The antimicrobial chemicals commonly used as preservatives in medicines are will be a stand alone article.
The properties that are normally required in such a preservative include the following:
- a broad spectrum of antimicrobial activity covering Gram-positive and Gram-negative bacteria, yeasts and moulds, and no vulnerability to resistance development;
- low toxicity for humans, enabling it to be used in topical, oral and parenteral products;
- good solubility in water and low oil solubility;
- stable and effective over a wide pH range and compatible with common excipients; and
- nonvolatile, odourless and tasteless.
Not surprisingly, no single preservative satisfies all these criteria; if there were such an agent, it would be universally used to the exclusion of all others.
Thus the selection of a preservative (or combination of preservatives) for a newly developed product is inevitably a compromise determined by the formulation characteristics and intended use of the product.
Unfortunately, the list of available preservatives is diminishing rather than expanding. This is due to both the high cost of safety testing that would be a prerequisite for the introduction of an entirely new preservative and toxicity concerns resulting in the use of some agents being largely discontinued (e.g. phenylmercury salts and chloroform, which were formerly used in ophthalmic/parenteral products and in oral medicines respectively).
Even parabens (p-hydroxybenzoates), which have been the most commonly used preservatives in medicines for many decades, are now viewed with some suspicion becausenof fears regarding their very weak oestrogenic action and their potential to stimulate proliferation of cultured breast cancer cells.
Because the function of a preservative is to kill, or at least prevent the growth of, microorganisms, it might be expected that the first item on the list would be a major determinant in preservative selection, but the intended use and route of administration of a product are usually the major factors limiting
The range of potential preservatives is
greatest for topical products, and becomes much more restricted when the toxicity considerations applying
to oral and parenteral products are applied. Thus there are several preservatives whose use is restricted
largely to topical medicines (e.g. bronopol, isothiazolones and imidazolidinyl ureas).
Despite the concerns regarding the toxicity of parabens, they remain by far the most frequently selected preservatives for topical and oral products, although sodium benzoate is also regularly chosen for oral medicines.
Multidose injections are now rarely
used in human medicine but are still used in veterinary practice. Again, parabens are used as preservatives,
although their suitability for this product category is also now questioned; benzyl alcohol, phenol and chlorbutanol are common alternatives.
Eye drops are usually, but not invariably, multidose products, which, although initially sterile, may require protection against patient-derived contaminants during use.
Benzalkonium chloride, often with EDTA, is more common in eye drops intended for the UK market than all other preservatives put together. Despite
this popularity, there is increasing concern about the potential for benzalkonium chloride to cause corneal
Single-dose or unpreserved eye drops are also used. Hiom (2012) has tabulated the commonly used preservatives and their application in different dosage forms.
Because of the limited and diminishing range of acceptable preservatives, in recent years increasing attention has been paid to the possible benefits of
using preservatives in combination.
Not only is there scope for reducing the concentrations of the agents, which should confer the benefits of reduced toxicity or irritancy, but use of two or more preservatives together might also result in a broader spectrum of
antimicrobial cover, a lower risk of resistance development and enhanced activity due to synergy.
There are combinations in which each component fills a gap in the antimicrobial spectrum of the other (e.g.
parabens and imidazolidinyl ureas, which, individually, have weak activity against Pseudomonas aeruginosa
and fungi respectively).
The practically useful examples of synergistic combinations have been considered by Hiom (2012). Generally, synergy is most likely to be exhibited when the two agents have dissimilar
modes of action.
If two agents from the same chemical class or with the same target site in the microbial cell are combined, the result is commonly found to be additive. Care is required, however, in the investigation and reporting of synergy for two reasons:
- It is well established that synergy might arise only at selected combination ratios, so it is unwise to assume that the effects displayed at one ratio will be seen at other ratios.
- Synergy must be divorced from the effects of concentration exponents.
AIt is tempting to assume that doubling the concentration of a preservative results in a doubling of its antimicrobial activity, and so two agents together producing more than twice the effect of either one alone must be synergy.
This logic is incorrect however, because some agents that have high concentration exponents (e.g. phenols) exhibit a large change in activity for a small change in concentration.
Combining two such agents can result in a dramatic increase in effect that might be erroneously interpreted as synergy, whereas the increase is only that to be expected from doubling the concentration of either component alone.