A review of paediatric injectable drug delivery to inform the study of product acceptability - An introduction.

AIM: The EMA defines acceptability as "the overall ability and willingness of the patient to use, and their caregiver to administer, the medicine as intended" [1]. This paper seeks to outline issues of acceptability in relation to injectable therapy, namely intravenous (IV), intramuscular (IM) and subcutaneous (SC) administration routes, and to lay a foundation to identify a minimum set of data that would satisfy Regulatory Authorities when discussing the acceptability of an injectable product. In addition, it will alert drug product developers to other factors that might contribute to good practice, alternative administration strategies and overall adherence to achieve successful treatment. Whilst the term 'parenteral' means "outside the intestine" [2,3] and so potentially covers a range of administration routes including intranasal and percutaneous administration, this review focuses on IV, IM and SC administration by injection. The use of indwelling canulae or catheters to reduce venepuncture and facilitate prolonged treatment is common and may impact acceptability [4]. This may be influenced by information provided by the manufacturer but is not always in their direct control. Other injectable products suitable for routes such as intradermal, intra-articular, intraosseous and intrathecal, share the requirement to be acceptable but are not specifically covered in this paper [2,5].

Stability and compatibility of parenteral nutrition solutions; a review of influencing factors.

Both stability and compatibility of parenteral nutrition solutions (PNS) with drug products are major concerns for clinicians and clinical pharmacists, especially when concurrent administration of PNS with intravenous medications (IVM) is unavoidable. Since the same physicochemical principles apply to both adult's and paediatrics' PNS, concerns about stability and compatibility may still apply to both. However, these concerns are relatively more common in paediatrics and neonatal clinical settings, where limited vascular access can be problematic and the coadministration of PNS and drugs is more common. In neonatal and paediatric populations, there have been few experimental studies and comprehensive evaluations looking at medication compatibility with frequently used PNS. This work is part of a larger research project concerned for compatibility of PNS with commonly used intravenous medication in paediatric and neonates. This paper captures and reviews published data on factors influencing stability and compatibility of parenteral nutrition solutions. This information will help clinicians and clinical pharmacists to understand the principals of the stability and compatibility of PNS, furthermore, it will inform better design of future compatibility studies, as it highlights the complexity of PNS and the multiple factors influencing the stability of PNS, and hence its compatibility with IVM. When preparing, prescribing, and administering the PNS, especially when co-administration with IVM is unavoidable, it is important to take into account the physicochemical properties of the PNS components and IVM as well as administration conditions and environmental factors. These factors should also be considered in the design of the compatibility studies of the PNS with the IVM.

Proposed Tool to Compare and Assess the Applicability of Taste Assessment Techniques for Pharmaceuticals.

Palatability is amongst the most important determinants of whether or not a child will take a medicine. In order to increase concordance with treatment regimens it is often necessary to utilise a range of formulation techniques to improve the palatability of medicines. These can include selecting a different molecule or version of a molecule (such as a different polymorph or salt form), various taste masking techniques and/or the inclusion of flavours and sweeteners. In order to be able to understand the taste of the Active Pharmaceutical Ingredient (API) and to validate the formulation approach used, it is necessary to be able to use the most reliable taste evaluation method possible. Multiple in vivo and in vitro methods exist nowadays or are proposed in the literature but are often little understood by the pharmaceutical product development community. In particular, different methods may be more relevant at different stages of product development. The aim of this article is to propose a tool to guide the selection of the most appropriate method for the desired evaluation. A spreadsheet-based tool is proposed that is designed to allow the systematic assessment of the applicability of any taste assessment technique existing or new to the users proposed application. A series of criteria are defined that will allow the user to assess the analytical, usability and availability factors for the technique that is being considered. Such a systematic review will help the user to understand the benefits and risks of using each methodology for that application. The use of the tool is illustrated based on currently available data and literature. As new/existing methods are developed/improved, the outcomes of the tool may change.

Development and optimisation of simulated salivary fluid for biorelevant oral cavity dissolution.

Drug release within the oral cavity can be of paramount importance for formulations that are designed for specific purposes such as taste-masking, faster onset of therapeutic action, localization of treatment or avoidance of first-pass metabolism. Preclinical methods for assessment of dissolution in the oral cavity are necessary for design and development of these formulation but currently there is no consensus on what variables should be defined to achieve biorelevance in these tests. In this study, biorelevant simulated salivary fluids (SSFs) that can be uniformly applied for oral cavity dissolution testing were developed. Unstimulated saliva (US) SSF and stimulated saliva (SS) SSF were separately developed since the two states significantly differ. Physicochemical properties including pH, buffer capacity, surface tension and viscosity were assessed during development and optimised to mimic human saliva (HS). In order to account for the salivary proteins in HS, use of bovine submaxillary mucin (BSM) and porcine gastric mucin (PGM) in SSFs was evaluated. Following optimisation of the SSFs, biorelevance of the developed SSFs to HS was assessed by their comparative physicochemical properties as well as dissolution profiles of three diverse model compounds (sildenafil citrate, efavirenz, and caffeine) which showed comparable profiles between the SSFs and HS. This work addresses the lack of uniformed biorelevant dissolution media for oral cavity dissolution studies and provides a basis for standardised dissolution tests that provide consistency and harmonisation in future oral cavity dissolution studies. We envisage that this will have a positive impact on the development of new medicines that require functionality in the oral cavity.

Bitter-blockers as a taste masking strategy: A systematic review towards their utility in pharmaceuticals.

Acceptable palatability of an oral dosage form is crucial to patient compliance. Excipients can be utilised within a formulation to mask the bitterness of a drug. One such category is the bitter-blockers. This term is used inconsistently within the literature and has historically been used to describe any additive which alters the taste of an unpleasant compound. This review defines a bitter-blocker as a compound which interacts with the molecular pathway of bitterness at a taste-cell level and compiles data obtained from publication screening of such compounds. Here, a novel scoring system is created to assess their potential utility in a medicinal product using factors such as usability, safety, efficacy and quality of evidence to understand their taste-masking ability. Sodium acetate, sodium gluconate and adenosine 5'monophophate each have a good usability and safety profile and are generally regarded as safe and have shown evidence of bitter-blocking in human sensory panels. These compounds could offer a much needed option to taste-mask particularly aversive medicines where traditional methods alone are insufficient.

Is rat a good model for assessment of particulate-based taste-masked formulations?

Recently there has been an increased interest to develop specialised dosage forms that are better suited to specific patient populations, such as paediatrics and geriatrics. In these patient populations the acceptability of the oral dosage form can be paramount to the products success. However, many Active Pharmaceutical Ingredients (APIs) are known to cause an aversive taste response. One way to increase the acceptability and to enhance the palatability of the formulation is to design coated taste-masked particulate-based dosage forms. The masking of poorly tasting drugs with physical barriers such as polymer coatings can be utilised to prevent the release of drug within the oral cavity, thus preventing a taste response. However, currently, there are few assessment tools and models available to test the efficiency of these particulate-based taste-masked formulations. The rat brief access taste aversion model has been shown to be useful in assessment of taste for liquid dosage forms. However, the applicability of the rat model for particulate-based taste masked formulations is yet to be assessed. It is not understood whether dissolution, solubility and thus exposure of the drug to taste receptors would be the same in rat and human. Therefore, rat saliva must be compared to human saliva to determine the likelihood that drug release would be similar within the oral cavity for both species. In this study rat saliva was characterised for parameters known to be important for drug dissolution, such as pH, buffer capacity, surface tension, and viscosity. Subsequently dissolution of model bitter tasting compounds, sildenafil citrate and efavirenz, in rat saliva was compared to dissolution in human saliva. For all parameters characterised and for the dissolution of both drugs in rat saliva, a substantial difference was observed when compared to human saliva. This discrepancy in saliva parameters and dissolution of model drugs suggests that preclinical taste evaluation of particulate-based taste-masked formulations suggests rat is not a good model for predicting taste of solid dosage forms or undissolved drug where dissolution is required. Alternative preclinical in vivo models in other species, or improved biorelevant in vitro models should be considered instead.

Age-appropriate and acceptable paediatric dosage forms: Insights into end-user perceptions, preferences and practices from the Children's Acceptability of Oral Formulations (CALF) Study.

A lack of evidence to guide the design of age-appropriate and acceptable dosage forms has been a longstanding knowledge gap in paediatric formulation development. The Children's Acceptability of Oral Formulations (CALF) study captured end-user perceptions and practices with a focus on solid oral dosage forms, namely tablets, capsules, chewables, orodispersibles, multiparticulates (administered with food) and mini-tablets (administered directly into the mouth). A rigorous development and testing phase produced age-adapted questionnaires as measurement tools with strong evidence of validity and reliability. Overall, 590 school children and adolescents, and 428 adult caregivers were surveyed across hospitals and various community settings. Attitudes towards dosage forms primarily differed based on age and prior use. Positive attitudes to tablets and capsules increased with age until around 14 years. Preference was seen for chewable and orodispersible preparations across ages, while multiparticulates were seemingly less favourable. Overall, 59.6% of school children reported willingness to take 10mm diameter tablets, although only 32.1% of caregivers perceived this size to be suitable. While not to be taken as prescriptive guidance, the results of this study provide some evidence towards rational dosage form design, as well as methodological approaches to help design tools for further evaluation of acceptability within paediatric studies.

Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients.

The development of paediatric medicines can be challenging since this is a diverse patient population with specific needs. For example, the toxicity of excipients may differ in children compared to adults and children have different taste preferences. Acceptable palatability of oral paediatric medicinal products is of great importance to facilitate patient adherence. This has been recognised by regulatory authorities and so is becoming a key aspect of paediatric pharmaceutical development studies. Many active pharmaceutical ingredients (APIs) have aversive taste characteristics and so it is necessary to utilise taste masking techniques to improve the palatability of paediatric oral formulations. The aim of this review is to provide an overview of different approaches to taste masking APIs in paediatric oral dosage forms, with a focus on the tolerability of excipients used. In addition, where possible, the provision of examples of some marketed products is made.