Neonates excipients

Many of these reactions are related to the quantity of excipient found in a dosage form. Benzyl alcohol benzalkonium chloride, propylene glycol, lactose, and polysorbates are all associated with dose-related toxic reactions [52-54], Large-volume parenterals containing 1.5% benzyl alcohol as a preservative have caused metabolic acidosis, cardiovascular collapse, and death in low birth weight premature neonates and infants. The cumulative dose of benzyl alcohol ranged from 99 to 234 mg/kg per day in these patients [55,56], Dose-related adverse effects to excipients are of particular concern in the preterm, low birth weight infant because... 

PG, similar to glycerin, is a multifunctional excipient that can be an effective preservative when used at concentrations of 15% to 30% in oral solutions. However, formulations containing 35% PG can cause hemolysis in humans. PG exhibits nonlinear pharmacokinetics and when elimination pathways are saturated, serum levels dramatically increase. Pyruvic and lactic acid are produced from the metabolic degradation of PG and can lead to acidosis. Neonates have a longer PG half-life (16.9 hours) compared with adults (5 hours) and seizures, and respiratory depression has occurred in children who have ingested oral liquid medications containing PG (9). Therefore, special consideration should be placed on the amount of PG in formulations that are intended for infants and children. 

Besides local toxicity, discussed above, there are numerous other modes of potential adverse interactions involving excipients (19,20). Many of these pose little threat provided the amounts of excipients are constrained to certain levels. Excessive amounts, however, can cause problems, particularly for patients who are intolerant of even modest levels. Commonly used phosphate buffers may cause calcium loss with formation of insoluble calcium phosphates when such buffers are administered in over-ambitious amounts (21). Calcium phosphate precipitation has been noted particularly in nutritional parenteral admixtures for neonates because of the high nutrient requirements. Similarly, renal toxicity has been associated with depletion of zinc and other trace metals caused by large parenteral doses of ethylenediaminete-traacetic acid (EDTA) (22). Excessive absorption of glycine solutions, when used as irrigants during transurethral resections, can cause hyponatremia, hypertension, and confusion (23). The use of preservatives has been associated with cardiac effects in a few patients (24). Premature neonates were found to be at risk for receiving toxic amounts of benzoic acid or benzyl alcohol in bacteriostatic solutions used to flush intravenous catheters (25). 

The delivery of aerosol powders by generation with minimal formulation has been an attractive prospect to many researchers. The early use of a dry powder artificial phospholipid in the treatment of neonatal respiratory distress syndrome proved very successful [181]. Because no delivery system was available to facilitate this treatment, a simple system was devised. A Laerdal neonatal resuscitation bag was modified to hold a capsule containing the artificial surfactant, as shown schematically in Fig. 11. However, where MDIs of the prescribed medication are available, both physicians and patients prefer their use. The powders themselves have to be prepared in the same way as those used in MDIs, by milling. Often, excipients are added to carry the fine powder. Lactose has been used in both cromolyn sodium and albuterol formulations. As a consequence of the interest in dry powders, a number of products have been... 

When preparations are applied to the skin of infants, particularly preterm neonates, the potential for systemic absorption of excipients as well as any active drug should always be considered. 

Formulation of liquids usually requires more excipients, in both type and quantity, than for solid dosage forms. They must be carefully selected in paediatric preparations because of possible pharmacological actions or toxic effects. Dose-related adverse effects of excipients are of particular concern in the preterm, low-birthweight neonate and infant due to immaturity of hepatic and renal function in this population. The following is not an exhaustive list but is intended to raise awareness of susceptible excipients to be used in paediatric medication. More emphasis is put on additional agents than on vehicles such as sweeteners and preservatives as they are of particular importance in paediatric liquid formulation and often not extensively taught at undergraduate levels. 

Administration usually creates pain, anxiety and phobia, and requires professionally trained staff. Topical anaesthesia (creams, gels, patches or simply cold to numb the area) is usually performed to help to manage the pain and associated fears, as well as to distract the child. There is no taste issue with the parenteral routes but the excipients used must be biodegradable imder the available metabolic processes. This can be a problem in neonates as not all pathways have fully matured. Moreover, formulation composition is critical as some excipients can be toxic. This includes vehicles, preservatives or even the antiseptic used to disinfect the surface of the skin prior to injection (e.g. iodine-containing antiseptic that can be absorbed through the skin). 

Skin Nicolau s syndrome (embolia cutis medicamentosa), a rare, acute, necrotic, livedoid dermatitis that can occur after intramuscular injection of various drugs, has been reported in infants who were given intramuscular vitamin Ki, a 713-g boy born at 24 weeks, a 600-g girl bom at 24 weeks [14 ], and another premature neonate [15" ]. These reactions can be regarded as between-the-eyes reactions of type 2 [16 ], at least to the whole formulation, although not necessarily to the vitamin Ki, since they could have been due, for example, to an excipient or to some aspect of the act of injection. 

Observational studies Neonatal exposure to benzyl alcohol and propylene glycol, pharmaceutical excipients present in parenteral medications, has been studied retrospectively in a neonatal and pediatric intensive unit in a tertiary care university hospital [8 ]. In 170 randomly selected episodes of exposure to parenteral medications containing benzyl alcohol ( = 88) or propylene glycol ( = 82), there were a wide range of cumulative doses of the excipients. The median cumulative dose was 4.5 mg/kg/day for benzyl alcohol and 205 mg/kg/day for... 

Shehab N, Lewis CL, Streetman DD, Donn SM. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatr... 

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