Active substance antimicrobial effect

Several factors may influence the success or failure of a preservative to protect a formulation against microbial contamination. These factors include the interaction of the preservative with surfactants, active substances, other components of the vehicle, sorption by the polymeric packaging materials, and product storage temperature. Although hundreds of chemicals can fimction as germicides, only a few substances have made it to the marketplace. The small list is not based as much on a compound s effectiveness as an antimicrobial agent as on the compound s safety and effectiveness in the final product. 

In 1983, Eklund developed a mathematical model for the antimicrobial activity of organic acids, which described the antimicrobial action of the dissociated as well as the undissociated organic acid. In contrast to a model assuming the activity of the acid form only, this model provided a good description of the actions of a variety of organic acids (Eklund, 1985). The model was suggested to have practical value, because the determination of MICs of a specific substance at only two different pH levels could be used to predict the MIC of that same substance at other pH levels. However, the model failed to consider the antimicrobial effect of the low pH on its own (Lambert and Bidlas, 2007). 

Despite fhe problems, however, some of the natural preparations were effective in relieving fhe symptoms and at times even eliminating the disease. In fact, we know today fhat fhe number of pharmacologically active substances produced by nature is large and fhe spectrum of biological activities of natural products is extraordinarily broad for example, antimicrobial, antineoplastic, CNS-active, anti-inflammatory, cardiovascular, etc., are only a few of the therapeutic classes of drugs from nature [7]. 

Sustainable antimicrobial (SAM) polymers (Figure 48) are relatively new development products from Degussa (tradename Amina T 100) with confident claims of being environmentally sustainable and continuously effective. Amina T 100 is apolymeric active substance with a high level of activity and a low degree of toxicity. It is promoted in the literature as an effective bacteriastat, fungisat and algistat. 

Objects for medical purposes made of plastics which are to have an antimicrobially active content of metals (or metal compounds) can be economically produced in that a plastic blank in foil, granulate or fibre form is coated with the desired metal (or metal compound) by the thin-film technique. The intermediate product thus obtained is then ground and mixed and processed further as the raw material for the desired final form. Sueh objects are thus antimicrobially active all over their surfaces and also on inner surfaces. Hence the full effect of the antimicrobially active substances, in this case oligodynamically active metals (or metal compounds) is obtained with only a small fraction of the quantities formerly required when they were included in the plastic in powdered form, thus resulting in considerable cost savings. 

Currently, researchers are trying to increase the low antimicrobial activity of chitosan to compare with commercially used chemicals. The recent advances include the use of composites and other biologically active substances (Table 3.3) that are known antimicrobial agents. The expected outcome is an increased antimicrobial effect due to the synergistic action of both antimicrobial agents. Moreover, the use of lesser synthetic agents to improve the naturally-derived polymer can be both economical and attractive. 

The ambient medium impairs the effectiveness of microbicides also if its constituents include those capable of interacting with a microbicide in competition with the constituents of the microbe cell. This is true of electrophilically active microbicides in general as far as the ambient medium contains nucleophilically active constituents with which the microbicide can react in competition with the corresponding cell constituents. It is also true, however, of membrane-active microbicides if adsorption of the microbicide on organic matter competes with the adsorptive processes on the cytoplasmic membrane or if such microbicides, e.g. phenol derivatives, become incorporated in micelles that are formed in certain media at levels above the critical micelle concentration with the result that the incorporated active substance molecules are no longer available for the antimicrobial effect (see III. 16, Fig. 34). 

The effectiveness and efficiency of microbicides result from the interplay of the chemicophysical properties of the active substance molecule, which are determined by the molecule s constitution. Solubility, polarity, ionicity and reactivity are examples of properties that influence effectiveness. Taking the N-trihalo-methylthio derivative as examples, Paulus Kiihle (1986) drew attention to an important principle that evidently applies to electrophilically active microbicides in general, namely that the relationship shown in Fig. 11 exists between the antimicrobial effectiveness and reactivity of microbicide molecules. As the reactivity increases, so, too, does the effectiveness—until it peaks at a moderately high reactivity level. Thereafter the antimicrobial activity decreases as the reactivity continues to rise because at this stage competition reactions — interactions of the reactive microbicide molecules with constituents of the surrounding medium — predominate. 

The antimicrobial efficacy of the amine-formaldehyde reaction products essentially corresponds to the formaldehyde content of these compounds. Known exceptions are HTA, hexahydro-oxadiazines and octahydro-s-tetrazines, which derive from ammonia respectively certain alkylolhydrazines (Paulus, 1980) here the detection of formaldehyde by the Taimenbaum methods gives a negative result, which means that these substances have no significant antimicrobial effect at neutral to alkaline pH they release formaldehyde in acidic media only. This pH dependency is broken off, if, for example, HTA is quatemized (Jacobs et al., 1916). In contrast to HTA the quaternary hexaminium salts release formaldehyde widely independent of pH and therefore may be used as preservatives also for media of neutral to alkaline pH. They are not comparable with the surface active conventional quaternary ammonium compounds (QACs see Section 16.1)... 

Also salicylanilides (2-hydroxybenzanilides), long chain A-alkyl-salicylamides and carbanilides (urea derivatives) belong to the amide compounds with antimicrobial action. They are membrane-active substances, i.e. very small concentrations suffice to achieve microbistatic effects whereas microbicidal effects call for much higher addition rates. 

The most commonly used vehicle is water, for solutions as well as suspensions, emulsions and solubilisates. If a solution is required, co-solvents may be added (see Sect. 5.4.4) such as ethanol, glycerol 85 % and propylene glycol. Then-toxic and adverse effects should be fuUy considered. They are miscible with water and often have an antimicrobial effect as well. Lipophilic active substances may be brought into solution by a lipophilic solvent such as acetem. Another way of processing lipophilic solvents is to convert them into an emulsion. 

Some active substances or excipients have an antimicrobial effect not only through reducing the water activity, but also through a specific antimicrobial mechanism. The best-known example is propylene glycol, but also ethanol, local anaesthetics, chlorpromazine hydrochloride, promethazine hydrochloride and essential oils exhibit a specific antimicrobial effect. In addition, the combination of weak antimicrobial effects of disodium edetate, borax, and boric acid appeared to justify prolongation of the shelf life of non-preserved eye drops over the standard limit of 24 h [48]. 

The electrophilically active substances have as toxophoric constituent an electrophilic group which is responsible for the antimicrobial effect, because it enables these active substances to react with specific nucleophilic entities of the microbial cell (Paulus, 1993) Examples of this class are aldehydes [II, 2.], e.g. Glutaraldehyde, compounds with activated halogen atoms [II, 17.], e.g. Bronopol, and microbiocides with an activated S-N-bond [II, 15.], for example Isothiazolinones. Since Isothiazolinones represent a major class of bactericides for industrial preservation, much research has been performed in this area. 

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