Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol.

In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.

Modelling the Compaction Step of a Platform Direct Compression Process.

The ability to predict formulation behaviour at production scale during formulation design can reduce the time to market and decrease product development costs. However, it is challenging to extrapolate compaction settings for direct compression formulations between tablet press models during scale-up and transfer from R&D to commercial production. The aim of this study was to develop statistical process models to predict tablet tensile strength, porosity and disintegration time from compaction parameters (pre-compression and main compression force, and press speed), for three formulations, with differing deformation characteristics (plastic, brittle and elastic), on three tablet press models (one pilot-scale tablet press (KG RoTab) and two production-scale presses (Fette 1200i and GEA Modul P)). The deformation characteristics of yield pressure and elastic recovery were determined for the model placebo formulations investigated. To facilitate comparison of dwell time settings between tablet press models, the design of experiments (DoE) approach was 9 individual 16-run response surface DoEs (3 formulation × 3 press models), whose results were combined to create a polynomial regression model for each tablet property. These models predicted tablet tensile strength, porosity and disintegration time and enabled the construction of design spaces to produce tablets with specified target properties, for each formulation on each press. The models were successfully validated. This modelling approach provides an understanding of the compaction behaviour of formulations with varying deformation behaviour on development and commercial tablet press models. This understanding can be applied to inform achievable production rates at a commercial scale, during the formulation development.

Investigating microcrystalline cellulose crystallinity using Raman spectroscopy.

Microcrystalline cellulose (MCC) is a semi-crystalline material with inherent variable crystallinity due to raw material source and variable manufacturing conditions. MCC crystallinity variability can result in downstream process variability. The aim of this study was to develop models to determine MCC crystallinity index (%CI) from Raman spectra of 30 commercial batches using Raman probes with spot sizes of 100 µm (MR probe) and 6 mm (PhAT probe). A principal component analysis model separated Raman spectra of the same samples captured using the different probes. The %CI was determined using a previously reported univariate model based on the ratio of the peaks at 380 and 1096 cm-1. The univariate model was adjusted for each probe. The %CI was also predicted from spectral data from each probe using partial least squares regression models (where Raman spectra and univariate %CI were the dependent and independent variables, respectively). Both models showed adequate predictive power. For these models a general reference amorphous spectrum was proposed for each instrument. The development of the PLS model substantially reduced the analysis time as it eliminates the need for spectral deconvolution. A web application containing all the models was developed. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10570-021-04093-1.

Process Model Approach to Predict Tablet Weight Variability for Direct Compression Formulations at Pilot and Production Scale.

Optimizing processing conditions to achieve a critical quality attribute (CQA) is an integral part of pharmaceutical quality by design (QbD). It identifies combinations of material and processing parameters ensuring that processing conditions achieve a targeted CQA. Optimum processing conditions are formulation and equipment-dependent. Therefore, it is challenging to translate a process design between formulations, pilot-scale and production-scale equipment. In this study, an empirical model was developed to determine optimum processing conditions for direct compression formulations with varying flow properties, across pilot- and production-scale tablet presses. The CQA of interest was tablet weight variability, expressed as percentage relative standard deviation. An experimental design was executed for three model placebo blends with varying flow properties. These blends were compacted on one pilot-scale and two production-scale presses. The process model developed enabled the optimization of processing parameters for each formulation, on each press, with respect to a target tablet weight variability of <1%RSD. The model developed was successfully validated using data for additional placebo and active formulations. Validation formulations were benchmarked to formulations used for model development, employing permeability index values to indicate blend flow.

Osteointegration, antimicrobial and antibiofilm activity of orthopaedic titanium surfaces coated with silver and strontium-doped hydroxyapatite using a novel blasting process.

Poor integration of orthopaedic devices with the host tissue owing to aseptic loosening and device-associated infections are two of the leading causes of implant failure, which represents a significant problem for both patients and the healthcare system. Novel strategies have focused on silver to combat antimicrobial infections as an alternative to drug therapeutics. In this study, we investigated the impact of increasing the % substitution (12% wt) of silver and strontium in hydroxyapatite (HA) coatings to enhance antimicrobial properties and stimulate osteoblasts, respectively. Additionally, we prepared a binary substituted coating containing both silver and strontium (AgSrA) at 12% wt as a comparison. All coatings were deposited using a novel blasting process, CoBlast, onto biomedical grade titanium (V). Surface physicochemical properties, cytocompatibility and antimicrobial functionality were determined. The anticolonising properties of the coatings were screened using Staphylococcus aureus ATCC 1448, and thereafter, the AgA coating was evaluated using clinically relevant strains. Strontium-doped surfaces demonstrated enhanced osteoblast viability; however, a lower inhibition of biofilm formation was observed compared with the other surfaces. A co-substituted AgSrA surface did not show enhanced osteoblast or anticolonising properties compared with the SrA and AgA surfaces, respectively. Due to its superior anticolonising performance in preliminary studies, AgA was chosen for further studies. The AgA coated surfaces demonstrated good antibacterial activity (eluted and immobilised ion) against methicillin-resistant S. aureus followed by methicillin-sensitive Staphylococcus aureus clinical isolates; however, the AgA surface displayed poor impact against Staphylococcus epidermidis. In conclusion, herein, we demonstrate that HA can be substituted with a range of ions to augment the properties of HA coatings on orthopaedic devices, which offer promising potential to combat orthopaedic device-associated infections and enhance device performance.

Determination of co-crystal phase purity by mid infrared spectroscopy and multiple curve resolution.

Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-crystals from mid infrared spectra. An in-silico coformer screening was used to choose one of ten potential coformers. This analysis used quantum chemistry simulation to predict which coformers are thermodynamically inclined to form cocrystals with the model drug, hydrochlorothiazide. The coformer chosen was nicotinamide. An experimental solvent screening by ultrasound assisted slurry co-crystallization was performed to evaluate the capacity of the method to determine phase purity. Afterwards, slurry and slow evaporation co-crystallizations were performed at 10, 25, and 40 °C using 7 solvent systems, and two levels of agitation for the evaporation co-crystallization (on and off). Mid infrared spectroscopy (MIRS) analysis of the products of these co-crystallizations was used to develop an MCR model to determine co-crystal phase purity. The MCR results were compared with a reference co-crystal. Experimental design (DoE) was used to investigate the effect of solvents, temperature, and agitation on the purity of co-crystals produced by slurry and evaporation co-crystallization. DoE revealed that evaporation co-crystallization with agitating at 65 rpm formed co-crystals with greater phase purity. The optimal temperature varied with the solvent used.

Application of percolation threshold to disintegration and dissolution of ibuprofen tablets with different microcrystalline cellulose grades.

The study presented was conducted to determine whether a percolation threshold value, previously determined for ibuprofen/microcrystalline cellulose (MCC) blends using percolation theory and compression data (Queiroz et al., 2019), could translate to tablet disintegration and dissolution data. The influence of MCC grade (air stream dried versus spray dried) on tablet disintegration and dissolution was also investigated. Complementary to conventional disintegration and dissolution testing, Raman imaging determined drug distribution within tablets, and in-line particle video microscopy (PVM) and focused-beam reflectance measurement (FBRM) monitored tablet disintegration. Tablets were prepared containing 0-30% w/w ibuprofen. Raman imaging confirmed the percolation threshold by quantifying the number and equivalent circular diameters of ibuprofen domains on tablet surfaces. Across the percolation threshold, a step change in dissolution behaviour occurred, and tablets containing air stream dried MCC showed slower disintegration rates compared to tablets containing spray dried MCC. Dissolution measurements confirmed experimentally a percolation threshold in agreement with that determined using percolation theory and compression data. An increase in drug domains, due to cluster formation, and less efficient tablet disintegration contributed to slower ibuprofen dissolution above the percolation threshold. Slower dissolution was measured for tablets containing air stream dried compared to spray dried MCC.

Comparison of Drug Release and Adsorption under Supersaturating Conditions for Ordered Mesoporous Silica with Indomethacin or Indomethacin Methyl Ester.

Incomplete drug release from mesoporous silica systems has been observed in several studies. This work aims to increase the understanding of this phenomenon by investigating the mechanism of drug-silica interactions and adsorption behavior from supersaturated aqueous solutions of two similar drug molecules with different hydrogen bonding capabilities. Drug-silica interactions between indomethacin or its methyl ester and SBA-15 were investigated using spectroscopic techniques (infrared, fluorescence and X-ray photoelectron) and adsorption experiments. The results demonstrate that the predominant mechanism of interaction of both drugs with silica is hydrogen bonding between drug acceptor carbonyl groups with donor groups on the silica surface. The presence of a drug hydrogen bond donor group did not enhance drug adsorption. No evidence was obtained for drug adsorption through nonspecific hydrophobic interactions. Drug adsorption onto the silica surface was investigated under supersaturating conditions through the generation of adsorption isotherms. Similar adsorption isotherms were observed for each compound when the concentration scale was normalized to the drug amorphous solubility. In other words, the equilibrium between the drug adsorbed on the silica surface and free drug in solution was related to the drug activity in solution. The high tendency of the drug to adsorb when the solution is supersaturated was, in turn, found to limit the extent of drug release during dissolution under nonsink conditions. Thus, adsorption provides an explanation for incomplete drug release.

Long-term stability of insulin glulisine loaded nanoparticles formulated using an amphiphilic cyclodextrin and designed for intestinal delivery.

Long-term stability is one of the main challenges for translation of therapeutic proteins into commercially viable biopharmaceutical products. During processing and storage, proteins are susceptible to denaturation. The aim of this work was to evaluate the stability of amphiphilic cyclodextrin-based nanoparticles (NPs) containing insulin glulisine. The stability of the NP dispersion was systematically evaluated following storage at three different temperatures (4 °C, room temperature (RT) and 40 °C). While the colloidal parameters of the NPs in terms of size and zeta potential were maintained (109 ± 9 nm, polydispersity index 0.272, negative zeta potential -25 ± 3 mV), insulin degraded over 60 days during storage. To enhance the shelf life of the product and to circumvent the need for cold-chain maintenance, a lyophilized formulation containing insulin glulisine NPs (1.75 mg/mL of NPs) and 25 mg/mL trehalose was produced. The freeze-dried powder extended the stability of the product for up to 30 days at ambient temperature and 90 days at 4 °C (with 95% and >80% insulin recovery, respectively). Following intra-intestinal administration of the freeze-dried formulation, while no lowering of blood glucose was seen, insulin glulisine was detected in both portal and systemic blood indicating that potential exists for further development of the formulation to simultaneously achieve prolonged stability and therapeutic efficacy.

Understanding the knowledge, attitudes and beliefs of community-dwelling older adults and their carers about the modification of oral medicines: A qualitative interview study to inform healthcare professional practice.

BACKGROUND: Oral medicines are commonly modified (e.g. tablets split/crushed) to meet the dosing and swallowing requirements of older adults. However, there is limited research investigating the opinions of community-dwelling patients and carers about medicine modification. OBJECTIVES: The aim of this study was to investigate the views of community-dwelling older adults and their carers about oral medicine modification. METHODS: Semi-structured, face-to-face interviews were conducted with community-dwelling older adults and carers of older adults who experienced difficulty swallowing medicines, or who required medicines to be modified. Participants were recruited from purposively selected community pharmacies using a combination of purposive, convenience and snowball sampling. Interviews were audio-recorded, transcribed verbatim and analysed thematically. The Francis method governed when data saturation had been reached. RESULTS: Twenty-six interviews (13 patients, 13 carers) were conducted (76.9% female, median length 11 min (IQR 8-16 min)). Four themes emerged from the data: variation in medical needs and preferences; balancing acceptance and resignation; healthcare professional engagement and; opportunities for optimising formulation suitability. The heterogeneity of medical conditions experienced by community-dwelling older adults resulted in a variety of modifications being required. Patients and carers are accepting of their medications and formulations. However, when challenges arise, they tend to feel resigned to coping within the constraints of the current medication regimen, resulting in a lack of focused communication with healthcare professionals. Thus, healthcare professionals were unaware of their difficulties and unable to offer advice or solutions. CONCLUSION: Healthcare professionals must engage proactively with this group. Whilst a holistic approach to medication management is ideal, the disadvantage is that no single healthcare professional may identify this as their responsibility. Whilst the input and expertise of all healthcare professionals will be required, as medication experts, the pharmacy profession should take ownership and become the champion of, and for, the patient.

Manufacturing classification system in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations, case studies from industry and considerations for continuous processing.

Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold.

Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS): A Novel Approach To Investigate the Wettability of Pharmaceutical Powder Blends.

The ability of broadband acoustic resonance dissolution spectroscopy (BARDS) to assess the wettability of powder blends is investigated. BARDS is a novel analytical technology developed on the basis of the change in acoustic phenomena observed when material is added into a solvent under resonance. Addition of solid material to the solvent results in the introduction of gas (air) into the solvent, changing the compressibility of the solvent system, and reducing the velocity of sound in the solvent. As a material is wetted and dissolved, the gas is released from the solvent and resonance frequency is altered. The main purpose of this work is to demonstrate the ability of BARDS to assess differences in the wetting behavior of tablet excipients (microcrystalline cellulose (MCC) and magnesium stearate (MgSt)) and a model drug (metoclopramide hydrochloride) as single component powders and multicomponent powder blends. BARDS acoustic responses showed a prolonged release of gas for the powdered blends with lubricant compared to unlubricated blends. As the elimination of gas from the solvent was assumed to follow first order elimination kinetics, a compressible gas elimination rate constant was calculated from the log plots of the gas volume profiles. The gas elimination rate constant was used as a parameter to compare the release of gas from the powder introduced to the solvent and hence the powder wetting behavior. A lower gas elimination rate constant was measured for lubricated blends compared to nonlubricated blends, suggesting the prolonged hydration of lubricated blends. Standard wetting techniques such as contact angle measurements and wetting time analysis were also used to analyze the blends and confirmed differences in wetting behavior determined by BARDS. The study results demonstrate the capability of BARDS as a rapid, analytical tool to determine the wetting behavior of the pharmaceutical powder blends and the potential of BARDS as a process analytical technology (PAT) tool.

Role of Drug Adsorption onto the Silica Surface in Drug Release from Mesoporous Silica Systems.

Factors contributing to incomplete drug release from a number of mesoporous silica formulations are not well understood. This study aims to address this gap in knowledge by exploring the role of drug adsorption onto silica substrates during the drug release process in dissolution media. Adsorption isotherms were generated to understand drug adsorption behavior onto the silica surface. Two silica materials were selected (SBA-15 (mesoporous) and Aerosil 200 (nonporous)) to investigate the influence of porous architecture on the adsorption/dissolution processes. The ability of the dissolution medium to wet the silica surface, particularly the porous network, was investigated by the addition of a surfactant to the dissolution medium. The results demonstrated that a larger amount of drug was bound/m2 to the nonporous surface than to the mesoporous material. Adsorption isotherms proved useful in understanding drug adsorption/release behavior for the nonporous silica formulation. However, the quantity of drug remaining on the mesoporous silica surface after dissolution was significantly higher than the amount predicted using adsorption isotherm data. These results suggest that a fraction of loaded drug molecules were tightly bound to the silica surface or attached to sites which are inaccessible for the dissolution media. The presence of surfactant, sodium dodecyl sulfate, in the media enhanced drug release from the silica surface. This behavior can be attributed to both the improved wetting characteristics of the media and adsorption of the surfactant to the silica surface. The findings of this study reinforce the significance of the role that silica porous architecture plays in the dissolution process and indicates that accessible surface area is an important parameter to consider for mesoporous systems in relation to drug release.

Continuous powder feeding for pharmaceutical solid dosage form manufacture: a short review.

There has been a noticeable shift from pharmaceutical batch processing towards a more continuous mode of manufacture for solid oral dosage forms. Continuous solid oral dose processes would not be possible in the absence of a highly accurate feeding system. The performance of feeders defines the content of formulations and is therefore a critical operation in continuous manufacturing of solid dosage forms. It was the purpose of this review to review the role of the initial powder feeding step in a continuous manufacturing process. Different feeding mechanisms are discussed with a particular emphasis on screw controlled loss in weight (LIW) feeding. The importance of understanding the physical properties of the raw materials and its impact on the feeding process is reviewed. Prior knowledge of materials provides an initial indication of how the powders will behave through processing and facilitates in the selection of the most suitable (i) feeder (capacity), (ii) feeding mechanism, and (iii) in the case of screw feeder - screw type. The studies identified in this review focus on the impact of material on powder feeding performance.

Oral medicine modification for older adults: a qualitative study of nurses.

OBJECTIVE: Oral medicines are frequently modified (eg, tablets crushed) for older adults. However, these modifications can have clinical, legal and/or ethical implications. Nurses bear responsibility for medicine administration and hence, perform these modifications. The aim of this study was to investigate the knowledge, attitudes and beliefs of nurses about oral medicine modification for older adults. DESIGN: A qualitative study was conducted using semi-structured, face-to-face interviews with nurses providing care to older adults in acute and long-term care settings. Interviews were audio-recorded, transcribed verbatim and analysed thematically. SETTINGS: Sixteen purposively selected care settings; 4 acute-care and 12 long-term care settings were included. Nurses were recruited by convenience sampling at these sites. PARTICIPANTS: Eighteen nurses participated (83% female, 67% long-term care, 33% acute-care, median age (IQR) 38 years (32.5-52.0)). RESULTS: Three major themes: modifying-a necessary evil, nurses' role as patient advocate and modifying-we are working very much as a team and two minor themes: fractional dosing, and covert administration emerged from the data. Nurses viewed oral medicine modifications as being a routine and necessary occurrence in geriatric patient care due to limitations of available formulations and the presence of age-related challenges in drug administration. Nurses' knowledge of residents' requirements ensured that they advocate for those with individualised formulation needs, however, nurses rely on pharmacists for information about modifications. Nurses expressed a desire for supports including increased education and ward-specific, pharmacist-developed recommendations on common modifications. CONCLUSIONS: This study has provided useful insights into the views of nurses regarding oral medicine modification for older adults. The unique and varied formulation requirements of older adults must be acknowledged. Increased engagement by healthcare professionals, the pharmaceutical industry, regulatory agencies and policy-makers is required to facilitate the development of age-appropriate formulations. In the interim, practical interventions, informed by the findings of this study, are required.

Near-infrared monitoring of roller compacted ribbon density: Investigating sources of variation contributing to noisy spectral data.

The aim of this study was to highlight how variability in roller compacted ribbon quality can impact on NIR spectral measurement and to propose a simple method of data selection to remove erroneous spectra. The use of NIR spectroscopy for monitoring ribbon envelope density has been previously demonstrated, however to date there has been limited discussion as to how spectral data sets can contain erroneous outliers due to poor sample presentation to the NIR probes. In this study compacted ribbon of variable quality was produced from three separate blends of microcrystalline cellulose (MCC)/lactose/magnesium stearate at 8 Roll Force settings (2-16kN/cm). The three blends differed only in the storage conditions of MCC prior to blending and compaction. MCC sublots were stored at ambient (41% RH/20°C), low humidity (11% RH/20°C) and high humidity (75% RH/40°C) conditions prior to blending. Ribbon envelope density was measured and ribbon NIR spectral data was acquired at line using a multi-probe spectrometer (MultiEye™ NIR). Initial inspection of the at-line NIR spectral data set showed a large degree of variability which indicated that some form of data cleaning was required. The source of variability in spectral measurements was investigated by subjective visual examination and by statistical analysis. Spectral variability was noted due to the storage conditions of MCC prior to compaction, Roll Force settings and between individual ribbon samples sampled at a set Roll Force/Blend combination. Variability was also caused by ribbon presentation to probes, such as differences in the presentation of broken, curved and flat intact ribbons. Based on the subjective visual examination of data, a Visual Discard method was applied and was found to be particularly successful for blends containing MCC stored at ambient and low humidity. However the Visual Discard method of spectra cleaning is subjective and therefore a non-subjective method capable of screening for erroneous probe readings was developed. For this data set a Trimmed Mean method was applied to set a limit on how data is cleaned from the data set allowing for the removal of a faulty probe reading (25% of data) or a poor sample (33% of data). The 33% Trimmed Mean reduced the impact of spectral variation or misreads between samples or probes and was found to be as successful as the Visual Discard method at cleaning the data set prior to development of the calibration equation.

In vitro dissolution models for the prediction of in vivo performance of an oral mesoporous silica formulation.

Drug release from mesoporous silica systems has been widely investigated in vitro using USP Type II (paddle) dissolution apparatus. However, it is not clear if the observed enhanced in vitro dissolution can forecast drug bioavailability in vivo. In this study, the ability of different in vitro dissolution models to predict in vivo oral bioavailability in a pig model was examined. The fenofibrate-loaded mesoporous silica formulation was compared directly to a commercial reference product, Lipantil Supra®. Three in vitro dissolution methods were considered; USP Type II (paddle) apparatus, USP Type IV (flow-through cell) apparatus and a USP IV Transfer model (incorporating a SGF to FaSSIF-V2 media transfer). In silico modelling, using a physiologically based pharmacokinetic modelling and simulation software package (Gastroplus™), to generate in vitro/in vivo relationships, was also investigated. The study demonstrates that the in vitro dissolution performance of a mesoporous silica formulation varies depending on the dissolution apparatus utilised and experimental design. The findings show that the USP IV transfer model was the best predictor of in vivo bioavailability. The USP Type II (paddle) apparatus was not effective at forecasting in vivo behaviour. This observation is likely due to hydrodynamic differences between the two apparatus and the ability of the transfer model to better simulate gastrointestinal transit. The transfer model is advantageous in forecasting in vivo behaviour for formulations which promote drug supersaturation and as a result are prone to precipitation to a more energetically favourable, less soluble form. The USP IV transfer model could prove useful in future mesoporous silica formulation development. In silico modelling has the potential to assist in this process. However, further investigation is required to overcome the limitations of the model for solubility enhancing formulations.

The knowledge, attitudes and beliefs of patients and their healthcare professionals around oral dosage form modification: A systematic review of the qualitative literature.

OBJECTIVES: The objective of this systematic review was to synthesize the available qualitative evidence on the knowledge, attitudes and beliefs of adult patients, healthcare professionals and carers about oral dosage form modification. DESIGN: A systematic review and synthesis of qualitative studies was undertaken, utilising the thematic synthesis approach. DATA SOURCES: The following databases were searched from inception to September 2015: PubMed, Medline (EBSCO), EMBASE, CINAHL, PsycINFO, Web of Science, ProQuest Databases, Scopus, Turning Research Into Practice (TRIP), Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR). Citation tracking and searching the references lists of included studies was also undertaken. Grey literature was searched using the OpenGrey database, internet searching and personal knowledge. An updated search was undertaken in June 2016. REVIEW METHODS: Studies meeting the following criteria were eligible for inclusion; (i) used qualitative data collection and analysis methods; (ii) full-text was available in English; (iii) included adult patients who require oral dosage forms to be modified to meet their needs or; (iv) carers or healthcare professionals of patients who require oral dosage forms to be modified. Two reviewers independently appraised the quality of the included studies using the Critical Appraisal Skills Programme Checklist. A thematic synthesis was conducted and analytical themes were generated. RESULTS: Of 5455 records screened, seven studies were eligible for inclusion; three involved healthcare professionals and the remaining four studies involved patients. Four analytical themes emerged from the thematic synthesis: (i) patient-centred individuality and variability; (ii) communication; (iii) knowledge and uncertainty and; (iv) complexity. The variability of individual patient's requirements, poor communication practices and lack of knowledge about oral dosage form modification, when combined with the complex and multi-faceted healthcare environment complicate decision making regarding oral dosage form modification and administration. CONCLUSIONS: This systematic review has highlighted the key factors influencing the knowledge, attitudes and beliefs of patients and healthcare professionals about oral dosage form modifications. The findings suggest that in order to optimise oral medicine modification practices the needs of individual patients should be routinely and systematically assessed and decision-making should be supported by evidence based recommendations with multidisciplinary input. Further research is needed to optimise oral dosage form modification practices and the factors identified in this review should be considered in the development of future interventions.

Modification of oral dosage forms for the older adult: An Irish prevalence study.

Age-related pharmacological changes complicate oral dosage form (ODF) suitability for older adults. The aim of this study was to investigate the appropriateness of ODF for older adults by determining the prevalence of ODF modifications in an aged care facility in Ireland. Drug charts for eligible patients were obtained. Details of all medications administered were recorded. ODF modifications were examined to determine if they were evidence-based: defined as complying with the product license or best practice guidelines (BPG). In total, of 111 patients, 35.1% received at least one modified medicine. Medicines were most commonly modified to facilitate fractional dosing (82.0%). Of the 68 instances of medicine modification, 35.3% complied with the product license. Of the 44 unlicensed modifications, 14 complied with BPG. Therefore, 44.1% of modifications were not evidence-based. This study highlights that clinicians have to routinely tailor commercial ODF to meet older patients' needs despite the lack of an evidence-base for almost half of these modifications. The main factor contributing to these modifications is the lack of appropriate, licensed dosage forms. However, reimbursement policies also play a role. Research is needed to optimise medicine administration and to provide clinicians with much needed evidence to support their daily practice.

Dissolvable microneedle fabrication using piezoelectric dispensing technology.

Dissolvable microneedle (DMN) patches are novel dosage forms for the percutaneous delivery of vaccines. DMN are routinely fabricated by dispensing liquid formulations into microneedle-shaped moulds. The liquid formulation within the mould is then dried to create dissolvable vaccine-loaded microneedles. The precision of the dispensing process is critical to the control of formulation volume loaded into each dissolvable microneedle structure. The dispensing process employed must maintain vaccine integrity. Wetting of mould surfaces by the dispensed formulation is also an important consideration for the fabrication of sharp-tipped DMN. Sharp-tipped DMN are essential for ease of percutaneous administration. In this paper, we demonstrate the ability of a piezoelectric dispensing system to dispense picolitre formulation volumes into PDMS moulds enabling the fabrication of bilayer DMN. The influence of formulation components (trehalose and polyvinyl alcohol (PVA) content) and piezoelectric actuation parameters (voltage, frequency and back pressure) on drop formation is described. The biological integrity of a seasonal influenza vaccine following dispensing was investigated and maintained voltage settings of 30 V but undermined at higher settings, 50 and 80 V. The results demonstrate the capability of piezoelectric dispensing technology to precisely fabricate bilayer DMN. They also highlight the importance of identifying formulation and actuation parameters to ensure controlled droplet formulation and vaccine stabilisation.