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Milap C. Nahata Professor of Pharmacy, Pediatrics and Internal Medicine Ohio State University Columbus, Ohio
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)
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
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
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)
6. Rootbeer cola 7. Strawberry syrup 8. Peppermint 9. Peanut butter or Nutella 10.Orange juice
FlavoRx expensive
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
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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
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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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