Pediatric Formulations

Milap C. Nahata Professor of Pharmacy, Pediatrics and Internal Medicine Ohio State University Columbus, Ohio

Need for Pediatric Formulations

25-40% of the world population is below 18 years of age Affected by acute and chronic diseases Pediatric patients have unique physiology, drug PK/PD and safety features Medicines do not work unless taken in proper amount and formulation

Lack of Drug Formulations

Three-fourths of drugs approved for adults not fully labeled for infants and children Unlabeled drugs often not available in proper formulations Many of these have potential uses in pediatric patients

Pediatric Drug Formulations

Liquid: drops, syrups, suspensions Tablets (regular, chewable, disintegrating) and capsules Parenteral (e.g., IV, IM, SC) Topical (cream, ointment, patch) Rectal

Oral and IV Formulation Needs

Infants, young children (<5 yr), patients with dysphasia or in ICU, unable to swallow solid dosage forms Doses tailored for body weight Volume of IV drugs from adult formulations too small for accuracy of doses for infants

Newer Anticonvulsants
Gabapentin (solution) Levetiracetam (solution) Lamotrigine (chewable/dispersible tablet) Topiramate (tablet/capsule) Tiagabine (tablet) Zonisamide (capsule) Oxcarbazepine (tablet)

Older Anticonvulsant
Clonazepam approved for infants and young children at initial dose of 0.01-0.03 mg/kg/d (BID-TID) Typical dose: 0.05-0.1 mg Only available as tablets (0.5, 1, and 2 mg each)

Oral Captopril Formulations

Dose in infants: 0.1-0.3 mg/kg Typical dose: 0.3-1.0 mg Available as 12.5, 25, 50 and 100 mg tablets

Options in the Absence of Oral Drug Formulations

Refuse or delay therapy Call manufacturer Prepare powder packets or capsules (time consuming) Prepare a liquid based on limited or no data

Reasons for Lack of Labeling

Only 5-10% of the market (smaller population, fewer chronic diseases) Delays approval for adults Complexity and cost of clinical studies Will use it anyway

Preparation of Oral Drug Formulations

Most drugs incompletely soluble Suspending agents: 1% methycellulose or commercially available preparations Syrup (e.g., Simple, Cherry) added Flavors, preservatives?

Pharmaceutical Ingredients and Excipients

Solvents/diluents, fillers and binders Suspending agents Flavors Colorants for appearance Sweeteners Preservatives

Commercially Available Liquid Vehicles

Ora-Plus, Ora-Sweet, Ora-Sweet SF and Ora-Blend (Paddock Lab, MN) SyrSpend SF (Gallipot Inc, MN) VersaBlend (Humco, TX) Citrucel (1% methylcellulose: 0.5 g in 50 ml water)

Dosage Form Development

Drug dissolution and bioavailability depends on particle size, solubility, pH and membrane permeability, etc. Physical and chemical suspendability, dose uniformity and palatability, efficacy, safety Packaging and storage

Drug Stability
Hydrolysis (reduce water; use glycerin, propylene glycol, alcohol, etc.) Oxidation (use sodium sulfite at high pH bisulfite at intermediate pH and metabisulfite at low pH, or ascorbic acid or hydrophosphorous acid) Storage at cool temperature decreases hydrolysis and oxidation

Stability Assessment
Chemical, physical, microbiologic, therapeutic and toxicologic Shelf-life >2 years for manufactured and days months for extemporaneous products Use USP guidelines

Analytical Methods
Accuracy Precision Specificity Stability-indicating Ruggedness

Captopril Stability
(Nahata et al. AJHP 1994)
Formula Captopril, 1 mg/mL Ascorbic Acid, 5 mg/mL in distilled water Temp Stability

4OC 22OC

8 weeks 4 weeks

Captopril, 1 mg/mL in purified water

4OC 22OC

2 weeks 1 week

Sildenafil Stability
No oral medication for pulmonary hypertension Use Viagra (25 mg) or Revatio (20 mg) tablet? Sildenafil, 2.5 mg/ml stable in 1% methylcellulose/syrup (1:1) or OraPlus/OraSweet (1:1) at 4o C and 22o C for 3 months

Taste and Flavor Perceptions (Clin Ther 2008;30:2120-32)

Five primary taste qualities: sweet, sour, salty, bitter and unami (savory) G-protein coupled receptors (GPCRs) play the most prominent roles Olfactory receptors (7-transmembrane GPCRs) consists of >1000 genes Well developed before birth

Palatability of Formulations
Infants and children prefer sweet taste (sucrose reduces pain in infants perhaps via endogenous opioid system) Sodium salts reduce bitterness (ranitidine, acetaminophen, pseudoephedrine) Preferences may vary among countries (bubble gum/grape in US, citrus/red berry in Europe and liquorice in Scandinavia)

Poorly Tasting Drugs

Captopril Clindamycin Dexamethasone Dicloxacillin Furosemide Iron Sulfate Metronidazole Midazolam Omeprazole Phenobarbital Prednisolone Prednisone Ranitidine TMP/SMX

Masking Taste of Unpalatable Drugs (Clin Ther2008;30:2102-11)

Bitter drugs: cocoa flavor Sour or acid-tasting drugs: fruit or citrus Salty drugs: cinnamon, orange, raspberry

Vehicles to Make Drugs Palatable: Top 10 List

1. Chocolate syrup or chocolate milk 2. Chocolate pudding 3. Cola beverage or Coke syrup 4. Cherry syrup 5. Popsicle

6. Rootbeer cola 7. Strawberry syrup 8. Peppermint 9. Peanut butter or Nutella 10.Orange juice

FlavoRx expensive

Pediatric Color and Flavor Preferences (Age 5-6 Yrs)

Color Red Green White Blue Brown Yellow % (n=25) 28 20 20 16 12 4 % (n=25) Bubblegum 38 Cherry 20 Mint 20 Banana 11 Liquorice 11 Flavor

Intravenous Drugs
Often too concentrated for use in infants/young children Measurement errors with small doses (<0.1 ml) Intoxication has occurred with digoxin and morphine

Compounding Sterile Preparations

Use USP guidelines (also available from ASHP) Absence of viable microorganism (it is sterile or it is not) Acceptable level of pyrogens (ideally none) Assure sterility during storage

Simulating Clinical Conditions

Drug concentrations Storage conditions (e.g., vials, temperatures and time) Diluents and compatibilities with other IV drugs

Injectable Drugs: Stability and Sterility

Methylprednisolone 40 to 4 mg/ml (Bacteriostatic water for injection) Lorazepam 4 to 1 mg/ml (same as above) Morphine 10 to 1 mg/ml (Bacteriostatic 0.9% sodium chloride injection) Clindamycin 150 to 15 mg/ml (same as above) Stable and sterile for 3 months at 4C

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Medication Safety
Dosing errors (e.g., calculations, measurements) Slurry and suspension more difficult than solutions to measure doses Excipient safety (e.g., propylene glycol, sorbitol, benzyl alcohol) Bacterial contamination

Administration Devices for Childrens Medicines

Device Measuring spoon Teaspoon Syringe (no needle) Cylindrical measure
J Appl Ther Res 2004

Device used by parent % (n=25) 52.0 20.0 16.0 4.0

Device selected by children % (n=25)__ 38.5 38.5 15.3 7.7

Preventing Bacterial Contamination (AJHP 2003; 60:2563)

Reinstate sterile compounding teaching Certify pharmacists and accredit pharmacies Clean room/barrier isolators Follow USP guidelines Enforce standards (NABP)

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Safety of Compounded Formulations?

Anecdotal adverse event reported to FDA over 15 years showed 2.53 deaths/year with compounded formulations Pharmacies not required by FDA to report adverse events to FDA so more may be occurring

Extemporaneous Formulations (J Pediatr Pharmacol Ther 2001)

Adequate data 76

Some data; need more 109 No Data 103

Need for Regulatory Changes

28 of 108 drugs on USP list of needed pediatric formulations available in UK, EU and Australia Few package inserts helpful (benazapril, clonazepam, lisinopril, losartan, rifampin)

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Challenges for Developing Countries

Are medicine, excipients, clean water and recipes available? Who can accurately prepare a formulation? Can quality be assured? Can it be packaged, transported and stored under refrigeration? Can caregivers pay and manage therapy? Will adherence be assured?

Challenges and Limitations I

Stability and sterility data Bioavailability, PK and PD studies Efficacy and safety concerns Funding for research

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Challenges and Limitations

Variations in formulations Coordination and sharing of data Reimbursement and payment issues Adverse event reporting

Potential Solutions
Develop prioritized list Give incentive to industry Improve package information e.g., for rifampin Fund center(s) for research Share research and experience Collaborate US, EU, WHO

Summary
Needs for extemporaneous formulations will continue Formulations should be prepared and used based on evidence Funding and incentives should be enhanced Regulatory changes and global collaborations are needed

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