Pharmaceutical Development: Paediatric Formulations - Drug ...

Pharmaceutical Development: Paediatric Formulations

Mr Terry B Ernest

03/11/2009

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Presentation Content • The Need for Paediatric Medicines • The Challenges associated with Developing Medicines for Children – Physiological differences across age groups • The Opportunity to ‘Focus on the Patient’ – Developing age appropriate products which are safe, tolerable and offer dose flexibility

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The Need • ‘Don’t waste money on shop cough remedies’. Daily Telegraph, 23rd January 2008, p10

• ‘U.K. Pulls Plug On Some Cough/Cold Products For Children Under 2’. 27 Mar 2008 Health News Daily

• Hospital incidences of overdosing. Multiple references.

• ‘She will only take the banana flavour’. Desperate Parent!

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The Challenge • Physiological and ADME differences between children & adults – Critical that we draw upon and exploit available knowledge

• Cater for appropriate paediatric stratum – Internationally agreed definitions “Know your patient”: – – – – –

Preterm newborn infants Term newborn infants (0 to 28 days); Infants & Toddlers (>28 days to 23 months) Children (2 to 11 years); Adolescents (12 to 16/18 years)

• Developmental variability through to adulthood – Careful when using age or weight criteria alone

• Development of specific formulations for paediatric dosing – Children’s compliance and effective dose administration – ‘Child-proof’ medicines

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Children are Different

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Developmental Variability Through to Adulthood Age and Physical State Age

Mass (kg)

Surface Area (cm2)

Surface/Mass ratio (cm2/kg)

Neonate

3.4

2,100

617.6

6 months

7.5

3,500

466.7

1 year

9.3

4,100

440.9

4 years

15.5

6,500

419.4

10 years

30.5

10,500

344.3

70

18,100

258.6

Adult

S Werfel et al, Besonderheiten der topischen, Hautarzt 49 (1998) 170-175)

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Factors Affecting Absorption/Bioavailability • Oral – – – –

Gastric pH/residence/volume etc GI transit rate Pre-systemic metabolism CYP450/PgP activity etc

• Other – Skin permeability (topical/transdermal) – Inspirational velocity (inhalation products)

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Product Development Considerations • Drug delivery route • Tolerability (e.g. taste) • Dose flexibility • Excipients www.diahome.org

Drug Delivery Route - Inhaled • • •

Airway anatomy differs in adults and children. Mostly fixed doses or combined doses. Metered Dose Inhalers (MDI) – require coordination during use – spacers can be used but they are bulky and inconvenient and different spacer models can lead to different exposures.

•

Dry Powder Inhalers (DPI) – inspirational force differences in younger children. – Children under 5years do not generally have enough inspirational force.

•

Nebulisers with air compressors – Relatively passive means of delivering inhaled drugs – Bulky, inconvenient & heavy! – Can result in imprecise dosing although some flexibility possible and There may be constraints in terms of total dose possible (compliance over long periods of dosing).

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Drug Delivery Route - Oral •

Tablets and capsules offer advantages such as stability, accuracy, portability, greater opportunity of modified release, but are not suitable for younger children Tablets/capsules

Oral liquids

Age From Schirm E et al. Lack of appropriate formulations of medicines for children in the community. Acta Paed 2003; 92: 1486-9

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Drug Delivery Route - Oral • Liquid formulations such as solutions, syrups, suspensions are the most appropriate for younger children who are unable to swallow capsules or tablets. – Taste can be an issue for liquid formulations – Dose volume is important, e.g.