Nasal preparations preservation

Sensitization reactions may follow the prolonged application of strong solutions to the skin, although patch tests have shown that chlorocresol is not a primary irritant at concentrations up to 0.2%. Cross sensitization with the related preservative chloroxylenol has also been reported. " "" At concentrations of 0.005% w/v, chlorocresol has been shown to produce a reversible reduction in the ciliary movement of human nasal epithelial cells in vitro and at concentrations of 0.1% chlorocresol produces irreversible ciliostasis therefore it should be used with caution in nasal preparations. " However, a clinical study in asthma patients challenged with chlorocresol or saline concluded that preservative might be used safely in nebulizer solution. ... 

Batts, A. H., C. Marriott, G. P. Martin, and S. W. Bond. 1989. The effect of some preservatives used in nasal preparations on mucociliary clearance./. Pharm. Pharmacol. 41 156-159. 

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]. 

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]. 

Dialyze the carrier protein against 10 mM potassium phosphate buffer, pH 7.2. At ust the carrier concentration to about 20 mg/mL. Weigh out the solid peptide and dissolve it in the same buffer at 5 mg/mL. Thiol-based scavengers, used to preserve free -SH groups in the peptide, are often present in peptide preparations and will need to be removed from the peptide solution by desalting on a Bio-Gel PIO column in 10 mM potassium phosphate buffer, pH 7.2. A brief nasal inspection is often sufficient to determine their presence. On the other hand, stock solutions of peptide (e.g., in PBS) may become oxidized if stored for extended periods, and so are best pretreated with 100 mMDTT (30 min at room temperature is adequate) to reduce the dissolved peptide before use. As the DTT will interfere with the conjugation, the reduced peptide should then be desalted on a PIO column as above. 

The other three classes of preservatives have been widely used in ophthalmic, nasal, and parenteral products, but not frequently in oral liquid preparations. The neutral preservatives are volatile alcohols their volatility introduces problems of odor and loss of preservative on aging in multidose preparations. The mercurials and quaternary ammonium compounds are excellent preservatives but are subject to incompatibilities.Mercurials are readily reduced to free mercury, and the quaternary compounds are inactivated by anionic substances. 

Phenylethyl alcohol is used as an antimicrobial preservative in nasal, ophthalmic, and otic formulations at 0.25-0.5% v/v concentration it is generally used in combination with other preservatives.Phenylethyl alcohol has also been used on its own as an antimicrobial preservative at concentrations up to 1% v/v in topical preparations. At this concentration, mycoplasmas are inactivated within 20 minutes, although enveloped viruses are resistant. " Phenylethyl alcohol is also used in flavors and as a perfumery component, especially in rose perfumes. 

Included in the FDA Inactive Ingredients Guide (IM and ophthalmic preparations). Included in nonparenteral medicines licensed in the UK. In the UK, the use of phenylmercuric salts in cosmetics is limited to 0.003% (calculated as mercury, equivalent to approximately 0.0047% of phenylmercuric nitrate) as a preservative in shampoos and hair creams, which contain nonionic emulsifiers that would render other preservatives ineffective. Total permitted concentration, as mercury, when mixed with other mercury compounds is 0.007% (equivalent up to approximately 0.011% of phenylmercuric nitrate). Included in the Canadian List of Acceptable Non-medicinal Ingredients (ophthalmic, nasal and otic preparations only there must be no other suitable alternative preservative). 

Freeze-dried preparations are generating a lot of interest for peptides because of potentially improved stability, the avoidance of preservatives, which can have a damaging effect on nasal mucosa during chronic treatment, and improved bioavailability. There are devices to deliver the powder, but this concept is still at the research stage and is likely to be expensive to market. 

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... 

In some Ucensed nasal sprays dosage delivery devices are used that make it possible to deliver doses free from microorganisms and at the same time maintain sterUity of preservative free solutions. The manner of crmstructimi is claimed to prevent envirorunental air coming into contact with the (sterile) content in the reservoir. Examples are the COMOD system and the Freepod pump system. These systems are not available for pharmacy preparations. 

---