infected cell. Here, we present a high-resolution structure of the tail complex of bacteriophage lambda determined by cryoelectron microscopy. Most component proteins of the lambda tail were determined at the atomic scale. The structure sheds light on the molecular organization of the extensively studied tail of bacteriophage lambda. [Display omitted] • The cryo-EM structure of bacteriophage lambda tail complex was determined • The tail tube protein TTP gpV forms a trimer of dimers • The TTP gpV trimers assemble into 31 hexameric rings forming the hollow tail tube • The central tail fiber is exclusively composed of trimeric C-terminal BHP gpJ proteins Bacteriophage lambda is an excellent model system to study the tail architecture of bacteriophages. Wang et al. present the cryo-EM structures of the components of the bacteriophage lambda tail complex and elucidate the tail's structural organization. [ABSTRACT FROM AUTHOR]

Several studies have shown that adherence to growth hormone therapy (GHT) is not optimal. There are several reasons why patients may not fully adhere to their treatment regimen and this may have implications on treatment success, patient outcomes and healthcare spending and resourcing. A change in healthcare practices, from a physician paternalistic to a more patient autonomous approach to healthcare, has encouraged a greater onus on a shared decision-making (SDM) process whereby patients are actively encouraged to participate in their own healthcare decisions. There is growing evidence to suggest that SDM may facilitate patient adherence to GHT. Improved adherence to therapy in this way may consequently positively impact treatment outcomes for patients. Whilst SDM is widely regarded as a healthcare imperative, there is little guidance on how it should be best implemented. Despite this, there are many opportunities for the implementation of SDM during the treatment journey of a patient with a GH-related disorder. Barriers to the successful practice of SDM within the clinic may include poor patient education surrounding their condition and treatment options, limited healthcare professional time, lack of support from clinics to use SDM, and healthcare resourcing restrictions. Here we discuss the opportunities for the implementation of SDM and the barriers that challenge its effective use within the clinic. We also review some of the potential solutions to overcome these challenges that may prove key to effective patient participation in treatment decisions. Encouraging a sense of empowerment for patients will ultimately enhance treatment adherence and improve clinical outcomes in GHT.

Introduction: Sirolimus is currently being explored as an alternative drug to paclitaxel for the treatment of peripheral artery disease (PAD). To date, sirolimus has only been used as drug coatings for stents and balloons and no studies have yet demonstrated the delivery of sirolimus in liquid form. The purpose of this pilot study was to investigate the feasibility of the delivery of liquid sirolimus into arterial segments in a benchtop peripheral artery bioreactor., Methods: The feasibility to deliver liquid therapy was first tested on four drug delivery devices using a fluorescently tagged liquid drug and an ex vivo porcine artery benchtop model. The four devices included the Bullfrog micro-infusion device, ClearWay RX catheter, Occlusion perfusion catheter (OPC), and the targeted adjustable pharmaceutical administration system (TAPAS). Penetration of the fluorescently tagged drug was measured via microscopic imaging and quantification of the depth of drug penetration into all device-treated tissue. Based on the penetration outcome, we then selected a single device to deliver liquid sirolimus into the ex vivo porcine artery model undergoing physiological flow and pressure conditions. The liquid sirolimus-treated arteries were collected from the ex vivo bioreactor at 1- and 24-hour post-delivery and arterial drug retention analyzed by liquid chromatography-tandem mass spectrometry., Results: Fluorescent microscopy demonstrated that drug delivery with the OPC had greater drug penetration into the medial wall as compared to other devices (OPC: 234 ± 161 µm; TAPAS: 127 ± 68 µm; ClearWay: 118 ± 77 µm; Bullfrog: 2.12 ± 3.78 µm; p  = 0.098). The results of the ex vivo flow-circuit bench top model showed that the OPC device successfully delivered the liquid sirolimus at 1-hour (5.17 ± 4.48 ng/mg) and 24-hour (0.78 ± 0.55 ng/mg)., Conclusions: These results demonstrate for the first time the ability to deliver liquid sirolimus directly to the medial layer of an artery via a liquid delivery catheter., Competing Interests: SY serves on the Scientific Advisory Board of Advanced Catheter Therapies and has received grant support from BD, OrbusNeich Medical, Advanced NanoTherapies and Biosensors International. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Todd, Liu, Saul and Yazdani.)

Several studies have shown that adherence to growth hormone therapy (GHT) is not optimal. There are several reasons why patients may not fully adhere to their treatment regimen and this may have implications on treatment success, patient outcomes and healthcare spending and resourcing. A change in healthcare practices, from a physician paternalistic to a more patient autonomous approach to healthcare, has encouraged a greater onus on a shared decision-making (SDM) process whereby patients are actively encouraged to participate in their own healthcare decisions. There is growing evidence to suggest that SDM may facilitate patient adherence to GHT. Improved adherence to therapy in this way may consequently positively impact treatment outcomes for patients. Whilst SDM is widely regarded as a healthcare imperative, there is little guidance on how it should be best implemented. Despite this, there are many opportunities for the implementation of SDM during the treatment journey of a patient with a GH-related disorder. Barriers to the successful practice of SDM within the clinic may include poor patient education surrounding their condition and treatment options, limited healthcare professional time, lack of support from clinics to use SDM, and healthcare resourcing restrictions. Here we discuss the opportunities for the implementation of SDM and the barriers that challenge its effective use within the clinic. We also review some of the potential solutions to overcome these challenges that may prove key to effective patient participation in treatment decisions. Encouraging a sense of empowerment for patients will ultimately enhance treatment adherence and improve clinical outcomes in GHT. [ABSTRACT FROM AUTHOR]

Objective: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). Methods: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, tmax, and t½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. Results: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (Cmax, AUC0-t, and AUC0-inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t½ values were similar across treatments. Salmeterol Cmax was 20% lower and AUC0-t and AUC0-inf were approximately 50% lower with FS MDPI versus FS DPI. Median tmax and geometric mean t½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. Conclusions: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences. [ABSTRACT FROM AUTHOR]

Vaccine delivery via mucosal surfaces is an interesting alternative to parenteral vaccine administration, as it avoids the use of a needle and syringe. Mucosal vaccine administration also targets the mucosal immune system, which is the largest lymphoid tissue in the human body. The mucosal immune response involves systemic, antigen-specific humoral and cellular immune response in addition to a local response which is characterised by a predominantly cytotoxic T cell response in combination with secreted IgA. This antibody facilitates pathogen recognition and deletion prior to entrance into the body. Hence, administration via the respiratory mucosa can be favoured for all pathogens which use the respiratory tract as entry to the body, such as influenza and for all diseases directly affecting the respiratory tract such as pneumonia. Additionally, the different mucosal tissues of the human body are interconnected via the so-called “common mucosal immune system”, which allows induction of an antigen-specific immune response in distant mucosal sites. Finally, mucosal administration is also interesting in the area of therapeutic vaccination, in which a predominant cellular immune response is required, as this can efficiently be induced by this route of delivery. The review gives an introduction to respiratory vaccination, formulation approaches and application strategies.

Background: The aim of this work is to use an experimental design approach to identify and study influential formulation and delivery device properties, which can be controlled by final product manufacturer, to establish design space, within which desired in vitro performance can be reached. Methods: Combining three factors, viscosity of suspension, nozzle orifice diameter (OD), and shot weight (SW), at three levels resulted in D-optimal experimental design with 20 runs. Responses within this study were droplet size distribution (DSD) and spray pattern (SP) in vitro tests. In addition, the amount of mechanical work needed for actuation was integrated from force profiles and used as a response. Results were fit to quadratic model by regression, which allowed also for determination of second-order and interaction effects between factors. Models were further optimized by keeping significant terms only. Optimized models were used to create response surfaces and design space with confidence levels. Results: Viscosity has a dominant effect on DSD and modest effect on SP, with lower viscosities related to generation of smaller DSD and larger SP. Orifice diameter was found to have the highest impact on SP, with larger diameter resulting in larger SP. This effect was additionally confirmed by results of Plume Geometry in vitro test. Shot weight factor exerts significant influence on all tested metrics. Work, however, did not vary greatly with suspension viscosity or orifice diameter. Shot weight is the most dominant factor for work and important for DSD having a positive effect on both responses. In the case of SP, its relationship with shot weight is described by second-order polynomial fit. Inspection of raw data revealed that density of droplets within SP area is different for different shot weights. Conclusion: Presented study elucidated an inherent relationship between factors and responses and established mathematical models (response surfaces) for predictive purposes to target specific in vitro performance of nasal sprays by appropriate specification of factors, taking into account control space with included risk and uncertainty analysis. [ABSTRACT FROM AUTHOR]

A variety of vaccine packaging and delivery technologies may benefit the immunization supply chain. These include alternative primary packaging, such as blow-fill-seal polymer containers, and novel delivery technologies, such intradermal delivery devices, microarray patches, and sublingual formulations of vaccines, and others in development. The potential timeline to availability of these technologies varies and depends on their stage of development and the type of data necessary to achieve licensure. Some new delivery devices are anticipated to be introduced in 2017, such as intradermal devices for delivery of inactivated poliovirus vaccine to stretch vaccine supplies due to a supply limitation. Other new technologies requiring vaccine reformulation, such as microarray patches and sublingual vaccines, may become available in the long term (2021 and beyond). Development of many new technologies requires partnership between vaccine and technology manufacturers and identification of the applicable regulatory pathway. Interaction with public-sector stakeholders early on (through engagement with forums such as the World Health Organization’s Immunization Practices Advisory Committee Delivery Technologies Working Group) is important to ensure suitability for immunization program use. Key considerations for programmatic suitability of a new vaccine, packaging, and delivery device include cold chain volume, costs, and health impact. [ABSTRACT FROM AUTHOR]

Intratracheal administration methods are used to conduct toxicological assessments of inhaled nanoparticles (NPs), and gavage needles or microsprayers are common intratracheal delivery devices. The NP suspension is delivered in a liquid state via gavage needle and as a liquid aerosol via microsprayer. The differences in local pulmonary NP distribution (called the microdistribution) arising from the different states of the NP suspension cause differential pulmonary responses; however, this has yet to be investigated. Herein, using microbeam X-ray fluorescence microscopy, we quantitatively evaluated the TiO2 pulmonary microdistribution (per mesh: 100 μm × 100 μm) in lung sections from rats administered an intratracheal dose of TiO2 NPs (6 mg kg−1) via gavage needle or microsprayer. The results revealed that: (i) using a microsprayer appears to reduce the variations in TiO2 content (ng mesh−1) among rats (e.g., coefficients of variation, n = 3, microsprayer vs gavage needle: 13% vs 30%, for the entire lungs); (ii) TiO2 appears to be deposited less in the right middle lobes than in the rest of the lung lobes, irrespective of the chosen intratracheal delivery device; and (iii) similar TiO2 contents (ng mesh−1) and frequencies are deposited in the lung lobes of rats administered TiO2 NPs via gavage needle or microsprayer. This suggests that the physical state of the administered NP suspension does not markedly alter TiO2 pulmonary microdistribution. The results of this investigation are important for the standardization of intratracheal administration methods. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The intratracheal (IT) test is useful for screening the pulmonary toxicity of inhaled materials, including nanomaterials. However, a standard procedure has not yet been authorized internationally, and the effects of different test parameters are unknown. To determine appropriate experimental conditions for the IT test, we intratracheally administered nano-sized TiO 2 to male F344 rats at 3.0 mg/kg body weight by using two delivery devices (gavage needle or microaerosolizer) and dose volumes of 0.5–3.0 mL/kg (gavage needle) or 0.5–2.0 mL/kg (microaerosolizer). We evaluated the pulmonary deposition and interlobar distribution of TiO 2 at both 30 min and 3 days after administration. In addition, the inflammatory components in bronchoalveolar lavage (BAL) fluid were measured 3 days after administration of TiO 2 . At dose volumes of 0.5–2.0 mL/kg, the BAL values were comparable regardless of the device used. In addition, pulmonary TiO 2 burden and lobar concentration patterns were equivalent at all combinations of dose volume and delivery device. In conclusion, the acute pulmonary toxicity of nanomaterials can be assessed effectively by using an IT test in which the test agent is provided to rats at a dose volume of 0.5–2.0 mL/kg with either a gavage needle or microaerosolizer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Intratracheal antibiotic administration is increasingly used for treating respiratory infections. Limited information is available on delivery devices, techniques, and safety. METHODS: An online survey on intratracheal administration of anti-infective agents in mechanically ventilated adults was answered by health-care workers from 192 ICUs to assess the most commonly used devices, current delivery practices, and safety issues. We investigated whether ICU usage experience (≥3 y) impacted its performance. RESULTS: Intratracheal antibiotic administration was a current practice in 87 ICUs (45.3%), with 40 (46%) having experience with the technique ≥S3 y). Sixty-six (78.6%) of 84 health-care workers reported avoiding intratracheal antibiotic administration due to an absence of evidence-based guidelines (78.6%). Jet nebulizers were the most commonly used devices for delivery, in 24 less experienced ICUs (27.6%) and in 18 (20.7%) experienced ICUs. Direct tracheal instillation (6; 6.9%) was still considered for drug prescription in 12 ICUs (6.9%). More experience resulted in neither greater adherence to measures improving the drug's delivery efficiency (93 measures in the experienced group; 27.9%) nor a greater adoption of measures to increase safety. Indeed, the expiratory filter was changed after each nebulization in only 2 experienced ICUs (6.9%), whereas 15 (51.7%) changed it daily instead. CONCLUSIONS: Intratracheal antibiotic administration is a common therapeutic modality in ICUs, but inadequate practices were widely encountered, independent of the level of experience with the technique. This suggests a need to develop standardization to reduce variability and improve safety and efficacy. [ABSTRACT FROM AUTHOR]

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In patients with ventilator-associated pneumonia, systemic use of antibiotics is the cornerstone of medical management. Supplemental use of aerosolized antibiotics with intravenous antibiotics in both experimental and clinical studies has been shown to have the following pharmacologic benefits: (1) aerosolized antibiotics reach the infected lung parenchyma without crossing the pulmonary alveolar capillary barrier; (2) aerosolized antibiotics increase anti-bacterial efficacy through increased local antibiotic concentration; and (3) aerosolized antibiotics decrease systemic toxicity. These benefits may be particularly beneficial to treat pneumonia caused by multidrug-resistant pathogens. Clinical data on the benefits of aerosolized antibiotics are more limited. Studies to date have not clearly shown improvements in time to extubation, mortality, or other patient-centered outcomes. At present, amikacin, colistin, and ceftazidime are the most frequently used and studied aerosolized antibiotics. This review summarizes the characteristics of aerosolized antibiotics, reviews the advantages and disadvantages of using aerosolized antibiotics, and calls for future investigations based on animal study data. [ABSTRACT FROM AUTHOR]

Rotavirus infection, which can be prevented by vaccination, is responsible for a high burden of acute gastroenteritis disease in children, especially in low-income countries. An appropriate formulation, packaging, and delivery device for oral rotavirus vaccine has the potential to reduce the manufacturing cost of the vaccine and the logistical impact associated with introduction of a new vaccine, simplify the vaccination procedure, and ensure that the vaccine is safely and accurately delivered to children. Single-dose prefilled presentations can be easy to use; however, they are typically more expensive, can be a bottleneck during production, and occupy a greater volume per dose vis-à-vis supply chain storage and medical waste disposal, which is a challenge in low-resource settings. Multi-dose presentations used thus far have other issues, including increased wastage of vaccine and the need for separate delivery devices. In this study, the goals were to evaluate both the technical feasibility of using preservatives to develop a liquid multi-dose formulation and the primary packaging alternatives for orally delivered, liquid rotavirus vaccines. The feasibility evaluation included evaluation of commonly used preservatives for compatibility with rotavirus vaccines and stability testing of rotavirus vaccine in various primary containers, including Lameplast's plastic tubes, BD's oral dispenser version of Uniject™ (Uniject DP), rommelag's blow-fill-seal containers, and MEDInstill's multi-dose vial and pouch. These presentations were compared to a standard glass vial. The results showed that none of the preservatives tested were compatible with a live attenuated rotavirus vaccine because they had a detrimental effect on the viability of the virus. In the presence of preservatives, vaccine virus titers declined to undetectable levels within 1 month. The vaccine formulation without preservatives maintained a stability profile over 12 months in all primary containers that was similar to its profile in standard glass vials. This study demonstrates that there are multiple options for the primary container for rotavirus vaccines intended for oral delivery. Selection of an optimal primary container should take into consideration additional factors, including stability as well as cold chain volume, usability, cost, and manufacturing feasibility. [ABSTRACT FROM AUTHOR]

Nose-to-central nervous system (CNS) drug delivery has shown promising results in preclinical efficacy models and exploratory human clinical trials. There are two primary limitations to direct CNS uptake of drugs following intranasal administration. Firstly, non-specific deposition in the nasal cavity leads to systemic absorption instead of CNS absorption, altering CNS bioavailability. Secondly, mucociliary clearance affects the residence time of the formulation at the site of deposition. In vivo results have demonstrated that therapeutic agents targeted to the olfactory region can translocate directly into the CNS via neuronal uptake. In this review, liquid and solid formulations are investigated for their effect on olfactory deposition and clearance based on their physical properties. The influence of delivery device and mode of administration is also reviewed. Case examples are provided to illustrate the importance of optimal deposition in olfactory region. [ABSTRACT FROM AUTHOR]

After centuries of discoveries and technological growth, aerosol therapy remains a cornerstone of care in the management of both acute and chronic respiratory conditions. Aerosol therapy embraces the concept that medicine is both an art and a science, where an explicit understanding of the science of aerosol therapy, the nuances of the different delivery devices, and the ability to provide accurate and reliable education to patients become increasingly important. The purpose of this article is to review recent literature regarding aerosol delivery devices in a style that readers of Respiratory Care may use as a key topic resource. [ABSTRACT FROM AUTHOR]

Objective The objective of the study is to evaluate the physical properties, in vitro release profile, and antibacterial efficiency of chitosan films prepared with ofloxacin. Procedure Mucoadhesive films were prepared by means of a casting and solvent evaporation technique performed in a 2 wt% acetic acid solution and distilled water. Physical properties were characterized by release and swelling studies, differential scanning calorimetry ( DSC) analysis, and attenuated total reflectance Fourier transformed infrared spectroscopy ( ATR- FTIR) analysis. The in vitro evaluation of the films was performed by inhibiting Staphylococcus aureus and Pseudomonas aeruginosa through activity studies. Results Circular ofloxacin-loaded chitosan-developed films with 0.3 mg of drug weighed 7 mg were 110 μm thick and 5 mm in diameter. The DSC curve of ofloxacin-loaded chitosan films suggests an amorphous dispersion of ofloxacin within these films. ATR- FTIR analysis showed that ofloxacin is indeed present in the matrix film. The drug was released in vitro over a 1-h period. No statistical difference could be observed between the ofloxacin-loaded chitosan films and sterile disk soaked for 1 min in 0.3% commercial ofloxacin ophthalmic solution for S. aureus and P. aeruginosa ( P = 0.1686, P = 0.1172, respectively).The films presented a significantly larger mean bacterial inhibition zone of S. aureus than did the commercial ciprofloxacin control disk ( P = 0.0002) and a significantly larger mean bacterial kill zone of P. aeruginosa than did the commercial enrofloxacin control disk ( P < 0.0001). Conclusions Ofloxacin was successively incorporated onto chitosan films and was not inactivated during the process of manufacturing, thus preserving antibacterial proprieties. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nebulized therapy is commonly used in spontaneously breathing tracheostomized patients, despite a lack of recommended devices and techniques. I compared albuterol dose delivered to a model of spontaneously breathing children with tracheostomy, using different nebulizers, tracheostomy tube sizes, inhalation techniques, and breathing patterns. METHODS: A tracheostomy model was connected in series to a breathing simulator, with a filter interposed. I simulated the breathing patterns of a 16-month-old child and 12-year-old child, and tested tracheostomy tubes with internal diameters of 3.5 mm and 5.5 mm. Albuterol nebulizer solution (2.5 mg/3 mL) was used. A breath-enhanced nebulizer (Pari LC Plus), a breath-actuated nebulizer (AeroEclipse), and a nebulizer that continuously delivers aerosol (Up-Draft II Opti-Neb) were operated for 5 min at 6 L/min with wall air. The Up-Draft II was tested with T-piece and mask interfaces, with an extension tube, and with and without assisted breathing (every breath and every other breath). The amount of albuterol delivered was analyzed via spectrophotometry. Particle size distribution was measured with a cascade impactor. RESULTS: The Pari LC Plus was more efficient than the Up-Draft II or AeroEclipse. Assisted breathing with the Up-Draft II with extension increased albuterol delivery with every other breath (second best device/configuration), being superior to every breath technique. Adding an extension tube increased delivered albuterol. T-piece was more efficient than mask. Breathing patterns with larger tidal volume increased albuterol delivery. Tracheostomy size had less impact on drug delivery. Mass median aerodynamic diameter decreased by 48-74% when passing through the tracheostomy tubes, and 0.8% of the nominal dose was deposited in the tracheostomy tube. CONCLUSIONS: Albuterol delivery in a model of spontaneously breathing children with tracheostomy is influenced by type of device and configuration, use of assisted breathing, breathing pattern, and tracheostomy tube size. Mass median aerodynamic diameter significantly decreases during passage through a tracheostomy tube. [ABSTRACT FROM AUTHOR]

New devices enabling freely selectable dosing of solid oral medications are urgently needed for personalized medicine. One approach is the use of the recently published Solid Dosage Pen, allowing flexible dosing of tablet-like sustained release slices from drug loaded extruded strands. Slices were suitable for oral single dosed application. The aim of the present study was the development of immediate release dosage forms for applications of the device, especially for young children. Using two model drugs, two different concepts were investigated and evaluated. Effervescent formulations were manufactured by an organic wet-extrusion process and immediate release formulations by a melt-extrusion process. Dissolution experiments were performed for both formulations to ensure the immediate release behavior. Extruded strands were individually dosed by the Solid Dosage Pen. Various doses of the two formulations were analyzed regarding uniformity of mass and content according to pharmacopoeial specifications. Proof of concept was demonstrated in both approaches as results comply with the regulatory requirements. Furthermore, storing stress tests were performed and drug formulations were characterized after storing. The results show that suitable packaging material has been selected and storage stability is probable. [ABSTRACT FROM AUTHOR]

The present study compared the efficacy and safety of chitosan coated ofloxacin mucoadhesive films developed with 0.3% ofloxacin commercial ophthalmic solution in rabbit model. In addition, it investigates inhibition of bacterial grows, and maximum release time of these implants in vivo. [ABSTRACT FROM AUTHOR]

The present study compared the efficacy and safety of chitosan coated timolol maleate mucoadhesive films developed with a 0.5% timolol maleate commercial ophthalmic solution in normotensive rabbits. [ABSTRACT FROM AUTHOR]

Background: Poor sputum clearance is a common problem encountered in intubated patients, which may cause airway obstruction, hypoxaemia, and increased risk of lower respiratory tract infection. This may result in longer intensive care unit (ICU) stay or even death. Dry powder mannitol has been shown to improve sputum clearance, and thus we developed a system to deliver it to intubated patients. Methods: This delivery system consists of a standard adult manual ventilation bag, a one-way duck-billed valve, and a dry powder inhaler (Osmohaler™) contained within a delivery chamber to allow positive pressure ventilation, which in turn, is connected in series to an endotracheal or tracheostomy tube. The aerosol is delivered by compressing the ventilation bag in a reproducible manner to generate positive pressure airflow to disperse the powder into the tracheal tube. We tested the powder output and characteristics of the powder in vitro from two endotracheal tubes (7.0 and 8.5 mm in diameter, 300 mm in length), and two tracheostomy tubes (7.0 mm in diameter and 95 mm in length; 90 mm in diameter and 115 mm in length). Results and Conclusions: Approximately 50 to 60% of the loaded dose of dry powder mannitol is delivered to the distal end of the tracheal tubes for both 4 × 40-mg and 4 × 80-mg capsules. The fine particle fraction (particles smaller than 5 μm) ranges from 20 to 31% of the loaded dose. Powder was emptied from each 40- and 80-mg capsule within 5 ± 1 puffs and 6 ± 1 puffs, respectively. This delivery system has been shown to consistently deliver a very high dose of powder with a favourable fine particle fraction to the distal end of a number of tracheal tubes. This has the potential for a number of clinical therapeutic applications in critically ill patients. [ABSTRACT FROM AUTHOR]

Abstract: There is an evident need for solid oral dosage forms allowing patients’ tailor-made dosing due to variations in metabolization or small therapeutic indexes of drug substances. The objective of this work is the development of a device equipped with a novel solid dosage form, containing carvedilol as model drug, for the delivery of monolithical drug carriers in individual doses. The device was developed and constructed enabling an exact feed rate and dose adjustment by a cutting mechanism. A twin-screw extruder was used for producing cylindrical solid dosage forms. Divided doses were characterized by mass variation, cutting behavior and drug dissolution in order to investigate their applicability for practical use. Different formulations could be extruded obtaining straight cylindrical rods, which are divisible in exact slices by using the novel device. Forces below 20N were needed to divide doses which comply with pharmacopoeial specification “conformity of mass”. The developed formulations exhibit a sustained release of carvedilol within a range from 7 up to 16h. A novel system consisting of a device and a cylindrical dosage form was developed. Patients’ individual doses can be applied as monolithical solid dosage forms for oral use. [Copyright &y& Elsevier]

To determine functionality and acceptability of a new teriparatide (Forteo, Eli Lilly and Company, Indianapolis, IN, USA) delivery device by patients with osteoporosis. This was an eight week, single-arm, multicenter, open-label clinical trial. Patients received teriparatide 20 µg/day by subcutaneous injection using a new delivery device. Men and postmenopausal women with osteoporosis at high risk for fracture were stratified to Current User (n = 92) or Not Current User (n = 107) groups. Current Users had used the original delivery device for ≥8 weeks, including uninterrupted use for four weeks before enrollment. ClinicalTrials.gov, NCT00577863. The primary objective was to detect common complaints (≥3% for all patients) regarding the functionality and acceptability of the new device. Complaints were categorized as functional (e.g., malfunction), nonfunctional (e.g., size), or user manual. Secondary objectives included questionnaire assessment of preference of the new versus original device, features of the new delivery device, and analysis of adverse events. A total of 31 patients (16%) reported 47 complaints (four functional, 27 nonfunctional, and 16 user manual). There were two common complaints: device size (4.0%) and lack of information on alcohol swabs (3.5%). Overall, patients agreed that the new device was easy to use (99.5%), easy to learn to use (99%), easy to attach a needle (97%), easy to hold while injecting (95%), and that it reduced their reluctance to take injections (90%). Most Current Users (92%) preferred the new delivery device over the original device. Adverse events reported by ≥2% of patients were upper respiratory infection (3.5%), urinary tract infection (2%), influenza (2%), and headache (2%). Limitations include the one-arm study design and the short (eight week) duration of the study. Patients found the new teriparatide delivery device easy to use and Current Users preferred the new delivery device over the original device. [ABSTRACT FROM AUTHOR]

Development of specific medical devices (MDs) is required to meet the healthcare needs of children and young people (CYP). In this context, MD development should address changes in growth and psychosocial maturation, physiology, and pathophysiology, and avoid inappropriate repurposing of adult technologies. Underpinning the development of MD for CYP is the need to ensure MD safety and effectiveness through pediatric MD-specific regulations. Contrary to current perceptions of limited market potential, the global pediatric healthcare market is expected to generate around USD 15,984 million by 2025. There are 1.8 billion young people in the world today; 40% of the global population is under 24, creating significant future healthcare market opportunities. This review highlights a number of technology areas that have led to successful pediatric MD, including 3D printing, advanced materials, drug delivery, and diagnostic imaging. To ensure the targeted development of MD for CYP, collaboration across multiple professional disciplines is required, facilitated by a platform to foster collaboration and drive innovation. The European Pediatric Translational Research Infrastructure (EPTRI) will be established as the European platform to support collaboration, including the life sciences industrial sector, to identify unmet needs in child health and support the development, adoption, and commercialization of pediatric MDs. [ABSTRACT FROM AUTHOR]

The dry powder inhaler, which has traditionally relied on the patient’s inspiratory force to deaggregate and deliver the active agent to the target region of the lung, has been a successful delivery device for the provision of locally active agents for the treatment of conditions such as asthma and chronic obstructive pulmonary disease (COPD). However, such devices can suffer from poor delivery characteristics and/or poor reproducibility. More recently, drugs for systemic delivery and more high value compounds have been put into DPI devices. Regulatory, dosing, manufacturing and economic concerns have demanded that a more efficient and reproducible performance is achieved by these devices. Recently strategies have been put in place to produce a more efficient DPI device/formulation combination. Using one novel device as an example the paper will examine which features are important in such a device and some of the strategies required to implement these features.All of these technological advances are invisible, and may be irrelevant, to the patient. However, their inability to use an inhaler device properly has significant implications for their therapy. Use of active device mechanisms, which reduce the dependence on patient inspiratory flow, and sensible industrial design, which give the patient the right clues to use, are important determinants of performance here. [Copyright &y& Elsevier]

The efficacy and safety of intravenous (i.v.) and subcutaneous recombinant human erythropoietin (rh‐EPO, epoetin) for the treatment of renal anaemia is well established. Subcutaneous administration of epoetin is recommended by current guidelines because it is more flexible and convenient than i.v. dosing, enables dose reduction of epoetin and results in cost benefits. Subcutaneous administration of epoetin β permits flexible dosing regimens that can be tailored to patients’ individual needs. This was demonstrated in a recent, large, randomized, controlled trial in which once‐weekly dosing of epoetin β was as effective as the same total dose administered two or three times weekly. New developments in delivery devices for self‐administration, which are more convenient and acceptable to patients, also contribute to the ability to individualize treatment. Furthermore, educating patients in the management of renal anaemia encourages collaboration between patients and health care providers, enabling more tailored treatment regimens to be developed. In conclusion, the use of flexible dosing frequencies, easy‐to‐use delivery devices and patient education may increase patient compliance and encourage self‐administration of epoetin β. The ability to individualize epoetin β therapy increases the number of options available to nephrologists and their patients, leading to greater opportunities to tailor treatment according to specific needs. [ABSTRACT FROM PUBLISHER]

[Display omitted] • Long bacteriophage tails are nanotube devices for delivery of viral DNA to the host cell cytoplasm. • Sequential program of protein interactions leading to assembly of phage SPP1 tail is uncovered. • Tail chaperones are essential to stabilize the TMP structure and for tail tube assembly. • Gp16.1, a highly conserved phage protein, acts during assembly of the tail interface for capsid binding. • SPP1 uses a minimal protein set to build long phage tails. Siphoviruses are main killers of bacteria. They use a long non-contractile tail to recognize the host cell and to deliver the genome from the viral capsid to the bacterial cytoplasm. Here, we define the molecular organization of the Bacillus subtilis bacteriophage SPP1 ~ 6.8 MDa tail and uncover its biogenesis mechanisms. A complex between gp21 and the tail distal protein (Dit) gp19.1 is assembled first to build the tail cap (gp19.1-gp21Nter) connected by a flexible hinge to the tail fiber (gp21Cter). The tip of the gp21Cter fiber is loosely associated to gp22. The cap provides a platform where tail tube proteins (TTPs) initiate polymerization around the tape measure protein gp18 (TMP), a reaction dependent on the non-structural tail assembly chaperones gp17.5 and gp17.5* (TACs). Gp17.5 is essential for stability of gp18 in the cell. Helical polymerization stops at a precise tube length followed by binding of proteins gp16.1 (TCP) and gp17 (THJP) to build the tail interface for attachment to the capsid portal system. This finding uncovers the function of the extensively conserved gp16.1-homologs in assembly of long tails. All SPP1 tail components, apart from gp22, share homology to conserved proteins whose coding genes' synteny is broadly maintained in siphoviruses. They conceivably represent the minimal essential protein set necessary to build functional long tails. Proteins homologous to SPP1 tail building blocks feature a variety of add-on modules that diversify extensively the tail core structure, expanding its capability to bind host cells and to deliver the viral genome to the bacterial cytoplasm. [ABSTRACT FROM AUTHOR]