Systematic screening of photopolymer resins for stereolithography (SLA) 3D printing of solid oral dosage forms: Investigation of formulation factors on printability outcomes.

Pharmaceutical three-dimensional printing (3DP) is now in its golden age. Recent years have seen a dramatic increase in the research in 3D printed pharmaceuticals due to their potential to deliver highly personalised medicines, thus revolutionising the way medicines are designed, manufactured, and dispensed. A particularly attractive 3DP technology used to manufacture medicines is stereolithography (SLA), which features key advantages in terms of printing resolution and compatibility with thermolabile drugs. Nevertheless, the enthusiasm for pharmaceutical SLA has not been followed by the introduction of novel excipients specifically designed for the fabrication of medicines; hence, the choice of biocompatible polymers and photoinitiators available is limited. This work provides an insight on how to maximise the usefulness of the limited materials available by evaluating how different formulation factors affect printability outcomes of SLA 3D printed medicines. 156 photopolymer formulations were systematically screened to evaluate the influence of factors including photoinitiator amount, photopolymer molecular size, and type and amount of liquid filler on the printability outcomes. Collectively, these factors were found highly influential in modulating the print quality of the final dosage forms. Findings provide enhanced understanding of formulation parameters informing the future of SLA 3D printed medicines and the personalised medicines revolution.

Virtual Clinical Trials Guided Design of an Age-Appropriate Formulation and Dosing Strategy of Nifedipine for Paediatric Use.

The rapid onset of action of nifedipine causes a precipitous reduction in blood pressure leading to adverse effects associated with reflex sympathetic nervous system (SNS) activation, including tachycardia and worsening myocardial and cerebrovascular ischemia. As a result, short acting nifedipine preparations are not recommended. However, importantly, there are no modified release preparations of nifedipine authorised for paediatric use, and hence a paucity of clinical studies reporting pharmacokinetics data in paediatrics. Pharmacokinetic parameters may differ significantly between children and adults due to anatomical and physiological differences, often resulting in sub therapeutic and/or toxic plasma concentrations of medication. However, in the field of paediatric pharmacokinetics, the use of pharmacokinetic modelling, particularly physiological-based pharmacokinetics (PBPK), has revolutionised the ability to extrapolate drug pharmacokinetics across age groups, allowing for pragmatic determination of paediatric plasma concentrations to support drug licensing and clinical dosing. In order to pragmatically assess the translation of resultant dissolution profiles to the paediatric populations, virtual clinical trials simulations were conducted. In the context of formulation development, the use of PBPK modelling allowed the determination of optimised formulations that achieved plasma concentrations within the target therapeutic window throughout the dosing strategy. A 5 mg sustained release mini-tablet was successfully developed with the duration of release extending over 24 h and an informed optimised dosing strategy of 450 µg/kg twice daily. The resulting formulation provides flexible dosing opportunities, improves patient adherence by reducing frequent administration burden and enhances patient safety profiles by maintaining efficacious levels of consistent drug plasma levels over a sustained period of time.

Paediatric specific dosage forms: Patient and formulation considerations.

The total number of paediatric formulations available only account for a small proportion of the full therapeutic plethora required to effectively treat paediatrics and, therefore, the availability of high quality medicines designed specifically for children remains an ongoing challenge. Currently, the World Health Organisation (WHO) report that around 50% of medication issued for long-term conditions are not taken as advised, whilst it has also been established that, in general practice, around one tenth of medicines prescribed for children are either off-label or unlicensed. Such off-label and unlicensed use is owing to the considerable anatomical and physiological differences observed between paediatric subsets. Identifying such differences, is essential for better informing paediatric drug development and assisting regulatory reviews, whilst ensuring safe and effective therapeutic concentrations of pharmacological substances. Points covered: The review discusses factors affecting the safety, toxicity and efficacy of paediatric drug delivery systems. The research highlights features of the gastrointestinal tract and reports anatomical and physiological differences between paediatrics and adults. Additionally, differences observed in paediatric pharmacokinetic profiles (absorption, distribution, metabolism and elimination) due to physiological differences are also discussed. Furthermore, this review considers the advantages and limitations of current paediatric specific dosage forms available and assesses the acceptability of innovative small flexible solid oral dosage forms. Lastly, this review highlights factors affecting paediatric medicine adherence and acceptability and discusses the techniques available to overcome barriers associated with non-adherence.

Development of an Age-Appropriate Mini Orally Disintegrating Carvedilol Tablet with Paediatric Biopharmaceutical Considerations.

Owing to considerable differences observed in anatomy and physiology between paediatric subsets, it has been well established that children respond to drugs differently compared to adults. Furthermore, from a formulation perspective, there is a distinct challenge to develop a dosage form that is capable of safely, accurately, and reliably delivering the dose across the whole paediatric population. Orally disintegrating mini-tablets (ODMT) have widely been considered as an age-appropriate formulation option that possess the ability for adequate dose flexibility, avoids swallowing difficulties, and exhibits superior stability due to its solid state. Within this study, two strengths (0.5 mg and 2 mg) of carvedilol ODMT formulations were developed using an excipient composition and load that is appropriate for paediatric use. The formulations demonstrated adequate mechanical strength (>20 N) and fast disintegration times (<30 s). Dissolution profiles observed were robust and comparable to the marketed conventional tablet formulation across various parts of the gastrointestinal (GI) tract in both the fed and fasted state, signifying appropriate efficacy, quality, and performance. As such, the formulations developed in this study show potential to address the need of an 'age-appropriate' formulation of carvedilol, as highlighted by the European Medicines Agency (EMA) Inventory of the Needs for Paediatric Medicine.

Social Distancing, Health Care Disruptions, Telemedicine Use, and Treatment Interruption During the COVID-19 Pandemic in Patients With or Without Autoimmune Rheumatic Disease.

BACKGROUND: We aimed to compare concerns, social distancing, health care disruptions, and telemedicine use in patients with autoimmune rheumatic disease (ARD) and non-ARD and to evaluate factors associated with immunomodulatory medication interruptions. METHODS: Patients in a multistate community rheumatology practice network completed surveys from April 2020 to May 2020. Adults with common ARD (rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus) or non-ARD (gout, osteoarthritis, osteoporosis) were evaluated. Concerns about coronavirus disease 2019 (COVID-19), social distancing, health care disruptions, and telemedicine use were compared in patients with ARD versus non-ARD, adjusting for demographics, rural residence, and zipcode-based measures of socioeconomic status and COVID-19 activity. Factors associated with medication interruptions were assessed in patients with ARD. RESULTS: Surveys were completed by 2319/36 193 (6.4%) patients with non-ARD and 6885/64 303 (10.7%) with ARD. Concerns about COVID-19 and social distancing behaviors were similar in both groups, although patients receiving a biologic or Janus kinase (JAK) inhibitor reported greater concerns and were more likely to avoid friends/family, stores, or leaving the house. Patients with ARD were less likely to avoid office visits (45.2% vs. 51.0%, odds ratio [OR] 0.79 [0.70-0.89]) with similar telemedicine use. Immunomodulatory medications were stopped in 9.7% of patients with ARD, usually (86.9%) without a physician recommendation. Compared with patients with an office visit, the likelihood of stopping medication was higher for patients with a telemedicine visit (OR 1.54 [1.19-1.99]) but highest for patients with no visits (OR 2.26 [1.79-2.86]). CONCLUSION: Patients with ARD and non-ARD reported similar concerns about COVID-19 and similar social distancing behaviors. Missed office visits were strongly associated with interruptions in immunomodulatory medication.

Multi-Analytical Framework to Assess the In Vitro Swallowability of Solid Oral Dosage Forms Targeting Patient Acceptability and Adherence.

A lack of effective intervention in addressing patient non-adherence and the acceptability of solid oral dosage forms combined with the clinical consequences of swallowing problems in an ageing world population highlight the need for developing methods to study the swallowability of tablets. Due to the absence of suitable techniques, this study developed various in vitro analytical tools to assess physical properties governing the swallowing process of tablets by mimicking static and dynamic stages of time-independent oral transitioning events. Non-anatomical models with oral mucosa-mimicking surfaces were developed to assess the swallowability of tablets; an SLA 3D printed in vitro oral apparatus derived the coefficient of sliding friction and a friction sledge for a modified tensometer measured the shear adhesion profile. Film coat hydration and in vitro wettability was evaluated using a high-speed recording camera that provided quantitative measurements of micro-thickness changes, simulating static in vivo tablet-mucosa oral processing stages with artificial saliva. In order to ascertain the discriminatory power and validate the multianalytical framework, a range of commonly available tablet coating solutions and new compositions developed in our lab were comparatively evaluated according to a quantitative swallowability index that describes the mathematical relationship between the critical physical forces governing swallowability. This study showed that the absence of a film coat significantly impeded the ease of tablet gliding properties and formed chalky residues caused by immediate tablet surface erosion. Novel gelatin- and λ-carrageenan-based film coats exhibited an enhanced lubricity, lesser resistance to tangential motion, and reduced stickiness than polyvinyl alcohol (PVA)-PEG graft copolymer, hydroxypropyl methylcellulose (HPMC), and PVA-coated tablets; however, Opadry® EZ possessed the lowest friction-adhesion profile at 1.53 a.u., with the lowest work of adhesion profile at 1.28 J/mm2. For the first time, the in vitro analytical framework in this study provides a fast, cost-effective, and repeatable swallowability ranking method to screen the in vitro swallowability of solid oral medicines in an effort to aid formulators and the pharmaceutical industry to develop easy-to-swallow formulations.

Stereolithography Apparatus Evolution: Enhancing Throughput and Efficiency of Pharmaceutical Formulation Development.

Pharmaceutical applications of 3D printing technologies are growing rapidly. Among these, vat photopolymerisation (VP) techniques, including Stereolithography (SLA) hold much promise for their potential to deliver personalised medicines on-demand. SLA 3D printing offers advantageous features for pharmaceutical production, such as operating at room temperature and offering an unrivaled printing resolution. However, since conventional SLA apparatus are designed to operate with large volumes of a single photopolymer resin, significant throughput limitations remain. This, coupled with the limited choice of biocompatible polymers and photoinitiators available, hold back the pharmaceutical development using such technologies. Hence, the aim of this work was to develop a novel SLA apparatus specifically designed to allow rapid and efficient screening of pharmaceutical photopolymer formulations. A commercially available SLA apparatus was modified by designing and fabricating a novel resin tank and build platform able to 3D print up to 12 different formulations at a single time, reducing the amount of sample resin required by 20-fold. The novel SLA apparatus was subsequently used to conduct a high throughput screening of 156 placebo photopolymer formulations. The efficiency of the equipment and formulation printability outcomes were evaluated. Improved time and cost efficiency by 91.66% and 94.99%, respectively, has been confirmed using the modified SLA apparatus to deliver high quality, highly printable outputs, thus evidencing that such modifications offer a robust and reliable tool to optimize the throughput and efficiency of vat photopolymerisation techniques in formulation development processes, which can, in turn, support future clinical applications.

A versatile and user-friendly approach for the analysis of proteins in ancient and historical objects.

Identification and characterization of ancient proteins still require technical developments towards non-invasiveness, sensitivity, versatility and ease of use of the analyses. We report that the enzyme functionalized films, described in Cicatiello et al. (2018), can be used efficiently on the surface of different objects ranging from fixative-coated paper to canvas to the coating on an albumen photograph, as well as the much harder surfaces of ivory objects and the proteinaceous binders in the decoration of a wooden Egyptian coffin. The mixture of digested peptides that are efficiently captured on the functionalized surface are also amenable to LC-MS/MS analysis, which is necessary to confidently identify chemical modifications induced upon degradation, in order to characterize the conservation state of proteins. Moreover, in a two-step procedure, we have combined the trypsin functionalized film with a PNGaseF functionalized film, which adds a deglycosylation pretreatment allowing improved detection of glycosylated proteins. SIGNIFICANCE: User friendly trypsin functionalized films were implemented to expand their potential as versatile, modular tools that can be widely exploited in the world of diagnosis of cultural heritage objects, ancient proteins, and palaeoproteomics: a procedure that could be carried out by conservators or archaeologists first on-site and later analysed with standard MS techniques.

Literature review of medication administration problems in paediatrics by parent/caregiver and the role of health literacy.

OBJECTIVE: To identify studies that highlighted medication administration problems experienced by parents and children, which also looked at health literacy aspect using a validated tool to assess for literacy. STUDY DESIGN: Ten electronic databases were systematically searched and supplemented by hand searching through reference lists using the following search terms: (1) paediatric, (2) medication error including dosing error, medication administration error, medication safety and medication optimisation and (3) health literacy. RESULTS: Of the (1230) records screened, 14 studies were eligible for inclusion. Three analytical themes emerged from the synthesis. The review highlighted that frequencies and magnitudes of dosing errors vary by the measurement tools used, the dose prescribed and by the administration instruction provided. Parent's sociodemographic, such as health literacy and language, is a key factor to be considered when designing an intervention aimed at averting medication administration errors at home. The review summarised some potential strategies that could help in reducing medication administration errors among children at home. Among these recommendations is to show the prescribed dose to the parents or young people along with the verbal instructions, as well as to match the prescribed dose with the measuring tool dispensed, to provide an explicit dose intervals and pictographic dosing instructions. CONCLUSION: The findings suggest that in order to optimise medication use by parents, further work is needed to address the nature of these issues at home. Counselling, medication administration instructions and measurement tools are some of the areas in addition to the sociodemographic characteristics of parents and young people that need to be considered when designing any future potential intervention aimed at reducing medication errors among children and young people at home.

Patient-Centric Medicine Design: Key Characteristics of Oral Solid Dosage Forms that Improve Adherence and Acceptance in Older People.

Older people represent a very heterogeneous patient population and are the major user group of medication. Age-related changes mean that this population can encounter barriers towards taking medicines orally. The aim of this study was to investigate the characteristics of oral solid dosage forms that contribute to an age appropriate dosage design, with an aim to improve overall medication adherence and acceptance in older people. Fifty-two semistructured interviews were conducted with older people, informal (family) carers, and health and social care professionals. Formulation characteristics impacted three stages of the medication taking process: (1) medication identification and memorability, (2) medication handling and (3) swallowability. Small round tablets (≤7 mm) are least accepted amongst older people and their carers and had a negative impact on all stages. The use of bright, two-coloured preparations and interesting shapes improves identification and further aids memorability of indications and the timing of tablets. Palatability, while useful to enhance swallowability, also has an impact on the visual appeal and memorability of medication. Environmental, patient, medication and disease characteristics also determine preferences for formulation. Developing an age appropriate dosage design for older people, therefore, requires a holistic, patient-centric approach to improve adherence and acceptance.

Does the Formulation of Oral Solid Dosage Forms Affect Acceptance and Adherence in Older Patients? A Mixed Methods Systematic Review.

OBJECTIVES: Age-related changes mean that the older population can encounter barriers toward taking medication orally. Further work is needed to identify the characteristics of oral solid dosage forms that will improve patient acceptance and adherence. The aim of this systematic review was to identify if and how formulation aspects of oral solid dosage forms affect acceptance and adherence in older people. DESIGN: Mixed methods systematic review using a data-based convergent synthesis design. SETTING AND PARTICIPANTS: Articles were selected if they included participants aged 60 years and older, or included health care professionals, social care professionals, and informal carers of patients aged 60 years and older. METHODS: A systematic search of the following databases was undertaken: Web of Science, MEDLINE, Scopus, and The Cochrane Databases. The search of databases was supplemented by a search of gray literature, and reference lists of included papers were manually searched. RESULTS: A total of 16 studies were included in the final synthesis. Three themes were generated from the thematic analysis: (1) dimensions, (2) palatability, and (3) appearance. The dimensions and palatability are often modified to improve swallowability by breaking tablets in half or taste masking with food. Polypharmacy can lead to patients using the appearance to identify tablets; however, this can lead to confusion when products appear similar. No study was identified that explored formulation characteristics across all 3 categories directly in the older population. CONCLUSION AND IMPLICATIONS: Manufacturers should take into account practical problems older people may encounter when considering the dimensions, palatability, and appearance of the final drug product. These characteristics should be optimized to aid visual identification and swallowability. Medical providers and pharmacists have an important role in ensuring that these patient-centric drug products are prescribed and dispensed appropriately so that patients receive the most suitable formulation.

Conceptualisation, Development, Fabrication and In Vivo Validation of a Novel Disintegration Tester for Orally Disintegrating Tablets.

Disintegration time is the key critical quality attribute for a tablet classed as an Orally Disintegrating Tablet (ODT). The currently accepted in vitro testing regimen for ODTs is the standard United States Pharmacopeia (USP) test for disintegration of immediate release tablets, which requires a large volume along with repeated submergence of the dosage form within the disintegration medium. The aim of this study was to develop an in vivo relevant ODT disintegration test that mimicked the environment of the oral cavity, including lower volume of disintegration medium, with relevant temperature and humidity that represent the conditions of the mouth. The results showed that the newly developed Aston test was able to differentiate between different ODTs with small disintegration time windows, as well as between immediate release tablets and ODTs. The Aston test provided higher correlations between ODT properties and disintegration time compared to the USP test method and most significantly, resulted in a linear in vitro/in vivo correlation (IVIVC) (R2 value of 0.98) compared with a "hockey stick" profile of the USP test. This study therefore concluded that the newly developed Aston test is an accurate, repeatable, relevant and robust test method for assessing ODT disintegration time which will provide the pharmaceutical industry and regulatory authorities across the world with a pragmatic ODT testing regime.

Liposomes: a promising carrier for respiratory syncytial virus therapeutics.

Introduction: Human respiratory syncytial virus (RSV) is a common respiratory virus that causes severe lower respiratory tract infection in infants, children and aged adults. Currently, there is no active prophylaxis present in the market for RSV infection; however, there are over a dozen compounds being tested in the laboratory as well as clinical trials. To increase the efficiency and safety of these therapeutics, there is a need for delivery vehicles. Areas covered: Liposomes can be used for delivering anti-RSV agents with the advantage of modulating and eliciting the desired adjuvant effect by the different combination of lipids. This review discusses the promising application of liposome for anti-RSV therapeutics. Expert opinion: Liposomes are attracting attention for delivery of pulmonary therapeutics, since they offer compatibility for delivering drugs, vaccines and other therapeutic molecules. Variation in liposome size and composition gives flexibility for the amount and number of deliverables, whilst targeted delivery with the capability for immunomodulation makes liposomes a promising candidate for RSV therapeutic applications.

A phase III, open-label, single-arm, study to evaluate the safety and immunogenicity of a trivalent, surface antigen inactivated subunit influenza virus vaccine produced in mammalian cell culture (Optaflu®) in healthy adults.

Vaccination is an essential tool in reducing the impact of seasonal influenza infections. The viral strains responsible for seasonal outbreaks vary annually, and preventive vaccines have to be adapted accordingly. The aim of this study was to evaluate the safety, clinical tolerability and the antibody response to each of the three influenza vaccine antigens after vaccination with a cell-derived, trivalent, surface antigen, inactivated influenza vaccine (TIVc), as measured by single radial haemolysis (SRH) or haemagglutination inhibition (HI) assay in accordance with European Union licensing guidelines in place for years 2013/2014. This phase 3, open-label, single-arm study enrolled 126 healthy adults divided into two age groups (63 subjects aged 18 to ≤ 60 years and 63 subjects aged ≥ 61 years). Antibody titres were measured before and 21 days after vaccination. Adverse events were determined using diary cards, interviews and reviews of the available medical records. One subject was lost to follow-up and three subjects had protocol deviations. Following vaccination, protective HI antibody titres (≥ 1:40) were detected in 100%, 97%, and 94% of the younger adults (18-≤ 60 years) and in 97%, 95%, and 80% of the older adults (≥ 61 years) against the A (H1N1), A (H3N2), and B influenza strains respectively. The antibody response licensing criteria were met in both age groups. Solicited adverse events were reported by 57% subjects 18 to ≤ 60 years and 35% subjects ≥ 61 years. Among the younger adults 51% had local and 27% had systemic adverse events, whereas of the older subjects 29% had local and 13% had systemic adverse events (mainly injection site pain or headache in both age groups). Unsolicited adverse events at least possibly related to the vaccine were mild and detected in 3% of the younger adults and none of the older adults. Overall, the trivalent, surface antigen, inactivated subunit influenza virus vaccine produced in mammalian cell culture proved to be safe and immunogenic in younger and older healthy adults.

Anti-RSV Peptide-Loaded Liposomes for the Inhibition of Respiratory Syncytial Virus.

Although respiratory syncytial virus (RSV) is one of the leading causes of acute respiratory tract infection in infants and adults, effective treatment options remain limited. To circumvent this issue, there is a novel approach, namely, the development of multifunctional liposomes for the delivery of anti RSV-peptides. While most of the peptides that are used for loading with the particulate delivery systems are the penetrating peptides, an alternative approach is the development of liposome-peptide systems, which are loaded with an RSV fusion peptide (RF-482), which has been designed to inhibit the RSV fusion and block infection. The results of this work have revealed that the liposomes themselves can serve as potential RSV inhibitors, whilst the anti-RSV-peptide with liposomes can significantly increase the RSV inhibition when compared with the anti-RSV peptide alone.

Activated carbon as a carrier for amorphous drug delivery: Effect of drug characteristics and carrier wettability.

Recent research on porous silica materials as drug carriers for amorphous and controlled drug delivery has shown promising results. However, due to contradictory literature reports on toxicity and high costs of production, it is important to explore alternative safe and inexpensive porous carriers. In this study, the potential of activated carbon (AC) as an amorphous drug carrier was investigated using paracetamol (PA) and ibuprofen (IBU) as model drugs. The solution impregnation method was used for drug loading, with loading efficiency determined by UV spectroscopy and drug release kinetics studied using USP II dissolution apparatus. The physical state of the drug in the complex was characterised using differential scanning calorimetry and X-ray diffractions techniques, whilst sites of drug adsorption were studied using Fourier transform infrared spectroscopy and N2 adsorption techniques. In addition, the cytotoxicity of AC on human colon carcinoma (Caco-2) cells was assessed using the MTT assay. Results presented here reveal that, for PA/AC and IBU/AC complexes, the saturation solubility of the drug in the loading solvent appears to have an effect on the drug loading efficiency and the physical state of the drug loaded, whilst drug release kinetics were affected by the wettability of the activated carbon particles. Furthermore, activated carbon microparticles exhibited very low cytotoxicity on Caco-2 cells at the concentrations tested (10-800µg/mL). This study, therefore, supports the potential of activated carbon as a carrier for amorphous drug delivery.

Environmental Scanning Electron Microscope Imaging of Vesicle Systems.

The structural characteristics of liposomes have been widely investigated and there is certainly a strong understanding of their morphological characteristics. Imaging of these systems, using techniques such as freeze-fracturing methods, transmission electron microscopy, and cryo-electron imaging, has allowed us to appreciate their bilayer structures and factors which can influence this. However, there are few methods which all us to study these systems in their natural hydrated state; commonly the liposomes are visualized after drying, staining, and/or fixation of the vesicles. Environmental Scanning Electron Microscopy (ESEM) offers the ability to image a liposome in its hydrated state without the need for prior sample preparation. Within our studies we were the first to use ESEM to study liposomes and niosomes and we have been able to dynamically follow the hydration of lipid films and changes in liposome suspensions as water condenses on to, or evaporates from, the sample in real time. This provides insight into the resistance of liposomes to coalescence during dehydration, thereby providing an alternative assay of liposome formulation and stability.

Microfluidics based manufacture of liposomes simultaneously entrapping hydrophilic and lipophilic drugs.

Despite the substantial body of research investigating the use of liposomes, niosomes and other bilayer vesicles for drug delivery, the translation of these systems into licensed products remains limited. Indeed, recent shortages in the supply of liposomal products demonstrate the need for new scalable production methods for liposomes. Therefore, the aim of our research has been to consider the application of microfluidics in the manufacture of liposomes containing either or both a water soluble and a lipid soluble drug to promote co-delivery of drugs. For the first time, we demonstrate the entrapment of a hydrophilic and a lipophilic drug (metformin and glipizide respectively) both individually, and in combination, using a scalable microfluidics manufacturing system. In terms of the operating parameters, the choice of solvents, lipid concentration and aqueous:solvent ratio all impact on liposome size with vesicle diameter ranging from ∼90 to 300nm. In terms of drug loading, microfluidics production promoted high loading within ∼100nm vesicles for both the water soluble drug (20-25% of initial amount added) and the bilayer embedded drug (40-42% of initial amount added) with co-loading of the drugs making no impact on entrapment efficacy. However, co-loading of glipizide and metformin within the same liposome formulation did impact on the drug release profiles; in both instances the presence of both drugs in the one formulation promoted faster (up to 2 fold) release compared to liposomes containing a single drug alone. Overall, these results demonstrate the application of microfluidics to prepare liposomal systems incorporating either or both an aqueous soluble drug and a bilayer loaded drug.

A Holistic Multi Evidence Approach to Study the Fragmentation Behaviour of Crystalline Mannitol.

Mannitol is an essential excipient employed in orally disintegrating tablets due to its high palatability. However its fundamental disadvantage is its fragmentation during direct compression, producing mechanically weak tablets. The primary aim of this study was to assess the fracture behaviour of crystalline mannitol in relation to the energy input during direct compression, utilising ball milling as the method of energy input, whilst assessing tablet characteristics of post-milled powders. Results indicated that crystalline mannitol fractured at the hydrophilic (011) plane, as observed through SEM, alongside a reduction in dispersive surface energy. Disintegration times of post-milled tablets were reduced due to the exposure of the hydrophilic plane, whilst more robust tablets were produced. This was shown through higher tablet hardness and increased plastic deformation profiles of the post-milled powders, as observed with a lower yield pressure through an out-of-die Heckel analysis. Evaluation of crystal state using x-ray diffraction/differential scanning calorimetry showed that mannitol predominantly retained the ß-polymorph; however x-ray diffraction provided a novel method to calculate energy input into the powders during ball milling. It can be concluded that particle size reduction is a pragmatic strategy to overcome the current limitation of mannitol fragmentation and provide improvements in tablet properties.

Rapid and cost-efficient enumeration of rare cancer cells from whole blood by low-loss centrifugo-magnetophoretic purification under stopped-flow conditions.

We present a substantially improved design and functionality of a centrifugo-magnetophoretic platform which integrates direct immunoseparation and cost-efficient, bright-field detection of cancer cells in whole blood. All liquid handling takes place in a disposable cartridge with geometry akin to a conventional compact disc (CD). The instrumentation required to process such a "lab-on-a-disc" cartridge can be as simple and cost-efficient as the rotor on a common optical disc drive. In a first step, target cells in a blood sample are specifically bound to paramagnetic microbeads. The sample is then placed into the disc cartridge and spun. In the second step, magnetically tagged target cells are separated by a co-rotating, essentially lateral magnetic field from the background population of abundant blood cells, and also from unbound magnetic beads. A stream of target cells centrifugally sediments through a stagnant liquid phase into a designated detection chamber. The continuous, multiforce immunoseparation proceeds very gently, i.e. the mechanical and hydrodynamic stress to the target cells is minimized to mitigate the risk of cell loss by collective entrapment in the background cells or vigorous snapping against a wall. We successfully demonstrate the extraction of MCF7 cancer cells at concentrations as low as 1 target cell per µl from a background of whole blood, with capture efficiencies of up to 88%. Its short time-to-answer is a notable characteristic of this system, with 10% of target cells collected in the first minute after their loading to the system and the remainder captured within the following 10 min. All the above-mentioned factors synergetically combine to leverage the development of a prospective point-of-care device for CTC detection.