Preservatives nasal formulations

Calcitonin is a peptide hormone produced in the thyroid gland that serves to lower serum calcium and phosphate levels by inhibiting bone resorption. Calcitonin has been used in the treatment of a variety of diseases, such as primary hyperparathyroidism, Paget s disease, and postmenopausal osteoporosis [99,100]. Salmon calcitonin has a longer half-life than human calcitonin. Salmon calcitonin, 3.6 kDa, is available as a nasal formulation that contains only benzalkonium chloride as a preservative, without an absorption enhancer, and as a parenteral product for injection. The direct effect of benzalkonium chloride on the nasal mucosa is under... 

A current trend is the development of nasal formulations without preservatives. In long-term treatments,... 

Bernstein, I. L. 2000. Is the use of benzalkonium chloride as a preservative for nasal formulations a safety concern A cautionary note based on compromised mucociliary transport./. Allergy Clin. Immunol. 

The pH of the nasal formulation is a very important parameter which can be set to avoid irritation of the nasal mucosa and influence on physiological ciliary movement, to ensure active substance solubility or availability in unionised form suitable for absorptiOTi, to prevent growth of pathogenic bacteria or to maintain functionaUty of preservatives... 

Benzalkonium chloride is so far the most widely used preservative, but thiomersal, chlorobutanol, phenylethanol, and parabens can also be found in nasal formulations. 

Major determinants of the efficiency of mucociliary clearance are cilia density, periciliary fluid, and composition of mucus. Some drugs and excipients, such as preservatives in drug formulations, may diminish the ciliary movement in the nasal cavity and trachea. A suggested adverse effect of ciliostasis (permanently or momentarily arrest or impairment of ciliary activity) is lower respiratory tract infection as a result of impaired nasal microbiological defense. 

Microbiological protection of multiple-dose presentations such as liquid inhalations, nasal sprays, oral liquids, creams, and lotions is more complex. Once opened they are susceptible to microbiological contamination. If they are aqueous-based, they are in principle susceptible to proliferation of these new contaminants. To avoid this, they are formulated with antimicrobial agents or preservatives and are expected to be able to comply with preservative efficacy standards specified in the pharmacopeias. Preservative efficacy tests (not harmonized) are described in Section 51 of the USP and Section VIII. 14 of the PhEur (Fig. 3). 

In nasal, and otic formulations a concentration of 0.002-0.02% w/v is used, sometimes in combination with 0.002-0.005% w/v thimerosal. Benzalkonium chloride 0.01% w/v is also employed as a preservative in small-volume parenteral products. Benzalkonium chloride was also shown to enhance the topical penetration of lorazepam. ... 

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. 

Hodges NA, Denyer SP, Hanlon GW, Reynolds JP. Preservative efficacy tests on formulated nasal products reproducibility and factors affecting preservative activity. ] Pharm Pharmacol 1996 48 1237-1242. 

Sodium acetate is used as a buffering agent in various intramuscular, intravenous, topical, ophthalmic, nasal, oral, otic, and subcutaneous formulations. It may be used to reduce the bitterness of oral pharmaceuticals. It can be used to enhance the antimicrobial properties of formulations it has been shown to inhibit the growth of S. aureus and E. coli, but not C. albicans in protein hydrolysate solutions. It is widely used in the food industry as a preservative. Sodium acetate has also been used therapeutically for the treatment of metabolic acidosis in premature infants, and in hemodialysis solutions. ... 

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]. 

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