Topically applied products, regardless of their use, usually contain water as one of the primary components. This water provides a medium in which microorganisms can survive or grow. Other ingredients in these formulations can also create a viable growth medium for these organisms, hence such formulations usually contain a preservative system. Preservative systems can be either a single agent or a combination of agents.
An ideal preservative system has a broad-spectrum of activity against all types of microorganisms, including yeast and mold, and gram-positive and gram-negative bacteria. The preservative is also ideally effective at low concentrations, to minimize expense and avoid irritation and/or sensitization reactions. The preservative should also be somewhat soluble in an aqueous portion of the formulation, but may also possess a limited solubility in an oleaginous portion of the formulation. Since microorganisms grow in water but fail to grow in media where water is absent, the preservative should be present in that portion of the product where it can be effectively assimilated by the microorganisms.
The preservative should also be compatible with the other ingredients in the formulation, and not react with or otherwise be inactivated by those ingredients. The preservative is ideally colorless and odorless, and remains so throughout the intended shelf-life of the product. It should also be stable throughout the expected life of the product, because many microorganisms can lay dormant in the composition until conditions are later appropriate for growth. If a preservative was unstable and degraded over the shelf-life of the product, contamination could occur once the preservative concentration fell below the threshold necessary to inhibit the growth of the microorganisms. Furthermore, the preservative is ideally stable to any changes in temperature and/or pH encountered during the manufacturing and packaging process, as well as the storage conditions encountered both prior to and after sale to the end user.
The preservative should also be safe, without exerting undesired biological effects on human skin cells. Even at typical use concentrations, many preservatives have the capacity to cause irritation and/or sensitization when in contact with human skin. Furthermore, since the concentrated preservative agents must be handled and incorporated into the product during the manufacturing process, these materials must not present an insurmountable hazard to the production workers making the product.
It is also helpful if the efficacy of the preservative can be assessed by an assay. Although preservative agents can be evaluated by conducting conventional preservative efficacy tests, such testing is slow and worker intensive. Therefore, it is often important to have a agent whose activity can be correlated to more conventional analytical methods for preservatives. Given the complexity of topical formulations and their respective preservative agents, it is unusual for a correlated analytical method to exist. Additionally, the preservative agents must be analyzable in order to ensure the quality of the material as it is received from the manufacturer.
The individual preservative agents are preferably easy to handle in their bulk state, prior to incorporation into a topical formulation, and inexpensive to use. More expensive preservatives are ideally effective at low concentrations to keep costs low.
No single preservative agent fulfills all of these criteria, and the requirements become even more complex when regulatory requirements are added to the criteria. Formulation scientists working in collaboration with microbiologists and analytical chemists expend a significant amount of effort in developing adequate preservative systems for topically applied products in an attempt to satisfy both practical and regulatory requirements.
Emulsion systems [for example, oil-in-water (o/w), water-in-oil (w/o), multiple emulsions including water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) systems], liposomal systems and aqueous-based liquid, gel or suspension systems are the major product forms used for topical delivery systems in cosmetic, skincare, personal care, OTC pharmaceutical, ophthalmic, otic, dermatological and other prescription pharmaceutical products. All of these topical delivery systems contain water, as well as ingredients that support and/or sustain the growth of microorganisms such as bacteria, yeast and molds. Theses products therefore contain preservatives to kill or at least inhibit the growth of microorganisms, usually in low amounts to avoid affecting human skin cells to which they are applied. Government regulatory agencies also may regulate the concentrations of preservatives used, to protect the consumer by reducing the potential for irritation and/or allergic sensitization from topical application.
Some of the more commonly used preservatives in topically applied products include the following materials listed according to their International Nomenclature for Cosmetic Ingredients (INCI) name:
______________________________________ Benzoic Acid (and salts) Benzyl Alcohol 2-bromo-2-nitropropane-1,3-diol Chlorhexidine Chloroxylenol Dehydroacetic Acid (and salts) Diazolidinyl Urea DMDM Hydantion Ethyl Alcohol Imidazolidinyl Urea Isothazolinones Paraben Esters Phenethyl Alcohol Phenoxyethanol Quaternim-15 Sorbic Acid (and salts) ______________________________________
The esters of p-hydrobenzoic acid are known as parabens, and include methyl, ethyl, propyl and butyl esters. Higher esters are even more active then the butyl esters, but decreasing solubility makes them less desirable to use. Alcohols that have been used as preservatives include ethyl and isopropyl alcohol, but benzyl and phenylethyl alcohol may also be used. Benzoic acid may be used either as the acid, or as a salt such as sodium benzoate.
Many of the topically applied products use either imidazolidinyl urea (Germall 115.RTM. from Sutton Labs) or diazolidinyl urea (Germall II.RTM. from Sutton Labs), in combination with parabens. However the inventors have found that this commonly used combination causes stinging and burning in many people.
Formaldehyde has been another prominent and potent antimicrobial agent; other agents gradually donate or release formaldehyde. Some countries, such as Japan, restrict the use of "formaldehyde-donating" preservative agents, such as imidazolidinyl urea and diazolidinyl urea, and prohibit the use of "formaldehyde-releasing" preservative agents such as Quaternium-15 and DMDM Hydantoin. Other countries, such as the European Union, are not as restrictive about the types of preservative agents that can be employed, however, they limit the concentration of each agent included in a product.
Which preservative agents to incorporate in a product formulation, and the amount of each agent needed, typically varies from one formulation to another. They may be determined empirically by preservative efficacy testing. Despite the expertise and knowledge in the art of formulation, a formulator often must test each combination of preservative agents and adjuvants used in a particular formulation for its effectiveness against a broad range of microorganisms. This is because it is often not well understood why a particular combination of preservative agents and adjuvants is effective. Moreover, given the potential for irritation and sensitization from preservative agents, an additional objective of the formulator is to create a preservative system that does not cause adverse reactions.
Developing a unique, safe and internationally acceptable preservative system is a complex problem that has been addressed by the present invention. The following description of the preservative system is meant to be representative of the overall technology. Anyone skilled in the art of formulation and/or microbiology will see variations and potential applications for this technology beyond the examples listed. Therefore, the invention is not limited to the formulations represented by these examples, but instead covers a variety of formulations.