Excipient benzyl alcohol

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

The hypothesis that the two excipients, benzyl alcohol and polysorbate 80, precipitated cardiogenic shock seems plausible, particularly because the plasma concentrations of amiodarone and desethylamiodarone never reached toxic concentrations. 

Observational studies Exposures to the potentially harmful pharmaceutical excipients benzyl alcohol and propylene glycol... 

The incorporation of certain excipients in products is deemed to be undesirable. Examples are the inclusion of mercurial preservatives, the inclusion of benzyl alcohol in parenteral products for use in children, the use of benzoic acid esters in injections, and the inclusion of sulfites and metabisulfites in products in general. If it is intended to use any of these materials, then a full justification will be required. 

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... 

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). 

InLammation by subcutaneous injection of cosolvents has not been published on extensively. Radwan [134] used aim vivo screening model to study the effect of various oils and cosolvents in oils on increasing skin fold thickness of rats after subcutaneous injection. With the exception of benzyl alcohol, ethyl oleate, and phospholipon 100, most excipients showed only miaanihnatory responses. 

Interferon alfa-2a formulations contain excipients sodium chloride, polysorbate, ammonium acetate, and benzyl alcohol as a preservative. Interferon alfa is also approved for use in the treatment of several other disorders. 

For this reason, a drug product that is to be used multiple times (multidose) must contain a preservative to prevent bacterial growth. A list of preservatives that have been used in pharmaceutical formulations is shown in Table 2. However, most of these are not usually compatible with protein formulations. Some, such as the parabens, are not active in the presence of nonionic surfactants—excipients that are typically required in protein formulations.Others may not be acceptable for a particular route of administration. Benzalkonium chloride, a commonly used preservative in topical formulations, causes ototoxicity when applied to the ear. As with buffering species, the list of preservatives available to the formulation scientist quickly narrows to just a few compounds including benzyl alcohol, phenol, w-cresol, and benzethonium chloride. A benzyl alcohol-containing formulation of epoetin alfa has been shown to be stable, even when dispensed in plastic syringes. ... 

Signals in the near UV region (250 00 nm) of the CD spectrum of a protein predominantly arise from absorption of the aromatic side chains of Trp, Tyr, and Phe. The dichroism in this region is highly dependent on the tertiary structure of the protein. For this reason, the near UV CD spectrum is often used to monitor changes in the native environment of proteins that result from instability. For example, Lam, Patapoff, and Nguyen used the near UV CD spectrum of IFN-y to determine that there was an incompatibility of the protein with a combination of excipients (succinate, benzyl alcohol) that resulted in a loss of structure. 

Buffers can also be provided in parenteral formulations to ensure the required pH needed for solubility and/or stability considerations. Other excipients included in parenteral products are preservatives (e.g., benzyl alcohol, p-hydroxybenzoate esters, and phenol), antioxidants (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, cysteine, and butyl hydroxy anisole), surfactants (e.g., polyoxyethylene sorbitan monooleate), and emulsifying agents (e.g., polysorbates). An inert gas (such as nitrogen) can also be used to enhance drug stability. Stability and solubility can also be enhanced by the addition of complexation and chelating agents such as the ethylenediaminetetraacetic acid salts. For a more detailed list of approved excipients in parenteral products, the reader should consult the monographs within the USP. 

Bacteriostatic Water for injection (USP), used to dilute or reconstitute medications for intravenous use. The content of benzyl alcohol in a lot of injectable pharmaceutical formulations needs to be considered carefully. The view still taken in many countries that the additives and excipients in medicines are trade secrets must be deplored. The duty to declare them is only realized in some countries. 

Reports of adverse reactions to benzyl alcohol used as an excipient include toxicity following intravenous administra-... 

Many excipients have been associated with adverse reactions in those ingesting drugs and vitamin/mineral formulations containing these compoundsJ78 79 Antioxidants (e.g., sodium sulfite, sodium and potassium bisulfites, and metabisulfites), bacterial preservatives (e.g., benzyl alcohol and benzalkonium chloride), artificial sweeteners (e.g., aspartame and saccharine), coloring agents (e.g., FD C yellow 5, blue 2, and red 40), and propylene glycol. A few examples of the toxic effects of these follow. 

It is estimated that 28% of all chemicals used in commerce could be neurotoxicJ42l Common household products including air fresheners, fragrance products, marking pens, and mattress covers contain known neurotoxins. I43 461 The neurotoxic effects of marking pens are attributed to chemical mixtures. I46l Aspertaine, saccharin, artificial food colors, benzyl alcohol, and other excipients used in pharmaceutical preparations and foods are neurotoxins. I47 48 ... 

FIGURE I HPLC chromatogram of midazolam hydrochloride injection. (Benzyl alcohol and benzaldehyde are excipient-related peaks desfluoromidazolam is an In-process impurity peak.)... 

Surfactants may be included in an ophthalmic suspension to disperse the drug effectively during manufacture and in the product during use. Non-ionic surfactants are generally preferred because they tend to be less toxic. The level of surfactant included in the formulation should be carefully evaluated, as excessive amounts can lead to irritation in the eye, foaming during manufacture and upon shaking the product, or interactions with other excipients. The most likely interaction is with the preservative. For example, polysorbate 80 interacts with chlorobutanol, benzyl alcohol, parabens and phenyl ethanol and may result in a reduced preservative effectiveness in the product. 

Other additives such as antimicrobial agents, antioxidants, buffers and tonicity-adjusting agents can be included in injection formulations and it is the responsibility of the pharmacist to check that all excipients and adjuvants are suitable (benzyl alcohol, ethanol, sulfites, sodium content, etc.). Nevertheless, one is left with a difficult choice over excipients, either those for which toxicity is known and therefore predictable, or those with safety profiles that have not been established in children (see under Critical excipients, page 55). The pH and osmo-larity of the preparation must also be checked before administration by another route. 

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... 

Currently, a pilot version of the STEP database compiling the data for 10 prioritised excipients, for example propylene glycol, ethanol and benzyl alcohol, is in process. If the pilot is proved to be successful, the database will be expanded to a fully released database and will eventually include many excipients [34]. 

If the product is not a standard formula, the names of all the active ingredients have to appear on the label, and preferably of all the excipients as well. At least preservatives and antioxidants should be mentioned. The EMA requires excipients known to have a recognised action or effect to be mentioned [1]. A list of such excipients is available on the EMA website [10]. Examples are ethanol and propylene glycol, and benzyl alcohol, especially in medicines for children. See also Sect 5.4.5. 

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