Oral Administration and Oral Liquid Preparations
6. Oral Administration:
The oral route is the preferred and most appropriate route of administration to paediatric patients. This route is generally acceptable in all age groups if the medicine is administered in a suitable dosage form, e.g. in liquid form for children in the youngest age groups who have difficulty in swallowing solid dosage forms. Strictly speaking, the choice of dosage form for oral administration depends on the gut function and, thus, on both age and clinical condition.
Consideration should be given to the effects of increased gastric pH and intestinal mobility at birth and in early infancy (2). In addition, gastric emptying of sick newborns is most erratic and can be delayed. Further information can be found in an EMA guideline on medicines for term and preterm neonates (31).
Mixing oral dosage forms with food or a beverage is not recommended, but may be performed to enhance compliance (see section 2.2). Potential effects of foods on bioavailability should be considered. When recommending mixing medicines with food, attention should be paid to the effect on the taste, as an unpleasant taste of medicine may cause aversion in children.
6.1 Oral Liquid Preparations:
Oral liquid preparations include aqueous solutions, suspensions, emulsions and
syrups. They are most appropriate for children in the youngest age groups who are
unable to swallow solid dosage forms. The advantage of oral liquid preparations
is that variable dose volumes can be measured and administered. The need for
stabilizing agents, e.g. antimicrobial preservatives, is a major drawback as is the
potential chemical instability, which may lead to a requirement for controlled storage conditions during distribution and use. Oral liquid preparations are less transportable than solid-dose preparations because of their relatively high bulk volume.
The dose volume is important for the acceptability of the preparation. High-dose volumes pose a risk of incomplete ingestion and, thus, underdosage. Efforts should, therefore, be made during pharmaceutical development to minimize the dose volume while recognizing the need to ensure accurate measurements of the dose over the anticipated range. Typical target dose volumes are 5 ml or less for children under 5 years and 10 ml or less for children of 5 years and older (32). There is some uncertainty about these limits because the more palatable the formulation, the higher the dose volume that will be accepted by the child. Target volumes and electrolyte contents are critical for neonates, especially in cases of immature renal function.
Oral liquid preparations may be supplied in multidose containers or single-dose containers. Usually, both forms require antimicrobial preservatives. Special attention has to be paid to the in-use stability of multidose preparations, both microbial and physicochemical.
Multidose preparations should be packaged together with an appropriate dosing device. The correct graduation of the device and the accuracy of the volumes measured must be checked by the manufacturer. Generally, oral syringes are preferable because of the flexibility in dose measurement and superior accuracy compared to other devices such as graduated pipettes or plastic spoons. The accuracy in measuring and delivering a volume of liquid is influenced by the liquid’s physical characteristics, especially its viscosity.
The risks associated with incorrect dosing should be considered. If correct dosing is critical, a single-dose preparation, e.g. a pre-filled oral syringe, should be considered.
Drops:
Some liquids are administered as drops in small volumes using a dropper or a graduated pipette to measure a volume to be dissolved or dispersed in water or another diluent before the dose is swallowed. The use of this dosage form should be evaluated using a risk-based approach to ensure it is suitable given the medicine’s potency and side-effect profile and the potential for dosing errors. The in-use performance of the dose-measuring device is critical for this dosage form.
Oral Suspensions:
Formulation of an oral suspension may be dictated by the aqueous solubility of the API and the balance between the dose of API and the dose volume. In certain cases, the unpleasant taste of an API can be reduced by choosing the suspended form.
Oral suspensions must be shaken before use to ensure a homogeneous liquid when the dose volume is measured. There might in some instances be a significant risk of dosing errors due to sedimentation or caking of the suspension during storage; therefore, resuspendability should be a stability parameter. The
control strategy for oral suspensions includes dissolution testing (18) unless otherwise justified.
Powders and Granules For Reconstitution:
Solid preparations for reconstitution as solutions or suspensions should be considered, especially when the liquid preparation has a short shelf-life due to instability (chemical, physical or microbiological). Powders and granules for reconstitution are produced as single-dose sachets or multi dose preparations,
usually provided in containers that can hold the reconstituted multi dose preparation. The liquid vehicle can be provided together with the dry preparation, especially when the product is intended for markets where access to clean water may be difficult. Alternatively, manufacturers can recommend on the product labels and summary of product characteristics (SmPCs) how to reconstitute the product, e.g. with boiled and cooled water.
To ensure their proper use, the solids must be easily wetted and dispersed or dissolved within a short time once the vehicle is added.
The major drawbacks of this type of formulation are the bulk volume of the preparation, i.e. it is less transportable, and the in-use microbial stability of multi dose preparations, which may require use of antimicrobial agents. For these reasons, single-dose preparations of the flexible types mentioned in section 3.1 are preferable.
Development of Paediatric Medicines: points to consider in formulation,
(Annex 5, WHO Technical Report Series 970, 2012)
