Drug Formulationin Pediatrics:

If it tastes bad it must be good for you

Jeffrey Blumer, Ph.D., M.D.Professor of Pediatrics and Pharmacology

Case Western Reserve University

Chief, Pediatric Pharmacology and Critical CareRainbow Babies and Children’s Hospital

Cleveland, Ohio

Determinants of Effective TherapyDeterminants of Effective TherapyPharmacokineticsPharmacokinetics

PharmacodynamicsPharmacodynamics PharmaceuticsPharmaceutics

• Absorption • Distribution • Metabolism • Excretion

• Absorption • Distribution • Metabolism • Excretion

• Mechanism of action • Safety profile• Mechanism of action • Safety profile

• Formulation • Inert ingredients • Taste

• Formulation • Inert ingredients • Taste

CHILDREN ARE

DIFFERENT

CHILDREN ARE

DIFFERENT

BUT — THEY'RE NOT MARTIANSBUT — THEY'RE NOT MARTIANS

Drug Treatmentfor Infants and Children

– The Challenge – Pediatric Patients are dynamic with respect to

drug disposition– Developmental changes in body

composition– Developmental changes in drug metabolism– Developmental changes in organ function

Drug Treatmentfor Infants and Children

– The Challenge – Pediatric patients are different with respect to drug

action– Ontogeny of receptor expression and function– Greater regenerative and recuperative potential– Unique disease processes– Patients with chronic diseases will undergo

growth and developmental changes during therapy

Practical Issuesin Pediatric Drug Dosing

Traditionally pediatric dosing is weight based (mg/kg)

Drug dose will often require change as the child grows

Parenteral dosage forms often require significant dilution prior to administration

Children are often unable to swallow pills or capsules until they are 6 (or 7 or 12 or never) years of age

Practical Issuesin Pediatric Drug Dosing

Complex solid dosage forms (e.g. sustained release preparations) are not engineered with consideration of pediatric GI physiology

Palatability is the major determinant of compliance with treatment with oral liquids and chewable/dissolving dosage forms

Dosing of young children generally depends on parent/guardian

Formulations Availablefor Treating Infants and Children Intravenous

– Solutions– Emulsions

Oral– Solutions– Suspensions– Elixirs– Syrups– Granules– Tablets– Effervescent tablets– Chewable tablets– Drops

Rectal– Solutions– Foams

Cutaneous– Creams– Ointments

Percutaneous– Patches

Potent Medications with Potential for “Dilution Intoxication” Due to Concentration Available in

Pharmaceutical PreparationsCalculated Individual

Dose

DrugAvailable

ConcentrationVolume

(ml) AmountDose

Delivered with Flush

Delivered Dose

(% Calculated)

Atropine 0.4 mg/ml 0.0025 0.01 mg 0.016 mg 160Diazepam 5 mg/ml 0.05 0.1 mg 0.18 mg 180Digoxin 100 µg/ml 0.05 5 µg 6.5 µg 130Epinephrine 1:10,000 0.10 10 µg 11.5 µg 115Hydralazine 20 mg/ml 0.05 1 mg 1.3 mg 130Insulin 100 U/ml 0.001 0.1 U 0.115 U 115Morphine 8 mg/ml 0.013 0.1 mg 0.22 mg 220Phenytoin 50 mg/ml 0.08 4 mg 4.75 mg 120

Pediatric Formulation Methods Bona fide pediatric formulations (e.g.,

drops, suspensions, chewable tablets or syrups)

Extemporaneous pediatric formulations made with “standardized” extemporaneous vehicles (e.g., NF, USP, or marketed vehicles)

Extemporaneous pediatric formulations made with food (e.g., sprinkles on applesauce or yogurt)

Determinants of the Typeof Formulation for Children Age Ability to handle solid dosage forms Disease / Disorder being treated

Recommended Drug Formulations for Infants

and Children Oral solutions Oral suspensions Rapidly dissolving tablets Sprinkles/sachets Transcutaneous delivery systems Implantable reservoirs

The Pediatric Holy GrailAn

OralLiquid

Preparation

Statement of thePediatric Pharmacy Advocacy Group

http://www.ppag.org/

For every new chemical entity and currently marketed drug still under patent, with or without safety and effectiveness data in children, where no oral liquid dosage form is available, the manufacturer should be required to provide a formulation that effectively converts an oral solid or intravenous dosage form to an oral solution or suspension dosage form.

Is This What We Really

Want / Need?

Pediatric Formulation Approaches

Proprietary – Liquids, suspensions, chewable tablets

Extemporaneous preparations

– Compounded with known vehicles

– Crushed solid dosage forms

Oral Formulations for Children– The Down Side –

Solutions often contain potentially toxic excipients

Suspensions often result in unequal drug delivery over time due to nonuniform dispersal

Suspensions often have palatability problems due to both taste and texture

Sprinkles/sachets often have erratic absorption Transcutaneous delivery systems depend on

uniform nature of integument

Issues Affecting Extemporaneous

Preparations Stability Bioavailability Nonuniform composition Variable effect of food

The Food Myth Generally accepted that food may

affect bioavailability “Not all applesauce is created equal”

S. Hirschfeld M.D., Ph.D.

Generally little impact No studies dealing with foods children

actually eat

Results to Date

Bona fide Many antivirals Atovaquone/proguanil Ibuprofen/

pseudoephedrine Gabapentin Midazolam

Extemporaneous “standardized” Enalapril Sotalol

Sprinkles Topiramate Montelukast

“Bona Fide” Applications – Pediatric AntiviralsZidovudine Oral SolutionDidanosine Powder (reconstitute with antacid)Lamivudine Oral SolutionAbacavir Oral SolutionNevirapine SuspensionEfavirenz Capsules (50 mg for 7 kg patient)Ritonavir SolutionNelfinavir mesylate Oral Powder (mix with foods)Amprenavir Oral Solution (propylene glycol)Lopinavir/Ritonavir Oral SolutionAcyclovir Oral SuspensionRibavirin Powder for Inhalation SolutionOseltamavir phosphate Suspension