1. Drug Formulation in 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 Care Rainbow Babies and Children’s Hospital Cleveland, Ohio

5. Drug Treatment for 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

6. Drug Treatment for 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

7. Practical Issues in 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

8. Practical Issues in 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

9. Formulations Available for 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

10. Potent Medications with Potential for “Dilution Intoxication” Due to Concentration Available in Pharmaceutical Preparations Calculated Individual Dose Drug Available Concentration Volume (ml) Amount Dose Delivered with Flush Delivered Dose (% Calculated) Atropine0.4 mg/ml0.00250.01 mg0.016 mg160 Diazepam5 mg/ml 0.050.1 mg0.18 mg 180 Digoxin100 µg/ml 0.055 µg6.5 µg 130 Epinephrine1:10,000 0.1010 µg11.5 µg 115 Hydralazine20 mg/ml 0.051 mg1.3 mg 130 Insulin100 U/ml 0.0010.1 U0.115 U 115 Morphine8 mg/ml 0.0130.1 mg0.22 mg 220 Phenytoin50 mg/ml 0.084 mg4.75 mg 120

11. 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)

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

13. Recommended Drug Formulations for Infants and Children Oral solutions Oral suspensions Rapidly dissolving tablets Sprinkles/sachets Transcutaneous delivery systems Implantable reservoirs

14. The Pediatric Holy Grail An Oral Liquid Preparation

15. Statement of the Pediatric 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.

16. Is This What We Really Want / Need?

17. Pediatric Formulation Approaches Proprietary – Liquids, suspensions, chewable tablets Extemporaneous preparations –Compounded with known vehicles –Crushed solid dosage forms

18. 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

19. Issues Affecting Extemporaneous Preparations Stability Bioavailability Nonuniform composition Variable effect of food

20. 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

21. Results to Date Bona fide  Many antivirals  Atovaquone/proguanil  Ibuprofen/ pseudoephedrine  Gabapentin  Midazolam Extemporaneous “standardized”  Enalapril  Sotalol Sprinkles  Topiramate  Montelukast

22. “Bona Fide” Applications – Pediatric Antivirals ZidovudineOral Solution DidanosinePowder (reconstitute with antacid) LamivudineOral Solution AbacavirOral Solution NevirapineSuspension EfavirenzCapsules (50 mg for 7 kg patient) RitonavirSolution Nelfinavir mesylateOral Powder (mix with foods) AmprenavirOral Solution (propylene glycol) Lopinavir/RitonavirOral Solution AcyclovirOral Suspension RibavirinPowder for Inhalation Solution Oseltamavir phosphateSuspension