Excipient-related toxicity

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... 

After the product has been filled (and sealed) in its final product container. QC personnel then remove representative samples of the product and carry out tests to ensure conformance to final product specification. The most important specifications will relate to product potency, sterility and final volume fill, as well as the absence of endotoxin or other potentially toxic substances. Detection and quantification of excipients added will also be undertaken. Product analysis is considered in Chapter 7. 

Due to repeat dose toxicity study findings being restricted to high dose levels with reversibility demonstrated, it is concluded that HP-P-CD is a well tolerated excipient. For carcinogenicity study, urinary tract changes were reported as due to osmotic necrosis, intestinal tumours were related to increased osmotic activity and pancreatic tumours were shown to be due to rat-specific hormonal stimulation... 

A challenging issue in nasal delivery is related to the safety aspects of excipients, especially absorption enhancers, in the formulation. For most kinds of enhancers, a direct relationship exists between absorptionenhancing ability and local toxic effect. However, the efficacy of some kinds of absorption enhancers may not be necessarily related to their damaging effects on the nasal epithelium. Thus the establishment of a benefit-to-risk ratio for nasal absorption enhancers is of major importance. 

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. 

This book series comprises of 38 volumes. It crnitains information about 533 substances and excipients. The Profiles series include for instance the physical and analytical characterisation of substances and excipients, information of clinical uses, pharmacology, pharmacokinetics, safety or toxicity. The first 29 volumes were published by the name Analytical Profiles of Drag Substances. Since volume 30 the name was changed into Profiles of Drag Substances, Excipients and Related Methodology. It is recommended for its chemical, physico-chemical and stability information. Published by Academic Press... 

---