Many drugs frequently used in infants and young children are not available in suitable dosage forms. Liquid dosage forms must be prepared extemporaneously, while using appropriate excipients. However, it is critical to determine the stability of various drugs at clinically important concentrations and practical storage conditions. It is of concern that few funding agencies are willing to support research on the development of stable liquid dosage forms for pediatric patients. The need for such data will continue, because it is unlikely that all drugs approved for adults will also be labeled simultaneously for potential use in infants and children. Presentations and publications on stable drug formulations will offer the opportunities for pediatric patients to receive the desired drugs and doses most effectively and safely.
Drug therapy plays an essential role in the management of infants and children suffering from a variety of acute and chronic diseases. The majority of drugs approved by the US Food and Drug Administration (FDA) for adults, however, have not been approved for use in pediatric patients. It is important to note that many of such medicines are used frequently in infants and children. One of the major impediments for their use, however, is the lack of suitable pediatric liquid dosage forms.1,,2 Most of the medications are available either as tablets, capsules, or solutions for injection. For example, captopril is currently available as tablets of 12.5 mg, 25 mg, 50 mg, or 100 mg each. The amount required in a newborn infant could be 0.1–0.2 mg/kg per dose. No liquid dosage form is commercially available to administer this dose based on body weight. In addition, the stability of captopril in a liquid vehicle must be known for storage in prescription bottles for continued therapy. The stability data are lacking for numerous drugs frequently used in pediatric patients.
In the absence of the stability data, it is difficult to provide an appropriate liquid dosage form of medications for infants and children. Moreover, either because of the lack of data or because of liability concerns, the manufacturers often are unable to recommend any formulation that has not been FDA-approved for pediatric patients. Research data are limited by an extremely low priority for funding of the stability studies by government, industry, or professional associations. The purpose of this article is to highlight the scope of this challenge and offer some potential solutions.
DRUGS NOT IN LIQUID FORMULATIONS
A large number of both old and new drugs used in infants and children are not in liquid dosage form. A list of such medications is provided in Table 1. This list is not comprehensive and only represents examples. When these drugs are prescribed, either a crushed tablet or contents of a capsule can be mixed with solid food or with a palatable drink. These steps require preparation of each dose by the caregiver and may result in delivery of incomplete doses or errors in dosage preparation. A preferred alternative would be to have a pharmacist prepare an extemporaneous liquid dosage form of the drug.
PREPARATION OF EXTEMPORANEOUS LIQUID DOSAGE FORMS
The contents of tablets or capsules, including the active drug and other inactive components or excipients, generally are mixed with an appropriate liquid vehicle to prepare an extemporaneous liquid dosage form. Most drugs are not completely soluble in water, thus, a suspending agent such as methylcellulose or carboxymethylcellulose is used. Agents such as antioxidants may be added to increase stability. Syrup and flavors improve palatability. Preservatives sometimes are added to minimize microbial growth during extended storage.
The suspension should dispense drug particles uniformly on brief shaking of the bottle, so that the desired dose is measured accurately. It should not be filtered, because of the possibility of losing active drug. The drug should be stable during the intended duration of therapy. Finally, it should be palatable and easy to prepare and store.
Pure crystalline powders of drugs usually are not accessible to pharmacies. The use of intravenous drugs to prepare a liquid dosage form is generally cost-prohibitive. In addition, some of the intravenous drugs, eg, cefuroxime and enalapril, have poor bioavailability after oral administration. Some excipients such as propylene glycol in many intravenous drugs may be undesired in large amounts.3 Medication-induced pneumatosis intestinalis attributable to excessive sorbitol has been reported recently.4 Finally, the taste may be unacceptable.
ASSURANCE OF DRUG STABILITY
This is one of the most important steps in deciding whether a drug can be administered and stored in a liquid dosage form. The chemical stability is determined immediately after preparation and during storage, using an accurate, reproducible, specific, and stability-indicating analytic method such as high-performance liquid chromatography. The degradation product(s) should not interfere with the measurement of drug. In addition, the pH is determined on each study day. The physical stability is assessed from changes in appearance, color, or odor. The studies are performed simulating clinical conditions for drug concentration, storage temperature (under refrigeration and at room temperature), type of container (plastic or glass prescription bottles), while using easily accessible liquid vehicles (sugared or sugar-free, with or without flavors). At least 90% of the drug should remain as an active component during storage for it to be considered stable.
The patient acceptance of a liquid dosage form is primarily dependent on its palatability. A better-tasting drug is easier to administer to infants and young children and, thus, loss of drug from spillage during dose administration is minimized. In general, compliance may be enhanced with improved taste.
The taste of drug formulations should be evaluated in children by using a five-point hedonic (facial expression) scale.5 The overall taste perception should reflect initial taste, aftertaste, flavor, and texture of the formulations. Interestingly, taste is rarely studied in children, even for commercially available formulations. These studies generally are performed in adult volunteers. It is difficult to predict whether the Human Subjects Research Committee would approve such comparative studies in children.
FUNDING IN RESEARCH
When a new drug is marketed for adults, the manufacturer generally has little interest in supporting research on developing a liquid formation for infants and children. Unfortunately, this lack of interest continues for years and decades, unless the drug is labeled for pediatric patients. There are many reasons for this lack of enthusiasm, including limited resources, small size of the pediatric market, and possible liability. In some cases, the manufacturer may not share the stability data of a drug in a liquid dosage form because they have not evaluated its efficacy and safety in pediatric patients. In addition, some manufacturers believe that supporting an independent researcher to develop a drug formulation may violate FDA regulations, because this would lead to its use in children without adequate efficacy/safety studies in the pediatric population.
The FDA's Orphan Drug program is designed to support clinical studies, not to develop stable liquid dosage forms. In addition, the funding from this program is not targeted toward the labeling of drugs for pediatric patients. This work is considered too applied for the typical National Institutes of Health applications.
Professional associations have made a plea to manufacturers to make the appropriate formulations available to children. However, they do not have sufficient financial resources to support research in this area. Recently, the Council on Professional Affairs of the American Society of Health System Pharmacists (ASHP) urged the organization to “directly fund such research” because “errors can occur in dilutions and formulations, leading to patient harm.” However, the Board felt that the “direct funding of such research” was not primary responsibility of ASHP and that “ASHP should encourage others to develop pediatric dosage forms of drug products.”6Universities have supported pilot projects for the faculty, but such support generally is not sustained.
The National Institute of Child health and Human Development, through its Pediatric Pharmacology Research Units grant, should commit a small portion of its budget to developing stable liquid dosage forms of drugs for infants and children. Once the studies are conducted and results disseminated through peer-reviewed journals,7–9any pharmacist can prepare the dosage form for their patients. Although this article focused on liquid dosage forms, many intravenous drugs, available at high concentrations appropriate for adults, should be diluted for accurate measurement of very small volumes for infants. However, the stability and sterility of such diluted dosage forms must be documented before use in pediatric patients.10,,11
NEW REGULATIONS FOR PEDIATRIC LABELING
The new regulations of the FDA encourage the manufacturers to study their prescription drugs in pediatric patients.12However, limited resources will always lead to a lag time between the approved labeling for adults and children for most drugs. Special incentives such as patient extension or tax reduction may improve this situation in the future, but currently this is uncertain. Finally, many drugs may not be viewed important for children at the time of marketing for adults, and several years may lapse before this is apparent. Thus, the extemporaneous liquid dosage forms will continue to play an important role in clinical pediatrics.
Numerous drugs used in infants and children are not available in suitable liquid dosage forms. The development of extemporaneous dosage form requires selection of appropriate drug concentration and excipients, assurance of stability and palatability, and adequate funding. Sharing of the research findings on formulations through presentations and publications should lead to their improved use in infants and children. Our patients should not be expected to wait for years and even decades for the drug to be labeled for the pediatric population.
- FDA =
- US Food and Drug Administration •
- ASHP =
- American Society of Health System Pharmacists
- ↵Nahata MC, Hipple TF. Pediatric Drug Formulation. 2nd ed. Cincinnati, OH: Harvey Whitney Books Co; 1992
- ↵Crawford SY, Dambroski SR. Extemporaneous compounding activities and the associated informational needs of pharmacists. Am J Hosp Pharm. 1991;1205–1210
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- ↵Nahata MC, Morosco RS, Hipple TF. Stability of captopril in three liquid dosage forms. Am J Hosp Pharm. 1994;51:85–86, 1707
- ↵US Dept of Health and Human Services, Food and Drug Administration. 21 CFR Part 201 (Docket No. 92N-0165). Specific requirements on the content and format for labeling for human prescription drugs; revision of “pediatric use” subsection in the labeling. Federal Register. December 13, 1994; 59(258):64240–64250
- ↵Nahata MC, Hipple TF. Pediatric Drug Formulations. 3rd ed. Cincinnati, OH: Harvey Whitney Books Co; 1997
- Copyright © 1999 American Academy of Pediatrics