PMC:7561592 / 2040-9182 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/7561592","sourcedb":"PMC","sourceid":"7561592","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7561592","text":"INTRODUCTION\nPaediatric oral drug development and administration remain challenging due to specific age-related problems. Availability of authorised, age-appropriate medicines is limited and there is no general rule of how to safely administer oral medicines to the paediatric population (1,2). Therefore, pharmacists and carers often manipulate adult dosage forms prior to administration.\nThe use of food and drinks as vehicles for medicine co-administration is common practice to deliver a specific dose and improve compliance, yet the scientific rationale for selecting a particular type of vehicle for mixing with the medicine is often not evident (3–5). The majority of vehicles suggested for medicine co-administration seem to be recommended more on the basis of their taste and texture for the paediatric population rather than their impact on in vivo drug product performance. In addition to the possible negative effects on dose accuracy (as often reported (5–7)), drug manipulation and mixing with different food and drinks can also affect drug stability, solubility and bioavailability, ultimately leading to either sub-therapeutic or toxic drug levels (8–10). These effects are still often unaddressed.\nIt has been shown that different food and drinks can have an effect on paediatric medicine performance. In a recently published study (the first part of this study) conducted by the research group, the physicochemical properties of a selection of (soft) food and drink vehicles, commonly reported to be mixed with paediatric medicines prior to administration, were measured and the impact of the co-administered vehicles on the solubility of two poorly soluble drugs commonly administered to children (montelukast (sodium) and mesalazine) was assessed (11). The solubility of both montelukast and mesalazine was significantly affected by the physicochemical properties (pH, buffer capacity, surface tension, osmolality, viscosity) and macronutrient composition (fat, sugar and protein content) of commonly used vehicles (11). Similarly, medicine co-administration with different vehicles may affect drug dissolution properties to a different extent. Dissolution of amlodipine (BCS class I; weak base, pKa 8.6; logP 3.0 (12)) from crushed tablets mixed with jam has been shown to be slower in comparison with mixing with other vehicles (yoghurt, honey, orange juice and water) (13). Dissolution studies of crushed warfarin (BCS class I; weak acid, pKa 5.1; logP 2.7 (14,15)) and carbamazepine (BCS class II; neutral compound; logP 2.5 (15,16)) tablets mixed with water or orange juice resulted in a faster drug dissolution in comparison with the direct introduction of whole tablets. In comparison, no differences were observed between drug dissolution from crushed tablets mixed with honey, jam or yoghurt and the direct introduction of tablets scenario (13). Compatibility studies of tegaserod (BCS class II; weak base, pKa 9.8; logP 2.6 (15,17)), from crushed tablets mixed with food/drinks (water, apple juice, orange juice and applesauce), revealed that whilst the drug was compatible with the vehicles, the dissolution profiles of the crushed tablets mixed with orange juice and applesauce were not comparable with those of intact tablets (18). The time between preparation and administration of the mixture may also have an effect on drug solubility, drug stability and consequently oral drug absorption (10). This vehicle-impact might be critical for certain medications (e.g. when immediate release is needed for a fast-therapeutic action), since food-drug interactions can have a significant impact on drug bioavailability and, consequently, therapeutic efficacy (19,20).\nRecently, the FDA issued a draft guidance addressing the recommended approaches for determination of the suitability of the vehicles intended for co-administration of paediatric medicines (21). Guidance is given on vehicle selection, description of standardised in vitro methods for evaluating vehicle compatibility and suggestions on product labelling for communication of acceptability of vehicles (21). It is necessary to conduct these investigations in order to fully understand the impact of this practice on drug formulation behaviour and better guide healthcare practitioners, patients and carers regarding medicine co-administration with vehicles, in the paediatric population.\nIn vitro dissolution testing is widely used as a predictive biopharmaceutics tool for drug product performance characterisation. Dissolution tests are used for several applications including the following: assessment of batch-to-batch quality process control and quality assurance, formulation development, identification of food effects on the dissolution and bioavailability of orally administered drugs, and of drug solubility limitations and stability issues (22,23). Dissolution tests have been shown to predict in vivo drug behaviour in adults by addressing both medicine administration practices and the physiological gastrointestinal (GI) conditions that can affect drug dissolution (22,24). However, these tests require modifications to assess drug performance in paediatrics. The use of dissolution tests to study the impact of medicine co-administration with vehicles on paediatric drug performance would require the incorporation of age-specific gastrointestinal (GI) tract parameters (namely, pH, media volumes and composition and different dosing scenarios) (25).\nThe aims of this study were two-fold: (i) to evaluate the effect of the co-administration with vehicles on the dissolution performance of formulations of two poorly soluble compounds; and (ii) to evaluate the effect of different administration practices (i.e. time between preparation and administration of the mixture formulation-vehicle) on drug dissolution. Considering that the fluid volumes available in the GI tract of younger age groups are smaller than in adults, in the present study, an adaptation of the standard USP II apparatus to a mini-paddle apparatus was tested as an appropriate method to address the need for small volume testing. Additionally, a two-stage dissolution protocol was used to simulate the fluid profile (e.g. pH, fluid volumes and transit times) when conditions are changed from the gastric to intestinal environment. To our knowledge, little attention has been devoted to the use of such in vitro dissolution testing setup to evaluate drug dissolution, whilst addressing typical paediatric dosing conditions such as the effect of medicine co-administration with vehicles. Similar to our first study, montelukast and mesalazine were selected as model compounds; they are poorly soluble compounds, with pH-dependent solubility and recommended to be mixed with vehicles to facilitate paediatric administration. The structures of montelukast sodium and mesalazine are presented in Fig. 1, respectively. Two formulations of each drug were studied (montelukast: Singulair® granules and Actavis® chewable tablets; mesalazine: Pentasa® and Salofalk® granules).\nFig. 1 Chemical structure of a montelukast sodium and b mesalazine (ChemDraw Professional 18.1)","divisions":[{"label":"title","span":{"begin":0,"end":12}},{"label":"p","span":{"begin":13,"end":389}},{"label":"p","span":{"begin":390,"end":1214}},{"label":"p","span":{"begin":1215,"end":3695}},{"label":"p","span":{"begin":3696,"end":4381}},{"label":"p","span":{"begin":4382,"end":5459}},{"label":"label","span":{"begin":7047,"end":7053}}],"tracks":[{"project":"2_test","denotations":[{"id":"33063245-23688279-28116","span":{"begin":289,"end":290},"obj":"23688279"},{"id":"33063245-24556465-28117","span":{"begin":291,"end":292},"obj":"24556465"},{"id":"33063245-27704550-28118","span":{"begin":653,"end":654},"obj":"27704550"},{"id":"33063245-22554162-28118","span":{"begin":653,"end":654},"obj":"22554162"},{"id":"33063245-26173937-28118","span":{"begin":653,"end":654},"obj":"26173937"},{"id":"33063245-26173937-28119","span":{"begin":967,"end":968},"obj":"26173937"},{"id":"33063245-22677416-28119","span":{"begin":967,"end":968},"obj":"22677416"},{"id":"33063245-16100296-28119","span":{"begin":967,"end":968},"obj":"16100296"},{"id":"33063245-18691989-28120","span":{"begin":1165,"end":1166},"obj":"18691989"},{"id":"33063245-32592045-28121","span":{"begin":1768,"end":1770},"obj":"32592045"},{"id":"33063245-32592045-28122","span":{"begin":2036,"end":2038},"obj":"32592045"},{"id":"33063245-9156957-28123","span":{"begin":2235,"end":2237},"obj":"9156957"},{"id":"33063245-24934549-28124","span":{"begin":2392,"end":2394},"obj":"24934549"},{"id":"33063245-24393551-28125","span":{"begin":2481,"end":2483},"obj":"24393551"},{"id":"33063245-18048412-28126","span":{"begin":2484,"end":2486},"obj":"18048412"},{"id":"33063245-18048412-28127","span":{"begin":2550,"end":2552},"obj":"18048412"},{"id":"33063245-24934549-28128","span":{"begin":2870,"end":2872},"obj":"24934549"},{"id":"33063245-18048412-28129","span":{"begin":2955,"end":2957},"obj":"18048412"},{"id":"33063245-21818695-28130","span":{"begin":2958,"end":2960},"obj":"21818695"},{"id":"33063245-21876444-28131","span":{"begin":3691,"end":3693},"obj":"21876444"},{"id":"33063245-23728620-28132","span":{"begin":4849,"end":4851},"obj":"23728620"},{"id":"33063245-23988843-28133","span":{"begin":5077,"end":5079},"obj":"23988843"},{"id":"33063245-29971768-28134","span":{"begin":5455,"end":5457},"obj":"29971768"}],"attributes":[{"subj":"33063245-23688279-28116","pred":"source","obj":"2_test"},{"subj":"33063245-24556465-28117","pred":"source","obj":"2_test"},{"subj":"33063245-27704550-28118","pred":"source","obj":"2_test"},{"subj":"33063245-22554162-28118","pred":"source","obj":"2_test"},{"subj":"33063245-26173937-28118","pred":"source","obj":"2_test"},{"subj":"33063245-26173937-28119","pred":"source","obj":"2_test"},{"subj":"33063245-22677416-28119","pred":"source","obj":"2_test"},{"subj":"33063245-16100296-28119","pred":"source","obj":"2_test"},{"subj":"33063245-18691989-28120","pred":"source","obj":"2_test"},{"subj":"33063245-32592045-28121","pred":"source","obj":"2_test"},{"subj":"33063245-32592045-28122","pred":"source","obj":"2_test"},{"subj":"33063245-9156957-28123","pred":"source","obj":"2_test"},{"subj":"33063245-24934549-28124","pred":"source","obj":"2_test"},{"subj":"33063245-24393551-28125","pred":"source","obj":"2_test"},{"subj":"33063245-18048412-28126","pred":"source","obj":"2_test"},{"subj":"33063245-18048412-28127","pred":"source","obj":"2_test"},{"subj":"33063245-24934549-28128","pred":"source","obj":"2_test"},{"subj":"33063245-18048412-28129","pred":"source","obj":"2_test"},{"subj":"33063245-21818695-28130","pred":"source","obj":"2_test"},{"subj":"33063245-21876444-28131","pred":"source","obj":"2_test"},{"subj":"33063245-23728620-28132","pred":"source","obj":"2_test"},{"subj":"33063245-23988843-28133","pred":"source","obj":"2_test"},{"subj":"33063245-29971768-28134","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#939aec","default":true}]}]}}