PAEDIATRIC FORMULATIONS OR EXTEMPORANEOUS DOSAGE FORM FOR ORAL LIQUIDS

CHALLENGES AND LIMITATIONS
Lack of Stability/Sterility Studies
The use of some extemporaneous formulations in pediatric patients is based on experience rather than data from specific stability and sterility studies. [5,6] Furthermore, published clinical studies in pediatric patients may also lack information about the dosage forms used in those studies. Standing et al searched 10 highly cited journals (5 adult medicine and 5 pediatric medicine) for studies published over a 2-year period evaluating the use of oral medications in children aged <12 years. [12] They found that <40% of the 76 articles identified provided adequate information regarding the dosage form for the study to be accurately reproduced. In addition, 20% of the articles neglected to provide the formulation used in the study. These results thus question the validity and reliability of pediatric trials where oral dosage forms are utilized. Because highly cited journals have allowed studies with inadequate dosage form information to be published, the investigators hypothesized that less highly cited journals may tend to provide even less specific dosage form information, further decreasing reliability and validity of results. PubMed was searched using the terms administration, and oral or oral medication, limiting those results to the English language, those in children aged 0 to 12 years, and those published in the last 6 years (2001-2006). [13] This produced >650 citations, and the abstracts were analyzed for inclusion into the study. Initial review of the first 100 citations has produced results mirroring the findings of Standing et al and in some instances were worse; only 27% of studies provided adequate formulation information, 52% provided some, and 21% provided none. Interestingly, studies published in pediatric journals were more likely to provide no information than nonpediatric journals. More highly cited journals were no more likely to require authors to provide adequate information on the dosage form used than less-cited journals. Randomized, placebo-controlled, prospective trials did no better at reporting formulations than studies that were less rigorous. Only 43% of publications documented their administration procedure, and only 14% documented education if a caregiver or parent was responsible for administration. Fifty-two percent assessed and documented adherence, and only 10% documented palatability and tolerability (taste and acceptance [not adverse effects]). Only 3 citations used extemporaneous preparations, but none have cited stability data. In no instance did impact factor have a statistically significant effect on dosage form reporting. Investigators speculated that results may show a substantial problem in the pediatric clinical trial literature that could influence pharmacotherapy.[9]

Chemical instability
Drugs in extemporaneously prepared liquids may be susceptible to chemical reactions leading to degradation. The most common reactions are hydrolysis, oxidation and reduction.[14] Usually the reaction rate or type is influenced by pH, for example, azathioprine is rapidly hydrolysed to 6-mercaptopurine at alkaline pH but is relatively stable in acidic or neutral conditions. [15] Other factors which may increase the rate of reaction include the presence of trace metals which catalyse the oxidation of captopril. [16] methyldopa [17] or exposure to light which catalyses the oxidative degradation of 6-mercaptopurine. [18] The rate of chemical degradation usually increases with temperature, a factor which is the basis for accelerated stability trials of pharmaceutical formulations. Preparations made from tablets contain excipents such as binders and disintegrating agents in addition to the active drug. These excipients may reduce chemical stability by changing the pH to a value at which more rapid degradation occurs. This probably explains why amiloride solution prepared from pure drug is more stable than an oral liquid prepared from tablets.
The drug in the preparation may be totally or partially in solution or predominantly in the solid state as a suspension. Drugs in solution are more susceptible to chemical degradation than drugs in the solid state (ie. suspensions), thus suspensions of acetazolamide and chlorothiazide are more stable than solutions.[19,20] However it cannot be assumed in all cases that an extemporaneously prepared suspension is more stable than a solution. In a suspension, an equilibrium exists between drug in the solid state and drug in solution and even though the amount of drug dissolved may be minimal the conditions could be optimal for degradation. Frusemide is a notable example which undergoes hydrolysis in acidic conditions where the solid state is predominant, but is much more stable at alkaline pH where it is totally in solution.[21]

Microbiological Instability
Microbial growth in an oral liquid may cause foul odour and turbidity and adversely effect palatability and appearance. High titres of micro-organisms may be hazardous to health especially in very young or immunocompromised patients. By-products of microbial metabolism may cause a change in the pH of the preparation and reduce the chemical stability or solubility of the drug. Microbial contamination during preparation must be minimised by using clean equipment, sterile water (Water for Irrigation BP) and avoiding contaminated raw materials and containers. If sodium benzoate or benzoic acid are used as antimicrobial preservatives the final pH must be less than 5 so that the active unionised form is predominant. Consequently the drug must also be stable at this pH. Effective preservative systems require rigorous evaluation which is seldom performed on extemporaneous formulations. Many factors can reduce the effectiveness of the preservative including use of contaminated materials, chemical degradation, binding of preservative to suspending agents or tablet excipients, incorrect storage or unhygienic use of the final product. [22]

Physical Instability
Extemporaneously prepared oral suspensions may be susceptible to sedimentation of insoluble drug causing caking. Difficulty in re-suspending the drug or rapid sedimentation following shaking can lead to erratic dosage measurement as demonstrated with chlorothiazide suspension and this inherent problem with extemporaneously prepared formulations is of considerable concern. Some spironolactone suspensions have been reported to be excessively thick and almost un-pourable. Refrigeration, whilst usually desirable to maximise chemical stability and reduce microbial growth, can also increase the viscosity of a suspension making re-suspension more difficult or cause the precipitation of active drug or preservatives. It is important to consider the effect on pH of all components of the formulation and the possible impact on stability. Syrup, for example, is relatively acidic and if used in phenobarbitone sodium oral solution it will cause the precipitation of unionised phenobarbitone. [23-25]

Lack of Bioavailability and Pharmacokinetic/ Pharmacodynamic Studies
Bioavailability and pharmacokinetic/pharmacodynamic studies are rarely conducted for most extemporaneously prepared medications. When a tablet or capsule with regular-release characteristics is used to prepare a suspension, it is assumed that the bioavailability and pharmacokinetics/pharmacodynamics will not be compromised in patients. However, those sustained-release properties can be lost when a tablet is crushed and converted to a liquid dosage form before administration. Bioavailability, pharmacokinetic, and pharmacodynamic studies are unlikely to be performed for most extemporaneous drugs due to lack of financial resources and the complexity of performing these studies at most health care facilities. Thus, treatments involving extemporaneous formulations should be observed to monitor efficacy and tolerability of these products in patients. [7]

Efficacy and Safety Concerns
Extemporaneous formulations have generally not been evaluated in controlled trials to establish effectiveness and tolerability in patients. Because these studies are even more expensive to perform than the bioavailability, pharmacokinetic, and pharmacodynamic studies, they are unlikely to be conducted for the majority of extemporaneous drug formulations. It is most important to monitor patients receiving extemporane-ously prepared medications to assure effectiveness and tolerability. Patients and caregivers should be encouraged to contact health care practitioners to confirm that the desired outcomes were achieved with therapies. [7]

Lack of Funding for Research
Most diseases are more prevalent in adults and thus the drugs are indicated for only this population at the time of approval by the US Food and Drug Administration (FDA). Manufacturers may have less interest in conducting expensive Phase I to III studies for labeling in pediatric patients-especially in neonates, infants, and young children-due to low return on investment. They may also be reluctant to fund studies nfor the development of pediatric drug formulations, as such funding may be viewed by the FDA as promoting a drug's use without conducting efficacy and safety studies in pediatric patients. The manufacturers of generic drugs would have even less interest in supporting such studies by independent researchers. Experience in the past 20 years has shown that the National Institutes of Health and many foundations may view these studies as "too applied" for consideration of funding, and funding should be provided by the individual drug companies for their specific products. A national professional association in pharmacy defined the need but could not devote financial resources to conduct studies on extemporaneous formulations. [7,10]

Variations in Practice
The need for extemporaneous formulations at various health care facilities may be similar for selected drugs, and yet different drug concentrations, excipients, and methods may be used to prepare certain formulations. This occurs because of a lack of established or "standard" formulations or a lack of information in the literature regarding stable formulations. Lack of information about extended stability creates waste of drugs, increased costs, and inconvenience to patients and caregivers because prescriptions then have to be refilled more than necessary. Conveniently located pharmacies may not have expertise in preparing extemporaneous formulations, and thus caregivers may have to travel to specialized pharmacies. The need for extemporaneous formulations may be unique at various facilities. In such cases, the facilities would have to make these drugs available in the desired formulation, even though the expertise to do so may not exist. This might include physicians and/or nurses preparing the formulation. If these practitioners are not well versed in the procedures, there is ample room for medication and compounding errors to occur. [7]

Poor Coordination and Sharing of Information
The efforts and activities of various health care facilities in preparing extemporaneous formulations are not generally coordinated. In addition, information and knowledge regarding these formulations may not be widely shared. Although investigators at academic institutions and health care facilities present papers and publish articles about extemporaneous formulations, most pharmacists involved daily with these activities may not do so. Thus, coordination and sharing of information must be improved to decrease duplication of efforts and to increase access to stable extemporaneous formulations for patients. [7]

Reimbursement and Payment Issues
Third-party payors do not always pay for compounded medications. They do pay for compounded medications in the hospital (eg, IV admixtures, pediatric formulations) but not always in the community pharmacy setting. This practice is undesirable for patients in the ambulatory setting, as caregivers must payout of pocket for the prescriptions when they are not covered by insurance. [7]

Adverse-Event Reporting
According to the USP compounding standards, adverse events occurring as the result of a compounded medication should be reported to the USP MEDMARX program. Some individual state boards request that these adverse events be reported to the FDA MedWatch program. However, neither of these programs is mandatory and neither was developed specifically to handle pharmaceutical compounding adverse events; rather, they were designed to handle adverse events from manufactured drug products. [7]