A mini-review of non-parenteral clonidine preparations for paediatric sedation.

OBJECTIVE: To provide an overview of non-parenteral clonidine formulations and assess the feasibility of their use for paediatric sedation. METHODS: A literature search was conducted using electronic databases and a combination of search terms. Forty articles met the inclusion criteria. Publications were grouped into different dosage forms and assessed for their potential application for sedation of children in intensive care. KEY FINDINGS: Several routes of clonidine administration have been investigated for numerous indications in children, including perioperative sedation and analgesia. These include oral liquids, tablets, oral transmucosal systems, nasal sprays and rectal suspensions. Conflicting studies on oral transmucosal clonidine formulations suggest that further research is required to fully establish efficacy. Nasal sprays and rectal suspensions have the advantages of rapid onset of action and potential for dose flexibility, but predictable absorption is difficult to obtain. CONCLUSIONS: Provided age-appropriate strengths are available, intravenous formulations remain the most predictable in terms of bioavailability and flexible in terms of dose adjustment. However, as with all routes, down-titration is difficult given the long half-life of clonidine. Oral transmucosal systems, nasal sprays and rectal suspensions have potential in a less acute setting, but significant clinical work is required to elucidate a full pharmacokinetic and pharmacodynamic profile.

Age-mediated changes in the gastrointestinal tract.

Physiological functions of the two extreme ends of the age spectrum, children (<18 y old) and older adults (aged 65 y and over), differ from healthy young adults. This consequently affects the pharmacokinetic profiles of administered drugs, which, in turn, impacts upon clinical practice and drug therapy. The gastrointestinal milieu acts as a distinct and vital organ regulating the dissolution, absorption and metabolism of orally ingested drugs. Age-mediated alteration in the physiology and function of the gut can reshape the pharmacokinetics of certain drugs. However, our understanding of this topic is limited. This article references the gut physiology of healthy adults to capture the available evidence in the literature on the extent and nature of the changes in childhood and older age. The gut, as an organ, is examined with regards to the effect of age on luminal fluid, microbiota, transit and motility, and the intestinal mucosa. Whilst drastic developmental changes were observed in certain aspects of the gastrointestinal environment, the examination reveals significant gaps in our knowledge in the physiology and function of the developing or ageing gut. The revelation of the unknown paves the way towards a better characterization of the human gastrointestinal tract for optimized drug therapy in children and older adults.

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project.

A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project.

Patient centric formulations for paediatrics and geriatrics: Similarities and differences.

Paediatrics and geriatrics both represent highly heterogenous populations and require special consideration when developing appropriate dosage forms. This paper discusses similarities, differences and considerations with respect to the development of appropriate medicine formulations for paediatrics and geriatrics. Arguably the most significant compliance challenge in older people is polypharmacy, whereas for children the largest barrier is taste. Pharmaceutical technology has progressed rapidly and technologies including FDCs, multi-particulates and orodispersible dosage forms provide unprecedented opportunities to develop novel and appropriate formulations for both old and new drugs. However, it is important for the formulation scientists to work closely with patients, carers and clinicians to develop such formulations for both the paediatric and geriatric population.

Older people's priorities in health and social care research and practice: a public engagement workshop.

PLAIN ENGLISH SUMMARY: A one day public engagement workshop was held to focus on the priorities of older people about research and practice in health and social care. Seventy-five older people from the general public and a variety of backgrounds attended this event to share their views and discuss what should be prioritised. The main aim of this workshop was to identify and prioritise issues that are important to older people that would benefit from further research, as well as create an environment for older people to share ideas and problems related to these important issues. Key priorities brought up by participants included loneliness and isolation, support and training for professional and family carers, post-surgical care, negative perceptions of older people and inequalities related to public services and healthcare. Participants further suggested older people should be actively involved in all stages of the research process. ABSTRACT: As the world's population ages, there is an increasing need for research that addresses the priorities of older people. A public engagement workshop focusing on the priorities of older people for research and practice in health and social care was attended by seventy-five people aged 70 years and above in London, United Kingdom (UK). The workshop aimed to identify and prioritise issues important to older people that would benefit from further research and act as a platform to promote sharing of ideas and problems related to these important issues. Key priorities emerged including loneliness and isolation, support and training for professional and family carers, post-surgical care, negative perceptions of older people and inequalities related to public services and healthcare. Participants further suggested older people should be actively involved in all stages of the research process.

Meeting commentary--"Parkinson's disease: From patient to product".

A meeting organised by the Academy of Pharmaceutical Sciences (APSGB) Age-Related Medicines Focus Group took place on the 19th of May 2015, in GlaxoSmithKline Ware, UK [*]. The meeting was the first of a planned series of disease specific meetings organised by APSGB. It was attended by a number of experts involved with the treatment and development of drugs for the older adult, including clinicians, pharmacists, academics, regulators and representatives from industry. The event created the platform to discuss the provision of medicines for the treatment of Parkinson's disease (PD) from a pharmaceutical sciences perspective. 'Medications are something you prescribe: something that gives me my life back' (A PD sufferer).

Formulation factors affecting acceptability of oral medicines in children.

Acceptability of medicines in children and caregivers affects safety and effectiveness of medicinal treatments. The pharmaceutical industry is required to demonstrate acceptability of new paediatric formulations in target age groups as an integrated part of the development of these products (Kozarewicz, 2014). Two questions arise when trying to tackle this task: "which dosage form to choose for each target age group?" and "how to formulate it once the dosage form is decided?". Inevitably, both the regulator and the developer turn to scientific evidence for answers. Research has emerged in recent years to demonstrate age-appropriateness and patient acceptability of different dosage forms; however, such information is still fragmented and far from satisfactory to define efficient formulation development strategies for a diverse patient subset (Ranmal and Tuleu, 2013). This paper highlights how formulation factors affect the acceptability of different oral medicines in children (Table 1), and it is based on a more extensive review article by Liu et al. (Liu et al., 2014). Gaps in knowledge are highlighted in order to stimulate further research. In some areas, findings from studies conducted in adult populations may provide useful guidance for paediatric development and this is also discussed.

Taking the guesswork out of supplying multicompartment compliance aids: do pharmacists require further guidance on medication stability?

OBJECTIVE: The purpose of this article is to identify information that is currently available to pharmacists concerning the stability of medications repackaged into multicompartment compliance aids (MCAs). This article explores the potential risks associated with repackaging medications into MCAs for pharmacists who supply and patients who use them. KEY FINDINGS: There is a paucity of information currently available to pharmacists concerning the stability of medications repackaged into MCAs as it is not routinely provided by pharmaceutical manufacturers. However, some studies have identified the potential for adverse effects on safety, bioavailability and stability that may have a clinical impact. There are also professional and legal implications of removing medications from their original packaging for storage in MCAs. CONCLUSION: There is a growing need for further information concerning the stability of medications repackaged into MCAs to guide pharmacists who are supplying these compliance aids to primary and secondary care. Pharmaceutical manufacturers and researchers should be advised to conduct stability testing in MCAs for orally administered medications. This information should be readily available, and pharmacists should be made aware of it via their pharmaceutical bodies. As a result, decisions regarding MCA preparation can be more informed, and pharmacist and patient risks associated with repackaging potentially unstable medications can be minimised.

Development of a model for robust and exploratory analysis of the rodent brief-access taste aversion data.

The rodent brief-access taste aversion (BATA) model is an efficient in vivo screening tool for taste assessment. A new E(max) (maximum effect attributable to the drug) model was developed and further investigated in comparison with three previously published models for analysing the rodent BATA data; the robustness of all the models was discussed. The rodent BATA data were obtained from a series of experiments conducted with a bitter reference compound, quinine hydrochloride dihydrate (QHD). A new E(max) model that could be applied to both "lick numbers" and "lick ratios" was built and three published models that used lick ratios were employed for analysing the BATA data. IC50, the concentration that inhibits 50% of the maximum lick numbers, quantified the oral aversiveness of QHD. One thousand bootstrap datasets were generated from the original data. All models were applied to estimate the confidence intervals of the IC50s without symmetric assumption. The IC50 value obtained from the new E(max) model was 0.0496 mM (95% CI 0.0297-0.0857) using the lick numbers for analysis, while an IC50 of 0.0502 mM (95% CI 0.0267-0.0859) was acquired with the lick ratios. Except one published model, the IC50 values have a similar range for the 95% CI. The new E(max) model enabled the analysis of both "lick numbers" and "lick ratios" whereas other models could only handle data presented as "lick ratios". IC50s obtained with these two types of datasets showed similarity among all models thereby justified the robustness of the new E(max) model.

Patient-centred pharmaceutical design to improve acceptability of medicines: similarities and differences in paediatric and geriatric populations.

Patient acceptability of a medicinal product is a key aspect in the development and prescribing of medicines. Children and older adults differ in many aspects from the other age subsets of population and require particular considerations in medication acceptability. This review highlights the similarities and differences in these two age groups in relation to factors affecting acceptability of medicines. New and conventional formulations of medicines are considered regarding their appropriateness for use in children and older people. Aspects of a formulation that impact acceptability in these patient groups are discussed, including, for example, taste/smell/viscosity of a liquid and size/shape of a tablet. A better understanding of the acceptability of existing formulations highlights opportunities for the development of new and more acceptable medicines and facilitates safe and effective prescribing for the young and older populations.

Novel encapsulation systems and processes for overcoming the challenges of polypharmacy.

The encapsulation process has been studied to develop smart drug delivery systems for decades. In particular, micro-encapsulation and nano-encapsulation approaches have gained wide interest in the development of particulate drug delivery and achieved progress in specialties such as nano-medicine. Encapsulation technologies have evolved through various platforms including emulsion solvent evaporation, spray drying and polymer conjugation. Among current encapsulation methods, electrohydrodynamic and microfluidic processes stand out by enabling the making of formulations with uniform shape and nanoscale size. Pressurized gyration is a new method of combining rotation and controlled pressure to produce encapsulated structures of various morphologies. In this review we address key developments in electrohydrodynamic, microfluidic, their combined and new approaches as well as their potential to obtain combined therapies with desired drug release profiles.

Utilization of microfluidic V-junction device to prepare surface itraconazole adsorbed nanospheres.

Itraconazole is widely used as an anti-fungal drug to treat infections. However, its poor aqueous solubility results in low bioavailability. The aim of the present study was to improve the drug release profile by preparing surface itraconazole adsorbed polymethylsilsesquioxane (PMSQ) nanospheres using a V-junction microfluidic (VJM) device. In order to generate nanospheres with rough surface, the process flow rate of perfluorohexane (PFH) was set between 50 and 300 µl min(-1) while the flow rate of PMSQ and itraconazole solution were constant at 300 µl min(-1). Variations in the PFH flow rate enable the controlled size generation of nanospheres. PMSQ nanospheres adsorbing itraconazole were characterized by SEM, FTIR and Zetasizer. The release of itraconazole from PMSQ nanosphere surface was measured using UV spectroscopy. Nanosphere formulations with a range of sphere size (120, 320 and 800 nm diameter) were generated and drug release was studied. 120 nm itraconazole coated PMSQ nanospheres were found to present highest drug encapsulation efficiency and 13% drug loading in a more reproducible manner compared to 320 nm and 800 nm sized nanosphere formulations. Moreover, 120 nm itraconazole coated PMSQ nanospheres (encapsulation efficiency: 88%) showed higher encapsulation efficiency compared to 320 nm (encapsulation efficiency: 74%) and 800 nm (encapsulation efficiency: 62%) sized nanosphere formulations. The itraconazole coated PMSQ nanospheres were prepared continuously at the rate of 2.6 × 10(6) per minute via VJM device. Overall the VJM device enabled the preparation of monodisperse surface itraconazole adsorbed nanospheres with controlled in vitro drug release profile.

Public engagement workshop: how to improve medicines for older people?

Public engagement in medication management has become more and more important in promoting population health. A public engagement workshop attended by 78 members of the geriatric community, family carers as well as professionals from academic research, industry and regulatory agencies entitled 'How to improve medicines for older people?' took place on the 2nd July 2013 at the University College London (UCL) School of Pharmacy. The main aim of the event was to provide a dynamic environment for information exchange and to identify ways of improving current and future geriatric drug therapy. The day opened with presentations from UCL School of Pharmacy researchers on the use of medicines at home, formulations, administration devices and multi-component compliance aids (MCAs) whilst a representative from UCL Interaction Centre gave an insightful presentation on human errors and resilience strategies regarding medication use. These opening presentations encouraged participants to share their own experiences as well as initiating a lively debate. Following the plenary presentations, the workshop was divided into 8 groups for parallel discussion session. These opinion sharing sessions witnessed fruitful discussions between patients, carers and researchers. The day closed with a panel session of representatives from the European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory Agency (MHRA), the Geriatric Medicines Society and Guy's and St. Thomas' NHS Foundation Trust (GSTT). Participants were encouraged to voice their questions, concerns and recommendations about medications. The main concern expressed by both patients and carers from the workshop were (but are not limited to) formulation changes, MCA accessibility difficulties, interactions of different medicines, carers' concerns with the administration of medicines and not having enough knowledge of services provided by community pharmacists i.e. medicines use reviews (MURs) or new medicine service (NMS). Overall, this workshop created a useful forum for members of the geriatric community, their carers as well as research and industrial professionals to have an input in the improvement and management of geriatric drug therapy and this event also provided an excellent opportunity for the researchers to share the latest research innovations with attendees.

Modeling the physiological factors that affect drug delivery from a nipple shield delivery system to breastfeeding infants.

An apparatus was designed to mimic lactation from a human breast. It was used to determine the influence of milk fat content and flow rate, and suction pulse rate of a breastfeeding infant upon the release of a model compound from a nipple shield delivery system (NSDS). The NSDS would be worn by a mother to deliver drugs and nutrients to her infant during breastfeeding. Sulforhodamine B dye (SB) was used as model compound and formulated as a dispersible tablet to be placed within the NSDS. Increasing suction pulse rate from 30 to 120 pulses/min clearly correlated with increased cumulative release of SB for the same volume of milk passed through the NSDS. No distinct correlation was found between flow rates (1, 5, and 8 mL/min) and SB release, possibly because of competing factors controlling release rate at different flow rates. A highly similar SB release rate into two fat content fluids (2.9 and 4.2 wt %) was observed for identical flow conditions. This proof of concept study outlines a novel method to mimic lactation from a breast, and future studies will lead to effective methods to identify key physiological factors that influence drug release from a NSDS.

Meeting commentary--"medicines for older adults: learning from practice to develop patient centric drug products".

A meeting jointly organised by the Academy of Pharmaceutical Sciences (APSGB), the Geriatric Medicine Society and the UCL School of Pharmacy took place on the 13th of March 2013, in Stevenage, UK. The meeting was attended by a number of experts involved with the treatment and development of drugs for the older adult, including clinicians, pharmacists, academics, regulators and representatives from industry. The event created the platform to discuss the provision of medicines for older adults from a pharmaceutical sciences perspective.

A new reconstitutable oral paediatric hydrocortisone solution containing hydroxypropyl-ß-cyclodextrin.

Hydrocortisone (HC) despite a low aqueous solubility and a very poor palatability is frequently used unlicensed in paediatric practice. Hence a reconstitutable taste masked hydrocortisone solution with the potential to be easily produced extemporaneously was developed. Excipients for the reconstitutable dry powder mix were selected based on their aqueous solubility, compatibility, safety profile in children and stability at the optimum pH for HC. Formulations were visually inspected and pH was checked. The chemical and microbiological stability was assessed by a validated HPLC method and the European Pharmacopeia tests. A taste assessment study was performed on 20 young healthy adults to determine the optimum sweetener. HC was flavored (orange tangerine), preserved (methyl paraben sodium salt/potassium sorbate), adjusted to pH 4.2 (citric acid buffer) and included in a 1:6 hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) complex which allowed complete solubilization of the drug following reconstitution within 1 min of handshake. Neotame 0.075% was found to be the sweetener of choice to mask the unpalatable taste and aftertaste of HC. All formulations tested at different storage conditions were found to be chemically stable after reconstitution with a HC recovery of >95% for 1 month. Microbiological assessment showed that the selected preservative combination was efficient and the presence of preservative ensured the recommended acceptance criteria for microbiological quality after reconstitution with repetitive sampling. The successfully developed 5 mg/mL reconstituted oral palatable paediatric HC solution was stable for 1 month after reconstitution and has the potential to facilitate dosing, acceptability, availability and affordability.

Needle-free and microneedle drug delivery in children: a case for disease-modifying antirheumatic drugs (DMARDs).

Parenteral routes of drug administration have poor acceptability and tolerability in children. Advances in transdermal drug delivery provide a potential alternative for improving drug administration in this patient group. Issues with parenteral delivery in children are highlighted and thus illustrate the scope for the application of needle-free and microneedle technologies. This mini-review discusses the opportunities and challenges for providing disease-modifying antirheumatic drugs (DMARDs) currently prescribed to paediatric rheumatology patients using such technologies. The aim is to raise further awareness of the need for age-appropriate formulations and drug delivery systems and stimulate exploration of these options for DMARDs, and in particular, rapidly emerging biologics on the market. The ability of needle-free and microneedle technologies to deliver monoclonal antibodies and fusion proteins still remains largely untested. Such an understanding is crucial for future drug design opportunities. The bioavailability, safety and tolerance of delivering biologics into the viable epidermis also need to be studied.