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Pharmaceutical Development: Paediatric Formulations
Mr Terry B Ernest
03/11/2009
Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated. These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, DIA and DIA logo are registered trademarks or trademarks of Drug Information Association Inc. All other trademarks are the property of their respective owners.
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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.
