Development and Preparation of Oral Suspensions for Paediatric Patients – a Challenge for Pharmacists

Introduction

Licensed medicinal products manufactured by the pharmaceutical industry are often not appropriate for the safe use in paediatric patients. Since the Paediatric Regulation came into effect in 2007, applications for marketing-authorisation of new medicinal products have to come along with a paediatric investigation plan (PIP). Of note, this refers only to medicinal products containing new active pharmaceutical ingredients (API) and has been successfully performed in some cases. By contrast, the marketing-authorisation of PUMA (paediatric-use marketing authorisation) has not reached the expected level [1]. Therefore pharmacists have to fill the gap in order to ensure the supply of appropriate dosage forms for paediatric patients. Innovative dosage forms, like orodispersible mini-tablets or orodispersible films, provide fixed single doses. The fixed single doses are a major drawback of these dosage forms because the administered dose depends on the weight and age of the patients. Mini-tablets may improve the flexibility in dosing by multiplying the number of single doses [2]. Nevertheless, oral liquid dosage forms represent the gold standard for paediatric patients because they allow appropriate dosing by means of withdrawing the appropriate volume from a multiple dose container.

Discussion

Prior to the preparation the added value of the pharmacy preparations prepared for the specific need of the patients has to be determined. Pharmacy preparations have to be prepared according to the regulations and an appropriate quality assurance system. Efficacy, safety and quality are essential objectives of the specific dosage forms prepared in pharmacies. Two-phase systems like suspensions present one of the most challenging dosage forms.

Basic considerations

The challenge for pharmacists is to prepare stable suspensions of appropriate concentrations, which allow safe and easy administration of the prescribed dose in each paediatric patient of the different age groups [3, 4].

The aim should be the limitation of excipients, because they may cause adverse effects. Issues to be regarded are:

1. Availability of the active pharmaceutical ingredient (API) fulfilling the specifications of the Pharmacopoeia or availability of solid dosage forms, such as tablets or capsules to be used as starting material

2. Stability of the API in the suspension vehicle (e.g. low solubility to avoid crystal growth of suspended particles, concentration of API in the dissolved phase of suspensions)

3. Compatibility of the excipients and stability of the formulation

4. Appropriate particle size of the API

5. Slow settling and, when shaken, readily dispersed

6. Availability of toxicological data regarding the excipients and suitability for formulations for paediatric use

7. Choice of preservatives

8. Choice of thickening agents

9. Choice of sweetener

10. Avoidance of additional wetting agents, e.g. polysorbate or polyvidone

11. Avoidance of flocculating agents, because the choice depends on the API and its concentration

12. Avoidance of flavouring agents due to their individual acceptance and age-appropriate use. Furthermore the choice would depend on the taste of the API

13. Setting to the desired pH-value

14. Palatability and acceptability

Preservatives

The most common preservatives used in liquid formulations are sodium benzoate, sorbic acid/potassium sorbate, methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate [5, 6, 7]. Clinical data about the toxicity of the compounds are rare. Some recommendations are made by the European Medicines Agency for the use of preservatives in children. Sodium benzoate and benzoic acid may displace bilirubin from albumin. Especially in newborns up to the age of eight weeks benzoic acid can accumulate and lead to clinical jaundice. Methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate may cause allergic reactions. The latter one binds to the oestrogen receptor and influence the maturation of the reproductive system. However, the hydroxybenzoates are widely used because they are effective in the pH interval of 1 to 8.5. Propylene glycol is sometimes used as preservative in oral formulations. Pharmacokinetic in neonates differs significantly from adult values leading to its accumulation following repeated administration and can cause alcohol-like symptoms. For children up to 5 years the maximum daily intake must be under 50 mg/kg/day and 1 mg/kg/day for pre-term and term neonates [8]. Comparing the risks and suitability of these preservatives (see Table 1), potassium sorbate shows the best risk-benefit-relationship but the effectiveness is limited to a pH-range of 3.5 to 5.5.

Thickening agents

Oral liquids containing active substances with low aqueous solubility often result in two-phase systems (solid particles dispersed in the liquid). Thickening agents increase the viscosity of the aqueous solution and prevent fast sedimentation of suspended particles and caking. Some of these substances may also increase the stability of suspensions due to their surfactant activity. Well-known thickening agents are semi-synthetic polysaccharides, e.g. hydroxyethylcellulose or hypromellose, and natural polysaccharides such as tragacanth and xanthan gum (see Table 2). Unfortunately, xanthan gum is not marketed in small quantities appropriate for pharmacies and with certified pharmaceutical quality. Raw-material suppliers in small amounts deliver tragacanth, but the microbiological burden must be considered and eventually the suspension vehicle has to be sterilized. Hydroxyethylcellulose (HEC) does not cover the bitterness of active substances such as tragacanth does. However, HEC is readily available on the market in assured quality, can be used in a wide pH-range, shows solubility in hot or cold water and exhibit the above-mentioned surfactant activity. These characteristics qualify HEC as advantageous thickening agent. One of the marketed suspension vehicles contains pregelatinised starch as thickening agent. This excipient is rather unknown and not available in certified pharmaceutical quality for pharmacy use [9, 10, 11].

Sweeteners

Sucrose is hydrolysed in the intestine to the monosaccharides glucose and fructose, which should avoided for paediatric patients suffering from fructose intolerance. Sorbitol and Sorbitol solution are also contraindicated to these patients and may cause osmotic diarrhoea, whereas an acceptable daily intake for artificial sweeteners like sodium saccharin, sodium cyclamate or aspartame must be appropriately taken into consideration. At high concentrations they may evolve a bitter aftertaste [12]. Therefore, glucose monohydrate seems to be the most suitable sweetener in spite of its caloric value and its risk to promote dental caries.

Stability

Undissolved substances are not subject to degradation and hydrolysis as if they are dissolved.

In suspensions, on the other hand, the particle size plays a significant aspect in physical stability. In order to influence the sedimentation rate the density and the viscosity of the medium should be adjusted to the particle size, as well as a narrow and small particle size distribution should be preferred.

Experimental stability testing is required to validate the preparation, distribution and the determination of the maximum shelf life and in-use stability after opening the container

Occasionally the lack of active pharmaceutical ingredients requires the use of tablets or capsules as starting material. In these cases the impact of the excipients contained in the solid oral dosage forms on the compatibility and stability of the resulting suspension must be considered. Furthermore the API content of the tablets and capsules used as starting material determines the content of the API in the extemporaneous preparation and has to be checked.

Marketed suspension vehicles

In Germany, a composition of a suspension vehicle, which can prepared in pharmacies, was published in 2001[13]. However, many pharmacies use industrially manufactured suspension vehicles [14], because they allow quick and easy preparation of oral formulations (see Table 3). The most important advantage of ready-to-use-vehicles is the proven stability of the products and provision of stability data for a huge number of APIs by the manufacturers of the suspension vehicles. This allows quick and easy preparation of oral liquid suspensions of many different APIs in every pharmacy. On the other hand marketed suspension vehicles can cause a relationship of dependence and may be subjected to product recalls and supply shortages. Such a recall and failure of deliver occurred in Germany at the end of 2017 for one of these products and caused a state of emergency especially in local pharmacies. Alternatives were not readily available and the company not able to predict the renewed availability.

Another disadvantage of the marketed suspension vehicles are the different and sometimes non-suitable ingredients for patients of special age groups. Some preservatives used in these products are not appropriate for the use in new-born or premature infants. Of note, vehicles without preservatives are problematic because of the microbiological instability of the multiple dosage form.

Development of an alternative compounded suspension vehicle

In order to overcome these disadvantages a dedicated suspension vehicle, which can be prepared by every pharmacy or ordered as ready-to-use vehicle from a pharmaceutical manufacturer, was developed in a joint project of Deutscher Arzneimittel-Codex/Neues Rezeptur-Formularium (DAC/NRF) and other groups, e.g. hospital pharmacists. Currently stability studies of this particular suspension vehicle are performed with the 10 most often used APIs in paediatric patients [15].

Conclusion

In spite of new regulations and the development of promising new dosage forms, the preparation of suspensions for the special needs of paediatric patients remains an important assignment in pharmacies. Whenever a marketed suspension vehicle is not available or not suitable, e.g. for newborn, pharmacies should be able to prepare a preparation for the particular needs. Due to the different components contained in suspensions stability testing and validation is commonly performed by validated high performance liquid chromatography (HPLC). Therefore sharing of information and cooperation in the development and analytics of suitable formulas are essential both on the national and international level of the professional bodies.