Excipient adverse effects

Golightly LK, Smolinske SS, Bennett ML, et al. Pharmaceutical excipients. Adverse effects associated with inactive ingredients in drug products (Part I). Med Tox 1988 3 128. 

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... 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

Pharmaceutical nonactive excipients have long been applied in a variety of pharmaceutical dosage forms to provide a wide range of functional characteristics that facilitate the optimal delivery of a drug to achieve the desired therapeutic effects. Pharmaceutical excipients are inert materials with no adverse effects on the safety and efficacy of therapeutic products. The Food and Drug Administration (FDA) website (1) provides a database listing all the FDA-approved nonactive pharmaceutical excipients. This provides formulation scientists a useful reference for efficient choices of the suitable excipients for the desired formulations of drug. 

Major determinants of the efficiency of mucociliary clearance are cilia density, periciliary fluid, and composition of mucus. Some drugs and excipients, such as preservatives in drug formulations, may diminish the ciliary movement in the nasal cavity and trachea. A suggested adverse effect of ciliostasis (permanently or momentarily arrest or impairment of ciliary activity) is lower respiratory tract infection as a result of impaired nasal microbiological defense. 

Excipients within cerumenolytic preparations or the solvent base itself may affect the potential effectiveness of a product or the risk of suffering adverse effects with use. An example of the latter is with preparations of an oily base, potentially causing external ear canal irritation and inflammation. An example of the former could be of the use of glycerol as an excipient, which also softens wax (in combination with other cerumenolytics). 

An anaphylactic reaction after the injection of crushed tablets equivalent to 45 mg of amfetamine occurred in a young woman in others injected with the same solution and at the same time there were no adverse effects (SED-9, 8). The reaction may have involved amfetamine or excipients. Scleroderma is a potential consequence of various stimulants used for appetite control (79). 

Wong YL. Adverse effects of pharmaceutical excipients in drug therapy. Ann Acad Med Singapore 1993 22 99-102. 

Certain excipients that are added to formulations to improve filling-machine performance can have an adverse effect on release,because they are hydrophobic in nature. This is true of lubricants, which are added to formulations to prevent adhesion and to improve flow. The most used excipient in capsule formulations in... 

Study shows that there are no adverse effects after administration of the material at the limit (high) dose generally used in the pharmaceutical industry. An investigative mass, balance, whole-body autoradiography study provides information on absorption, distribution, metabolism, and excretion. This study also involves an investigation of suitable labeling of the material. An in vitro metabolism study (e.g., in rat vs. human hepatocytes) may also be useful for modified food additives and excipients to compare the break-down process and to show possible differences between rat and human in these processes. 

Table 3 Adverse effects encountered with various pharmaceutical excipients...

Overall, even in early drug development, a consideration of the excipient profile of the final product is important. If use of the established excipients is planned, an awareness of potential adverse effects in humans is necessary. Development should use pharmacopoeia-listed materials. For new excipients, this information is not available, and safety will be assessed in the preclinical evaluation. Extrapolation may only be possible if the new excipient is in the same class or is structurally similar to established materials, but such a comparison would not necessarily be reliable. 

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