Preservatives nasal drops

Benzalkonium chloride in vitro has a ciliotoxic effect, which develops slowly, but is irreversible. Benzalkonium chloride slows down the ciliary movement and disorganises the mucus layer. This stmcture change is supposed to be the result of an interaction of anionic substances in the mucus with the cationic benzalkonium. The ciliotoxic effect of benzalkonium chloride increases when pH is lowered from 7 to 5. Therefore nasal drops preserved with benzalkonium chloride should preferably have a pH around 7. In vivo however, long-term use of benzalkonium chloride 0.02 % did not change the rate of mucociliary clearance and the... 

An alternative to the pulmonary route of administration is the nasal route, which is less demanding when it comes to formulation. With regard to, for example, particle size and simpler device development (5,90), examples are Minirin (Ferring), desmopression, and Suprecur (Sanofi-Aventis), buserelin, which are proteins formulated as nasal drops or nasal spray, where bioavailabdities of approximately 3% to 10% can be obtained. The formulations are just protein dissolved in purified water containing preservatives chlorbutanol and benzalkonium chloride (91,92). However, more advanced delivery systems are also used, for example, chitosan formulations where bioavailabihties of 14% to 15% compared to subcutaneous administration can be obtained (90). A recent review by nium (2007) gives more details on nanoparticulate systems used for nasal delivery (93) or consult Costantino et al. (2007) on the physiochemical and therapeutic aspects (5). 

As the mucosa is highly sensitive to irritation, nasal toxicity of active substances and excipients is an important issue in formulating nasal preparations, especially when they are intended for treatment of chronic diseases [11]. Nearly all substances used in nasal preparations have a negative influence on the ciliary beat, and are therefore ciliotoxic. The influence may vary from a temporary (reversible) effect up to an irreversible inhibition of the ciliary beat [30]. In many nasal drops and nasal sprays preservatives cause the toxic effect on cilia [31], but the active substance itself may also have a negative influence on the ciliary epithelium. Nasal drops with decongestants have been shown to exhibit relatively low cUiotoxicity (e.g. Xylometazoline nasal drops 0.025 %, 0.05 % and 0.1 % (see Table 8.4) as well as a number of licensed preparations) [32]. 

Aqueous nasal drops and nasal sprays are preserved when they are supplied in multidose containers. In order to get a low level of microbiological contamination at the start, the use of sterilised water or sterilised solutions of preservatives as primary materials is recommended. 

Balancing advantages and disadvantages the combination of benzalkonium chloride 0.01 % and disodium edetate 0.1 % is the preferred preservative for nasal drops and sprays. Second choice would be methyl parahydroxybenzoate 0.1 %. Detailed information about the efficacy of preservatives in nasal preparations can be found in [47]. 

When preservation of a nasal gel is needed, like in nasal drops the combination of benzalkonium chloride and disodium edetate (0.01 % and 0.1 % respectively) is preferred. According to the NRF the concentration of benzalkonium chloride should preferably be doubled to 0.02 %, because the antimicrobial action is not always sufficient in the presence of viscosity enhancers [50]. Methyl parahydroxybenzoate is the second choice. 

In the preparation of nasal drops and liquid nasal sprays the active substances are dissolved or suspended and the excipients are dissolved in the preservative solution or sterilised water. For viscous nasal drops the components... 

Preservative free nasal drops should be supplied in singledose containers (see Sect. 24.4.14). 

Benzalkonium chloride is composed of a mixture of alkyldimethylbenzylammonium chlorides. The hydro-phobic alkyl residues are paraffinic chains with 8-18 carbon atoms. Benzalkonium chloride is used as a preservative in suspensions and solutions for nasal sprays and in eye-drops. Depending on the concentration of the solution, local irritant effects can occur. In nasal sprays it can exacerbate rhinitis (1) and in eye-drops it can cause irritation or keratitis (2). 

In the past, mercurous chloride was widely used in medicinal products such as laxatives, worming medications, and teething powders. These older medicines should be properly disposed of and replaced with safer and more effective medicines. Other chemicals containing mercury, such as mercurochrome and thimerosal (sold as Merthiolate and other brands), are still used as antiseptics or as preservatives in eye drops, eye ointments, nasal sprays, and vaccines. Some... 

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