Administration Through Feeding Tubes and Oral Solid Dosage Forms
6.2 Administration Through Feeding Tubes:
For neonates and seriously ill infants, enteral administration of liquids via feeding tubes is used. Hence the preparation will not be subject to the normal effects of saliva and/or gastric juice, which may affect its bioavailability.
Dosing accuracy should be considered, taking into account the ease of transfer along the feeding tube (including viscosity, particle size and amount of suspended components), potential absorption of the API into the tube material and rinsing by flushing of the tube. The rinsing volume should be appropriate to the target age group and an acceptable fluid intake.
These considerations should be highlighted in the SmPCs.
6.3 Oral Solid Dosage Forms:
Oral solid dosage forms include a variety of final forms from powders to coated tablets intended to be swallowed directly or after application to the mouth (chewable tablets, orally dissolving tablets or orodispersible tablets). Some are intended for swallowing after dissolution, dispersion in water or other suitable liquids. Their advantages over oral liquid preparations are improved stability, good dosage uniformity and options for different doses. The ease of administration depends on the child and the particular dosage form. These forms are convenient for packaging and ease of transport.
While powders and multiparticulate preparations mixed with food or beverages may be acceptable from the moment when the infant is able to accept solid food, i.e. about 6 months, there are uncertainties with regard to the age at which intact tablets and capsules are acceptable. It has been thought generally
that even small tablets and capsules to be taken whole are not acceptable for children below the age of 6 years. However, no good scientific evidence exists to support this notion. Recent preliminary evidence indicates that mini-tablets (with a diameter of less than 4 mm) may be acceptable even by the majority of small children (2–4 years old) (33).
Powders and Multiparticulate Preparations:
Powders and multiparticulates are provided in sachets or in hard capsules that allow the contents to be taken directly or after manipulation, e.g. following preparation of oral liquids or to be sprinkled on to food or liquids.
Multiparticulate preparations are granules, rounded granules of uniform size (often called pellets) and mini-tablets. Pellets are often prepared by extrusion/spheronization technology, which produces uniform particles within the size range 0.5–2 mm. Mini-tablets are prepared by compression into units
with a diameter of not more than 4 mm. Especially when only a portion of the provided dose is administered, the particle size distribution of the API may be critical to dosing accuracy. Control of dose uniformity should be performed on a level corresponding to the dose to be taken by the target age group.
Multiparticulate preparations offer the same advantages as conventional tablets and capsules with regard to the use of excipients, opportunities for taste masking (e.g. by coating), stability and opportunities for modifying the release profile. Furthermore, they possess great flexibility. An age-related dose may be obtained by taking an appropriate number of pellets or mini-tablets. A counting device may be necessary when a large number of pellets or minitablets is required. In addition, pellets and mini-tablets are suited for the platform technology mentioned in section 3.2.
Immediate-Release Tablets:
Conventional tablets are either uncoated, film-coated or sugar-coated and are intended for immediate disintegration, release and absorption when swallowed. The coating may cover an unpleasant taste and smell and will, in general, improve palatability. Film-coating is preferable because sugar-coated tablets resemble sweets or candies and hence may be too attractive to the child. It is critical to differentiate the appearance of tablet packs from that of confectionery packs.
Break-marks intended to enable accurate subdivision of the tablet to provide doses of less than one tablet should be proven to result in parts that comply with the requirements for uniformity of mass or uniformity of content, as appropriate. The decision whether or not to provide scored tablets will depend
on a risk analysis, taking into account the safety and dose of the API. A suitable test is provided in the monograph on tablets in The International Pharmacopoeia (34). It is preferable that the single part of the broken tablet contains the amount of API suited to the youngest intended age group. Specially designed tablets and tablet punches may be needed.
Caregivers often crush tablets to increase user-friendliness and adherence. Crushing may, however, affect the bioavailability of some medicines. The effect of crushing of tablets should be investigated by the manufacturer and this information should be provided in the patient information leaflet.
Tablets should not be crushed unless instructions allowing crushing are provided on the label by the manufacturer. Generally a multiparticulate formulation supplied in sachets, hard capsules or blister packs is preferred.
Chewable Tablets:
Chewable tablets are intended to be chewed and swallowed. They should possess good organoleptic properties including a good mouth feel, which is influenced by the solubility, particle size and shape of the API, and they should not leave a bitter or unpleasant aftertaste. They are usually formulated with a high content of a water-soluble sweetener, such as mannitol, which provides a sweet, cooling taste,
and microcrystalline cellulose, which assists in obtaining a good mouth feel and reduces grittiness. Other sweetening agents such as sorbitol and xylitol suitable for direct compression are also used.
A potential problem with chewable tablets is that they may be swallowed by a patient before being properly chewed or without being chewed at all. It is, therefore, strongly recommended that chewable tablets are formulated so that they may be swallowed whole and, thus, labelled as “tablets that may be chewed or swallowed whole”, or “tablets that may be chewed, swallowed or crushed and mixed with food or liquid”.
It is a consequence of the above that tablets that may be chewed or swallowed whole should meet the quality requirements for conventional tablets, including dissolution testing. Where applicable, dissolution test conditions should be the same as used for conventional tablets of the same API, but
because of their non-disintegrating nature it may be necessary to alter the test conditions (18).
Effervescent Dosage Forms:
Effervescent dosage forms are tablets, granules or powders that are dissolved in water prior to administration. The use of these dosage forms usually requires a relatively large volume of water, the intake of which may be problematic for children. It is helpful when an indication of the minimum volume of water is given on the label. Furthermore, the label should give instructions that the solution is
not to be drunk before effervescence has subsided, in order to minimize ingestion of hydrogen carbonate. Effervescent tablets require continuous attention to levels of moisture and humidity during manufacture, packaging and storage.
The drawbacks of effervescent dosage forms are the need for clean water for dissolution and the ingestion of potassium or sodium, which may make them unsuitable for patients with renal insufficiency.
Dispersible and Soluble Tablets:
Dispersible and soluble tablets are intended to be used in the same way as effervescent tablets. Their advantage is that problems with hydrogen carbonate, potassium and sodium are avoided. For the convenience of users, the formulations should disintegrate or dissolve within a short time of being added to water. It is helpful when an indication of the minimum volume of water is provided on the label.
Dispersible and soluble tablets are flexible dosage forms, the formulation of which may be suited for several water-soluble APIs (see section 3.1).
Sustained-Release Formulations:
Sustained-release formulations are designed to slow the rate of release of the API in the gastrointestinal fluids. They may be provided in a variety of formulations, e.g. as multiparticulate solids provided with a barrier coating, in sachets, hard capsules or in quickly disintegrating tablets, coated tablets and matrix tablets. Among the advantages of the sustained-release design is the reduced dosing frequency compared to conventional formulations of the same API, a feature which may improve adherence (see section 2.3). Not all APIs can be formulated as sustained-release products. This will also depend on other factors such as aqueous solubility, intestinal permeability and plasma elimination half-life,
which may differ between children and adults.
In the development of sustained-release formulations for paediatric use, special attention must be given to the physiological conditions of the child to be treated and their variability, e.g. gastric pH and emptying rate and intestinal mobility.
The majority of sustained-release formulations, especially coated tablets and matrix tablets, must not be broken or chewed and some will not withstand being mixed with food or a beverage. It is, therefore vital that clear instructions on the proper use of the formulation are included on the label.
Capsules:
Capsule formulations are provided either as soft capsules, usually with a liquid or semi-solid content or as hard capsules containing powder or a multiparticulate formulation.
Capsules may be taken whole. The limitations mentioned for tablets apply with regard to the ability of the child to swallow them (see introduction to section 5.3). Hard capsules may be opened and their contents taken as such or taken after mixing with food or sprinkling on to food, but this is not always
appropriate.
Instructions on the proper use of a capsule formulation should be provided on the label, e.g. whether the capsule has to be taken whole or whether the capsule contents can be mixed with food to facilitate intake and improve palatability.
Orodispersible Dosage Forms:
Orodispersible dosage forms are orodispersible tablets, oral lyophilisates and thin films, to be placed on the tongue where they disperse rapidly into small-sized particles or “melt” by dissolution in the saliva, after which the dose is swallowed.
Orodispersible tablets designed to disintegrate rapidly are prepared by compression of a formulation containing, for example, mannitol, a superdisintegrant, and a flavouring agent. The amount of API that can be incorporated depends on its physical properties. The product may be moisture-sensitive.
Orodispersible tablets are flexible dosage forms (see section 3.1), particularly well-suited for highly water-soluble APIs.
Oral lyophilisates are prepared by freeze-drying of aqueous liquids into porous units shaped like tablets. Typical excipients are gelatin or alginate, which act as structure-forming agents, and mannitol, which facilitates formation of the porous structure and contributes to palatability. Instead of mannitol, sorbitol
may be used as a crystallization inhibitor. The amount of water-soluble API to be incorporated is limited (35). Oral lyophilisates are sensitive to moisture and require a vapour-tight package.
Thin, flat films (wafers) to be placed in the oral cavity are prepared by casting water-soluble polymers containing the API in dissolved or dispersed form. The amount of dissolved API that can be incorporated is limited. The release profile depends on the polymer, film thickness and API solubility. The so-called flash-release wafers may have dissolution times of less than 30 seconds.
Orodispersible and orosoluble dosage forms are attractive for several reasons. They may be acceptable to the same age groups as liquid preparations, and it is possible for children who cannot swallow a whole tablet to take an orodispersible dosage form. In some situations, especially with younger children, the orodispersible dosage form may need to be dissolved in a small volume of
liquid prior to administration.
Orodispersible dosage forms are intended for systemic effect after being swallowed but absorption may also take place in the mouth and pharynx. Taste masking may be necessary using water-soluble sweeteners and flavourings.
Development of Paediatric Medicines: points to consider in formulation,
(Annex 5, WHO Technical Report Series 970, 2012)
