Excipient parabens

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. ... 

Reference is an excellent resource on the safety and adverse reaction to several excipients. Sensitization reactions have been reported for the parabens, thi-merosal, and propyl gallate. Sorbitol is metabolized... 

Butylparaben is thus more active than methylparaben. Activity may be improved by using combinations of parabens since synergistic effects occur. Activity has also been reported to be improved by the addition of other excipients see Methylparaben for further information. 

The activity of the parabens increases with increasing chain length of the alkyl moiety, but solubility decreases. Activity may be improved by using combinations of parabens since synergistic effects occur. Ethylparaben is commonly used with methylparaben and propylparaben in oral and topical formulations (such mixtures are commercially available for example, Nipasept (Nipa Laboratories Inc.). Activity has also been reported to be improved by the addition of other excipients see Methylparaben for further information. 

It remains unclear as to whether all the adverse reactions were to the pharmaceuticals themselves or to excipients that are added to most formulations. Adverse reactions have been reported for preservatives (e.g., ben-zalkonium chloride, parabens, thimerosal), colorants, emulsifiers, and sulfites. Ironically, bronchospasm reactions have been observed following the use of inhaled asthma preparations. I ... 

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. 

In emulsion systems, the existence of two distinct phases (oil and water) results in a distribution of the parabens according to their physicochemical characteristics. This distribution can be influenced by the presence of other ingredients, such as co-solvents and surfactants. Furthermore, these excipients may also affect skin barrier properties. Thus, Dal Pozzo and Pastori (1996) found that permeation of the parabens from two O/W emulsions was higher than expected, based on their data using simple vehicles (described above), and that permeation from the O/W emusions was higher than that from the W/O emulsion. These results were rationalised on the basis of permeant release from the formulation, and it was assumed that the external lipid phase of the W/O emulsion retained the parabens. 

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