Kinetic and Thermodynamic Interplay of Polymer-Mediated Liquid-Liquid Phase Separation for Poorly Water-Soluble Drugs.

Understanding the interplay between kinetics and thermodynamics of polymer-mediated liquid-liquid phase separation is crucial for designing and implementing an amorphous solid dispersion formulation strategy for poorly water-soluble drugs. This work investigates the phase behaviors of a poorly water-soluble model drug, celecoxib (CXB), in a supersaturated aqueous solution with and without polymeric additives (PVP, PVPVA, HPMCAS, and HPMCP). Drug-polymer-water ternary phase diagrams were also constructed to estimate the thermodynamic behaviors of the mixtures at room temperature. The liquid-liquid phase separation onset point for CXB was detected using an inline UV/vis spectrometer equipped with a fiber optic probe. Varying CXB concentrations were achieved using an accurate syringe pump throughout this study. The appearance of the transient nanodroplets was verified by cryo-EM and total internal reflection fluoresence microscopic techniques. The impacts of various factors, such as polymer composition, drug stock solution pumping rates, and the types of drug-polymer interactions, are tested against the onset points of the CXB liquid-liquid phase separation (LLPS). It was found that the types of drug-polymer interactions, i.e., hydrogen bonding and hydrophobic interactions, are vital to the position and shapes of LLPS in the supersaturation drug solution. A relation between the behaviors of LLPS and its location in the CXB-polymer-water ternary phase diagram was drawn from the findings.

Towards a greater understanding of the deep eutectic phenomenon through examination of the lidocaine-NSAID therapeutic deep eutectic systems.

Therapeutic deep eutectic solvents (THEDES) have been attracting increasing attention in the pharmaceutical literature as a promising enabling technology capable of improving physicochemical and biopharmaceutical properties for difficult-to-deliver drug compounds. The current literature has explored amide local anaesthetics and carboxylic acid nonsteroidal anti-inflammatories (NSAIDs) as commonly used THEDES formers for their active hydrogen-bonding functionality. However, little is known about what happens within the "deep eutectic" region where a range of binary compositions present simply as a liquid with no melting events detectable across experimentally achievable conditions. There is also very limited understanding of how parent compounds' physicochemical properties could impact upon the formation, interaction mechanism, and stability of the formed liquid systems, despite the significance of these information in dose adjustment, industrial handling, and scaling-up of these liquids. In the current work, we probed the "deep eutectic" phenomenon by investigating the formation and physicochemical behaviours of some chosen lidocaine-NSAID systems across a wide range of composition ratios. Our data revealed that successfully formed THEDES exhibited composition dependent Tg variations with strong positive deviations from predicted Tg values using the Gordon-Taylor theory, suggesting substantial interactions within the formed supramolecular structure. Interestingly, it was found that the parent compound's glass forming ability had a noticeable impact upon such profound interaction and hence could dictate the success of THEDES formation. It has also been confirmed that all successful systems were formed based on charge-assisted hydrogen bonding within their THEDES network, affirming the significant role of partial protonisation on achieving a profound melting point depression. More importantly, the work found that within the "deep eutectic" region there was still an ideal, or thermodynamically preferrable "THEDES point", which would exhibit excellent stability upon exposure to stress storage conditions. The discoveries of this study bring the literature one step closer to fully understanding the "therapeutic deep eutectic" phenomenon. Through correlation between parent reagents' physicochemical properties and the synthesised products' characteristics, we establish a more educated process for the prediction and engineering of THEDES.

Mucoadhesive Polymeric Polyologels Designed for the Treatment of Periodontal and Related Diseases of the Oral Cavity.

The study objective was to design and characterise herein unreported polyologels composed of a range of diol and triol solvents and polyvinyl methyl ether-co-maleic acid (PVM/MA) and, determine their potential suitability for the treatment of periodontal and related diseases in the oral cavity using suitable in vitro methodologies. Polyologel flow and viscoelastic properties were controlled by the choice of solvent and the concentration of polymer. At equivalent polymer concentrations, polyologels prepared with glycerol (a triol) exhibited the greatest elasticity and resistance to deformation. Within the diol solvents (PEG 400, pentane 1,5-diol, propane 1,2-diol, propane 1,3-diol, and ethylene glycol), PEG 400 polyologels possessed the greatest elasticity and resistance to deformation, suggesting the importance of distance of separation between the diol groups. Using Raman spectroscopy bond formation between the polymer carbonyl group and the diol hydroxyl groups was observed. Polyologel mucoadhesion was influenced by viscoelasticity; maximum mucoadhesion was shown by glycerol polyologels at the highest polymer concentration (20% w/w). Similarly, the choice of solvent and concentration of PVM/MA affected the release of tetracycline from the polyologels. The controlled release of tetracycline for at least 10 h was observed for several polyologels, which, in combination with their excellent mucoadhesion and flow properties, offer possibilities for the clinical use of these systems to treat diseases within the oral cavity.

Use of solid thermolytic salts to facilitate microwave-induced in situ amorphization.

Moisture was frequently used as dielectric heating source in classical microwave-able systems to facilitate microwave-induced in situ amorphization, however such systems may face the potential of drug hydrolysis. In this study, solid thermolytic salts were proposed to function as moisture substitutes and their feasibility and impacts on microwave-induced in situ amorphization were investigated. It was found that NH4HCO3 was a promising solid alkaline salt to facilitate both microwave-induced in situ amorphization and in situ salt formation of acidic indomethacin (IND). Moreover, it could improve the chemical stability of the drug and the dissolution performance of compacts relative to classical moisture-based compacts upon microwaving. Further mechanistic study suggested that the in situ amorphization occurred prior to the in situ salt formation, especially in formulations with low drug loadings and high solid salt mass ratios. For compacts with low polymer ratios, in situ salt formation took place subsequently, where the previously amorphized IND within compacts could interact with the NH3 gas produced in situ by the decomposition of NH4HCO3 and form the ammonium IND salt. Microwaving time showed great impacts on the decomposition of NH4HCO3 and the in situ generation of water and NH3, which indirectly affected the amorphization and salt formation of IND. In comparison to the moisture-based systems, the NH4HCO3-based system showed a number of advantages, including the reduced potential of IND hydrolysis due to the absence of absorbed moisture, a wider category of applicable polymeric carriers other than hygroscopic polymers, and an increase in drug loading up to 50% (w/w).

Friendly Visiting Programs for Older People Experiencing Social Isolation: A Realist Review of what Works, for whom, and under what Conditions.

Many social interventions have been developed with the hopes of reducing and preventing social isolation among older people (e.g., recreation, arts-based programs and social prescription). Friendly visiting programs, also known as befriending schemes, have been a mainstay in this area for decades and are largely thought to be effective at reconnecting older people (≥ 60 years of age) experiencing isolation. Research and evaluations have yet to determine, however, how and why these programs may be most successful, and under what conditions. This article presents the findings of a realist synthesis aimed at identifying the critical mechanisms and contextual factors that lead to successful outcomes in friendly visiting programs. Seven studies are synthesized to inform a friendly visiting program theory accounting for key mechanisms (e.g., provision of informal support) and underlying contexts (e.g., training of volunteers) that can be used to inform future programs. Recommendations for future research are also presented.

Photosensitiser-incorporated microparticles for photodynamic inactivation of bacteria.

Antimicrobial resistance is an ever-growing global concern, making the development of alternative antimicrobial agents and techniques an urgent priority to protect public health. Antimicrobial photodynamic therapy (aPDT) is one such promising alternative, which harnesses the cytotoxic action of reactive oxygen species (ROS) generated upon irradiation of photosensitisers (PSs) with visible light to destroy microorganisms. In this study we report a convenient and facile method to produce highly photoactive antimicrobial microparticles, exhibiting minimal PS leaching, and examine the effect of particle size on antimicrobial activity. A ball milling technique produced a range of sizes of anionic p(HEMA-co-MAA) microparticles, providing large surface areas available for electrostatic attachment of the cationic PS, Toluidine Blue O (TBO). The TBO-incorporated microparticles showed a size-dependent effect on antimicrobial activity, with a decrease in microparticle size resulting in an increase in the bacterial reductions achieved when irradiated with red light. The >6 log10Pseudomonas aeruginosa and Staphylococcus aureus reductions (>99.9999%) achieved within 30 and 60 min, respectively, by TBO-incorporated >90 µm microparticles were attributed to the cytotoxic action of the ROS generated by TBO molecules bound to the microparticles, with no PS leaching from these particles detected over this timeframe. TBO-incorporated microparticles capable of significantly reducing the bioburden of solutions with short durations of low intensity red light irradiation and minimal leaching present an attractive platform for various antimicrobial applications.

Therapeutic deep eutectic solvents: A comprehensive review of their thermodynamics, microstructure and drug delivery applications.

Deep eutectic solvents (DES) are multicomponent liquids that are usually formed by coupling a hydrogen bond donor and acceptor leading to strong non-covalent (NC) intermolecular networking and profound depression in the melting point of the system. Pharmaceutically, this phenomenon has been exploited to improve drugs' physicochemical properties, with an established DES therapeutic subcategory, therapeutic deep eutectic solvents (THEDES). THEDES preparation is usually via straightforward synthetic processes with little involvement of sophisticated techniques, which, in addition to its thermodynamic stability, make these multi-component molecular adducts a very attractive alternative for drug enabling purposes. Other NC bonded binary systems (e.g., co-crystals and ionic liquids) are utilized in the pharmaceutical field for enhancing drug's behaviours. However, a clear distinction between these systems and THEDES is scarcely discussed in the current literature. Accordingly, this review provides a structure-based categorization for DES formers, a discussion of its thermodynamic properties and phase behaviour, and it clarifies the physicochemical and microstructure boundaries between DES and other NC systems. Additionally, a summary of its preparation techniques and their experimental conditions preparation is supplied. Instrumental analysis techniques can be used to characterize and differentiate DES from other NC mixtures, hence this review draws a road map to for this purpose. Since this work mainly focuses on pharmaceutical applications of DES, all types of THEDES including the highly discussed types (conventional, drugs dissolved in DES and polymer based) in addition to the less discussed categories are covered. Finally, the regulatory status of THEDES was investigated despite the current unclear situation.

The effects of surfactants on the performance of polymer-based microwave-induced in situ amorphization.

Microwave-induced in situ amorphization is a novel technology for preparing amorphous solid dispersions (ASDs) to address the challenges of their long-term physical stability and downstream processing. To date, only few types of dielectric materials have been reported for microwave-induced in situ amorphization, which restricted the extensive research of this technology. This study aimed to investigate the feasibility and mechanisms of utilizing the non-ionic surfactants, i.e. Kollisolv P124, Kolliphor RH40, D-ɑ-tocopheryl polyethylene glycol succinate (TPGS), Tween (T) 60 (T60), T65, T80 and T85, as plasticizers to facilitate microwave-induced in situ amorphization. It was found that the successful application of surfactants could be related with their low Tm, low Mw and high HLB. Kolliphor RH40 was selected as a typical surfactant due to its excellent dielectric heating ability, plasticizing effect and solubilizing effect when facilitating amorphization. Then, the dissolution-mediated in situ amorphization mechanism was investigated and intuitively demonstrated. For the most promising formulation, i.e. microwaved systems with Korlliphor RH40 at 1.5 (w/w) plasticizer/polymer ratio, a complete and fast in vitro dissolution was observed relative to the untreated systems. In conclusion, non-ionic surfactants had the potential to facilitate microwave-induced in situ amorphization, which provided a new direction in the formulation designation for microwave-able systems.

High drug loading nanosized amorphous solid dispersion (NASD) with enhanced in vitro solubility and permeability: Benchmarking conventional ASD.

Through liquid-liquid phase separation (LLPS), it is possible to generate drug-rich nanoparticles during the dissolution of conventional amorphous solid dispersions (ASDs). These self-generated nanoparticles may improve the oral absorption of poorly water-soluble drugs by enhancing the drug's apparent solubility and effective membrane permeability. However, due to the high concentration threshold required for LLPS, conventional ASDs that can consistently generate drug-rich nanoparticles during dissolution are rare. More importantly, the quality of these meta-stable drug-rich nanoparticles is hard to control during dissolution, leading to inconsistency in formulation performances. This work has described a continuous twin-screw extrusion process capable of producing nanosized ASD (NASD) formulations that can offer better solubility and permeability enhancements over conventional ASD formulations. Two polymeric carriers, polyvinylpyrrolidone-co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), with a model hydrophobic drug celecoxib (BCS II), were formulated into both ASD and NASD formulations. Compared to the conventional ASD formulation, the prefabricated NASD (sizes ranging between 40 and 200 nm) embedded within a polyol matrix can be rapidly dispersed into a nanoparticle suspension in the presence of aqueous media. The resulting NASDs achieved drug loadings up to 80 % w/w and a maximum of 98 % encapsulation efficiency. Because of the TSE platform's high drug-loading capacity and high scalability, the developed method may be useful for continuously producing personalized nanomedicines.

A new mathematical model derived from transient (creep) analysis to estimate the vaginal retention of semi-solid dosage forms.

The performance of vaginal drug delivery systems is dependent on their retention. This study presents a novel mathematical method to estimate the vaginal retention of semi-solids. Using creep analysis, the elastic and residual compliances are determined from the discrete retardation spectrum and used to determine the retention times (RT), defined as the time required for the formulations to enter the terminal viscous zone of deformation and hence flow. RT of commercially available products (CAP) and selected prototype formulations were determined, the estimated RT of CAP broadly aligning with their prescribed clinical usage. Candidate formulations composed of hydroxyethylcellulose (HEC, 3%/5%w/w) and polyacrylic acid (PAA, 1%/3%w/w) were manufactured using, and further diluted with simulant vaginal fluid (SVF) or simulant seminal fluid (SSF) and their RT subsequently determined. Increasing polymer concentration and pH enhanced the estimated RT whereas dilution reduced RT. Notably, the formulation composed of 5%HEC/3% PAA (SSF) maintained its RT on dilution due to swelling of suspended PAA particles, thus representing a strategy to develop vaginal semi-solids that are resistant to dilution and hence removal. The mathematical model described is reproducible, straightforward to use and is recommended as a tool in formulation development to estimate the retention of vaginal semi-solids.

Evaluating the effectiveness of a universal eHealth school-based prevention programme for depression and anxiety, and the moderating role of friendship network characteristics.

BACKGROUND: Lifetime trajectories of mental ill-health are often established during adolescence. Effective interventions to prevent the emergence of mental health problems are needed. In the current study we assessed the efficacy of the cognitive behavioural therapy (CBT)-informed Climate Schools universal eHealth preventive mental health programme, relative to a control. We also explored whether the intervention had differential effects on students with varying degrees of social connectedness. METHOD: We evaluated the efficacy of the Climate Schools mental health programme (19 participating schools; average age at baseline was 13.6) v. a control group (18 participating schools; average age at baseline was 13.5) which formed part of a large cluster randomised controlled trial in Australian schools. Measures of internalising problems, depression and anxiety were collected at baseline, immediately following the intervention and at 6-, 12- and 18-months post intervention. Immediately following the intervention, 2539 students provided data on at least one outcome of interest (2065 students at 18 months post intervention). RESULTS: Compared to controls, we found evidence that the standalone mental health intervention improved knowledge of mental health, however there was no evidence that the intervention improved other mental health outcomes, relative to a control. Student's social connectedness did not influence intervention outcomes. CONCLUSION: These results are consistent with recent findings that universal school-based, CBT-informed, preventive interventions for mental health have limited efficacy in improving symptoms of anxiety and depression when delivered alone. We highlight the potential for combined intervention approaches, and more targeted interventions, to better improve mental health outcomes.

Design and scale-up of amorphous drug nanoparticles production via a one-step anhydrous continuous process.

Polymeric nanoparticle drug delivery systems are increasingly viewed as crucial building blocks for efficacious treatments of disease conditions. However, production methods at commercially practical scales pose a significant challenge for successfully translating such technology. This paper describes a novel, anhydrous, twin-screw extrusion (TSE) platform-based technology to overcome the issues associated with developing and scale-up production of nanoparticulate drug delivery systems. With polyol as the process medium, the proposed TSE platform enables the encapsulation of the drug and reduction of particle size in a one-step process without the requirement for organic solvents or water. pH-responsive nanoparticle drug delivery of two nonsteroidal anti-inflammatory drugs, naproxen, and celecoxib, was successfully produced using the TSE process. Remarkably, these resulted in nanoparticles with sizes ranging from 80 to 240 nm, up to 98 % drug encapsulation efficiency, and maximum production throughput of 400 g/hour. pH-responsive drug release for both naproxen and celecoxib was also achieved: immediate drug release with enhanced solubility was obtained for naproxen-Eudragit®E nanoparticles (6 times higher) at pH 1.2 and celecoxib-HPMCAS nanoparticles (15 times higher) at pH 6.8, whilst sustained drug release was achieved for naproxen-Eudragit®E nanoparticles at pH 6.8 and celecoxib-HPMCAS nanoparticles at pH 1.2. We expect this platform technology to streamline the development and scale-up production of various polymeric nanoparticle drug delivery systems.

Internet-delivered cognitive behaviour therapy for post-traumatic stress disorder: a randomised controlled trial and outcomes in routine care.

BACKGROUND: Despite its potential scalability, little is known about the outcomes of internet-based cognitive behaviour therapy (iCBT) for post-traumatic stress disorder (PTSD) when it is provided with minimal guidance from a clinician. AIM: To evaluate the outcomes of minimally guided iCBT for PTSD in a randomised control trial (RCT, Study 1) and in an open trial in routine community care (Study 2). METHOD: A RCT compared the iCBT course (n=21) to a waitlist control (WLC, n=19) among participants diagnosed with PTSD. The iCBT group was followed up 3 months post-treatment. In Study 2, treatment outcomes were evaluated among 117 adults in routine community care. PTSD symptom severity was the primary outcome in both studies, with psychological distress and co-morbid anxiety and depressive symptoms providing secondary outcomes. RESULTS: iCBT participants in both studies experienced significant reductions in PTSD symptom severity from pre- to post-treatment treatment (within-group Hedges' g=.72-1.02), with RCT findings showing maintenance of gains at 3-month follow-up. The WLC group in the RCT also significantly improved, but Study 1 was under-powered and the medium between-group effect favouring iCBT did not reach significance (g=0.64; 95% CI, -0.10-1.38). CONCLUSIONS: This research provides preliminary support for the utility of iCBT for PTSD when provided with minimal clinician guidance. Future studies are needed to clarify the effect of differing levels of clinician support on PTSD iCBT outcomes, as well as exploring how best to integrate iCBT into large-scale, routine clinical care of PTSD.

Exploiting hydrogen bonding to enhance lidocaine loading and stability in a poly ethylene-co-vinyl acetate carrier matrix.

Sustained release of lidocaine from poly ethylene-co-vinyl acetate (EVA) implants can significantly improve pain management outcomes; however, poor drug loading is a major limitation. Recently, myristic acid was found to improve drug loading in EVA by inhibiting the crystallization of lidocaine. Here, lidocaine's interaction with myristic acid was studied by differential scanning calorimetry. Spectra of lidocaine-myristic acid mixtures were analysed using two-dimensional correlation (2DCOS) maps. Furthermore, spectroscopic analysis of EVA matrices containing lidocaine, alone and in combination with myristic acid, was also performed and drug release was evaluated in vitro. A eutectic was obtained on combining lidocaine and myristic acid at the molar ratio of 1:1 due to loss of myristic acid's dimeric conformation resulting in hydrogen bonding of its COOH group with lidocaine's amide I moieties. In EVA, hydrogen bonding between adjacent lidocaine molecules caused crystallization above a threshold concentration and could be inhibited by incorporation of myristic acid by eutectic formation. By altering the molecular confirmation and solid state properties of lidocaine in EVA, myristic acid reduces lidocaine crystallization, increases drug loading and influences drug release kinetics. Exploiting these interactions and promoting further hydrogen bonding through the addition of specific excipients presents a viable strategy to enhance and stabilise drug loading in polymer matrices for various applications.

The Current States, Challenges, Ongoing Efforts, and Future Perspectives of Pharmaceutical Excipients in Pediatric Patients in Each Country and Region.

A major hurdle in pediatric formulation development is the lack of safety and toxicity data on some of the commonly used excipients. While the maximum oral safe dose for several kinds of excipients is known in the adult population, the doses in pediatric patients, including preterm neonates, are not established yet due to the lack of evidence-based data. This paper consists of four parts: (1) country-specific perspectives in different parts of the world (current state, challenges in excipients, and ongoing efforts) for ensuring the use of safe excipients, (2) comparing and contrasting the country-specific perspectives, (3) past and ongoing collaborative efforts, and (4) future perspectives on excipients for pediatric formulation. The regulatory process for pharmaceutical excipients has been developed. However, there are gaps between each region where a lack of information and an insufficient regulation process was found. Ongoing efforts include raising issues on excipient exposure, building a region-specific database, and improving excipient regulation; however, there is a lack of evidence-based information on safety for the pediatric population. More progress on clear safety limits, quantitative information on excipients of concern in the pediatric population, and international harmonization of excipients' regulatory processes for the pediatric population are required.

Recent advances in carbon quantum dots for virus detection, as well as inhibition and treatment of viral infection.

In the last decade, carbon quantum dots (CQDs), as a novel class of carbon-based nanomaterials, have received increasing attention due to their distinct properties. CQDs are ultimately small nanoparticles with an average size below 10 nm, possessing high water solubility, alluring photoluminescence, photostability, excellent biocompatibility, low/none toxicity, environmental friendliness, and high sustainability, etc. In history, there are intermittent threats from viruses to humans, animals and plants worldwide, resulting in enormous crises and impacts on our life, environment, economy and society. Some recent studies have unveiled that certain types of CQDs exhibited high and potent antiviral activities against various viruses such as human coronavirus, arterivirus, norovirus and herpesvirus. Moreover, they have been successfully explored and developed for different virus detections including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This article exclusively overviews and discusses the recent progress of designing, synthesizing, modifying/functionalizing and developing CQDs towards effective virus detection as well as the inhibition and treatment of viral infection. Their mechanisms and applications against various pathogenic viruses are addressed. The latest outcomes for combating the coronavirus disease 2019 (COVID-19) utilizing CQDs are also highlighted. It can be envisaged that CQDs could further benefit the development of virus detectors and antiviral agents with added broad-spectrum activity and cost-effective production.

The development and optimisation of gastro-retentive floating tablets using fused deposition modelling 3D printing.

OBJECTIVES: To develop a robust tablet design for the manufacture of gastro-retentive tablets using fused deposition modelling three-dimensional printing (FDM-3DP) that can provide prolonged gastric residence time with instant floating and minimum influence of process and/or formulation variables. METHODS: Three different polymers, such as polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC) and Soluplus were used, separately, for the manufacture of tablets using FDM-3DP. Tablets were designed in a sandwich model that included voids in the internal structure to support buoyancy. KEY FINDINGS: Fabricated tablets from all polymers were instantly buoyant with no floating lag time. Floating duration was in the order: HPC > Soluplus > PVA which can be explained by the density of the tablets. PVA tablets exhibited significantly (P < 0.05) higher density values (0.86 ± 0.02 mg/mm3) than HPC and Soluplus (0.69 ± 0.03 and 0.72 ± 0.02 mg/mm3, respectively). HPC and Soluplus showed similar zero-order drug release profiles (f2 > 50) and were able to sustain the release of theophylline for 12 h, whereas complete drug release was achieved from PVA tablets after 3 h. CONCLUSIONS: Robust gastro-retentive tablets that show instant buoyancy regardless of the polymeric carrier type and composition were successfully manufactured utilising FDM-3DP. This allows for overcoming the restrictions posed by process/formulation parameters on the floatability of gastro-retentive tablets.

3D printing of pharmaceutical oral solid dosage forms by fused deposition: The enhancement of printability using plasticised HPMCAS.

3D printing (3DP) by fused deposition modelling (FDM) is one of the most extensively developed methods in additive manufacturing. Optimizing printability by improving feedability, nozzle extrusion, and layer deposition is crucial for manufacturing solid oral dosage forms with desirable properties. This work aimed to use HPMCAS (AffinisolTM HPMCAS 716) to prepare filaments for FDM-3DP using hot-melt extrusion (HME). It explored and demonstrated the effect of HME-filament composition and fabrication on printability by evaluating thermal, mechanical, and thermo-rheological properties. It also showed that the HME-Polymer filament composition used in FDM-3DP manufacture of oral solid dosage forms provides a tailored drug release profile. HME (HAAKE MiniLab) and FDM-3DP (MakerBot) were used to prepare HME-filaments and printed objects, respectively. Two diverse ways of improving the mechanical properties of HME-filaments were deduced by changing the formulation to enable feeding through the roller gears of the printer nozzle. These include plasticizing the polymer and adding an insoluble structuring agent (talc) into the formulation. Experimental feedability was predicted using texture analysis results was a function of PEG concentration, and glass-transition temperature (Tg) values of HME-filaments. The effect of high HME screw speed (100 rpm) resulted in inhomogeneity of HME-filament, which resulted in inconsistency of the printer nozzle extrudate and printed layers. The variability of the glass-transition temperature (Tg) of the HME-filament supported by scanning electron microscopy (SEM) images of nozzle extrudates and the lateral wall of the printed tablet helped explain this result. The melt viscosity of HPMCAS formulations was investigated using a capillary rheometer. The high viscosity of unplasticized HPMCAS was concluded to be an additional restriction for nozzle extrusion. The plasticization of HPMCAS and the addition of talc into the formulation were shown to improve thickness consistency of printed layers (using homogeneous HME-filaments). A good correlation (R2 = 0.9546) between the solidification threshold (low-frequency oscillation test determined by parallel-plate rheometer) and Tg of HME-filaments was also established. Drug-loaded and placebo HPMCAS-based formulations were shown to be successfully printed, with the former providing tailored drug release profiles based on variation of internal geometry (infill).

A national effectiveness trial of an eHealth program to prevent alcohol and cannabis misuse: responding to the replication crisis.

BACKGROUND: The burden of disease attributable to alcohol and other drug (AOD) use in young people is considerable. Prevention can be effective, yet few programs have demonstrated replicable effects. This study aimed to replicate research behind Climate Schools: Alcohol and Cannabis course among a large cohort of adolescents. METHODS: Seventy-one secondary schools across three States participated in a cluster-randomised controlled trial. Year 8 students received either the web-based Climate Schools: Alcohol and Cannabis course (Climate, n = 3236), or health education as usual (Control, n = 3150). Outcomes were measured via self-report and reported here for baseline, 6- and 12-months for alcohol and cannabis knowledge, alcohol, cannabis use and alcohol-related harms. RESULTS: Compared to Controls, students in the Climate group showed greater increases in alcohol- [standardised mean difference (SMD) 0.51, p < 0.001] and cannabis-related knowledge (SMD 0.49, p < 0.001), less increases in the odds of drinking a full standard drink[(odds ratio (OR) 0.62, p = 0.014], and heavy episodic drinking (OR 0.49, p = 0.022). There was no evidence for differences in change over time in the odds of cannabis use (OR 0.57, p = 0.22) or alcohol harms (OR 0.73, p = 0.17). CONCLUSIONS: The current study provides support for the effectiveness of the web-based Climate Schools: Alcohol and Cannabis course in increasing knowledge and reducing the uptake of alcohol. It represents one of the first trials of a web-based AOD prevention program to replicate alcohol effects in a large and diverse sample of students. Future research and/or adaptation of the program may be warranted with respect to prevention of cannabis use and alcohol harms.